The Blood-Brain Barrier (BBB), a dynamic and highly selective interface, regulates the exchange of molecules between the circulatory system and the Central Nervous System (CNS). While it protects the brain from toxins and pathogens, it also restricts the delivery of therapeutic agents, posing a significant challenge in treating CNS disorders such as Alzheimer's disease, Parkinson's disease, and glioblastoma. This manuscript explores the structural and functional complexity of the BBB, including the roles of tight junctions, adherens junctions, astrocytes, pericytes, and endothelial cells. It highlights the influence of drug physicochemical properties, such as lipophilicity, molecular weight, and hydrogen bonding, on BBB penetration. Current strategies to enhance drug delivery include nanotechnology-based carriers (liposomes, solid lipid nanoparticles, polymer-based carriers), receptor-mediated transcytosis, and cell-penetrating peptides. Emerging approaches like focused ultrasound with microbubbles, intranasal delivery, and exosome-mediated transport demonstrate significant potential for bypassing BBB constraints. Gene therapy, employing both viral and nonviral vectors, offers promise for addressing genetic CNS disorders. Despite advances, limitations, such as offtarget effects, limited delivery efficiency, and potential toxicity, remain critical barriers to clinical translation. Future research must prioritize multidisciplinary approaches integrating nanotechnology, personalized medicine, and enhanced understanding of BBB biology. Innovations in non-invasive, targeted delivery systems are essential to overcoming existing challenges and enabling effective treatment of CNS disorders. This review underscores the need for further exploration of these technologies to achieve sustained, site-specific drug delivery, thereby advancing therapeutic interventions for neurological diseases. Significance Statement: The blood-brain barrier (BBB) is a critical interface that protects the brain but limits drug delivery, posing challenges in treating CNS disorders. Advancing multidisciplinary approaches and innovative delivery systems is essential to overcome these limitations and enable effective therapies for neurological diseases.}, }
@article {pmid40264302, year = {2025}, author = {Durosini, E and Anyanwu, M and Vendrame, T and Gianoncelli, A and Ribaudo, G}, title = {Mechanistic investigation on compounds from Amorpha fruticosa L. targeting acetylcholinesterase.}, journal = {Natural product research}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/14786419.2025.2495856}, pmid = {40264302}, issn = {1478-6427}, abstract = {Acetylcholinesterase (AChE) is the enzyme targeted by drugs used for the symptomatic treatment of cognitive decline associated with Alzheimer's disease. While in vitro data suggest the AChE inhibitory potential of A. fruticosa extracts and components such as rotenoids, in-depth mechanistic investigations are missing. A wide array of computational techniques, including ligand-based approaches, molecular docking, molecular dynamics, and machine learning-assisted toxicity prediction were enrolled in the current study, highlighting the rotenoid 6α,12α-dehydrodeguelin as a promising lead for the development of AChE inhibitors.}, }
@article {pmid40264239, year = {2025}, author = {Zhang, W and Lukacsovich, D and Young, JI and Gomez, L and Schmidt, MA and Martin, ER and Kunkle, BW and Chen, XS and O'Shea, DM and Galvin, JE and Wang, L}, title = {DNA methylation signature of a lifestyle-based resilience index for cognitive health.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {88}, pmid = {40264239}, issn = {1758-9193}, support = {R01AG062634//US National Institutes of Health/ ; R01AG062634//US National Institutes of Health/ ; R01NS101483//US National Institutes of Health/ ; R61NS135587//US National Institutes of Health/ ; AWD-Neuro TSA-01//University of Miami Team Science Funding Program/ ; AWD-Neuro TSA-01//University of Miami Team Science Funding Program/ ; AWD-Neuro TSA-01//University of Miami Team Science Funding Program/ ; K12TR004555//Miami Clinical and Translational Science Institute/ ; }, mesh = {Humans ; *DNA Methylation ; Male ; Female ; Aged ; *Life Style ; *Resilience, Psychological ; *Cognition/physiology ; Alzheimer Disease/genetics ; Aged, 80 and over ; *Cognitive Dysfunction/genetics ; Cohort Studies ; Epigenesis, Genetic ; }, abstract = {Cognitive resilience (CR) contributes to the variability in risk for developing and progressing in Alzheimer's disease (AD) among individuals. Beyond genetics, recent studies highlight the critical role of lifestyle factors in enhancing CR and delaying cognitive decline. DNA methylation (DNAm), an epigenetic mechanism influenced by both genetic and environmental factors, including CR-related lifestyle factors, offers a promising pathway for understanding the biology of CR. We studied DNAm changes associated with the Resilience Index (RI), a composite measure of lifestyle factors, using blood samples from the Healthy Brain Initiative (HBI) cohort. After corrections for multiple comparisons, our analysis identified 19 CpGs and 24 differentially methylated regions significantly associated with the RI, adjusting for covariates age, sex, APOE ε4, and immune cell composition. The RI-associated methylation changes are significantly enriched in pathways related to lipid metabolism, synaptic plasticity, and neuroinflammation, and highlight the connection between cardiovascular health and cognitive function. By identifying RI-associated DNAm, our study provided an alternative approach to discovering future targets and treatment strategies for AD, complementary to the traditional approach of identifying disease-associated variants directly. Furthermore, we developed a Methylation-based Resilience Score (MRS) that successfully predicted future cognitive decline in an external dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), even after accounting for age, sex, APOE ε4, years of education, baseline diagnosis, and baseline MMSE score. Our findings are particularly relevant for a better understanding of epigenetic architecture underlying cognitive resilience. Importantly, the significant association between baseline MRS and future cognitive decline demonstrated that DNAm could be a predictive marker for AD, laying the foundation for future studies on personalized AD prevention.}, }
@article {pmid40264187, year = {2025}, author = {Wang, S and Qi, C and Rajpurohit, C and Ghosh, B and Xiong, W and Wang, B and Qi, Y and Hwang, SH and Hammock, BD and Li, H and Gan, L and Zheng, H}, title = {Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {44}, pmid = {40264187}, issn = {1750-1326}, support = {093652/NS/NINDS NIH HHS/United States ; 020670/AG/NIA NIH HHS/United States ; 068031/AG/NIA NIH HHS/United States ; 066606/AG/NIA NIH HHS/United States ; Not applicable//Cure Alzheimer's Fund/ ; A25-1690//Harrington Discovery Institute, University Hospitals/ ; }, mesh = {Animals ; *Epoxide Hydrolases/antagonists & inhibitors/metabolism ; *Microglia/drug effects/metabolism ; *Tauopathies/metabolism/drug therapy/pathology ; Mice ; Disease Models, Animal ; *Neuroprotection/drug effects/physiology ; Homeostasis/drug effects/physiology ; Mice, Knockout ; Humans ; Mice, Transgenic ; Neuroprotective Agents/pharmacology ; }, abstract = {BACKGROUND: The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer's disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood.
METHODS: Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the PS19 mice with Ephx2 (gene encoding sEH) knockout mice. This was followed by single-nucleus RNA-sequencing (snRNA-seq), biochemical and immunohistochemical analysis, and behavioral assessments. Additionally, we examined the effects of the sEH-EET pathway in primary microglia cultures and human induced pluripotent stem cell (iPSC)-derived neurons exhibiting seeding-induced Tau inclusions.
RESULTS: sEH inhibition improved cognitive function, rescued neuronal cell loss, and reduced Tau pathology and microglial reactivity. snRNA-seq revealed that TPPU treatment upregulated genes involved in actin cytoskeleton and excitatory synaptic pathways. Treatment of human iPSC-derived neurons with TPPU enhanced synaptic density without affecting Tau accumulation, suggesting a cell-autonomous neuroprotective effect of sEH blockade. Furthermore, sEH inhibition reversed disease-associated and interferon-responsive microglial states in PS19 mice, while EET supplementation promoted Tau phagocytosis and clearance in primary microglia cultures.
CONCLUSION: These findings demonstrate that sEH blockade or EET augmentation confers therapeutic benefit in neurodegenerative tauopathies by simultaneously targeting neuronal and microglial pathways.}, }
@article {pmid40263406, year = {2025}, author = {Slimi, H and Abid, S and Sayadi, M}, title = {Revolutionizing Alzheimer's disease detection with a cutting-edge CAPCBAM deep learning framework.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {13925}, pmid = {40263406}, issn = {2045-2322}, mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; *Deep Learning ; Magnetic Resonance Imaging/methods ; Image Processing, Computer-Assisted/methods ; Neural Networks, Computer ; }, abstract = {Early and accurate diagnosis of Alzheimer's disease (AD) is crucial for effective treatment. While the integration of deep learning techniques for AD classification is not entirely new, this study introduces CAPCBAM-a framework that extends prior approaches by combining Capsule Networks with a Convolutional Block Attention Module (CBAM). In CAPCBAM, standardized preprocessing of MRI images is followed by feature extraction using Capsule Networks, which preserve spatial hierarchies and capture intricate relationships among image features. The subsequent application of CBAM, employing both channel and spatial attention mechanisms, refines the feature maps to highlight the most clinically relevant regions. This dual-attention strategy offers clear advantages over conventional CNN methods, particularly in enhancing model generalization and mitigating information loss due to pooling. On the ADNI dataset, CAPCBAM achieved an impressive accuracy of 99.95%, with precision and recall both at 99.8%, an AUC of 0.99, and an F1-Score of 99.92%. Although the use of Capsule Networks and attention mechanisms has been explored previously, CAPCBAM distinguishes itself by its robust integration of these components. The study's advantages include improved feature extraction, faster convergence, and superior classification performance, making it a promising tool for the early detection of Alzheimer's disease.}, }
@article {pmid40262935, year = {2025}, author = {Lai, LF and Li, X and Li, HZ and Li, ZM and Liu, L and Zhang, YY and Yang, H and Luo, BY and Yi, W and Xu, NG and Zhao, JY}, title = {[Electroacupuncture improves synaptic plasticity and cognitive dysfunction via down-regulating HDAC3 in mice of Alzheimer's disease].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {50}, number = {4}, pages = {375-383}, doi = {10.13702/j.1000-0607.20240214}, pmid = {40262935}, issn = {1000-0607}, mesh = {Animals ; *Electroacupuncture ; *Alzheimer Disease/therapy/genetics/enzymology/physiopathology/psychology/metabolism ; Mice ; *Neuronal Plasticity ; *Histone Deacetylases/genetics/metabolism ; Humans ; Male ; *Cognitive Dysfunction/therapy/genetics/enzymology/physiopathology/psychology ; Receptors, N-Methyl-D-Aspartate/metabolism/genetics ; Hippocampus/enzymology/metabolism ; Down-Regulation ; Female ; Acupuncture Points ; }, abstract = {OBJECTIVES: To observe the effect of electroacupuncture(EA) on histone deacetylase 3 (HDAC3), synaptic plasticity and N-methyl-D-aspartate (NMDA) receptors in the hippocampus of mice with Alzheimer's disease(AD), so as to explore the underlying mechanism of EA in treatment of AD.
METHODS: 5XFAD mice were randomly divided into EA group, model group and sham-acupuncture group, with 13 mice in both the EA group and the model group, and 7 mice in the sham-acupuncture group. Thirteen wild-type mice from the same litter were taken as the normal control group. The mice in the EA group received EA at "Baihui" (GV20)and "Dazhui" (GV14) for 15 min once daily, 6 times a week for 4 weeks. The mice in the sham-acupuncture group received sham EA, i.e., the needle was inserted into the rubber clay which was placed on the surface of the corresponding acupoints. The novel object recognition(NOR), Y-maze and Morris water maze(MWM) tests were used to observe the cognitive functions of mice. Electrophysiological technique was used to detect long-term potentiation (LTP) of the hippocampal neurons and Western blot was used to detect the relative expressions of HDAC3 and NMDAR-related receptors (NMDAR1, NMDAR2A, NMDAR2B) in the hippocampus.
RESULTS: Compared with the normal control group, 5XFAD mice in the model group showed decreased(P<0.01, P<0.05) preference index for new object recognition, alternative arm ratio (AAR), number of times crossing the original platform, percentage of time and distance traveled in the target quadrant, NMDAR2B, NMDAR2A and NMDAR1 protein expression levels, with prolonged(P<0.01) escape latency, and increased (P<0.05) protein relative expression of HDAC3. At the same time, with high-frequency stimulation, the slope of fEPSP was decreased(P<0.01, P<0.05)in the 5XFAD mice. After EA intervention, comparison between the EA and the model groups revealed that, the preference index for new object recognition, AAR were increased (P<0.01, P<0.05) in the EA group, the escape latency was shortened (P<0.05), and the number of times crossing the platform, percentage of time and distance traveled in the target quadrant, the slope of fEPSP, and the protein relative expressions of NMDAR2B, NMDAR2A and NMDAR1 in the hippocampus were increased (P<0.01, P<0.05), while the protein relative expression of HDAC3 decreased (P<0.01). Compared with sham-acupuncture group, the above indexes improved to different degree in the EA group (P<0.01, P<0.05).
CONCLUSIONS: EA of GV20 and GV14 can restore the impaired LTP and improve the cognitive impairment, which may be related to increasing the expressions of NMDA-related receptor proteins and down-regulating the expression of HDAC3 in the hippocampus of 5XFAD mice.}, }
@article {pmid40262568, year = {2025}, author = {Tuna, RW and Achmad, NA and Kurniawan, I and Khairiyah, and Asaf, MB and Sapiun, Z and Himawan, A and Dominguez-Robles, J and Aswad, M and Permana, AD}, title = {Development of thermosensitive mucoadhesive gel incorporated lipid microspheres of donepezil for enhanced nose-to-brain delivery.}, journal = {Journal of biomaterials science. Polymer edition}, volume = {}, number = {}, pages = {1-28}, doi = {10.1080/09205063.2025.2492455}, pmid = {40262568}, issn = {1568-5624}, abstract = {Alzheimer's disease (ALZ) is a chronic disease that affects the brain neurons leading to dementia. Donepezil (DPZ), a first-line treatment for ALZ is a potent symptomatic therapeutic agent. However, the oral and transdermal route represents non-targeted delivery, causing various adverse effects. This study presents the successful incorporation of a DPZ-loaded lipid microsphere (DPZ-LM) system into a thermosensitive-mucoadhesive gel (TMG), thereby enhancing the delivery of DPZ through the nose-to-brain route. To optimize the formulations, several evaluations were conducted, resulting in an optimized formulation of LM using Compritol[®] exhibited particle size of 8.75 µm, 98.44% of DPZ entrapped, and 93.40% of DPZ loaded in the system with a sustained release manner in the in vitro studies. The TMG-DPZ-LM was prepared using Pluronic[®] F127 and F68, as the gelling agents, with the addition of sodium alginate, as the mucoadhesive polymer. Following incorporation into TMG-DPZ-LM, the system exhibited excellent physicochemical properties and effective nasal delivery in ex vivo permeation has found that 88.58 ± 12.53 µg/cm[2] and retention studies with a mean concentration of 0.0077 mg of retention DPZ in porcine nasal mucosa. The in vivo pharmacokinetic studies demonstrated that the administration of TMG-DPZ-LM via the nose-to-brain route resulted in a significant (p < 0.05) increase in the Cmax, with 207.24 ± 5.16 µg/cm[3] of DPZ in the brain that exhibited a significantly different profile compared to the other route and formulation. The TMG-DPZ-LM system that was developed in this study was considered to have improved its efficacy in the treatment of ALZ.}, }
@article {pmid40261286, year = {2025}, author = {Bannon, SM and McCage, S and Walker, K and Brewer, J and Ahmad, N and Cornelius, T and Parker, RA and Dams-O'Connor, K and Dickerson, B and Ritchie, CS and Vranceanu, AM}, title = {Resilient together for dementia: A qualitative study of couples' treatment preferences to address distress early after diagnosis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251332658}, doi = {10.1177/13872877251332658}, pmid = {40261286}, issn = {1875-8908}, abstract = {BackgroundDespite technological advances and earlier and more confident diagnoses, there is a lack of post-diagnosis support for couples navigating the challenges of early dementia. Clinically elevated emotional distress is common for both partners after diagnosis, and interferes with the health, relationships, and adjustment of both partners if not addressed.ObjectiveOur objective was to gather in-depth information on couples' preferences to inform the development of a proposed dyadic intervention addressing emotional distress early (within 6 months) after one partners' receipt of a dementia diagnosis.MethodsWe recruited couples after a recent dementia diagnosis (N = 16 dyads; 32 participants) from a large academic medical center via direct provider referrals for 60-min virtual dyadic interviews. Data were analyzed using a hybrid inductive-deductive approach to thematic analysis.ResultsWe identified themes within 3 a-priori determined domains. For dyadic intervention format (domain 1), couples preferred to participate in sessions together and to have flexible options for telehealth and in-person participation. Preferences for intervention content (domain 2) included information on dementia, skills to reduce distress and promote resiliency, and support to communicate about the diagnosis and related stress. Barriers and facilitators (domain 3) included denial or hesitation, resource constraints, and interests in learning skills and connecting to others.ConclusionsWe gathered comprehensive information that could be used to adapt existing dyadic interventions and to tailor support to match couples' preferences early after dementia diagnoses. Early interventions should prioritize flexible delivery of information and skills to couples to support adaptive coping following dementia diagnoses.}, }
@article {pmid40260186, year = {2025}, author = {Piñol-Ripoll, G and Salas Carrillo, M and , }, title = {Clinicians' Perspectives of Twice-Weekly Rivastigmine Patches for Alzheimer's Disease Treatment in Spain: The VIITAL 2S Study.}, journal = {Patient preference and adherence}, volume = {19}, number = {}, pages = {1105-1118}, pmid = {40260186}, issn = {1177-889X}, abstract = {PURPOSE: Administration routes and dosage significantly impact Alzheimer's disease (AD) treatment effectiveness, as compliance in older patients depends on interactions between concomitant treatments, complex dosages, adverse effects, or medication tolerance. This study aims to describe patient and caregiver preferences concerning treatment with rivastigmine twice-weekly transdermal patches from the neurologists' and geriatricians' perspectives.
METHODS: VIITAL-2S was an ecological study based on aggregated data. A total of 250 Spanish neurologists and geriatricians answered a survey on the use, adherence, patient and caregiver satisfaction, and safety (skin tolerability) of twice-weekly rivastigmine patches.
RESULTS: Most participating physicians reported having over 11 years of experience in their specialty. According to their responses, patients with AD attending Neurology and Geriatrics were usually in mild-moderate condition, and a mean of 61.4% received rivastigmine. Around 60% of patients lived with a family member, and over 80% had a caregiver, mainly their partner/spouse or other relative. Of note, more than half of patients attending Neurology and nearly 75% of patients in Geriatrics received 4-10 medications daily. Both specialists recommended the transdermal formulation to patients receiving rivastigmine. In 33.8% and 41.0% of patients receiving daily patches, neurologists and geriatricians, respectively, recommended switching to twice-weekly patches, considering higher administration comfort and caregiver preferences. Physicians reported high/very high satisfaction with twice-weekly patches in nearly 80% of patients. Comparing twice-weekly to daily patches, they observed higher comfort, more caregiver satisfaction, and enhanced adherence. Both specialists manifested preferring twice-weekly rivastigmine patches over daily ones, especially to increase caregivers' comfort, for patients without full-week caregiver support, and in cases of poor compliance with previous treatments.
CONCLUSION: Neurologists and geriatricians consider the twice-weekly rivastigmine patch formulation beneficial for AD treatment in terms of treatment compliance, skin tolerability, satisfaction and comfort for patients and caregivers.}, }
@article {pmid40259559, year = {2025}, author = {Wu, H and Sun, Z and Gan, J and Wen, C and Shi, Z and Liu, S and Ji, Y}, title = {Efficacy of cholinesterase inhibitors treatment in dementia with Lewy bodies: A 3-year follow-up 'real world' study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251330902}, doi = {10.1177/13872877251330902}, pmid = {40259559}, issn = {1875-8908}, abstract = {BackgroundDementia with Lewy bodies (DLB) is the second most common dementia after Alzheimer's disease. Currently, no specific therapeutic agents are available for DLB. However, evidence of cholinergic deficits suggests that enhancing central cholinergic function may be a viable therapeutic approach.ObjectiveTo assess cognitive changes in DLB patients treated with cholinesterase inhibitors (ChEIs) in a real-world setting.MethodsThis retrospective study in a prospective database analyzed data from three dementia clinics between May 2012 and December 2022. Patients with DLB were divided into two groups: those treated with ChEIs and those untreated. Differences in changes in multiple cognitive-related scales between the two groups were analyzed.ResultsThe study included 204 DLB patients, with 133 (65.2%) in the ChEIs group and 71 (34.8%) in the non-ChEIs group. Initial demographic and clinical characteristics were similar between groups. Over time, patients in the ChEIs group showed significantly higher scores on the Mini-Mental State Examination and the Montreal Cognitive Assessment compared to the non-ChEIs group, indicating improved cognitive function. No significant differences were observed in activities of daily living scores.ConclusionsChEIs improved cognitive symptoms in DLB patients in the "real world" study. These findings are consistent with those from a previous small-sample randomized controlled trial. Longitudinal data indicate sustained benefits with continuous ChEIs use in three years. Overall, ChEIs show substantial potential for improving cognitive symptoms in DLB patients.}, }
@article {pmid40258814, year = {2025}, author = {Chen, J and Chen, H and Wei, Q and Lu, Y and Wang, T and Pang, X and Xing, G and Chen, Z and Cao, X and Yao, J}, title = {APOE4 impairs macrophage lipophagy and promotes demyelination of spiral ganglion neurons in mouse cochleae.}, journal = {Cell death discovery}, volume = {11}, number = {1}, pages = {190}, pmid = {40258814}, issn = {2058-7716}, support = {82071052//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82200642//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32070587//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {The ApoE-ε4 gene is a well-established genetic risk factor for neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis, which are characterized by axonal demyelination in the central nervous system. Recent studies have implicated ApoE-ε4 in age-related hearing loss (ARHL), suggesting a potential role of APOE4 isoform in peripheral nervous system degeneration. However, the role of APOE4 in ARHL are still unclear. In this study, we explored the potential role of APOE4 in axonal demyelination of spiral ganglion neurons (SGNs). ApoE-ε4/ε4 (APOE4) and ApoE-ε3/ε3 (APOE3) mice were used to characterize SGNs. The effect of APOE4 on phagocytosis and autophagy as well as intracellular cholesterol level was evaluated in resident cochlear macrophages (RCMs) and mouse bone marrow-derived macrophages (BMDMs). The results showed that significant axonal demyelination was observed in SGNs of 10-month-old APOE4 mice, accompanied by the presence of myelin debris engulfed by RCMs. Meanwhile, inhibited phagocytosis of myelin debris and impaired lipophagy were detected in APOE4 RCMs and APOE4 BMDMs with an aberrant accumulation of lipid droplets (LDs), which could be reversed by trehalose treatment. This study provided a deep insight into the pathogenesis of APOE4-induced axonal demyelination of SGNs associated with the impaired lipophagy in RCMs, which helped to elucidate the underlying mechanism of ApoE-ε4 in ARHL.}, }
@article {pmid40257938, year = {2025}, author = {Cont, C and Reinboth, BS and Schütz, C and Stute, N and Galli, A and Schulte, C and Wojtecki, L}, title = {Transcranial Pulse Stimulation for Alzheimer's Patients.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {218}, pages = {}, doi = {10.3791/67176}, pmid = {40257938}, issn = {1940-087X}, mesh = {*Alzheimer Disease/therapy ; Humans ; Magnetic Resonance Imaging/methods ; *Transcranial Direct Current Stimulation/methods/instrumentation ; *Transcranial Magnetic Stimulation/methods/instrumentation ; }, abstract = {Transcranial pulse stimulation (TPS) is a noninvasive neuromodulation therapy with Conformité Européenne (CE) marking for the treatment of Alzheimer's disease (AD). Initial pilot studies have demonstrated promising effects on cognitive function. This article focuses on the procedure for treating patients with AD using an MRI-guided, neuro-navigated TPS device. The protocol to be followed for this is described in detail, including the necessary procedures and device settings. A brief overview of the representative clinical results published to date is also provided. In addition to significant clinical improvements in cognition and affect, adverse events (AE) and possible adverse device events (ADE) are presented to provide safety data. Finally, the method is critically discussed. In the future, randomized controlled trials should be conducted to rule out any placebo effects. There is also currently a lack of long-term studies with a larger number of patients. Despite these unresolved questions, TPS has the potential as an adjunct treatment for Alzheimer's patients when used in a controlled, scientifically guided setting.}, }
@article {pmid40257754, year = {2025}, author = {Lazli, L}, title = {Improved Alzheimer Disease Diagnosis With a Machine Learning Approach and Neuroimaging: Case Study Development.}, journal = {JMIRx med}, volume = {6}, number = {}, pages = {e60866}, doi = {10.2196/60866}, pmid = {40257754}, issn = {2563-6316}, abstract = {BACKGROUND: Alzheimer disease (AD) is a severe neurological brain disorder. While not curable, earlier detection can help improve symptoms substantially. Machine learning (ML) models are popular and well suited for medical image processing tasks such as computer-aided diagnosis. These techniques can improve the process for an accurate diagnosis of AD.
OBJECTIVE: In this paper, a complete computer-aided diagnosis system for the diagnosis of AD has been presented. We investigate the performance of some of the most used ML techniques for AD detection and classification using neuroimages from the Open Access Series of Imaging Studies (OASIS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) datasets.
METHODS: The system uses artificial neural networks (ANNs) and support vector machines (SVMs) as classifiers, and dimensionality reduction techniques as feature extractors. To retrieve features from the neuroimages, we used principal component analysis (PCA), linear discriminant analysis, and t-distributed stochastic neighbor embedding. These features are fed into feedforward neural networks (FFNNs) and SVM-based ML classifiers. Furthermore, we applied the vision transformer (ViT)-based ANNs in conjunction with data augmentation to distinguish patients with AD from healthy controls.
RESULTS: Experiments were performed on magnetic resonance imaging and positron emission tomography scans. The OASIS dataset included a total of 300 patients, while the ADNI dataset included 231 patients. For OASIS, 90 (30%) patients were healthy and 210 (70%) were severely impaired by AD. Likewise for the ADNI database, a total of 149 (64.5%) patients with AD were detected and 82 (35.5%) patients were used as healthy controls. An important difference was established between healthy patients and patients with AD (P=.02). We examined the effectiveness of the three feature extractors and classifiers using 5-fold cross-validation and confusion matrix-based standard classification metrics, namely, accuracy, sensitivity, specificity, precision, F1-score, and area under the receiver operating characteristic curve (AUROC). Compared with the state-of-the-art performing methods, the success rate was satisfactory for all the created ML models, but SVM and FFNN performed best with the PCA extractor, while the ViT classifier performed best with more data. The data augmentation/ViT approach worked better overall, achieving accuracies of 93.2% (sensitivity=87.2, specificity=90.5, precision=87.6, F1-score=88.7, and AUROC=92) for OASIS and 90.4% (sensitivity=85.4, specificity=88.6, precision=86.9, F1-score=88, and AUROC=90) for ADNI.
CONCLUSIONS: Effective ML models using neuroimaging data could help physicians working on AD diagnosis and will assist them in prescribing timely treatment to patients with AD. Good results were obtained on the OASIS and ADNI datasets with all the proposed classifiers, namely, SVM, FFNN, and ViTs. However, the results show that the ViT model is much better at predicting AD than the other models when a sufficient amount of data are available to perform the training. This highlights that the data augmentation process could impact the overall performance of the ViT model.}, }
@article {pmid40257689, year = {2025}, author = {Sharma, A and Mehra, V and Kumar, V and Jain, A and Prakash, H}, title = {Tailoring MAPK Pathways: New Therapeutic Avenues for Treating Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40257689}, issn = {1559-1182}, abstract = {Alzheimer's disease (AD) is irreversible, progressive, and refractory in nature and is managed very poorly clinically due to very limited treatment outcomes. Unfortunately, most of the multiple clinical trials involving AD patients were unsuccessful in improving the disease prognosis. At the cellular level, many signaling pathways have been proposed to be involved in the sterile/refractory behavior of degenerating neurons in AD. Due to the involvement of p38MAPK in the pathogenesis of Alzheimer's disease, numerous investigations have attempted to determine the beneficial effects of MAPK targeting on memory, inflammatory programming of the brain, and synaptic plasticity. In view of this, various clinical trials involving several MAPK inhibitors (with good safety profiles and few side effects) have yielded positive results in AD patients, suggesting that MAPK targeting may be effective for reducing the pathogenesis of AD, but due to selectivity, dosing, and patient stratification, this aspect still needs further development. In view of their selectivity and off-target effects, only a few MAPK inhibitors have been employed in clinical trials against AD, indicating the scope of their development in this area. Therefore, this study focused on MAPK-based interventions as an upcoming and innovative approach for alleviating AD, with a special emphasis on clinical studies.}, }
@article {pmid40257662, year = {2025}, author = {Zhou, J and Sun, X and Wang, K and Shen, M and Yu, J and Yao, Q and Hong, H and Tang, C and Wang, Q}, title = {What Information do Systemic Pathological Changes Bring to the Diagnosis and Treatment of Alzheimer's Disease?.}, journal = {Neuroscience bulletin}, volume = {}, number = {}, pages = {}, pmid = {40257662}, issn = {1995-8218}, abstract = {Alzheimer's disease (AD) is regarded as a neurodegenerative disease, and it has been proposed that AD may be a systemic disease. Studies have reported associations between non-neurological diseases and AD. The correlations between AD pathology and systemic (non-neurological) pathological changes are intricate, and the mechanisms underlying these correlations and their causality are unclear. In this article, we review the association between AD and disorders of other systems. In addition, we summarize the possible mechanisms associated with AD and disorders of other systems, mainly from the perspective of AD pathology. Regarding the relationship between AD and systemic pathological changes, we aim to provide a new outlook on the early warning signs and treatment of AD, such as establishing a diagnostic and screening system based on more accessible peripheral samples.}, }
@article {pmid40257023, year = {2025}, author = {Zheng, Q and Wang, S and Wang, T and Zhang, G}, title = {Efficacy of Stem Cell-derived Extracellular Vesicles in the Treatment of Alzheimer's Disease Model Mice: A Systematic Review and Meta-analysis.}, journal = {Current stem cell research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.2174/011574888X352270250407170235}, pmid = {40257023}, issn = {2212-3946}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that is still incurable. Therapy with stem cell or extracellular vesicles is a promising strategy for AD treatment. Therefore, we evaluated whether stem cell-derived extracellular vesicles could improve cognitive function and pathological features in AD model mice.
METHODS: PubMed, Web of Science, Embase, and The Cochrane Library were searched for studies reporting stem cell-derived extracellular vesicles treatment of AD mice from the establishment of each database to 1st August 2023. SYRCLE was used to assess the risk of bias. The extracted data were analyzed using RevMan 5.4 and Stata 15 software.
RESULTS: 19 studies were included in the analysis. Meta-analysis showed that treatment with stem cell-derived extracellular vesicles significantly improved cognitive performance of AD mice in the Morris water maze test and the novel object recognition test, reduced β-amyloid deposition, alleviated neuroinflammation and decreased levels of the proinflammatory cytokines and glial fibrillary acidic protein (GFAP) in the brain of AD mice. However, stem cell-derived extracellular vesicle did not affect the level of brain phosphorylated tau (p-Tau).
CONCLUSIONS: stem cell-derived extracellular vesicles may promote the degradation of β-amyloid plaques in the brain, regulate immunity and protect nerves, which result in cognitive improvement in AD mice.}, }
@article {pmid40256965, year = {2025}, author = {Loring, DW and Lah, JJ and Head, EN and Hale, CL and McIntosh, RL}, title = {County Health Departments Facilitate Telehealth Dementia Evaluation: The Georgia Memory Net Collaboration.}, journal = {Telemedicine journal and e-health : the official journal of the American Telemedicine Association}, volume = {}, number = {}, pages = {}, doi = {10.1089/tmj.2024.0580}, pmid = {40256965}, issn = {1556-3669}, abstract = {Objective: To establish partnerships with county public health departments to expand telehealth access for referrals to Georgia Memory Net (GMN), a state-funded program focused on improving the early and accurate diagnosis of Alzheimer's disease and other dementias. Method: Funding from the Coronavirus Aid, Relief, and Economic Security Act, and the Building Our Largest Dementia (BOLD) Infrastructure for Alzheimer's Act supported GMN partnership development with Georgia Department of Public Health county health departments. Results: Telehealth infrastructure, including remote video neurological assessments and neuropsychological testing, is now available in 10 Georgia county health departments. Expansion efforts are in progress to bring telehealth services to additional counties, broadening GMN reach. Conclusion: Telehealth evaluations delivered through county health departments provide an effective platform for expanding access to specialized dementia diagnosis and treatment, particularly in rural and underserved areas, enhancing early detection and care for patients throughout the state.}, }
@article {pmid40256625, year = {2025}, author = {Wu, Z and Long, W and Yin, Y and Tan, B and Liu, C and Li, H and Ge, S}, title = {Outer membrane vesicles of Porphyromonas gingivalis: recent advances in pathogenicity and associated mechanisms.}, journal = {Frontiers in microbiology}, volume = {16}, number = {}, pages = {1555868}, pmid = {40256625}, issn = {1664-302X}, abstract = {Periodontitis is a chronic infectious inflammatory disease primarily caused by periodontal pathogenic bacteria, which poses a significant threat to human health. The pathogenic mechanisms associated with Porphyromonas gingivalis (P. gingivalis), a principal causative agent of periodontitis, are particularly complex and warrant thorough investigation. The extensive array of virulence factors released by this bacterium during its growth and pathogenesis not only inflicts localized damage to periodontal tissues but is also intricately linked to the development of systemic diseases through various mechanisms. The outer membrane vesicles (OMVs) produced by P. gingivalis play a key role in this process. These OMVs serve as important mediators of communication between bacteria and host cells and other bacteria, carrying and delivering virulence factors to host cells and distant tissues, thereby damaging host cells and exacerbating inflammatory responses. The ability of these OMVs to disseminate and deliver bacterial virulence factors allows P. gingivalis to play a pathogenic role far beyond the confines of the periodontal tissue and has been closely associated with the development of a variety of systemic diseases such as cardiovascular disease, Alzheimer's disease, rheumatoid arthritis, diabetes mellitus, non-alcoholic hepatitis, and cancer. In view of this, it is of great pathophysiological and clinical significance to deeply investigate its pathogenic role and related mechanisms. This will not only help to better understand the pathogenesis of periodontitis and its related systemic diseases but also provide new ideas and more effective and precise strategies for the early diagnosis, prevention, and treatment of these diseases. However, the current research in this field is still insufficient and in-depth, and many key issues and mechanisms need to be further elucidated. This article summarizes the recent research progress on the role of P. gingivalis OMVs (P. g-OMVs) in related diseases, with the aim of providing a theoretical basis and direction for future research and revealing the pathogenic mechanism of P. g-OMVs more comprehensively.}, }
@article {pmid40256246, year = {2025}, author = {Li, H and Xiao, Q and Zhu, L and Kang, J and Zhan, Q and Peng, W}, title = {Targeting ceramide-induced microglial pyroptosis: Icariin is a promising therapy for Alzheimer's disease.}, journal = {Journal of pharmaceutical analysis}, volume = {15}, number = {4}, pages = {101106}, pmid = {40256246}, issn = {2214-0883}, abstract = {Alzheimer's disease (AD), a progressive dementia, is one of the most common neurodegenerative diseases. Clinical trial results of amyloid-β (Aβ) and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing. There are currently no effective strategies for slowing the progression of AD. Herein, we spotlight the dysregulation of lipid metabolism, particularly the elevation of ceramides (Cers), as a critical yet underexplored facet of AD pathogenesis. Our study delineates the role of Cers in promoting microglial pyroptosis, a form of programmed cell death distinct from apoptosis and necroptosis, characterized by cellular swelling, and membrane rupture mediated by the NLRP3 inflammasome pathway. Utilizing both in vivo experiments with amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice and in vitro assays with BV-2 microglial cells, we investigate the activation of microglial pyroptosis by Cers and its inhibition by icariin (ICA), a flavonoid with known antioxidant and anti-inflammatory properties. Our findings reveal a significant increase in Cers levels and pyroptosis markers (NOD-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, gasdermin D (gasdermin D (GSDMD)), and interleukin-18 (IL-18)) in the brains of AD model mice, indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis. Conversely, ICA treatment effectively reduces these pyroptotic markers and Cer levels, thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD. This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy, capable of mitigating neuroinflammation and pyroptosis through the cyclooxygenase-2 (COX-2)-NLRP3 inflammasome-gasdermin D (GSDMD) axis. Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.}, }
@article {pmid40255124, year = {2025}, author = {Sheng, X and Du, Z and Gao, Z and Xu, J and Li, L and Shen, G}, title = {An Implantable In-Hydrogel Wireless Supercapacitor-Activated Neuron System Enables Bidirectional Modulation.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {}, number = {}, pages = {e2504558}, doi = {10.1002/adma.202504558}, pmid = {40255124}, issn = {1521-4095}, abstract = {The bidirectional modulation of cerebral neurons in the brain possesses enhancement and inhibition of neural activity, which is of great interest in the treatment of motor nerve disorders and emotional disorders, and cognitive defects. However, existing approaches usually rely on electrical/electrochemical stimulations, which show low security by implanting metal probes and unidirectional currents with single modulation. Herein, an implantable in-hydrogel wireless supercapacitor-activated neuron system consisting of the coil, diode bridge circuit, in-hydrogel supercapacitor, and stimulation electrodes is fabricated, which provides a bidirectional and adjustable ion diffusion current to safely and effectively excite and inhibit brain neurons. The designed in-hydrogel supercapacitor exhibits a high storage charge ability of ≈90 times larger than the devices without hydrogel encapsulation, owing to the in situ radical addition mechanism. Moreover, the in-hydrogel electrodes are implanted into the thalamus, amygdala, and prefrontal lobes of the brain to evoke the corresponding changes in potential intensity and frequency through the external chargeable coil and diode bridge circuit, which verifies the potential of the multimodule supercapacitor in amelioration and treatment Parkinson's, severe depression, and Alzheimer's disease.}, }
@article {pmid40255041, year = {2025}, author = {Jamal, R and Shaikh, MA and Taleuzzaman, M and Haque, Z and Albratty, M and Alam, MS and Makeen, HA and Zoghebi, K and Saleh, SF}, title = {Key biomarkers in Alzheimer's disease: Insights for diagnosis and treatment strategies.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251330500}, doi = {10.1177/13872877251330500}, pmid = {40255041}, issn = {1875-8908}, abstract = {Alzheimer's disease (AD) remains a significant global health challenge, characterized by its progressive neurodegeneration and cognitive decline. The urgent need for early diagnosis and effective treatment necessitates the identification of reliable biomarkers that can illuminate the underlying pathophysiology of AD. This review provides a comprehensive overview of the latest advancements in biomarker research, focusing on their applications in diagnosis, prognosis, and therapeutic development. We delve into the multifaceted landscape of AD biomarkers, encompassing molecular, imaging, and fluid-based markers. The integration of these biomarkers, including amyloid-β and tau proteins, neuroimaging modalities, cerebrospinal fluid analysis, and genetic risk factors, offers a more nuanced understanding of AD's complex etiology. By leveraging the power of precision medicine, biomarker-driven approaches can enable personalized treatment strategies and enhance diagnostic accuracy. Moreover, this review highlights the potential of biomarker research to accelerate drug discovery and development. By identifying novel therapeutic targets and monitoring disease progression, biomarkers can facilitate the evaluation of experimental treatments and ultimately improve patient outcomes. In conclusion, this review underscores the critical role of biomarkers in advancing our comprehension of AD and driving the development of effective interventions. By providing a comprehensive overview of the current state-of-the-art, this work aims to inspire future research and contribute to the goal of conquering AD.}, }
@article {pmid40255038, year = {2025}, author = {Malek, J and Levchenko, A and Robinson, JO and Fong, J and Lin, CR and Jackson, GR and Blumenthal-Barby, J and Shulman, JM and McGuire, AL}, title = {Dilemmas in diagnosing Alzheimer's disease: The peril and promise of self-fulfilling prophecies.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251331236}, doi = {10.1177/13872877251331236}, pmid = {40255038}, issn = {1875-8908}, abstract = {To date, there are limited empirical data to inform various approaches to communication with patients receiving information on Alzheimer's disease (AD) risk or diagnosis during the pre-symptomatic or minimally symptomatic stages. This article explores the ethical implications of psychological responses known as self-fulfilling prophecies that may impact cognitive decline among individuals diagnosed with or at risk for AD. We describe questions these potential effects raise about the ways clinicians communicate with patients, as well as how caregivers may interact with patients. Recent advancements in biomarkers and treatment for AD underscore the urgency of understanding these phenomena and developing appropriate responses.}, }
@article {pmid40254895, year = {2025}, author = {Schworer, EK and Handen, BL and Krinsky-McHale, S and Hom, CL and Clare, ICH and Harp, JP and Pulsifer, MB and Mapstone, M and Head, E and Christian, BT and Hartley, SL and , }, title = {Modified Cued Recall Test: Longitudinal Analysis of Test Versions and Item Recall in Adults With Down Syndrome.}, journal = {Journal of intellectual disability research : JIDR}, volume = {}, number = {}, pages = {}, doi = {10.1111/jir.13237}, pmid = {40254895}, issn = {1365-2788}, support = {UL1 TR001873/TR/NCATS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; U01 AG051406/AG/NIA NIH HHS/United States ; U01 AG051412/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; K99AG084738/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P50 AG16537//National Institutes of Health Programs: The Alzheimers Disease Research Centers Program/ ; P50 AG005133/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; U54 HD090256/HD/NICHD NIH HHS/United States ; U54 HD087011/HD/NICHD NIH HHS/United States ; P50 HD105353/HD/NICHD NIH HHS/United States ; U24 AG21886//National Centralized Repository for Alzheimer Disease and Related Dementias/ ; T32HD007489//Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; //NIHR Applied Research Collaboration East of England/ ; }, abstract = {BACKGROUND: Adults with Down syndrome (DS) have an elevated risk and early age of onset for Alzheimer's disease (AD). To support upcoming clinical AD trials, there is a critical need to establish cognitive outcome measures that can be used to capture intervention effects. One measure that has successfully been used to detect AD-related cognitive decline in the DS population is a measure of episodic memory, the modified Cued Recall Test (mCRT). Demonstrated utility of the mCRT warrants further investigation into comparisons between the A and B versions, free versus cued recall and changes in performance over time to better understand sensitivity for tracking memory decline over time based on age and AD clinical status.
METHOD: Participants were 272 adults with DS aged 25-81 (mean age = 43.12 years, SD = 9.79). Study procedures were completed at three cycles of data collection: baseline, 16-month follow-up and 32-month follow-up. Participants were enrolled in the Alzheimer Biomarker Consortium-Down Syndrome longitudinal study and completed the mCRT as part of a multiday evaluation. Comparisons were made between the A and B versions of the mCRT in recall and intrusion scores. Participants' ratio of free relative to cued recall was also examined at baseline and longitudinally. Participant performance was compared by age group, clinical AD status (cognitively stable [CS], mild cognitive impairment [MCI] or AD dementia) and premorbid level of intellectual disability (ID).
RESULTS: Version differences were identified, with the most salient differences in the moderate and severe/profound ID groups. The mCRT free recall declined with age in CS participants. Free and cued recall scores were lower in those with MCI and AD dementia, with the exception of the mild ID MCI group, whose cued recall scores were not significantly different from the CS group. Decline across 32 months (mCRT total score decline of 1.29 points/year) was observed for CS participants beginning at ≥ 50 years old, with more pronounced declines in adults with DS with an MCI or AD dementia diagnosis (3.36 and 4.20 points/year, respectively).
CONCLUSION: Characterising test version differences and participant free versus cued recall performance on the mCRT is important for understanding performance under testing conditions and to maximise the sensitivity of clinical interventions to capture meaningful effects. Our findings suggest that clinical AD trials for DS should be cautious about using both versions of the mCRT. Examining the profile of free relative to cued recall may enhance sensitivity for detecting treatment benefits for adults with DS across the range of premorbid ID levels.}, }
@article {pmid40254847, year = {2025}, author = {Song, M and Zhang, S and Gan, Y and Ding, T and Li, Z and Fan, X}, title = {Poria cocos Polysaccharide Reshapes Gut Microbiota to Regulate Short-Chain Fatty Acids and Alleviate Neuroinflammation-Related Cognitive Impairment in Alzheimer's Disease.}, journal = {Journal of agricultural and food chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.5c01042}, pmid = {40254847}, issn = {1520-5118}, abstract = {Evidence indicates that Poria cocos polysaccharide (PCP) improves cognitive impairment in Alzheimer's disease (AD); however, its underlying mechanism, particularly its relationship with the gut microbiota, remains unclear. In the current study, we aimed to investigate the mechanism of PCP in improving cognitive impairment in AD. The results demonstrated that PCP markedly enhanced cognitive function and mitigated AD-related pathological alterations in 3 × Tg-AD mice. PCP treatment reversed the age-dependent gut microbiota dysbiosis in 3 × Tg-AD mice by 16S rDNA sequencing. The contents of propanoic acid, butanoic acid and isohexanoic acid were increased by short-chain fatty acid determination. In addition, PCP could restore both the intestinal barrier and the blood-brain barrier, as demonstrated by immunofluorescence staining of tight junction proteins. Furthermore, PCP alleviated systemic inflammation and neuroinflammation, as evidenced by reduced LPS levels in circulation and decreased IL-6 levels in the brain, likely by inhibiting the TLR4/NF-κB signaling pathway. In conclusion, PCP can reshape gut microbiota to regulate short-chain fatty acids and alleviate neuroinflammation-related cognitive impairment in AD mice.}, }
@article {pmid40254603, year = {2025}, author = {Peralta Ramos, JM and Castellani, G and Kviatcovsky, D and Croese, T and Tsitsou-Kampeli, A and Burgaletto, C and Abellanas, MA and Cahalon, L and Phoebeluc Colaiuta, S and Salame, TM and Kuperman, Y and Savidor, A and Itkin, M and Malitsky, S and Ovadia, S and Ferrera, S and Kalfon, L and Kadmani, S and Samra, N and Paz, R and Rokach, L and Furlan, R and Aharon-Peretz, J and Falik-Zaccai, TC and Schwartz, M}, title = {Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in a mouse model of Alzheimer's disease.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3736}, pmid = {40254603}, issn = {2041-1723}, mesh = {Animals ; *Alzheimer Disease/immunology/metabolism/drug therapy ; *ADP-ribosyl Cyclase 1/metabolism/immunology/antagonists & inhibitors ; Disease Models, Animal ; Female ; Mice ; Humans ; Mice, Transgenic ; *Cognition/drug effects ; *Membrane Glycoproteins/metabolism/immunology/antagonists & inhibitors ; CD4-Positive T-Lymphocytes/immunology/metabolism ; Th17 Cells/immunology/metabolism/drug effects ; Interleukin-17/metabolism/immunology ; Male ; Interleukin-1beta/metabolism/immunology ; Meninges/immunology ; }, abstract = {Protective immunity, essential for brain maintenance and repair, may be compromised in Alzheimer's disease (AD). Here, using high-dimensional single-cell mass cytometry, we find a unique immunometabolic signature in circulating CD4[+] T cells preceding symptom onset in individuals with familial AD, featured by the elevation of CD38 expression. Using female 5xFAD mice, a mouse model of AD, we show that treatment with an antibody directed to CD38 leads to restored metabolic fitness, improved cognitive performance, and attenuated local neuroinflammation. Comprehensive profiling across distinct immunological niches in 5xFAD mice, reveals a high level of disease-associated CD4[+] T cells that produce IL-17A in the dural meninges, previously linked to cognitive decline. Targeting CD38 leads to abrogation of meningeal TH17 immunity and cortical IL-1β, breaking the negative feedback loop between these two compartments. Taken together, the present findings suggest CD38 as an immunometabolic checkpoint that could be adopted as a pre-symptomatic biomarker for early diagnosis of AD, and might also be therapeutically targeted alone or in combination with other immunotherapies for disease modification.}, }
@article {pmid40254404, year = {2025}, author = {Muraleva, NA and Zhdankina, AA and Khlebnikov, AI and Kolosova, NG}, title = {JNK Signaling Pathway Activity Alterations in the Rat Hippocampus: Effect of Age, Alzheimer's Disease-Like Pathology Development, and the JNK Inhibitor IQ-1S.}, journal = {Biochemistry. Biokhimiia}, volume = {90}, number = {2}, pages = {265-275}, doi = {10.1134/S0006297924603903}, pmid = {40254404}, issn = {1608-3040}, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Hippocampus/metabolism/pathology/drug effects ; Rats ; Rats, Wistar ; *MAP Kinase Signaling System/drug effects ; Male ; *Aging/metabolism ; *Protein Kinase Inhibitors/pharmacology ; Mitogen-Activated Protein Kinase 10/metabolism/antagonists & inhibitors ; Phosphorylation ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of senile dementia. The key risk factor for a more common (>95% of cases) sporadic form of AD is age. So far, there are no effective methods for AD prevention or treatment. A growing body of evidence indicates that the development of AD and other neurodegenerative diseases is associated with the activation of mitogen-activated protein kinase (MAPK) pathways, and JNK signaling pathway is considered as a potential target for the prevention and treatment of AD. However, the information on alterations in its activity in ontogenesis, which are evaluated by changes in the phosphorylation of its components, is extremely limited. The aim of this study was to compare age-related changes in the activity of JNK signaling pathway in the hippocampus of Wistar rats and senescence-accelerated OXYS rats (which spontaneously develop the key symptoms of AD-like pathology) and to evaluate the effect of the selective JNK3 inhibitor IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt). The ability of IQ-1S to suppress accelerated brain aging in OXYS rat has been proven previously, but the effect of this inhibitor on the JNK activity has not been studied. Here, we showed that with age, the activity of the JNK signaling pathway increased in the hippocampus of rats of both strains. At the same time, the manifestation and active progression of AD-like pathology in OXYS rats was accompanied by the increase in the phosphorylation level of the key kinase of this signaling pathway, JNK3, and its target proteins compared to Wistar rats, which allowed us to suggest JNK3 as a potential target for interventions aimed at preventing neurodegenerative processes. This suggestion was supported by the fact that the neuroprotective effect of the selective JNK3 inhibitor IQ-1S and its ability to suppress the development of neurodegenerative processes in OXYS rats were associated with a decrease in the phosphorylation levels of JNK3, c-Jun, APP, and Tau in the hippocampus.}, }
@article {pmid40253707, year = {2025}, author = {Fredriksen-Goldsen, KI and Kim, HJ and Teri, L and Jones-Cobb, BR and Fazia, D and Petros, R and Berridge, C and Prasad, A and Oswald, A and Emlet, CA}, title = {Older adults living with Alzheimer's Disease, dementia or mild cognitive impairment with no informal caregiver or care partner: IDEA Café, the first pilot randomized trial intervention for this underserved populations.}, journal = {Aging & mental health}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/13607863.2025.2468893}, pmid = {40253707}, issn = {1364-6915}, abstract = {OBJECTIVES: This study presents findings from IDEA Café, for older adults aged 50 and older living with early dementia, dementia, Alzheimer's Disease or cognitive impairment (ED/CI) with no informal caregiver or care partner. IDEA Café is a group adaptation of Innovations in Dementia Empowerment and Action (IDEA) (built upon the foundation of RDAD). It was tested with sexual and gender minority (SGM) older adults, as an underserved population.
METHOD: Employing a two-group randomized controlled pilot trial, thirty participants were randomly assigned to IDEA Café (n = 15) or routine medical care (RMC; n = 15). Feasibility and acceptability were assessed. We conducted pre- and post-treatment assessments of primary and secondary outcomes.
RESULTS: IDEA Café was feasible (attendance, participation), acceptable (helpfulness of the program), and met enrollment goals, with 85% of participants reporting treatment as helpful. The treatment group showed significant improvement in physical functioning (p = 0.04), depressive symptomology (p = 0.03), quality of life (p = 0.04), and a reduction in microaggressions (p = 0.05) and social exclusion (p = 0.03). The RMC showed no statistical change from pretest to posttest.
CONCLUSION: A future randomized controlled trial is needed to test the efficacy and sustainability of the intervention and to bring the intervention to scale.}, }
@article {pmid40253583, year = {2025}, author = {El-Molla, AM and Aboul Fetouh, F and Bawazir, S and Alwahby, YA and Ali, YA and Basseet, AA and Albanna, AH}, title = {Epinephrine as a Therapeutic Agent for Hyperferritinemia in Diabetes Mellitus and Hypertension.}, journal = {The American journal of case reports}, volume = {26}, number = {}, pages = {e947289}, doi = {10.12659/AJCR.947289}, pmid = {40253583}, issn = {1941-5923}, mesh = {Humans ; *Diabetes Mellitus, Type 2/complications/drug therapy ; *Epinephrine/therapeutic use ; *Hypertension/complications/drug therapy ; *Hyperferritinemia/drug therapy/etiology ; Male ; Middle Aged ; Ferritins/blood ; COVID-19 ; }, abstract = {BACKGROUND Diabetes mellitus was the first non-communicable disease to be recognized as a 21st century pandemic. Type 2 diabetes (T2DM) results from increased insulin resistance (IR) or relative insulin deficiency. IR impairs glucose disposal, leading to a compensatory hyper-insulinemic state. Increased iron stores as reflected by high serum ferritin (SF) have been associated with the development T2DM and affect glucose homeostasis by impairing tissue response to insulin. Iron overload (IO) is quite common in essential hypertension (HTN). The first clinical effect of epinephrine on SF was reported in 2024, showing that epinephrine resulted in normalization of SF and recovery from severe COVID-19 infection. CASE REPORT A patient with T2DM, HTN, and dyslipidemia associated with hyperferritinemia received the conventional treatment of T2DM and HTN, with a poor control of hyperglycemia and HTN. Since the patient had elevated SF, we obtained informed written consent for epinephrine's use to lower SF. Epinephrine 0.6 mcg/kg was injected subcutaneously under hemodynamic monitoring, and the results showed normalization of SF and complete recovery of T2DM and HTN. CONCLUSIONS Epinephrine can normalize elevated SF by its iron chelating effect; therefore, it can relieve IO and alleviate IR associated with T2DM and HTN. Epinephrine has an anti-inflammatory and scavenging properties that can inhibit ferroptosis. As a new clinical indication, extensive studies are required for further assessment and possible therapeutic uses in IO disorders such as hereditary hemochromatosis (HH), Alzheimer disease (AD), Parkinsonian disease (PD), and multiple sclerosis (MS).}, }
@article {pmid40253440, year = {2025}, author = {Khan, S and Choudhury, A and Mohammad, T and Shamsi, A and Hassan, MI and Islam, A}, title = {Structure-guided screening identified bioactive phytoconstituents Hernandonine and Anolobine as potential inhibitors of dual specificity protein kinase CLK1.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {13604}, pmid = {40253440}, issn = {2045-2322}, mesh = {*Protein Serine-Threonine Kinases/antagonists & inhibitors/chemistry/metabolism ; Molecular Docking Simulation ; *Protein Kinase Inhibitors/chemistry/pharmacology ; *Protein-Tyrosine Kinases/antagonists & inhibitors/chemistry/metabolism ; Humans ; *Phytochemicals/chemistry/pharmacology ; Molecular Dynamics Simulation ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD) are becoming a global health concern because of their progressive nature and the extent of the disability they cause to the affected individuals. Existing therapies for neurodegenerative diseases are primarily limited to symptomatic management and have shown diminishing efficacy over time, often leading to resistance. Therefore, there is an urgent need for novel therapeutic interventions that offer improved effectiveness with fewer side effects. A promising approach that has been suggested in neurodegenerative diseases, especially AD, is the prevention of tau phosphorylation by using kinase inhibitors. CDC2-like kinase 1 (CLK1) is a dual-specificity proline-directed protein kinase that is involved in both tau phosphorylation and splicing regulation and is thus a potential drug target. Currently, there are several small molecular CLK1 inhibitors, but problems like drug resistance and side effects still exist. In this study, we have used a structure-guided virtual screening approach to screen the bioactive phytoconstituents of Indian medicinal plants for potential CLK1 inhibitors. The systematic virtual screening involving molecular docking, density functional theory (DFT), and pharmacokinetic profiling, pinpointed Hernandonine and Anolobine as promising compounds due to their druglike properties and high binding affinity with CLK1. To assess the stability and interaction of these compounds with CLK1, all-atom molecular dynamics (MD) simulations and essential dynamics were performed for 500 ns. The results indicate that Hernandonine and Anolobine have a high potential for CLK1 inhibition and can be used as promising leads for developing novel effective drugs against neurodegeneration. This work underlines the importance of the combined use of virtual screening and MD simulations in the search for phytochemical-based CLK1 inhibitors, which can lead to the development of new therapeutic approaches in the treatment of neurodegenerative diseases such as AD.}, }
@article {pmid40253240, year = {2025}, author = {Angioni, D and Middleton, L and Bateman, R and Aisen, P and Boxer, A and Sha, S and Zhou, J and Gerlach, I and Raman, R and Fillit, H and Salloway, S and Sperling, R and Vellas, B and Cummings, J}, title = {Challenges and opportunities for novel combination therapies in Alzheimer's disease: a report from the EU/US CTAD Task Force.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100163}, doi = {10.1016/j.tjpad.2025.100163}, pmid = {40253240}, issn = {2426-0266}, abstract = {Following the recent approvals of anti-amyloid immunotherapies as "first-in-kind" disease-modifying agents for Alzheimer's disease (AD), there is an emerging emphasis in combination therapies, given the complex and multifactorial etiopathogenesis and pathophysiology of the disease. The EU/US CTAD Task Force met in Madrid in October 2024, to discuss biological rationale and methodological issues and outline potential directions for future research in combination therapies. The Task Force agreed on the necessity and urgency of advancing combination therapies for AD treatment. As of January 1, 2024, in the drug development pipeline, there were 21 combination trials (13 % of all trials). The combination of anti-amyloid and anti-tau therapies could become a central focus of the field. Combinations involving anti-inflammatory and immune mechanisms with anti-amyloid or other therapies also have promise. To facilitate the development and implementation of combination therapies, collaborations between sponsors and public-private partnerships are essential. Optimizing the likelihood of success primarily requires leveraging the use of biomarkers and a clearer understanding of the biological mechanisms underpinning AD and their interactions, especially those involving amyloid, tau, and inflammation, that lead to cognitive decline and progression.}, }
@article {pmid40253039, year = {2025}, author = {Malaiya, A and Kenwat, R and Mamgain, A and Nayak, P and Parker, A and Paliwal, SR and Paliwal, R}, title = {Intranasal resveratrol delivery to the brain with chitosan-decorated bovine serum albumin nanoparticles: Advancing Alzheimer's management in old female rats through QbD-based optimization, in vitro evaluation, and in vivo exploration.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {143300}, doi = {10.1016/j.ijbiomac.2025.143300}, pmid = {40253039}, issn = {1879-0003}, abstract = {This study aims to prepare, characterize, and evaluate the potential of chitosan-coated bovine serum albumin nanoparticles (CS-BSANPs) loaded with resveratrol (RES) to enhance the therapeutic properties of RES and target Alzheimer's disease in elderly females. As confirmed by morphological analysis, the BSANPs were synthesized using desolvation techniques, resulting in spherical and smooth nanoparticles. Both RES-BSANPs and CS-RES-BSANPs exhibited stability for 90 days at ambient refrigerated temperatures. Through optimization using a Box-Behnken design, RES-BSANPs with favorable colloidal properties were achieved. Differential scanning calorimetry and powder X-ray diffraction confirmed the amorphous dispersion of RES within the nanocarriers. In vitro drug release studies demonstrated a biphasic release pattern aligned with the Korsmeyer-Peppas model, exhibiting both burst and sustained release phases. Stability tests indicated that RES-BSA-NPs and CS-RES-NPs remain stable at 4 °C. Ex vivo studies verified the safety of RES-loaded nanoparticles, and behavioral tests on the Wistar rat model showed that intranasally administered CS-RES-BSANPs were more effective than plain RES dispersion. These results emphasize the potential of biodegradable and mucoadhesive CS-RES-BSANPs as effective drug carriers for intranasal delivery to the brain, offering safety and high tolerability for Alzheimer's disease treatment.}, }
@article {pmid40252967, year = {2025}, author = {Aghamoosa, S and Nolin, SA and Chen, A and Caulfield, KA and Lopez, J and Rbeiz, K and Fleischmann, HH and Horn, O and Madden, K and Antonucci, M and Revuelta, G and McTeague, LM and Benitez, A}, title = {Accelerated iTBS-Induced Changes in Resting-State Functional Connectivity Correspond with Cognitive Improvement in Amnestic MCI.}, journal = {Brain stimulation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.brs.2025.04.012}, pmid = {40252967}, issn = {1876-4754}, abstract = {BACKGROUND: Published results of our Phase I safety and feasibility trial of accelerated intermittent theta burst stimulation (a-iTBS) in mild cognitive impairment (MCI) due to Alzheimer's disease showed a large effect-size improvement in cognition.
OBJECTIVE: Further demonstrate target engagement by identifying whether changes in local and network-level functional connectivity relate to the observed cognitive improvement.
METHODS: Eighteen patients with MCI received 3-day a-iTBS (8 sessions/day) to the left dorsolateral prefrontal cortex at Beam F3 (14,400 total pulses) and completed MRI and cognitive testing at pre- and post-treatment. Based on electric field models, we selected 3 stimulated target regions of interest (ROIs) which belonged to the frontoparietal (FPN), default mode (DMN), and ventral attention (VAT) networks (3 target networks). Metrics of resting-state functional connectivity were computed at the ROI level (within-network degree: number of connections) and network level (segregation: strength of connectivity within network relative to other networks). We correlated changes in cognition and connectivity for the target ROIs and networks; off-target ROI (primary visual) and networks serve as negative controls.
RESULTS: Improvements in cognition were associated with connectivity changes in the target ROIs and networks, but not in off-target negative controls. Positive associations were observed for degree of the l-DMN and segregation of target networks overall, with significant effects for DMN and VAT.
CONCLUSION: Cognitive improvement following a-iTBS in MCI may be attributable to local and network-level reconfigurations in functional connectivity. These findings will inform larger trials designed to further evaluate the neural mechanisms of a-iTBS for cognition in MCI.}, }
@article {pmid40252920, year = {2025}, author = {Vigil Díaz, C and Paredes Rodríguez, P and Perissinotti, A and Fernando Guillén, E and López Mora, D and Lojo Ramírez, JA and Aguiar Fernández, P and Camacho Martí, MV and Nieves Cabrera-Martín, M and , }, title = {Procedure update and interpretation guide for the brain [18]F-FDG PET study.}, journal = {Revista espanola de medicina nuclear e imagen molecular}, volume = {}, number = {}, pages = {500159}, doi = {10.1016/j.remnie.2025.500159}, pmid = {40252920}, issn = {2253-8089}, abstract = {The increase in the prevalence of dementia in our clinical setting poses a diagnostic challenge for the Nuclear Medicine specialist. The aim of this study is to review the modifications in the procedure and to describe the usefulness of the use of brain PET with [18]F-FDG in different clinical indications, both classic and emerging ones. The SEMNIM Neuroimaging working group has considered it appropriate to update the procedures available in Spanish, in order to optimize the quality of this technique and the interpretation of its findings, both for the specialist in Nuclear Medicine and the rest of the professionals involved in the diagnosis and treatment of neurodegenerative diseases.}, }
@article {pmid40252828, year = {2025}, author = {Zhao, Y and Zhao, W and Chai, X and Sun, P and Huang, J and Guo, X and Zhang, L and Ren, D and Yi, C and Zhu, X and Zhao, S}, title = {Reshaping the gut microbiota: A novel oppinion of Eucommiae cortex polysaccharide alleviate learning and memory impairments in Alzheimer's disease.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2025.04.025}, pmid = {40252828}, issn = {2090-1224}, abstract = {BACKGROUND: Alzheimer's disease (AD), which is a chronic neurodegenerative disorder, is marked by the progressive deteriorations in learning and memory capabilities. The microbiota-gut-brain axis has come to be regarded as a crucial element in relation to the pathogenesis as well as the treatment of AD. Eucommiae cortex polysaccharides (EPs), being among the most plentiful substances present in the Eucommiae cortex, show the potential to exert immunomodulatory and neuroprotective function. However, whether EPs are protective against AD and their mechanism of action remain to be investigated OBJECTIVES: We hypothesize that EPs can regulate brain glutamine metabolism through gut microbiota and the butyric acid metabolized by them, improve oxidative stress and autophagy in the brain, and thus alleviate AD.
METHODS: In the present study, we used EPs (0.25 % w/w in food) and fecal microbiota transplantation, as well as butyrate supplementation (0.1 M in water), to intervene in AD mice. Multi-omics were used to determine the mechanism by which EPs improve AD-related learning and memory impairments.
RESULTS: Our results suggest that EPs, functioning as a prebiotic, alleviated learning and memory impairments in AD mice. Mechanistically, EPs are able to reshape the gut microbiota, promote the growth of gut microbiota involved in short-chain fatty acid metabolism, particularly butyrate-producing microbes. The butyrate produced by these microbes improves the brain microenvironment by modulating oxidative stress and autophagy mediated by brain glutamate metabolism, improving learning and memory impairments in AD mice, and inhibiting the formation and deposition of beta-amyloid proteins. Fecal microbiota transplantation (FMT) and butyrate supplementation further confirm this conclusion.
CONCLUSIONS: Our results highlighted that EPs can alleviate learning and memory impairments in AD with a gut microbiota-dependent manner and that butyric acid metabolized by butyric acid-metabolizing bacteria in the gut plays a central role in regulating brain glutamine metabolism to improve brain microenvironmental homeostasis. Meanwhile, the present study provides new insights into the treatment of AD with natural products.}, }
@article {pmid40251832, year = {2025}, author = {Bresque, M and Esteve, D and Balmer, G and Hamilton, HL and Stephany, JS and Pehar, M and Vargas, MR}, title = {FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.}, journal = {Glia}, volume = {}, number = {}, pages = {}, doi = {10.1002/glia.70023}, pmid = {40251832}, issn = {1098-1136}, support = {R01NS122973/NH/NIH HHS/United States ; R01NS132760/NH/NIH HHS/United States ; }, abstract = {Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.}, }
@article {pmid40251199, year = {2025}, author = {Sangeet, S and Khan, A}, title = {Bacopa monnieri phytochemicals as promising BACE1 inhibitors for Alzheimer's disease therapy.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {13504}, pmid = {40251199}, issn = {2045-2322}, mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors/chemistry/metabolism ; *Alzheimer Disease/drug therapy ; *Bacopa/chemistry ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism/chemistry ; Molecular Docking Simulation ; Humans ; *Phytochemicals/pharmacology/chemistry/therapeutic use ; Protein Binding ; Triterpenes/chemistry/pharmacology ; }, abstract = {Alzheimer's disease (AD) remains a formidable challenge, necessitating the discovery of effective therapeutic agents targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1). This study investigates the inhibitory potential of phytochemicals derived from Bacopa monnieri, a plant renowned for its cognitive-enhancing properties, in comparison to established synthetic inhibitors such as Atabecestat, Lanabecestat, and Verubecestat. Utilizing molecular docking and advanced computational simulations, we demonstrate that Bacopaside I exhibits superior binding affinity and a unique interaction profile with BACE1, suggesting a more nuanced inhibitory mechanism. Our findings highlight the promising role of Bacopa monnieri phytochemicals as viable alternatives to synthetic drugs, emphasizing their potential to overcome limitations faced in clinical settings. Furthermore, the development of the SIMANA (https://simana.streamlit.app/) platform enhances the visualization and analysis of protein-ligand interactions, facilitating a deeper understanding of the dynamics involved. This research not only underscores the therapeutic promise of natural compounds in AD treatment but also advocates for a paradigm shift towards integrating traditional medicinal knowledge into contemporary drug discovery efforts.}, }
@article {pmid40250750, year = {2025}, author = {Noda, K and Kageyama, I and Kobayashi, Y and Lim, Y and Sengoku, S and Kodama, K}, title = {Leveraging mHealth wearables for managing patients with Alzheimer's disease: a scoping review.}, journal = {Drug discovery today}, volume = {}, number = {}, pages = {104363}, doi = {10.1016/j.drudis.2025.104363}, pmid = {40250750}, issn = {1878-5832}, abstract = {In this scoping review, we examine the role of wearable devices in diagnosing, treating, and monitoring Alzheimer's disease (AD) and mild cognitive impairment (MCI). It identifies various devices, including fitness trackers, smartwatches, electroencephalographic equipment, and sensors, which are used for monitoring physical activity, sleep patterns, and cognitive functions. Our review highlights the potential of these devices for early diagnosis and treatment, improving patient autonomy and quality of life. However, challenges, such as data privacy, device adherence, and technical limitations, remain. Future research should focus on integrating wearable devices with advanced diagnostic tools and validating their effectiveness across diverse populations.}, }
@article {pmid40250748, year = {2025}, author = {Ahsan, R and Khan, MM and Mishra, A and Noor, G and Ahmad, U}, title = {Plumbagin as a potential therapeutic agent for scopolamine-induced Alzheimer's disease: Mechanistic insights into GSK-3β inhibition.}, journal = {Brain research}, volume = {}, number = {}, pages = {149650}, doi = {10.1016/j.brainres.2025.149650}, pmid = {40250748}, issn = {1872-6240}, abstract = {BACKGROUND: The study aimed to evaluate Plumbagin's neuroprotective potential against scopolamine-induced Alzheimer's disease, proposing that its effects may involve GSK-3β inhibition, a key factor in tau hyperphosphorylation, to promote neuroprotection in Wistar rats.
METHODS: Alzheimer's was induced in male Wistar rats. After acclimatization, the rats were subjected to daily intraperitoneal treatment with scopolamine (0.7 mg/kg) and oral administration of Plumbagin (10 mg/kg) for 13 days. The cognitive function of treated rats was evaluated using the Morris water maze test, along with assessments of locomotor activity, acetylcholinesterase activity (AChE), protein levels, antioxidant parameters, cytokines and Brain-Derived Neurotrophic Factor (BDNF) and brain histopathology (hippocampus).
RESULTS: The Plumbagin (10 mg/kg, oral) as given orally significantly improved neurobehavioral alterations compared to Alzheimer's induced group. Scopolamine impaired cognitive function and increased locomotor activity ([#]P < 0.05). Treatments improved Morris water maze performance, reducing Escape latency time and increasing Time spent in the target quadrant (*P < 0.05). Biochemically, treatments significantly improved BDNF (*P < 0.05), decreased AChE activity, oxidative stress, reduced Interleukin-6 and Tumor Necrosis Factor Alpha (*P < 0.05) and reversed Scopolamine induced hippocampal neuronal loss ([##]P < 0.01). Plumbagin showed significant (*P < 0.05) neuroprotective effects, improving cognitive function, reducing AChE activity, Malondialdehyde, oxidative stress, and neuroinflammatory markers exceeding individual treatments in the scopolamine-induced Alzheimer's disease model. These improvements suggest a possible mechanism through the inhibition of GSK-3β, which may contribute to the observed neuroprotective effects.
CONCLUSION: This study suggests that Plumbagin's neuroprotective effects in scopolamine-induced Alzheimer's disease may involve GSK-3β inhibition. Plumbagin shows significant therapeutic potential for Alzheimer's treatment, warranting further investigation of its mechanism.}, }
@article {pmid40249069, year = {2025}, author = {Behera, P and Mishra, M}, title = {Lipid Droplet in Lipodystrophy and Neurodegeneration.}, journal = {Biology of the cell}, volume = {117}, number = {4}, pages = {e70009}, doi = {10.1111/boc.70009}, pmid = {40249069}, issn = {1768-322X}, support = {221610052028//UGC/ ; }, mesh = {Humans ; *Lipodystrophy/metabolism/pathology ; *Lipid Droplets/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Lipid Metabolism ; }, abstract = {Lipid droplets are ubiquitous yet distinct intracellular organelles that are gaining attention for their uses outside of energy storage. Their formation, role in the physiological function, and the onset of the pathology have been gaining attention recently. Their structure, synthesis, and turnover play dynamic roles in both lipodystrophy and neurodegeneration. Factors like development, aging, inflammation, and cellular stress regulate the synthesis of lipid droplets. The biogenesis of lipid droplets has a critical role in reducing cellular stress. Lipid droplets, in response to stress, sequester hazardous lipids into their neutral lipid core, preserving energy and redox balance while guarding against lipotoxicity. Thus, the maintenance of lipid droplet homeostasis in adipose tissue, CNS, and other body tissues is essential for maintaining organismal health. Insulin resistance, hypertriglyceridemia, and lipid droplet accumulation are the severe metabolic abnormalities that accompany lipodystrophy-related fat deficit. Accumulation of lipid droplets is detected in almost all neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and Hereditary spastic paraplegia. Hence, the regulation of lipid droplets can be used as an alternative approach to the treatment of several diseases. The current review summarizes the structure, composition, biogenesis, and turnover of lipid droplets, with an emphasis on the factors responsible for the accumulation and importance of lipid droplets in lipodystrophy and neurodegenerative disease.}, }
@article {pmid40248597, year = {2025}, author = {Guo, Z and Jiang, Y and He, J and Jiang, N}, title = {Repetitive transcranial magnetic stimulation may promote the reversion of mild cognitive impairment to normal cognition.}, journal = {Frontiers in psychiatry}, volume = {16}, number = {}, pages = {1544728}, pmid = {40248597}, issn = {1664-0640}, abstract = {PURPOSE: This study aimed to investigate the potential effects of repetitive transcranial magnetic stimulation (rTMS) on the reversion of mild cognitive impairment (MCI) to normal cognitive function and to elucidate the underlying mechanisms.
METHODS: The study enrolled 25 MCI participants, who underwent a 10-day of rTMS treatment and an 18-month follow-up, along with 15 healthy subjects. Participants with MCI were categorized into MCI reverters (MCI-R) and MCI maintainers (MCI-M). We assessed differences in baseline cognitive performance, functional connectivity, and changes of cognitive functions after rTMS between MCI-R and MCI-M to identify possible predictors of reversion of MCI and explore the neural modulation mechanisms.
RESULTS: MCI-M exhibited more severe cognitive impairments across more domains, particularly in language function (p < 0.05). Functional connectivity was more severely damaged in MCI-M participants, notably within the default mode network (DMN), executive control network (ECN), and frontoparietal network (FPN). After rTMS therapy, MCI-R participants demonstrated more significantly improved immediate and delayed recall memory scores (p < 0.05). These memory function changes and baseline functional connectivity of DMN, ECN, and FPN were predictive of the reversion of MCI.
CONCLUSIONS: The efficacy of rTMS in memory function may promote the reversion of MCI to normal cognition, with the functional connectivity of DMN, ECN, and FPN playing a crucial important role. The severity of cognitive impairment and functional connectivity damage correlated with the likelihood of the reversion of MCI to normal cognition, underscoring the importance of early rTMS intervention for dementia prevention.}, }
@article {pmid40248168, year = {2024}, author = {Park, J and Lee, C and Lin, L and Galvin, J and Fain, MJ and Allen, A and Park, L and Ahn, H}, title = {Efficacy of Home-Based Remotely Supervised Transcranial Direct Current Stimulation for Managing Neuropsychiatric Symptoms in Older Adults With Alzheimer's Disease and Related Dementias.}, journal = {Integrative and complementary therapies}, volume = {30}, number = {5}, pages = {209-219}, pmid = {40248168}, issn = {2768-3206}, abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent among persons with Alzheimer's disease and related dementias (ADRD). However, there are limited safe and effective nonpharmacological treatments for controlling NPS. Transcranial direct current stimulation (tDCS) is a promising noninvasive and safe treatment.
MATERIALS AND METHODS: This study investigated the effects of remotely supervised tDCS in managing NPS in older adults with mild to moderate ADRD. Forty older adults diagnosed with early-stage ADRD were randomly assigned in a 1:1 ratio to receive home-based active tDCS (n = 20) or sham tDCS (n = 20).
RESULTS: Results showed a significantly greater improvement in the following NPS: scratching (P = 0.052, Hedges' g = -0.60 [confidence interval {CI}: -1.24, 0.04], Cliff's δ = -0.41 [CI: -0.67, -0.06]), nighttime behaviors (P = 0.041; Hedges' g = -0.62 [CI: -1.26, 0.03]; Cliff's δ = -0.41 [CI: -0.67, -0.06], and appetite/eating changes (P = 0.010; Hedges' g = -0.78 [CI: -1.43, -0.13]; Cliff's δ = -0.41 [CI: - 0.56, -0.10]).
CONCLUSION: This study shows promising initial results for using home-based, remotely supervised tDCS to manage NPS, such as nighttime behaviors, changes in eating and appetite, and scratching. Larger studies with more participants are needed to explore various tDCS doses and their long-term effects on NPS.}, }
@article {pmid40248108, year = {2025}, author = {Lee, S and Liu, R and Cheng, F and Zhang, P}, title = {A Deep Subgrouping Framework for Precision Drug Repurposing via Emulating Clinical Trials on Real-world Patient Data.}, journal = {KDD : proceedings. International Conference on Knowledge Discovery & Data Mining}, volume = {2025}, number = {v1}, pages = {2347-2358}, pmid = {40248108}, issn = {2154-817X}, abstract = {Drug repurposing identifies new therapeutic uses for existing drugs, reducing the time and costs compared to traditional de novo drug discovery. Most existing drug repurposing studies using real-world patient data often treat the entire population as homogeneous, ignoring the heterogeneity of treatment responses across patient subgroups. This approach may overlook promising drugs that benefit specific subgroups but lack notable treatment effects across the entire population, potentially limiting the number of repurposable candidates identified. To address this, we introduce STEDR, a novel drug repurposing framework that integrates subgroup analysis with treatment effect estimation. Our approach first identifies repurposing candidates by emulating multiple clinical trials on real-world patient data and then characterizes patient subgroups by learning subgroup-specific treatment effects. We deploy STEDR to Alzheimer's Disease (AD), a condition with few approved drugs and known heterogeneity in treatment responses. We emulate trials for over one thousand medications on a large-scale real-world database covering over 8 million patients, identifying 14 drug candidates with beneficial effects to AD in characterized subgroups. Experiments demonstrate STEDR's superior capability in identifying repurposing candidates compared to existing approaches. Additionally, our method can characterize clinically relevant patient subgroups associated with important AD-related risk factors, paving the way for precision drug repurposing.}, }
@article {pmid40248097, year = {2025}, author = {Jia, J and Zhao, S and Zhao, J and Gao, Y}, title = {Engineered nanoparticles for the treatment of Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1510798}, pmid = {40248097}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is one of the most common diseases characterized by neurodegeneration and is becoming a major public health problem worldwide. AD is manifested mainly by progressive impairments in cognition, emotion, language and memory in the elderly population. Many treatment strategies have been explored for decades; however, there is still no effective way to address the root cause of AD pathogenesis, only to target symptoms to improve patient cognitive outcomes. Intracerebral administration is difficult because of the challenges posed by the blood‒brain barrier (BBB). NPs are materials with sizes between 1 and 100 nm that can improve biocompatibility, extend the half-life, transport macromolecules, be delivered across the BBB to the central nervous system, and exhibit good targeting capabilities. NPs can provide new ideas for the treatment of AD in terms of their antiaging, antineuroinflammatory, antioxidative, and nerve repair-promoting effects. In this manuscript, we first describe the relationship between AD and the BBB. Second, we introduce the application of nanoparticles for AD treatment. Finally, we summarize the challenges faced by nanoparticles in the treatment of AD.}, }
@article {pmid40247766, year = {2025}, author = {Randhawa, S and Saini, TC and Bathla, M and Teji, N and Acharya, A}, title = {Biofilm Biology to Brain Health: Harnessing Microbial Wisdom to Uncover Amyloid Dissociating Bifunctional Nano Chaperones for Alzheimer's Therapeutics.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.4c00868}, pmid = {40247766}, issn = {1948-7193}, abstract = {Microbial infections have long been implicated in the gut-brain link to Alzheimer's disease (AD). These infections may influence AD development either directly, through brain invasion, or indirectly via bacterial metabolites crossing the blood-brain-barrier (BBB) or interacting with the enteric nervous system (ENS). Such findings have inspired clinicians to repurpose antimicrobial drugs for AD, yielding promising results. However, the sole bacterial link to AD may be insufficiently understood. Bacterial amyloid presence in biofilms is well-documented, with certain bacterial proteins exacerbating amyloid formation while others inhibit it. For instance, Curli-specific gene protein C (CsgC) in E. coli suppresses curli amyloid formation. This review investigates the possibility of human CsgC-like proteins, identifying beta-2 microglobulin (β2M) and E3 ubiquitin ligases (E3s) as potential analogs that may influence amyloid degradation. We propose that nanoparticles (NPs) could serve as platforms to anchor these proteins, forming Amyloid Dissociating Bifunctional NanoChaperones (ADBiNaCs) with enhanced antiamyloidogenic activity. This innovative approach holds promise for novel AD treatment strategies, meriting further investigation into the role of bacterial and human amyloid-modulating proteins in AD pathology.}, }
@article {pmid40247604, year = {2025}, author = {Rahman, SM and Tan, C and Kakita, A and Moruno-Manchon, JF}, title = {Sex differences in brain iron deposition and microglial ferritin in Alzheimer's disease.}, journal = {Science progress}, volume = {108}, number = {2}, pages = {368504251336080}, doi = {10.1177/00368504251336080}, pmid = {40247604}, issn = {2047-7163}, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Microglia/metabolism/pathology ; Female ; Male ; *Iron/metabolism ; *Brain/metabolism/pathology ; Aged ; *Ferritins/metabolism ; *Sex Characteristics ; Aged, 80 and over ; Apoferritins/metabolism ; Sex Factors ; }, abstract = {ObjectiveIron is the most abundant metal in the human brain, and plays a crucial role in many biological processes. However, disruptions in brain iron metabolism can lead to iron buildup, which occurs with aging and is linked to several brain disorders, including Alzheimer's disease. Microglia, the brain's resident immune cells, have the highest capacity to store iron, which is stored intracellularly within ferritin complexes. Importantly, women are at a higher risk of developing Alzheimer's disease and experience faster disease progression compared to men.MethodsWe used postmortem brain samples from patients with Alzheimer's disease and small vessel disease patients of both sexes for immunohistochemical studies. Samples were stained with the Prussian blue method to visualize iron deposits and with antibodies against the microglia marker Iba1 and ferritin light chain.ResultsOur study reveals that the number of iron deposits and the levels of ferritin light chain in microglia are positively correlated in men with Alzheimer's disease, but negatively correlated in women. There is no correlation between brain iron deposition and ferritin in samples from patients with small vessel disease of both sexes.ConclusionsThese results could inform more tailored approaches to the treatment and management of Alzheimer's disease based on sex-specific differences in brain iron metabolism and microglial iron storage capacity.}, }
@article {pmid40246821, year = {2025}, author = {Li, X and Chen, J and Yang, Y and Cai, H and Ao, Z and Xing, Y and Li, K and Yang, K and Guan, W and Friend, J and Lee, LP and Wang, N and Guo, F}, title = {Extracellular vesicle-based point-of-care testing for diagnosis and monitoring of Alzheimer's disease.}, journal = {Microsystems & nanoengineering}, volume = {11}, number = {1}, pages = {65}, pmid = {40246821}, issn = {2055-7434}, abstract = {Extracellular vesicles (EVs) show potential for early diagnosis of Alzheimer's disease (AD) and monitoring of its progression. However, EV-based AD diagnosis faces challenges due to the small size and low abundance of biomarkers. Here, we report a fully integrated organic electrochemical transistor (OECT) sensor for ultrafast, accurate, and convenient point-of-care testing (POCT) of serum EVs from AD patients. By utilizing acoustoelectric enrichment, the EVs can be quickly propelled, significantly enriched, and specifically bound to the OECT detection area, achieving a gain of over 280 times response in 30 s. The integrated POCT sensor can detect serum EVs from AD patients with a limit of detection as low as 500 EV particles/mL and a reduced detection time of just two minutes. Furthermore, the integrated POCT sensors were used to monitor AD progression in an AD mouse model by testing the mouse Aβ EVs at different time courses (up to 18 months) and compared with the Aβ accumulation using high-resolution magnetic resonance imaging (MRI). This innovative technology has the potential for accurate and rapid diagnosis of Alzheimer's and other neurodegenerative diseases, and monitoring of disease progression and treatment response.}, }
@article {pmid40246680, year = {2025}, author = {Akter, S and Liu, Z and Simoes, EJ and Rao, P}, title = {Using machine learning and electronic health record (EHR) data for the early prediction of Alzheimer's Disease and Related Dementias.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100169}, doi = {10.1016/j.tjpad.2025.100169}, pmid = {40246680}, issn = {2426-0266}, abstract = {BACKGROUND: Over 6 million patients in the United States are affected by Alzheimer's Disease and Related Dementias (ADRD). Early detection of ADRD can significantly improve patient outcomes through timely treatment.
OBJECTIVE: To develop and validate machine learning (ML) models for early ADRD diagnosis and prediction using de-identified EHR data from the University of Missouri (MU) Healthcare.
DESIGN: Retrospective case-control study.
SETTING: The study used de-identified EHR data provided by the MU NextGen Biomedical Informatics, modeled with the PCORnet Common Data Model (CDM).
PARTICIPANTS: An initial cohort of 380,269 patients aged 40 or older with at least two healthcare encounters was narrowed to a final dataset of 4,012 ADRD cases and 119,723 controls.
METHODS: Six ML classifier models: Gradient-Boosted Trees (GBT), Light Gradient-Boosting Machine (LightGBM), Random Forest (RF), eXtreme Gradient-Boosting (XGBoost), Logistic Regression (LR), and Adaptive Boosting (AdaBoost) were evaluated using Area Under the Receiver Operating Characteristic Curve (AUC-ROC), accuracy, sensitivity, specificity, and F1 score. SHAP (SHapley Additive exPlanations) analysis was applied to interpret predictions.
RESULTS: The GBT model achieved the best AUC-ROC scores of 0.809-0.833 across 1- to 5-year prediction windows. SHAP analysis identified depressive disorder, age groups 80-90 yrs and 70-80 yrs, heart disease, anxiety, and the novel risk factors of sleep apnea, and headache.
CONCLUSION: This study underscores the potential of ML models for leveraging EHR data to enable early ADRD prediction, supporting timely interventions, and improving patient outcomes. By identifying both established and novel risk factors, these findings offer new opportunities for personalized screening and management strategies, advancing both clinical and informatics science.}, }
@article {pmid40248131, year = {2023}, author = {Millar, CL and Iloputaife, I and Baldyga, K and Kuo, J and Tchkonia, T and Kirkland, JL and Travison, TG and Lipsitz, LA}, title = {Rationale and Design of STAMINA: Senolytics To Alleviate Mobility Issues and Neurological Impairments in Aging, A Geroscience Feasibility Study.}, journal = {Translational medicine of aging}, volume = {7}, number = {}, pages = {109-117}, pmid = {40248131}, issn = {2468-5011}, abstract = {The process of cellular senescence is hypothesized to play a critical role in the development of age-related mobility and cognitive impairments, both of which precede the development of Alzheimer's disease. Therefore, senolytic compounds that eliminate senescent cells represent an alternative strategy that may help improve mobility and cognition in older adults; however, clinical trials are lacking. The goal of this paper is to describe the rationale and study design of a 12-week single arm, open label, pre-post pilot study that administers intermittent doses of two senolytic compounds, Dasatinib and quercetin (DQ), in 12 older adults ≥ 65 years with slow gait speed (<1.0 m/sec) and mild cognitive impairment. Eligible participants are asked to take 1250 mg of and 100 mg of Dasatinib orally once a day for 2 days every 2 weeks, for 6 cycles over 12 consecutive weeks. Both physical and cognitive functional assessments are administered before treatment, as well as 6- and 12- weeks after treatment. Blood and urine samples are taken pre- and post-treatment to assess biomarkers of cellular senescence. The primary outcomes of this trial are feasibility and safety of the intervention, as well as preliminary efficacy on several clinical outcomes (e.g., cerebral blood flow velocity, gait speed, and biomarkers of cellular senescence). The study is approved by the Advarra IRB (#Pro00053594) and a Data Safety Monitoring Board. It is registered at Clinicaltrials.gov (Identifier:NCT05422885). The future results of this study may identify a novel approach for improving mobility and cognition in older adults, thereby preventing progression to Alzheimer's disease.}, }
@article {pmid40246050, year = {2025}, author = {Neto, DCF and de Almeida, JSFD and Guimarães, SJA and Dos Santos, EM and Nascimento, MDDSB and de Azevedo-Santos, APS and França, TCC and LaPlante, SR and do Nascimento, CJ and Lima, JA}, title = {Guanylhydrazone and semicarbazone derivatives as potential prototypes for the design of cholinesterase inhibitors against Alzheimer's disease: biological evaluation and molecular modeling studies.}, journal = {Chemico-biological interactions}, volume = {}, number = {}, pages = {111515}, doi = {10.1016/j.cbi.2025.111515}, pmid = {40246050}, issn = {1872-7786}, abstract = {Despite being present in many drugs, guanylhydrazones and semicarbazones are two functional groups that have been little investigated as potential therapeutic strategies for the treatment of Alzheimer's disease (AD). For this reason, we initiated the synthesis and evaluation of these compounds as potential anticholinesterase agents, aiming to offer new alternatives for drug development against AD. In the severe phase of AD, butyrylcholinesterase (BChE) becomes the main enzyme responsible for the hydrolysis of acetylcholine (ACh). Therefore, in this project, we present the results of BChE inhibitory activity, enzyme kinetics, cytotoxicity, and molecular modeling studies for three guanylhydrazone and two semicarbazone derivatives that were previously synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Among the compounds tested, guanylhydrazones (1, 2, and 3) showed inhibitory activity against BChE, exhibiting a mixed non-competitive inhibition profile. Specifically, compound 2 (phenanthrenequinone) demonstrated superior inhibitory potency with an IC50 of 0.68 μM, compared to compound 1 (acridinone) with an IC50 of 3.87 μM, and compound 3 (benzodioxole) with an IC50 of 101.7 μM. In contrast, semicarbazones (4 and 5) showed no BChE inhibition up to the highest concentration tested (300 μM). Importantly, all five compounds were found to be non-cytotoxic. Our results suggest that these compounds have potential as drug prototypes targeting different phases of AD. Compounds 3, 4, and 5 may be more effective in the early phase, when AChE activity remains high; compound 1 could be useful in the intermediate phase; and compound 2 appears particularly promising for the severe phase, when BChE plays a more dominant role.}, }
@article {pmid40245823, year = {2025}, author = {Zhao, Y and Wei, S and Liu, Y and He, X and Li, J and Gao, T and Wang, X and Li, Y and Nan, J and Wang, Y and Ma, Y}, title = {The prevalence and influencing factors of reversion from mild cognitive impairment to normal cognition: A systemic review and meta-analysis.}, journal = {Geriatric nursing (New York, N.Y.)}, volume = {63}, number = {}, pages = {379-387}, doi = {10.1016/j.gerinurse.2025.03.013}, pmid = {40245823}, issn = {1528-3984}, abstract = {OBJECTIVE: The aim was to investigate the pooled prevalence of reversion from mild cognitive impairment (MCI) to normal cognition people, and the influencing factors for reversion.
METHODS: PubMed, Embase, Web of Science, The Cochrane Library, Wanfang Database, China Knowledge Resource Integrated Database (CNKI), Weipu Database, SinoMed were systematically searched from the inception to June 1, 2023. Participants were diagnosis as MCI adults.
RESULTS: In total, 4075 studies were screened and data from 48 studies involving 31876 subjects were used in meta-analysis. The pooled prevalence of reversion from MCI to normal cognition was 31%. The following risk factors were associated with the reversion from MCI to normal cognition: education (low to high), age, Mini-Mental State Examination (MMSE), Functional Activities Questionnaire (FAQ), Auditory Verbal Learning Test (AVLT) delay recall test, Apolipoprotein E (APOE) positive, multiple domain impaired, live along, depression, doing house work daily/exercise once a week.
CONCLUSIONS: The study shows the pooled prevalence of reversion from MCI to normal cognition was high, and there are controllable factors. Understanding the controllable factors of reversion from MCI to normal cognition can provide the clinicians with the theoretical basis for the management and treatment of the patients.}, }
@article {pmid40245529, year = {2025}, author = {Radin, DP and Cerne, R and Smith, JL and Witkin, JM and Lippa, A}, title = {Antipsychotic-like pharmacological profile of the low impact ampakine CX691 (farampator): Implications for the use of low impact ampakines in the treatment of schizophrenia.}, journal = {Journal of psychiatric research}, volume = {186}, number = {}, pages = {145-153}, doi = {10.1016/j.jpsychires.2025.04.019}, pmid = {40245529}, issn = {1879-1379}, abstract = {Ampakines, positive allosteric modulators of AMPA-glutamate receptors (AMPAR), have therapeutic implications in neuropsychiatric and neurological disorders in which AMPAR signaling is compromised such as Alzheimer's, ADHD, and schizophrenia. Low impact ampakines are a distinct subset of ampakines that only partially offset receptor desensitization and do not meaningfully alter binding affinity of AMPAR agonists, which may explain their lack of seizurogenic effects seen with other AMPAR positive modulators. Herein, we describe the preclinical pharmacology and antipsychotic activity of the low impact ampakine 1-(benzofurazan-5-ylcarbonyl)piperidine (CX691). CX691 moderately offsets desensitization in hippocampal patches, supporting its designation as a low impact ampakine and penetrates the blood-brain barrier. CX691 is more potent than well characterized high impact ampakines CX614 and CX546 and low impact ampakine CX516 in abrogating amphetamine-stimulated locomotor activity in Sprague Dawley rats. Low-dose CX691 synergistically reduces methamphetamine-induced locomotor activity when paired with approved antipsychotics clozapine and olanzapine. In rats treated chronically with amphetamine, CX691 retains antipsychotic activity whereas high doses of CX516 lack therapeutic effects. In contrast to haloperidol, CX691 is devoid of cataleptic activity at supratherapeutic doses in rats. CX691 enhances performance in the eight-arm radial maze, a spatial task that assesses hippocampal function, an activity of potential value for ameliorating cognitive deficits in schizophrenia. Taken together, these findings illustrate that low impact ampakines with improved potency might be useful therapeutic interventions in schizophrenic patients when given alone or as adjuncts to ongoing traditional antipsychotic drug therapies.}, }
@article {pmid40245392, year = {2025}, author = {Ferré, F and Allassonnière, S and Chadebec, C and Minville, V}, title = {Generating Artificial Patients With Reliable Clinical Characteristics Using a Geometry-Based Variational Autoencoder: Proof-of-Concept Feasibility Study.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e63130}, doi = {10.2196/63130}, pmid = {40245392}, issn = {1438-8871}, mesh = {Humans ; Feasibility Studies ; Proof of Concept Study ; *Deep Learning ; Autoencoder ; }, abstract = {BACKGROUND: Artificial patient technology could transform health care by accelerating diagnosis, treatment, and mapping clinical pathways. Deep learning methods for generating artificial data in health care include data augmentation by variational autoencoders (VAE) technology.
OBJECTIVE: We aimed to test the feasibility of generating artificial patients with reliable clinical characteristics by using a geometry-based VAE applied, for the first time, on high-dimension, low-sample-size tabular data.
METHODS: Clinical tabular data were extracted from 521 real patients of the "MAX" digital conversational agent (BOTdesign) created for preparing patients for anesthesia. A 3-stage methodological approach was implemented to generate up to 10,000 artificial patients: training the model and generating artificial data, assessing the consistency and confidentiality of artificial data, and validating the plausibility of the newly created artificial patients.
RESULTS: We demonstrated the feasibility of applying the VAE technique to tabular data to generate large artificial patient cohorts with high consistency (fidelity scores>94%). Moreover, artificial patients could not be matched with real patients (filter similarity scores>99%, κ coefficients of agreement<0.2), thus guaranteeing the essential ethical concern of confidentiality.
CONCLUSIONS: This proof-of-concept study has demonstrated our ability to augment real tabular data to generate artificial patients. These promising results make it possible to envisage in silico trials carried out on large cohorts of artificial patients, thereby overcoming the pitfalls usually encountered in in vivo trials. Further studies integrating longitudinal dynamics are needed to map patient trajectories.}, }
@article {pmid40245176, year = {2025}, author = {Liu, Z and Zhang, J and Jiang, F and Liu, C and Shao, Y and Le, W}, title = {Biological Effects of Dietary Restriction on Alzheimer's Disease: Experimental and Clinical Investigations.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {4}, pages = {e70392}, doi = {10.1111/cns.70392}, pmid = {40245176}, issn = {1755-5949}, support = {YDZX20213100001002//Shanghai Municipal Central Government Funds for Guiding Local Scientific and Technological Development/ ; XLYC2403127//Young Top Talents in the Xingliao Talents Program of Liaoning Province/ ; 32220103006//National Natural Science Foundation of China/ ; 82271524//National Natural Science Foundation of China/ ; 2024RY003//Dalian Science and Technology Talent Innovation Support Program/ ; }, mesh = {*Alzheimer Disease/diet therapy/metabolism ; Humans ; Animals ; *Caloric Restriction/methods ; Brain/metabolism ; }, abstract = {BACKGROUNDS: Dementia can impose a heavy economic burden on both society and families. Alzheimer's disease (AD), the most prevalent form of dementia, is a complex neurodegenerative disease characterized by the abnormal deposition of extracellular amyloid β-protein (Aβ) and the aggregation of intracellular Tau protein to form neurofibrillary tangles (NFTs). Given the limited efficacy of pharmacological treatment, scientists have already paid more attention to non-pharmacological strategies, including dietary restriction (DR). DR refers to a nutritional paradigm aimed at promoting overall health by modifying the balance between energy consumption and expenditure. Studies have demonstrated that DR effectively extends the healthy lifespan, delays the aging process, and achieves promising results in the prevention and treatment of AD in preclinical studies.
METHODS: In this review we collected related studies and viewpoints by searching on PubMed database using the keywords. Most of the citations were published between 2015 and 2025. A few older literatures were also included due to their relevance and significance in this field.
RESULTS: We first provide a concise overview of the current therapeutic and preventive strategies for AD. Then, we introduce several specific DR protocols and their favorable effects on AD. Furthermore, the potential mechanisms underlying the benefits of DR on AD are discussed. Finally, we briefly highlight the role of DR in maintaining brain health.
CONCLUSION: This review may offer valuable insights into the development of innovative non-pharmacological strategies for AD treatment.}, }
@article {pmid40244500, year = {2025}, author = {Lu, H and Xu, C and Liang, J}, title = {Evaluation of AccuBrain-based MRI quantitative analysis in diagnosing Alzheimer's disease and assessing behavioral and psychological symptoms of dementia.}, journal = {Aging clinical and experimental research}, volume = {37}, number = {1}, pages = {126}, pmid = {40244500}, issn = {1720-8319}, support = {2220001004730//the project of Foshan Science and Technology Bureau/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/psychology/diagnosis ; Male ; Female ; *Magnetic Resonance Imaging/methods ; Aged ; Retrospective Studies ; *Cognitive Dysfunction/diagnostic imaging/diagnosis ; Aged, 80 and over ; ROC Curve ; Atrophy ; Hippocampus/diagnostic imaging/pathology ; Neuropsychological Tests ; Biomarkers ; Middle Aged ; *Dementia/psychology/diagnostic imaging ; }, abstract = {AIM: Alzheimer's disease (AD) is a major cause of dementia, marked by cognitive decline and behavioral and psychological symptoms of dementia (BPSD). Early differentiation between AD, mild cognitive impairment (MCI), and healthy controls (HC) is essential for improving diagnostic accuracy and guiding effective treatment strategies.
METHODS: This retrospective study included 120 participants divided into AD (n = 40), MCI (n = 40), and HC (n = 40) groups. Brain MRI data were analyzed using the AccuBrain system to quantify AD Resemblance Atrophy Index (AD-RAI), Quantitative Medial Temporal Atrophy (QMTA), hippocampal volume, and white matter hyperintensities. Correlation analyses were conducted between imaging biomarkers and cognitive function scores (Mini-Mental State Examination, MMSE; Neuropsychiatric Inventory, NPI). Receiver operating characteristic (ROC) curve analysis was used to evaluated the diagnostic performance of the biomarkers.
RESULTS: AD patients had significantly higher AD-RAI (0.91 ± 0.25) and more pronounced hippocampal atrophy (0.36 ± 0.09) compared to MCI and HC (P < 0.001). Correlation analyses showed that AD-RAI and QMTA were negatively correlated with MMSE scores (r = -0.718, P < 0.001; r = -0.463, P < 0.001), while hippocampal volume was positively correlated with MMSE (r = 0.408, P < 0.001). ROC analysis revealed that AD-RAI had an AUC of 0.777 for distinguishing AD from MCI, while QMTA had an AUC of 0.938 for distinguishing AD from HC. BPSD patients exhibited higher AD-RAI (1.09 ± 0.18) and greater hippocampal atrophy, with ROC AUC > 0.9 for distinguishing BPSD from non-BPSD patients.
CONCLUSION: The AccuBrain MRI system demonstrated high sensitivity and diagnostic value in distinguishing AD from MCI and HC, as well as in identifying patients with BPSD. Correlation and ROC analyses support the use of these imaging biomarkers for early diagnosis and personalized treatment strategies in AD.}, }
@article {pmid40244482, year = {2025}, author = {Das, A and Manna, R and Chowdhury, D and Sharma, D and Bodakhe, SH}, title = {Oxymatrine impedes Alzheimer's progression via the attenuation of hypercholesterolemia and fibrosis.}, journal = {Metabolic brain disease}, volume = {40}, number = {5}, pages = {187}, pmid = {40244482}, issn = {1573-7365}, mesh = {Animals ; *Alkaloids/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Quinolizines/pharmacology/therapeutic use ; Rats ; Male ; *Hypercholesterolemia/drug therapy/metabolism ; Disease Progression ; Fibrosis/drug therapy/metabolism ; Brain/drug effects/metabolism/pathology ; Maze Learning/drug effects ; Rats, Wistar ; Matrines ; }, abstract = {This study highlights the potential therapeutic benefits of oxymatrine (OMT), a quinolizidine alkaloid found in Sophora flavescens, for Alzheimer's disease (AD). This study connects the dots between metabolic and neuronal origins by exploring the effects of oxymatrine in slowing down hypercholesterolemic and fibrotic changes that contribute to cognitive deficits. In our study, laboratory rats were fed a high-cholesterol diet for eight weeks. Cognitive abilities were assessed weekly using Hebb's Williams Maze and Radial arm mazes. Additionally, intraperitoneal doses of OMT were administered (20 mg/kg, 40 mg/kg, and 80 mg/kg) for 21 days. Furthermore, using ELISA, plasma and brain oxysterols, transforming growth factor β, amyloid β, matrix metalloproteinase- 9, claudin- 5, and ATP Binding Cassette Transporter A1 levels were measured biweekly. High-density lipoprotein, low-density lipoprotein, aspartate aminotransferase, and alanine transaminase levels were estimated using diagnostic kits. The findings demonstrate that The administration of oxymatrine to experimental animals resulted in a dose-dependent synergistic decline in several biomarkers, including oxysterols, transforming growth factor β, amyloid β, matrix metalloproteinase- 9, low-density lipoprotein, aspartate aminotransferase, and alanine transaminase levels. At the same time, a concomitant increase in the levels of Claudin- 5, ATP Binding Cassette transporter A1, high-density lipoprotein, and antioxidants in the same animals was observed, especially at a dose of 80 mg/kg. This study aims to establish a link between metabolic and neural origins by investigating the effects of oxymatrine in reducing the progression of hypercholesterolemia and fibrosis, which contribute to cognitive impairment in AD. The research explores how oxymatrine regulates mediators involved in oxysterol production and fibrotic alterations in AD. Preliminary results suggest that oxymatrine has the potential to significantly delay the development and progression of AD, offering a promising treatment alternative for those affected by the disease. The findings of the present study strongly suggest that OMT effectively retards the progression of AD, which is commonly associated with the intake of high-cholesterol diets. Subsequent investigations ought to examine the molecular mechanisms behind oxymatrine's interaction with oxysterols and lipid metabolism, including sophisticated imaging methodologies and metabolomics. Longitudinal studies are essential to evaluate the long-term efficacy and safety of oxymatrine in both animal models and people. Exploring its possible synergistic effects with current medications may yield more effective therapeutic techniques. Identifying biomarkers for personalised medication may also be beneficial. Clinical trials and research on oxymatrine's potential as a prophylactic medication may yield significant insights.}, }
@article {pmid40244274, year = {2025}, author = {Ostergaard, JR}, title = {A New Perspective on Agitation in Alzheimer's Disease: A Potential Paradigm Shift.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26073370}, pmid = {40244274}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/physiopathology/complications/therapy ; *Psychomotor Agitation/physiopathology/therapy/etiology ; Autonomic Nervous System/physiopathology ; Aged ; }, abstract = {Agitation is a common and difficult-to-manage neuropsychiatric syndrome in dementia. Recently, an association with the autonomous nervous system has been suggested. From the literature researched, however, only two studies investigating autonomic function concomitant to agitation situations appeared; one case series comprised two American veterans with vascular and Alzheimer's dementia, respectively, and in a case series of patients with CLN3 (juvenile neuronal ceroid lipofuscinosis), this was found to be the most common neurodegenerative disease leading to dementia in childhood. In both case series, the measurement of the autonomic system disclosed a parasympathetic withdrawal and sympathetic hyperactivity in the temporal context with agitated behavior. If the time-wise-related autonomic imbalance shown previously can be demonstrated in a larger cohort of patients with Alzheimer's disease, the use of transcutaneous vagal stimulation might be a potential paradigm shift in the treatment of agitation in Alzheimer's disease.}, }
@article {pmid40244061, year = {2025}, author = {Tseriotis, VS and Liampas, A and Lazaridou, IZ and Karachrysafi, S and Vavougios, GD and Hadjigeorgiou, GM and Papamitsou, T and Kouvelas, D and Arnaoutoglou, M and Pourzitaki, C and Mavridis, T}, title = {Repulsive Guidance Molecule-A as a Therapeutic Target Across Neurological Disorders: An Update.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26073221}, pmid = {40244061}, issn = {1422-0067}, mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Nerve Tissue Proteins/metabolism/antagonists & inhibitors/genetics ; *GPI-Linked Proteins/metabolism/antagonists & inhibitors/genetics ; Molecular Targeted Therapy ; Neurodegenerative Diseases/metabolism/drug therapy ; }, abstract = {Repulsive guidance molecule-a (RGMa) has emerged as a significant therapeutic target in a variety of neurological disorders, including neurodegenerative diseases and acute conditions. This review comprehensively examines the multifaceted role of RGMa in central nervous system (CNS) pathologies such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuromyelitis optica spectrum disorder, spinal cord injury, stroke, vascular dementia, auditory neuropathy, and epilepsy. The mechanisms through which RGMa contributes to neuroinflammation, neuronal degeneration, and impaired axonal regeneration are herein discussed. Evidence from preclinical studies associate RGMa overexpression with negative outcomes, such as increased neuroinflammation and synaptic loss, while RGMa inhibition, particularly the use of agents like elezanumab, has shown promise in enhancing neuronal survival and functional recovery. RGMa's responses concerning immunomodulation and neurogenesis highlight its potential as a therapeutic avenue. We emphasize RGMa's critical role in CNS pathology and its potential to pave the way for innovative treatment strategies in neurological disorders. While preclinical findings are encouraging so far, further clinical trials are needed to validate the safety and efficacy of RGMa-targeted therapies.}, }
@article {pmid40243843, year = {2025}, author = {Lui, M and Salamone, S and Pollastro, F and Mazzon, E and Artimagnella, O}, title = {Cannabinerol Restores mRNA Splicing Defects Induced by β-Amyloid in an In Vitro Model of Alzheimer's Disease: A Transcriptomic Study.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26073113}, pmid = {40243843}, issn = {1422-0067}, support = {Current Research Funds 2024//Ministry of Health, Italy/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/drug therapy/pathology ; *Amyloid beta-Peptides/metabolism ; *Transcriptome/drug effects ; *RNA, Messenger/genetics ; *Alternative Splicing/drug effects ; *RNA Splicing/drug effects ; Cell Line, Tumor ; Gene Expression Profiling ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia, characterized by β-amyloid (Aβ) plaques and neurofibrillary tangles, leading to neuronal loss and cognitive impairments. Recent studies have reported the dysregulation of RNA splicing in AD pathogenesis. Our previous transcriptomic study demonstrated the neuroprotective effect of the phytocannabinoid cannabinerol (CBNR) against the cell viability loss induced by Aβ in differentiated SH-SY5Y cells. This study also highlighted the deregulation of genes involved in mRNA splicing after Aβ exposure or CBNR pre-treatment. Here, we investigated whether CBNR could restore the splicing defects induced by Aβ in an AD in vitro model. Using the rMATS computational tool for detecting differential alternative splicing events (DASEs) from RNA-Seq data, we obtained 96 DASEs regulated in both conditions and, remarkably, they were all restored by CBNR pre-treatment. The pathway analysis indicated an over-representation of the "Alzheimer's disease-amyloid secretase pathway". Additionally, we observed that Aβ exposure increased the frequency of retained introns (RIs) among the shared DASEs, and that this frequency returned to normality by CBNR pre-treatment. Interestingly, most of these RIs contain a premature in-frame stop codon within the RNA sequence. Finally, analyzing the DASE regions for miRNA hybridization, we found 33 potential DASE/miRNA interactions that were relevant in AD pathogenesis. These findings revealed a novel trans-gene regulation by CBNR, potentially explaining part of its neuroprotective role. This is the first study demonstrating the involvement of a cannabinoid in the regulation of mRNA splicing in an AD model.}, }
@article {pmid40243772, year = {2025}, author = {Mosalam, EM and Atya, SM and Mesbah, NM and Allam, S and Mehanna, ET}, title = {Neuroprotective Effects of Cilomilast and Chlorogenic Acid Against Scopolamine-Induced Memory Deficits via Modulation of the cAMP/PKA-CREB-BDNF Pathway.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26073108}, pmid = {40243772}, issn = {1422-0067}, mesh = {Animals ; Brain-Derived Neurotrophic Factor/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Scopolamine/adverse effects ; Male ; Cyclic AMP/metabolism ; *Memory Disorders/drug therapy/chemically induced/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; *Chlorogenic Acid/pharmacology ; Cyclic AMP Response Element-Binding Protein/metabolism ; *Signal Transduction/drug effects ; Disease Models, Animal ; Phosphodiesterase 4 Inhibitors/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, neuroinflammation and neuronal damage. This study aimed to investigate the neuroprotective effects of cilomilast (CILO), a phosphodiesterase-4 (PDE4) inhibitor, alone and in combination with chlorogenic acid (CGA), a natural polyphenol, against scopolamine (SCOP)-induced cognitive impairment in mice. Forty male albino mice were divided into five groups: normal control, SCOP control, CGA + SCOP, CILO + SCOP and CILO + CGA + SCOP. Behavioral assessments, including the Y-maze and pole climbing tests, demonstrated that SCOP significantly impaired cognition, while treatment with CILO and CGA reversed these deficits, with the combination group showing the greatest improvement. Histopathological analyses revealed that CILO and CGA reduced neuronal damage and amyloid beta (Aβ) accumulation. Immunohistochemical and biochemical assessments confirmed a decrease in neuroinflammatory markers, including tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa B (NF-κB). Molecular analyses showed that CILO restored cyclic adenosine monophosphate (cAMP) levels, leading to activation of protein kinase A (PKA), cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), key regulators of neuronal plasticity and survival. CGA enhanced these effects by further inhibiting PDE4, amplifying the neuroprotective response. These findings suggest that PDE4 inhibitors, particularly in combination with CGA, may represent promising therapeutic strategies for AD-related cognitive impairment.}, }
@article {pmid40243521, year = {2025}, author = {Palachai, N and Buranrat, B and Noisa, P and Mairuae, N}, title = {Oroxylum indicum (L.) Leaf Extract Attenuates β-Amyloid-Induced Neurotoxicity in SH-SY5Y Cells.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26072917}, pmid = {40243521}, issn = {1422-0067}, support = {//Thailand Science Research and Innovation/ ; }, mesh = {Humans ; *Plant Extracts/pharmacology/chemistry ; *Amyloid beta-Peptides/toxicity ; *Plant Leaves/chemistry ; *Neuroprotective Agents/pharmacology/chemistry ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Cell Survival/drug effects ; *Bignoniaceae/chemistry ; Caspase 3/metabolism ; Antioxidants/pharmacology ; *Peptide Fragments/toxicity ; Neurons/drug effects/metabolism ; Malondialdehyde/metabolism ; }, abstract = {Alzheimer's disease (AD) is characterized by the presence of amyloid-beta (Aβ) plaques, which trigger oxidative stress and neuronal cell death. The present study investigated the neuroprotective effects of Oroxylum indicum (L.) leaf (OIL) extract against Aβ-induced oxidative stress and cellular damage in SH-SY5Y cells. The cells were treated with OIL extract with and without Aβ25-35, and their viability was investigated. Moreover, the mechanism of action of OIL was assessed by determining caspase-3 levels, reactive oxygen species (ROS) and malondialdehyde (MDA) levels, enzymatic activity of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), phosphorylation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and cAMP-responsive element-binding protein (CREB), and expression of B-cell lymphoma-2 (Bcl-2) proteins. The results indicated that OIL reduced Aβ-induced neurotoxicity in a concentration-dependent manner, improving cell viability, reducing ROS levels and MDA production, increasing antioxidant enzyme activity of CAT, SOD, and GSH-Px, and decreasing caspase-3 expression. In addition, OIL enhanced phosphorylation of Akt, ERK1/2, and CREB and upregulated Bcl-2 protein expression. High-performance liquid chromatography (HPLC) analysis identified oroxylin A, baicalein, and chrysin as the major phenolic constituents of the OIL extract. The findings suggest that the extract holds promise as a therapeutic intervention against Aβ-induced neurotoxicity, offering potential implications for the treatment of AD. Further studies are needed to investigate the activity of OIL in primary neurons or in vivo.}, }
@article {pmid40243451, year = {2025}, author = {Arsić, B and Petrović, S and Ilić, BS and Vrecl, M and Trobec, T and Sepčić, K and Frangež, R and Glišić, SM and Milićević, JS}, title = {Inhibitory Potential of Boscalid and Abamectin Towards Acetylcholinesterase and Butyrylcholinesterase: Computational and In Vitro Studies.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26072865}, pmid = {40243451}, issn = {1422-0067}, support = {337-00-21/2020-09/19//Ministry of Education, Science and Technological Development of the Republic of Serbia/ ; contract numbers 451-03-47/2023-01/200124 and 451-03-66/2024-03/200124 (B. Arsić, S. Petrović), and 451-03-47/2023-01/200017 and 451-03-66/2024-03/200017 (S. M. Glišić, J. S. Milićević)//Ministry of Science, Technological Development and Innovations of the Republic of Serbia/ ; research programs P4-0053 and P1-0207//Slovenian Research and innovation Agency/ ; }, mesh = {*Butyrylcholinesterase/chemistry/metabolism ; Humans ; *Ivermectin/analogs & derivatives/chemistry/pharmacology ; *Cholinesterase Inhibitors/pharmacology/chemistry ; *Acetylcholinesterase/chemistry/metabolism ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; *Niacinamide/analogs & derivatives/chemistry/pharmacology ; }, abstract = {The growing demand for agricultural products has led to the misuse of pesticides, resulting in the use of higher concentrations of these substances. This has led to an increase in toxicity imposed on other beneficial organisms and to the bioaccumulation of toxic pesticide concentrations in the bodies of both pests and non-target organisms, as well as in their end users, including humans. In this study, the neurotoxic potential of the commonly used pesticides abamectin (an insecticide) and boscalid (a fungicide) was evaluated. Both in vitro and in silico studies showed that human butyrylcholinesterase is not a target for abamectins B1A and B1B. Boscalid showed a modest Glide score (-28.8 kJ/mol) and a considerably higher IC50 (308.8 µM) against human butyrylcholinesterase than the approved inhibitor (2-((1-(benzenesulfonyl)-1H-indol-4-yl)oxy)ethyl)(benzyl)amine (IC50 = 0.473 µM). However, due to its non-mutagenicity and low toxicity, structural analogues of boscalid might be considered as candidates for the symptomatic treatment of Alzheimer's disease. Molecular dynamics simulations over 100 ns confirmed the stability of boscalid within the active site of butyrylcholinesterase, where it maintained key interactions with catalytic residues such as Trp82 and His438. These findings highlight its potential as a starting point for structure-based drug design strategies aimed at optimizing cholinesterase inhibitors with improved pharmacokinetic properties. According to absorption, distribution, metabolism, elimination, and toxicity studies, boscalid is orally active, which cannot be attributed to abamectins B1A and B1B.}, }
@article {pmid40243219, year = {2025}, author = {Xu, J and Liu, B and Shang, G and Feng, Z and Yang, H and Chen, Y and Yu, X and Mao, Z}, title = {Efficacy and Safety of Bilateral Deep Brain Stimulation (DBS) for Severe Alzheimer's Disease: A Comparative Analysis of Fornix Versus Basal Ganglia of Meynert.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {4}, pages = {e70285}, doi = {10.1111/cns.70285}, pmid = {40243219}, issn = {1755-5949}, support = {2021ZD0200407//STI 2030-Major Projects/ ; }, mesh = {Humans ; *Deep Brain Stimulation/methods/adverse effects ; Male ; Female ; *Alzheimer Disease/therapy/psychology ; *Fornix, Brain/physiology ; Aged ; Middle Aged ; Prospective Studies ; Treatment Outcome ; *Basal Nucleus of Meynert/physiology ; }, abstract = {BACKGROUND: Deep brain stimulation (DBS) is a novel therapy for severe Alzheimer's disease (AD). However, there is an ongoing debate regarding the optimal target for DBS, particularly the fornix and the basal ganglia of Meynert (NBM).
OBJECTIVE: This study aimed to investigate the safety and efficacy of DBS for severe AD and to compare the fornix and the NBM as potential targets.
METHODS: We conducted a prospective, nonrandomized clinical study involving 20 patients with severe AD (MMSE score 0 to 10, CDR level 3) from January 2015 to August 2022, comprising 12 males and eight females, with a mean age of 59.05 ± 6.45 years. All patients underwent DBS treatment, among which 14 received bilateral fornix implantation, while six received bilateral implantation in the NBM. Electrical stimulation commenced 1 month postoperatively. We assessed the patients before surgery, followed by evaluations at 1 month, 3 months, 6 months, and 12 months poststimulation. Primary outcome measures focused on changes in cognitive function, assessed using the MMSE, MoCA, ADAS-Cog, and CDR scales. Secondary measures encompassed quality of life, caregiver burden, neuropsychiatric symptoms, and sleep disturbances, evaluated through the BI, FAQ, FIM, ZBI, NPI, HAMA, HAMD, and PSQI scales.
RESULTS: All patients tolerated DBS well, with no serious adverse effects reported. Early on, DBS significantly improved cognitive function and quality of life. Long-term benefits include the improvement of neuropsychiatric symptoms and sleep disorders and the alleviation of caregiver burden. Comparison between DBS targeting the NBM and fornix revealed no significant differences in overall scale scores. However, upon deeper analysis, NBM-DBS exhibited a more pronounced improvement in neuropsychiatric symptoms, particularly in NPI scores.
CONCLUSION: DBS is a potential therapeutic approach for severe AD, capable of improving patients' cognitive function, quality of life, and neuropsychiatric symptoms. Notably, NBM-DBS showed distinct advantages in ameliorating neuropsychiatric symptoms, providing valuable insights for clinically selecting the optimal DBS target.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03115814.}, }
@article {pmid40242567, year = {2025}, author = {Li, X and Singh, S and Rasouli, B and Lyons, J and Cocoros, NM and Platt, R and Abi-Elias, I and Gurwitz, JH}, title = {Generating real-world evidence in early Alzheimer's disease: Considerations for applying the target trial emulation framework to study the safety of anti-amyloid therapies.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {2}, pages = {e70080}, pmid = {40242567}, issn = {2352-8737}, abstract = {UNLABELLED: Anti-amyloid beta monoclonal antibodies (anti-Aβ mAbs) have received approval from the US Food and Drug Administration for the treatment of patients with mild cognitive impairment or mild dementia due to Alzheimer's disease (collectively known as early AD) based on evidence from clinical trials. However, whether findings from these trials are generalizable to the real world is uncertain. We need reliable evidence on the real-world safety of these treatments to inform decision making for clinicians, patients, and caregivers. Using lecanemab as an exemplar, we outline the key considerations in designing and implementing an observational study on safety and utilization outcomes using established administrative healthcare claims data sources with the target trial emulation framework. The target trial emulation framework is a rigorous causal inference framework that minimizes common biases in observational studies. The approach proposed here can be applied to evaluation of additional mAbs as they become available.
HIGHLIGHTS: Little is known about real-world safety of anti-amyloid beta monoclonal antibodies for early Alzheimer's disease.Existing real-world data can support studies of their safety and utilization outcomes.Target trial emulation can guide the design of these studies while minimizing bias.We provide key design and analytical considerations for future studies.}, }
@article {pmid40242445, year = {2025}, author = {Yan, L and Zhang, L and Xu, Z and Luo, Z}, title = {A real-world disproportionality analysis of FDA adverse event reporting system (FAERS) events for lecanemab.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1559447}, pmid = {40242445}, issn = {1663-9812}, abstract = {BACKGROUND: Lecanemab is a humanized murine IgG1 antibody. Recent Phase 3 clinical trials have demonstrated its ability to reduce brain amyloid-β (Aβ) load and slow cognitive decline in patients with early Alzheimer's disease (AD). However, since its approval, reports on adverse effects (AEs) associated with lecanemab have been limited. To better understand the AEs related to lecanemab and provide guidance for future clinical use, we analyzed lecanemab-associated AEs using data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).
METHODS: We extracted all AEs reports from the FAERS database for the period from the first quarter of 2023 to the third quarter of 2024. Using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) algorithms, we conducted a comprehensive analysis of lecanemab-related AEs, restricting the analysis to AEs with the role code of primary suspect (PS).
RESULTS: A total of 811 AEs reports related to lecanemab used in AD patients and 506 AEs in Non-AD patients were included. The preferred terms (PTs) identified as positive across all four algorithms included headache, Amyloid Related Imaging Abnormalities-oedema/effusion (ARIA-E), chills, Amyloid Related Imaging Abnormalities-haemosiderosis/microhaemorrhage (ARIA-H), fatigue, infusion-related reaction, nausea, pyrexia, pain, influenza like illness, and so on. Among these, ARIA-E, ARIA-H, brain oedema and status epilepticus were associated with Important Medical Events (IMEs) for AD patients, and brain oedema, cerebral haemorrhage, cerebral microhaemorrhage, subdural haematoma, ischaemic stroke, cerebral infarction were associated with IMEs for Non-AD patients. At the system organ class (SOC) level, the highest signal detection for lecanemab was observed in nervous system disorders among AD and Non-AD patients [ROR for AD: 2.42 (2.2-2.65); ROR for Non-AD: 6.97 (6.12-7.95)]. The median time to the occurrence of these AEs was 44 days after administration in AD patients and 30 days for Non-AD patients.
CONCLUSION: This study utilized the FAERS database to evaluate lecanemab-associated AEs in AD and non-AD patients, along with their temporal patterns post-marketing authorization, thereby establishing a foundation for subsequent clinical pharmacovigilance. A biweekly 10 mg/kg was identified as the optimal therapeutic dosage. ARIA emerged as frequent treatment-related AEs, with APOEɛ4 carriers demonstrating heightened susceptibility. This necessitates serial brain MRI surveillance for all patients during treatment, aimed not only at early ARIA detection but also vigilant monitoring of IMEs including cerebral haemorrhage, cerebral microhaemorrhages, subdural haematoma, cerebral edema, ischaemic stroke, and cerebral infarction. While AD patients predominantly exhibited non-specific clinical manifestations, non-AD cohorts showed elevated risks of stroke-related complications. Consequently, dynamic neurological deficit monitoring is indispensable for non-AD populations receiving lecanemab to mitigate adverse outcomes. Finally, comprehensive reassessment of anticoagulant or antiplatelet therapy indications is warranted in both AD and non-AD patients to reduce hemorrhagic risks.}, }
@article {pmid40242161, year = {2025}, author = {Xie, W and Li, Y and Wang, X and Blokhina, E and Krupitsky, E and Vetrova, M and Hu, J and Yuan, TF and Chen, J and Wang, H and Chen, X}, title = {GABAB Receptor: Structure, Biological Functions, and Therapy for Diseases.}, journal = {MedComm}, volume = {6}, number = {5}, pages = {e70163}, pmid = {40242161}, issn = {2688-2663}, abstract = {Gamma-aminobutyric acid (GABA) B receptors (GABABRs) that acts slowly and maintains the inhibitory tone are versatile regulators in the complex nervous behaviors and their involvement in various neuropsychiatric disorders, such as anxiety, epilepsy, pain, drug addiction, and Alzheimer's disease. Additional study advances have implied the crucial roles of GABABRs in regulating feeding-related behaviors, yet their therapeutic potential in addressing the neuropsychiatric disorders, binge eating, and feeding-related disorders remains underutilized. This general review summarized the physiological structure and functions of GABABR, explored the regulation in various psychiatric disorders, feeding behaviors, binge eating, and metabolism disorders, and fully discussed the potential of targeting GABABRs and its regulator-binding sites for the treatment of different psychiatric disorders, binge eating and even obesity. While agonists that directly bind to GABABR1 have some negative side effects, positive allosteric modulators (PAMs) that bind to GABABR2 demonstrate excellent therapeutic efficacy and tolerability and have better safety and therapeutic indexes. Moreover, phosphorylation sites of downstream GABABRs regulators may be novel therapeutic targets for psychiatric disorders, binge eating, and obesity. Further studies, clinical trials in particular, will be essential for confirming the therapeutic value of PAMs and other agents targeting the GABABR pathways in a clinical setting.}, }
@article {pmid40241196, year = {2025}, author = {Lim, J and Gu, H and Sang, H and Jeong, SJ and Kim, HI}, title = {Impact of nucleos(t)ide analogue therapy on the incidence of Alzheimer's disease in patients with chronic hepatitis B virus infection.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {84}, pmid = {40241196}, issn = {1758-9193}, support = {2023//The Korean Association for the Study of the Liver and The Korean Liver Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/epidemiology/prevention & control ; Male ; Female ; *Hepatitis B, Chronic/drug therapy/epidemiology ; Retrospective Studies ; Incidence ; Middle Aged ; Aged ; *Antiviral Agents/therapeutic use ; Republic of Korea/epidemiology ; *Nucleosides/therapeutic use ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND: Long-term therapy with nucleos(t)ide analogs (NUCs) is inevitable for chronic hepatitis B (CHB) patients. However, how NUC therapy on the developing Alzheimer's disease (AD) in these patients remains controversial.
METHODS: This retrospective cohort study used the Korean National Health Insurance Service claims database from January 1, 2013, to December 31, 2013, treatment naïve CHB patients and those without previously diagnosed with AD. Participants were followed from the index date until either the diagnosis of AD or the study's conclusion on December 31, 2021. The primary outcome was the incidence of AD, compared between the group with initiated NUC therapy (n = 18,365) at cohort entry and the group without NUC therapy (n = 212,820).
RESULTS: During the study, 416 patients were diagnosed with AD. After propensity-score matching (18,365 pairs), the 5- to 7-year follow-up showed a significantly lower hazard ratio (HR) in the NUC-treated group compared to the untreated group (HR 0.31-0.40), with HRs remaining constant over time. Subgroup analysis showed more pronounced benefits of NUC therapy in patients under 65 years (HRs: 0.22 vs. 1.23; P < 0.05) and those without dyslipidemia (HRs: 0.14 vs. 1.09; P < 0.05). Protective effects were also observed across subgroups with hypertension, chronic kidney disease, heart disease, and a history of brain trauma, consistent with AD risk factor trends.
CONCLUSIONS: Our study analyses suggest that NUC therapy appears to have a protective effect against the development of AD in patients with CHB.}, }
@article {pmid40240849, year = {2025}, author = {Makin, S}, title = {The future of Alzheimer's treatment.}, journal = {Nature}, volume = {640}, number = {8059}, pages = {S4-S6}, pmid = {40240849}, issn = {1476-4687}, }
@article {pmid40240844, year = {2025}, author = {Vargas-Parada, L}, title = {The unusual genetic inheritance that could change Alzheimer's treatment.}, journal = {Nature}, volume = {640}, number = {8059}, pages = {S7}, pmid = {40240844}, issn = {1476-4687}, }
@article {pmid40240764, year = {2025}, author = {Kömür, M and Kıyan, HT and Öztürk, AA}, title = {Development of donepezil hydrochloride-loaded PLGA-based nanoparticles for Alzheimer's disease treatment.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {13184}, pmid = {40240764}, issn = {2045-2322}, support = {Project number: 2304S027, Project ID: 1956//Anadolu University Scientific Research Project Commission/ ; }, mesh = {*Donepezil/chemistry/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy ; *Nanoparticles/chemistry ; *Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Drug Liberation ; Particle Size ; Animals ; Drug Carriers/chemistry ; Humans ; Chick Embryo ; }, abstract = {In recent years, nanoparticle (NP) systems have demonstrated significant promise in pharmaceutical applications. This study focused on the development of donepezil hydrochloride-loaded PLGA-NPs, prepared using the 'Double Emulsion Solvent Evaporation' method. The impact of varying concentrations of polyvinyl alcohol-(PVA) in the aqueous phase and sonication time on NP characteristics was comprehensively examined. Results showed that increasing PVA concentration and sonication time resulted in a reduction in NP size, with an optimal formulation (I-DNP) achieving a particle size of 136.37 nm ± 0.93 and a PDI of 0.122 ± 0.011, indicating uniformity. The zeta potential was measured at - 24.17mV ± 1.21, confirming the electrostatic stability of the formulation, essential for long-term stability. Trehalose was incorporated to enhance stability, and gastrointestinal stability testing revealed that I-DNP degraded faster in acidic environments. The encapsulation efficiency reached 69.22 ± 4.84%, suggesting effective drug loading, and release studies exhibited a sustained release profile, with a Fickian and non-Fickian release mechanism. DSC, FT-IR, and [1]H-NMR analyses confirmed the encapsulation and structural integrity of the formulation. In biological activity studies, I-DNP exhibited potent anti-AChE and anti-BuChE activities, with Chorioallantoic Membrane (CAM) assays showing significant inhibition of angiogenesis. These findings highlight the potential of I-DNP as a promising therapeutic strategy for Alzheimer's disease, demonstrating its ability to enhance drug stability, controlled release, and potential blood-brain barrier (BBB) penetration. Future studies will focus on long-term stability testing and in vivo Alzheimer's models to further validate its clinical applicability. This research contributes to the advancement of nanoparticle-based drug delivery systems for neurodegenerative diseases, paving the way for innovative therapeutic approaches.}, }
@article {pmid40240583, year = {2025}, author = {Sahoo, TA and Chand, J and Kandy, AT and Antony, S and Subramanian, G}, title = {Unravelling the Proteinopathic Engagement of α-Synuclein, Tau, and Amyloid Beta in Parkinson's Disease: Mitochondrial Collapse as a Pivotal Driver of Neurodegeneration.}, journal = {Neurochemical research}, volume = {50}, number = {3}, pages = {145}, pmid = {40240583}, issn = {1573-6903}, mesh = {*alpha-Synuclein/metabolism ; *tau Proteins/metabolism ; Humans ; *Parkinson Disease/metabolism/pathology ; *Mitochondria/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Animals ; *Nerve Degeneration/metabolism/pathology ; }, abstract = {Parkinson's disease is a complex neurological ailment manifested by dopaminergic neurodegeneration in the substantia nigra of the brain. This study investigates the molecular tripartite interaction between Lewy bodies, amyloid beta, and tau protein in the pathogenesis of Parkinson's disease. Lewy bodies which have been found as the important pathological hallmark in the degenerative neurons of Parkinson's patients, are mainly composed of α-synuclein. The accumulation of α-synuclein has been directly and indirectly linked to the severity and degree of progression of the disease. In addition, approximately 50% of Parkinson's disease cases are also described by hyperphosphorylation of tau protein indicating its significant involvement in the disease. The study further explains how α-synuclein, tau and amyloid beta can spread via cross-seeding mechanisms and accelerate each other's aggregation leading to neuronal death. Both GSK-3β and CDK5 are involved in phosphorylation which among other effects contributes to the misfolding of both α-synuclein and tau proteins that lead to neurodegeneration in Alzheimer's disease. Several mediators, that contribute to mitochondrial damage through elevated oxidative stress pathology are clearly described. Because of the increase in the incidence of Parkinson's disease, as predicted to be 17 million when the study was being conducted, studying these pathological mechanisms is very important in trying to establish treatments. This work contributes a path to finding a multi-target treatment regimen to alleviate the burden of this devastating disease.}, }
@article {pmid40240578, year = {2025}, author = {Du, K and Zuo, YL and Zhang, ZM and Li, A and Zuo, QH and Zhang, CY and Guo, R and Ping, C and Du, WS and Li, SM}, title = {The role of the hippocampus and SLC39A8 in chronic musculoskeletal pain-induced dementia: a Mendelian randomization study.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {13211}, pmid = {40240578}, issn = {2045-2322}, mesh = {Humans ; Mendelian Randomization Analysis ; *Dementia/etiology/genetics ; *Hippocampus/metabolism ; *Musculoskeletal Pain/complications/genetics ; *Chronic Pain/complications/genetics ; *Cation Transport Proteins/genetics/metabolism ; Polymorphism, Single Nucleotide ; }, abstract = {Despite observational studies suggesting a link between chronic musculoskeletal pain (CMP) and increased risk of cognitive decline and dementia, the causal nature of this relationship remains uncertain due to potential confounding factors and reverse causality. We employed two-sample Mendelian Randomization (TSMR), bidirectional MR, mediation MR, drug-target MR, and colocalization analysis, along with gene set enrichment and protein-protein interaction (PPI) analyses. TSMR assessed the causal associations between CMP and the risk of dementia and its subtypes, including Alzheimer's disease (AD), vascular dementia (VaD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and Parkinson's disease (PD). Bidirectional MR evaluated reverse causality, while mediation analyses identified potential mediators, focusing on neuroimaging and cognitive phenotypes. Drug-target MR investigated the role of the SLC39A8 gene, and colocalization analysis determined shared causal genetic variants. Gene set enrichment and PPI analyses elucidated the biological pathways implicated in the CMP-dementia relationship. Robust evidence established a causal relationship between chronic low back pain (LBP) and increased risk of PD, with knee osteoarthritis identified as a partial mediator, suggesting a pathway involving chronic inflammation. Bidirectional MR analysis revealed no evidence of reverse causality, further supporting the unidirectional causal link from LBP to PD. Colocalization analysis confirmed distinct genetic architectures for LBP and PD, while drug-target MR implicated the SLC39A8 gene as a potential mediator. Gene set enrichment and PPI analyses highlighted critical biological pathways, such as purine metabolism and glutamate receptor signaling. Suggestive evidence indicated potential causal links between limb pain and overall dementia, myalgia and VaD, as well as potential protective effects of Polymyalgia Rheumatica (PMR) against AD and rheumatism against PD. This study reveals a complex causal relationship between CMP and neurodegenerative diseases, particularly the robust link between LBP and PD. The findings underscore the need for further research to elucidate the underlying mechanisms and inform targeted prevention and treatment strategies.}, }
@article {pmid40239917, year = {2025}, author = {Zhang, T and Zhang, Y and Chameau, P and Chen, T and Marmolejo-Garza, A and Douwenga, W and Dolga, AM and Kessels, HW and Schmidt, M and Eisel, ULM}, title = {Activation of Epac2 improves Aβ-induced impairment of memory retrieval in an acute model of Alzheimer's disease.}, journal = {Neuropharmacology}, volume = {}, number = {}, pages = {110468}, doi = {10.1016/j.neuropharm.2025.110468}, pmid = {40239917}, issn = {1873-7064}, abstract = {Impaired memory retrieval is one of the cognitive markers in the early stage of Alzheimer's Disease (AD). Previous studies report that exchange protein directly activated by cAMP 2 (Epac2) plays a specific and time-limited role in promoting memory retrieval. In this study, we investigated the effect of a novel Epac2 activator, S220, on neuronal and synaptic activities, and memory impairment in an acute AD mouse model. S220 treatment increased the firing rate of action potential and intracellular calcium in primary neurons. Moreover, S220 treatment increased synaptic currents in CA1 neurons. In the acute AD mouse model, intrahippocampal injection of amyloid-β (Aβ) oligomers impaired memory performance. Notably, administering S220 20 minutes before retention of contextual fear conditioning recovered the Aβ-induced memory impairment, suggesting an enhancing effect on memory retrieval. Collectively, our data demonstrate that the novel Epac2 activator S220 promotes synaptic communication and neuronal firing, and thereby improves Aβ-induced memory impairment via enhancing memory retrieval, indicating the role of Epac2 as a potential treatment target for AD.}, }
@article {pmid40237798, year = {2025}, author = {Ahmed, HS}, title = {Neuropharmacological effects of calycosin: a translational review of molecular mechanisms and therapeutic applications.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40237798}, issn = {1432-1912}, abstract = {Calycosin, a naturally occurring isoflavonoid found predominantly in Astragalus membranaceus, exhibits significant therapeutic potential in various neurological conditions. Its multifaceted bioactive properties-antioxidant, anti-inflammatory, and anti-apoptotic-position it as a promising candidate for neuroprotection and neuroregeneration. This review explores calycosin's mechanisms of action, including its modulation of key signaling pathways such as HMGB1/TLR4/NF-κB (high mobility group box 1/toll-like receptor 4/nuclear factor kappa B), phosphatidylinositol-3-kinase (PI3 K)/Akt, ERK1/2 (extracellular signal-regulated kinase 1/2), and Hsp90/Akt/p38. In cerebral ischemia/reperfusion injury, calycosin reduces oxidative stress markers like ROS (reactive oxygen species) and MDA (malondialdehyde), enhances antioxidant enzymes (SOD (superoxide dismutase) and GPX (glutathione peroxidase)), and downregulates pro-inflammatory cytokines (TNF-α, IL-1β) through the HMGB1/TLR4/NF-κB pathway. It also inhibits autophagy via the STAT3/FOXO3a pathway and apoptosis by modulating Bax and Bcl-2 expression. In neuro-oncology, calycosin inhibits glioblastoma cell migration and invasion by modulating the TGF-β-mediated mesenchymal properties and suppressing the c-Met and CXCL10 signaling pathways. Additionally, it enhances the efficacy of temozolomide in glioma treatment through apoptotic pathways involving caspase-3 and caspase-9. Calycosin shows promise in Alzheimer's disease by reducing β-amyloid production and tau hyperphosphorylation via the GSK-3β pathway and improving mitochondrial function through the peroxisome proliferator-activated receptor gamma coactivator 1-Alpha (PGC-1α)/mitochondrial transcription factor A (TFAM) signaling pathway. In Parkinson's disease, calycosin mitigates oxidative stress, prevents dopaminergic neuronal death, and reduces neuroinflammation by inhibiting the TLR/NF-κB and MAPK pathways. It has also shown therapeutic potential in meningitis and even neuroprotective effects against hyperbilirubinemia-induced nerve injury. Despite these promising findings, further research, including detailed mechanistic studies and clinical trials, is needed to fully understand calycosin's therapeutic mechanisms and validate its potential in human subjects. Developing advanced delivery systems and exploring synergistic therapeutic strategies could further enhance its clinical application and effectiveness.}, }
@article {pmid40237393, year = {2025}, author = {Brendborg, N and Febbraio, MA}, title = {Intervention points for the role of physical activity in prevention and treatment of Alzheimer's disease.}, journal = {The Journal of physiology}, volume = {}, number = {}, pages = {}, doi = {10.1113/JP286747}, pmid = {40237393}, issn = {1469-7793}, support = {1194141//DHAC | National Health and Medical Research Council (NHMRC)/ ; }, abstract = {Alzheimer's disease (AD) is a growing global health challenge with limited pharmacological treatments. Epidemiological studies link regular physical activity with a lower risk of AD and cognitive decline in general, whereas randomized controlled trials show that aerobic exercise slows disease progression and improves cognitive function. However the underlying mechanisms remain incompletely understood. In this review we discuss five likely intervention points through which physical activity may influence AD progression and pathology: (1) reducing neuroinflammation and amyloid beta (Aβ) aggregation, (2) enhancing clearance of Aβ aggregates, (3) increasing neuronal resilience, (4) promoting hippocampal neurogenesis and (5) strengthening cognitive reserve. Understanding which of these mechanistic links are most likely to drive the AD-protective effects of exercise could help refine lifestyle-based interventions to complement pharmacological treatments and inform future prevention strategies.}, }
@article {pmid40237381, year = {2025}, author = {Isik, M and Sari, HK and Caglayan, MG and Yilmaz, R and Derkus, B}, title = {Whispers in the Brain: Extracellular Vesicles in Neuropathology and the Diagnostic Alchemy of Neurological Diseases.}, journal = {The European journal of neuroscience}, volume = {61}, number = {8}, pages = {e70090}, doi = {10.1111/ejn.70090}, pmid = {40237381}, issn = {1460-9568}, support = {TSA-2023-2648//Ankara University Scientific Research Projects Coordination Unit/ ; TSA-2024-3217//Ankara University Scientific Research Projects Coordination Unit/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism/pathology ; Animals ; *Nervous System Diseases/diagnosis/metabolism/pathology ; Biomarkers/metabolism ; *Brain/metabolism/pathology ; Neurodegenerative Diseases/diagnosis/metabolism ; }, abstract = {Extracellular vesicles (EVs) have emerged as pivotal mediators in neurological diseases, showcasing multifaceted potential roles ranging from pathogenesis to diagnosis. These nano-sized membranous structures, released by various cell types including neurons, astrocytes, and microglia, encapsulate a diverse cargo of proteins, lipids, RNA species, and even DNA fragments. In neuropathology, EVs contribute significantly to intercellular communication within the central nervous system (CNS), influencing physiological or pathological cascades. Through the transfer of bioactive molecules, EVs modulate neuroinflammation, neuronal survival, synaptic plasticity, and the propagation of protein aggregates characteristic of neurodegenerative disorders. Moreover, their presence in biofluids such as cerebrospinal fluid (CSF), blood, and urine reflects the pathophysiological state of the CNS, offering a window into the diagnosis, monitoring and treatment of neurological diseases. Recent advancements in EV isolation techniques, coupled with high-throughput omics technologies, have facilitated the profiling of EV cargo, enabling the identification of disease-specific biomarkers with high sensitivity and specificity. This review explores the intricate roles of EVs in neuropathology, highlighting their involvement in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and other neurological disorders. Furthermore, it delves into the diagnostic potential of EVs, discussing current challenges and prospects in harnessing EV-derived biomarkers for precision medicine in neurology. Ultimately, understanding the biology of EVs in neurological contexts promises transformative insights into disease mechanisms and therapeutic strategies, paving the way for innovative diagnostic tools and targeted interventions in clinical practice.}, }
@article {pmid40237235, year = {2025}, author = {Fertan, E and Lam, JYL and Albertini, G and Dewilde, M and Wu, Y and Akingbade, OES and Böken, D and English, EA and De Strooper, B and Klenerman, D}, title = {Lecanemab preferentially binds to smaller aggregates present at early Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {4}, pages = {e70086}, doi = {10.1002/alz.70086}, pmid = {40237235}, issn = {1552-5279}, support = {ERC-834682//European Union's Horizon 2020 Research and Innovation Program/ ; AARF-22-968623//Alzheimer's Association USA/ ; MR/Y014847/1//UK Medical Research Council/ ; //UK Dementia Research Institute/ ; //The Royal Society/ ; }, mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; Humans ; *Amyloid beta-Peptides/metabolism ; *Antibodies, Monoclonal, Humanized/metabolism/pharmacology ; *Brain/metabolism/pathology ; *Antibodies, Monoclonal/metabolism ; }, abstract = {INTRODUCTION: The monoclonal antibodies Aducanumab, Lecanemab, Gantenerumab, and Donanemab were developed for the treatment of Alzheimer's disease (AD).
METHODS: We used single-molecule detection and super-resolution imaging to characterize the binding of these antibodies to diffusible amyloid beta (Aβ) aggregates generated in-vitro and harvested from human brains.
RESULTS: Lecanemab showed the best performance in terms of binding to the small-diffusible Aβ aggregates, affinity, aggregate coating, and the ability to bind to post-translationally modified species, providing an explanation for its therapeutic success. We observed a Braak stage-dependent increase in small-diffusible aggregate quantity and size, which was detectable with Aducanumab and Gantenerumab, but not Lecanemab, showing that the diffusible Aβ aggregates change with disease progression and the smaller aggregates to which Lecanemab preferably binds exist at higher quantities during earlier stages.
DISCUSSION: These findings provide an explanation for the success of Lecanemab in clinical trials and suggests that Lecanemab will be more effective when used in early-stage AD.
HIGHLIGHTS: Anti amyloid beta therapeutics are compared by their diffusible aggregate binding characteristics. In-vitro and brain-derived aggregates are tested using single-molecule detection. Lecanemab shows therapeutic success by binding to aggregates formed in early disease. Lecanemab binds to these aggregates with high affinity and coats them better.}, }
@article {pmid40237061, year = {2025}, author = {Öztürk, B and Demir, H and Günay, MS and Akdag, Y and Sahin, S and Gulsun, T}, title = {Photodynamic and Photothermal Therapies using Nanotechnology Approach in Alzheimer's Disease.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X370790250317045223}, pmid = {40237061}, issn = {1875-6190}, abstract = {Alzheimer's disease is a neurodegenerative disease that impairs cognitive function. The incidence of Alzheimer's disease increases with the increase in the elderly population. Although the clear pathogenesis of Alzheimer's disease is not yet known, the formation of amyloid plaques and tau fibrils, diminished acetylcholine levels, and increased inflammation can be observed in patients. Alzheimer's disease, whose pathogenesis is not fully demonstrated, cannot be treated radically. Since it has been observed that only pharmacological treatment alone isn't sufficient, alternative approaches have become essential. Among these approaches, nanocarriers greatly facilitate the transport of drugs since the blood-brain barrier is an important obstacle to the penetration of drugs into the brain. Photosensitizers trigger activation after exposure to near-infrared radiation light of a suitable wavelength or laser light, resulting in the selective destruction of Aβ plaques. Photodynamic therapy and photothermal therapy have been investigated for their potential to inhibit Aβ plaques through photosensitizers. By encapsulating photosensitizers in nanocarriers, the limitations of photosensitizers can be overcome. By using these photosensitizers, near-infrared radiation fluorescence imaging can be used as a theranostic. In this review, potential treatment options for photodynamic therapy and photothermal therapy for Alzheimer's disease are summarised, and a simultaneous or combined approach is discussed, taking into account potential nanotheranostics.}, }
@article {pmid40236239, year = {2025}, author = {Chakroborty, A and Ejaz, S and Sternburg, JO and Asadi, Y and Cai, M and Dwamena, AA and Giri, S and Adeniji, O and Ahammed, MS and Gilstrap, EA and Uddin, MG and McDowell, C and Liu, J and Wang, H and Wang, X}, title = {Homeostatic Activation of 26S Proteasomes by Protein Kinase A Protects against Cardiac and Neurobehavior Malfunction in Alzheimer's Disease Mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.03.28.645869}, pmid = {40236239}, issn = {2692-8205}, abstract = {Alzheimer's Disease (AD) patients often show brain and cardiac malfunction. AD represents a leading cause of morbidity and mortality worldwide, but the demand for effective treatment for AD is far from being met. This is primarily because AD pathogenesis, including brain-heart interaction, is poorly understood. Proteasome functional insufficiency is implicated in AD; as such, proteasome enhancement promises a potentially new strategy to treat AD. The proteasome can be activated by protein kinase A (PKA) via selectively phosphorylating Ser14-RPN6/PSMD11 (p-S14-RPN6); however, whether p-S14-RPN6 is altered and what role p-S14-RPN6 plays in AD remain unclear. Hence, this study was conducted to address these critical gaps. We found that genetic blockade of the homeostatic p-S14-Rpn6 via germline knock-in of Rpn6 [S14A] (referred to as S14A) significantly reduced proteasome activities in the cerebral cortex but did not discernibly impair learning and memory function in 4-month-old mice or cause cardiac dysfunction before 12 months of age. Increases in Ser14-phosphorylated Rpn6 in the cerebral cortex and markedly elevated Aβ proteins in the myocardium were observed in young 5XFAD mice, a commonly used AD model. When introduced into the 5XFAD mice, S14A significantly aggravated the learning and memory deficits as revealed by the radial arm water maze tests and accelerated cardiac malfunction as measured by serial echocardiography in the same cohort of 5XFAD mice. Thus, the present study establishes for the first time that homeostatic activation of 26S proteasomes by basal p-S14-RPN6 or PKA activity protects against both the brain and heart malfunction in the 5XFAD mice.}, }
@article {pmid40235602, year = {2025}, author = {Teixeira, AL and Gregg, A and Gentry, MT and Gujral, S and Rapp, E and Oberlin, L and Ajilore, O and Weisenbach, S and Patrick, R}, title = {Cognitive Deficits in Late-Life Depression: From Symptoms and Assessment to Therapeutics.}, journal = {Focus (American Psychiatric Publishing)}, volume = {23}, number = {2}, pages = {183-194}, pmid = {40235602}, issn = {1541-4094}, abstract = {Cognitive symptoms and deficits are core features of late-life depression (LLD), with an estimated 20%-50% of affected individuals meeting diagnostic criteria for mild cognitive impairment (MCI). Cognitive deficits, especially executive dysfunction, have consistently been associated with poorer treatment outcomes among people with LLD. Furthermore, distinguishing depression with cognitive complaints or cognitive impairment from the early stages of Alzheimer's disease (AD) can be challenging. Cognitive concerns are often emphasized among those with LLD, although, paradoxically, their description of memory difficulty may include detailed recall of specific memory lapses. Conversely, people with AD often have limited insight into their progressive cognitive decline, minimizing and concealing their cognitive difficulties. Neuropsychological assessment is one of the most useful means of clarifying this differential diagnosis. A subcortical cognitive pattern is commonly observed among people with LLD, including psychomotor slowing, variable attention, and executive dysfunction, which can affect memory encoding and free recall. A broad range of therapeutic approaches have been applied to older adults experiencing LLD along with cognitive symptoms, MCI, or dementia. Most studies focus on treatments to address LLD or MCI, with relatively fewer examining treatments specifically at this intersection. Nonpharmacological strategies, including aerobic exercise, cognitive remediation, and neuromodulation, are highly recommended to improve both depression and cognition. Antidepressants may have benefits for elements of cognition among people with LLD, but they have less evidence for their efficacy for people with cognitive deficits and dementia. This review provides an updated conceptual and practical framework for clinicians evaluating and treating LLD.}, }
@article {pmid40235521, year = {2025}, author = {Pala, M and Yilmaz, SG}, title = {Circular RNAs, miRNAs, and Exosomes: Their Roles and Importance in Amyloid-Beta and Tau Pathologies in Alzheimer's Disease.}, journal = {Neural plasticity}, volume = {2025}, number = {}, pages = {9581369}, pmid = {40235521}, issn = {1687-5443}, mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Humans ; *RNA, Circular/metabolism ; *Exosomes/metabolism ; *Amyloid beta-Peptides/metabolism ; *MicroRNAs/metabolism ; *tau Proteins/metabolism ; Animals ; }, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder. The pathology of this disease is based on two basic mechanisms: amyloid-beta (Aβ) and tau fibrillation. Many genes and mechanisms have been identified as the primary causes of AD in clinical settings, and there have been exciting developments in drug treatments. Several molecules and biological structures regulate the genome outside of the standard DNA function. As in many diseases, circular RNAs (circRNAs), microRNAs (miRNAs), and exosomes (EXOs), investigated from different aspects of AD, are useful for treatment and diagnosis. This review examines two biological elements regarding their roles in the Aβ-tau pathology of AD and their potential as treatment targets. Importantly, the activities of miRNAs that play a role in these processes were evaluated. Trial Registration: ClinicalTrials.gov identifiers: NCT04120493, NCT04969172, NCT04388982.}, }
@article {pmid40235513, year = {2025}, author = {Rabiei, K and Petrella, JR and Lenhart, S and Liu, C and Doraiswamy, PM and Hao, W}, title = {Data-Driven Modeling of Amyloid-beta Targeted Antibodies for Alzheimer's Disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-6316455/v1}, pmid = {40235513}, issn = {2693-5015}, abstract = {Alzheimer's disease (AD) is caused by the build-up of amyloid beta (A$\beta$) proteins in the brain, leading to memory loss and cognitive decline. Despite the approval of monoclonal antibodies targeting A$\beta$, optimizing treatment strategies while minimizing side effects remains a challenge. This study develops a mathematical framework to model A$\beta$ aggregation dynamics, capturing the transition from monomers to higher-order aggregates, including protofibrils, toxic oligomers, and fibrils, using mass-action kinetics and coarse-grained modeling. Parameter estimation, sensitivity analysis, and data-driven calibration ensure model robustness. An optimal control framework is introduced to identify the optimal dose of the drug as a control function that reduces toxic oligomers and fibrils while minimizing adverse effects, such as amyloid-related imaging abnormalities (ARIA). The results indicate that Donanemab achieves the most significant reduction in fibrils. These findings provide a quantitative basis for optimizing AD treatments, providing valuable insight into the balance between therapeutic efficacy and safety.}, }
@article {pmid40235143, year = {2025}, author = {Jaberian Asl, B and Nazeri, Z and Pezeshki, SP and Kheirollah, A and Azizidoost, S and Adelipour, M and Cheraghzadeh, M}, title = {Effect of Amyloid Beta on Cholesterol Metabolism-Correlated microRNAs in Primary Cultured Astrocytes of C57BL/6J Mice: A Focus on CYP46A1 and APOE Genes.}, journal = {Cell journal}, volume = {26}, number = {11}, pages = {625-631}, doi = {10.22074/cellj.2025.2029261.1587}, pmid = {40235143}, issn = {2228-5814}, abstract = {OBJECTIVE: The accumulation of amyloid plaques and disturbance of cholesterol homeostasis are implicated in the pathophysiology of Alzheimer's disease. Apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46A1) are key proteins involved in the efflux and metabolism of excess cholesterol, and small non-coding RNAs (miRNAs), can help to regulate the expression of the genes encoding these proteins. The aim of the present study was to investigate the alterations in the expression of APOE and CYP46A1 genes, as well as their respective regulatory miRNAs, in astrocytes treated with amyloid beta (Aβ).
MATERIALS AND METHODS: In this experimental study, isolated astrocyte cells were cultured and treated with Aβ for 24 hours. Changes in the expression of APOE and CYP46A1 genes, as well as their regulating miRNAs, were assessed using the realtime polymerase chain reaction (PCR) technique.
RESULTS: The expression of APOE and CYP46A1 genes increased with Aβ treatment. MiR-33a-5p, as the negative regulator of the APOE gene exhibited significant decrease. Additionally, miR-let-7a-5p, as the positive regulator of the APOE gene, showed an increase in the Aβ treated group. Moreover, miR-98-5p, as the negative regulator of the CYP46A1 gene, showed a half-fold decrease. While, miR-27a-3p as the positive regulator of the CYP46A1 gene, increased significantly with Aβ treatment.
CONCLUSION: Alterations in the expression of APOE and CYP46A1 genes, as well as the expression of miRNAs regulating these genes, in astrocytes treated with Aβ suggests that the cell is attempting to modify the regulatory pathways of cholesterol homeostasis in the brain under pathological conditions, such as Alzheimer's disease.}, }
@article {pmid40235082, year = {2025}, author = {Wang, G and Li, Y and Xiong, C and Cao, Y and Schindler, SE and McDade, E and Blennow, K and Hansson, O and Dage, JL and Jack, CR and Teunissen, CE and Shaw, LM and Zetterberg, H and Ibanez, L and Timsina, J and Carlos, C and , and Bateman, RJ}, title = {The CentiMarker project: Standardizing quantitative Alzheimer's disease fluid biomarkers for biologic interpretation.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {4}, pages = {e14587}, doi = {10.1002/alz.14587}, pmid = {40235082}, issn = {1552-5279}, support = {/AG/NIA NIH HHS/United States ; U01 AG024904/NH/NIH HHS/United States ; U01AG042791-S1/NH/NIH HHS/United States ; R01AG046179//FNIH and Accelerating Medicines Partnership/ ; R01AG053267-S1//FNIH and Accelerating Medicines Partnership/ ; /ALZ/Alzheimer's Association/United States ; //Eli Lilly and Company/ ; //F. Hoffman-LaRoche Ltd./ ; //Avid Radiopharmaceuticals/ ; //GHR Foundation/ ; //The Dominantly Inherited Alzheimer Network/ ; //National Institute on Aging (NIA)/ ; //German Center for Neurodegenerative Diseases (DZNE)/ ; //Raul Carrea Institute for Neurological Research (FLENI)/ ; //Japan Agency for Medical Research and Development (AMED)/ ; //Korea Health Technology R&D/ ; //Korea Health Industry Development Institute (KHIDI)/ ; //Korea Dementia Research Center (KDRC)/ ; HI21C0066//the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; //Spanish Institute of Health Carlos III (ISCIII)/ ; //Alzheimer's Disease Neuroimaging Initiative/ ; W81XWH-12-2-0012//Department of Defense/ ; /EB/NIBIB NIH HHS/United States ; //AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd/ ; //Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research/ ; U01AG052564//Foundation for the National Institutes of Health/ ; }, mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/genetics ; *Biomarkers/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Female ; Amyloid beta-Peptides/cerebrospinal fluid ; Male ; Aged ; Peptide Fragments/cerebrospinal fluid ; }, abstract = {INTRODUCTION: Biomarkers play a crucial role in understanding Alzheimer's disease (AD) pathogenesis and treatment effects. However, comparing biomarker measures without standardization and appreciating their magnitude relative to the disease can be challenging.
METHODS: To address this issue, we propose the CentiMarker approach, similar to Centiloid, which provides a standardized scale between normal (0) and nearly maximum abnormal AD (100) ranges. We applied this scale to cerebrospinal fluid (CSF) biomarkers in dominantly inherited AD and sporadic AD cohorts.
RESULTS: CentiMarkers facilitated the interpretation of disease abnormality, demonstrating comparable changes and distributions of AD biomarkers across disease stages. CentiMarkers make the treatment effect more comparable than their original scales across various biomarkers.
DISCUSSION: The versatility of CentiMarkers makes it a valuable tool for standardized biomarker comparison in AD research, enabling informed cross-study comparisons and contributing to accelerated therapeutic development. Adoption of the CentiMarker scale could enhance biomarker reporting and advance our understanding of AD.
HIGHLIGHTS: Comparing fluid biomarkers without appreciating their magnitude relative to the disease can be challenging. We propose a CentiMarker metric to standardize biomarker measures from normal (0) and nearly maximum abnormal AD (100) ranges. CentiMarkers make the treatment effect more comparable across various biomarkers than when using the original scales.}, }
@article {pmid40234998, year = {2025}, author = {Iraji, A and Hariri, R and Hashempur, MH and Ghasemi, M and Pourtaher, H and Saeedi, M and Akbarzadeh, T}, title = {Design and synthesis of new 1,2,3-triazole-methoxyphenyl-1,3,4-oxadiazole derivatives: selective butyrylcholinesterase inhibitors against Alzheimer's disease.}, journal = {BMC chemistry}, volume = {19}, number = {1}, pages = {97}, pmid = {40234998}, issn = {2661-801X}, abstract = {Alzheimer's disease (AD) remains a significant public health challenge due to its progressive cognitive impairment and the absence of proven treatments. In this study, several novel 1,2,3-triazole-methoxyphenyl-1,3,4-oxadiazole derivatives were synthesized and evaluated for their ability to inhibit key enzymes associated with AD: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Structure-activity relationship (SAR) analysis revealed that derivatives featuring electron-withdrawing groups, particularly nitro and fluorine substituents, exhibited remarkable inhibitory activity against BChE while showing minimal effectiveness against AChE. Among these, compound 13s (R = 4-CH3, R' = 4-NO2) demonstrated the highest potency, selectively targeting BChE with an IC50 value of 11.01 µM. Molecular docking and molecular dynamics (MD) simulations provided deeper insights into the favorable interactions between these compounds and BChE. Additionally, cytotoxicity studies confirmed the active compound's limited toxicity toward normal cells, indicating a promising therapeutic profile. These findings suggest that the synthesized selective anti-BChE compounds hold potential for consideration in the later stages of AD treatment.}, }
@article {pmid40234956, year = {2025}, author = {Pang, RK and Shi, J and Peng, XY and Su, S and Zheng, JY and Le, K and Keng, VW and Zhang, SJ and Li, XX}, title = {Huang-Lian-Jie-Du decoction alleviates cognitive deficits in Alzheimer's disease model 5xFAD mice by inhibiting Trem2/Dap12 signaling pathway.}, journal = {Chinese medicine}, volume = {20}, number = {1}, pages = {50}, pmid = {40234956}, issn = {1749-8546}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder predominantly affecting the elderly population. It is characterized by cognitive deficits associated with the accumulation of amyloid-beta plaques and neurofibrillary tangles. Huang-Lian-Jie-Du (HLJD) decoction, recognized as a representative formulation with heat-clearing and detoxification effects, has been demonstrated to be effective in treating AD. However, the underlying mechanisms require further investigation.
METHODS: 5xFAD mice were administrated low and high doses of HLJD. The Morris water maze test was conducted to assess the effects of HLJD. Aβ42 and total tau protein levels were evaluated. Additionally, network pharmacology analysis was performed to identify therapeutic targets of HLJD's active components and their relevance to AD. ELISA, qPCR, Western Blot, and immunofluorescence assays were employed to confirm the identified pathways. Finally, primary microglia isolated from 5xFAD mice were used to validate the candidate targets of HLJD.
RESULTS: HLJD improved cognitive deficits in 5xFAD mice and reduced amyloid plaque deposition and tau protein levels. Network pharmacology analysis indicated that HLJD influences the neuroinflammatory response, particularly through the Dap12 signaling pathway. This was confirmed by reduced levels of neuroinflammation markers, including TNF-α, IL-1β, IL-6, and indicators of microglial activation and polarization. The expression of Trem2 and Dap12 in the hippocampus (HIP) of 5xFAD mice, as well as in the isolated primary microglia, were downregulated following HLJD treatment.
CONCLUSION: Our study indicates that HLJD alleviates cognitive deficits in AD by suppressing the Trem2/Dap12 signaling pathway in the HIP of 5xFAD mice, thereby inhibiting microglial neuroinflammation.}, }
@article {pmid40234291, year = {2025}, author = {Bogadi, S and Bhaskaran, M and Ravichandran, V and Nesamony, J and Chelliah, S and Kuppusamy, G and Prakash, GM and Karri, VVSR and Mallick, S and Farahim, F and Ali, T and Babu, DR and Subramaniyan, V}, title = {Functionalized Nanoparticles: A Promising Approach for Effective Management of Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40234291}, issn = {1559-1182}, abstract = {The severe neurodegenerative disease known as Alzheimer's disease (AD) is typified by a progressive loss of memory and cognitive function. The prevalence of AD is rising due to an aging global population, calling for novel treatment strategies. A potential treatment option for AD that shows promise is the use of functionalized nanoparticles (NPs). Recent developments in the synthesis, design, and use of functionalized NPs in AD therapy are examined in this review. An outline of the pathophysiological mechanisms underlying AD is given in the first section, focusing on the roles played by tau protein aggregates and amyloid-beta plaques in the development of the illness. We then explore the many approaches used to functionalize NPs, such as surface alterations and bioconjugation methods, which enable accurate drug administration, targeted delivery, and enhanced biocompatibility. The review also emphasizes the therapeutic potential of functionalized NPs, highlighting their capacity to improve neuroprotection, lower amyloid-beta aggregation, and improve blood-brain barrier penetration. The potential of NPs as a tool for disease modification and symptom relief is highlighted by recent pre-clinical and clinical research. Concerns about toxicity and safety are also covered, underscoring the significance of thorough testing and the field's future directions. Functionalized NPs have great promise as a multimodal strategy to treat AD, offering patients hope for better quality of life, early diagnosis, and efficient disease treatment. This study highlights the growing role of nanotechnology in the search for novel and potent therapies for AD.}, }
@article {pmid40234095, year = {2025}, author = {Xiong, Y and Yang, Y and Ruan, Y and Ou, W and Hu, Z and Li, W and Xiao, N and Liao, W and Liu, J and Liu, Z and Luo, Q and Liu, F and Liu, J}, title = {Magnesium-L-threonate Ameliorates Cognitive Deficit by Attenuating Adult Hippocampal Neurogenesis Impairment in a Mouse Model of Alzheimer's Disease.}, journal = {Experimental neurobiology}, volume = {}, number = {}, pages = {}, doi = {10.5607/en24030}, pmid = {40234095}, issn = {1226-2560}, abstract = {Impaired adult hippocampal neurogenesis is a key pathological mechanism contributing to memory deficits in Alzheimer's disease (AD). Recent studies have shown that elevating magnesium levels promotes neurogenesis by enhancing the neuronal differentiation of adult neural progenitor cells in vitro. Therefore, this in vivo study aims to determine if magnesium-L-threonate (MgT) can ameliorate cognitive deficit of AD mice by attenuating adult hippocampal neurogenesis impairment and to reveal the underlying mechanisms. APPswe/PS1dE9 mice were treated with different doses of MgT and ERK inhibitor PD0325901. The memory ability of each mouse was recorded by Morris Water Maze test. After cognitive test, hippocampus tissues were collected to measure the proportion of BrdU/doublecortin double-labeled cells using the flow cytometry test and assess the expression of doublecortin using PCR and Western blot. Furthermore, the activations of CREB, ERK, P38 and JNK were measured by Western blot to identify the involved mechanisms. The cognitive test confirmed that MgT treatment attenuated the memory impairment of APPswe/PS1dE9 mice. Flow cytometry test showed that Brdu/doublecortin labeled newborn neurons gradually increased following MgT administration. In line with the flow cytometry results, Western blot and PCR confirmed that MgT administration significantly increased doublecortin expression levels. Furthermore, the ratios of p-ERK/ERK and p-CREB/CREB increased with MgT elevation. In addition, these effects of MgT treatment were markedly reversed by PD0325901 supplementation. In conclusion, MgT treatment improved cognitive decline by ameliorating adult hippocampal neurogenesis impairment in this AD model, possibly via ERK/CREB activation.}, }
@article {pmid40233108, year = {2025}, author = {Amin, H and Bukhari, SA and Chauhdary, Z and Akhter, N and Saleem, M}, title = {Vigna radiata extracts in pumpkin and soya bean oil: A novel therapeutic approach for Alzheimer's disease.}, journal = {PloS one}, volume = {20}, number = {4}, pages = {e0321183}, doi = {10.1371/journal.pone.0321183}, pmid = {40233108}, issn = {1932-6203}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology/chemically induced ; *Cucurbita/chemistry ; Rats ; *Plant Extracts/pharmacology/therapeutic use/chemistry ; *Soybean Oil/chemistry ; *Vigna/chemistry ; Male ; Disease Models, Animal ; Rats, Wistar ; Antioxidants ; Neuroprotective Agents/pharmacology ; }, abstract = {Vigna radiate also known as mung beans, contains various bioactive compounds like polyphenols, flavonoids, and saponins. V. radiata therapeutic potential is enhanced by preparation of its extract in Pumpkin oil and soya bean oil by enrichment of bioactive compounds holding antioxidant, anti-inflammatory, and neuro-protective properties. The research study was aimed was to explore the healing endeavors of V. radiate pumpkin and soya bean oil extract in rectification of neuro-motor dysfunction and mental health decline in Alzheimer's disease (AD) rat model. After preliminary physico-phytochemical characterization and GC-MS analysis, AD model was established by administration of oral D-galactose and aluminum chloride 150 mg/kg each for 42 days daily. V. radiate extract in pumpkin and soya bean oil at doses 250 and 500 mg/kg was administered and rivastigmine (3 milligrams per kilogram) to treatment animals. To determine the cognitive decline and neuro-coordination dysfunctions behavioral tests were performed along with biochemical, neurochemical and histopathological analysis. ELISA and real time polymerase chain reaction were carried out to estimate the expression of tumor necrosis factor-α, Interleukine-6 and mRNA expression of neurodegenerative biomarkers. Gas chromatography Mass Spectrometry findings revealed the existence of favorable amount of neuro-defensive bioactive compounds in both oil extracts.V. radiate pumpkin and soya bean oil extract dose proportionally alleviated the behavioral dysfunctions, modulated the first line antioxidant enzymes and neurotransmitters s' level with anticholinesterase pursuits. The mRNA expression of AChE, IL-1β, TNF-α, IL-1α and β secretase were downregulated by these extracts treatment. V. radiate oil extracts also modulated the neuro-inflammatory protein expression and histopathological hallmarks in AD model animals. Therefore, it is purposed that V. radiate enriched extract in pumpkin and soya bean oil could be used to treat AD like memory dysfunction and motor symptoms.}, }
@article {pmid40232090, year = {2025}, author = {Hamdi, A and Córdoba-Rojano, MA and Monje-Moreno, JM and Guillén-Izquierdo, E and Rodríguez-Arcos, R and Jiménez-Araujo, A and Muñoz-Ruiz, MJ and Guillén-Bejarano, R}, title = {Harnessing the Potential of Walnut Leaves from Nerpio: Unveiling Extraction Techniques and Bioactivity Through Caenorhabditis elegans Studies.}, journal = {Foods (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, doi = {10.3390/foods14061048}, pmid = {40232090}, issn = {2304-8158}, support = {research contract number 20232315//Asociación de Productores de Nuez de Nerpio/ ; }, abstract = {This study used Juglans regia leaves from the Gran Jefe variety; this indigenous cultivar from Nerpio is highly valued for its quality and distinct characteristics. This type of walnut is traditionally cultivated in the region and is noted for its organoleptic properties and adaptation to local climatic conditions. Two solvents were tested to determine the optimal extraction conditions for phenolic compounds: 80% ethanol and water. Direct homogenization with an Ultra-Turrax, direct ultrasound, and indirect ultrasound treatments were compared for ethanol extraction. Water extractions were conducted using direct and indirect ultrasound, infusion, and decoction. Compared to water extraction, 80% ethanol proved to be more efficient. Extracting phenolic compounds from 'Gran Jefe' walnut leaves was most effective when using direct extraction methods without either ultrasound assistance or indirect ultrasound treatment. The main compounds identified were trans-3-caffeoylquinic acid and quercetin-3-hexoside isomer 1. The ethanolic extract obtained through direct extraction was selected to study further the bioactivities of 'Gran Jefe' walnut leaves using C. elegans as an in vivo model. Results indicated that the leaf extract enhanced thermal and oxidative stress resistance, promoted fertility, and exhibited neuroprotective effects in models of Alzheimer's and Parkinson's diseases. The observed bioactivities were attributed to the free phenolics present in the ethanolic extract.}, }
@article {pmid40231700, year = {2025}, author = {Young, Y and Liu, Y and Tu, Y and Chiu, WY and Shayya, A and O'Grady, T}, title = {Advance Care Planning and Unlimited Treatment Preferences in Dementia Scenarios: Insights From Community-Dwelling Adults.}, journal = {The American journal of hospice & palliative care}, volume = {}, number = {}, pages = {10499091251334090}, doi = {10.1177/10499091251334090}, pmid = {40231700}, issn = {1938-2715}, abstract = {Introduction: Dementia leads to progressive cognitive decline, impairing self-care and decision making. Advance directives (AdvDirs) enable individuals to document healthcare preferences while cognitively capable, ensuring value-aligned care and reducing caregiver burden. This study explores factors influencing preferences for unlimited medical treatment in hypothetical Alzheimer's disease/dementia scenarios among community-dwelling adults. Methods: This cross-sectional study surveyed 163 community-dwelling adults (18+), using structured questionnaires to collect sociodemographic, health, and AdvDir-related data. Key predictors included attitudes toward life-sustaining treatments, comfort discussing death, religious practices, and interest in quality-of-life information related to end-of-life care. The primary outcome was preference for unlimited medical treatment in hypothetical dementia scenarios. Bivariate and multivariate logistic analyses assessed associations, adjusting for covariates. Results: In the dementia scenario, 26.9% of participants preferred unlimited medical treatment. This preference was strongly associated with a pre-existing attitude favoring life-sustaining treatments (OR = 4.24, 95% CI: 1.73 - 10.37, P = 0.002) and religious beliefs (OR = 5.68, 95% CI: 1.51-21.43, P = 0.01). Conversely, an interest in learning about quality of life at the end of life was negatively associated with preferring unlimited treatment (OR = 0.29, 95% CI: 0.09-0.89, P = 0.03). Discussion: Our findings highlight the need to align advance care planning with individuals' values, beliefs, and religious practices. Raising awareness of quality-of-life considerations in end-of-life care may lead to a shift in preference toward palliative care rather than aggressive treatment. Healthcare providers should discuss treatment trade-offs with cultural and religious sensitivity to support informed decision making.}, }
@article {pmid40231539, year = {2025}, author = {Liye, A and Saichao, Z and Zhang, X and Loktionova, M and Gavrikov, LK and Glazachev, O}, title = {Influence of Inflammation, Gut Microbiota, and Stress on Cognition and Oral Health Therapies.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050361661250327061024}, pmid = {40231539}, issn = {1875-5828}, abstract = {BACKGROUND: Prolonged or repeated psychological stress triggers dental and orthodontic diseases via inflammatory pathways and oxidative stress. This review aims to elucidate the role of inflammation, gut microbiota, stress, and cognition, exploring their impact on the development of therapeutics to enhance oral health.
OBJECTIVE: The primary aim pertinent to this systematic review is to elucidate the significant implications of cognition and stress in dental and orthodontic health. Specifically, the review aims to (1) investigate the association between emotional stress and the incidence or progression of periodontal disease; (2) explore the impact of physiological and emotional stress on cellular and molecular inflammatory responses in orthodontics; (3) examine the influence of gut-mediated psychophysiological factors on emotional changes in mental health and cognition with a focus on periodontics and orthodontics; and (4) investigate the potential of gut microbiota alterations to influence oral and cognitive/mental health, including the impact of probiotic supplementation and dietary interventions.
METHODS: A systematic review was conducted without comprehensive meta-analysis, focusing on literature from 1960 to 2024. Databases searched included PubMed, Embase, ReleMed, National Library of Medicine (NLM), Scopus, and Google Scholar. Keywords used were "cognition," "emotional stress," "gut microbiota," "orthodontics," "prosthetics," "pathophysiology," and "mental health." Studies were selected based on relevance, publication date, access to full texts, and adherence to PRISMA guidelines. The review integrated findings on the impact of emotional stress on periodontal disease and orthodontic health through pathophysiological implications.
RESULTS: Age-related neurodegeneration causes Alzheimer's disease and severe dementia that subsequently promotes poor oral health. The review identified a complex interplay between emotional stress and periodontal disease. While a direct association remains to be conclusively proven, several studies highlight the influence of stress on the severity and incidence of periodontal disease through inflammatory and immunological pathways. Stress manifests in various ways, such as increased masticatory muscle tone, changes in eating behavior, and the initiation of bruxism, all of which can affect dental health. Physiological stress induces an inflammatory response to orthodontic tooth movement, impacting orthodontic treatment outcomes. Furthermore, the review elucidates the role of gut-mediated psychophysiological factors in emotional changes, influencing periodontal and orthodontic health. Emerging evidence suggests that gut microbiota alterations can significantly impact oral and cognitive health through systemic inflammation and neuroimmune mechanisms.
CONCLUSION: This review highlights the significant impact of physiological and emotional stress on periodontal and orthodontic health. Detailed exploration of cellular and molecular inflammatory responses provides insights into the pathophysiology of orthodontic diseases and their impact on oral health. Gut-brain-oral axis has significance in oral health, exploring how alterations in gut microbiota influence oral and cognitive health. It is essential to investigate the impact of probiotic supplementation and dietary modifications on gut microbiota composition, systemic inflammation, and their influence on both cognitive and oral health. Clinical trials assessing the effectiveness of anti-inflammatory treatments in reducing periodontal disease and cognitive decline could offer valuable insights. Integrating advanced microbiome analysis techniques and neuroimaging can help clarify the mechanisms linking gut health, systemic inflammation, and cognitive function. Exploring specific gut microbiota strains that regulate systemic inflammation and cognitive function may lead to targeted probiotic therapies, potentially alleviating neuroinflammation and enhancing cognitive performance. Additionally, understanding the role of oral probiotics in periodontal health and their effects on gut microbiota and systemic inflammation could contribute to the development of innovative treatment approaches. This knowledge can aid molecular biologists, dentists, and researchers in managing oral and gut health more effectively.}, }
@article {pmid40231534, year = {2025}, author = {Rathi, KM and Sakle, NS and Undale, VR and Wavhale, RD and Bhole, RP and Karwa, PN}, title = {Exploring the Potential of Dolutegravir in Alzheimer's Disease Treatment: Insights from Network Pharmacology and In Silico Docking Studies.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249350698250317041551}, pmid = {40231534}, issn = {1875-6166}, abstract = {BACKGROUND: The search for effective treatments for neurodegenerative diseases, particularly Alzheimer's disease, has been fraught with challenges. Alzheimer's disease accounts for 60-80% of dementia cases globally, affecting approximately about 50 million people. Currently, drug repurposing has emerged as a promising strategy in new drug development, attracting significant attention from regulatory agencies, such as the US FDA.
AIM: This study aimed to investigate the potential therapeutic role of dolutegravir in Alzheimer's disease (AD) treatment using a novel network pharmacology approach. Specifically, it explored the interaction of dolutegravir with key molecular targets involved in AD pathology, predicted its effects on relevant biological pathways, and evaluated its viability as a new therapeutic candidate.
OBJECTIVE: This study employed a network pharmacology framework to evaluate dolutegravir, an antiretroviral drug, as a potential treatment for Alzheimer's disease, shedding light on its possible therapeutic mechanisms.
METHOD: A network pharmacology approach was used to predict the drug targets of dolutegravir. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify interacting pathways. Additionally, protein- protein interaction (PPI) network analysis was conducted to assess key interactions and molecular docking studies were performed to evaluate the binding affinity of dolutegravir to the predicted targets.
RESULT: PPI network analysis revealed that dolutegravir interacted with several key targets, including BRAF, mTOR, MAPK1, MAPK3, NOS1, BACE1, CAPN1, CASP3, CASP7, CASP8, CHUK, IKBKB, PIK3CA, and PIK3CD. KEGG pathway analysis suggested that dolutegravir could influence amyloid-beta formation, amyloid precursor protein metabolism, and the cellular response to amyloid-beta. Molecular docking results showed the highest binding affinity of dolutegravir for PI3KCD (-8.5 kcal/mol) and MTOR (-8.7 kcal/mol).
CONCLUSION: The findings indicated that dolutegravir holds significant potential in modulating key pathways involved in Alzheimer's disease pathogenesis. These results provide a strong foundation for further investigations into the therapeutic efficacy and safety of dolutegravir in the treatment of Alzheimer's disease. The use of drug repurposing strategies, leveraging Dolutegravir's established pharmacological profile, offers a promising route for accelerated therapeutic development in AD.}, }
@article {pmid40231522, year = {2025}, author = {Bianchini, MC and Franscescon, F and Soares, AA and Ansolin, V and Pretto, KP and Vieira da Cunha, ML and de Resende E Silva, DT}, title = {Potential Benefits of Quercetin through P2X7 Modulation against Neuroinflammation in Alzheimer's Disease.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X355614250130100132}, pmid = {40231522}, issn = {1875-6190}, abstract = {Alzheimer's disease is the leading cause of dementia worldwide. It belongs to the group of neurodegenerative ailments caused by the accumulation of extracellular β-amyloid plaques (Aβ) and intracellular neurofibrillary tau tangles, which damage brain tissue. One of the mechanisms proposed involves protein neurotoxicity and neuroinflammation through the purinergic system pathway. Several endogenous nucleotides, such as Adenosine 5'-triphosphate (ATP), are involved in cell signaling. High ATP levels can cause P2X7 receptor hyper-stimulation, resulting in an exacerbated inflammatory process and in apoptosis of cells. From this perspective, searching for new therapies becomes important to assist in the patient's treatment and quality of life. As a flavonoid with several properties, including anti-inflammatory activity, Quercetin may be an alternative to alleviate the damage and symptoms caused by Alzheimer's disease. Therefore, this review aims to examine the potential of Quercetin through P2X7 modulation against neuroinflammation in Alzheimer's disease, as it affects the P2X7 receptor by direct and indirect interactions, resulting in decreased inflammation levels. Therefore, we believe that Quercetin may have significant power in modulating the P2X7 receptor, demonstrating that the purinergic system has the potential to modulate neuroinflammation and can add to the treatment, reduce disease progression, and result in better prognoses. Furthermore, technological alternatives such as Quercetin micronization might improve its delivery to target tissues.}, }
@article {pmid40230933, year = {2024}, author = {Sujatha, DM and Shafy, SM and Francis, AA and Rajkumar, V and Jagdeesh, KD and Krishna, S and Pradeep, S and Gudapati, N}, title = {Neurologists' approaches and challenges in managing early-stage Alzheimer's disease: A survey of clinical practices.}, journal = {Bioinformation}, volume = {20}, number = {12}, pages = {1954-1958}, pmid = {40230933}, issn = {0973-2063}, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, requires early intervention to delay cognitive decline and enhance quality of life. This national survey of 100 neurologists explored their clinical practices in managing early-stage AD, including diagnostic approaches, treatment selection, patient counseling and perceived barriers. While neurologists acknowledged the importance of early intervention, challenges such as limited resources, time constraints and patient non-cooperation hindered optimal care. Variability in diagnostic and counseling practices often stemmed from disparities in resources and training. These findings highlight the need for revised guidelines, enhanced training and improved resources to support neurologists in providing consistent and effective early-stage AD care.}, }
@article {pmid40229578, year = {2025}, author = {Castro-Aldrete, L and Einsiedler, M and Novakova Martinkova, J and Depypere, H and Alvin Ang, TF and Mielke, MM and Sindi, S and Eyre, HA and Au, R and Schumacher Dimech, AM and Dé, A and Szoeke, C and Tartaglia, MC and Santuccione Chadha, A}, title = {Alzheimer disease seen through the lens of sex and gender.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {40229578}, issn = {1759-4766}, abstract = {Alzheimer disease (AD) is a life-limiting neurodegenerative disorder that disproportionately affects women. Indeed, sex and gender are emerging as crucial modifiers of diagnostic and therapeutic pathways in AD. This Review provides an overview of the interactions of sex and gender with important developments in AD and offers insights into priorities for future research to facilitate the development and implementation of personalized approaches in the shifting paradigm of AD care. In particular, this Review focuses on the influence of sex and gender on important advances in the treatment and diagnosis of AD, including disease-modifying therapies, fluid-based biomarkers, cognitive assessment tools and multidomain lifestyle interventional studies.}, }
@article {pmid40228446, year = {2025}, author = {Wang, Z and Zhang, HT and Li, SY and Song, XP and Shi, CZ and Zhang, YW and Han, F}, title = {An integrative study on the effects of Lingguizhugan decoction in treating Alzheimer's disease rats through modulation of multiple pathways involving various components.}, journal = {Computers in biology and medicine}, volume = {191}, number = {}, pages = {110149}, doi = {10.1016/j.compbiomed.2025.110149}, pmid = {40228446}, issn = {1879-0534}, abstract = {OBJECTIVE: To explore the active components and mechanisms of Lingguizhugan decoction (LGZGD) in the treatment of Alzheimer's disease (AD) through an integrated approach.
METHODS: The active components of LGZGD in rat serum were identified using HPLC-FTICR MS. Network pharmacology and molecular docking analyses were conducted, and their findings were validated using an Aβ1-42-induced AD rat model.
RESULTS: Twenty-four active components and 324 common targets were identified and used to construct the networks. KEGG pathway enrichment analysis linked key target genes with MAPK, Rap1, and NF-κB signaling pathways. Molecular docking results indicated that three key targets (IL-6, TNF, and EGFR) and 10 core components are closely associated with LGZGD in the treatment of AD. LGZGD improved the spatial learning and memory abilities of AD rats. LGZGD reduced neuronal damage and increased the number of neurons in the cortex and hippocampal CA1 region of AD rats. LGZGD decreased Aβ1-42 expression in the rat hippocampus, alleviated oxidative stress in AD rats, and decreased TNF-α, IL-6, IL-1β, and HMGB1 levels in the cerebral cortical tissue. LGZGD markedly decreased Iba-1 and iNOS expression and increased CD206 levels to inhibit M1 activation and promote M2 activation. LGZGD increased the expression of p-GSK-3β, ERK, and p-ERK, while decreasing the expression of p-Tau, IKKβ, p-IκBα, p-p65, p-p38, and p-JNK in the hippocampus of AD rats.
CONCLUSION: LGZGD treats AD by modulating targets like IL-6, TNF, MAPK3, and BCL2, thereby alleviating cognitive impairments in rats. Its neuroprotective effects in treating AD are mediated through the NF-κB/MAPK signaling pathways.}, }
@article {pmid40228423, year = {2025}, author = {Tang, C and Wang, J and Ge, M and Fu, L and Huang, J and Yadav, H and Shi, J and Feng, S and Wu, F}, title = {DSS-induced colitis exacerbates Alzheimer's pathology via neutrophil elastase and cathepsin B activation.}, journal = {International immunopharmacology}, volume = {155}, number = {}, pages = {114666}, doi = {10.1016/j.intimp.2025.114666}, pmid = {40228423}, issn = {1878-1705}, abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid plaques and neuroinflammation, which collectively result in cognitive decline. Peripheral inflammation, particularly intestinal inflammation, has been implicated in exacerbating AD pathology via the gut-brain axis. This study investigated the effects of dextran sulfate sodium (DSS)-induced colitis on amyloid-beta (Aβ) pathology, synaptic integrity, and cognitive function in 5xFAD mice, and explored the roles of neutrophil elastase (NE) and Cathepsin B in these processes. DSS-induced colitis significantly worsened Aβ pathology, evidenced by increased Aβ plaque deposition and elevated soluble Aβ1-42 levels in the brain of 5xFAD mice. The inflammatory state triggered extensive neutrophil infiltration and elevated NE levels in the hippocampus, which were closely associated with Cathepsin B activation. This enzymatic cascade is associated with synaptic damage and cognitive deficits. Treatment with the NE inhibitor Sivelestat effectively suppressed NE-mediated Cathepsin B activation, reduced Aβ pathology, restored dendritic spine density, and improved cognitive performance. Additionally, the Cathepsin B inhibitor CA-074 methyl ester (CA-074Me) mitigated the adverse effects of DSS-induced colitis, further emphasizing the role of Cathepsin B in mediating inflammation-driven AD pathology. These findings reveal that the NE-Cathepsin B axis links peripheral inflammation to exacerbated Aβ pathology, synaptic damage, and cognitive impairment, underscoring the potential of targeting NE and Cathepsin B as therapeutic strategies for inflammation-driven AD progression.}, }
@article {pmid40227985, year = {2025}, author = {Zhang, G and Ren, X and Zhou, B and Gu, W and Li, Y and Sun, YL and Ta, D and Liu, X}, title = {Two-Dimensional Super-Resolution Visualization of Rat Brain Microvasculature Using Ultrasound Localization Microscopy.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {217}, pages = {}, doi = {10.3791/67813}, pmid = {40227985}, issn = {1940-087X}, mesh = {Animals ; Rats ; *Microvessels/diagnostic imaging ; *Brain/blood supply/diagnostic imaging ; Microbubbles ; *Microscopy, Acoustic/methods ; Male ; Rats, Sprague-Dawley ; }, abstract = {The cerebral microvasculature forms a complex network of vessels essential for maintaining brain function. Diseases such as stroke, Alzheimer's disease, gliomas, and vascular dementia can profoundly disrupt the microvascular system. Unfortunately, current medical imaging modalities offer only indirect observations at this scale. Inspired by optical microscopy, ultrasound localization microscopy (ULM) overcomes the classical trade-off between penetration depth and spatial resolution. By localizing and tracking individual injected microbubbles (MBs) with sub-wavelength precision, vascular and velocity maps can be generated at the micrometer scale. Here, we present a robust protocol for super-resolution imaging of the brain microvasculature in vivo in rats using a commercial ultrasound platform. This method achieves 12.5 µm spatial resolution, reconstructing the microvascular architecture and providing detailed information on blood flow direction and velocity, greatly enhancing our understanding of cerebral microcirculation. The protocol can be extended to rat disease models, offering a powerful tool for the early diagnosis and treatment of neurovascular diseases.}, }
@article {pmid40227723, year = {2025}, author = {Zawar, I and Quigg, M and Johnson, EL and Ghosal, S and Manning, C and Kapur, J}, title = {Risk Factors Associated With Late-Onset Epilepsy in Dementia and Mild Cognitive Impairment.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2025.0552}, pmid = {40227723}, issn = {2168-6157}, abstract = {IMPORTANCE: The risk of developing epilepsy substantially increases after the age of 60 years (late-onset epilepsy [LOE]), particularly in people with cognitive decline ([PWCD] ie, dementia and/or mild cognitive impairment). Epilepsy is associated with worse cognitive and mortality outcomes in PWCD. Identifying PWCD at risk for developing LOE can facilitate early screening and treatment of epilepsy.
OBJECTIVE: To investigate factors associated with LOE in PWCD.
This longitudinal, multicenter study is based on participants from 39 US Alzheimer's Disease Research Centers from September 2005 through December 2021. Of 44 713 participants, 25 119 PWCD were identified. Of these, 14 685 were included who did not have epilepsy at enrollment, had 2 or more visits, and were 60 years or older at the most recent follow-up.
EXPOSURE: The association between various factors and LOE development in PWCD was investigated.
MAIN OUTCOMES AND MEASURES: The primary outcome was LOE, defined as seizures starting at or after 60 years of age. Those who did not develop LOE but were 60 years or older at follow-up served as controls. A multivariable Cox regression analysis assessed the association between various factors and LOE. Independent variables included age, sex, and socioeconomic factors (education, race, ethnicity), cardiovascular risks (hypertension, diabetes, hyperlipidemia), cerebrovascular disease (stroke or history of transient ischemic attack [TIA]), other neurologic comorbidities (Parkinson disease [PD], traumatic brain injury), cognition (age at dementia onset, dementia severity, type of dementia [Alzheimer disease (AD) vs non-AD]), genetics (apolipoprotein E4 [APOE4] status), lifestyle (alcohol misuse, smoking), and depression.
RESULTS: Of the 14 685 participants (7355 female [50%] and 7330 male [50%]; mean [SD] age, 73.8 [8.5] years) who met the inclusion criteria, 221 participants (1.5%) developed LOE during follow-up. After adjusting for demographics, cardiovascular risks, neurologic comorbidities, genetics, cognitive factors, and depression, the following were associated with a higher risk of developing LOE: APOE4 allele (adjusted hazard ratio [aHR], 1.39; 95% CI, 1.04-1.86; P = .03), dementia onset before age 60 years (aHR, 2.46; 95% CI, 1.53-3.95; P < .001), worse cognition (aHR, 2.35; 95% CI, 1.97-2.79; P < .001), AD dementia subtype (aHR, 1.68; 95% CI, 1.13-2.49; P = .01), stroke/TIA (aHR, 2.03; 95% CI, 1.37-3.01; P < .001), and PD (aHR, 2.53; 95% CI, 1.08-5.95; P = .03). In sensitivity analysis, using an alternative LOE definition of epilepsy onset after age 65 years revealed the same factors associated with LOE.
CONCLUSION AND RELEVANCE: This study showed that the APOE4 allele, dementia onset before age 60 years, AD dementia subtype, worse cognition, stroke/TIA, and PD are associated with LOE development in PWCD. PWCD with these risk factors may be considered for routine screening with an electroencephalogram for early identification of LOE.}, }
@article {pmid40227330, year = {2025}, author = {Banerjee, P and Wang, Y and Carnevale, LN and Patel, P and Raspur, CK and Tran, N and Zhang, X and Natarajan, R and Roberts, AJ and Baran, PS and Lipton, SA}, title = {diAcCA, a Pro-Drug for Carnosic Acid That Activates the Nrf2 Transcriptional Pathway, Shows Efficacy in the 5xFAD Transgenic Mouse Model of Alzheimer's Disease.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/antiox14030293}, pmid = {40227330}, issn = {2076-3921}, support = {U01 AG088679, R01 AG056259, R35 AG071734, RF1 AG057409, R01 AG056259, R56 AG065372, R01 DA048882, DP1 DA041722 , S10 OD030332/GF/NIH HHS/United States ; }, abstract = {The antioxidant/anti-inflammatory compound carnosic acid (CA) is a phenolic diterpene found in the herbs rosemary and sage. Upon activation, CA manifests electrophilic properties to stimulate the Nrf2 transcriptional pathway via reaction with Keap1. However, purified CA is readily oxidized and thus highly unstable. To develop CA as an Alzheimer's disease (AD) therapeutic, we synthesized pro-drug derivatives, among which the di-acetylated form (diAcCA) showed excellent drug-like properties. diAcCA converted to CA in the stomach prior to absorption into the bloodstream, and exhibited improved stability and bioavailability as well as comparable pharmacokinetics (PK) and efficacy to CA. To test the efficacy of diAcCA in AD transgenic mice, 5xFAD mice (or littermate controls) received the drug for 3 months, followed by behavioral and immunohistochemical studies. Notably, in addition to amyloid plaques and tau tangles, a hallmark of human AD is synapse loss, a major correlate to cognitive decline. The 5xFAD animals receiving diAcCA displayed synaptic rescue on immunohistochemical analysis accompanied by improved learning and memory in the water maze test. Treatment with diAcCA reduced astrocytic and microglial inflammation, amyloid plaque formation, and phospho-tau neuritic aggregates. In toxicity studies, diAcCA was as safe or safer than CA, which is listed by the FDA as "generally regarded as safe", indicating diAcCA is suitable for human clinical trials in AD.}, }
@article {pmid40226882, year = {2025}, author = {Zhao, YY and Lei, K and Liu, Y and Tan, Y and Ismail, N and Ridzuan Mohd Tajuddin, R and Liu, R and Huang, C and , }, title = {Single-Index Measurement Error Jump Regression Model in Alzheimer's Disease Studies.}, journal = {Statistics in medicine}, volume = {44}, number = {7}, pages = {e70081}, doi = {10.1002/sim.70081}, pmid = {40226882}, issn = {1097-0258}, support = {DMS-1953087//National Science Foundation/ ; 12071220//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; Regression Analysis ; Computer Simulation ; *Models, Statistical ; Neuroimaging/statistics & numerical data ; Aged ; Female ; Male ; }, abstract = {Alzheimer's disease (AD) is the major cause of dementia in the elderly, and investigations on the impact of risk factors on neurocognitive performance are crucial in preventative treatment. While existing statistical regression models, such as single-index models, have proven effective tools for uncovering the relationship between the neurocognitive scores and covariates of interest such as demographic information, clinical variables, and neuroimaging features, limited research has explored scenarios where jump discontinuities exist in the regression patterns and the covariates are unobservable but measured with errors, which are common in real applications. To address these challenges, we propose a single-index measurement error jump regression model (SMEJRM) that can handle both jump discontinuities and measurement errors in image covariates introduced by different image processing software. This development is motivated by data from 168 patients in the Alzheimer's Disease Neuroimaging Initiative. We establish both the estimation procedure and the corresponding asymptotic results. Simulation studies are conducted to evaluate the finite sample performance of our SMEJRM and the estimation procedure. The real application reveals that jump discontinuities do exist in the relationship between neurocognitive scores and some covariates of interest in this study.}, }
@article {pmid40226022, year = {2025}, author = {Wang, H and Lv, P}, title = {Safety and efficacy of rivastigmine and memantine combined for treatment of patients with Alzheimer's disease: a retrospective study.}, journal = {American journal of translational research}, volume = {17}, number = {3}, pages = {2240-2249}, pmid = {40226022}, issn = {1943-8141}, abstract = {OBJECTIVE: To assess the effects and safety of combining rivastigmine hydrogen tartrate capsules with memantine tablets for Alzheimer's disease (AD).
METHODS: A retrospective study was conducted on AD patients admitted to The Third People's Hospital of Yongkang from November 2021 to June 2023. There were two groups: a single drug group (n=21) given only memantine tablets, and a combination group (n=39) treated with both rivastigmine hydrogen tartrate capsules and memantine tablets. Data were collected, including age, gender, education, overall response rate, adverse reaction rate, mini-mental state examination (MMSE), activity of daily living (ADL), behavioral pathology in Alzheimer's disease scale (BEHAVE-AD), serum tumor necrosis factor-α (TNF-α), serum interleukin-6 (IL-6) and serum Tau at baseline and at week 12.
RESULTS: In both groups, compared to baseline, at week 12, MMSE increased, while ADL, BEHAVE-AD, serum TNF-α, IL-6, and Tau decreased (all P<0.05). After treatment, compared with the single drug group at week 12, the combination group had a higher MMSE (t=2.519, P=0.015), better effectiveness (χ[2]=4.331, P=0.037), and lower ADL (t=2.418, P=0.019), BEHAVE-AD (t=3.231, P=0.002), TNF-α (t=3.496, P=0.001), IL-6 (t=2.513, P=0.015) and Tau (t=2.290, P=0.026) levels.
CONCLUSION: The combination of the two drugs was more effective in alleviating AD symptoms with comparable safety. It also showed an edge in suppressing pro-inflammatory cytokines and Tau in AD.}, }
@article {pmid40225236, year = {2025}, author = {Teipel, S and Tang, Y and Khachaturian, A}, title = {Clinical efficacy of anti-amyloid antibodies in apolipoprotein E ε4 homozygotes: A Bayesian reanalysis of lecanemab and donanemab phase 3 results.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {2}, pages = {e70083}, pmid = {40225236}, issn = {2352-8737}, abstract = {INTRODUCTION: We aimed to determine the clinical efficacy of treating apolipoprotein E (ApoE) ε4 homozygotes with recently approved anti-amyloid antibodies.
METHODS: Data were derived from supplementary analyses in the regulatory studies Clarity (lecanemab) and TRAILBLAZER-ALZ2 (donanemab). We used Bayesian reanalysis with an independent t-statistic to determine evidence for or against an effect of antibody treatment on Clinical Dementia Rating scale Sum of Boxes (CDR-SB) in ApoE ε4 homozygotes, and a Bayesian random-effect meta-analysis to determine the effect size.
RESULTS: The Bayesian reanalysis showed moderate evidence of no effect for both antibodies. For donanemab and lecanemab, the odds of no difference in treatment effect were nearly three times greater than the odds of a difference. The meta-analysis revealed a small effect of -0.06 CDR-SB points in favor of treatment with a moderate heterogeneity estimate. The Bayes factor was 0.26, indicating that the absence of an effect was almost four times more likely than the presence of an effect.
DISCUSSION: The most likely explanation for our results is the lack of a treatment effect for lecanemab and donanemab in ApoE ε4 homozygotes. This could reflect inadequate exposure to the antibody due to more severe side effects, subsequent treatment interruptions, and lower dosing or a biologically driven lack of efficacy in a genetically determined disease. Our results support the view that excluding these cases from treatment is justifiable because of the higher risk of side effects and the lack of clinical efficacy.
HIGHLIGHTS: Lecanemab and donanemab were clinically ineffective in ApoE ε4 homozygotes.ApoE ε4 homozygotes should not receive these treatments due to inefficacy.Future trials should adopt Bayesian analysis strategies.Bayesian analysis provides evidence for or against treatment effects.Bayesian inference provides clinically interpretable results.}, }
@article {pmid40224553, year = {2025}, author = {Rissardo, JP and Caprara, ALF}, title = {Movement disorders associated with acetylcholinesterase inhibitors in Alzheimer's dementia: A systematic review.}, journal = {Brain circulation}, volume = {11}, number = {1}, pages = {9-23}, pmid = {40224553}, issn = {2455-4626}, abstract = {BACKGROUND: Acetylcholinesterase inhibitors (AChEIs) are widely used in Alzheimer's disease (AD). This study aims to systematically review the literature about movement disorders (MDs) associated with AChEIs for AD, which include donepezil, galantamine, rivastigmine, tacrine, and ipidacrine.
METHODOLOGY: Two reviewers conducted a comprehensive review of relevant studies across six databases, without language restrictions, covering publications from 1992 to 2024.
RESULTS: Overall, 74 studies containing 92 cases were found of MDs related to ACHEIs. The MDs found were Pisa syndrome in 33 patients, parkinsonism in 31, myoclonus in 11, dystonia in 10, dyskinesia in 6, and extrapyramidal symptoms in 1. Regarding the medications, the abnormal movements were associated with donepezil in 62 cases, rivastigmine in 15, galantamine in 10, and tacrine in 5. No case of ipidacrine-induced MD was found. Overall, the most commonly affected sex was the female, accounting for 61.9% of the cases. The mean and median age was 74.1 (standard deviation: 8.9) and 75 years (range: 49-93 years). The MD occurred within 6 months of the starting of AChEI in approximately 70% of the patients. Furthermore, the full recovery of the MD after the main management was noticed within 6 months in about 80% of the patients. About 86.3% of the individuals fully recovered after treatment, which included AChEI discontinuation, dose adjustment, and prescription of additional therapy.
CONCLUSIONS: The occurrence of tacrine-induced tremor indicated a potential predisposition to movement disorders associated with AChEI therapy. Based on the drug class side effect profile, it is possible that future studies may observe abnormal movements with other AChEIs.}, }
@article {pmid40224521, year = {2025}, author = {Hao, X and Ding, N and Zhang, Y and Wu, M and Tao, Y and Li, Z}, title = {Acupuncture Ameliorates Alzheimer's-Like Cognitive Impairment and Pathological Changes via Regulating the Intestinal Fungal Community in APP/PS1 Mice.}, journal = {Neuropsychiatric disease and treatment}, volume = {21}, number = {}, pages = {799-813}, pmid = {40224521}, issn = {1176-6328}, abstract = {BACKGROUND: The disorder of the intestinal fungal community is closely associated with Alzheimer's disease (AD). Gut fungal dysbiosis exacerbates β-amyloid (Aβ) plaque burden through the brain-gut axis, thereby promoting the progression of AD. Previous research has demonstrated that acupuncture can ameliorate AD symptoms by modulating the gut bacterial community. However, the potential regulatory effects of acupuncture on the fungal microbiota have been largely overlooked.
METHODS: APP/PS1 mice were used as AD animal model and randomly divided into the AD model (AD) group, the acupuncture (Ac) group, and the probiotics (Pr) group. Mice in the Ac group received acupuncture treatment. In the Pr group, mice were treated with probiotics. Morris water maze, ITS sequencing, immunofluorescence (IF) staining, enzyme-linked immunosorbent assay (ELISA), Hematoxylin and eosin analysis, and Nissl staining were employed to validate our hypothesis.
RESULTS: Acupuncture and probiotics significantly improved the behavioral performance of APP/PS1 mice, reduced the level of Aβ in the brain, and alleviated neuronal damage. Moreover, acupuncture improved the Sobs, Chao and Ace indices, decreased the abundance of Ascomycota, Aspergilaceae, Trichocomaceae, Candida, and unclassified-penicillium, while simultaneously increasing the abundance of Basidiomycota, which differed from the fungal regulation observed with probiotics.
CONCLUSION: Acupuncture may improve the cognitive impairment of APP/PS1 mice, reduce Aβ plaque burden in the brain, protect neurons, and mitigate intestinal fungi dysbiosis. The beneficial effects of acupuncture on Aβ deposition and cognitive function in APP/PS1 mice may be achieved by regulating the intestinal fungal community.}, }
@article {pmid40223913, year = {2025}, author = {Alenezi, HFF and Naguy, A}, title = {Incretin Mimetics (GLP-1 Agonists) as an Addition to the Psychopharmacology Armamentarium.}, journal = {Psychopharmacology bulletin}, volume = {55}, number = {3}, pages = {26-30}, pmid = {40223913}, issn = {2472-2448}, mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Incretins/therapeutic use ; *Mental Disorders/drug therapy ; *Substance-Related Disorders/drug therapy ; Animals ; *Glucagon-Like Peptide 1/agonists ; }, abstract = {The exploration of GLP-1 receptor agonists as pleiotropic agents in the treatment of neuropsychiatric disorders and substance use disorders is a rapidly evolving field. While early studies have shown promising results, much of the research is still nascent, and larger clinical trials are definitely needed to confirm the safety and efficacy of these agents on real grounds.}, }
@article {pmid40223238, year = {2025}, author = {Swain, S and Metya, AK}, title = {Exploring Metformin's Therapeutic Potential for Alzheimer's Disease: An In-Silico Perspective Using Well-Tempered Funnel Metadynamics.}, journal = {Journal of chemical information and modeling}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jcim.5c00106}, pmid = {40223238}, issn = {1549-960X}, abstract = {Alzheimer's disease (AD), often referred to as the "diabetes of the brain", is intricately linked to insulin resistance. Metformin, a first-line antidiabetic drug, has been anticipated as a potential treatment for AD and is currently undergoing phase 3 clinical trials. The potential success of metformin in treating AD could herald a new era in the management of this debilitating disease, providing hope for millions of people affected worldwide. Despite this fact, the precise molecular mechanisms underlying the therapeutic effects of metformin on AD remain poorly understood. To pursue this, in this present work, we implement a comprehensive computational approach combining classical molecular dynamics (MD) simulations and the advanced enhanced sampling technique funnel metadynamics (FM) to explore the dynamics and affinity of metformin and acetylcholinesterase (AChE), a novel target for AD. The MD and FM simulations suggest that metformin induces significant configurational changes within the AChE, resulting in weak and nonspecific binding. Furthermore, the presence of metformin alters the conformational landscape of AChE causing the emergence of metastable states and less rigid binding patterns. The binding energies for the metformin-AChE complex are -4.89 ± 1.2 kcal/mol and -1.68 ± 0.2 kcal/mol, as estimated through the molecular mechanics Poisson-Boltzmann surface area (MMPBSA) and FM approaches, respectively. To elucidate the binding energy relevance calculated by MMPBSA and FM approach with experimental inhibitory potency, ΔGexp is calculated using IC50 value reported in prior experimental studies. ΔGexp is estimated to be -3.59 kcal/mol. A comparison of these binding energy values with different methods highlights the moderate inhibitory potency of metformin toward AChE. This work provides molecular-level insights emphasizing the dynamic configurational changes induced by metformin within AChE and underscores its translational potential in the repurposing of AD.}, }
@article {pmid40222965, year = {2025}, author = {Wu, M and Chen, YF and Yao, W and Zhou, S and Xie, Z and Tao, Y and Zhong, Y and Ma, W}, title = {The anti-inflammatory drug Montelukast ameliorates cognitive deficits by rescuing the inflammatory levels in young AD animal models.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {12720}, pmid = {40222965}, issn = {2045-2322}, support = {Z191100007619006//Beijing Municipal Science and Technology Commission/ ; 2022ZD0204900//STI2030-Major Projects/ ; 32021002//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Sulfides/pharmacology ; *Cyclopropanes/pharmacology ; Mice ; Disease Models, Animal ; *Quinolines/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Acetates/pharmacology/therapeutic use ; *Cognitive Dysfunction/drug therapy ; Cytokines/metabolism ; Mice, Transgenic ; Inflammation/drug therapy ; }, abstract = {Neuroinflammation precedes the clinical symptoms onset of Alzheimer's disease (AD) by decades. However, the anti-inflammatory drugs were not always effective at all stages of the disease. Here, using the fly and mouse AD models, we evaluated the effects of anti-inflammatory drugs on inflammatory-related factors and the proinflammatory cytokines at different ages of AD animals. We also performed behavioral tests to evaluate the cognitive aspects of AD. Combined with the bioinformatics analysis, we would like to exhibit a better understanding of AD. Based on the previous studies and reanalysis of published database, we found aged AD animals might better represent the inflammatory status of symptomatic AD. Our results showed that mRNA levels of antimicrobial peptides (AMPs) were highly expressed in 10-day-old AD flies, while no significant difference was observed in 40-day-old AD. In aged APP/PS1 mice (22.5 months), inflammatory-related factors NF-κB, IBA1, and the mRNA levels of proinflammatory cytokines Il-1β and Il-6 were not differentially expressed. In contrast, a significant increase was observed in 7.5-month-old APP/PS1 mice. Moreover, the anti-inflammatory drug Montelukast (MON) did not ameliorate the inflammatory and cognitive defects in 22.5-month-old aged mice but showed a rescue effect in 7.5-month-old young APP/PS1 mice. Altogether, our study demonstrates the different inflammatory status might lead to variations of anti-inflammatory drug efficacy, which helps to clarify the importance of considering the pathological stage of the disease when administering treatment.}, }
@article {pmid40222695, year = {2025}, author = {Yuan, J and Huang, R and Nao, J and Dong, X}, title = {The Role of Semaphorin 3A in the Pathogenesis and Progression of Alzheimer's Disease and Other Aging-Related Diseases: A Comprehensive Review.}, journal = {Pharmacological research}, volume = {}, number = {}, pages = {107732}, doi = {10.1016/j.phrs.2025.107732}, pmid = {40222695}, issn = {1096-1186}, abstract = {Aging serves as a pivotal factor in the etiology of numerous diseases, such as Alzheimer's disease (AD), Parkinson's disease, diabetes, osteoarthritis, atherosclerosis and aging-related macular degeneration. Notably, these diseases often interact with AD through various pathways, facilitating the onset or progression of one another. Semaphorin 3A (Sema3A), a protein that is essential for axonal guidance during neural development, has recently been identified as a novel regulator in the pathogenesis and progression of multiple aging-related diseases. This article provides a comprehensive review of the expression patterns and mechanisms of action of Sema3A in these diseases. Specifically, Sema3A influences the occurrence and development of aging-related diseases by participating in oxidative stress, inflammatory responses, apoptosis, and synaptic plasticity. Therefore, therapeutic strategies targeting Sema3A present promising avenues for delaying the progression of aging-related diseases and offer novel insights and strategies for their treatment.}, }
@article {pmid40222459, year = {2025}, author = {Turton, SM and Padgett, S and Maisel, MT and Johnson, CE and Buzinova, VA and Barth, SE and Kohler, K and Spearman, HM and Macheda, T and Manauis, EC and Guo, LZ and Whitlock, HR and Bachstetter, AD and Sunderam, S and O'Hara, BF and Duncan, MJ and Murphy, MP}, title = {Interactions between daily sleep-wake rhythms, γ-secretase, and amyloid-β peptide pathology point to complex underlying relationships.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {}, number = {}, pages = {167840}, doi = {10.1016/j.bbadis.2025.167840}, pmid = {40222459}, issn = {1879-260X}, abstract = {Disrupted or insufficient sleep is a well-documented risk factor for Alzheimer's disease (AD) and related dementias. Previous studies in our lab and others have shown that chronic fragmentation of the daily sleep-wake rhythm in mice can accelerate the development of AD-related neuropathology in the brain, including increases in the levels of amyloid-β (Aβ). Although sleep is known to increase clearance of Aβ via the glymphatic system, little is known about the effect of sleep on Aβ production and the role this might play in amyloid deposition. To examine the relationship of Aβ production and its interaction with sleep and sleep dysfunction, we treated mice from an APP × PS1 mutant knock-in line (APP[ΔNLh/ΔNLh] × PS1[P264L/P264L]) with an inhibitor of γ-secretase (LY-450,139; Semagacestat®) during a protocol of mild sleep fragmentation (SF). Compared to the male mice, the female mice slept less, and had more Aβ pathology. Semagacestat treatment reduced Aβ, but only in the most soluble extractable fraction. Although the female mice showed an increase in the amount of Aβ following SF, this effect was blocked by Semagacestat, an effect that was not seen in the male mice. SF also led to a significant, sex-dependent changes in the relative amounts of C-terminal fragments of the amyloid precursor protein, the immediate substrate of the γ-secretase enzyme. These findings indicate that the relationship between disruption of the daily sleep-wake rhythm and the development of AD-related pathology is complex, and may involve unappreciated interactions with biological sex. Consideration of these factors is necessary for a better understanding of AD risk, especially the elevated risk in women.}, }
@article {pmid40222458, year = {2025}, author = {Pradeepkiran, JA and Kshirsagar, S and Alvir, RV and Motakatla, PI and Reddy, PH}, title = {Small molecule DDQ involvement of ERK-mediated signaling pathway with enhanced mitophagy in HT22 cells transfected with mTau.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {}, number = {}, pages = {167850}, doi = {10.1016/j.bbadis.2025.167850}, pmid = {40222458}, issn = {1879-260X}, abstract = {Tau hyperphosphorylation was the initial recognized pathogenic tau protein post-translational modification in Alzheimer's disease. In our present research, treatment of diethyl (3,4-dihydroxy phenethylamine) (quinolin-4-yl) methylphosphonate (DDQ) HT22 cells with mTau transfected HT22 cells decreased the phosphorylation of tau at Tau5, p-ERK, and increased LC3B, and TOM20 as detected by Western blots. Moreover, DDQ p-tau and p-ERK inhibition of phosphorylation also contributed to significant mitochondrial protection in the presence of mTau. Taken together, for the first time, we found that DDQ is involved in phosphorylation inhibition to restore the mitophagy, which may relate to the Sirt3 activation of the ERK-CREB mediated pathway.}, }
@article {pmid40222353, year = {2025}, author = {Felbecker, A and Rouaud, O and Lathuilliere, A and Allali, G and Sollberger, M and Meyer-Heim, T and Monsch, AU and Lövblad, KO and Becker, S and Barro-Belaygues, N and Popp, J and Bürge, M and Lindheimer, K and Gietl, A and Jung, HH and Georgescu, D and Meyer, R and Frisoni, GB}, title = {Anti-amyloid monoclonal antibodies for the treatment of Alzheimer disease: Intersocietal recommendations for their appropriate use in Switzerland.}, journal = {Neuro-degenerative diseases}, volume = {}, number = {}, pages = {}, doi = {10.1159/000545799}, pmid = {40222353}, issn = {1660-2862}, abstract = {The association of Swiss Memory Clinics (SMC) provides intersocietal recommendations for the use of anti-amyloid monoclonal antibodies (mAbs) in Switzerland. The recommendations are the result of extensive interdisciplinary discussions in a group of Swiss dementia experts from August 2023 until December 2024. They reflect the opinion of all societies involved in diagnosis and treatment of dementia patients in Switzerland. Special emphasis is given to aspects that are specific to the Swiss landscape, including recommendations for infrastructural and personnel standards for institutions aiming to administer anti-amyloid mAbs in Switzerland.}, }
@article {pmid40221538, year = {2025}, author = {Wang, Y and Li, P and Liang, Y and Wang, D}, title = {ANO6 Targets TMEM30A to Regulate Endoplasmic Reticulum Stress-Induced Lipid Peroxidation and Ferroptosis in Alzheimer's Cells.}, journal = {Cell biochemistry and biophysics}, volume = {}, number = {}, pages = {}, pmid = {40221538}, issn = {1559-0283}, support = {20230303070456//Project of Scientific Research of Heilongjiang Provincial Health and Wellness Commission/ ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder, and the role of ANO6 in its progression remains largely unexplored. GSE118553 database was analyzed for ANO6 expression in AD. A total of 1 μmol/L Aβ1-42 treated SH-SY5Y cells were constructed as a cell model of AD. qRT-PCR and ELISA were used to detect the expression of ANO6, GPX4, ATF6, GRP78, IREIα expression and lipid peroxidation level. Endoplasmic reticulum(ER) stress was induced by using clindamycin and lipid peroxidation indicators were detected. ANO6 was concurrently regulated in ER stress induced by clindamycin treatment. The STRING-DB database was utilized to predict potential target molecules of ANO6, while Western blot analysis was conducted to detect the expression levels of TMEM30A and evaluate the impact of ANO6-targeted TMEM30A on the protein levels within the PERK-eIF2α-ATF4-CHOP pathway. ANO6 was highly expressed in AD model, Aβ1-42 induced ANO6 enrichment in SH-SY5Y cells. ANO6 interference increased the proliferation level of AD model cells, decreased the levels of GPX4, an indicator of ferroptosis, and lipid peroxidation, and down-regulated the expression of the ER stress-related proteins ATF6, GRP78, and IREIα. Clotrimazole-induced ER stress in AD model cells showed elevated expression of ANO6. ANO6 could target and inhibit TMEM30A to affect PERK-eIF2α-ATF4-CHOP pathway activity, regulate ER stress-dependent ferroptosis, and reduce neuronal loss injury. ANO6 can target inhibition of TMEM30A affecting PERK- IF2α- ATF4- CHOP pathway activity, modulate ER stress-dependent ferroptosis-induced AD progression to reduce neuronal loss injury.}, }
@article {pmid40221434, year = {2025}, author = {Fanelli, G and Franke, B and Fabbri, C and Werme, J and Erdogan, I and De Witte, W and Poelmans, G and Ruisch, IH and Reus, LM and van Gils, V and Jansen, WJ and Vos, SJB and Alam, KA and Martinez, A and Haavik, J and Wimberley, T and Dalsgaard, S and Fóthi, Á and Barta, C and Fernandez-Aranda, F and Jimenez-Murcia, S and Berkel, S and Matura, S and Salas-Salvadó, J and Arenella, M and Serretti, A and Mota, NR and Bralten, J}, title = {Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {145}, pmid = {40221434}, issn = {2158-3188}, mesh = {Humans ; *Insulin Resistance/genetics ; Genome-Wide Association Study ; *Diabetes Mellitus, Type 2/genetics ; *Metabolic Syndrome/genetics ; *Obesity/genetics ; Quantitative Trait Loci ; *Mental Disorders/genetics ; Phenotype ; Genetic Predisposition to Disease ; }, abstract = {The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a major public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N = 9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg| = 0.21-1, pFDR < 0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer's disease, bipolar disorder, and Tourette's syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings highlight the complex genetic architecture of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.}, }
@article {pmid40221303, year = {2025}, author = {Kargar, A and Fetratjoo, DH and Moattar, R and Tarki, A and Golsokhan, A and Pouyan, N and Amjadi-Goojgi, Z and Mostafaei, H and Kakeri, F and Zendehbad, AS and Lima, BS and Esmaily, H and Noroozian, M}, title = {Efficacy of Add-On Agomelatine on Agitation, Aggression, and Neuroprotection in Alzheimer's Disease: A Randomized, Blinded, Controlled Trial.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jagp.2025.03.001}, pmid = {40221303}, issn = {1545-7214}, abstract = {BACKGROUND: Agitation and aggression are challenging behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD), which is diagnosed based on NINCDS-ADRDA criteria. Limited efficacy and safety of existing pharmacotherapies complicate treatment. Agomelatine, a melatonergic agonist and serotonergic antagonist, may provide a safer and more effective alternative.
OBJECTIVES: The primary outcome is to evaluate the efficacy of agomelatine as an add-on therapy to nonpharmacological treatment in reducing agitation and aggression in patients with AD, with secondary outcomes assessing its safety and potential neuroprotective effects.
METHODS: In a randomized, triple-blind, placebo-controlled trial, 56 patients with AD (aged ≥65) experiencing agitation and aggression received 12.5 mg agomelatine (n = 28) or placebo (n = 28) daily for 6 weeks. The primary outcome was the Cohen-Mansfield Agitation Inventory (CMAI) score change. Secondary outcomes included serum brain-derived neurotrophic factor (BDNF) levels and safety.
RESULTS: At 6 weeks, the agomelatine group showed a greater reduction in CMAI scores than placebo (mean difference: -12.39, 95% CI: -19.37 to -5.42; p = 0.001). No significant BDNF changes were detected (p = 0.848). Total adverse events (AEs) were more common in the agomelatine group (50.0% vs. 21.4%, p = 0.050), but no serious AEs or liver enzyme abnormalities were reported.
CONCLUSION: A daily dose of 12.5 mg agomelatine may effectively and safely reduce agitation and aggression in patients with AD when used as an add-on therapy. However, further studies with larger samples and extended durations are needed to definitively confirm agomelatine's role in managing BPSD in AD.}, }
@article {pmid40220956, year = {2025}, author = {Han, HJ and Kim, H and Kim, DJ}, title = {Systematic review for VNS vs. Pharmaceutical modulations for multifaceted neurological disorder management through cross-case, network meta-analysis.}, journal = {Brain stimulation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.brs.2025.04.007}, pmid = {40220956}, issn = {1876-4754}, abstract = {BACKGROUND: As an adjunct or alternative to conventional pharmacotherapy, vagus nerve stimulation (VNS) which is FDA-approved has arisen as a novel means for various neurological disorders.
METHOD: We searched multiple databases (through 2024) for randomised trials and observational studies of VNS (invasive and transcutaneous) and pharmacological treatments (e.g. cholinergic agents, antiepileptics, antidepressants) across several neurological disorders. Prior to comparing between VNS and pharmacological treatments, subgroup analyses of VNS studies were performed for disorder type, patient demographics, VNS stimulation parameters, and treatment duration to illustrate whether VNS itself can be effective to a satisfactory extent to be compared against the conventional method. Efficacy and adverse effects were evaluated, based on the proportion of patients achieving more than 50% symptom reduction or equivalent clinical improvement, or all-cause mortality where applicable. Evaluation between VNS and pharmacological treatments was performed through network meta-analysis, followed by assessment of heterogeneity (I[2]) and meta-regression. Risk of bias was evaluated with Cochrane criteria, and all studies (including those with high risk of bias) were included in the primary analysis (with sensitivity analyses excluding high-bias studies).
RESULTS: We included 56 VNS-related studies (n = 5773 participants) and 29 pharmacological drug-based studies (n = 14827 participants) from spanning epilepsy, depression, migraine/headache, Alzheimer's disease, inflammatory disorders, and heart failure. A network meta-analysis directly comparing VNS to pharmacological drugs yielded an overall advantage for VNS (summary SMD = 0.27 favouring VNS, 95% CI 0.19-0.35). However, the high heterogeneity and risk of bias have been assessed, indicating potential issues with the VNS studies.
CONCLUSION: Overall, VNS was shown to be a viable therapeutic modality across diverse neurological disorders, superior to standard pharmacological treatments with a distinct adverse effect profile. It appears particularly beneficial in conditions where conventional drugs have limited success (e.g. refractory epilepsy, depression), although patient-specific factors influence outcomes. Further high-quality trials are anticipated to optimise stimulation parameters, confirm long-term benefits, and manage patient selection for VNS.}, }
@article {pmid40220916, year = {2025}, author = {Shi, J and Zhang, M and Hu, Y and Liu, J and Li, K and Sun, X and Chen, S and Liu, J and Ye, L and Fan, J and Jia, J}, title = {Differences in transcriptome characteristics and drug repositioning of Alzheimer's disease according to sex.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106909}, doi = {10.1016/j.nbd.2025.106909}, pmid = {40220916}, issn = {1095-953X}, abstract = {BACKGROUND: Previous studies have shown significant sex differences in AD with regarding its epidemiology, pathophysiology, clinical presentation, and treatment response. However, the transcriptome variances associated with sex in AD remain unclear.
METHODS: RNA sequencing (RNA-seq) and transcriptomic analyses were performed on peripheral blood samples from total of 54 patients, including male AD patients (n = 15), female AD patients (n = 10), male MCI patients (n = 7), female MCI patients (n = 11), male healthy controls (n = 6), female healthy controls (n = 5). The snRNA-seq dataset (GSE167494, GSE157827) of prefrontal cortex tissues was obtained from the Gene Expression Omnibus (GEO). We conducted an investigation into differentially expressed genes and pathways in the peripheral blood cells as well as prefrontal cortex tissues of both male and female AD patients with consideration to sex-related factors. Additionally, we analyzed the distribution and characteristics of cells in the cerebral cortex as well as the interaction and communication between cells of male and female AD patients. Connectivity Map (CMap) was utilized for predicting and screening potential sex-specific drugs for AD.
RESULTS: The transcriptome profile and associated biological processes in the peripheral blood of male and female AD and MCI patients exhibit discernible differences, including upregulation of BASP1 in AD male patients and arousing TNS1 in AD female patients. The distribution of various cell types in the prefrontal cortex tissues differs between male and female AD patients, like neuron and oligodendrocyte decreased and endothelial cell and astrocyte increased in female compared with male, while a multitude of genes exhibit significant differential expression. The results of cell communication analysis, such as collagen signaling pathway, suggest that sex disparities impact intercellular interactions within prefrontal cortex tissues among individuals with AD. By drug repositioning, several drugs, including torin-2 and YM-298198, might have the potential to therapeutic value of MCI or AD, while drugs like homoharringtonine and teniposide have potential opposite effects in different sexes.
CONCLUSION: The characteristics of the transcriptome in peripheral blood and single-cell transcriptome in the prefrontal cortex exhibit significant differences between male and female patients with AD, which providing a basis for future sex stratified treatment of AD.}, }
@article {pmid40220824, year = {2025}, author = {Xu, C and Xu, E and Xiao, Y and Yang, D and Wu, G and Chen, M}, title = {A multiscale model to explain the spatiotemporal progression of amyloid beta and tau pathology in Alzheimer's disease.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {142887}, doi = {10.1016/j.ijbiomac.2025.142887}, pmid = {40220824}, issn = {1879-0003}, abstract = {Amyloid-beta (Aβ) and tubulin-associated unit (tau) proteins are key biomarkers of Alzheimer's disease (AD), detectable by Positron Emission Tomography (PET) imaging and Cerebrospinal Fluid (CSF) assays. They reflect insoluble fibrils in the brain and soluble monomers in the cerebrospinal fluid, respectively. PET and CSF biomarkers have been utilized in diagnosing AD; however, their incomplete agreement significantly confounds the early detection. Additionally, the molecular mechanisms underlying the dynamics of AD biomarkers remain elusive and are yet to be quantitatively revealed. To answer these questions, we develop a multiscale mathematical model that characterizes various forms of AD biomarkers, including soluble molecules in cerebrospinal fluid, diffusive biomarkers across brain regions, and insoluble fibrils in the brain. Mathematical modeling of soluble and insoluble molecules enables the explanation of the asynchronous trajectory of AD biomarkers. Our model captures the spatiotemporal dynamics of Aβ and tau with neurodegeneration in AD. Simulation results demonstrate that the PET-CSF discordance is a typical stage in the natural history of protein aggregation, with CSF becoming abnormal before the onset of PET abnormality. Furthermore, correlation analysis reveals that neurodegeneration is more strongly associated with tau-PET than Aβ-PET. These findings suggest CSF Aβ is recognized as a biomarker at the early stage of AD, while tau-PET is more suitable for neurodegeneration assessment. The proposed multiscale model explains the underlying neurobiological factors contributing to neurodegeneration and offers a valuable tool for improving early detection and treatment strategies in clinical trials.}, }
@article {pmid40220719, year = {2025}, author = {He, Y and He, MH and Jin, T and Siju-Li, and Wang, HQ and He, F}, title = {Tangeretin protects against Aβ1-42-induced toxicity and exploring mitochondria-lysosome interactions in HT22 cells.}, journal = {Biochemical and biophysical research communications}, volume = {762}, number = {}, pages = {151769}, doi = {10.1016/j.bbrc.2025.151769}, pmid = {40220719}, issn = {1090-2104}, abstract = {Tangeretin, a flavonoid from Citri Reticulatae Pericarpium, is known for its neuroprotective effects, but the mechanisms are not fully understood. Alzheimer's disease, a leading neurodegenerative disorder, characterized by amyloid-beta (Aβ) accumulation, represents a significant therapeutic challenge. This study investigates the protective effects of tangeretin against Aβ1-42-induced neurotoxicity using HT22 cells and zebrafish larvae as experimental models. Tangeretin mitigated Aβ1-42-induced cytotoxicity, as evidenced by enhanced cell viability and reduced apoptosis. Tangeretin treatment mitigated Aβ1-42-induced cytotoxicity in HT22 cells, as evidenced by enhanced cell viability and reduced apoptosis. Mechanistically, tangeretin ameliorated mitochondrial dysfunction by reducing mitochondrial fragmentation, decreasing donut-shaped mitochondria, restoring mitochondrial membrane potential, and attenuating reactive oxygen species (ROS) production. Moreover, tangeretin modulated mitochondria-lysosome interactions by promoting mitophagy and normalizing the prolonged mitochondria-lysosome contact induced by Aβ1-42. In zebrafish larvae, Aβ1-42 exposure resulted in developmental malformations, including pericardial and yolk sac edema, elevated ROS levels, increased apoptosis, and impaired neurodevelopment. Tangeretin effectively counteracted these deficits, as revealed by live imaging, supporting its neuroprotective role observed in cellular models. Collectively, our study suggests that tangeretin may serve as a promising protective agent against Aβ1-42-induced neurotoxicity.}, }
@article {pmid40220014, year = {2025}, author = {Akgul, YSS and Gultekin, M and Demirel Ozsoy, S}, title = {Electroconvulsive therapy ameliorates treatment-resistant depression in patient with Lewy body dementia.}, journal = {Neurocase}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/13554794.2025.2490785}, pmid = {40220014}, issn = {1465-3656}, abstract = {Lewy body dementia (LBD), the second most common degenerative dementia after Alzheimer's disease, is frequently associated with neuropsychiatric symptoms such as depression, anxiety, and apathy. These symptoms may precede cognitive decline, often resulting in misdiagnosis and inappropriate treatment. Electroconvulsive therapy (ECT) has emerged as a promising option for treatment-resistant depression in LBD. This report describes a 68-year-old female patient with LBD who received multiple ECT sessions for persistent severe depression and suicidal ideation. ECT led to marked symptom improvement across several hospitalizations. This case underscores the diagnostic and therapeutic challenges of neuropsychiatric symptoms in LBD and highlights ECT as a potential alternative when pharmacotherapy is inadequate. Early identification of LBD in patients with late-onset depression is essential to guide individualized treatment strategies.}, }
@article {pmid40219025, year = {2025}, author = {Shabbir, I and Liu, K and Riaz, B and Rahim, MF and Zhong, S and Aweya, JJ and Cheong, KL}, title = {Investigating the Therapeutic Potential of the Ketogenic Diet in Modulating Neurodegenerative Pathophysiology: An Interdisciplinary Approach.}, journal = {Nutrients}, volume = {17}, number = {7}, pages = {}, doi = {10.3390/nu17071268}, pmid = {40219025}, issn = {2072-6643}, mesh = {*Diet, Ketogenic/methods ; Humans ; *Neurodegenerative Diseases/diet therapy/physiopathology ; Ketone Bodies/metabolism ; Ketosis ; Animals ; 3-Hydroxybutyric Acid/metabolism ; Oxidative Stress ; }, abstract = {The ketogenic diet (KD) is a dietary intervention comprising a high-fat, low-carbohydrate, and moderate-protein intake designed to induce a metabolic state known as ketosis, whereby ketone bodies are produced as an alternative source of energy. Initially established as a treatment for intractable epilepsy, the KD has subsequently gained significant attention for its potential to manage neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's disease. Ketone bodies, such as beta-hydroxybutyrate (BHB), have been demonstrated to possess neuroprotective properties. The increasing prevalence of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's disease, poses a significant public health challenge worldwide. With neurological disorders being the second-leading cause of death globally, the need for effective therapeutic interventions has never been more urgent. Recent evidence suggests that dietary interventions, particularly the ketogenic diet, offer promising potential in mitigating the progression of these diseases by influencing metabolic processes and providing neuroprotective benefits. The ketogenic diet, characterized by high-fat and low-carbohydrate intake, induces ketosis, leading to the production of ketone bodies like beta-hydroxybutyrate, which enhance mitochondrial efficiency, reduce oxidative stress, and modulate inflammatory pathways-mechanisms critical in neurodegenerative pathophysiology. This review explores the role of the ketogenic diet in managing neurological conditions, examining its mechanisms of action, historical context, and therapeutic efficacy. The paper also discusses emerging evidence linking the ketogenic diet to improved cognitive function, reduced motor symptoms, and enhanced mitochondrial activity in patients with neurodegenerative disorders. Additionally, the review highlights the need for further research to refine the therapeutic applications of the ketogenic diet, investigate its impact on various neurodegenerative diseases, and better understand its potential long-term effects. This study underscores the importance of nutrition as a vital aspect of the treatment strategy for neurological diseases, advocating for continued exploration of dietary interventions to improve brain health and function.}, }
@article {pmid40218960, year = {2025}, author = {Yavari, M and Kalupahana, NS and Harris, BN and Ramalingam, L and Zu, Y and Kahathuduwa, CN and Moustaid-Moussa, N}, title = {Mechanisms Linking Obesity, Insulin Resistance, and Alzheimer's Disease: Effects of Polyphenols and Omega-3 Polyunsaturated Fatty Acids.}, journal = {Nutrients}, volume = {17}, number = {7}, pages = {}, doi = {10.3390/nu17071203}, pmid = {40218960}, issn = {2072-6643}, support = {R15AT008879-01A1S1/GF/NIH HHS/United States ; R15 AT008879-01A1S1/GF/NIH HHS/United States ; }, mesh = {*Alzheimer Disease/drug therapy/etiology/metabolism ; Humans ; *Insulin Resistance ; *Polyphenols/pharmacology/therapeutic use ; *Fatty Acids, Omega-3/pharmacology/therapeutic use ; *Obesity/complications/drug therapy ; Animals ; Amyloid beta-Peptides/metabolism ; Diabetes Mellitus, Type 2/complications ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and behavioral changes. It poses a significant global health challenge. AD is associated with the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain, along with chronic inflammation, dysfunctional neurons, and synapse loss. While the prevalence of AD continues to rise, the current FDA-approved drugs offer only limited effectiveness. Emerging evidence suggests that obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM) are also implicated in AD pathogenesis, with epidemiological studies and animal models confirming the impact of IR on Aβ accumulation, and high-fat diets also exacerbating Aβ accumulation. Since neuroinflammation activated by Aβ involves the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) pathway, the inhibition of NF-κB and NLRP3 inflammasome activation are potential therapeutic strategies in AD. Bioactive compounds, including polyphenols (resveratrol, epigallocatechin-3-gallate, curcumin, and quercetin), and omega-3 polyunsaturated fatty acids, show promising results in animal studies and clinical trials for reducing Aβ levels, improving cognition and modulating the signaling pathways implicated in AD. This review explores the interplay between obesity, IR, inflammation, and AD pathology, emphasizing the potential of dietary compounds and their role in reducing inflammation, oxidative stress, and cognitive decline, as viable strategies for AD prevention and treatment. By integrating epidemiological findings, observational studies, and clinical trials, this review aims to provide a comprehensive understating of how metabolic dysfunctions and bioactive compounds influence AD progression.}, }
@article {pmid40216249, year = {2025}, author = {Mitchell, CL and Matveyenka, M and Kurouski, D}, title = {Neuroprotective Properties of Transition Metal Dichalcogenide Nanoflowers Alleviate Acute and Chronic Neurological Conditions Linked to Mitochondrial Dysfunction.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {108498}, doi = {10.1016/j.jbc.2025.108498}, pmid = {40216249}, issn = {1083-351X}, abstract = {Mitochondrial dysfunction is an expected cause of etiology and progression in numerous human neurological pathologies, including stroke, Alzheimer's, and Parkinson's diseases. Therefore, a neuroprotective treatment is an urgent and unmet need. Transition metal dichalcogenide nanoflowers (TMD NFs) exhibit unique biological properties. However, neuroprotective properties of these nanomaterials remain poorly understood. In the current study, the biological effect of molybdenum disulfide (MoS2) and molybdenum diselenide (MoSe2) TMD NFs on neurons and astrocytes was investigated. It was found that both nanomaterials lowered reactive oxygen species (ROS) levels, reduced mitochondrial impairment, and increased mitochondrial biogenesis. Neuroprotective effects of both TMD NFs resulted from upregulation of the PGC-1α pathway, the biological system responsible for mitochondrial biogenesis. Furthermore, administration of TMD NFs to C. elegans extended lifespan of the nematodes. These results indicate that TMD NFs can be used as novel neuroprotective therapeutic agents against acute and chronic neurological condition linked to mitochondrial dysfunction.}, }
@article {pmid40216186, year = {2025}, author = {Roy, KK and Mehta, DK and Das, R}, title = {Reevaluating Alzheimer's disease treatment: Can phytochemicals bridge the therapeutic Gap?.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2025.04.014}, pmid = {40216186}, issn = {1873-7544}, abstract = {Alzheimer's disease (AD) is a growing neurological disorder giving impact cognition and memory, posing a global health challenge with over 55 million individuals affected. It is the 7th foremost cause of dying worldwide, and its pervasiveness is expected to twofold in each five years, reaching 115 million by 2050. AD is characterized by neurofibrillary tangles, senile plaques, and oxidative stress, leading to synaptic failure and cognitive decline. Currently, there is no cure, and available FDA-approved drugs provide only symptomatic relief. The disease progresses through five phases- mild cognitive impairment (MCI), very severe, severe, moderate and mild AD. Research on AD focuses on various neurodegenerative pathways, including inflammation, oxidative stress, genetic factors, environmental variables, and amyloid-beta accumulation. Existing FDA-accepted drugs, like rivastigmine, memantine, galantamine, and donepezil, primarily address early symptoms but have limitations, including side effects and high costs. In this context, phytochemicals from plants, such as resveratrol, huperzine, quercetin, galantamine, and rosmarinic acid, show promise as potential treatments for AD and overcome the challenges and limitation of conventional treatment. These natural substances are being investigated for their ability to lower the risk of AD safely. However, there is a lack of comprehensive knowledge about their application, necessitating further research and clinical trials to explore their potential benefits and limitations. This review serves as an essential reference for advancing future studies on Alzheimer's disease. By thoroughly analyzing neurodegenerative pathways, addressing drug limitations, and highlighting the potential of phytochemicals, we establish a strong foundation for developing innovative therapeutic strategies. Closing the knowledge gap related to the use of phytochemicals in Alzheimer's management is not just important; it is critical for creating novel and more effective treatments for this challenging neurological condition.}, }
@article {pmid40216183, year = {2025}, author = {Khalid, H and Mohamed, H and Elthoukhy, A and Saeed, MT and Song, Y}, title = {Harnessing Marine Resources for Alzheimer's Therapy: A Review Integrating Bioactivity and Molecular Docking.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {177611}, doi = {10.1016/j.ejphar.2025.177611}, pmid = {40216183}, issn = {1879-0712}, abstract = {Alzheimer's disease (AD) is a neurodegenerative condition resulting in cognitive impairment and the formation of neurofibrillary tangles and plaques in the brain. The drivers of AD's molecular progression and pathology include the accumulation of amyloid β protein (Aβ); thus, Aβ is an intervention target. However, the limitations in clinical trials of Aβ-targeted medicine and the failure to intervene in disease progression have raised concerns about the use of this drug and its veracious route. In particular, we comprehensively reviewed the potential effect of marine compounds and the mechanism of isolation and extraction from marine organisms resulting in the optimization of AD treatment. Furthermore, the hub compounds were docked with Beta-secretase receptors to strengthen the extrapolation of mechanistic interactions thus inhibiting the activity of an enzyme. An extensive review revealed that marine aquaculture and its byproducts are a promising source and isolated with green methods or less investment, ensuring their sustainability. MNPs harbor specific pharmacological features that enable them to exert neuroprotective effects by minimizing events such as Aβ peptide formation and reactive oxygen species (ROS) generation.}, }
@article {pmid40216042, year = {2025}, author = {Ma, H and Qiao, Q and Yu, Z and Wang, W and Li, Z and Xie, Z and Su, Y and Zhang, X and Sun, Y and Wang, P and Zhang, Z}, title = {Integrated multi-omics analysis and experimental validation reveals the mechanism of tenuifoliside A activity in Alzheimer's disease.}, journal = {Journal of ethnopharmacology}, volume = {}, number = {}, pages = {119797}, doi = {10.1016/j.jep.2025.119797}, pmid = {40216042}, issn = {1872-7573}, abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive dysfunction and memory loss. Tenuifoliside A (TFSA) is a constituent of RADIX POLYGALAE, a medicinal herb traditionally used in the clinical treatment of AD in China. However, the therapeutic mechanism of this compound is unknown.
AIM OF THE STUDY: To investigate the effects and pharmacological mechanisms of TFSA in ameliorating AD symptoms in APP/PS1 mice.
MATERIALS AND METHODS: The neuroprotective effects of TFSA were assessed using behavioral tests, transmission electron microscopy, and immunofluorescence staining. The differential metabolites in the feces of model mice were obtained from non-targeted metabolomics analysis. Differential abundances of microbiota in the gut were investigated by 16S rRNA sequencing, and correlations among differential metabolites and microbiota were investigated using an integrated approach.
RESULTS: Cognitive impairment and Aβ burden were mitigated in APP/PS1 mice treated with TFSA. TFSA intervention led to an increase in the diversity of gut microbiota and a reduction in the relative abundance of Firmicutes, Bacteroidetes, and Proteobacteria. There were 71 differential metabolites in mice given high dose of TFSA. In comparison to the AD group, the mice treated with TFSA exhibited a notable enrichment in various pathways including glucose and lipid metabolism, tryptophan metabolism. Based on integrated metabolomics and 16S rRNA sequencing, 23 metabolite-microbiota pairs were different between the TFSA and AD groups, and there was an especially strong correlation between Alistipes and 2,3-dinor-8-epi-prostaglandin F2α. Validation experiment demonstrated TFSA ameliorates AD by regulating metabolism pathways and inhibiting neuroinflammation.
CONCLUSIONS: This study offers a theoretical basis for elucidating the molecular mechanism of TFSA's amelioration of AD. Although the potential pharmacological mechanisms of TFSA are still unknown, we have demonstrated that TFSA inhibits neuroinflammation and improves AD symptoms in APP/PS1 mice by remodeling the microbiota and its metabolites.}, }
@article {pmid40215924, year = {2025}, author = {Al-Bagmi, MS and Alokail, MS and Al-Daghri, NM and Altwaijry, N and Aziz, IM and Almajhdi, FN and Khan, MS}, title = {Phenolic fractions of Heliotropium Bacciferum inhibit human insulin aggregation and protect against amyloid-induced cytotoxicity: Structural and biophysical analysis.}, journal = {Biophysical chemistry}, volume = {322}, number = {}, pages = {107437}, doi = {10.1016/j.bpc.2025.107437}, pmid = {40215924}, issn = {1873-4200}, abstract = {In humans, more than 50 diseases are related to protein fibrillation, including Alzheimer's and Parkinson's diseases. Inhibition of amyloid fibril formation using natural products is one of the main therapeutic strategies for preventing the progression of these diseases. In this context, phenolic extract fractions from Heliotropium bacciferum leaves were evaluated for their ability to inhibit the aggregation of human insulin (HI), an appropriate model protein for fibrillation under physiological conditions and agitation at 600 rpm. Our results exhibited HI fibrillation under studied conditions, with aggregation kinetic fitting a sigmoidal curve with tlag and kapp values of 44.4 h and 0.16 h[-1], respectively. Structural changes preceding the onset of fibril formation were detected by 8-Anilino-1-naphthalene-sulphonic acid (ANS) probe, revealed the exposure of hydrophobic regions in the HI peptide to the solvent, with tlag and kapp values of 18.2 h 0.12 h[-1], respectively. CD spectroscopy calculated the formed fibrils comprised of 51.6 % β-sheet structure and 43.0 % unordered structure. In vitro studies demonstrated a dose-dependent inhibitory effect of H. bacciferum extracts on HI fibrillation. The free phenolic fraction (FPF) at 200 μg/mL exhibited nearly complete inhibition, whereas the bound phenolic fraction (BPF) demonstrated a 52 % reduction in fibrillation. These findings were further validated using Rayleigh light scattering (RLS) and circular dichroism analyses. Transmission electron microscopy (TEM) validated the formation of insulin fibrillation and its inhibition by extract fractions. Moreover, MTT assay results on SH-SY5Y cells showed that both extract fractions attenuated HI fibril-induced neuronal toxicity in a dose-dependent manner. Furthermore, RT-PCR analysis revealed that co-treatment with a low concentration (7.8 μg/mL) of H. bacciferum extracts led to a significant reduction in the expression levels of pro-apoptotic genes (Casp3 and Bax) and an increase in the anti-apoptotic gene Bcl-2 in SH-SY5Y cells treated with fibrillated HI. This study highlights the potential of H. bacciferum extracts as therapeutic agents against protein fibrillation-related diseases and underscores the importance of polyphenols in preventing amyloid fibril formation.}, }
@article {pmid40215814, year = {2025}, author = {Cao, T and Liao, P and Lu, J and Liang, G and Wei, Q and Song, W and Lan, Y and Zeng, J and Zou, C and Pan, M and Su, L and Zou, D}, title = {Single-nucleus RNA sequencing and network pharmacology reveal the mediation of fisetin on neuroinflammation in Alzheimer's disease.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {141}, number = {}, pages = {156724}, doi = {10.1016/j.phymed.2025.156724}, pmid = {40215814}, issn = {1618-095X}, abstract = {BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive function and memory. This study explores cellular subgroups in AD using single-nucleus RNA sequencing (snRNA-seq). It integrates the pharmacological network of traditional Chinese medicine (TCM) to identify potential therapeutic targets, providing a theoretical basis for the development of clinical AD.
METHODS: We obtained data information from the Gene Expression Omnibus (GEO) for snRNA-seq analysis. Enrichment and pseudotime analysis were performed to explore the functions and differentiation pathways of cellular subgroups. Cellular communication networks were mapped to reveal subgroup interactions. Additionally, a pharmacological network for AD was constructed using the TCM pharmacology database.
RESULTS: We identified several cell subgroups associated with AD pathology, contributing to disease progression in various ways. Notably, the TNC[+] CD44[+] astrocyte subgroup activated the I-kappa B kinase/ NF-κB signaling pathway, leading to increased expression of inflammatory cytokines. In the pharmacological network, fisetin was identified as a promising compound with the potential to bind to the CD44 protein, mitigating the inflammatory response and preventing further neuronal damage.
CONCLUSIONS: By exploring the ecological landscape of various cellular subgroups in AD and investigating the roles and mechanisms, combined with molecular docking and pharmacological network screening, our findings provide new insights and therapeutic possibilities for AD treatment.}, }
@article {pmid40215776, year = {2025}, author = {Sun, C and Gao, X and Sha, S and Wang, S and Shan, Y and Li, L and Xing, C and Guan, H and Du, H}, title = {Berberine alleviates Alzheimer's disease by activating autophagy and inhibiting ferroptosis through the JNK-p38MAPK signaling pathway.}, journal = {International immunopharmacology}, volume = {155}, number = {}, pages = {114550}, doi = {10.1016/j.intimp.2025.114550}, pmid = {40215776}, issn = {1878-1705}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid beta (Aβ) deposition, phosphorylated Tau protein aggregation, inflammation, and neuronal damage. Neuronal autophagy plays an important role in ameliorating central nervous system diseases such as AD. As an emerging form of iron-dependent cell death, ferroptosis has attracted great attention in the field of neurodegenerative diseases. Berberine (BBR), a natural alkaloid, has demonstrated excellent in inflammation reduction, inhibition of Aβ production, and neuroprotection, making it a potential candidate for AD treatment. However, the mechanisms of autophagy and ferroptosis in BBR treatment of AD have not been elucidated.
OBJECTIVES: This study aimed to investigate the potential of BBR in alleviating AD and evaluate its molecular mechanism through a combination of network pharmacology and biological experiments.
METHODS: We assessed alterations in Aβ plaques, neurons, neuroinflammation, and autophagy-related markers in the mice brain using immunofluorescence staining. Network pharmacology and molecular docking were used to analyze the potential targets and signaling pathways of BBR in the treatment of AD. Morris Water Maze (MWM) and new object recognition (NOR) experiments were used to test the spatial memory ability of mice. In addition, we validated the relationship between JNK-P38MAPK, autophagy, ferroptosis, and BBR treatment in 5xFAD mice and A β-induced SH-SY5Y cell models.
RESULTS: The results of immunofluorescence staining showed that BBR effectively mitigated Aβ plaque deposition, ameliorated neuronal damage and neuroinflammation. The autophagy-related markers Beclin1 and LC3B were upregulated and P62 was downregulated after BBR treatment. The expression levels of ROS and lipid peroxide MDA decreased significantly after BBR treatment. qPCR results showed that the expression levels of ferroptosis-related genes TFR1, ASCL4, DMT1, and IREB2 were decreased, while the expression levels of FTH1 and SLC7A11 increased after BBR treatment. Behavioral experiments showed that BBR treatment enhanced spatial memory impairment in 5xFAD mice. Network pharmacological and in vitro analyses demonstrated that BBR activated autophagy and inhibited ferroptosis by inhibiting the JNK-P38MAPK signaling pathway. Following treatment with an autophagy inhibitor on SH-SY5Y cells, autophagy was markedly suppressed, and ferroptosis was induced.
CONCLUSION: In summary, we found that BBR alleviates AD by inhibiting the JNK-P38MAPK pathway to enhance autophagy and inhibit ferroptosis, further reducing Aβ plaque deposition, inhibiting inflammatory response, and improving neuronal damage.}, }
@article {pmid40215558, year = {2025}, author = {Divecha, YA and Rampes, S and Tromp, S and Boyanova, ST and Fleckney, A and Fidanboylu, M and Thomas, SA}, title = {The microcirculation, the blood-brain barrier, and the neurovascular unit in health and Alzheimer disease: The aberrant pericyte is a central player.}, journal = {Pharmacological reviews}, volume = {77}, number = {3}, pages = {100052}, doi = {10.1016/j.pharmr.2025.100052}, pmid = {40215558}, issn = {1521-0081}, abstract = {High fidelity neuronal signaling is enabled by a stable local microenvironment. A high degree of homeostatic regulation of the brain microenvironment, and its separation from the variable and potentially neurotoxic contents of the blood, is brought about by the central nervous system barriers. Evidence from clinical and preclinical studies implicates brain microcirculation, cerebral hypoperfusion, blood-brain barrier dysfunction, and reduced amyloid clearance in Alzheimer pathophysiology. Studying this dysregulation is key to understanding Alzheimer disease (AD), identifying drug targets, developing treatment strategies, and improving prescribing to this vulnerable population. This review has 2 parts: part 1 describes the cerebral microcirculation, cerebral blood flow, extracellular fluid drainage, and the neurovascular unit components with an emphasis on the blood-brain barrier, and part 2 summarizes how each aspect is altered in AD. Discussing the neurovascular unit structures separately allows us to conclude that aberrant pericytes are an early contributor and central to understanding AD pathophysiology. Pericytes have multiple functions including maintenance of blood-brain barrier integrity and the control of capillary blood flow, capillary stalling, neurovascular coupling, intramural periarterial drainage, glia-lymphatic (glymphatic) drainage, and consequently amyloid and tau clearance. Pericytes are vasoactive, express cholinergic and adrenergic receptors, and exhibit apolipoprotein E isoform-specific transport pathways. Hypoperfusion in AD is linked to a pericyte-mediated response. Deficient endothelial cell-pericyte (PDGBB-PDGFRβ) signaling loops cause pericyte dysfunction, which contributes and even initiates AD degeneration. We conclude that pericytes are central to understanding AD pathophysiology, are an interesting therapeutic target in AD, and have an emerging role in regenerative therapy. SIGNIFICANCE STATEMENT: Dysregulation and dysfunction of the neurovascular unit and fluid circulation (including blood, cerebrospinal fluid, and interstitial fluid) occurs in Alzheimer disease. A central player is the aberrant pericyte. This has fundamental implications to understanding disease pathophysiology and the development of therapies.}, }
@article {pmid40215195, year = {2025}, author = {Zhang, C and Song, G and Di, W and Gao, Y and Chang, S and Chen, Z and Tang, L and Kong, R}, title = {Identify natural compounds as novel phosphodiesterase-2A inhibitors.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/07391102.2025.2487193}, pmid = {40215195}, issn = {1538-0254}, abstract = {Phosphodiesterase-2A (PDE2A) is a potential therapeutic target for the treatment of ganglion dysfunction-related diseases such as Alzheimer's disease, schizophrenia, cognitive impairment, anxiety, and depression. However, most current PDE2A inhibitors have moderate selectivity compared to other PDEs. In this study, we described the discovery of 6 novel PDE2A inhibitors by bioassays, molecular docking, and molecular dynamics simulations. Six molecules out of 2592 compounds from the L6000-Natural Compound Library inhibited PDE2A with affinity ranging from 4.03 to 39.84 μM. Selective experiments were carried out on PDE4D, PDE5A, PDE9A, and PDE10A, among which 5-5H and 16-2H exhibited good dual inhibition against both PDE2A and PDE4D. Their IC50 values for PDE2A were 4.03 and 9.08 μM, respectively, and for PDE4D they were 3.89 and 10.96 μM, respectively. Molecular docking and molecular dynamics simulation were used to explore the binding modes of active compounds with PDE2A. It is shown that in addition to the common interactions with Gln859 and Phe862 of PDE2A, 6 molecules formed extra hydrogen bonds with Ile826 and Leu809. These molecules may serve as starting points for further optimization of selective PDE2A inhibitors.}, }
@article {pmid40214479, year = {2025}, author = {Kola, A and Costanti, F and Kahfi, J and Emwas, AH and Jaremko, M and Valensin, D}, title = {NMR Metabolomic Profiling of Differentiated SH-SY5Y Neuronal Cells: Amyloid-β Toxicity and Protective Effects of Galantamine and Lycorine.}, journal = {Cells}, volume = {14}, number = {7}, pages = {}, doi = {10.3390/cells14070525}, pmid = {40214479}, issn = {2073-4409}, mesh = {Humans ; *Galantamine/pharmacology ; *Amaryllidaceae Alkaloids/pharmacology ; *Amyloid beta-Peptides/toxicity ; *Metabolomics/methods ; *Phenanthridines/pharmacology ; Cell Line, Tumor ; *Neurons/metabolism/drug effects/pathology ; *Neuroprotective Agents/pharmacology ; *Cell Differentiation/drug effects ; Magnetic Resonance Spectroscopy ; Mitochondria/metabolism/drug effects ; *Metabolome/drug effects ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by metabolic dysregulation, oxidative stress, amyloid-β (Aβ) aggregation, metal dyshomeostasis, and mitochondrial dysfunction. Current treatments provide only symptomatic relief, highlighting the need for novel therapeutic strategies. This study investigates the metabolic effects of the alkaloids galantamine (GAL) and lycorine (LYC) in differentiated SH-SY5Y neuroblastoma cells, an established in vitro model for AD, which acquire a neuronal phenotype upon differentiation. Using untargeted and targeted NMR-based metabolomics combined with multivariate statistical analysis, we analyzed extracellular metabolic profiles under basal conditions and following Aβ42 exposure, both in the presence and absence of GAL and LYC. Our findings reveal distinct metabolic responses to Aβ toxicity, with significant alterations in pyruvate and glutamine metabolism. Both GAL and LYC contributed to the restoration of glutamine and lysine homeostasis, but LYC had a more pronounced effect, better sustaining cellular energy balance and mitochondrial function. Unlike LYC, GAL treatment was associated with pyruvate accumulation, highlighting a distinct metabolic response between the two compounds. These variations may reflect distinct mechanisms of action, potentially influencing their therapeutic roles in counteracting Aβ-induced toxicity. This study highlights the value of metabolic profiling for assessing neuroprotective agents and reinforces the potential of natural alkaloids in this context.}, }
@article {pmid40213389, year = {2025}, author = {Zhang, Y and Xie, K and Jiang, T}, title = {Roles and regulation of δ-catenin in tumorigenesis and neuronal diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1559059}, pmid = {40213389}, issn = {2296-634X}, abstract = {CTNND2 gene is located on the short arm of human chromosome 5 and encodes δ-catenin protein, which interacts with different proteins and plays different cell functions. Studies have demonstrated that δ-catenin plays an important role in regulating synaptic maturation and neuronal integrity. The CTNND2 gene is closely associated with a variety of neurological diseases, including Cri-du-Chat syndrome, Autism spectrum disorders, Alzheimer's disease, and Epilepsy. Furthermore, an increasing number of studies have demonstrated that CTNND2 is involved in various cancers and may serve as a novel biomarker for the diagnosis and treatment for these diseases. In this review, we will focus on the signaling regulatory functions of CTNND2 and its encoded protein δ-catenin in neuro-related diseases and cancers, and discuss the limitations of previous investigative studies and the challenges of the future researches on CTNND2 and δ-catenin signaling.}, }
@article {pmid40212564, year = {2025}, author = {He, C and Chen, B and Yang, H and Zhou, X}, title = {The dual role of microglia in Alzheimer's disease: from immune regulation to pathological progression.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1554398}, pmid = {40212564}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a widespread neurodegenerative disorder and one of the major challenges for public health. Despite extensive research, the role of microglia in AD remains complex and dual. The aim of this review is to summarize the most recent advances in research regarding the dual role of microglia in AD concerning both immunomodulation and pathological progression by considering mechanisms of activation of microglia, effects on Aβ clearance, tau pathology, and impacts due to genetic variations on microglial functions. Among these findings are the dual role of microglia, the status of activation for M1 and M2 phenotypes, and the crucial role that genetic variants like TREM2 have in modulating the response of microglia. This review describes how modulation of the microglial signaling pathway might be exploited therapeutically for AD treatment and underlines the relevance of a personalized medicine approach.}, }
@article {pmid40211464, year = {2025}, author = {Sun, M and Wang, X and Lu, Z and Yang, Y and Lv, S and Miao, M and Chen, WM and Wu, SY and Zhang, J}, title = {Sodium-glucose cotransporter-2 inhibitors and subtype-specific dementia risk: A multinational and multiethnic cohort study.}, journal = {Diabetes, obesity & metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1111/dom.16403}, pmid = {40211464}, issn = {1463-1326}, support = {2023YFC2506903//National Key Research and Development Program of China/ ; 11403//Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital/ ; 11404//Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital/ ; }, abstract = {AIMS: Type 2 diabetes mellitus (T2DM) significantly increases the risk of dementia, including Alzheimer's disease (AD), vascular dementia (VaD) and mixed dementia. Although sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown potential neuroprotective effects, previous studies were limited by small sample sizes, single-country datasets and a lack of detailed analyses of dementia subtypes.
MATERIALS AND METHODS: This retrospective cohort study utilized the TriNetX database, comprising de-identified electronic health records from over 100 million patients across 98 healthcare organizations worldwide. Adults with T2DM initiating treatment with either SGLT2i or dipeptidyl peptidase-4 inhibitors (DPP4i) between November 20, 2004, and November 20, 2024, were included. Propensity score matching (PSM) at a 1:1 ratio ensured balanced baseline characteristics. Primary outcomes included overall dementia and specific dementia subtypes (VaD, AD, other dementias), while secondary outcomes included all-cause mortality.
RESULTS: After 1:1 propensity score matching, 278 689 patients per group were analysed. SGLT2i use was associated with a lower incidence of overall dementia (2.9% vs. 6.7%; adjusted hazard ratio [AHR] 0.77, 95% confidence interval [CI], 0.75-0.79) and a lower risk of vascular dementia (AHR 0.80), Alzheimer's disease (AHR 0.82) and other dementias (AHR 0.68). These associations remained consistent across age, sex, baseline glycaemic control and concurrent medication use in subgroup analyses. SGLT2i use was also linked to lower all-cause mortality (4.1% vs. 11.2%; AHR 0.66, 95% CI, 0.65-0.68). Findings were robust across sensitivity and subgroup analyses, supporting the potential neuroprotective effects of SGLT2i.
CONCLUSIONS: This large-scale observational study suggests that SGLT2i use is associated with lower risks of multiple dementia subtypes and all-cause mortality in patients with T2DM.}, }
@article {pmid40210453, year = {2025}, author = {De Giorgi, R and Ghenciulescu, A and Yotter, C and Taquet, M and Koychev, I}, title = {Glucagon-like peptide-1 receptor agonists for major neurocognitive disorders.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-335593}, pmid = {40210453}, issn = {1468-330X}, abstract = {Disease-modifying treatments for major neurocognitive disorders, including Alzheimer's disease, Parkinson's disease and other cognitive deficits, are among the main unmet needs in modern medicine. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), currently licensed for the treatment of type 2 diabetes mellitus and obesity, offer a novel, multilayered mechanism for intervention in neurodegeneration through intermediate, aetiology-agnostic pathways, likely involving metabolic, inflammatory and several other relevant neurobiological processes. In vitro and animal studies have revealed promising signals of neuroprotection, with preliminary supportive evidence emerging from recent pharmacoepidemiological investigations and clinical trials. In this article, we comprehensively review studies that investigate the impact of GLP-1RAs on the various aetiologies of cognitive impairment and dementia syndromes. Focusing on evidence from human studies, we highlight how brain energy homeostasis, neurogenesis, synaptic functioning, neuroinflammation and other cellular stress responses, pathological protein aggregates, proteostasis, cerebrovascular system and blood-brain barrier dynamics may underlie GLP-1RA putative neuroprotective effects. We then report and appraise evidence from clinical studies, including observational investigations, clinical trials and pooled analyses. Finally, we discuss current challenges and perspectives ahead for research and clinical implementation of GLP-1RAs for the care of people with major neurocognitive disorders, including their individual brain penetrance potential, the need for response biomarkers and disease stage-based indications, their possible non-specific effects on brain health, their profile in terms of adverse events and other unwanted effects, the lack of long-term data for efficacy and safety, and issues surrounding cost and availability of treatment.}, }
@article {pmid40210369, year = {2025}, author = {Markos, S and Galibov, M}, title = {Rehabilitation of Women with Neurodegenerative Diseases.}, journal = {Physical medicine and rehabilitation clinics of North America}, volume = {36}, number = {2}, pages = {389-398}, doi = {10.1016/j.pmr.2024.11.006}, pmid = {40210369}, issn = {1558-1381}, mesh = {Humans ; Female ; *Neurodegenerative Diseases/rehabilitation/epidemiology ; Sex Factors ; Parkinson Disease/rehabilitation ; Alzheimer Disease/rehabilitation ; }, abstract = {Parkinson's disease, multiple sclerosis, and Alzheimer's disease are 3 prevalent neurodegenerative diseases. Beyond disparate disease incidences between men and women, additional sex-related differences exist. Disease presentation, natural course, treatment considerations, genetic factors, hormonal factors, health care utilization patterns, and outcomes can vary between men and women in general. These disease processes represent examples of well-defined discrepancies between men and women afflicted. Other neurodegenerative conditions, such as motor neuron disorders, progressive supranuclear palsy, and multisystem atrophy, have shown to have a slight predilection toward men compared to women, yet have not been as extensively studied.}, }
@article {pmid40209354, year = {2025}, author = {Zhang, YL and Yang, HY and Gou, J and Qi, XM and Qiao, YB and Li, QS}, title = {Carvacrol/thymol derivatives as highly selective BuChE inhibitors with anti-inflammatory activities: Discovery and bio-evaluation.}, journal = {Bioorganic chemistry}, volume = {160}, number = {}, pages = {108430}, doi = {10.1016/j.bioorg.2025.108430}, pmid = {40209354}, issn = {1090-2120}, abstract = {In this study, nine novel carvacrol/thymol derivatives incorporating carbamate groups were designed, synthesized, and evaluated as multifunctional anti-AD agents. These derivatives displayed superior BuChE inhibitory and anti-inflammatory characteristics compared to the parent compounds. While the derivatives exhibited AChE IC50 values exceeding the detectable limit (>100 μM), they demonstrated high potency as BuChE inhibitors, with IC50 values ranging from 0.05 to 9.62 μM. In an inflammation model of BV2 microglial cells induced by lipopolysaccharide (LPS), the derivatives effectively reduced the levels of the pro-inflammatory cytokine interleukin-1β (IL1β), with inhibition rates of IL1β exceeding 50 % at 10 μM. Notably, compound SXF3 attained the highest BuChE inhibition efficacy (eqBuChE IC50 = 0.05 ± 0.003 μM, hBuChE IC50 = 0.04 ± 0.001 μM), the highest selectivity for BuChE (with a selectivity index, SI, exceeding 2000, calculated as the ratio of eeAChE IC50 to eqBuChE IC50) and high anti-inflammatory activity (inhibition of IL1β, IC50 = 8.33 ± 0.08 μM). In a scopolamine-induced AD mouse model, SXF3 (15 mg/kg) significantly reduced the latency to the platform and attenuated memory deficits. Biochemical analysis confirmed that SXF3 significantly increased acetylcholine (ACh) levels in the mice hippocampus, primarily due to the inhibition of BuChE rather than AChE, and that SXF3 significantly reduced IL1β levels to normal, further confirming its anti-inflammatory activities. Hence, the selective BuChE inhibitory properties and anti-inflammatory attributes of SXF3 render it a promising candidate for further investigation in the treatment of AD.}, }
@article {pmid40209306, year = {2025}, author = {Meanti, R and Bresciani, E and Rizzi, L and Molteni, L and Coco, S and Omeljaniuk, RJ and Torsello, A}, title = {Cannabinoid Receptor 2 (CB2R) as potential target for the pharmacological treatment of neurodegenerative diseases.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {186}, number = {}, pages = {118044}, doi = {10.1016/j.biopha.2025.118044}, pmid = {40209306}, issn = {1950-6007}, abstract = {The endocannabinoid system (ECS) is a ubiquitous physiological system that plays a crucial role in maintaining CNS homeostasis and regulating its functions. It includes cannabinoid receptors (CBRs), endogenous cannabinoids (eCBs), and the enzymes responsible for their synthesis and degradation. In recent years, growing evidence has highlighted the therapeutic potential of the ECS and CBRs, in a wide range of severe diseases and pathological conditions, including Alzheimer's and Parkinson's diseases, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Huntington's Disease, HIV-1 associated neurocognitive disorders, neuropathic pain and migraine. Targeting the cannabinoid type 2 receptor (CB2R) has gained attention due to its ability to (i) mitigate neuroinflammatory responses, (ii) regulate mitochondrial function and (iii) provide trophic support, all without eliciting the psychotropic actions associated with CB1R activation. This review aims to explore the potential of CB2R modulation as a strategy for the prevention and treatment of neurologic disorders, exploring both preclinical and clinical findings.}, }
@article {pmid40208552, year = {2025}, author = {Sirimaharaj, N and Thiankhaw, K and Chattipakorn, N and Chattipakorn, SC}, title = {Unveiling the Protective Roles of Melatonin on Glial Cells in the Battle Against Alzheimer's Disease-Insights from In Vivo and In Vitro Studies.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40208552}, issn = {1559-1182}, support = {N42A670594//National Research Council of Thailand/ ; N42A660301//National Research Council of Thailand/ ; CMU excellent center award//Chiang Mai University/ ; }, abstract = {Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder that predominantly affects the elderly. Characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles, AD leads to memory loss, cognitive decline, and severe behavioral changes. As the most common form of dementia, AD imposes a significant global health burden, highlighting the need for interventions that address underlying disease mechanisms rather than only symptomatic treatment. Glial cells, including microglia and astrocytes, play a crucial role in AD progression by mediating neuroinflammatory responses and modulating Aβ clearance and neuronal health. Dysfunction in these cells can exacerbate neuroinflammation and neuronal damage, making glial cells an important target for therapeutic intervention. This review synthesizes findings from in vivo and in vitro studies on melatonin's effects on glial cell dysfunction in AD, emphasizing the multi-mechanistic nature of its neuroprotective properties. Recent studies highlight melatonin's potential as a therapeutic agent that addresses AD-related mechanisms through its interactions with glial cells. Melatonin has demonstrated protective effects, including reducing oxidative stress, apoptosis, and inflammation, inhibiting Aβ fibrillogenesis, and modulating amyloid precursor proteins. Additionally, its influence on glial cell activity, through melatonin receptor pathways, suggests it can alleviate neuroinflammation, a key component of AD progression. The collective evidence points to melatonin's promise as a therapeutic tool with potential roles in both preventive and adjunctive treatments for AD. However, further research is necessary to establish its efficacy and safety in clinical settings.}, }
@article {pmid40208330, year = {2025}, author = {Qin, R and Xu, W and Xu, H and Qin, Q and Liang, X and Lai, X and Shao, L and Xie, M and Xiong, X and Tang, Q and Chen, L}, title = {The burden of common neurological disorders in Asia: insights from the Global Burden of Disease Study (1990-2021).}, journal = {Journal of neurology}, volume = {272}, number = {5}, pages = {333}, pmid = {40208330}, issn = {1432-1459}, support = {82271371//National Natural Science Foundation of China/ ; 82260367//National Natural Science Foundation of China/ ; S2021107//the Guangxi Medical and Health Appropriate Technology Development and Application Project/ ; YYZS2021002//the Clinical Research "Climbing" Program of the First Affiliated Hospital of Guangxi Medical University/ ; YCSW2023242//the Innovation Project of Guangxi Graduate Education/ ; }, mesh = {Humans ; *Global Burden of Disease/trends ; *Nervous System Diseases/epidemiology/mortality ; Female ; Male ; Asia/epidemiology ; Disability-Adjusted Life Years ; Middle Aged ; Aged ; Adult ; Prevalence ; Young Adult ; Aged, 80 and over ; Cost of Illness ; Incidence ; Adolescent ; }, abstract = {BACKGROUND: Neurological disorders represent a significant global health issue, leading to severe cognitive impairments and being a major cause of premature mortality and disability. This study aims to utilize data from the Global Burden of Disease (GBD) research website to assess the burden of neurological disorders in the Asian region and its individual countries and territory from 1990 to 2021, with the goal of providing reference for global efforts and decision-making in the prevention, treatment, and management of neurological disorders.
METHODS: Based on the Global Burden of Disease data, this study assessed the incidence, prevalence, mortality, and disability-adjusted life years (DALYs) of 13 neurological disorders in the Asian region from 1990 to 2021. The epidemiological characteristics of neurological disorders across these Asian regions were analyzed. Joinpoint regression analysis was employed to assess the temporal patterns of the burden of neurological disorders, and the average annual percent change (AAPC) was calculated to determine the overall trend throughout the study period.
RESULTS: In 2021, stroke, migraine, and Alzheimer's disease and other dementias emerged as the primary contributors to neurological burden in Asia, with stroke accounting for 112.87 million disability-adjusted life years (DALYs), followed by migraine (25.4 million) and Alzheimer's disease and other dementias (20.0 million). Stroke was also the leading cause of neurological mortality (5.03 million deaths), trailed by Alzheimer's disease and other dementias (1.0 million). Stroke, migraine, and tension-type headache had the highest prevalence rates among neurological disorders, with 57.3 million, 683.5 million, and 1130.2 million. Temporal trends from 1990 to 2021 revealed a significant decline in age-standardized DALY rates for stroke (estimated annual percentage change [EAPC]: - 1.65%), though absolute DALYs increased (EAPC: 0.06%). In contrast, Alzheimer's disease and other dementias exhibited rising age-standardized (EAPC: 0.14%) and absolute DALYs (EAPC: 2.8%), while infectious neurological diseases (e.g., meningitis, tetanus) demonstrated marked reductions in burden. Sex-specific disparities were evident, with males experiencing a higher total DALY burden (84.8 million vs. 77.05 million), driven by stroke and Parkinson's disease, whereas Alzheimer's disease and other dementias and migraine disproportionately affected females. Geographically, stroke dominated Southeast Asia (67.6% of regional DALYs), while migraine contributed most substantially to West Asia (16%). Nationally, stroke ranked as the leading cause of neurological DALYs in most Asian countries, contrasting with migraine in Israel, Kuwait, Qatar, and the United Arab Emirates. Longitudinal analyses highlighted accelerated declines in stroke DALYs post- 2004 but escalating burdens for Alzheimer's disease and other dementias after 2019, reflecting divergent epidemiological trajectories.
CONCLUSIONS: In 2021, the burden of neurological disorders in Asia remained substantial, with stroke, migraine, and Alzheimer's disease and other dementias being the top three contributors to DALYs. The study also revealed significant differences in the burden of neurological disorders across various subregions and countries in Asia, highlighting the need for enhanced international collaboration, sharing of best practices, provision of technical support, and optimization of healthcare resource allocation.}, }
@article {pmid40208086, year = {2025}, author = {Liu, T and Mao, T and Fan, J and Shen, Y and Xue, L and Du, K and Li, Y and Wang, L and Wang, X}, title = {IL-17A Induces Circadian Disruptions Through the Epigenetic Repression of BMAL1 in Mice With Alzheimer's Disease.}, journal = {Journal of cellular and molecular medicine}, volume = {29}, number = {7}, pages = {e70546}, doi = {10.1111/jcmm.70546}, pmid = {40208086}, issn = {1582-4934}, support = {20210302124255//Natural Science Foundation of Shanxi Province/ ; 2021L207//Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi/ ; XD2115//Science Research Start-up Fund for Doctor of Shanxi Medical University/ ; YDZJSX20231A053//Central Guiding Local Science and Technology Development Fund Projects/ ; 82201640//National Natural Science Foundation of China/ ; 82271523//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *ARNTL Transcription Factors/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism/pathology ; DNA Methylation/genetics ; *Interleukin-17/metabolism/genetics ; *Epigenesis, Genetic ; Mice ; *Circadian Rhythm/genetics ; Promoter Regions, Genetic/genetics ; Disease Models, Animal ; DNA (Cytosine-5-)-Methyltransferase 1/metabolism/genetics ; Mice, Transgenic ; Amyloid beta-Peptides ; Humans ; Mice, Inbred C57BL ; }, abstract = {Circadian disruptions and neuroinflammation impact nearly all people with Alzheimer's disease (AD), but their relationships with each other and the impact of their interaction on AD remain to be addressed. Here, we found that amyloid (A)-β treatment downregulated brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL) 1 through the hypermethylation of its promoter region in HT22 cells and that the inhibition of DNA methylation ameliorated circadian rhythm disorders and restored BMAL1 protein expression by reversing its hypermethylation in APPswe/PSEN1dE9 (APP/PS1) mice. Critically, increased levels of interleukin (IL)-17A contributed to BMAL1 downregulation through the hypermethylation of its promoter region, thus leading to circadian disruptions in APP/PS1 mice. Moreover, we revealed that the mitogen-activated protein kinase (MAPK) pathway was responsible for IL-17A-induced DNA methyltransferase (DNMT) 1 upregulation. Taken together, we elucidate a new mechanism connecting IL-17A with altered DNA methylation of Bmal1, which results in circadian disturbances in an AD mouse model.}, }
@article {pmid40207815, year = {2025}, author = {Li, C and Chen, Y and Yao, Y and Zhang, Y and Tong, S and Shang, Y}, title = {Analysis of the Relationship Between NLRP3 and Alzheimer's Disease in Oligodendrocytes based on Bioinformatics and In Vitro Experiments.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050376534250310061951}, pmid = {40207815}, issn = {1875-5828}, abstract = {AIM: This study aims to explore the potential association between nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in oligodendrocytes and Alzheimer's disease (AD), utilizing a combination of bioinformatics analysis and molecular biology experiments to validate this relationship.
METHODS: Public datasets related to AD were systematically retrieved and downloaded from the Gene Expression Omnibus (GEO) database at the National Center for Biotechnology Information (NCBI). Subsequently, the SVA package was employed to merge the data and eliminate batch effects, allowing for the precise identification of differentially expressed genes (DEGs) between AD patients and healthy controls. Advanced machine learning techniques, including LASSO regression analysis, random forest algorithms, and support vector machines (SVM), were utilized to analyze further the DEGs associated with the NLRP3 inflammasome to determine the gene set most closely related to AD. The effectiveness and clinical value of the gene-based diagnostic model were comprehensively assessed through receiver operating characteristic (ROC) curve analysis, nomogram construction, and decision curve analysis (DCA). Immune infiltration analysis evaluated the extent of various immune cell infiltrations in the brain tissue of AD patients. Single-cell transcriptomics and in vitro experiments were conducted to verify the molecular expression of NLRP3 in oligodendrocytes within the AD model.
RESULTS: A total of 11 significant DEGs were identified, with 4 genes showing downregulation and 7 genes exhibiting upregulation. All three algorithms-LASSO regression, random forest, and SVM-consistently identified PANX1, APP, P2RX7, MEFV, and NLRP3 as key genes closely associated with AD. ROC curve analysis, nomogram modeling, and DCA results demonstrated that the diagnostic model constructed based on these five genes exhibited high diagnostic accuracy and clinical applicability. Immune infiltration analysis revealed a significant correlation between key genes associated with AD and various immune cells, particularly CD8+ T cells, monocytes, activated NK cells, and neutrophils, suggesting that these cells may play important roles in the immunopathological process of AD. Single-cell transcriptomics indicated that the expression level of NLRP3 in oligodendrocytes was higher in the AD group compared to the control group (p < 0.05). Additionally, in vitro cell experiments using RT-PCR, immunofluorescence, and Western blot analysis confirmed that the expression level of NLRP3 in oligodendrocytes was elevated in the AD model relative to the control group (p < 0.05).
CONCLUSION: This study corroborates the high expression of NLRP3 in AD and its close relationship with the disease through integrated bioinformatics analysis and molecular biology experiments. Furthermore, the diagnostic model constructed based on the five key genes-PANX1, APP, P2RX7, MEFV, and NLRP3-not only provides a robust tool for early diagnosis of AD but also offers new insights for the development of treatment targets for AD.}, }
@article {pmid40207637, year = {2025}, author = {Parks, AL and Thacker, A and Dohan, D and Gomez, LAR and Ritchie, CS and Paladino, J and Shah, SJ}, title = {A qualitative study of people with Alzheimer's disease in a memory clinic considering lecanemab treatment.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251329519}, doi = {10.1177/13872877251329519}, pmid = {40207637}, issn = {1875-8908}, abstract = {BackgroundPeople with Alzheimer's disease (AD) now have access to disease-modifying treatment with anti-amyloid monoclonal antibodies (mAbs). Their perception of risks and benefits and approach to treatment decisions remain unknown.ObjectiveWe aimed to understand how people with AD weigh the benefits and costs of anti amyloid mAbs and incorporate these into decisions about treatment.MethodsWe conducted semi-structured interviews with people with biomarker- or imaging-confirmed AD and mild or moderate cognitive impairment who were seen at memory care clinics and discussed lecanemab with a clinician. Interviews were recorded, transcribed, and deidentified. Thematic analysis identified themes and subthemes.ResultsAmong 22 participants (mean age 70, 8 [36%] women, 22 [100%] White), analysis revealed 3 major themes and associated subthemes: (1) People with AD sought and obtained information from different sources-advocacy organizations, the Internet, and clinicians; (2) Hopes, expected benefits, and the existential threat of dementia drove willingness and readiness to start lecanemab; (3) Individual traits, family factors, and degree of trust in expertise influenced how people balanced risks and benefits. Some would accept treatment at any cost; others carefully weighed risks and burdens, but were motivated by supportive families, insurance coverage, and trust in expertise; for a few, costs decidedly outweighed their personal benefits. People with AD desired more individualized information and to hear more from patients who took the medication.ConclusionsResults from this first qualitative study of people with AD considering treatment with anti-amyloid mAbs can inform clinician, health system and policy efforts to individualize decisions.}, }
@article {pmid40207435, year = {2025}, author = {McKinley, J and Brumley, AW and Williams, CL and Tognoli, E and Beetle, C}, title = {Evidence-based facilitator strategies for enhancing social engagement in groups of older adults with ADRD.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {4}, pages = {e70131}, doi = {10.1002/alz.70131}, pmid = {40207435}, issn = {1552-5279}, support = {R56AG064094/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Aged ; Female ; Male ; *Alzheimer Disease/psychology ; *Social Isolation/psychology ; Aged, 80 and over ; *Social Participation ; *Social Interaction ; *Group Processes ; }, abstract = {INTRODUCTION: Alzheimer's disease and related dementias (ADRD) is exacerbated by social isolation. One potential intervention for improving the health outcomes of individuals with ADRD is by providing opportunities for socialization that are highly engaging.
METHODS: To identify strategies for enhancing social engagement, we studied recorded virtual group sessions of older adults aged ≥ 65, with mild to moderate ADRD who interacted with younger adult facilitators. We developed multivariate regression models that use data describing group behavior, activity, and composition to predict enhanced engagement.
RESULTS: We identified predictors of enhanced engagement related to group composition, structure, leadership, and mode of delivery. These results inform strategies for designing group settings which maximize engagement by using the synergistic influence of whole social groups on individuals.
DISCUSSION: We make evidence-based treatment recommendations for facilitators seeking to maximize engagement and make recommendations for future research investigating the preservation or loss of social engagement.
HIGHLIGHTS: Social isolation is a major contributing factor to the development of Alzheimer's disease and related dementias. Virtual socialization can help mitigate lack of opportunity for social contact. Audio-video data describing group activity were used to predict social engagement. Group size, behavior, composition, and time spoken contributed to social engagement. Experienced group facilitators maximized engagement by supporting conversation.}, }
@article {pmid40207431, year = {2025}, author = {Oeckl, P and Mayer, B and Bateman, RJ and Day, GS and Fox, NC and Huey, ED and Ibanez, L and Ikeuchi, T and Jucker, M and Lee, JH and Levin, J and Llibre-Guerra, JJ and Lopera, F and McDade, E and Morris, JC and Niimi, Y and Roh, JH and Sánchez-Valle, R and Schofield, PR and Otto, M and , }, title = {Early increase of the synaptic blood marker β-synuclein in asymptomatic autosomal dominant Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {4}, pages = {e70146}, doi = {10.1002/alz.70146}, pmid = {40207431}, issn = {1552-5279}, support = {/AG/NIA NIH HHS/United States ; SG-20-690363-DIAN/ALZ/Alzheimer's Association/United States ; //German Center for Neurodegenerative Diseases/ ; //Raul Carrea Institute for Neurological Research/ ; AMED JP24dk0207066//Research and Development Grants for Dementia from Japan Agency for Medical Research and Development/ ; //Korea Health Technology R&D Project/ ; HI21C0066//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; //Spanish Institute of Health Carlos III/ ; //Cure Alzheimer´s Fund/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/blood/pathology ; Male ; Female ; Biomarkers/blood ; Middle Aged ; Mutation/genetics ; *beta-Synuclein/blood ; Aged ; Brain/pathology/diagnostic imaging ; Synapses ; Cognitive Dysfunction/blood ; Longitudinal Studies ; }, abstract = {INTRODUCTION: β-synuclein is a promising blood marker to track synaptic degeneration in Alzheimer's disease (AD) but changes in preclinical AD are unclear.
METHODS: We investigated serum β-synuclein in 69 cognitively unimpaired mutation non-carriers, 78 cognitively unimpaired AD mutation carriers (asymptomatic AD), and 31 symptomatic mutation carriers from the Dominantly Inherited Alzheimer Network.
RESULTS: β-synuclein levels were already higher in asymptomatic AD mutation carriers compared to non-carriers and highest in symptomatic carriers. Longitudinal trajectories and correlation analyses indicated that β-synuclein levels start to rise after amyloid deposition preceding axonal degeneration, brain atrophy and hypometabolism, and cognitive decline. β-synuclein levels were associated with cognitive impairment and gradually increased with declining cognition.
DISCUSSION: Our study supports the use of blood β-synuclein to track synaptic changes in preclinical AD and as a surrogate marker for cognitive impairment which might be used in early diagnosis and to support patient selection and monitoring of treatment effects in clinical trials.
HIGHLIGHTS: Blood β-synuclein levels were already higher in asymptomatic Alzheimer's disease (AD) mutation carriers. Blood β-synuclein levels were highest in symptomatic AD mutation carriers. Blood β-synuclein levels start to rise 11 years before symptom onset. Rise of β-synuclein precedes axonal degeneration, brain atrophy, and cognitive decline. β-synuclein levels gradually increased with declining cognition.}, }
@article {pmid40207239, year = {2025}, author = {Torres, AK and Mira, RG and Pinto, C and Inestrosa, NC}, title = {Studying the mechanisms of neurodegeneration: C. elegans advantages and opportunities.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1559151}, doi = {10.3389/fncel.2025.1559151}, pmid = {40207239}, issn = {1662-5102}, abstract = {Caenorhabditis elegans has been widely used as a model organism in neurodevelopment for several decades due to its simplicity, rapid growth, short life cycle, transparency, and rather simple genetics. It has been useful in modeling neurodegenerative diseases by the heterologous expression of the major proteins that form neurodegenerative-linked aggregates such as amyloid-β peptide, tau protein, and α-synuclein, among others. Furthermore, chemical treatments as well as the existence of several interference RNA libraries, transgenic worm lines, and the possibility of generating new transgenic strains create a magnificent range of possible tools to study the signaling pathways that could confer protection against protein aggregates or, on the contrary, are playing a detrimental role. In this review, we summarize the different C. elegans models of neurodegenerative diseases with a focus on Alzheimer's and Parkinson's diseases and how genetic tools could be used to dissect the signaling pathways involved in their pathogenesis mentioning several examples. Finally, we discuss the use of pharmacological agents in C. elegans models that could help to study these disease-associated signaling pathways and the powerful combinations of experimental designs with genetic tools. This review highlights the advantages of C. elegans as a valuable intermediary between in vitro and mammalian in vivo models in the development of potential new therapies.}, }
@article {pmid40206871, year = {2025}, author = {Chae, SU and Min, JS and Jo, SJ and Lee, CB and Park, J and Bae, SH and Bae, SK}, title = {Prediction of first-in-human dose for new composition bee venom based on allometric scaling and pharmacokinetic modeling approach.}, journal = {Translational and clinical pharmacology}, volume = {33}, number = {1}, pages = {27-39}, doi = {10.12793/tcp.2025.33.e4}, pmid = {40206871}, issn = {2289-0882}, abstract = {Bee venom is a traditional remedy used to treat conditions related to the nervous and musculoskeletal systems, as well as autoimmune diseases. Recently, we developed a new composition bee venom (NCBV), a fortified content of bee venom phospholipase A2 (bvPLA2), which may be effective in the treatment of Alzheimer's disease. NCBV is currently preparing to conduct a phase 1 clinical trial, and this study aimed to predict the first-in-human (FIH) dose using a mechanistic approach. First, animal pharmacokinetic (PK) studies from three different species were explored and integrated to build a PK model using nonlinear mixed-effect modeling. The final models were described by two-compartment model with first order absorption and elimination, and were used to define the PK parameters for each species. To predict human PK parameters, simple, brain weight (BrW) or maximum lifespan potential (MLP) incorporated allometric scaling approaches were used, with the BrW method showing the highest correlation (R[2] = 0.974). The initial FIH dose was back-calculated based on the area under the concentration-time curve of 0.397 μg·h/mL after the injection of an efficacious dose of 0.1 mg/kg in mice using the developed PK model. The predicted initial doses for a 70 kg human were 5.5, 1.3, and 3.5 mg, when using the simple, BrW, and MLP incorporated model, respectively. A subcutaneous FIH dose of 1.3 mg NCBV was ultimately recommended for a 70-kg human. Based on the no observed adverse effect level, the suggested FIH dose ranges for NCBV are 0.1 to 3 mg, which correspond with our proposed dose.}, }
@article {pmid40206658, year = {2025}, author = {Iwata-Endo, K and Sahashi, K and Kawai, K and Fujioka, Y and Okada, Y and Watanabe, E and Iwade, N and Ishibashi, M and Mohammad, M and Aldoghachi, AF and Tuerde, D and Fujiwara, T and Hirai, S and Okado, H and Katsuno, M and Watanabe, H and Kanamitsu, K and Neya, M and Ishigaki, S and Sobue, G}, title = {Correcting tau isoform ratios with a long-acting antisense oligonucleotide alleviates 4R-tauopathy phenotypes.}, journal = {Molecular therapy. Nucleic acids}, volume = {36}, number = {2}, pages = {102503}, doi = {10.1016/j.omtn.2025.102503}, pmid = {40206658}, issn = {2162-2531}, abstract = {Tau, a microtubule-binding protein linked to tauopathies like Alzheimer's disease and frontotemporal lobar degeneration (FTLD), has 3-repeat (3R) and 4-repeat (4R) isoforms. Accumulation of the 4R-tau is associated with FTLD, progressive supranuclear palsy (PSP), and cortico-basal degeneration (CBD). We previously showed that a loss of fused in sarcoma (FUS) or splicing factor, proline- and glutamine-rich (SFPQ) promoted 4R-tau accumulation, which induced FTLD-like behaviors and neurodegeneration in mice. Here, we developed antisense oligonucleotides (ASOs) modified with 2'-O, 4'-C-ethylene-bridged nucleic acids (ENAs), reducing the 4R-tau/3R-tau ratio while maintaining total tau expression from the MAPT gene. In vitro screening identified EN-06 as the most effective ENA. Intracerebroventricular (ICV) administration of EN-06 corrected the 4R/3R-tau ratio in FUS-silenced humanized tau mice and human iPSC-derived neurons. This treatment ameliorated disease phenotypes, including aberrant behaviors, spine dysmorphology, and neurodegeneration. The half-life of EN-06 after a single ICV administration was approximately 6 months in the brain, with splicing correction effects that persisted for 2 years. The efficacy of EN-06 was higher than that of 2'-O-methoxyethyl (MOE)-modified ASO (MO-06). These findings highlight the potential of ENA-modified ASOs to reduce 4R-tau while preserving total MAPT expression, thus offering a safe and long-acting treatment for 4R-tau-associated tauopathies.}, }
@article {pmid40206484, year = {2025}, author = {Satyanarayanan, SK and Yip, TF and Han, Z and Zhu, H and Qin, D and Lee, SMY}, title = {Role of toll-like receptors in post-COVID-19 associated neurodegenerative disorders?.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1458281}, doi = {10.3389/fmed.2025.1458281}, pmid = {40206484}, issn = {2296-858X}, abstract = {In the intricate realm of interactions between hosts and pathogens, Toll-like receptors (TLRs), which play a crucial role in the innate immune response, possess the ability to identify specific molecular signatures. This includes components originating from pathogens such as SARS-CoV-2, as well as the resulting damage-associated molecular patterns (DAMPs), the endogenous molecules released after cellular damage. A developing perspective suggests that TLRs play a central role in neuroinflammation, a fundamental factor in neurodegenerative conditions like Alzheimer's and Parkinson's disease (PD). This comprehensive review consolidates current research investigating the potential interplay between TLRs, their signaling mechanisms, and the processes of neurodegeneration following SARS-CoV-2 infection with an aim to elucidate the involvement of TLRs in the long-term neurological complications of COVID-19 and explore the potential of targeting TLRs as a means of implementing intervention strategies for the prevention or treatment of COVID-19-associated long-term brain outcomes.}, }
@article {pmid40205735, year = {2025}, author = {, }, title = {[Recommendations for the disease-modifying treatments of early Alzheimer's disease].}, journal = {Zhonghua nei ke za zhi}, volume = {64}, number = {}, pages = {9-19}, doi = {10.3760/cma.j.cn112138-20241028-00709}, pmid = {40205735}, issn = {0578-1426}, abstract = {Monoclonal antibodies targeting β-amyloid (Aβ)(represented by Lecanemab) have been approved in the United States, Japan and China for the treatment of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or mild AD dementia, and AD treatment has moved towards the era of disease modifying therapy (DMT). In view of the lack of use experience with DMT in China, this article presents recommendations for Aβ-based DMT clinical practice based on its clinical evidence, as well as its existing usage experience and research regarding AD. These recommendations include the mechanism of action, patient selection, standardized use, effectiveness, and safety monitoring, intending to help guide the rational use in real-world clinical practice.}, }
@article {pmid40204225, year = {2025}, author = {Lu, Z and Jiang, Z and Huang, X and Chen, Y and Feng, L and Mai, J and Lao, L and Li, L and Chen, WH and Hu, J}, title = {Anti-Alzheimer effects of an HDAC6 inhibitor, WY118, alone and in combination of lithium chloride: Synergistic suppression of ferroptosis via the modulation of tau phosphorylation and MAPK signaling.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {177605}, doi = {10.1016/j.ejphar.2025.177605}, pmid = {40204225}, issn = {1879-0712}, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder, and current therapies mainly offer symptomatic relief. Given that the pathophysiology of AD is multifaceted, a multimodal therapeutic strategy targeting multiple molecular pathways implicated in AD-related pathogenesis represents a pragmatic avenue for impeding the advancement of AD. In this study, we evaluated the anti-Alzheimer effects of an HDAC6 inhibitor WY118, both alone and in combination with lithium chloride (LiCl), a GSK-3β inhibitor, to synergistically suppress ferroptosis. The combination of compound WY118 and LiCl demonstrated significant synergistic effects in both cellular models of AD induced by glutamate and streptozotocin. The findings suggest that compound WY118, in particular in combination with LiCl, exhibits potent anti-Alzheimer effects by synergistically suppressing ferroptosis. Studies on the mechanism of action indicated that the combination treatment significantly reduced tau phosphorylation and inhibited p38 MAPK signaling. This combination therapy holds promise for developing more effective treatments for AD.}, }
@article {pmid40204151, year = {2025}, author = {Ansari, S and Maurya, VK and Kumar, S and Tiwari, M and Abdel-Moneime, AS and Saxena, SK}, title = {Neuroprotective effects of Centella asiatica against LPS/amyloid beta-induced neurodegeneration through inhibition of neuroinflammation.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2025.04.011}, pmid = {40204151}, issn = {1873-7544}, abstract = {Protein aggregation and microglia-mediated neuroinflammation are the major contributors to the progression of neurodegeneration. Currently, available drugs for neurodegenerative diseases have limited efficacy and are associated with several side effects; suggesting a need to discover novel therapeutic agents. Therefore, we aim to evaluate the neuroprotective effects of C. asiatica against amyloid beta (Aβ) and lipopolysaccharides (LPS)-induced neurodegeneration using human microglia and neuronal cell-based models. To identify potential molecular targets of C. asiatica, network pharmacology-based approaches were used along with molecular docking, followed by experimental validation via indirect ELISA, Western blotting, and indirect immunofluorescence assays. Our results from network pharmacology, molecular docking, and cell-based models, exhibited that AKT1, TNF-α, STAT3, CASP3, PTGS2, MAPK1, APP, and NF-κB are the potential molecular targets of C. asiatica. Further, we have found that C. asiatica treatment reduces LPS/Aβ-induced cell death, NO production, and LDH release in microglia and neuronal cells. The anti-neuroinflammatory effect of C. asiatica was further observed via the reduction of LPS, Aβ, and LPS+Aβ-induced neuroinflammatory markers; TNF-α, IL6, IL-1β, AKT1, INOS, NF-κB, MAPK3, and PTGS2 in microglia cells. Moreover, neurodegenerative and apoptotic markers; APP, α-syn, P-tau STAT3, and CASP3 were reduced upon C. asiatica treatment in neuronal cells, suggesting its neuroprotective properties. For the first time, we have shown the neuroprotective effects of C. asiatica against LPS, Aβ, and LPS+Aβ -induced neurodegeneration via inhibition of neuroinflammation and neurodegenerative markers. The outcomes of the study suggested that C. asiatica could be a promising candidate for neuroinflammation-mediated neurodegenerative diseases like Parkinson's and Alzheimer's.}, }
@article {pmid40204048, year = {2025}, author = {Wang, SM and Ji, WS and Chen, LJ and Shan, LH and Li, X and Gao, F and Xu, JB}, title = {Design, synthesis, and bio-evaluation of C1-aryl galantamine derivatives.}, journal = {Fitoterapia}, volume = {}, number = {}, pages = {106535}, doi = {10.1016/j.fitote.2025.106535}, pmid = {40204048}, issn = {1873-6971}, abstract = {For exploring the naturally-inspired multifunctional molecules for treatment of AD, a series of C1-aryl galantamine derivatives 4a-x were designed and synthesized. The cholinesterase inhibition activity and neuroprotection ability of 4a-x were evaluated. Among them, meta-tbutylbenzene derivative 4b (IC50 = 0.12 ± 0.03 μM) and para-hydroxybenzene derivative 4 h (IC50 = 3.86 ± 0.82 μM) exhibited selective inhibition effect against EeAChE and EqBChE, respectively. Compound 4 k containing meta-methylthio benzene group exhibited dual inhibitory activity against EeAChE (IC50 = 0.47 ± 0.13 μM) and EqBChE (IC50 = 2.98 ± 0.80 μM). Furthermore, the neuroprotection experiment revealed that eight synthesized derivatives had significant effect to protect SH-SY5Y cells from H2O2-induced damage at a concentration of 25 μM. Notably, the dual AChE and BChE inhibitor 4 k also exhibited the good neuroprotective activity, which deserves to be further explored for developing potential multifunctional AD drug.}, }
@article {pmid40203905, year = {2025}, author = {Chaudhary, S and Kumar, P and Kaushik, M}, title = {Physicochemical and molecular docking studies of the single nucleotide polymorphisms (SNPs) of apolipoprotein E (APOE) gene associated with Alzheimer's disease: Interaction with Amiloride.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {142896}, doi = {10.1016/j.ijbiomac.2025.142896}, pmid = {40203905}, issn = {1879-0003}, abstract = {The apolipoprotein E (APOE) gene's APOE4 variant is frequently associated with an elevated risk of Alzheimer's disease, while APOE3 isoform is found in normal individuals. Both the isoforms differ by only one base (Single nucleotide polymorphisms, SNPs). In this study, Amiloride hydrochloride (AM), a diuretic drug, was utilized to investigate its interaction with the DNA sequence of APOE isoforms, APOE3 and APOE4. Na[+]/H[+] exchangers (NHEs) are inhibited by AM, thus making these transporters as amiloride-sensitive. Various physicochemical and molecular docking methods were employed to explore the AM binding site on the 22-mer apo3 and apo4 DNA sequences. Present study revealed that AM binds to the minor groove via vander Waals forces or H-bonding. The binding constants obtained from both the absorbance and fluorescence studies depict that AM strongly interacts with apo4 sequence. Competitive analysis with Acridine Orange and Hoechst supported the minor groove binding property of AM. Molecular docking results, including LigPlots, further support the experimental analysis, revealing the interacting nitrogenous bases of the studied sequences. This study helps in facilitating our understanding regarding the DNA-drug binding interactions, which may further be utilized for designing a better and more target specific drug for Alzheimer's disease treatment.}, }
@article {pmid40203197, year = {2025}, author = {Zhao, S and Yang, Q and Gao, C}, title = {The mechanism of super-enhancer regulation of gene expression and research progress in neurodegenerative diseases.}, journal = {Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion}, volume = {}, number = {}, pages = {}, doi = {10.24875/RIC.24000246}, pmid = {40203197}, issn = {0034-8376}, abstract = {Super-enhancers (SEs) play a key role in cell fate determination by regulating the transcription of cell-specific target genes and may contribute to the pathogenesis of neurodegenerative diseases. Targeted inhibition of the activity of SEs or knockout of SEs fragments may represent a novel therapeutic strategy for neurodegenerative diseases. This article mainly outlines the discovery, structure, and identification methods of SEs; lists the current SE database platforms; summarizes the main regulatory mechanisms of SEs and strategies to acquire disease-specific SEs; and reviews recent research advances on SEs in neurodegenerative diseases. These findings provide new insights into the molecular mechanisms and development of treatment for neurodegenerative diseases.}, }
@article {pmid40202070, year = {2025}, author = {Chang, S and Ding, N and Li, Y and Li, Y and Tang, Z and Pan, J and Yan, L and Chen, J}, title = {Sanshen San Formula Hinders Cognitive Function and Pathology in Alzheimer's Disease Through Potentiating the Function of Synapse.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {4}, pages = {e70349}, doi = {10.1111/cns.70349}, pmid = {40202070}, issn = {1755-5949}, support = {202102010014//Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine/ ; 201911//Huang Zhendong Research Fund for Traditional Chinese Medicine of Jinan University/ ; SL2023A03J01072//Guangzhou Basic Research Plan City-School Joint Funding Project/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; *Synapses/drug effects ; *Cognition/drug effects ; Amyloid beta-Peptides/toxicity ; Male ; Mice, Inbred C57BL ; Disease Models, Animal ; Humans ; Peptide Fragments ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) constitutes a devastating neurodegenerative disorder, manifested by amyloid-β aggregation, phosphorylated tau accumulation, and progressive cognitive deterioration. Current therapeutic interventions remain predominantly symptomatic, underscoring the urgency for more efficacious treatment strategies.
PURPOSE: This study elucidated the therapeutic potential of Sanshen San (SSS), a traditional Chinese herbal formula encompassing Polygala Radix, Pini Radix in Poria, and Acori Tatarinowii Rhizoma, on cognitive function and AD pathology.
METHODS: We implemented both acute Aβ1-42-injected mice and 5xFAD transgenic mouse models. The therapeutic efficacy of SSS was assessed through behavioral paradigms including Y-maze, Novel Object Recognition, and Morris Water Maze. Molecular mechanisms were delineated utilizing RNA sequencing, metabolomics analysis, immunofluorescence staining, Golgi-Cox staining, transmission electron microscopy, and Western blotting.
RESULTS: Chemical analysis unveiled 10 principal bioactive compounds in SSS. The formula substantially ameliorated cognitive performance in both Aβ1-42-injected and 5xFAD mouse models, attenuated Aβ plaque burden, and augmented microglial phagocytosis. SSS safeguarded synaptic integrity, enhanced mitochondrial function, and facilitated autophagy. Transcriptomic and metabolomic analyses demonstrated that SSS predominantly operates by reinstating synaptic transmission and neurotransmitter function, particularly in the dopaminergic system.
CONCLUSION: SSS efficaciously mitigates AD pathology through potentiating synaptic function, optimizing mitochondrial homeostasis, and restoring neurotransmitter balance, exemplifying a promising multi-target therapeutic strategy for the treatment of AD.}, }
@article {pmid40201802, year = {2025}, author = {Mataram, MBA and Kustiati, U and Wihadmadyatami, H and Nugrahaningsih, DAA and Salasia, SIO and Kusindarta, DL}, title = {Analysis of CA1, CA3, and DG areas of the hippocampus, substance-P, and brain-derived neurotrophic factors expression in the presence of Ocimum sanctum Linn on the brain of the rat model Alzheimer's disease.}, journal = {Open veterinary journal}, volume = {15}, number = {2}, pages = {630-639}, pmid = {40201802}, issn = {2218-6050}, mesh = {Animals ; *Alzheimer Disease/drug therapy/veterinary ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; Rats ; *Plant Extracts/pharmacology ; Disease Models, Animal ; *Hippocampus/drug effects/metabolism ; *Ocimum sanctum/chemistry ; *Substance P/metabolism/genetics ; Male ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurological condition characterized by impaired cognitive dysfunction and abnormal behavior. Thirty-five million individuals worldwide suffer from dementia, making it the most frequent cause of dementia. Canine cognitive dysfunction (CCD) affects 28% of dogs aged 11-12 years. It is a prevalent disease in canines. Amyloid-β peptides accumulate neurotoxicity, resulting in problems in the central nervous system and neurotransmitters. Treatments for both AD and CCD have not yet shown acceptable outcomes. It is crucial to comprehend disease mechanisms and identify novel therapeutics using animal models.
AIM: Using a rat model of AD, this study attempted to determine the effects of an ethanolic extract from Ocimum sanctum on the number and shape of neurons in the CA1, CA3, and DG sections of the hippocampus along with the expression of neurotrophic factors.
METHODS: The animal model will be split into five treatment groups, one of which will be a control group. The treatments will be administered for 14, 21, and 28 days, and samples will be analyzed by BDNF by ELISA, SP expression by immunohistochemical staining, and the number of neurons in CA1, CA3, and DG using cresyl violet staining.
RESULTS: Results of the study revealed increased neuronal density in the CA1, CA3, and DG regions, and these neurons were more highly expressed in the neurotrophic factor BDNF and neuropeptide SP.
CONCLUSION: By upregulating the expression of SP and BDNF, the ethanolic extract of O. sanctum increased the neuronal counts (pyramidal and granular cells) in the hippocampal CA1, CA3, and DG regions.}, }
@article {pmid40201594, year = {2025}, author = {Bagnati, PM and Londoño Castaño, M and Fernández, ML and Henao, BM and Chrem, P and Aguillón, D and Varela, LE and Barbaran, JD and Leon, Y and Surace, E and Madrigal, CC and Picasso, JP and Ramos, CP and Fernández, CMR and Vigo, G and Aguilar, LR and VargasCuadros, GA and Arcos-Burgos, M and Longoria, EM and Ziegemeier, E and McDade, E and Bateman, RJ and Allegri, RF and Lopera, F and Llibre-Guerra, JJ}, title = {Impact of genetic counseling and testing in individuals at high risk of familial Alzheimer's disease from Latin America: a non-randomized controlled trial.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {2}, pages = {e70102}, pmid = {40201594}, issn = {2352-8729}, abstract = {INTRODUCTION: This study involved evaluating a tailored genetic counseling and testing (GCT) protocol for families at risk of autosomal dominant Alzheimer's disease (ADAD) in Latin America (LatAm), focusing on essential cultural and regional adaptations.
METHODS: We conducted a non-randomized controlled trial among ADAD families in Colombia and Argentina. Participants were categorized based on their decision to learn their genetic status (GS), with further comparisons between mutation-positive versus mutation-negative participants who learned their status. Psychological impacts were measured using validated scales for anxiety and depression.
RESULTS: Of the 122 eligible participants, 97 completed the GCT protocol, and 87 opted to learn their GS. There were no clinically significant differences in psychological distress between those who learned their status and those who did not, nor between mutation-positive and mutation-negative individuals.
DISCUSSION: The GCT protocol effectively managed psychological impacts in ADAD families and was positively received, demonstrating the importance of culturally adapted GCT protocols.
HIGHLIGHTS: We examined the adaptation and efficacy of a GCT protocol in LatAm for families at risk of ADAD.The GCT protocol mitigated psychological distress among at-risk ADAD families.The study confirms the protocol's cultural appropriateness and psychological safety.Future studies should explore the long-term psychological and public health impacts of GCT and use of GCT for treatment options.}, }
@article {pmid40201498, year = {2025}, author = {Obaid Saleh, BH and Salman, MD and Salman, AD and Alardhi, SM and Mohammed, MM and Gyurika, IG and Le, PC and Ali, OI}, title = {Retraction notice to "In silico analysis of the use of solanine derivatives as a treatment for Alzheimer's disease" [Heliyon 10 (2024) e32209].}, journal = {Heliyon}, volume = {11}, number = {6}, pages = {e43086}, doi = {10.1016/j.heliyon.2025.e43086}, pmid = {40201498}, issn = {2405-8440}, abstract = {[This retracts the article DOI: 10.1016/j.heliyon.2024.e32209.].}, }
@article {pmid40201476, year = {2025}, author = {Olawande, TI and Ajayi, MP and Amoo, EO and Olawole-Isaac, A}, title = {Retraction notice to "Treatment pathways of Alzheimer in Nigeria" [Heliyon 6 (2020) e05724].}, journal = {Heliyon}, volume = {11}, number = {6}, pages = {e43077}, doi = {10.1016/j.heliyon.2025.e43077}, pmid = {40201476}, issn = {2405-8440}, abstract = {[This retracts the article DOI: 10.1016/j.heliyon.2020.e05724.].}, }
@article {pmid40201042, year = {2025}, author = {Ongtanasup, T and Eawsakul, K}, title = {Developing Novel Beta-Secretase Inhibitors in a Computer Model as a Possible Treatment for Alzheimer's Disease.}, journal = {Advances in pharmacological and pharmaceutical sciences}, volume = {2025}, number = {}, pages = {5528793}, pmid = {40201042}, issn = {2633-4690}, abstract = {Alzheimer's disease (AD) is a neurological condition that causes neurons and axons in the brain to deteriorate over time and in a specific pattern. The enzyme beta-secretase-1 (BACE-1) plays a crucial role in the onset and progression of AD. In silico approaches, or computer-aided drug design, have become useful tools for reducing the number of therapeutic candidates that need to be evaluated in human clinical trials. Finding chemicals that bind to BACE-1's active site and inhibit its activity is key for preventing AD. A pharmacophore model was developed in this study based on potent BACE-1 inhibitors previously identified, and subsequently employed to screen a commercially available compound database for similar compounds. ZINC35883784 was identified with high binding affinities and hydrogen bonding interactions. Moreover, similar properties to donepezil were found in a compound made by altering the structure of ZINC35883784 called (4R,5R)-2-[1-(2-ethylcyclohexyl)ethyl]-4-hydroxy-5-(4-hydroxybutyl)cyclohexanolate (M4). Compounds were tested for interactions with BACE-1 and favorable properties. Binding scores were confirmed after molecular docking. The assessment of drug-likeness was conducted utilizing Swiss ADME analysis. Molecular dynamics simulations assessed the stability of compound interactions with BACE-1. MMPBSA calculated binding free energy and contribution energy. Results showed that M4 had strong and steady interactions with BACE-1. M4 was also analyzed by predicted NMR and retrosynthesis. However, further experiments are needed to evaluate M4's potential as a BACE-1 inhibitor.}, }
@article {pmid40199891, year = {2025}, author = {Bhatnagar, A and Thomas, CM and Nge, GG and Zaya, A and Dasari, R and Chongtham, N and Manandhar, B and Kortagere, S and Elefant, F}, title = {Tip60 HAT activators as therapeutic modulators for Alzheimer's disease.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3347}, pmid = {40199891}, issn = {2041-1723}, support = {RF1NS095799//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {*Alzheimer Disease/drug therapy/genetics/metabolism ; Animals ; *Lysine Acetyltransferase 5/metabolism/genetics ; Humans ; Disease Models, Animal ; Acetylation/drug effects ; *Drosophila Proteins/metabolism/genetics ; Histones/metabolism ; *Histone Acetyltransferases/metabolism/genetics ; Drosophila melanogaster ; Brain/metabolism/drug effects ; Neurons/drug effects/metabolism ; Amyloid beta-Protein Precursor/metabolism/genetics ; Neuronal Plasticity/drug effects/genetics ; }, abstract = {Reduced histone acetylation in the brain causes transcriptional dysregulation and cognitive impairment that are key initial steps in Alzheimer's disease (AD) etiology. Unfortunately, current treatment strategies primarily focus on histone deacetylase inhibition (HDACi) that causes detrimental side effects due to non-specific acetylation. Here, we test Tip60 histone acetyltransferase (HAT) activation as a therapeutic strategy for selectively restoring cognition-associated histone acetylation depleted in AD by developing compounds that enhance Tip60's neuroprotective HAT function. Several compounds show high Tip60-binding affinity predictions in silico, enhanced Tip60 HAT action in vitro, and restore Tip60 knockdown mediated functional deficits in Drosophila in vivo. Furthermore, compounds prevent neuronal deficits and lethality in an AD-associated amyloid precursor protein neurodegenerative Drosophila model and remarkably, restore expression of repressed neuroplasticity genes in the AD brain, underscoring compound specificity and therapeutic effectiveness. Our results highlight Tip60 HAT activators as a promising therapeutic neuroepigenetic modulator strategy for AD treatment.}, }
@article {pmid40199808, year = {2025}, author = {Castedo, N and Alfonso, A and Alvariño, R and Vieytes, MR and Botana, LM}, title = {Cyclophilin A and C are the Main Components of Extracellular Vesicles in Response to Hyperglycemia in BV2 Microglial Cells.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40199808}, issn = {1559-1182}, support = {ED481A_2023//Xunta de Galicia/ ; }, abstract = {Cyclophilins (Cyps) and CD147 receptor play a crucial role in the inflammatory responses. Chronic inflammation causes tissue damage and is a common condition of several inflammation-based pathologies as diabetes or Alzheimer´s disease. Under high glucose (HG) conditions, microglia is activated and releases inflammatory mediators. In this process the role of Cyps is unknown, so this study was aimed to investigate the profile of Cyps in microglia and their release through extracellular vesicles (EVs) under hyperglycemia. An increase in reactive oxygen species (ROS) and nitric oxide (NO) levels was observed when BV2 glia cells were incubated with HG concentration. These effects were mitigated by the Cyps inhibitor cyclosporine A (CsA), suggesting the implication of Cyps in BV2 activation. In these conditions the intracellular expression of CypA, B, C and D, as well as the membrane expression of CD147 receptor was increased. In addition, only CypA and CypC were detected in the extracellular medium. Then, the presence of Cyps inside EVs was explored as an alternative secretion route. Interestingly, under HG treatment, an increase in the levels of the four Cyps in EVs was observed. When neurons were treated with EVs derived from HG-treated glia cells, their viability was reduced and EVs were detected in cytosol neurons pointing to an EVs-Cyps neurotoxic effect. These findings provide novel insights into the relationship between Cyps and EVs in neuroinflammation in hyperglycemia conditions. The current results strengthen the role of Cyps in cell communication and its potential role in brain function under pathological conditions.}, }
@article {pmid40199685, year = {2025}, author = {Soni, P and Sharma, SM and Pieper, AA and Paul, BD and Thomas, B}, title = {Nrf2/Bach1 signaling axis: A promising multifaceted therapeutic strategy for Alzheimer's disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {}, number = {}, pages = {e00586}, doi = {10.1016/j.neurot.2025.e00586}, pmid = {40199685}, issn = {1878-7479}, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia, which continues to elude effective treatment despite decades of research and numerous clinical trials. While existing therapeutic strategies have primarily targeted neuropathological hallmarks such as amyloid plaques and tau tangles, they have failed to halt disease progression, leaving patients with limited options. This persistent failure reveals a critical gap in our understanding of AD and calls for a fresh perspective - one that goes beyond the traditional targets and dives deeper into the fundamental cellular processes that drive neurodegeneration. Recent advances in molecular biology underscore the significance of nuclear factor E2-related factor 2 (Nrf2), often termed the "guardian of redox homeostasis," in the pathophysiology of AD. Nrf2 orchestrates cellular responses to oxidative stress and neuroinflammation - two interlinked pathological features of AD. In the brains of AD patients, Nrf2 activity is diminished, weakening the brain's ability to counteract oxidative damage. Additionally, the BTB and CNC homology 1 (Bach1) protein, a transcriptional repressor of Nrf2, has emerged as a potential therapeutic target. Here, we review the current landscape of clinical trials in AD and identify the limitations of the conventional approaches. We then explore the prospects of a novel approach that combines Nrf2 activation with Bach1 inhibition to achieve a multipronged defense against oxidative stress, neuroinflammation, and other molecular culprits driving AD. This innovative strategy holds promise for synergistically modulating multiple neuroprotective pathways to advance AD treatment.}, }
@article {pmid40199587, year = {2025}, author = {Na, D and Yang, Y and Xie, L and Piekna-Przybylska, D and Bunn, D and Shamambo, M and White, P}, title = {The Auditory Brainstem Response Diagnoses Alzheimer-Like Disease in the 5xFAD Mouse Model.}, journal = {eNeuro}, volume = {}, number = {}, pages = {}, doi = {10.1523/ENEURO.0049-25.2025}, pmid = {40199587}, issn = {2373-2822}, abstract = {Early and accurate diagnosis of Alzheimer's Disease (AD) will be key for effective personalized treatment plans (Cummings, 2023). Significant difficulties in auditory processing have been frequently reported in many patients with mild cognitive impairment (MCI), the prodromal form of AD (Tarawneh et al., 2022), making it an outstanding candidate as AD diagnostic biomarker. However, the efficiency of diagnosis with this parameter has not been explored. Here we show that when male mice with amyloidosis begin to show memory decline, changes in the auditory brainstem response (ABR) to clicks enable the reliable diagnosis of disease using a machine learning algorithm. Interpretation of the machine learning diagnosis revealed that the upper levels of the auditory pathway, including the inferior colliculus, were the probable sources of the defects. Histological analyses show that in these locations, neuroinflammation and plaque deposition temporally correlate with behavioral changes consistent with memory loss. While these findings are tempered by the caveat that they derive from amyloidosis mice, we propose that ABR measurements be evaluated as an additional rapid, low-cost, non-invasive biomarker to assist the diagnostic testing of early-stage AD.Significance Statement New disease modifying treatments for AD only work for a subset of patients and require precise disease staging. AD is highly correlated with both central auditory dysfunction and hearing loss, but these are not diagnostic. We find that characteristics of the passive auditory brainstem response test reliably diagnose the onset of memory decline in a mouse model of AD, correlating with the initiation of amyloid deposits and neuroinflammation in the upper auditory nuclei. We further highlight the role that one region, the inferior colliculus, plays in multi-sensory integration, speculating that dementia becomes evident when the plaque-burdened cortex is unable to compensate for the degradation of pre-conscious sensory processing.}, }
@article {pmid40199086, year = {2025}, author = {Bansal, N and Parvez, MK and Babu, MA and Al-Dosari, MS and Singh, TG and Ali, N and Tyagi, Y and Dadwal, A and Yadav, U and Dwivedi, AR}, title = {Identification and investigation of hits targeting the N-methyl-D-aspartate receptor via drug repurposing: A plausible approach for anti-Alzheimer drug discovery.}, journal = {Journal of molecular graphics & modelling}, volume = {138}, number = {}, pages = {109036}, doi = {10.1016/j.jmgm.2025.109036}, pmid = {40199086}, issn = {1873-4243}, abstract = {The effective treatment of neurological diseases, particularly Alzheimer's disease (AD), is a significant source of frustration for drug discovery scientists. The lengthy process of drug discovery further makes this task exceedingly challenging. To enable a rapid stride in drug discovery, we focused on the drug repurposing strategy to identify new N-methyl-D-aspartate receptor (NMDAR) inhibitors from the pool of 1827 approved USFDA drugs. The high throughput virtual screening (HTVS) followed by molecular docking and molecular mechanics studies enabled us to identify two drugs, Ertugliflozin (Dock Score: -9.43 kcal/mol, MMGBSA: -104.50 kcal/mol) and Selpercatinib (Dock Score: 8.11 kcal/mol, MMGBSA: 83.62 kcal/mol), with a high affinity towards the NMDAR. The molecular dynamics analysis on these identified drugs led us to choose Ertugliflozin for its better stability as a lead for further studies. The corroboration of in silico findings led us to deduce that Ertugliflozin can inhibit NMDAR with an IC50 of 613.19 nM. These results were confirmed by the anti-NMDAR ELISA-based analysis, which was further deduced via western blotting. The work is further supported by strong literature evidence that concludes the impact of antidiabetic molecules on AD progression, along with the evidence that Ertugliflozin possesses efficacy against AD with unequivocal evidence on the biological target and the mechanism. Further work, however, is required to establish this association in the in vivo or suitable model that could mimic the AD microenvironment as a part of future research.}, }
@article {pmid40198478, year = {2025}, author = {Rodrigues Salles, G and Granato, AEC and Viero, FT and Pacheco-Soares, C and Ferreira, ST and Porcionatto, M and Ulrich, H}, title = {Self-assembly and 3D Bioprinting of Neurospheres and Evaluation of Caffeine and Photobiomodulation Effects in an Alzheimer's Disease In Vitro Model.}, journal = {Stem cell reviews and reports}, volume = {}, number = {}, pages = {}, doi = {10.1007/s12015-025-10850-7}, pmid = {40198478}, issn = {2629-3277}, support = {Grants 2022/08664-4//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2018/12605-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2018/2018/0763-4//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; Grants 406258/2022-8 (INCT Model3D)//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 311026/2022-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 152384/2024-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 406396/2021-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 308012/2021-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; NCT-REGENERA; Grant 465656/2014-5)//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; NCT-REGENERA; Grant 465656/2014-5)//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 150903/2024-3//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; }, abstract = {Several in vitro models of Alzheimer's disease (AD) rely on 2D cell culture, and, more recently, 3D cultures represented by free-floating neurospheres have been used as models for the disease. The advantage of 3D over 2D cell culture is that cell-extracellular matrix and cell-cell interactions can be assessed, better representing the molecular and cellular hallmarks of the disease. In the current study, we developed two complementary 3D neurosphere models using SH-SY5Y human neuroblastoma cells to investigate AD pathology and evaluate potential therapies. First, self-assembled neurospheres were exposed to hydrogen peroxide (H2O2) and amyloid-beta oligomers (AβOs), inducing AD-like features such as increased production of reactive oxygen species (ROS), amyloid aggregation, and apoptosis. Treatment with caffeine or photobiomodulation (PBM) using LED irradiation significantly reduced Aβ1-42 accumulation, ROS generation, and decreased apoptosis markers. Second, 3D bioprinting of SH-SY5Y cells resulted in neurospheres with enhanced cellular organization and differentiation. These findings emphasize the advantages of 3D models for studying neurodegeneration and evaluating therapeutic strategies, bridging the gap between traditional 2D cultures and complex in vitro systems.}, }
@article {pmid40196845, year = {2025}, author = {Yang, D and Deng, Z and Zhou, H and Zhang, Q and Zhang, X and Gong, J}, title = {Exosome-mediated dual drug delivery of curcumin and methylene blue for enhanced cognitive function and mechanistic elucidation in Alzheimer's disease therapy.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1562565}, pmid = {40196845}, issn = {2296-634X}, abstract = {Alzheimer's disease (AD) is one of the neurodegenerative disorders, characterized by complex pathogenic mechanisms, including the deposition of beta-amyloid protein and hyperphosphorylation of Tau protein. There is currently a lack of effective therapeutic approaches for AD treatment. The aim of this study was to design exosomes (EXO) as a specifically designed carrier able to carry Curcumin (Cur) and Methylene Blue (MB) to improve cognitive function and to elucidate its underlying mechanisms. Our study results indicated that EXO-Cur+MB inhibited Tau protein phosphorylation by activating the AKT/GSK-3β pathway, while reversing cognitive dysfunction in AD mice by reducing apoptosis induced by okadaic acid (OA). Thus, our results suggested that EXO-Cur+MB would be of potential use for the treatment of AD.}, }
@article {pmid40196718, year = {2025}, author = {Zhuang, C and Yan, H and Lu, J and Zhou, Y and Liu, Y and Shi, G and Li, Y}, title = {Compensatory enhancement of orexinergic system functionality induced by amyloid-β protein: a neuroprotective response in Alzheimer's disease.}, journal = {Frontiers in physiology}, volume = {16}, number = {}, pages = {1529981}, pmid = {40196718}, issn = {1664-042X}, abstract = {BACKGROUND: Amyloid-β protein (Aβ) accumulation is a defining characteristic of Alzheimer's disease (AD), resulting in neurodegeneration and a decline in cognitive function. Given orexin's well-documented role in enhancing memory and cognition, this study investigates its potential to regulate Aβ-induced neurotoxicity, offering new perspectives into AD management.
METHODS: This paper simulated Aβ accumulation in the hippocampus of AD patients by administering Aβ1-42 oligomers into the bilateral hippocampal dentate gyrus of ICR mice. Inflammatory cytokines (IL-6, TNF-α) and orexin-A levels were measured by ELISA. Additionally, the excitability of orexinergic neurons was assessed by IHC targeting c-Fos expression. These methodologies evaluated the Aβ-induced neuroinflammation, orexinergic system functionality, and dexamethasone's (Dex) effects on these processes.
RESULTS: Injection of Aβ1-42 oligomer resulted in elevated levels of IL-6, TNF-α, and orexin-A in the hippocampus, as well as increased excitability of orexinergic neurons in the lateral hypothalamus (LH). Dex treatment reduced neuroinflammation, causing a reduction in orexin-A levels and the excitability of orexinergic neurons.
CONCLUSION: Aβ-induced neuroinflammation is accompanied by enhanced levels of orexin-A and orexinergic neuron excitability. These findings suggest that the enhanced functionality of the orexinergic system may become a compensatory neuroprotective mechanism to counteract neuroinflammation and enhance cognitive function.}, }
@article {pmid40196602, year = {2025}, author = {Iturria-Medina, Y and Poole, VN and Zammit, AR and Yu, L and Tasaki, S and Hong, JH and Lopes, KP and Batalha, C and Ridwan, AR and Vialle, RA and Sanchez-Rodriguez, L and Geddes, MR and Abadir, P and Ortlund, E and De Jager, P and Menon, V and Beeri, MS and Buchman, AS and Levin, Y and Morgenstern, D and Schneider, JA and Daouk, RK and Wyss-Coray, T and Seyfried, NT and Arfanakis, K and Rosa-Neto, P and Wang, Y and Bennett, DA}, title = {Translating the Post-Mortem Brain Multi-Omics Molecular Taxonomy of Alzheimer's Dementia to Living Humans.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.03.20.644323}, pmid = {40196602}, issn = {2692-8205}, abstract = {Alzheimer's disease (AD) dementia is characterized by significant molecular and phenotypic heterogeneity, which confounds its mechanistic understanding, diagnosis, and effective treatment. In this study, we harness the most comprehensive dataset of paired ante-mortem blood omics, clinical, psychological, and post-mortem brain multi-omics data and neuroimaging to extensively characterize and translate the molecular taxonomy of AD dementia to living individuals. First, utilizing a comprehensive integration of eight complementary molecular layers from brain multi-omics data (N = 1,189), we identified three distinct molecular AD dementia subtypes exhibiting strong associations with cognitive decline, sex, psychological traits, brain morphology, and characterized by specific cellular and molecular drivers involving immune, vascular, and oligodendrocyte precursor cells. Next, in a significant translational effort, we developed predictive models to convert these advanced brain-derived molecular profiles (AD dementia pseudotimes and subtypes) into blood-, MRI- and psychological traits-based markers. The translation results underscore both the promise of these models and the opportunities for further enhancement. Our findings enhance the understanding of AD heterogeneity, underscore the value of multi-scale molecular approaches for elucidating causal mechanisms, and lay the groundwork for the development of novel therapies in living persons that target multi-level brain molecular subtypes of AD dementia.}, }
@article {pmid40195966, year = {2025}, author = {Rajanna, S and Gundale, PP and Dev Mahadevaiah, A}, title = {Advancements in the treatment of Alzheimer's disease: a comprehensive review.}, journal = {Dementia & neuropsychologia}, volume = {19}, number = {}, pages = {e20240204}, pmid = {40195966}, issn = {1980-5764}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes. Despite being the most common cause of dementia, effective treatments have been elusive. However, recent years have witnessed significant advancements in understanding and treating Alzheimer's. Key to these advancements is the shift toward targeted therapies tailored to individual genetic and biomarker profiles, promising more effective outcomes while minimizing side effects. The integration of advanced neuroimaging techniques has revolutionized early diagnosis and disease monitoring, enabling proactive intervention strategies that may alter disease trajectories. This review provides an overview of these advancements, focusing on disease-modifying therapies, symptomatic treatments, combination therapies, lifestyle interventions, biomarker development, innovative drug delivery systems, immunotherapy, gene therapy, and neuroprotective agents.}, }
@article {pmid40195962, year = {2025}, author = {de Oliveira Andrade, LJ and Matos, G and Matos de Oliveira, L}, title = {Intranasal insulin in Alzheimer disease (diabetes in situ?): a systematic review and meta-analysis.}, journal = {Dementia & neuropsychologia}, volume = {19}, number = {}, pages = {e20240191}, pmid = {40195962}, issn = {1980-5764}, abstract = {UNLABELLED: Alzheimer disease (AD) is a neurodegenerative disorder. Evidence suggests that AD shares pathophysiological similarities with type 2 diabetes. Intranasal insulin (INI) has emerged as a potential therapeutic approach for AD by directly targeting the brain and modulating insulin signaling pathways.
OBJECTIVE: To evaluate the efficacy and safety of INI therapy for AD through a systematic review and meta-analysis of randomized controlled trials.
METHODS: A search of electronic databases, including PubMed, Web of Science, Scopus, and Embase, was conducted to identify relevant studies published up to June 2024. Inclusion criteria encompassed peer-reviewed original research articles focused on humans, investigating the therapeutic effects of INI administration on cognitive impairment associated with AD, and reporting quantitative data on cognitive outcomes, biomarkers, or pathological markers relevant to AD. A meta-analysis was conducted to quantitatively synthesize the effects of INI on cognitive outcomes.
RESULTS: A total of 647 articles were identified, and eight studies met the inclusion criteria. The overall odds ratio was 3.75 (95%CI 1.49-9.40). The test for overall effect showed a statistically significant difference (p<0.05). However, the I[2] value indicated a high level of heterogeneity (85.5%), suggesting significant variability among the studies.
CONCLUSION: While the current data is not yet conclusive enough to definitively establish INI as a standard treatment for AD, the evidence supporting its safety, efficacy, and reduced risk of systemic side effects suggests potential cognitive benefits for improving global cognition in patients with AD.}, }
@article {pmid40195959, year = {2025}, author = {Fan, X and Xie, Y and Cao, S and Zhu, L and Wang, X}, title = {VPS35-Retromer: Multifunctional Roles in Various Biological Processes - A Focus on Neurodegenerative Diseases and Cancer.}, journal = {Journal of inflammation research}, volume = {18}, number = {}, pages = {4665-4680}, pmid = {40195959}, issn = {1178-7031}, abstract = {The Vacuolar Protein Sorting 35 (VPS35)-Retromer complex plays a pivotal role in intracellular protein trafficking and recycling. As an integral component of the Retromer complex, VPS35 selectively recognizes and retrogradely transports membrane protein receptors to the trans-Golgi network, thereby preventing the degradation of transmembrane proteins by lysosomes after they have fulfilled their physiological functions, and facilitating their continued activity. VPS35 regulates autophagy, mitophagy, mitochondrial homeostasis, and various other biological processes, including epidermal regeneration, neuronal iron homeostasis, and synaptic function. Studies have shown that mutations or dysfunctions in VPS35 disrupt the normal operation of Retromer, impair neuronal health and survival, and contribute to the onset of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Additionally, VPS35 modulates tumor growth and metastasis in cancers such as liver and breast cancer through the regulation of multiple signaling pathways. Targeting VPS35 might be a potential therapy in clinic treatment of neurodegenerative diseases and cancers.}, }
@article {pmid40195847, year = {2025}, author = {İğdeli, G and Fritzen, L and Pietrzik, CU and Temel, BA}, title = {Folic acid-conjugated amphiphilic copolymers for the enhanced delivery of donepezil: synthesis, characterization and blood-brain barrier permeability in a co-culture model.}, journal = {Journal of biomaterials science. Polymer edition}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/09205063.2025.2486863}, pmid = {40195847}, issn = {1568-5624}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with limited therapeutic options, largely due to challenges in delivering drugs across the blood-brain barrier (BBB). In this study, we synthesized folic acid (FA) conjugated amphiphilic copolymers via reversible addition-fragmentation chain transfer (RAFT) polymerization to enhance the targeted delivery of donepezil (DZP) to the brain. The copolymers were self-assembled into micelles and extensively characterized for their size, zeta potential, and stability using dynamic light scattering (DLS) and transmission electron microscopy (TEM). The micelles were further evaluated for their ability to cross an in vitro BBB model and their cellular uptake by brain endothelial cells. FA conjugation was employed to exploit the folate receptor-mediated transport mechanism, which has shown potential for improving drug delivery across the BBB. This study demonstrates the feasibility of using FA functionalized micelles as a targeted delivery system, offering potential advancements in the treatment of Alzheimer's disease.}, }
@article {pmid40195677, year = {2025}, author = {Homkajorn, B and Nilsu, T and Suntararuks, S and Saparpakorn, P and Ingkaninan, K and Limpeanchob, N and Satayavivad, J and Ruchirawat, S and Thasana, N}, title = {Synthesis, Biological Evaluation, Molecular Docking, and In Silico ADME Predictions of Huperzine: A Derivative for the Novel Protective Application Against Neurodegenerations.}, journal = {Chemistry, an Asian journal}, volume = {}, number = {}, pages = {e202401950}, doi = {10.1002/asia.202401950}, pmid = {40195677}, issn = {1861-471X}, support = {BRG6080013//Thailand Science Research and Innovation/ ; FRB660044/0240//Thailand Science Research and Innovation/ ; 48296/4691997//Ministry of Higher Education, Science, Research and Innovation, Thailand/ ; 50250/4772844//Ministry of Higher Education, Science, Research and Innovation, Thailand/ ; }, abstract = {To date, there has been no effective treatment available for the Alzheimer's disease (AD); hence, novel compounds with AD inhibitory effects are highly desirable. Huperzine A (HupA), a natural Lycopodium alkaloid, is a potent acetylcholinesterase (AChE) inhibitor for AD treatment. In this study, HupA derivatives, huperzil, N-hippurylhuperzine A, pyrrolhuperzine A, maleicamide-huperzine A and phthaleicamide-huperzine A, were synthesized and their in silico computation as the central nervous system (CNS) drug was performed. All derivatives exhibited lower anti-AChE activity than HupA. However, we found other non-cholinergic functions in AD-mimicking models using differentiated SH-SY5Y. HupA and derivatives significantly suppressed the Aβ25-35 cytotoxicity and showed recovery effects against arsenic- induced AD pathologies including reactive oxygen species generation, neurite outgrowth shortening, amyloid precursor protein suppression and the elevation of β-secretase, endogenous Aβ peptide, and Tau and neurofilament light proteins. In summary, we prepared three potential compounds with dual-AChE cholinergic and non-cholinergic functions. Further development of these compounds will be beneficial for the future use as an alternate compound against AD.}, }
@article {pmid40195333, year = {2025}, author = {Wang, MY and Chen, KL and Huang, YY and Chen, SF and Wang, RZ and Zhang, Y and Hu, HY and Ma, LZ and Liu, WS and Wang, J and Xin, JW and Zhang, X and Li, MM and Guo, Y and Dong, Q and Cheng, W and Tan, L and Cui, M and Zhang, YR and Yu, JT}, title = {Clinical utility of cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic workup of complex patients with cognitive impairment.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {130}, pmid = {40195333}, issn = {2158-3188}, support = {92249305//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; Male ; Female ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Biomarkers/cerebrospinal fluid ; *Cognitive Dysfunction/cerebrospinal fluid/diagnosis ; Middle Aged ; Aged ; *Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; China ; Peptide Fragments/cerebrospinal fluid ; }, abstract = {Cerebrospinal fluid (CSF) biomarkers have been widely adopted in Alzheimer's disease (AD) diagnosis. However, no studies focused on the application of CSF biomarkers in the clinical practice of complex and atypical patients with cognitive impairment in China. This study aimed to evaluate the added value of CSF AD biomarkers in cognitively impaired patients with complex conditions in a memory clinical setting. A total of 633 participants were included from the National Center for Neurological Disorders in Shanghai, China. The CSF AD biomarkers were measured with ELISA. Cutoff values were firstly identified using Youden's index. The neurologists proposed etiology diagnosis with a percentage estimate of their confidence and prescribed medication before and after CSF disclosure. Changes in etiological diagnosis, diagnostic confidence, and management plan were compared across the groups. Of the 633 patients (mean [SD] age, 61.1 [11.3] years; 295 males [46.6%]), 372 (58.8%) were diagnosed with dementia, 103 (16.3%) with mild cognitive impairment, and 158 (24.9%) with subjective cognitive decline. Using those pre-defined cutoffs, we categorized patients into 3 groups: Alzheimer's continuum (68.1%), non-AD pathologic change (11.1%), and normal AD biomarkers (20.8%). After CSF disclosure, the proposed etiology changed in 158 (25.0%) participants and the prescribed medication changed in 200 (31.6%) patients. Mean diagnostic confidence increased from 69.5-83.0% (+13.5%; P < 0.001). In conclusion, CSF AD biomarkers significantly impacted the diagnosis, diagnostic confidence, and treatment plans for Chinese patients with complex cognitive impairment. CSF AD biomarkers are a useful tool for clinicians beyond routine clinical assessment.}, }
@article {pmid40195175, year = {2025}, author = {Shaw, S and Porel, P and Aran, KR}, title = {Transthyretin as a therapeutic target: the future of disease-modifying therapies for Alzheimer's disease.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {370}, pmid = {40195175}, issn = {1573-4978}, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Prealbumin/metabolism/genetics ; Animals ; Blood-Brain Barrier/metabolism ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Molecular Targeted Therapy ; tau Proteins/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease for causing memory deficits and primarily characterized by extracellular deposition of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles (NFTs), and hyperphosphorylation of tau protein, all are pathological hallmarks for AD. Transthyretin (TTR) is a highly conserved homo-tetrameric protein, primarily synthesized in liver and choroid plexus, and most importantly involved in transport of T3-T4 hormones and retinol.
OBJECTIVES: This review explores the dual role of TTR, with a greater emphasis on its neuroprotective action, particularly in AD.
METHODS: Based on the available literature, TTR's potential as a biomarker in the central nervous system (CNS), focusing its role in stabilizing Aβ aggregation and the senile plaque formation during neurodegeneration. Additionally, TTR's dual roles, in neurodegeneration and neuroprotection are studied, emphasizing its potential for improving AD diagnosis and treatment strategies.
RESULTS: Recent research has revealed that TTR is gradually showcasing its promise in neuroprotection and neuronal viability in AD by binding with Aβ and mitigating its neurotoxic effects. Current preclinical and clinical studies also support that TTR is actively involved in maintaining the blood-brain barrier (BBB) integrity and maintain neurotransmitter balance, all of which offer significant therapeutic promise through TTR stabilizers, such as Tafamidis, Acoramidis, and Vutrisiran, highlighting their potential in AD treatment CONCLUSION: This review concludes that TTR plays bidirectional role and gaining interest as a potential biomarker, though several challenges must be addressed before it can be established a novel therapeutic target in AD management in the modern era of drug discovery.}, }
@article {pmid40194896, year = {2025}, author = {Tang, JM and Lu, Q and Lin, HX and Li, JQ and Zhu, XC and Ma, T}, title = {C-reactive protein-mediated dementia.}, journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society}, volume = {25}, number = {3}, pages = {e70032}, doi = {10.1111/psyg.70032}, pmid = {40194896}, issn = {1479-8301}, support = {BJ2020023//Wuxi Health and Family Planning Commission/ ; }, mesh = {Humans ; *C-Reactive Protein/metabolism ; *Dementia/diagnosis/metabolism/blood ; *Alzheimer Disease/diagnosis/metabolism/blood ; Biomarkers/blood ; *Cognitive Dysfunction ; Risk Factors ; *Inflammation/metabolism ; Aged ; Disease Progression ; }, abstract = {Loss of memory is the main feature of dementia, accompanied by personality changes. Alzheimer's disease (AD) is the most prevalent type of dementia globally and a major contributor to disability and mortality in older individuals. Most notably, the neurological damage caused by AD is irreversible, but the current market still lacks effective medications for the treatment of dementia. Numerous research studies have indicated that the inflammatory response is significantly involved in the development of cognitive impairment, and elevated C-reactive protein (CRP) levels in healthy people increases the likelihood of future AD. CRP is a nonspecific indicator of inflammation. In clinical practice, CRP has long been proven to be one of the risk factors and powerful predictors of neurodegenerative diseases. Given the accessibility and cost-effectiveness of CRP testing, it is reasonable to anticipate its utilisation for early screening and monitoring the progression of AD in the future. This review therefore focuses on the specific relationship between CRP and various types of dementia and explores how CRP contributes to cognitive impairment.}, }
@article {pmid40194646, year = {2025}, author = {Chauhan, D and Bagri, K and Deshmukh, R}, title = {Neuroprotective Effect of Perillyl alcohol in Sporadic Alzheimer's disease in Rats.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {177558}, doi = {10.1016/j.ejphar.2025.177558}, pmid = {40194646}, issn = {1879-0712}, abstract = {As people age, Alzheimer's disease, a neurological disorder that develops gradually, affects their memory and cognitive abilities. The two hallmarks of Alzheimer's disease are intracellular buildup of neurofibrillary tangles and extracellular β-amyloid plaques. In this work, the effects of Perillyl alcohol on experimental sporadic Alzheimer-type dementia produced by intracerebroventricular streptozotocin were investigated. Rats that received streptozotocin infusion experienced cholinergic hypofunction, increased oxidative-nitritive stress, and impaired memory and learning. Between 15 and 27 days following the initial streptozotocin infusion, 13 days of treatment with Perillyl alcohol (25, 50, and 100 mg/kg p.o.) significantly improved learning and memory in Morris water maze and object recognition test paradigms. Perillyl also significantly reduced oxidative-nitritive stress, as seen by a decrease in malondialdehyde and nitrite, and restored reduced glutathione and catalase levels. Acetylcholinesterase activity significantly increased in the current model, indicating cholinergic hypofunction and enhanced neuronal cell damage. Treatment with Perillyl alcohol also significantly decreased the increase in acetylcholinesterase activity, indicating that Perillyl alcohol may be able to prevent neuronal damage and restore cholinergic functions. Perillyl alcohol has been shown to improve spatial memory processing, which may be due to its antioxidant properties and capacity to restore cholinergic functioning. However, more study is required to understand the molecular mechanisms of POH that enhance cognition or prevent neurotoxic damage, which could support its application in neuroprotective effect.}, }
@article {pmid40194268, year = {2025}, author = {Jeremic, D and Navarro-Lopez, JD and Jimenez-Diaz, L}, title = {Clinical Benefits and Risks of Antiamyloid Antibodies in Sporadic Alzheimer Disease: Systematic Review and Network Meta-Analysis With a Web Application.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e68454}, doi = {10.2196/68454}, pmid = {40194268}, issn = {1438-8871}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Network Meta-Analysis as Topic ; *Internet ; Bayes Theorem ; Risk Assessment ; }, abstract = {BACKGROUND: Despite the increasing approval of antiamyloid antibodies for Alzheimer disease (AD), their clinical relevance and risk-benefit profile remain uncertain. The heterogeneity of AD and the limited availability of long-term clinical data make it difficult to establish a clear rationale for selecting one treatment over another.
OBJECTIVE: The aim of this work was to assess and compare the efficacy and safety of antiamyloid antibodies through an interactive online meta-analytic approach by performing conventional pair-wise meta-analyses and frequentist and Bayesian network meta-analyses of phase II and III clinical trial results. To achieve this, we developed AlzMeta.app 2.0, a freely accessible web application that enables researchers and clinicians to evaluate the relative and absolute risks and benefits of these therapies in real time, incorporating different prior choices and assumptions of baseline risks of disease progression and adverse events.
METHODS: We adhered to PRISMA-NMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for reporting of systematic reviews with network meta-analysis) and GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) guidelines for reporting and rating the certainty of evidence. Clinical trial reports (until September 30, 2024) were retrieved from PubMed, Google Scholar, and clinical trial databases (including ClinicalTrials.gov). Studies with <20 sporadic AD patients and a modified Jadad score <3 were excluded. Risk of bias was assessed with the RoB-2 tool. Relative risks and benefits have been expressed as risk ratios and standardized mean differences, with confidence, credible, and prediction intervals calculated for all outcomes. For significant results, the intervention effects were ranked in frequentist and Bayesian frameworks, and their clinical relevance was determined by the absolute risk per 1000 people and number needed to treat (NNT) for a wide range of control responses.
RESULTS: Among 7 treatments tested in 21,236 patients (26 studies with low risk of bias or with some concerns), donanemab was the best-ranked treatment on cognitive and functional measures, and it was almost 2 times more effective than aducanumab and lecanemab and significantly more beneficial than other treatments on the global (cognitive and functional) Clinical Dementia Rating Scale-Sum of Boxes (NNT=10, 95% CI 8-16). Special caution is required regarding cerebral edema and microbleeding due to the clinically relevant risks of edema for donanemab (NNT=8, 95% CI 5-16), aducanumab (NNT=10, 95% CI 6-17), and lecanemab (NNT=14, 95% CI 7-31), which may outweigh the benefits.
CONCLUSIONS: Our results showed that donanemab is more effective and has a safety profile similar to aducanumab and lecanemab, highlighting the need for treatment options with improved safety. Potential bias may have been introduced in the included trials due to unblinding caused by frequent cerebral edema and microbleeds, as well as the impact of the COVID-19 pandemic.}, }
@article {pmid40193955, year = {2025}, author = {Alruily, M and Abd El-Aziz, AA and Mostafa, AM and Ezz, M and Mostafa, E and Alsayat, A and El-Ghany, SA}, title = {Ensemble deep learning for Alzheimer's disease diagnosis using MRI: Integrating features from VGG16, MobileNet, and InceptionResNetV2 models.}, journal = {PloS one}, volume = {20}, number = {4}, pages = {e0318620}, pmid = {40193955}, issn = {1932-6203}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; Aged ; Brain/diagnostic imaging ; Male ; Female ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, leading to distinctive patterns of neuronal dysfunction and the cognitive decline emblematic of dementia. Currently, over 5 million individuals aged 65 and above are living with AD in the United States, a number projected to rise by 2050. Traditional diagnostic methods are fraught with challenges, including low accuracy and a significant propensity for misdiagnosis. In response to these diagnostic challenges, our study develops and evaluates an innovative deep learning (DL) ensemble model that integrates features from three pre-trained models-VGG16, MobileNet, and InceptionResNetV2-for the precise identification of AD markers from MRI scans. This approach aims to overcome the limitations of individual models in handling varying image shapes and textures, thereby improving diagnostic accuracy. The ultimate goal is to support primary radiologists by streamlining the diagnostic process, facilitating early detection, and enabling timely treatment of AD. Upon rigorous evaluation, our ensemble model demonstrated superior performance over contemporary classifiers, achieving a notable accuracy of 97.93%, along with a specificity of 98.04%, sensitivity of 95.89%, precision of 95.94%, and an F1-score of 87.50%. These results not only underscore the efficacy of the ensemble approach but also highlight the potential for DL to revolutionize AD diagnosis, offering a promising pathway to more accurate, early detection and intervention.}, }
@article {pmid40193643, year = {2025}, author = {Wang, X and Li, B and Ma, Y and Cui, Y and Yang, X and Li, Y and Jing, A and Zhou, Y and Li, M and Wang, S and Tu, Y}, title = {Acupuncture clinical hotspots and trends from 2013 to 2022: A bibliometric and visualized analysis.}, journal = {Medicine}, volume = {104}, number = {14}, pages = {e41890}, pmid = {40193643}, issn = {1536-5964}, mesh = {*Bibliometrics ; Humans ; *Acupuncture Therapy/trends ; Biomedical Research/trends ; }, abstract = {Through bibliometric analysis, trends in international acupuncture clinical development, key research areas, and current scientific issues were identified based on literature published from 2013 to 2022. Literature on acupuncture in clinical settings was retrieved and analyzed in this study utilizing the Web of Science database. A visualization analysis of the scientific landscape was performed using CiteSpace, VOSviewer, and GraphPad Prism. General statistics regarding the literature were examined, encompassing annual publication trends, citation frequencies, journal distributions, distributions across subject fields. Co-occurrence and cluster analyses of authors, countries, institutions, high-quality literature, and keywords were performed to explore the developmental trends, hotspots, and frontiers in acupuncture research comprehensively and intuitively. A total of 4554 studies were included, with an increasing trend in the number of publications related to the annual acupuncture Scientific Citation Index (SCI). The impact factors of the top 10 journals were mostly 1 to 3 points. The 10 most cited articles primarily concentrated on the use of acupuncture for pain-related disorders. Acupuncture and electroacupuncture are the dominant keywords, with terms such as "ischemic stroke" and "Alzheimer's disease" emerging from 2019 to 2022. From 2013 to 2022, the output of clinical SCI literature on acupuncture increased, acupuncture research gradually gained international recognition, and China gradually moved toward a dominant position. The most significant clinical research area of acupuncture is its application for analgesia, particularly through acupuncture and electroacupuncture. Future research directions may include the treatment of knee osteoarthritis, cognitive disorders, and assisted reproduction utilizing acupuncture.}, }
@article {pmid40193596, year = {2025}, author = {Trepczyk, K and Er, S and Hlushchuk, I and Airavaara, M and Alwani, A and Maziarz, K and Chmielarz, P and Słomska, K and Wieczerzak, E and Jankowska, E}, title = {Peptidomimetics Activating the Proteasome: A New Perspective for Parkinson's Treatment.}, journal = {Journal of medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jmedchem.5c00645}, pmid = {40193596}, issn = {1520-4804}, abstract = {The development of age-related neurodegenerative diseases is associated with the accumulation of damaged and misfolded proteins. Such proteins are eliminated from cells by proteolytic systems, mainly by 20S proteasomes, whose activity declines with age. Its stimulation has been recognized as a promising approach to delay the onset or ameliorate the symptoms of neurodegenerative disorders. Here we present peptidomimetics that are very effective in stimulating the proteasome in biochemical assays and in cell culture. They are stable in human plasma and capable of penetrating the cell membranes. The activators demonstrated the ability to enhance h20S degradation of α-synuclein and tau, whose aggregates are involved in the development of Parkinson's and Alzheimer's diseases, respectively. The peptidomimetics did not show cytotoxicity to HEK293T and primary hippocampal cells. Additionally, these compounds were highly effective in reducing the amount of phosphorylated α-synuclein aggregates in hippocampal neurons in a mouse embryonic cell model.}, }
@article {pmid40193122, year = {2025}, author = {Seminer, A and Mulihano, A and O'Brien, C and Krewer, F and Costello, M and Judge, C and O'Donnell, M and Reddin, C}, title = {Cardioprotective Glucose-Lowering Agents and Dementia Risk: A Systematic Review and Meta-Analysis.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {40193122}, issn = {2168-6157}, abstract = {IMPORTANCE: Although diabetes is a risk factor for dementia, the effect of glucose-lowering therapy for prevention of incident dementia is uncertain.
OBJECTIVE: To determine whether cardioprotective glucose-lowering therapy (sodium-glucose cotransporter-2 inhibitors [SGLT2is], glucagon-like peptide-1 receptor agonists [GLP-1RAs], metformin, and pioglitazone), compared with controls, was associated with a reduction in risk of dementia or cognitive impairment, and among primary dementia subtypes.
DATA SOURCES: The PubMed and Embase databases were searched for studies published from inception of the database to July 11, 2024.
STUDY SELECTION: Randomized clinical trials comparing cardioprotective glucose-lowering therapy with controls that reported dementia or change in cognitive scores. Cardioprotective glucose-lowering therapies were defined as drug classes recommended by guidelines for reduction of cardiovascular events, based on evidence from phase III randomized clinical trials. Inclusion criteria were assessed independently and inconsistencies were resolved by consensus.
DATA EXTRACTION AND SYNTHESIS: Data were screened and extracted independently by 2 authors adhering to the PRISMA guidelines in August 2024. Random-effects meta-analysis models were used to estimate a pooled treatment effect.
MAIN OUTCOMES AND MEASURES: The primary outcome measure was dementia or cognitive impairment. The secondary outcomes were primary dementia subtypes, including vascular and Alzheimer dementia, and change in cognitive scores.
RESULTS: Twenty-six randomized clinical trials were eligible for inclusion (N = 164 531 participants), of which 23 trials (n = 160 191 participants) reported the incidence of dementia or cognitive impairment, including 12 trials evaluating SGLT2is, 10 trials evaluating GLP-1RAs, and 1 trial evaluating pioglitazone (no trials of metformin were identified). The mean (SD) age of trial participants was 64.4 (3.5) years and 57 470 (34.9%) were women. Overall, cardioprotective glucose-lowering therapy was not significantly associated with a reduction in cognitive impairment or dementia (odds ratio [OR], 0.83 [95% CI, 0.60-1.14]). Among drug classes, GLP-1RAs were associated with a statistically significant reduction in dementia (OR, 0.55 [95% CI, 0.35-0.86]), but not SGLT2is (OR, 1.20 [95% CI, 0.67-2.17]; P value for heterogeneity = .04).
CONCLUSIONS AND RELEVANCE: While cardioprotective glucose-lowering therapies were not associated with an overall reduction in all-cause dementia, this meta-analysis of randomized clinical trials found that glucose lowering with GLP-1RAs was associated with a statistically significant reduction in all-cause dementia.}, }
@article {pmid40193118, year = {2025}, author = {Tang, H and Donahoo, WT and DeKosky, ST and Lee, YA and Kotecha, P and Svensson, M and Bian, J and Guo, J}, title = {GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {40193118}, issn = {2168-6157}, abstract = {IMPORTANCE: The association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) and risk of Alzheimer disease and related dementias (ADRD) remains to be confirmed.
OBJECTIVE: To assess the risk of ADRD associated with GLP-1RAs and SGLT2is in people with type 2 diabetes (T2D).
This target trial emulation study used electronic health record data from OneFlorida+ Clinical Research Consortium from January 2014 to June 2023. Patients were 50 years or older with T2D and no prior diagnosis of ADRD or antidementia treatment. Among the 396 963 eligible patients with T2D, 33 858 were included in the GLP-1RA vs other glucose-lowering drug (GLD) cohort, 34 185 in the SGLT2i vs other GLD cohort, and 24 117 in the GLP-1RA vs SGLT2i cohort.
EXPOSURES: Initiation of treatment with a GLP-1RA, SGLT2i, or other second-line GLD.
MAIN OUTCOMES AND MEASURES: ADRD was identified using clinical diagnosis codes. Hazard ratios (HRs) with 95% CIs were estimated using Cox proportional hazard regression models with inverse probability of treatment weighting (IPTW) to adjust for potential confounders.
RESULTS: This study included 33 858 patients in the GLP-1RA vs other GLD cohort (mean age, 65 years; 53.1% female), 34 185 patients in the SGLT2i vs other GLD cohort (mean age, 65.8 years; 49.3% female), and 24 117 patients in the GLP-1RA vs SGLT2i cohort (mean age, 63.8 years; 51.7% female). In IPTW-weighted cohorts, the incidence rate of ADRD was lower in GLP-1RA initiators compared with other GLD initiators (rate difference [RD], -2.26 per 1000 person-years [95% CI, -2.88 to -1.64]), yielding an HR of 0.67 (95% CI, 0.47-0.96). SGLT2i initiators had a lower incidence than other GLD initiators (RD, -3.05 per 1000 person-years [95% CI, -3.68 to -2.42]), yielding an HR of 0.57 (95% CI, 0.43-0.75). There was no difference between GLP-1RAs and SGLT2is, with an RD of -0.09 per 1000 person-years (95% CI, -0.80 to 0.63) and an HR of 0.97 (95% CI, 0.72-1.32).
CONCLUSION AND RELEVANCE: In people with T2D, both GLP-1RAs and SGLT2is were statistically significantly associated with decreased risk of ADRD compared with other GLDs, and no difference was observed between both drugs.}, }
@article {pmid40192926, year = {2025}, author = {Galvin, JE and Kleiman, MJ and Harris, HM and Estes, PW}, title = {The Cognivue Amyloid Risk Measure (CARM): A Novel Method to Predict the Presence of Amyloid with Cognivue Clarity.}, journal = {Neurology and therapy}, volume = {}, number = {}, pages = {}, pmid = {40192926}, issn = {2193-8253}, abstract = {INTRODUCTION: At the present time, clinical detection of individuals who have amyloid in their brain is not possible without expensive biomarkers. The objective of the study was to test whether Cognivue Clarity[®] can differentiate True Controls, preclinical Alzheimer's disease (pAD), mild cognitive impairment (MCI) due to Alzheimer's disease (MCI-AD), AD, and MCI and dementia due to non-AD etiologies enrolled in the Bio-Hermes Study.
METHODS: A total of 887 individuals completed Cognivue Clarity, amyloid PET scan, and blood-based AD biomarkers. Three Cognivue Clarity subtests differentiated between True Controls and pAD, and between cognitive impairment due to AD versus non-AD processes. This finding was leveraged to develop an amyloid-specific marker, combining the three subtests with age using machine learning to create the 4-point Cognivue Amyloid Risk Measure (CARM).
RESULTS: Cognivue Clarity discriminated cognitively normal from cognitively impaired individuals (p < 0.001, Cohen's d = 0.732). The CARM differentiated between individuals with amyloid and without amyloid by PET (p < 0.001, Cohen's d = 0.618) and blood-based biomarkers (p's < 0.001). Amyloid positivity and cognitive impairment increased across four CARM thresholds (p < 0.001). Dichotomizing CARM thresholds into low (CARM1/CARM2) and high (CARM3/CARM4) likelihood provided excellent discrimination for amyloid PET positivity (OR: 3.67; 95% CI 2.76-4.89). CARM categories differentiated between True Controls, pAD, MCI-AD, AD, and cognitive impairment due to non-AD etiologies (χ[2] = 137.6, p < 0.001) with the majority of True Controls and non-AD etiologies being in CARM1/CARM2, and the majority of pAD, MCI-AD, and AD being in CARM3/CARM4.
CONCLUSIONS: Cognivue Clarity detects individuals with cognitive impairment, and a derivation benchmarked against amyloid PET was used to develop the CARM to predict the presence of amyloid. Combining the CARM and the Cognivue Clarity overall score could help identify individuals with and without cognitive impairment due to AD or non-AD etiologies, help screen for treatment protocols with anti-amyloid therapies, enrich clinical trial recruitment, and help to identify pAD for prevention studies.
TRIAL REGISTRATION: ClinicalTrials. gov identifier, NCT04733989.}, }
@article {pmid40192212, year = {2025}, author = {Vidoni, ED and Parks, AC and Brunette, A and Kreszyn, K and Townley, RA and Arthur, AK and Gillen, L and Puchalt, JP and Lewandowski, T and Mudaranthakam, DP and Morris, JK and Smith, TR and Woodward, J and Burns, JM}, title = {Scaling Alzheimer's Care: The Case for Specialized Treatment Clinics.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.19461}, pmid = {40192212}, issn = {1532-5415}, support = {P30 AG072973/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: The approval of amyloid-targeting monoclonal antibodies has transformed Alzheimer's disease (AD) treatment, shifting the field from symptomatic management to targeting the underlying pathology. These therapies require specialized care models to manage the selection, treatment, and monitoring of eligible patients.
METHODS: Here, we describe the implementation of the Anti-Amyloid Treatment Clinic (KU-AATC) at the University of Kansas Health System, a dedicated clinic model designed to streamline access to amyloid-clearing therapies and to provide safe, efficient patient care. We detail the KU-AATC's structured approach, including a multidisciplinary team with advanced practice providers (APPs), leading patient evaluation and shared decision-making, and tailored workflows to ensure timely access to treatment. We review data from the clinic's first 18 months.
RESULTS: The KU-AATC model demonstrates a feasible approach to managing the complex needs of amyloid-targeting therapy for AD.
CONCLUSIONS: Our findings suggest that a specialized clinic structure can support safe, accessible, and efficient care for AD patients, potentially serving as a scalable model for healthcare systems adapting to the demands of emerging AD treatments. Expanding similar clinics may address neurologist shortages and improve equitable access to advanced therapies.}, }
@article {pmid40192032, year = {2025}, author = {Liang, P and Wang, Y and Liu, J and Huang, H and Li, Y and Kang, J and Li, G and Wu, H}, title = {Identification and Exploration of Immunity-Related Genes and Natural Products for Alzheimer's Disease Based on Bioinformatics, Molecular Docking, and Molecular Dynamics.}, journal = {Immunity, inflammation and disease}, volume = {13}, number = {4}, pages = {e70166}, pmid = {40192032}, issn = {2050-4527}, support = {//This research was supported by the Sanming Project of Medicine in Shenzen Municipality (No. SZZYSM202201007) and Soft Science Research Program Projects in Luohu District (Nos. LX202302129 and LX202302101)./ ; }, mesh = {Datasets as Topic ; Biomarkers/metabolism ; *Immunity/genetics ; *Biological Products/chemistry/pharmacology/therapeutic use ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Computational Biology ; *Alzheimer Disease/diagnosis/drug therapy/genetics/immunology ; Gene Expression/drug effects ; Oxidative Phosphorylation ; Tobacco Use Disorder/genetics ; Hippo Signaling Pathway/genetics ; Machine Learning ; Humans ; *Drugs, Chinese Herbal/chemistry/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Recent research highlights the immune system's role in AD pathogenesis and promising prospects of natural compounds in treatment. This study explores immunity-related biomarkers and potential natural products using bioinformatics, machine learning, molecular docking, and kinetic simulation.
METHODS: Differentially expressed genes (DEGs) in AD were analyzed using GSE5281 and GSE132903 datasets. Important AD module genes were identified using a weighted co-expression algorithm (WGCNA), and immune-related genes (IRGs) were obtained from the ImmPortPortal database. Intersecting these genes yielded important IRGs. Then, the least absolute shrinkage and selection operator (LASSO) and other methods screened common immune-related AD markers. Biological pathways were explored through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). The accuracy of these markers was assessed by subject operator signature (ROC) curves and validated in the GSE122063 dataset. The datasets was then subjected to immunoinfiltration analysis. Multiple compound databases were used to analyze core Chinese medicines and components. Molecular docking and kinetic simulation verification were used for further verification.
RESULTS: A total of 1360 differential genes and 5 biomarkers (PGF, GFAP, GPI, SST, NFKBIA) were identified, showing excellent diagnostic efficiency. GSEA revealed markers associated with Oxidative phosphorylation, Nicotine addiction, and Hippo signaling pathway. Immune infiltration analysis showed dysregulation in multiple immune cell types in AD brains, with significant interactions between markers and 5 immune cell types. A total of 27 possible herbs and 7 core compounds were eventually identified. The binding environment of GPI-luteolin and GPI-stigasterol was relatively stable and showed good affinity.
CONCLUSIONS: PGF, GFAP, SST, GPI, and NFKBIA were identified for early AD diagnosis, associated with immune cells and pathways in AD brains. 7 promising natural compounds, including luteolin and stigmasterol, were screened for targeting these biomarkers.}, }
@article {pmid40191787, year = {2025}, author = {Lin, X and Li, Q and Pu, M and Dong, H and Zhang, Q}, title = {Significance of nicotine and nicotinic acetylcholine receptors in Parkinson's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1535310}, pmid = {40191787}, issn = {1663-4365}, abstract = {Parkinson's disease (PD) is a multifaceted neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra and the aggregation of α-synuclein. According to epidemiological data, PD is the second most prevalent neurodegenerative disorder after Alzheimer's disease (AD) and has emerged as a significant global health concern. This review examines the intricate pathological mechanisms and high-risk factors associated with PD, and discusses the challenges in its clinical diagnosis and treatment. We elucidate the relationship between smoking and the reduced risk of PD, highlighting the potential neuroprotective effects of nicotine present in tobacco. The interaction between nicotine and nicotinic acetylcholine receptors (nAChRs) is analyzed in detail, emphasizing their neuroprotective capabilities and underlying molecular mechanisms. Furthermore, we analyze the structural and functional diversity of nAChRs and their roles in the pathological progression of PD. Our review aims to elucidate the complex interplay of genetic, environmental, and biochemical factors in PD and to propose future research directions that may facilitate therapeutic development.}, }
@article {pmid40191452, year = {2025}, author = {Patel, Y and Solanki, N and Dwivedi, PSR and Shah, B and Shastry, CS and Azad, S and Vejpara, D and Patel, M and Shah, U and Patel, S and Ahmed, S}, title = {Integrating network pharmacology and in vivo study to explore the anti-Alzheimer's potential of Bergenia ligulata and Nelumbo nucifera.}, journal = {3 Biotech}, volume = {15}, number = {5}, pages = {112}, pmid = {40191452}, issn = {2190-572X}, abstract = {UNLABELLED: Amyloid plaque buildup, tau protein tangles, oxidative stress, and neuronal death are the hallmarks of Alzheimer's disease (AD). Using network pharmacology, molecular docking, and in vivo experiments, this study investigated the neuroprotective potential of Bergenia ligulata (BL) and Nelumbo nucifera (NN) against aluminum chloride (AlCl3)-induced AD. Network pharmacology focused on important biomarker proteins like acetylcholinesterase (AChE), BCL2, and caspase-3 to identify 74 bioactive targets linked to AD. The evaluation of ligand-protein interactions was done using molecular docking. Male Wistar rats were exposed to AlCl3 to cause AD-like pathology in vivo, and a combination treatment of BL and NN at varying doses was provided. Apoptosis markers (BCL2, caspase-3), biochemical investigations (AChE activity, oxidative stress markers-GSH, SOD, catalase, and lipid peroxidation), behavioral evaluations (elevated plus maze, conditioned avoidance test), and histopathological analyses were investigated. The combination of BL and NN demonstrated substantial neuroprotection in a dose-dependent manner. Reduced AChE levels point out improved cholinergic activity. Oxidative stress indicators showed improvement, with lower levels of malondialdehyde and higher anti-oxidant levels of GSH, SOD, and catalase. Apoptotic markers showed an increase in BCL2 expression and a decrease in caspase-3, suggesting anti-apoptotic effects. Reduced neuronal degeneration in the cortex and hippocampal regions was confirmed by histopathology of the brain. The synergistic potential of BL and NN demonstrated potent neuroprotective effects by modulating AChE activity, reducing oxidative stress, increasing anti-oxidant levels, and inhibiting apoptosis. These findings highlighted the potential of BL and NN as a new therapeutic approach for the AD.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04274-w.}, }
@article {pmid40191032, year = {2025}, author = {Bhattacharya, S and Prusty, S and Pande, SP and Gulhane, M and Lavate, SH and Rakesh, N and Veerasamy, S}, title = {Integration of multimodal imaging data with machine learning for improved diagnosis and prognosis in neuroimaging.}, journal = {Frontiers in human neuroscience}, volume = {19}, number = {}, pages = {1552178}, pmid = {40191032}, issn = {1662-5161}, abstract = {INTRODUCTION: Combining many types of imaging data-especially structural MRI (sMRI) and functional MRI (fMRI)-may greatly assist in the diagnosis and treatment of brain disorders like Alzheimer's. Current approaches are less helpful for forecasting, however, as they do not always blend spatial and temporal patterns from different sources properly. This work presents a novel mixed deep learning (DL) method combining data from many sources using CNN, GRU, and attention techniques. This work introduces a novel hybrid deep learning method combining CNN, GRU, and a Dynamic Cross-Modality Attention Module to help more efficiently blend spatial and temporal brain data. Through working around issues with current multimodal fusion techniques, our approach increases the accuracy and readability of diagnoses.
METHODS: Utilizing CNNs and models of temporal dynamics from fMRI connection measures utilizing GRUs, the proposed approach extracts spatial characteristics from sMRI. Strong multimodal integration is made possible by including an attention mechanism to give diagnostically important features top priority. Training and evaluation of the model took place using the Human Connectome Project (HCP) dataset including behavioral data, fMRI, and sMRI. Measures include accuracy, recall, precision and F1-score used to evaluate performance.
RESULTS: It was correct 96.79% of the time using the combined structure. Regarding the identification of brain disorders, the proposed model was more successful than existing ones.
DISCUSSION: These findings indicate that the hybrid strategy makes sense for using complimentary information from several kinds of photos. Attention to detail helped one choose which aspects to concentrate on, thereby enhancing the readability and diagnostic accuracy.
CONCLUSION: The proposed method offers a fresh benchmark for multimodal neuroimaging analysis and has great potential for use in real-world brain assessment and prediction. Researchers will investigate future applications of this technique to new picture kinds and clinical data.}, }
@article {pmid40190585, year = {2025}, author = {Greenberg, KS and Lynch, HF and Nwakama, C and Frumovitz, J and Setru, S and Johnson, AM and Shah, SM and Schadt, L and McCoy, MS and Hoffman, AK and Largent, EA}, title = {A review of public comments submitted to the Centers for Medicare and Medicaid Services in response to the 2022 National Coverage Decision on treatment for Alzheimer's disease.}, journal = {Journal of law and the biosciences}, volume = {12}, number = {1}, pages = {lsaf004}, doi = {10.1093/jlb/lsaf004}, pmid = {40190585}, issn = {2053-9711}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with devastating personal and social consequences. In June 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to aducanumab (Aduhelm; Biogen), a first-in-class monoclonal antibody (mAb) for treatment of AD. In July 2021, responding to the significant controversy sparked by aducanumab's approval, the Centers for Medicare and Medicaid Services (CMS) opened a National Coverage Determination (NCD) analysis for mAbs intended for the treatment of AD. CMS received a record number of public comments on the proposed NCD, which included a proposal for coverage with evidence development (CED). We undertook an in-depth qualitative analysis of those comments. Broad themes included: the appropriateness of FDA's approval of aducanumab; the nature of the relationship between CMS and FDA; anticipated downstream effects of CED on innovation and health equity; aducanumab's cost, value, and affordability; and whether aducanumab offered patients hope. The aducanumab controversy occurred at the intersection of multiple contentious issues; in the discussion, we contextualize our findings within these broader debates. Though Biogen pulled aducanumab from the market in early 2024, the effects of the public discourse surrounding its approval and coverage have been long-lasting and far-reaching, affecting health law, policy, and clinical practice.}, }
@article {pmid40190514, year = {2024}, author = {Ma, X and Wang, J}, title = {Research progress on the role of ginsenoside Rd in central nervous system diseases.}, journal = {African health sciences}, volume = {24}, number = {4}, pages = {325-331}, pmid = {40190514}, issn = {1729-0503}, mesh = {*Ginsenosides/therapeutic use/pharmacology ; Humans ; *Central Nervous System Diseases/drug therapy ; Blood-Brain Barrier/drug effects ; Panax/chemistry ; Animals ; }, abstract = {Ginsenoside Rd (GSRd) is one of the rare saponin monomers extracted from ginseng. Most importantly, GSRd could effectively cross the intact blood-brain barrier (BBB). Studies have shown that it plays an important role in the treatment of neurological diseases such as ischemic stroke (IS), spinal cord injury (SCI), Alzheimer's disease (AD) and Parkinson's disease (PD). The results of these studies are of great significance for the clinical application of GSRd in the treatment in neurological diseases. This article reviewed the protective effects of GSRd in central nervous system diseases and analysed the related mechanism.}, }
@article {pmid40189792, year = {2025}, author = {Ercan, H and Reumiller, CM and Mühlberger, J and Hsu, F and Schmidt, GJ and Umlauf, E and Miller, I and Rappold, E and Attems, J and Oehler, R and Zellner, M}, title = {Platelets mirror changes in the frontal lobe antioxidant system in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {4}, pages = {e70117}, pmid = {40189792}, issn = {1552-5279}, support = {FP7-PEOPLE-2011-IAPP-286337//European Commission/ ; }, mesh = {Humans ; *Alzheimer Disease/blood/genetics/pathology/metabolism ; *Blood Platelets/metabolism ; Male ; Female ; *Frontal Lobe/metabolism ; Aged ; Superoxide Dismutase-1/metabolism ; Biomarkers/blood ; Cognitive Dysfunction/blood/metabolism ; Glutathione Peroxidase/metabolism/blood ; Glutathione Peroxidase GPX1 ; Proteomics ; Superoxide Dismutase/metabolism ; Aged, 80 and over ; Glutathione Transferase/metabolism ; Polymorphism, Single Nucleotide/genetics ; *Antioxidants/metabolism ; }, abstract = {INTRODUCTION: Blood biomarkers reflecting Alzheimer's disease (AD) pathophysiology can improve diagnosis and treatment.
METHODS: We applied top-down proteomics to compare frontal lobe from 17 AD cases and 11 controls to blood platelets from a second independent study group of 124 AD patients, 61 with mild cognitive impairment (MCI), and 168 controls. Findings were immunologically validated.
RESULTS: Sixty AD-associated proteoforms were identified in frontal lobe, with 26 identically represented in platelets. Validation in platelet samples confirmed elevated glutathione S-transferase omega 1 (GSTO1) levels linked to single nucleotide polymorphism (SNP) rs4925 and increased superoxide dismutase 1 (SOD1) levels in AD. Bioinformatics revealed copper chaperone for superoxide dismutase (CCS) and glutathione peroxidase 1 (GPX1) as integral partners of these antioxidant enzymes. Both were detected to be reduced in frontal lobes and platelets in AD. SOD1 and CCS are already changed in MCI.
DISCUSSION: These four novel blood biomarkers, integrated with traditional AD biomarkers, may facilitate patient risk assessment and treatment, with SOD1 and CCS alterations in MCI offering early diagnostic potential.
HIGHLIGHTS: Platelets mirror several Alzheimer's disease (AD)-dependent neuronal changes, valuable for blood tests. As a start, 60 AD-associated frontal lobe proteins were identified by top-down proteomics. Fifty percent of these 60 AD-affected brain proteins are represented identically in platelets. Among these, glutathione S-transferase omega 1 (GSTO1), superoxide dismutase 1 (SOD1), copper chaperone for superoxide dismutase (CCS), and glutathione peroxidase 1 (GPX1) are identically AD related in brain and platelets. SOD1 and its crucial activating partner CCS are altered in the platelets of patients with mild cognitive impairment.}, }
@article {pmid40189473, year = {2025}, author = {Chen, C and Katayama, S and Lee, JH and Lee, JY and Nakagawa, M and Torii, K and Ogawa, T and Dash, A and Irizarry, M and Dhadda, S and Kanekiyo, M and Hersch, S and Iwatsubo, T}, title = {Clarity AD: Asian regional analysis of a phase III trial of lecanemab in early Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100160}, doi = {10.1016/j.tjpad.2025.100160}, pmid = {40189473}, issn = {2426-0266}, abstract = {BACKGROUND: Across Asia, Alzheimer's disease prevalence is expected to rise dramatically due to, among other factors, rapidly aging populations. Alzheimer's disease pathology is triggered by the accumulation of soluble and insoluble aggregated Aβ peptides (oligomers, protofibrils, and fibrils). Lecanemab is a recently approved humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (oligomers, protofibrils), with activity at insoluble fibrils. In the recent 18-month phase 3 Clarity AD study, lecanemab demonstrated a consistent slowing of decline in clinical (global, cognitive, functional, and quality of life) outcomes, and reduction in brain amyloid in early Alzheimer's disease. Lecanemab was well tolerated in Clarity AD, with an increase in incidence of infusion related reactions and amyloid-related imaging abnormalities (ARIA) versus placebo.
OBJECTIVES: The objective of this manuscript is to present the results for the Asian region population of Clarity AD.
DESIGN: The core Clarity AD study was an 18-month, multicenter, double-blind, placebo-controlled, parallel-group study.
SETTING: Academic and clinical centers in Asia PARTICIPANTS: A total of 294 individuals with early Alzheimer's disease (i.e., mild cognitive impairment or mild Alzheimer's disease).
INTERVENTION: Eligible patients were randomized across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly) according to a fixed 1:1 schedule.
MEASUREMENTS: The primary efficacy endpoint in the core study was change in the Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) from baseline at 18 months. Key secondary endpoints included change from baseline at 18 months in amyloid PET Centiloids (in patients participating in the amyloid PET sub-study), AD COMposite Score (ADCOMS) and AD Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14). Safety was monitored throughout the study in a blinded manner by the sponsor and in an unblinded manner by an independent data safety monitoring committee.
RESULTS: Of the total of 1795 subjects randomized in Clarity AD, 294 subjects were in the Asian region (Japan:152; Korea:129; Singapore:13). The efficacy of lecanemab was consistent with the overall population. For the primary endpoint, there was a slowing of decline with lecanemab in the CDR-SB at 18 months compared to placebo in the Asian region (adjusted mean difference: -0.349; 95 % confidence intervals: -0.773, 0.076; 24 % slowing of decline). Results for the secondary efficacy endpoints also favored lecanemab versus placebo in Asians. Lecanemab was well tolerated in Asian subjects, with a safety profile in Asian subjects similar to the overall Clarity AD population. The most common adverse events of special interest were ARIA-H (lecanemab:14.4 %; placebo:16.2 %), ARIA-E (lecanemab:6.2 %; placebo:1.4 %), and infusion-related reactions (lecanemab:12.3 %; placebo:1.4 %). Incidence of adverse events leading to study drug dose interruption or withdrawal, infusion-related reactions, ARIA-E and ARIA-H was lower for the lecanemab treated group in the Asian region relative to the overall Clarity AD population. Results from quality of life and biomarker assessments in the Asia region were also generally similar to the overall Clarity AD population.
CONCLUSION: In the Clarity AD Asian region cohort, the overall efficacy, biomarker changes and safety profile of lecanemab were consistent with the overall population, with a favorable risk-benefit profile and manageable risks. ARIA events and infusion-related reactions occurred less commonly with lecanemab in the Asian region subgroup than the overall population.}, }
@article {pmid40189284, year = {2025}, author = {Kakeda, S and Miki, Y and Kudo, K and Mori, H and Tokumaru, AM and Abe, O and Aoki, S and , }, title = {Practical Brain MRI Guidelines for Anti-Aβ Antibody Treatment in Early Symptomatic Alzheimer's Disease.}, journal = {Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2463/mrms.gl.2025-1000}, pmid = {40189284}, issn = {1880-2206}, abstract = {PURPOSE: These guidelines aim to support MRI diagnosis in patients receiving anti-amyloid β (Aβ) antibody treatment without restricting treatment eligibility.
MATERIALS AND METHODS: These guidelines were collaboratively established by Japan Radiological Society, The Japanese Society of Neuroradiology, and Japanese Society for Magnetic Resonance in Medicine by reviewing existing literature and the results of clinical trials.
RESULTS: Facility standards should comply with the "Optimal Use Promotion Guidelines" of Japan, and physicians should possess comprehensive knowledge of amyloid-related imaging abnormalities (ARIA) and expertise in brain MRI interpretation. The acquisition of knowledge regarding amyloid-related imaging abnormalities, brain MRI, anti-Aβ antibody introduction, and post-treatment diagnosis are also recommended.
CONCLUSION: These guidelines facilitate the accurate diagnosis and effective management of ARIA; ensure the safe administration of anti-Aβ drugs; and provide a framework for MRI facilities, includes staffing requirements and the use of MRI management systems.}, }
@article {pmid40188375, year = {2025}, author = {Prajapati, JL and Dhurandhar, Y and Singh, AP and Gupta, DK and Baghel, VS and Kushwaha, U and Namdeo, KP}, title = {Redox chemical delivery system: an innovative strategy for the treatment of neurodegenerative diseases.}, journal = {Expert opinion on drug delivery}, volume = {}, number = {}, pages = {}, doi = {10.1080/17425247.2025.2489558}, pmid = {40188375}, issn = {1744-7593}, abstract = {INTRODUCTION: It is anticipated that the prevalence of illnesses affecting the central nervous system (CNS) will rise significantly due to longer lifespans and changing demography. Age-related decline in brain function and neuronal death are features of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, which provide formidable treatment challenges. Because most therapeutic drugs cannot pass across the blood-brain barrier (BBB) to reach the brain, there are still few treatment alternatives available despite a great deal of research.
AREAS COVERED: This study explores the role of redox chemical delivery systems in CNS drug delivery and addresses challenges associated with neurodegenerative disease (ND). Redox Chemical Delivery System offers a promising approach to enhancing leveraging redox reactions that facilitate the transport of therapeutic agents across the BBB. Through the optimization of medication delivery pathways to the brain, this technology has the potential to greatly improve the treatment of ND.
EXPERT OPINION: As our understanding of the biological underpinnings of ND deepens, the potential for effective interventions increases. Refining drug delivery strategies, such as RCDS, is essential for advancing CNS therapies from research to clinical practice. These advancements could transform the management of ND, improving both treatment efficacy and patient outcomes.}, }
@article {pmid40188044, year = {2025}, author = {Chen, H and Li, N and Liu, N and Zhu, H and Ma, C and Ye, Y and Shi, X and Luo, G and Dong, X and Tan, T and Wei, X and Yin, H}, title = {Photobiomodulation modulates mitochondrial energy metabolism and ameliorates neurological damage in an APP/PS1 mousmodel of Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {72}, pmid = {40188044}, issn = {1758-9193}, support = {F2024110001//The Natural Science Foundation of Hebei Province/ ; 82471536//The National Natural Science Foundation of China/ ; 62175261//The National Natural Science Foundation of China/ ; OJQD2022002//The Oujiang Laboratory/ ; 2023ZM006//Wenzhou Science and Technology Projects/ ; 2021-I2M-1-058//The Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; *Low-Level Light Therapy/methods ; *Energy Metabolism/radiation effects/physiology ; *Mitochondria/metabolism/radiation effects ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Microglia/metabolism/radiation effects ; Amyloid beta-Protein Precursor/genetics ; Male ; Presenilin-1/genetics ; Cognitive Dysfunction ; Neurons/metabolism/pathology ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease. Amyloid β-protein (Aβ) is one of the key pathological features of AD, which is cytotoxic and can damage neurons, thereby causing cognitive dysfunction. Photobiomodulation (PBM) is a non-invasive physical therapy that induces changes in the intrinsic mechanisms of cells and tissues through low-power light exposure. Although PBM has been employed in the treatment of AD, the effect and precise mechanism of PBM on AD-induced neurological damage are still unclear.
METHODS: In vivo experiments, PBM (808 nm, 20 mW/cm[2]) was used to continuously interfere with APP/PS1 mice for 6 weeks, and then their cognitive function and AD pathological changes were evaluated. In vitro experiments, lipopolysaccharide (LPS) was used to induce microglia to model inflammation, and the effect of PBM treatment on microglia polarization status and phagocytic Aβ ability was evaluated. Hexokinase 2 (HK2) inhibitor 3-bromopyruvate (3BP) was used to study the effect of PBM treatment on mitochondrial energy metabolism in microglia.
RESULTS: PBM further ameliorates AD-induced cognitive impairment by alleviating neuroinflammation and neuronal apoptosis, thereby attenuating nerve damage. In addition, PBM can also reduce neuroinflammation by promoting microglial anti-inflammatory phenotypic polarization; Promotes Aβ clearance by enhancing the ability of microglia to engulf Aβ. Among them, PBM regulates microglial polarization and inhibits neuronal apoptosis, which may be related to its regulation of mitochondrial energy metabolism, promotion of oxidative phosphorylation, and inhibition of glycolysis.
CONCLUSION: PBM regulates neuroinflammatory response and inhibits neuronal apoptosis, thereby repairing Aβ-induced neuronal damage and cognitive dysfunction. Mitochondrial energy metabolism plays an important role in PBM in improving nerve injury in AD mice. This study provides theoretical support for the subsequent application of PBM in the treatment of AD.}, }
@article {pmid40187700, year = {2025}, author = {Prabakaran, A and Rakshit, D and Patel, I and Susanna, KJ and Mishra, A and Radhakrishnanand, P and Sarma, P and Alexander, A}, title = {Enhanced cognitive function in mice through intranasal delivery of sinapic acid via chitosan-coated solid lipid nanoparticles.}, journal = {International journal of pharmaceutics}, volume = {}, number = {}, pages = {125565}, doi = {10.1016/j.ijpharm.2025.125565}, pmid = {40187700}, issn = {1873-3476}, abstract = {Sinapic acid (SAc) is a plant-based antioxidant known for its neuroprotective effects. However, its therapeutic potential for Alzheimer's disease (AD) remains limited because of its low bioavailability in the brain. Therefore, the present study hypothesized safe and effective delivery of SAc using chitosan-coated solid lipid nanoparticles (Cs-SAc-SLNs) via the intranasal route for AD treatment. The characterization of Cs-SAc-SLNs using AFM, SEM, and TEM confirmed their spherical morphology with a particle size of less than 200 nm. Moreover, the Cs-SAc-SLNs demonstrated a sustained drug release of 61.3 ± 1.7 % in 24 h. Remarkably, Cs-SAc-SLNs showed significant cellular uptake (P < 0.05) than uncoated SLNs in the Neuro-2a cell line. The histopathology study using nasal mucosa demonstrated the safety of the formulation, which makes it ideal for intranasal administration. The in vitro sustained drug release is well mapped with the in vivo pharmacokinetics study, indicating a 1.7-fold increase in the half-life (t1/2) of SAc. Interestingly, the chitosan-coated Cs-SAc-SLNs (i.n.) demonstrated superior AUC0-∞ (3128.05 ± 129.42 ng/g*h) and significantly enhanced drug targeting efficiency in the brain. This improved brain delivery contributed to substantial neuroprotective effects in Aβ1-42-induced cognitively impaired mice. The study also supported the decreased biochemical markers levels of oxidative stress, cholinergic activity, and inflammatory cytokine levels (TNF-α) in the hippocampus and cortex of Aβ1-42-injected mice. Overall, the present study highlights the safe and enhanced cognitive function using chitosan-coated SLNs for AD treatment.}, }
@article {pmid40187517, year = {2025}, author = {Radbakhsh, S and Abrego-Guandique, DM and Bacchetti, T and Aghaee-Bakhtiari, SH and Mahmoudi, A and Manteghi, AA and Bazyari, MJ and Cione, E and Ferretti, G and Sahebkar, A}, title = {Direct hybridization and bioinformatics analysis of circulating microRNAs in patients with Alzheimer's disease under intravenous trehalose treatment.}, journal = {Brain research}, volume = {1857}, number = {}, pages = {149607}, doi = {10.1016/j.brainres.2025.149607}, pmid = {40187517}, issn = {1872-6240}, abstract = {Trehalose has been proposed as a possible therapeutic option for attenuating the neuropathological changes associated with neurodegeneration, including Alzheimer's disease (AD). The administration of trehalose in human and murine models was linked to restoring antioxidant status, decreasing lipoperoxidation, and alleviating neuroinflammation. This latter biochemical mechanism was associated with the upregulation of specific brain-enriched microRNAs (miRNA). Herein, using a direct hybridization approach, we evaluate trehalose intravenous treatment in AD patients, conducting a phase two clinical trial (IRCT20130829014521N15) examining the alteration of microRNA profiles before and after the treatment. Twenty patients were recruited and randomly assigned to two groups: the intervention group received 15 g/week of intravenous trehalose. The control group received placebo in the form of normal saline. The period chosen was 12 weeks. Blood samples were obtained at the beginning and end of the study. Circulating microRNAs expression data between the placebo and treatment groups were assessed using microarray analysis. Subsequently, differentially expressed (DE) miRNAs specific to the trehalose-treated group were identified, and their gene targets were determined by bioinformatics-based approaches. The analysis of DE miRNAs pointed out modulation in unique miRNAs between treatment and placebo groups. Specifically, hsa-miR-1268a, -3605-3p, -555, and -6511a-3p were significantly downregulated, while hsa-miR-324-3p and -539-5p showed significant upregulation. Of the 147 overlapped validated genes identified in the bioinformatics analysis, several are related to autophagy, protein aggregation, oxidative stress, and inflammation. KEGG enrichment pathways reveal regulation of actin cytoskeleton, axon guidance, and neurotrophin signaling pathways. The results identify significant modulation in unique miRNAs in AD patients under trehalose. These findings suggest the potential utility of these microRNAs as biomarkers for trehalose pharmacological monitoring in AD.}, }
@article {pmid40187044, year = {2025}, author = {Fu, Y and Zhang, J and Qin, R and Ren, Y and Zhou, T and Han, B and Liu, B}, title = {Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases.}, journal = {Pharmacological reviews}, volume = {77}, number = {3}, pages = {100053}, doi = {10.1016/j.pharmr.2025.100053}, pmid = {40187044}, issn = {1521-0081}, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.}, }
@article {pmid40186896, year = {2025}, author = {Di Paolo, ML and Salerno, S and Nordio, G and Piazzola, F and Sarno, S and Sarno, G and Natale, B and Poggetti, V and Borreca, A and Baglini, E and Barresi, E and Da Settimo, F and Cosconati, S and Castellano, S and Taliani, S and Dalla Via, L}, title = {2-(Phenylamino)-7,8-dihydroquinazolin-5(6H)-one, a promising scaffold for MAO-B inhibitors with potential GSK3β targeting.}, journal = {European journal of medicinal chemistry}, volume = {291}, number = {}, pages = {117580}, doi = {10.1016/j.ejmech.2025.117580}, pmid = {40186896}, issn = {1768-3254}, abstract = {Neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, constitute pathological conditions of great relevance on health span and quality of life. The identification of novel therapeutic options, able to modulate the processes involved in the insurgence and progression of neurodegenerative disorders, represents an intriguing challenge of current research. Herein, a library of 36-membered 2-(phenylamino)-7,8-dihydroquinazolinone derivatives was synthesized and biologically evaluated as human MAO inhibitors. Some compounds able to inhibit MAO-B potently and selectively (Ki in the nanomolar range) were identified, and robust structure-activity relationships were drawn, supported by computational studies. Further biological assays revealed a safe profile for all derivatives and, for compounds selected as the best MAO-B inhibitors (4, 5, 13, 14) the following properties also emerged: (i) the ability to inhibit MAO-B activity in whole cells, with an effectiveness comparable or slight lower with respect to the reference safinamide; (ii) physicochemical parameters suggesting drug-likeness properties; (iii) the ability to inhibit, albeit weakly, GSK3β kinase (for compound 4). Within the whole series, compound 4 stood out as a promising lead for future optimization campaigns aimed to obtain useful drugs for the treatment of Alzheimer's and Parkinson's diseases.}, }
@article {pmid40186323, year = {2025}, author = {Sun, X and Hu, X and Wei, J and An, H}, title = {Uncovering leading compounds for alzheimer's disease treatment: mendelian randomization and virtual screening insights into plasma protein modulation.}, journal = {Biological research}, volume = {58}, number = {1}, pages = {19}, pmid = {40186323}, issn = {0717-6287}, support = {cstc2021jcyj-msxmX0148//Natural Science Foundation of Chongqing Municipality/ ; 2023-ZZ-002//Beijing Postdoctoral Science Foundation/ ; 2023M742438//China Postdoctoral Science Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy/blood ; *Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Blood Proteins/genetics/analysis/metabolism ; Genetic Predisposition to Disease ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder influenced by both genetic and environmental factors. Identifying therapeutic targets and interventions remains challenging. This study utilized Mendelian Randomization (MR) to investigate causal relationships between plasma proteins, lifestyle factors, and AD, along with virtual screening to identify potential drug compounds. A two-sample MR analysis assessed associations between plasma proteins, identified through genome-wide association studies (GWAS), and AD risk. Co-localization analysis (CA) confirmed the overlap between protein expression and AD susceptibility loci, and reverse MR ruled out reverse causality. A protein-protein interaction (PPI) network was constructed to explore therapeutic targets, followed by virtual screening to identify small-molecule inhibitors for selected proteins. The analysis found significant associations between eight plasma proteins and AD, with five proteins (GSTP1, BIN1, Siglec-3, SERPINF2, and GRN) showing strong evidence of involvement in AD pathogenesis. Virtual screening identified six compounds as potential inhibitors of GSTP1 and four compounds as potential inhibitors of BIN1. Furthermore, MR analysis of lifestyle factors, such as dietary behaviors and smoking cessation, indicated they may influence AD risk through their effects on specific proteins. These findings offer novel insights into the genetic mechanisms underlying AD and highlight the potential of combining MR with virtual screening to identify therapeutic targets. The study also suggests that lifestyle modifications could offer alternative prevention and treatment strategies for AD. Future research should focus on the experimental validation of the identified compounds and further explore the mechanisms linking lifestyle factors to AD.}, }
@article {pmid40186275, year = {2025}, author = {Zhang, X and Zhu, L and Li, Y and Yu, H and Wang, T and Chu, X}, title = {Therapeutic potential and mechanisms of repetitive transcranial magnetic stimulation in Alzheimer's disease: a literature review.}, journal = {European journal of medical research}, volume = {30}, number = {1}, pages = {233}, pmid = {40186275}, issn = {2047-783X}, support = {202,103,070,325//Shandong Medical and Health Technology Development Fund/ ; 202,103,070,325//Shandong Medical and Health Technology Development Fund/ ; M-2, 022,216//Shandong Province Traditional Chinese Medicine Science and Technology Project/ ; M-2, 022,216//Shandong Province Traditional Chinese Medicine Science and Technology Project/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology ; *Transcranial Magnetic Stimulation/methods ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, affecting tens of millions worldwide with projections indicating increasing prevalence in coming decades. Characterized by progressive cognitive decline, AD manifests with varying degrees of executive, language, and visuospatial impairments that worsen over time, eventually leading to severe psychiatric symptoms, mobility difficulties, sleep disturbances, and incontinence. While pharmacological treatments remain the primary intervention approach, their efficacy often diminishes over time and may produce significant adverse effects. Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive neuromodulation technique, has emerged as a promising alternative or complementary therapy. This literature review examines the therapeutic potential and mechanisms of rTMS in Alzheimer's disease. Through electromagnetic induction, rTMS can selectively modulate cortical excitability, with high-frequency stimulation (≥ 5 Hz) enhancing neural excitability and low-frequency stimulation (≤ 1 Hz) producing inhibitory effects. Recent clinical evidence demonstrates that rTMS can significantly improve cognitive function, memory, language abilities, and motor performance in AD patients, particularly when administered with optimized parameters targeting key brain regions, such as the dorsolateral prefrontal cortex. The neurobiological mechanisms underlying these effects include enhanced synaptic plasticity, increased expression of neurotrophic factors, modulation of neurotransmitter systems, and reduction of pathological protein aggregation. Meta-analyses indicate that high-frequency protocols (particularly 20 Hz) delivered over at least 3 weeks with a minimum of 20 sessions produce the most significant cognitive improvements, with effects potentially persisting for months post-treatment. Combined approaches integrating rTMS with cognitive training show particular promise through synergistic enhancement of neuroplasticity. Despite encouraging results, standardization of treatment protocols and larger clinical trials are needed to establish definitive guidelines and determine long-term efficacy. This review synthesizes current evidence supporting rTMS as an effective intervention for alleviating clinical symptoms of Alzheimer's disease while highlighting opportunities for advancing its therapeutic application.}, }
@article {pmid40185902, year = {2025}, author = {Yao, W and Hou, X and Zheng, W and Shi, X and Zhang, J and Bai, F}, title = {Brain overlapping system-level architecture influenced by external magnetic stimulation and internal gene expression in AD-spectrum patients.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {40185902}, issn = {1476-5578}, support = {82371437//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {The brain overlapping system-level architecture is associated with functional information integration in the multiple roles of the same region, and it has been developed as an underlying novel biomarker of brain disease and may characterise the indicators for the treatment of Alzheimer's disease (AD). However, it remains uncertain whether these changes are influenced by external magnetic stimulation and internal gene expression. A total of 73 AD-spectrum patients (52 with true stimulation and 21 with sham stimulation) were underwent four-week neuronavigated transcranial magnetic stimulation (rTMS). Shannon-entropy diversity coefficient analysis was used to explore the brain overlapping system of the neuroimaging data in these pre- and posttreatment patients. Transcription-neuroimaging association analysis was further performed via gene expression data from the Allen Human Brain Atlas. Compared with the rTMS_sham stimulation group, the rTMS_true stimulation group achieved the goal of cognitive improvement through the reconstruction of functional information integration in the multiple roles of 27 regions associated with the brain overlapping system, involving the attentional network, sensorimotor network, default mode network and limbic network. Furthermore, these overlapping regions were closely linked to gene expression on cellular homeostasis and immune inflammation, and support vector regression analysis revealed that the baseline diversity coefficients of the attentional and sensorimotor networks can effectively predict memory improvement after rTMS treatment. These findings highlight the brain overlapping system associated with cognitive improvement, and provide the first evidence that external magnetic stimulation and internal gene expression could influence these overlapping regions in AD-spectrum patients.}, }
@article {pmid40185767, year = {2025}, author = {Hussain, MZ and Shahzad, T and Mehmood, S and Akram, K and Khan, MA and Tariq, MU and Ahmed, A}, title = {A fine-tuned convolutional neural network model for accurate Alzheimer's disease classification.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {11616}, pmid = {40185767}, issn = {2045-2322}, mesh = {*Alzheimer Disease/classification/diagnostic imaging/diagnosis ; Humans ; *Neural Networks, Computer ; Magnetic Resonance Imaging/methods ; Deep Learning ; Machine Learning ; Convolutional Neural Networks ; }, abstract = {Alzheimer's disease (AD) is one of the primary causes of dementia in the older population, affecting memories, cognitive levels, and the ability to accomplish simple activities gradually. Timely intervention and efficient control of the disease prove to be possible through early diagnosis. The conventional machine learning models designed for AD detection work well only up to a certain point. They usually require a lot of labeled data and do not transfer well to new datasets. Additionally, they incur long periods of retraining. Relatively powerful models of deep learning, however, also are very demanding in computational resources and data. In light of these, we put forward a new way of diagnosing AD using magnetic resonance imaging (MRI) scans and transfer learned convolutional neural networks (CNN). Transfer learning makes it easier to reduce the costs involved in training and improves performance because it allows the use of models which have been trained previously and which generalize very well even when there is very little training data available. In this research, we used three different pre-trained CNN based architectures (AlexNet, GoogleNet, and MobileNetV2) each implemented with several solvers (e.g. Adam, Stochastic Gradient Descent or SGD, and Root Mean Square Propagation or RMSprop). Our model achieved impressive classification results of 99.4% on the Kaggle MRI dataset as well as 98.2% on the Open Access Series of Imaging Studies (OASIS) database. Such results serve to demonstrate how transfer learning is an effective solution to the issues related to conventional models that limits the accuracy of diagnosis of AD, thus enabling their earlier and more accurate diagnosis. This would in turn benefit the patients by improving the treatment management and providing insights on the disease progression.}, }
@article {pmid40185739, year = {2025}, author = {Zou, Y and Yang, L and Zhu, J and Fan, J and Zheng, H and Liao, X and Yang, Z and Zhang, K and Jia, H and Konnerth, A and Wang, YJ and Zhang, C and Zhang, Y and Li, SC and Chen, X}, title = {Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer's disease.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {126}, pmid = {40185739}, issn = {2158-3188}, support = {31925018//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32127801//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/physiopathology ; Disease Models, Animal ; Mice ; *Piperidines/pharmacology ; *Cognitive Dysfunction/drug therapy/physiopathology ; *Brain/drug effects/physiopathology ; *Histamine H3 Antagonists/pharmacology ; Male ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Behavior, Animal/drug effects ; }, abstract = {Histamine H3 receptor (H3R) antagonists regulate histamine release that modulates neuronal activity and cognitive function. Although H3R is elevated in Alzheimer's disease (AD) patients, whether H3R antagonists can rescue AD-associated neural impairments and cognitive deficits remains unknown. Pitolisant is a clinically approved H3R antagonist/inverse agonist that treats narcolepsy. Here, we find that pitolisant reverses AD-like pathophysiology and cognitive impairments in an AD mouse model. Behavioral assays and in vivo wide-field Ca[2+] imaging revealed that recognition memory, learning flexibility, and slow-wave impairment were all improved following the 15-day pitolisant treatment. Improved recognition memory was tightly correlated with slow-wave coherence, suggesting slow waves serve as a biomarker for treatment response and for AD drug screening. Furthermore, pitolisant reduced amyloid-β deposition and dystrophic neurites surrounding plaques, and enhanced neuronal lysosomal activity, inhibiting which blocked cognitive and slow-wave restoration. Our findings identify pitolisant as a potential therapeutic agent for AD treatments.}, }
@article {pmid40185388, year = {2025}, author = {Kaur, A and Aran, KR}, title = {Unraveling the cGAS-STING pathway in Alzheimer's disease: A new Frontier in neuroinflammation and therapeutic strategies.}, journal = {Neuroscience}, volume = {573}, number = {}, pages = {430-441}, doi = {10.1016/j.neuroscience.2025.04.001}, pmid = {40185388}, issn = {1873-7544}, abstract = {Alzheimer's disease (AD) is the most prevalent type of neurological disorder characterized by cognitive decline and memory loss, marked by the accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau protein, causing extensive neuronal death and neuroinflammation. There is growing evidence that AD development extends beyond the neuronal compartment and has a major impact on the immunological functions of the brain. The cyclic GMP-AMP synthase (cGAS) detects cytosolic DNA, including pathogenic foreign DNA and self-DNA from cellular injury, triggering a type I interferon (IFN-I) response through activation of the stimulator of interferon genes (STING). The activation of the cGAS-STING pathway in response to mitochondrial dysfunction drives neuroinflammation in AD, which is mediated by the release of IFN-I cytokines. Furthermore, the release of oxidized mtDNA is necessary for the stimulation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, which is a family of protein complexes that macrophages can produce to induce inflammation. AD becomes severe by the stimulation of the cGAS-STING pathway, which results in sterile inflammation and microglial dysfunction. This review aims to explore the potential impact of the cGAS-STING signaling pathway in the pathogenesis and progression of AD. Additionally; after overviewing recent findings, this article highlights the molecular mechanism involved in the onset of disease and its modulation regarding the therapeutic approach of AD. Finally, deliberated a deep insight, the cGAS-STING axis could provide novel therapeutic avenues for slowing or halting the progression of AD, thereby offering new prospects for treatment development.}, }
@article {pmid40185252, year = {2025}, author = {Mirehei, M and Motamedi, F and Maghsoudi, N and Mansouri, Z and Naderi, S and Khodagholi, F and Abbaszadeh, F}, title = {Effects of Bufexamac, a class IIb HDAC inhibitor, on behavior and neuropathological features in an Aβ-induced rat model of Alzheimer's disease.}, journal = {Experimental gerontology}, volume = {204}, number = {}, pages = {112746}, doi = {10.1016/j.exger.2025.112746}, pmid = {40185252}, issn = {1873-6815}, abstract = {It has been suggested that Alzheimer's disease (AD), a progressive neurological condition, can potentially be treated through epigenetic means by targeting histone deacetylases (HDACs), enzymes that regulate gene expression. In this study, we investigated the molecular mechanisms of Bufexamac, in an animal model of AD. Bufexamac specifically targets Class IIb HDACs, which are particularly relevant in the context of neuroinflammation and neurodegeneration. This selectivity may reduce off-target effects commonly associated with broader-spectrum HDAC inhibitors, such as pan-HDAC inhibitors, which can affect multiple HDAC classes and potentially lead to undesirable side effects. Male rats injected with Aβ25-35 for AD-like symptoms were treated with 20 μg/rat Bufexamac for 8 days. Cognitive function, depression, and anxiety were assessed through behavioral tests, while Western blotting, H&E staining, and ELISA were used to detect protein expression, morphological changes, and enzyme activity. Bufexamac treatment markedly improved cognitive and behavioral impairments in Aβ-injected rats and regulated the key proteins related to neuroinflammation (GFAP, Iba1), histone, and α-tubulin acetylation. Simultaneously, it decreased the expression of proteins in the stromal interaction molecule (STIM) pathway. Furthermore, Bufexamac lowered the activity of monoamine oxidase enzymes, elevated the count of healthy neurons, and ameliorated neuronal structure in the hippocampus. Overall, these findings suggest that Bufexamac could be a more targeted therapy for AD than other non-selective HDAC inhibitors, which often have diverse functions and potential side effects. Bufexamac enhances cognitive function and alleviates depression and anxiety by regulating proteins related to neuroinflammation, histone, and α-tubulin acetylation, as well as modulating STIM levels and MAO activity.}, }
@article {pmid40185057, year = {2025}, author = {Sarangi, NK and Mondal, S and Keyes, TE}, title = {Receptor modulated assembly and drug induced disassembly of amyloid beta aggregates at asymmetric neuronal model biomembranes.}, journal = {Biophysical chemistry}, volume = {322}, number = {}, pages = {107441}, doi = {10.1016/j.bpc.2025.107441}, pmid = {40185057}, issn = {1873-4200}, abstract = {Amyloid peptide non-fibrillar oligomers cause neurotoxicity and may contribute to Alzheimer's disease (AD) pathogenesis. Mounting evidence indicates that Aβ1-42 oligomers disrupt and remodel neuronal membrane, causing neuronal cell death. The involvement of individual neuronal membrane constituents in real-time Aβ1-42 aggregate assembly is unclear due to complexity of neuronal cell membrane. We used non-Faradaic electrochemical impedance spectroscopy (EIS) to track monomeric Aβ1-42 peptide binding and aggregation pathways in real-time in asymmetric micropore suspended lipid bilayer membranes with anionic phospholipids and glycosphingolipids. Anionic DOPC:PIP2 pore suspended membrane showed pore-formation within 2 h of incubation, but peptide insertion occurred over 6 h, with an onset time of ∼6-8 h for peptide aggregation at the membrane surface. Among different gangliosides, peptide binding to GM1- and GM3-containing membranes did not result pore development, but receptor mediated peptide aggregation formation caused membrane admittance to decrease within 2 h. In contrast, partial peptide insertion in the membrane surface increases membrane admittance at GD1a and mixed GSL membranes, arresting aggregation. Time-lapsed AFM imaging at asymmetric solid supported lipid bilayers (aSLBs) corroborated EIS findings, capturing pore-formation and receptor mediated peptide assembly routes. Fluorescence lifetime imaging (FLIM) imaging and spatial resolved single-point fluorescence correlation spectroscopy (FCS) at aSLBs revealed membrane-peptide interaction, assembly, and peptide induced membrane reorganization. Treatment with antidepressants fluoxetine and imipramine therapeutics, in synergy, which are cost-effective and capable of crossing the central nervous system (CNS+), resulted in the disassembly of membrane mediated Aβ1-42 aggregates, but not fibrils. Overall, the data suggests that membrane-mediated aggregate disassembly at the correct timing of AD progression may halt or reverse amyloid assembly through the use of repurposed drugs.}, }
@article {pmid40184642, year = {2025}, author = {Li, ZD and Kang, S and Li, H and Yu, P and Xie, R and Li, C and Jing, Q and Gong, Z and Li, L and Li, Z and Geng, M and Zhang, Z and Li, Y and Chang, YZ}, title = {Absence of astrocytic ceruloplasmin reverses the senescence process with aging of learning and memory abilities.}, journal = {Redox biology}, volume = {82}, number = {}, pages = {103611}, doi = {10.1016/j.redox.2025.103611}, pmid = {40184642}, issn = {2213-2317}, abstract = {Ceruloplasmin (CP) is a multi-copper ferroxidase mainly synthesized by liver, secreted into the peripheral blood, playing a critical role in regulating the iron homeostasis. In the central nervous system (CNS), the CP expressed by astrocytes plays an important role in the transportation of iron from the blood across the blood-brain barrier (BBB) into the brain. Our previous study showed that conditional knockout of astrocytic CP with Cre-LoxP system (Cp[Gfap]cKO) not only improved the learning and memory abilities of elderly mice, but also impaired the learning and memory abilities of young mice. In order to further investigate the effects of CP on learning and memory with aging, we constructed mice model with tamoxifen-induced astrocyte specific knockout of CP, induced CP knockout at 12 months old, and observed the effects on mouse learning and memory at 18 months old. We were delighted to found that ablation of astrocytic CP by tamoxifen at 12 months old could similarly enhance the learning, memory and recognition abilities in 18-month-old mice. Iron deposition in the hippocampus associated with aging was mitigated, leading to a reduction in oxidative stress. The MAPK/JNK pathway exhibited attenuation, while the PI3K/Akt/GSK3 pathway showed enhancement. This combination is expected to result in the reduction of the phosphorylation level of MYC and the elevation of the nuclear translocation of MYC, which might then contribute to reduced cellular senescence. Additionally, the ROS/MAPK/Erk and ROS/MAPK/p38 pathways-dependent cell apoptosis in hippocampus was diminished. The hallmarks of Alzheimer's Disease (AD) were all significantly reduced. Ultimately, the alleviated cellular senescence along with the reduction in AD-related markers, coincided with an improvement in learning, memory, and recognition abilities. These findings further elucidated the role of CP in brain iron metabolism, offering a novel target and strategy for the prevention and treatment of neurodegenerative diseases, such as AD associated with aging.}, }
@article {pmid40184204, year = {2025}, author = {Gliozzo, J and Soto Gomez, MA and Bonometti, A and Patak, A and Casiraghi, E and Valentini, G}, title = {miss-SNF: a multimodal patient similarity network integration approach to handle completely missing data sources.}, journal = {Bioinformatics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/bioinformatics/btaf150}, pmid = {40184204}, issn = {1367-4811}, abstract = {MOTIVATION: Precision medicine leverages patient-specific multimodal data to improve prevention, diagnosis, prognosis and treatment of diseases. Advancing precision medicine requires the non-trivial integration of complex, heterogeneous and potentially high-dimensional data sources, such as multi-omics and clinical data. In the literature several approaches have been proposed to manage missing data, but are usually limited to the recovery of subsets of features for a subset of patients. A largely overlooked problem is the integration of multiple sources of data when one or more of them are completely missing for a subset of patients, a relatively common condition in clinical practice.
RESULTS: We propose miss-Similarity Network Fusion (miss-SNF), a novel general-purpose data integration approach designed to manage completely missing data in the context of patient similarity networks. Miss-SNF integrates incomplete unimodal patient similarity networks by leveraging a non-linear message-passing strategy borrowed from the SNF algorithm. Miss-SNF is able to recover missing patient similarities and is "task agnostic", in the sense that can integrate partial data for both unsupervised and supervised prediction tasks. Experimental analyses on nine cancer datasets from The Cancer Genome Atlas (TCGA) demonstrate that miss-SNF achieves state-of-the-art results in recovering similarities and in identifying patients subgroups enriched in clinically relevant variables and having differential survival. Moreover, amputation experiments show that miss-SNF supervised prediction of cancer clinical outcomes and Alzheimer's disease diagnosis with completely missing data achieves results comparable to those obtained when all the data are available.
miss-SNF code, implemented in R, is available at https://github.com/AnacletoLAB/missSNF.
SUPPLEMENTARY INFORMATION: Supplementary information are available at Bioinformatics online.}, }
@article {pmid40183098, year = {2025}, author = {Kour, D and Khajuria, P and Sharma, K and Sharma, A and Sharma, A and Ali, SM and Wazir, P and Ramajayan, P and Sawant, SD and Nandi, U and Ahmed, Z and Kumar, A}, title = {Isobavachalcone ameliorates Alzheimer disease pathology by autophagy-mediated clearance of amyloid beta and inhibition of NLRP3 inflammasome in primary astrocytes and 5x-FAD mice.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1525364}, pmid = {40183098}, issn = {1663-9812}, abstract = {BACKGROUND AND AIM: Alzheimer's disease (AD) progresses with Aβ plaque deposition and neuroinflammation. Given the complexity of AD pathology, single-target therapies have frequently failed in clinical trials. We hypothesized that a multitarget approach could yield better therapeutic outcomes. To this end, we identified isobavachalcone (IBC), a natural compound with dual pharmacological activity in reducing Aβ plaques and neuroinflammation.
EXPERIMENTAL PROCEDURE: Primary astrocytes were isolated from 3 to 4 days old C57BL/6J mice pups for in-vitro assays, while in-vivo studies were conducted on 5x-FAD mice. Protein alterations were evaluated using ELISA, western blotting, immunocytochemistry, and immunohistochemistry. Behavioral analyses included the radial arm maze, open field, and rotarod tests. Data from all in vitro and in vivo experiments were analyzed by using one-way ANOVA and post-hoc Bonferroni tests.
RESULTS: In-vitro analyses in astrocytes demonstrated that IBC at 5 and 10 μM concentrations induce AMPK phosphorylation through CAMKK2, promoting autophagy and inhibiting the NLRP3 inflammasome in primary astrocytes. IBC-treated astrocytes exhibited significant clearance of extracellular amyloid beta. Mechanistic studies highlighted autophagy as a key factor in reducing both NLRP3 inflammasome activity and Aβ levels. Two months of treatment of 5x-FAD mice with IBC at 25 and 50 mg/kg significantly improved cognitive functions, as evidenced by enhanced memory and motor performance in behavioral tests. Subsequent brain tissue analysis revealed that IBC upregulated autophagic proteins to reduce the brain's amyloid beta levels, resulting in decreased expression of neuroinflammation markers.
CONCLUSION: IBC effectively ameliorates AD pathology through autophagy-mediated clearance of Aβ and suppressing neuroinflammation in 5x-FAD mice.}, }
@article {pmid40182757, year = {2025}, author = {Guo, S and Yi, L and Luo, M and Dong, Z and Du, Y}, title = {Parishin A ameliorates cognitive decline by promoting PS1 autophagy in Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1516190}, pmid = {40182757}, issn = {1663-4365}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly. Its pathological features include: A lot of misfolding and abnormal aggregation of amyloid protein (Aβ); Autophagy disorder, oxidative stress, neuroinflammation, abnormal phosphorylated tau protein and synaptic dysfunction. Modern pharmacological studies have found that Paisinhin A (PA) has beneficial effects on the prevention and treatment of central nervous system diseases. This study aims to explore the role and mechanism of PA in AD through autophagy pathway, and lay a scientific foundation for the development of clinical prevention and treatment strategies for AD.
METHODS: N2A[APP] cells were treated with different concentrations of PA. Cell viability was detected by CCK-8 method. Western blotting detected the expression levels of proteins related to amyloid production, autophagy pathway, and phosphorylated Tau expression levels. Autophagy flow was detected by transfecting Lc3 double fluorescent plasmid. After Aβ was injected into the hippocampus of WT mice and PA was injected intraperitoneally, the learning and memory ability of WT mice were tested by new object recognition, y maze and water maze. The oxidative stress level was detected by the kit. The levels of inflammatory factors were detected by RT-qpcr.
RESULTS: The viability of N2A[APP] cells was not affected at different concentrations of PA, but PS1 was significantly decreased at 40μM. PA can obviously improve the accumulation of autophagy in AD, and to some extent save the autophagy inhibition of CQ. Behavioral studies have shown that PA can also improve learning and memory impairments caused by Aβ injections. In addition, in vivo experiments, PA can also improve oxidative stress levels, inflammation levels and salvage dysfunctions of synapses. PA also reduces the levels of total and phosphorylated Tau in N2A[Tau].
DISCUSSION: Our study provides the first evidence that PA improves learning and memory in Aβ-induced AD mice. This effect appears to be mediated by PA by promoting autophagy and reducing oxidative stress. It was also found that PA may have a role in regulating inflammation, improving abnormally phosphorylated tau, and salvaging damaged synaptic function, providing valuable insights into potential applications in the treatment and prevention of AD.}, }
@article {pmid40182055, year = {2025}, author = {Zheng, C and Xia, W and Zhang, J}, title = {Rock inhibitors in Alzheimer's disease.}, journal = {Frontiers in aging}, volume = {6}, number = {}, pages = {1547883}, pmid = {40182055}, issn = {2673-6217}, abstract = {Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and cause of dementia. AD pathology primarily involves the formation of amyloid β (Aβ) plaques and neurofibrillary tangles containing hyperphosphorylated tau (p-tau). While Aβ targeted treatments have shown clinical promise, other aspects of AD pathology such as microgliosis, astrocytosis, synaptic loss, and hypometabolism may be viable targets for treatment. Among notable novel therapeutic approaches, the Ras homolog (Rho)-associated kinases (ROCKs) are being investigated as targets for AD treatment, based on the observations that ROCK1/2 levels are elevated in AD, and activation or inhibition of ROCKs changes dendritic/synaptic structures, protein aggregate accumulation, inflammation, and gliosis. This review will highlight key findings on the effects of ROCK inhibition in Aβ and ptau pathologies, as well as its effects on neuroinflammation, synaptic density, and potentially metabolism and bioenergetics.}, }
@article {pmid40181198, year = {2025}, author = {Manolopoulos, A and Yao, PJ and Kapogiannis, D}, title = {Extracellular vesicles: translational research and applications in neurology.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {40181198}, issn = {1759-4766}, abstract = {Over the past few decades, extensive basic, translational and clinical research has been devoted to deciphering the physiological and pathogenic roles of extracellular vesicles (EVs) in the nervous system. The presence of brain cell-derived EVs in the blood, carrying diverse cargoes, has enabled the development of predictive, diagnostic, prognostic, disease-monitoring and treatment-response biomarkers for various neurological disorders. In this Review, we consider how EV biomarkers can bring us closer to understanding the complex pathogenesis of neurological disorders such as Alzheimer disease, Parkinson disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis and multiple sclerosis. We describe how translational research on EVs might unfold bidirectionally, proceeding from basic to clinical studies but also in the opposite direction, with biomarker findings in the clinic leading to novel hypotheses that can be tested in the laboratory. We demonstrate the potential value of EVs across all stages of the therapeutic development pipeline, from identifying therapeutic targets to the use of EVs as reporters in model systems and biomarkers in clinical research. Finally, we discuss how the cargo and physicochemical properties of naturally occurring and custom-engineered EVs can be leveraged as novel treatments and vehicles for drug delivery, potentially revolutionizing neurotherapeutics.}, }
@article {pmid40180804, year = {2025}, author = {Mostafa, M and Disouky, A and Lazarov, O}, title = {Therapeutic modulation of neurogenesis to improve hippocampal plasticity and cognition in aging and Alzheimer's disease.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {}, number = {}, pages = {e00580}, doi = {10.1016/j.neurot.2025.e00580}, pmid = {40180804}, issn = {1878-7479}, abstract = {Alzheimer's disease is characterized by progressive memory loss and cognitive decline. The hippocampal formation is the most vulnerable brain area in Alzheimer's disease. Neurons in layer II of the entorhinal cortex and the CA1 region of the hippocampus are lost at early stages of the disease. A unique feature of the hippocampus is the formation of new neurons that incorporate in the dentate gyrus of the hippocampus. New neurons form synapses with neurons in layer II of the entorhinal cortex and with the CA3 region. Immature and new neurons are characterized by high level of plasticity. They play important roles in learning and memory. Hippocampal neurogenesis is impaired early in mouse models of Alzheimer's disease and in human patients. In fact, neurogenesis is compromised in mild cognitive impairment (MCI), suggesting that rescuing neurogenesis may restore hippocampal plasticity and attenuate neuronal vulnerability and memory loss. This review will discuss the current understanding of therapies that target neurogenesis or modulate it, for the treatment of Alzheimer's disease.}, }
@article {pmid40180019, year = {2025}, author = {Li, Y and Wang, T and Li, H and Jiang, Y and Shen, X and Kang, N and Guo, Z and Zhang, R and Lu, X and Kang, T and Li, M and Hou, Y and Wu, Y}, title = {Targeting LKB1-AMPK-SIRT1-induced autophagy and mitophagy pathways improves cerebrovascular homeostasis in APP/PS1 mice.}, journal = {Free radical biology & medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.freeradbiomed.2025.03.045}, pmid = {40180019}, issn = {1873-4596}, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common and severe degenerative disorder of the central nervous system in the elderly, profoundly impacting patients' quality of life. However, effective therapeutic agents for AD are still lacking. Bazi Bushen (BZBS) is a traditional Chinese herbal compound with potential neuroprotective effects, yet its underlying mechanisms remain poorly understood.
METHODS: In this study, we utilized APP/PS1 transgenic mice to assess the therapeutic efficacy of BZBS. Initially, we evaluated the spatial learning and memory of the mice using the Barnes maze. The brain microcirculation was assessed through a small-animal ultrasound system, two-photon in vivo imaging, and micro-computed tomography angiography. Molecular, biochemical, and pathological analyses were conducted on brain tissues. Through network pharmacology, we identified potential intervention pathways and targets for BZBS in the treatment of AD, which we subsequently validated both in vivo and in vitro. Additionally, we employed molecular virtual docking screening and bio-layer interferometry to elucidate the direct interactions of ginsenoside Rg5 and ginsenoside Ro in BZBS with AMPK and LKB1 proteins.
RESULTS: The BZBS intervention significantly enhanced spatial learning and memory in APP/PS1 mice while decreasing Aβ deposition. Furthermore, BZBS protected cerebrovascular homeostasis and mitigated neuroinflammation, as evidenced by decreased blood-brain barrier permeability, increased expression of tight-junction proteins, and restored cerebral blood flow. Mechanistically, ginsenosides Rg5 and Ro in BZBS directly bind to AMPK and LKB1 proteins, activating the LKB1-AMPK-SIRT1 signaling pathway, promoting autophagy and mitochondrial autophagy, and alleviating oxidative stress damage in endothelial cells.
CONCLUSIONS: BZBS enhances autophagy-related activity, decreases Aβ deposition, and improves endothelial cell homeostasis through the activation of the LKB1-AMPK-SIRT1 signaling pathway, ultimately leading to improved cognitive function in mice with AD. This study highlights the importance of enhancing autophagic activity and maintaining cerebrovascular homeostasis in mitigating cognitive decline in AD, providing evidence and new insights into the application of compound medicines for treating age-related neurological disorders.}, }
@article {pmid40179995, year = {2025}, author = {Landon, B and Subasinghe, K and Sumien, N and Phillips, N}, title = {miRNA and piRNA differential expression profiles in Alzheimer's disease: A potential source of pathology and tool for diagnosis.}, journal = {Experimental gerontology}, volume = {204}, number = {}, pages = {112745}, doi = {10.1016/j.exger.2025.112745}, pmid = {40179995}, issn = {1873-6815}, abstract = {Alzheimer's Disease (AD) is the most prevalent form of dementia and one of the leading causes of death in the United States, and despite our best efforts and recent advancements, a treatment that stops or substantially slows its progression has remained elusive. Small extracellular vesicles (sEVs), hold the potential to alleviate some of the common issues in the field by serving to better differentiate AD and non-AD individuals. These vesicles could provide insights into therapeutic targets, and potentially an avenue towards early detection. We compared the sEV cargo profiles of AD and non-AD brains (n = 6) and identified significant differences in both the micro RNA (miRNA) and Piwi-interacting RNA (piRNA) cargo through sEV isolation from temporal cortex tissue, followed by small RNA sequencing, and differential expression analysis. Differentially expressed miRNAs targeting systems relevant to AD included miR-206, miR-4516, miR-219a-5p, and miR-486-5p. Significant piRNAs included piR-6,565,525, piR-2,947,194, piR-7,181,973, and piR-7,326,987. These targets warrant further study for their potential role in the progression of AD pathology by dysregulating cellular activity; additionally, future large-scale studies of neuronal sEV miRNA profiles may facilitate the development of diagnostic tools which can aid in clinical trial design and recruitment. Longitudinal analysis of sEV data, perhaps accessible through plasma surveyance, will help determine at what point these miRNA and/or piRNA profiles begin to diverge between AD and non-AD individuals.}, }
@article {pmid40179541, year = {2025}, author = {Ng, TKS and Beck, T and Liu, X and Desai, P and Holland, T and Dhana, K and Krueger, K and Wilson, RS and Evans, DA and Rajan, KB}, title = {Longitudinal associations between lipid panel and cognitive decline modified by APOE 4 carrier status in biracial community-dwelling older adults: Findings from the Chicago health and aging project.}, journal = {Archives of gerontology and geriatrics}, volume = {134}, number = {}, pages = {105825}, doi = {10.1016/j.archger.2025.105825}, pmid = {40179541}, issn = {1872-6976}, support = {P30 AG072972/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: There have been contradictory findings on the associations between lipids and cognitive decline (CD), which may be attributed to the heterogeneity in the APOE4 carrier status, given APOE's lipid transportation roles. However, extant studies rarely examined the modifying effects of APOE4 carrier status on the associations between lipids and CD.
METHODS: We analyzed the Chicago Health and Aging Project, a 20-year cohort study comprising older adults with lipid panel assayed, i.e., total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL), and longitudinal cognitive tests. We ran adjusted linear mixed-effects models, regressing cognitive test composite on each of the four lipids independently, first with the total sample and subsequently using interaction and stratified subgroup analyses, examining the modifying effects of APOE4 carrier status on the associations.
RESULTS: 3,496 biracial community-dwelling older adults were recruited from the South side of Chicago (58% African American & 64% women; mean follow-up = 4.6 years). In the total sample, there was a borderline association between TG and CD, estimate (SD, p-value) = 0.0001 (0.0000,0.0565). No associations were detected with other lipids. In the interaction and subgroup analyses, only in ε4 carriers that higher TC levels were significantly associated with accelerated CD, -0.020 (0.009,0.035), whereas higher TG levels were significantly associated with decelerated CD, 0.001 (0.001,0.045). No modifying effects of ε4 carrier status were detected with other lipids.
DISCUSSION: Specific lipids, i.e., TC and TG, were associated with CD only in the ε4 carriers, highlighting the potential importance of measuring APOE4 status to better inform risk prediction and treatment.}, }
@article {pmid40177541, year = {2025}, author = {Wei, Y and Xia, X and Wang, X and Yang, W and He, S and Wang, L and Chen, Y and Zhou, Y and Chen, F and Li, H and Peng, F and Li, G and Xu, Z and Fu, J and Gao, H}, title = {Enhanced BBB penetration and microglia-targeting nanomodulator for the two-pronged modulation of chronically activated microglia-mediated neuroinflammation in Alzheimer's disease.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {2}, pages = {1098-1111}, pmid = {40177541}, issn = {2211-3835}, abstract = {Intervention in chronically activated microglia-mediated neuroinflammation is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood‒brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acid-cleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 peptides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improvements in late APP/PS1 mice.}, }
@article {pmid40177269, year = {2025}, author = {Haque, A and Alenezi, KM and Abdul Rasheed, MSM and Rahman, MA and Anwar, S and Ahamad, S and Gupta, D}, title = {Experimental and theoretical studies on structural changes in the microtubule affinity-regulating kinase 4 (MARK4) protein induced by N-hetarenes: a new class of therapeutic candidates for Alzheimer's disease.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1529845}, pmid = {40177269}, issn = {2296-858X}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder that progressively affects the cognitive function and memory of the affected person. Unfortunately, only a handful of effective prevention or treatment options are available today. Microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine protein that plays a critical role in regulating microtubule dynamics and facilitating cell division. The dysregulated expression of MARK4 has been associated with a range of diseases, including AD.
METHODS: In this study, we synthesized a series of N-hetarenes via Pd(0)-catalyzed Suzuki-Miyaura cross coupling reaction. All compounds were characterized using multi-spectroscopic techniques and evaluated for their activity against the MARK4 enzyme through ATPase inhibition assays. The experimental data was further supported by computational and quantum chemical calculations. We also computed the drug-likeness, bioavailability, and toxicity (ADME/T) profiles of the compounds.
RESULTS: Six new 4-(6-(arylpyrimidin-4-yl)piperazine-1-carboximidamides 5-10 were prepared in good yields. ATPase inhibition assay conducted on these compounds demonstrated IC50 values in micromolar range (5.35 ± 0.22 to 16.53 ± 1.71 μM). Among the tested compounds, 4-(6-(p-tolyl)pyrimidin-4-yl)piperazine-1-carboximidamide (5; IC50 = 5.35 ± 0.22 μM) and 4-(6-(benzo[b]thiophen-2-yl)pyrimidin-4-yl)piperazine-1-carboximidamide (9; IC50 = 6.68 ± 0.80 μM) showed the best activity. The binding constant (K), as determined by the fluorescence quenching assay was estimated to be 1.5 ± 0.51 × 10[5] M[-1] for 5 and 1.14 ± 0.26 × 10[5] M[-1] for 9. The results of molecular docking and MD simulation studies against MARK4 (PDB: 5ES1) indicated that compounds were able to bind the ATP binding pocket of the MARK4, leading to its stabilization. Additionally, ADME/T analysis revealed a high degree of drug-likeness of the compounds.
CONCLUSION: We demonstrated that 4-(6-(arylpyrimidin-4-yl)piperazine-1-carboximidamides) are a promising class of N-hetarenes for developing next-generation anti-AD drugs. The reported class of compounds inhibited MARK4 activity in-vitro at micromolar concentration by targeting the ATP-binding pocket. These findings provide valuable insights for future drug design.}, }
@article {pmid40177166, year = {2025}, author = {Sun, Y and Liu, Z and Zhang, Z and Kang, Y and Wang, X and Zhang, Y and Liu, Y and Zhao, P}, title = {Human induced pluripotent stem cell models for Alzheimer's disease research: a bibliometric analysis.}, journal = {Frontiers in human neuroscience}, volume = {19}, number = {}, pages = {1548701}, pmid = {40177166}, issn = {1662-5161}, abstract = {INTRODUCTION: Alzheimer's disease (AD), the leading cause of dementia, remains without adequate treatment. Current models do not fully replicate human physiology and pathology. The advent of human induced pluripotent stem cell (hiPSC) technology offers a novel approach to studying AD.
METHODS: Our study conducted a bibliometric analysis to assess the application and development of hiPSC technology in AD research. We retrieved 531 articles on hiPSC models of AD from the Web of Science Core Collection, published between January 2010 and June 2024. CiteSpace and VOSviewer were used to analyze authorship, geographic contributions, journal influence, and citation patterns.
RESULTS: Our findings reveal a steady increase in publications over 14 years, with the United States leading in contributions, followed by China. Li-Huei Tsai from the Massachusetts Institute of Technology is a prominent researcher. PLoS One emerges as the most influential journal. Research trends have focused on inflammation, astrocytes, microglia, apolipoprotein E (ApoE), and tau.
DISCUSSION: Bibliometric analysis is crucial in identifying research gaps and trends and guiding future studies to address unmet needs in understanding and modeling human physiology and pathology. Leveraging hiPSC models to investigate the molecular mechanisms of familial and sporadic AD is expected to provide a crucial foundation for developing future treatment strategies.
CONCLUSION: In summary, the bibliometric findings from this study provide a comprehensive overview of the current research landscape in hiPSC models for AD. It also highlights emerging trends and research gaps, crucial for guiding future research efforts, particularly in exploring novel therapeutic targets and improving understanding of disease mechanisms.}, }
@article {pmid40176122, year = {2025}, author = {Koch, G and Casula, EP and Bonnì, S and Borghi, I and Assogna, M and Di Lorenzo, F and Esposito, R and Maiella, M and D'Acunto, A and Ferraresi, M and Mencarelli, L and Pezzopane, V and Motta, C and Santarnecchi, E and Bozzali, M and Martorana, A}, title = {Effects of 52 weeks of precuneus rTMS in Alzheimer's disease patients: a randomized trial.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {69}, pmid = {40176122}, issn = {1758-9193}, support = {A2019523S//BrightFocus Foundation/ ; A2019523S//BrightFocus Foundation/ ; 2016-02364718//Ministero della Salute/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology/psychology ; Male ; *Transcranial Magnetic Stimulation/methods ; Female ; Aged ; *Parietal Lobe/physiopathology ; Treatment Outcome ; Electroencephalography ; Aged, 80 and over ; Neuropsychological Tests ; Middle Aged ; Mental Status and Dementia Tests ; }, abstract = {BACKGROUND: Personalized repetitive transcranial magnetic stimulation (rTMS) of the precuneus (PC) is emerging as a new non-invasive therapeutic approach in treating Alzheimer's disease (AD). Here we sought to investigate the effects of 52 weeks of rTMS applied over the PC on cognitive functions in patients with mild-to-moderate dementia due to AD.
METHODS: Forty-eight patients with mild-to-moderate dementia due to AD were enrolled for the study. Of those 31 patients were extended to 52 weeks after being included in a 24-week trial (NCT03778151) with the same experimental design. The trial included a 52-week treatment with a 2-week intensive course where rTMS (or sham) was applied over the PC daily (5 times per week, Monday to Friday), followed by a 50-week maintenance phase in which the same stimulation was applied once weekly. Personalization of rTMS treatment was established using neuronavigated TMS in combination with electroencephalography (TMS-EEG). The primary outcome measure was change from baseline to week 52 of the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). Secondary outcomes included score changes in the Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog)11, Mini Mental State Examination (MMSE), Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL) and Neuropsychiatric Inventory (NPI). Changes in cortical activity and connectivity were monitored by TMS-EEG.
RESULTS: Among 48 patients randomized (mean age 72.8 years; 56% women), 32 (68%) completed the study. Repetitive TMS of the PC (PC-rTMS) had a significant effect on the primary outcome measure. The estimated mean change in CDR-SB after 52 week was 1.36 for PC-rTMS (95% confidence interval (CI) [0.68, 2.04]) and 2.45 for sham-rTMS group (95%CI [1.85, 3.05]). There were also significant effects for the secondary outcomes ADAS-Cog11, ADCS-ADL and NPI scores. Stronger DMN connectivity at baseline was associated with favorable response to rTMS treatment.
CONCLUSIONS: Fifty-two weeks of PC-rTMS may slow down the impairment of cognitive functions, activities of daily living and behavioral disturbances in patients with mild-to-moderate AD. Further multicenter studies are needed to confirm the clinical potential of DMN personalized rTMS.
TRIAL REGISTRATION: The study was registered on the clinicaltrial.gov website on 07-07-2022 (NCT05454540).}, }
@article {pmid40172923, year = {2025}, author = {Luong, TV and Hansen, KV and Hansen, AK and Cunnane, SC and Møller, N and Søndergaard, E and Gormsen, LC and Svart, M}, title = {A three-week Ketogenic Diet increases Global Cerebral Blood Flow and Brain-Derived Neurotrophic Factor.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1210/clinem/dgaf207}, pmid = {40172923}, issn = {1945-7197}, abstract = {PURPOSE: The beneficial effects of a ketogenic diet (KD) on neurodegenerative conditions such as mild cognitive impairment (MCI) and Alzheimer's disease (AD) are increasingly acknowledged, with potential implications for the general population as well. Thus, our study aimed to explore the effect of a KD on cerebral blood flow (CBF) and Brain-Derived Neurotrophic Factor (BDNF) in healthy individuals. We hypothesized that a KD would increase CBF and BDNF, thereby presenting itself as an approach to prevent cognitive decline.
METHODS: In total, 11 cognitively healthy individuals with overweight participated in a randomized, crossover trial consisting of two three-week interventions: 1) a KD and 2) a standard diet. Each diet period concluded with a positron emission tomography (PET) study day, accompanied by a separate magnetic resonance imaging (MRI) scan. Blood samples were collected prior to the PET scan to measure β-hydroxybutyrate (β-OHB) and BDNF levels. CBF was assessed using a [15O]H2O PET scan co-registered with an MRI scan.
RESULTS: A KD led to increased basal plasma β-OHB levels compared to the SDD (647 (418-724) vs. 50 (50-60) μmol/l, p<0.05), increased CBF by 22% (p=0.02), and elevated BDNF levels by 47% (p=0.04). Moreover, a correlation was observed between β-OHB levels and CBF measurements across the two diets (R2=0.54, p<0.001).
CONCLUSION: Implementing a KD improved CBF and raised BDNF levels in cognitively healthy individuals, indicating that a KD should be assessed for as a potential treatment for conditions associated with reduced CBF.}, }
@article {pmid40172827, year = {2025}, author = {West, J and Li, M and Wong, S and Le, GH and Teopiz, KM and Valentino, K and Dri, CE and McIntyre, RS}, title = {Are Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists Central Nervous System (CNS) Penetrant: A Narrative Review.}, journal = {Neurology and therapy}, volume = {}, number = {}, pages = {}, pmid = {40172827}, issn = {2193-8253}, abstract = {INTRODUCTION: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that modulates glucose metabolism and insulin secretion. Recent translational and clinical research has evaluated the effects of GLP-1 receptor agonists (GLP-1 RAs), a class of drugs that mimic the action of native GLP-1 in the central nervous system (CNS). In addition to the efficacy of GLP-1 for the treatment of diabetes mellitus and obesity, preliminary evidence indicates GLP-1s have neuroprotective, therapeutic, and disease modification effects for select neurodegenerative disorders (e.g. Parkinson's disease, Alzheimer's disease). Among the available GLP-1 RAs, relatively few have been shown to be CNS penetrant. This article synthesizes extant literature reporting on CNS penetrants of GLP-1 RAs as proxied by brain imaging studies. Where available, studies that reported on the bioavailability of GLP-1 RAs in the CNS were identified.
METHODS: A comprehensive search of PubMed, Ovid, and Web of Science from database inception to July 2024 was conducted. Inclusion criteria were English language publications with no date restrictions, preclinical and clinical studies with participants aged 18-80 and studies which focused on GLP-1 RAs including: "Semaglutide" or "Ozempic" or "Rybelsus" or "Wegovy" or "Dulaglutide" or "Trulicity" or "Exenatide" or "Byetta" or "Bydureon" or "Liraglutide" or "Lixisenatide" or "Tirzepatide" or "Mounjaro" or "Zepbound" or "Bydureon BCise" or "Adlyxin" or "Victoza" or "Saxenda".
RESULTS: We identified 14 studies that were included in this synthesis. Preclinical studies suggest that select GLP-1 RAs cross the blood-brain barrier (BBB) (i.e. liraglutide, semaglutide, and exenatide). Replicated evidence suggests that CNS penetration of GLP-1 RAs can be proxied by reported effects of GLP-1 RAs on brain connectivity in human participants.
CONCLUSION: Preclinical studies indicate that select GLP-1 RAs are CNS penetrant; whether GLP-1 RAs reproducibly engage neural targets hypothesized to subserve dimensions of psychopathology (e.g., general cognitive functions) remains incompletely characterized.}, }
@article {pmid40172120, year = {2025}, author = {Yue, C and Chen, B and Pan, F and Wang, Z and Yu, H and Liu, G and Li, W and Wang, R and Tang, Y}, title = {TCnet: A Novel Strategy to Predict Target Combination of Alzheimer's Disease via Network-Based Methods.}, journal = {Journal of chemical information and modeling}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jcim.5c00172}, pmid = {40172120}, issn = {1549-960X}, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder with an unclear pathogenesis; the traditional ″single gene-single target-single drug″ strategy is insufficient for effective treatment. This study explores a novel strategy for the multitarget therapy of AD by integrating multiomics data and employing network analysis. Different from conventional single-target methods, TCnet adopts a mechanism-driven strategy, utilizing multiomics data to decompose disease mechanisms, construct potential target combinations, and prioritize the optimal combinations using a scoring function. TCnet not only advances our understanding of disease mechanisms but also facilitates large-scale drug screening. This approach was further employed to screen active compounds from Huang-Lian-Jie-Du-Tang (HLJDT), identifying quercetin as a candidate targeting GSK3β and ADAM17. Subsequent in vitro experiments confirmed the neuroprotective and anti-inflammatory effects of quercetin. Overall, TCnet offers a promising approach for predicting target combinations and provides new insights and directions for drug discovery in AD.}, }
@article {pmid40172089, year = {2025}, author = {Aslan, FS and Akdag, MB and Doganyigit, Z and Okan, A and Shaikh, MF and Akyuz, E}, title = {Synaptic Function and Dysfunction: New Frontiers in CNS Disorders.}, journal = {Journal of neuroscience research}, volume = {103}, number = {4}, pages = {e70033}, doi = {10.1002/jnr.70033}, pmid = {40172089}, issn = {1097-4547}, mesh = {Humans ; *Neuronal Plasticity/physiology ; Animals ; *Central Nervous System Diseases/physiopathology ; *Synapses/physiology ; Brain/physiopathology ; }, abstract = {Central nervous system (CNS) disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and migraines, rank among the most prevalent and concerning conditions worldwide. Despite ongoing research, the pathophysiology of these disorders remains incompletely understood, primarily due to their complex etiology. Current pharmacological treatments mainly focus on alleviating symptoms rather than addressing the underlying causes of these diseases. CNS disorders are marked by impairments in neurocognitive and neuromuscular functions, and cognitive processes like learning and memory. This deterioration not only impacts the quality of life of affected individuals but also places a significant burden on their families. Neuroplasticity is a key property of the nervous system that enables brain repair and functional recovery. However, in CNS disorders, neuroplasticity is often compromised. Neuroplasticity, which is regulated by gene expression, is also modulated by environmental factors and epigenetic mechanisms, thereby reshaping neuronal networks in response to various biological and environmental stimuli and brain function. Importantly, neuroplasticity plays a critical role in repairing the brain, especially in the context of neurodegenerative diseases, where damaged neurons can reorganize and re-establish lost functions. Targeting neuroplasticity mechanisms holds significant potential for developing therapeutic interventions to improve treatment outcomes and prevent CNS disorders. A deeper understanding of neuroplasticity in neurological diseases could open new avenues for enhancing patient quality of life. This review aims to provide a comprehensive overview of synaptic function and the neuroplasticity mechanisms that are disrupted in neurological disorders.}, }
@article {pmid40172080, year = {2025}, author = {de Ceballos, ML}, title = {The endocannabinoid system offers a target for Alzheimer's disease treatment through inhibition of fatty acid amide hydrolase (FAAH).}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.70082}, pmid = {40172080}, issn = {1742-4658}, abstract = {Oddi et al. report the effects of chronic treatment via intranasal delivery with URB597, a fatty acid amide hydrolase (FAAH) inhibitor, on an Alzheimer's disease (AD) transgenic mouse model. They found that prolonged treatment with URB597 reduced the learning and memory deficits of these mice. Mechanistically, the inhibitor modified several genes related to amyloidosis and inflammatory responses or anandamide signaling. FAAH inhibition induced a decrease in the accumulation, synthesis, and release of β-Amyloid, along with diminished expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), and this change may be associated with epigenetic changes induced by the drug. In summary, prolonged treatment with URB597 impinges on different aspects of AD pathophysiology, suggesting its therapeutic relevance in treating AD.}, }
@article {pmid40171303, year = {2025}, author = {Wang, Q and Yang, F and Quan, L and Fu, M and Yang, Z and Wang, J}, title = {Knowledge graph and its application in the study of neurological and mental disorders.}, journal = {Frontiers in psychiatry}, volume = {16}, number = {}, pages = {1452557}, pmid = {40171303}, issn = {1664-0640}, abstract = {Neurological disorders (e.g., Alzheimer's disease and Parkinson's disease) and mental disorders (e.g., depression and anxiety), pose huge challenges to global public health. The pathogenesis of these diseases can usually be attributed to many factors, such as genetic, environmental and socioeconomic status, which make the diagnosis and treatment of the diseases difficult. As research on the diseases advances, so does the body of medical data. The accumulation of such data provides unique opportunities for the basic and clinical study of these diseases, but the vast and diverse nature of the data also make it difficult for physicians and researchers to precisely extract the information and utilize it in their work. A powerful tool to extract the necessary knowledge from large amounts of data is knowledge graph (KG). KG, as an organized form of information, has great potential for the study neurological and mental disorders when it is paired with big data and deep learning technologies. In this study, we reviewed the application of KGs in common neurological and mental disorders in recent years. We also discussed the current state of medical knowledge graphs, highlighting the obstacles and constraints that still need to be overcome.}, }
@article {pmid40170724, year = {2025}, author = {Huang, J and Long, X and Chen, C}, title = {A real-world safety surveillance study of aducanumab through the FDA adverse event reporting system.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1522058}, pmid = {40170724}, issn = {1663-9812}, abstract = {BACKGROUND: Alzheimer's disease poses a major public health challenge, with aducanumab's approval in 2021 as the first disease-modifying therapy raising important safety considerations. This study analyzed the Food Drug Administration Adverse Event Reporting System (FAERS) database to evaluate aducanumab's real-world safety profile and identify potential risk factors.
METHODS: We conducted a comprehensive pharmacovigilance study using the FAERS database from January 2004 to June 2024, analyzing 510 aducanumab-associated reports from integrated databases containing over 18 million demographic records and 66 million drug records. Safety signals were evaluated using four complementary disproportionality methods: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). Analyses were stratified by age and sex, with adverse events examined at both System Organ Class (SOC) and Preferred Term (PT) levels using SAS 9.4.
RESULTS: Among 510 aducanumab-associated adverse event reports, predominantly from elderly patients (55.49% aged ≥65 years), nervous system disorders were the most frequent (53.24%, n = 583). Amyloid related imaging abnormality-oedema/effusion (ARIA-E) and Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits (ARIA-H) emerged as the most significant safety signals (ROR: 53,538.3 and 38,187.9, respectively). Sex-stratified analysis showed comparable safety profiles between males and females, with ARIA-E related events, ARIA-H related events, maintaining strong signals across all age groups, particularly in patients ≥75 years. The median time to adverse event onset was 146.0 days (IQR: 80.0-195.0). Temporal analysis revealed increasing signal strength for ARIA-related events from 2004-2024, with notable intensification during 2022-2023.
CONCLUSION: Our real-world analysis identified ARIA-related events as the primary safety concern for aducanumab, typically occurring within 146 days of treatment initiation, with comparable safety profiles across sex but heightened risks in patients ≥75 years. These findings support aducanumab's viability as a therapeutic option while emphasizing the critical importance of rigorous monitoring protocols, particularly for ARIA events during the first year of treatment.}, }
@article {pmid40170395, year = {2025}, author = {Wang, A and Since, M and Dallemagne, P and Rochais, C}, title = {Implication of Central β2 Adrenergic Receptor for the Development of Novel Drugs Against Alzheimer's Disease.}, journal = {Archiv der Pharmazie}, volume = {358}, number = {4}, pages = {e2400750}, pmid = {40170395}, issn = {1521-4184}, support = {//The authors gratefully acknowledge the Conseil Régional de Normandie for funding (A.W.)./ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Receptors, Adrenergic, beta-2/metabolism/drug effects ; Animals ; *Adrenergic beta-2 Receptor Agonists/pharmacology ; Drug Development ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive onset of symptoms, including memory loss, accompanied by other neurological impairments. This progression is attributed to the deterioration of neuronal connections and a decrease in neurotransmission. Although this phenomenon has been extensively studied in the cholinergic system, it also affects other neurobiological pathways, particularly adrenergic transmission. In this context, the use of agonists, in particular, β2-adrenergic receptor (β2AR) agonists, may represent a promising therapeutic approach. After reviewing the main pharmacological aspects related to these receptors, we will first present the different existing modulators and their peripheral effects. We will then analyze the results of studies investigating their use in disease models. Finally, we will discuss the conditions and prospects for the development of a new treatment for Alzheimer's disease using a β2AR agonist.}, }
@article {pmid40170213, year = {2025}, author = {Wang, Y and Wu, Z and Zheng, Y and Wang, H and Cheng, B and Xia, J}, title = {Unraveling the genetic underpinnings of mitochondrial traits and associated circulating inflammatory proteins in Alzheimer's disease: Mitochondrial HtrA2-T cell CD5 negative axis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251329517}, doi = {10.1177/13872877251329517}, pmid = {40170213}, issn = {1875-8908}, abstract = {BackgroundPrevious studies with limited sample sizes have indicated a link between mitochondrial traits, inflammatory proteins, and Alzheimer's disease. The exact causality and their mediation relationships remain unclear.ObjectiveOur study aimed to delve into the genetic underpinnings of mitochondrial function and circulating inflammatory proteins in the pathogenesis of Alzheimer's disease.MethodsWe leveraged aggregated data from the largest genome-wide association study, including 69 mitochondrial traits, 91 circulating inflammatory proteins, and Alzheimer's disease. Bidirectional mendelian randomization (MR) analyses were performed to investigate their primary causal relationships. Thereafter a two-step MR mediation analysis was utilized to clarify the modulating effects of inflammatory proteins on mitochondria and Alzheimer's disease.ResultsOur study identified mitochondrial phenylalanine-tRNA ligase and 4-hydroxy-2-oxoglutarate aldolase as risk factors for Alzheimer's disease, and serine protease HtrA2 and carbonic anhydrase 5A as protective factors against Alzheimer's disease. Four inflammatory proteins (T-cell surface glycoprotein CD5, C-X-C motif chemokine 11, TGF-α, and TNF-related apoptosis-inducing ligand) played protective roles against Alzheimer's disease. Axin-1 and IL-6 increased the risk of Alzheimer's disease. Furthermore, T-cell surface glycoprotein CD5 was found to be a significant mediator between mitochondrial serine protease HTRA2 and Alzheimer's disease with the two-step MR method, accounting for 10.83% of the total effect.ConclusionsOur study emphasized mitochondrial HtrA2-T cell CD5 as a negative axis in Alzheimer's disease, offering novel perspectives on its etiology, pathogenesis, and treatment.}, }
@article {pmid40170189, year = {2025}, author = {Lapid, MI and Pagali, SR and Basso, MR and Croarkin, PE and Geske, JR and Huston, J and Islam, K and Joseph, B and Kennebeck, WW and Kang, D and Kung, S and LeMahieu, AM and Lundstrom, BN and Petersen, RC and Sarran, MM and Shu, Y and Swanson, IM and Louis, EKS and Wang, MK and Varatharajah, Y and Wagh, N and Welker, KM and Worrell, GA and Boeve, BF}, title = {A pilot randomized controlled double-blind trial of intermittent theta burst stimulation (iTBS) repetitive transcranial magnetic stimulation (rTMS) to improve memory in mild cognitive impairment (MCI): a study protocol.}, journal = {Pilot and feasibility studies}, volume = {11}, number = {1}, pages = {35}, pmid = {40170189}, issn = {2055-5784}, abstract = {BACKGROUND: Mild cognitive impairment (MCI), prevalent among older adults, often precedes Alzheimer's disease (AD) or Alzheimer's disease-related dementias (ADRD), emphasizing the need for effective interventions. Early intervention in MCI is crucial, not only to alleviate symptoms but to potentially delay the progression of cognitive decline. The lack of definitive treatments for MCI has prompted the exploration into alternative non-pharmacological therapeutic approaches. Specifically, noninvasive brain stimulation using repetitive transcranial magnetic stimulation (rTMS) has demonstrated promise in improving cognition in MCI and AD.
OBJECTIVES: Our study will test the feasibility of using intermittent theta burst stimulation (iTBS) technique of rTMS in MCI, pilot test the study design, and collect pilot data on the effect of iTBS over three different brain regions on working memory, new learning, and executive function in MCI. Exploratory objectives are to assess the feasibility and usefulness of functional magnetic resonance imaging (fMRI), high-density electroencephalography (HD-EEG), and sleep architecture as potential biomarkers in response to iTBS.
METHODS: A pilot randomized double-blind controlled cross-over trial of iTBS on 20 MCI participants randomized to 10 days of active iTBS (left dorsolateral prefrontal cortex or left lateral parietal cortex) or control (vertex). After 4-6-week washout period, they cross over to the alternative treatment arm for another 10 days. Each participant will undergo a total of 20 iTBS sessions. Pre- and post-iTBS assessments include neuropsychological tests, fMRI, HD-EEG, and sleep architecture.
DISCUSSION: This innovative study aims to test the feasibility of iTBS as a cognitive enhancement strategy in MCI. If our study is feasible, it could lead to a future larger trial to further test whether iTBS can modulate underlying neurobiology and offer a therapeutic avenue to remediate cognitive decline in MCI or ultimately delay progression to dementia.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT05327257. Registered 04 April 2022.}, }
@article {pmid40169354, year = {2025}, author = {Lee, M and Lee, KJ and Kim, J and Lee, DY and Park, RW and Rhee, SY and Cha, JM and Yang, HJ and Jang, JW and Jung, S and Lee, J and Lee, SH and Kim, C and Bae, JS and Kim, YJ and Lee, JH and Bae, H and Kim, Y}, title = {Low-density lipoprotein cholesterol levels and risk of incident dementia: a distributed network analysis using common data models.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-334708}, pmid = {40169354}, issn = {1468-330X}, abstract = {BACKGROUND: The link between low-density lipoprotein cholesterol (LDL-C) levels and dementia risk is poorly understood, with conflicting evidence on the role of LDL-C and the impact of statin therapy on cognitive outcomes. Thus, we aimed to examine the association between low-density LDL-C levels and the risk of dementia and assess the influence of statin therapy.
METHODS: We retrospectively analysed data from 11 university hospitals participating in the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). Participants with a prior diagnosis of dementia or those with <180 days of observation before cohort inclusion, and those included in both cohorts were excluded. The primary outcome was all-cause dementia, with the secondary outcome being Alzheimer's disease-related dementia (ADRD). The study utilised 1:1 propensity score matching to compare individuals with LDL-C levels below 70 mg/dL (1.8 mmol/L) against those with levels above 130 mg/dL (3.4 mmol/L), resulting in a primary analysis cohort of 108 980 matched patients. Secondary analyses further examined LDL-C thresholds below 55 mg/dL (1.4 mmol/L) and the influence of statin use.
RESULTS: The LDL-C levels below 70 mg/dL (1.8 mmol/L) were associated with a 26% reduction in the risk of all-cause dementia and a 28% reduction in the risk of ADRD, compared with levels above 130 mg/dL (3.4 mmol/L). For LDL-C levels below 55 mg/dL (1.4 mmol/L), there was an 18% risk reduction for both outcomes. Among those with LDL-C <70 mg/dL (<1.8 mmol/L), statin use was associated with a 13% reduction in all-cause dementia risk and a 12% decrease in ADRD risk compared with non-users.
CONCLUSION: Low LDL-C levels (<70 mg/dL (<1.8 mmol/L)) are significantly associated with a reduced risk of dementia, including ADRD, with statin therapy providing additional protective effects. These findings support the necessity of targeted lipid management as a preventive strategy against dementia, indicating the importance of personalised treatment approaches.}, }
@article {pmid40169058, year = {2025}, author = {Wattanalaorsomboon, S and Mansalai, P and Payaka, A and Baiya, S and Sansenya, S}, title = {The inhibition effect of oleamide for acetylcholinesterase and α-glucosidase from edible wild mushroom by in vitro, in silico and fluorescence analysis.}, journal = {International journal of biological macromolecules}, volume = {308}, number = {Pt 4}, pages = {142681}, doi = {10.1016/j.ijbiomac.2025.142681}, pmid = {40169058}, issn = {1879-0003}, abstract = {Lipid compounds from edible wild mushrooms have been reported for their biological activities related to Alzheimer's disease (AD) and diabetes mellitus (DM) treatment. This research investigated purified oleamide (PEWM) from edible wide mushroom and determined its antioxidant activity and inhibition potential against acetylcholinesterase (AChE) and α-glucosidase. The PEWM was purified by preparative thin-layer chromatography (PTLC) with methanol: chloroform: water (6:6:1 v/v). The antioxidant activity against ABTS[·+] and DPPH· radical of crude extracts (CEWM) had higher potent than PEWM. On the other hand, the inhibition potential of PEWM against AChE and α-glucosidase had higher potency than CEWM. Moreover, the inhibition potency of PEWM and oleamide against AChE was higher than α-glucosidase. The inhibition mode of CEWM, PEWM and oleamide exhibited mixed-type inhibition on AChE and α-glucosidase. Inhibition constant (Ki) also supported that CEWM, PEWM and oleamide have the highest potent on AChE. CEWM, PEWM and oleamide showed fluorescence quenching by increasing the inhibitors' concentration against AChE and α-glucosidase. Docking analysis revealed that oleamide was located in peripheral anionic sites of AChE. The results suggest that edible wild mushrooms as the source of lipids related to AChE and α-glucosidase inhibitory activity might be applied for AD and DM management.}, }
@article {pmid40168720, year = {2025}, author = {Ambamba, BDA and Paka, GD and Takuissu, GRN and Nongni, QCP and Ntepe, LJM and Ella, FA and Mandob, DE and Fonkoua, M and Ngondi, JL}, title = {Glycosyl terpenoid-rich fraction of TeMac™ attenuates oxidative stress, inhibits cholinesterases enzyme activities, and protects brain against scopolamine-induced histopathological alterations in rats.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {186}, number = {}, pages = {118010}, doi = {10.1016/j.biopha.2025.118010}, pmid = {40168720}, issn = {1950-6007}, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most commonly diagnosed form of senile dementia, with limited therapeutic options. Neuronal damage is caused by factors secreted by inflammatory cells but also, the lack of antioxidants to prevent oxidative stress and help maintain neuronal integrity, which is crucial for cognition and memory are mediators of AD. Terminalia macroptera barks contain glycosyl terpenoids, known for their strong antioxidant properties. This study investigated the antioxidant and neuroprotective effects of the glycosylic terpenoid-rich fraction of Terminalia macroptera (GT-TeMac™) in scopolamine-treated rats.
METHODS: Glycosylic terpenoids were identified by LC-MS and antiradical activity tests (DPPH and ORAC) were performed. Cholinergic cognitive dysfunction and oxidative stress were induced in male wistar rats, by intraperitoneal injection of scopolamine (1 mg/kg BW/day) for seven consecutive days. GT-TeMac™ at 100 mg/kg and Donepezil at 5 mg/kg body weight were administered orally 60 min after scopolamine. After treatment, rat were sacrificed and brains were collected for the evaluation of cholinergic enzyme activity, oxidative stress markers and histopathological analysis. In vitro study was carried out to assess the ability of GT-TeMac™ to scavenge free radicals and suppress H2O2-induced ROS production in SK-N-SH cells. In addition, the ability of GT-TeMac™ to restore cell viability reduced by acrolein was performed.
RESULTS: Chebuloside II, Sericoside, 24-deoxysericoside, arjunglucoside 1 and 23-galloylarjunolic acid 28-O-glucopyranosylester were identified by LC-MS. GT-TeMac™ has a SC50 of 9.54 μg/mL and an ORAC value of 1130 µM Trolox equivalent per mg of GT-TeMac™. The administration of GT-TeMac™ protected against cognitive decline in AD by inhibiting cholinesterase metabolism, modulating oxidative stress parameters and protecting hippocampal areas. Additionally, GT-TeMac™ absorbed and eliminated ROS produced by hydrogen peroxide in SKNSH cells and restored cell viability reduced by acrolein.
CONCLUSION: These findings suggest that the active ingredients in GT-TeMac™ are promising drug candidates for the treatment of cognitive disorders associated with oxidative stress in AD.}, }
@article {pmid40167883, year = {2025}, author = {Yang, W and Wei, Z and Wang, T}, title = {Unraveling the Role of LRP1 in Alzheimer's Disease: A Focus on Aβ Clearance and the Liver-Brain Axis.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {2}, pages = {43}, pmid = {40167883}, issn = {1559-1166}, mesh = {*Alzheimer Disease/metabolism ; *Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; Humans ; *Liver/metabolism ; *Brain/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia, significantly contributing to the global health burden. The progressive accumulation of amyloid-beta (Aβ) plaques and tau tangles triggers neuroinflammation, oxidative stress, and neuronal damage, highlighting the critical need for effective clearance mechanisms. Recent research has identified low-density lipoprotein receptor-related protein 1 (LRP1) as a key factor in the regulation of Aβ clearance, neuroinflammation, and blood-brain barrier integrity, particularly in relation to the liver-brain axis. This review provides a comprehensive examination of the role of LRP1 in AD, focusing on its expression in the brain and liver, its contribution to Aβ metabolism, and its potential as a therapeutic target. Using a systematic literature review, LRP1's multifaceted roles across various biological processes were explored, including its involvement in Aβ transport, clearance via the liver, and modulation of neuroinflammation. Additionally, the impact of physical exercise, pharmacological interventions, and dietary factors on LRP1 expression levels was investigated, elucidating how these approaches may enhance Aβ clearance. The findings demonstrate that LRP1 expression decreases progressively as AD advances, and that augmenting LRP1 activity-particularly through exercise and drug therapies-can improve Aβ clearance and reduce neuroinflammatory responses. Furthermore, LRP1's involvement in the liver-brain axis reveals its broader systemic role in AD pathology. In conclusion, targeting LRP1 offers a promising avenue for AD prevention and treatment, providing new insights into the therapeutic potential of enhancing Aβ clearance pathways through the liver-brain axis.}, }
@article {pmid40167846, year = {2025}, author = {Sharma, V and Sharma, P and Singh, TG}, title = {Ferroptosis and Alzheimer's: unveiling new avenues for the treatment and prevention.}, journal = {Metabolic brain disease}, volume = {40}, number = {4}, pages = {167}, pmid = {40167846}, issn = {1573-7365}, mesh = {*Ferroptosis/drug effects/physiology ; *Alzheimer Disease/metabolism/drug therapy ; Humans ; Animals ; Oxidative Stress/physiology/drug effects ; Amyloid beta-Peptides/metabolism ; Signal Transduction/drug effects/physiology ; Lipid Peroxidation/drug effects/physiology ; Iron/metabolism ; }, abstract = {Alzheimer's disease (AD), one of the most prevalent neurodegenerative illnesses worldwide, has a devastating effect on individual, families and society. Despite the extensive research and effort, various clinical trials aimed against amyloid-β, which is suspected to have a causative role in the illness, have not yet shown any clinically significant success to date. Emerging evidence suggests that ferroptosis, a kind of programmed cell death triggered by lipid peroxidation and dependent on iron, plays a role in AD. There is a complex relationship between AD and ferroptosis. In both the processes iron dysregulation, altered anti-oxidant mechanisms and lipid peroxidation is involved. Ferroptotic processes contributes to the neuro-inflammation, oxidative stress and damage to the neurons as observed in AD. Additionally, amyloid-β, a hallmark of AD, may influence the ferroptosis, further linked the two pathways. Numerous signalling pathways such as Phospho inositide 3-kinase, Glycogen synthase kinase-3β, 5'-AMP-activated protein kinase, nuclear factor erythroid 2-related factor-2 and Sirtuin pathway plays a part in the pathophysiology of AD. Through a comprehensive review of current research and experimentation, this investigation elucidates the interactions between novel pharmacological agents (ferroptotic inhibitors) and AD-related pathways. Furthermore, this review highlights the various ferroptotic inhibitors as the therapeutic agents for the slowing down the progression of AD. The crosstalk between these processes could unveil the potential therapeutic targets for the AD treatment.}, }
@article {pmid40167826, year = {2025}, author = {Abbas, K and Mustafa, M and Alam, M and Habib, S and Ahmad, W and Adnan, M and Hassan, MI and Usmani, N}, title = {Multi-target approach to Alzheimer's disease prevention and treatment: antioxidant, anti-inflammatory, and amyloid- modulating mechanisms.}, journal = {Neurogenetics}, volume = {26}, number = {1}, pages = {39}, pmid = {40167826}, issn = {1364-6753}, support = {Grant No. 3-69/2020- CCRUM/Tech//Central Council for Research in Unani Medicine/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/prevention & control/metabolism ; *Antioxidants/therapeutic use/pharmacology ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Animals ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Polyphenols/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; }, abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation, neurofibrillary tangles, neuroinflammation, and progressive cognitive decline, posing a significant global health challenge. Growing evidence suggests that dietary polyphenols may reduce the risk and progression of AD through multifaceted neuroprotective mechanisms. Polyphenols regulate amyloid proteostasis by inhibiting β/γ-secretase activity, preventing Aβ aggregation, and enhancing clearance pathways. Their strong antioxidant properties neutralize reactive oxygen species, chelate redox-active metals, and activate cytoprotective enzymes via Nrf2 signaling. This review examines the potential therapeutic targets, signaling pathways, and molecular mechanisms by which dietary polyphenols exert neuroprotective effects in AD, focusing on their roles in modulating amyloid proteostasis, oxidative stress, neuroinflammation, and cerebrovascular health. Polyphenols mitigate neuroinflammation by suppressing NF-κB signaling and upregulating brain-derived neurotrophic factor, supporting neuroplasticity and neurogenesis. They also enhance cerebrovascular health by improving cerebral blood flow, maintaining blood-brain barrier integrity, and modulating angiogenesis. This review examines the molecular and cellular pathways through which polyphenols exert neuroprotective effects, focusing on their antioxidant, anti-inflammatory, and amyloid-modulating roles. We also discuss their influence on key AD pathologies, including Aβ deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Insights from clinical and preclinical studies highlight the potential of polyphenols in preventing or slowing AD progression. Future research should explore personalized dietary strategies that integrate genetic and lifestyle factors to optimize the neuroprotective effects of polyphenols.}, }
@article {pmid40166852, year = {2025}, author = {Tewolde, S and Rosenberg, SB and Estrada, JAG and Jimenez, MP and Scott, A and Higgins, A and Rubenstein, E}, title = {Epidemiology of Alzheimer Disease and Related Dementia Among Medicare and Medicaid Enrolled Autistic Adults, 2011-2019.}, journal = {Autism research : official journal of the International Society for Autism Research}, volume = {}, number = {}, pages = {}, doi = {10.1002/aur.70035}, pmid = {40166852}, issn = {1939-3806}, support = {R01AG073179/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease and related dementias (ADRD) are burdensome and lethal conditions that have been hypothesized to be related to autism through shared genetic etiologies and environmental risk factors. Our objective was to use longitudinal Medicaid and Medicare data to describe the epidemiology of ADRD in publicly insured autistic adults. We used all claims and encounters from 2011 to 2019 to identify autism and ADRD. We calculated prevalence, incidence, age at onset, and created survival curves. There were 90,229 autistic adults ≥ 30 years of age and enrolled for at least 1 year in Medicaid and/or Medicare and 267 ADRD cases. Prevalence of ADRD was 2.09% (95% CI: 1.99%, 2.20%) in 2011 and 8.11% (95% CI: 7.92%, 8.30%) in 2019. Mean age at ADRD onset was 59.3 years (SD: 14.2). Mean age among men was 58.3 years (SD: 13.8) and 61.0 years among females. Incidence of ADRD was higher in autistic adults with intellectual disability with no difference by sex. ADRD is a prevalent condition in middle- and older-aged adults identified with autism in the Medicaid and Medicare system. Understanding the diagnostic process and phenotype of ADRD will be important to improve identification and treatment.}, }
@article {pmid40166757, year = {2025}, author = {Guo, L and Wang, D and Lai, X and Chi, Y and Liu, S and Su, X and Chen, H and Su, B and Xie, H}, title = {Relationship Between Peripheral Serum Adiponectin and Cerebrospinal Fluid TNF-α, IL-1β, Lactic Acid, Pyruvic Acid and Perioperative Neurocognitive Dysfunction in Elderly Patients Undergoing Hip Arthroplasty.}, journal = {Clinical interventions in aging}, volume = {20}, number = {}, pages = {381-393}, pmid = {40166757}, issn = {1178-1998}, mesh = {Humans ; *Adiponectin/blood ; Female ; Male ; Aged ; *Arthroplasty, Replacement, Hip/adverse effects ; *Lactic Acid/blood/cerebrospinal fluid ; *Interleukin-1beta/blood/cerebrospinal fluid ; *Tumor Necrosis Factor-alpha/blood ; *Pyruvic Acid/blood/cerebrospinal fluid ; Postoperative Cognitive Complications/etiology ; Aged, 80 and over ; Postoperative Complications/etiology/blood ; Cognitive Dysfunction/etiology ; Biomarkers/blood/cerebrospinal fluid ; Mental Status and Dementia Tests ; Neurocognitive Disorders/etiology ; }, abstract = {BACKGROUND: Postoperative neurocognitive dysfunction (PND) represents a form of cognitive impairment related to surgery and anesthesia, which may manifest hours or even weeks after the surgical procedure, persist, and potentially progress into Alzheimer's disease. The etiology of PND is intricate, with central nervous inflammation playing a crucial role. The clinical manifestations of PND are not distinctive, no obvious image alterations are observable, and the diagnosis rate is relatively low, thereby influencing prognosis and augmenting postoperative complications and mortality. The optimal treatment approach for PND lies in timely identification and management of the high-risk factors causing PND and implementing early prevention. We hypothesize that the level of peripheral blood adiponectin (APN) is correlated with PND, potentially through inhibiting the central inflammatory response and regulating brain energy metabolism.
METHODS: Fifty elderly patients undergoing elective hip arthroplasty under continuous epidural spinal anesthesia (CESA) were included. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) preoperatively and postoperatively at 1, 2, 3, and 7 days. Serum APN and CSF levels of TNF-α, IL-1β, lactic acid, and pyruvic acid were measured. The occurrence of PND was recorded, and the patients were divided into a PND group and a non-PND group.
RESULTS: PND occurred in 16 patients (34.04%). The PND group had lower serum APN levels and higher cerebrospinal fluid (CSF) concentrations of TNF-α, IL-1β, and lactic acid compared to the non-PND group. CSF TNF-α and IL-1β levels were negatively correlated with serum APN concentration. These biomarkers are associated with PND occurrence and have high diagnostic value.
CONCLUSION: Decreases in serum APN and increases in TNF-α, IL-1β, and lactic acid in CSF may be involved in the pathophysiological process of PND in elderly patients after surgery.}, }
@article {pmid40166719, year = {2025}, author = {Xiong, J and Chen, X and Huang, K and Pan, Y}, title = {Successful Guselkumab Treatment in a Patient with Comorbid Psoriasis and Amyotrophic Lateral Sclerosis: A Case Study and Literature Review.}, journal = {Clinical, cosmetic and investigational dermatology}, volume = {18}, number = {}, pages = {735-741}, pmid = {40166719}, issn = {1178-7015}, abstract = {Psoriasis is genetically influenced and can be triggered by factors such as infections, stress, and lifestyle. Chronic plaque psoriasis, the most prevalent form, involves key roles for IL-17 and IL-23 in its pathogenesis. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons, resulting in muscle weakness and atrophy. Currently, there is no cure for ALS, and treatment is symptomatic, aimed at improving quality of life. The combination of psoriasis and ALS is relatively rare. Although biologic agents have shown remarkable efficacy in the treatment of chronic plaque psoriasis, we have not found any case reports regarding the use of biologic agents for treating psoriasis accompanied by ALS. Our study presents a patient with severe plaque psoriasis and ALS who exhibited a positive response to Guselkumab, without worsening of ALS symptoms, suggesting a promising therapeutic strategy. This could provide a treatment option for patients with psoriasis combined with ALS.We conducted a comprehensive review of the literature on the comorbidity of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ALS, with plaque psoriasis. This review highlights the differential impact of treatment modalities. Specifically, we found that TNF-α inhibitors may have adverse effects in MS but could provide protective benefits in AD and PD. In ALS patients with psoriasis, IL-17A and IL-23 inhibitors, exemplified by Guselkumab, are suggested as a more suitable alternative due to their lower risk of worsening ALS symptoms.}, }
@article {pmid40166615, year = {2025}, author = {Chen, Y and Touboul, R and Chen, Y and Chang, CL}, title = {Strategic delivery of omega-3 fatty acids for modulating inflammatory neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1535094}, pmid = {40166615}, issn = {1663-4365}, abstract = {OBJECTIVES: Early-life inflammatory events like infections and injuries may predispose the brain to Alzheimer's disease (AD) by disrupting neurodevelopment and raising vulnerability. The association between early neuroinflammation and subsequent neurodegeneration leading to dementia remains unclear. We hypothesize that omega-3 (n-3) fatty acids (FA), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), positively regulate neuro-immune cells, preserving their cell membrane structure and metabolic homeostasis. Our study examined whether strategic delivery of n-3 FA via injectable n-3 triglycerides (TG) can influence microglial lipid metabolism to prevent or delay AD progression.
METHODS AND RESULTS: We characterized n-3 treatment effects on modulating lipid and metabolic homeostasis in microglia during the critical window of brain development. Our preliminary studies on determining the effects of early n-3 treatment on brain cell homeostasis indicate that perinatal bolus n-3 TG injections suppressed activation of gliosis-associated markers in young mice predisposed to AD (5xFAD) and yielded sustained regulatory effects on the expression of inflammatory molecules, such as interleukin-6 (Il6) and tumor necrosis factor-alpha (Tnfα), in adult brains. A significant increase in high-frequency ultrasonic vocalizations (USV) was observed in P6 5xFAD mice that received perinatal n-3 compared to vehicle control, implicating enhanced active communication patterns. Improvement in behavior deficits was observed in n-3-treated adult AD mice. Perinatal n-3 TG treatment modified brain lipid composition in young offspring, increasing key membrane lipid species, such as phospholipids (PL) and lysophospholipids (lysoPL). Pro-inflammatory sphingolipids associated with neurodegeneration, including lactosylceramide, were significantly lower in mice treated with n-3 than those in saline-treated AD mice.
CONCLUSION: Our study establishes a proof of principle for targeting brain immune cell metabolism with injectable n-3 TG to mitigate neuroinflammation in AD pathogenesis, paving the way for future research into early treatments for related central nervous system (CNS) disorders.}, }
@article {pmid40166579, year = {2025}, author = {Zammit, MD and Price, JC and Christian, BT and Rafii, MS and , }, title = {A head-to-head comparison of multiple amyloid PET radiotracers for Down syndrome clinical trials.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.03.18.25324200}, pmid = {40166579}, abstract = {Adults with Down syndrome carry high risk of developing Alzheimer's disease and efforts to include this population in clinical trials remain limited. A barrier to recruitment for anti-amyloid trials includes the availability of the same amyloid PET radiotracer to multiple treatment centers. 237 adults with Down syndrome from the Trial-Ready Cohort - Down syndrome and Alzheimer Biomarker Consortium - Down syndrome studies were imaged using T1-w MRI and using PET images of PiB, Florbetapir (FBP), NAV4694 (NAV) or Flutemetamol (FMM) to screen for amyloid plaque (Aβ) burden. PiB displayed the largest effect size to measure amyloid change while FBP had a small effect size. NAV and PiB, which are structurally similar compounds, displayed similar sensitivity to measure longitudinal amyloid increase. The estimated age at amyloid onset showed no significant difference between PiB, FBP, NAV or FMM. The findings suggest that different amyloid PET radiotracers provide consistent estimates of amyloid onset age for adults with Down syndrome. Multicenter studies of Alzheimer's disease therapeutics can utilize multiple amyloid PET radiotracers to facilitate recruitment, however, PiB and NAV displayed the greatest sensitivity to detect longitudinal change.}, }
@article {pmid40166467, year = {2025}, author = {Ma, L and Wang, J and Zhou, R and Chen, M and Huang, Z and Lin, S}, title = {Traditional Chinese Medicine-derived formulations and extracts modulating the PI3K/AKT pathway in Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1528919}, pmid = {40166467}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by memory decline, cognitive impairment, and behavioral abnormalities. Pathologically, AD is marked by neurofibrillary tangles caused by excessive phosphorylation of Tau protein and abnormal deposition of β-amyloid (Aβ) in the brain. The PI3K/AKT signaling pathway plays a crucial role in the development, survival, and metabolic regulation of the central nervous system, particularly in neuronal growth, differentiation, and apoptosis. However, this pathway is often inhibited in AD patients.In recent years, studies have shown that herbal formulations and extracts derived from Traditional Chinese Medicine (TCM) can regulate the PI3K/AKT signaling pathway, thereby improving AD pathological models. This study reviews fundamental research on both active metabolites and compound formulations from TCM for the treatment of AD, targeting the PI3K/AKT signaling pathway.Keywords include "Alzheimer's disease" "AD" "dementia" "PI3K" "AKT" "Traditional Chinese Medicine" "Chinese herbology" "Chinese medicine" and "TCM".The study is based on relevant literature published over the past 15 years, primarily sourced from electronic databases such as Web of Science, PubMed, CNKI, Wanfang, and VIP databases.The findings indicate that herbal formulations and extracts derived from TCM can mitigate AD pathology by regulating the PI3K/AKT signaling pathway, reducing Tau protein phosphorylation and Aβ deposition, inhibiting inflammatory responses and oxidative stress, and alleviating neuronal apoptosis. This study enhances our understanding of the anti-AD mechanisms of TCM through the PI3K/AKT pathway and offers new insights for the future.}, }
@article {pmid40166175, year = {2025}, author = {Laroche, VT and Cavill, R and Kouhsar, M and Reijnders, RA and Harvey, J and Smith, AR and Imm, J and Koetsier, J and Weymouth, L and MacBean, L and Pegoraro, G and Eijssen, L and Creese, B and Kenis, G and Tijms, BM and van den Hove, D and Lunnon, K and Pishva, E}, title = {Epigenomic subtypes of late-onset Alzheimer's disease reveal distinct microglial signatures.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40166175}, issn = {2692-8205}, abstract = {Growing evidence suggests that clinical, pathological, and genetic heterogeneity in late-onset Alzheimer's disease contributes to variable therapeutic outcomes, potentially explaining many trial failures. Advances in molecular subtyping through proteomic and transcriptomic profiling reveal distinct patient subgroups, highlighting disease complexity beyond amyloid-beta plaques and tau tangles. This insight underscores the need to expand molecular subtyping across new molecular layers, to identify novel drug targets for different patient subgroups. In this study, we analyzed genome-wide DNA methylation data from three independent postmortem brain cohorts (n = 831) to identify epigenetic subtypes of late-onset Alzheimer's disease. Unsupervised clustering approaches were employed to identify distinct DNA methylation patterns, with subsequent cross-cohort validation to ensure robustness and reproducibility. To explore the cell-type specificity of the identified epigenomic subtypes, we characterized their methylation signatures utilizing DNA methylation profiles derived from purified brain cells. Transcriptomic data from bulk and single-cell RNA sequencing were integrated to examine the functional impact of epigenetic subtypes on gene expression profiles. Finally, we performed statistical analyses to investigate associations between these DNA methylation-defined subtypes and clinical or neuropathological features, aiming to elucidate their biological significance and clinical implications. We identified two distinct epigenomic subtypes of late-onset Alzheimer's disease, each defined by reproducible DNA methylation patterns across three cohorts. Both subtypes exhibit cell-type-specific DNA methylation profiles. Subtype 1 and subtype 2 show significant microglial methylation enrichment, with odds ratios (OR) of 1.6 and 1.3, respectively. The minimal overlap between them suggests distinct microglial states. Additionally, subtype 2 displays strong neuronal (OR = 1.6) and oligodendrocyte (OR = 3.6) enrichment. Bulk transcriptomic analyses further highlighted divergent biological mechanisms underpinning these subtypes, with subtype 1 enriched for immune-related processes, and subtype 2 characterized predominantly by neuronal and synaptic functional pathways. Single-cell transcriptional profiling of microglia revealed subtype-specific inflammatory states: subtype 1 represented a state of chronic innate immune hyperactivation with impaired resolution, while subtype 2 exhibited a more dynamic inflammatory profile balancing pro-inflammatory signaling with reparative and regulatory mechanisms. This study highlights the molecular heterogeneity of late-onset Alzheimer's disease by identifying two epigenetic subtypes with distinct cell-type-specific DNA methylation patterns. Their alignment with previously defined molecular classifications underscores their relevance in disease pathogenesis. By linking these subtypes to inflammatory microglial activity, our findings provide a foundation for future precision medicine approaches in Alzheimer's research and treatment.}, }
@article {pmid40166037, year = {2025}, author = {Cruchaga, C and Heo, G and Thomas, A and Wang, E and Oh, H and Ali, M and Timsina, J and Song, S and Liu, M and Gong, K and Western, D and Chen, Y and Kohlfeld, P and Flynn, A and Lowery, J and Morris, J and Holtzman, D and Perlmutter, J and Schindler, S and Zhang, B and Bennett, D and Benzinger, T and Wyss-Coray, T and Ibanez, L and Sung, YJ and Xu, Y and Losada, PM and Anastasi, F and Gonzalez-Escalante, A and Puerta, R and Vilor-Tejedor, N and Suárez-Calvet, M and Garcia-Gonzalez, P and Fernández, M and Boada, M and Cano, A and Ruiz, A}, title = {Large-scale Plasma Proteomic Profiling Unveils Novel Diagnostic Biomarkers and Pathways for Alzheimer's Disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-5167552/v1}, pmid = {40166037}, issn = {2693-5015}, abstract = {Alzheimer disease (AD) is a complex neurodegenerative disorder. Proteomic studies have been instrumental in identifying AD-related proteins present in the brain, cerebrospinal fluid, and plasma. This study comprehensively examined 6,905 plasma proteins in more than 3,300 well-characterized individuals to identify new proteins, pathways, and predictive model for AD. With three-stage analysis (discovery, replication, and meta-analysis) we identified 416 proteins (294 novel) associated with clinical AD status and the findings were further validated in two external datasets including more than 7,000 samples and seven previous studies. Pathway analysis revealed that these proteins were involved in endothelial and blood hemostatic (ACHE, SMOC1, SMOC2, VEGFA, VEGFB, SPARC), capturing blood brain barrier (BBB) disruption due to disease. Other pathways were capturing known processes implicated in AD, such as lipid dysregulation (APOE, BIN1, CLU, SMPD1, PLA2G12A, CTSF) or immune response (C5, CFB, DEFA5, FBXL4), which includes proteins known to be part of the causal pathway indicating that some of the identified proteins and pathways are involved in disease pathogenesis. An enrichment of brain and neural pathways (axonal guidance signaling or myelination signaling) indicates that, in fact, blood proteomics capture brain- and disease-related changes, which can lead to the identification of novel biomarkers and predictive models. Machine learning model was employed to identify a set of seven proteins that were highly predictive of both clinical AD (AUC > 0.72) and biomarker-defined AD status (AUC > 0.88), that were replicated in multiple external cohorts as well as with orthogonal platforms. These extensive findings underscore the potential of using plasma proteins as biomarkers for early detection and monitoring of AD, as well as potentially guiding treatment decisions.}, }
@article {pmid40166019, year = {2025}, author = {Lin, AL and Aware, C and Neher, C and Hamdi, M and Ericsson, A and Khegai, O and Patrie, J and Kurt, M and Govindarajan, M and Woods, C and Ivanich, K and Beversdorf, D and Cheng, J and Balchandani, P and Gonzales, M and Altes, T}, title = {Rapamycin enhances neurovascular, peripheral metabolic, and immune function in cognitively normal, middle-aged APOE4 Carriers: genotype-dependent effects compared to non-carriers.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-6214340/v1}, pmid = {40166019}, issn = {2693-5015}, abstract = {Rapamycin, known for its anti-aging properties, shows promise as a preventive strategy for Alzheimer's disease (AD) in APOE4 carriers-the highest-risk group for late-onset AD. Here we show that a 4-week open-label trial of low-dose Rapamycin (Sirolimus; 1 mg/day) significantly improved cerebral blood flow (CBF) relative to baseline in cognitively normal APOE4 carriers (E4(+)) aged 45-65. It also reduced inflammatory cytokines, enhanced lipid metabolism, increased short-chain fatty acids (SCFA) and enriched gut microbiome composition linked to SCFA production. Conversely, non-carriers (E4(-)) displayed stable baseline-to-post-treatment CBF and SCFA and demonstrated different treatment-related patterns of metabolic and anti-inflammatory effects than E4(+). Serum amyloid A and tau remained unchanged for both groups. These findings suggest Rapamycin may counter early vascular and metabolic deficits in E4(+) individuals, with genotype-specific effects. By bridging anti-aging research and AD prevention, this study highlights a novel, safe, and precision-based approach to mitigating AD risk in APOE4 carriers.}, }
@article {pmid40165664, year = {2025}, author = {Feng, G and Lan, X and Qin, S and Shi, Y and Zhao, Q and Li, Q and Zhong, L}, title = {Advances in Research on Exosomal miRNAs in Central Nervous System Diseases.}, journal = {ASN neuro}, volume = {17}, number = {1}, pages = {2465546}, doi = {10.1080/17590914.2025.2465546}, pmid = {40165664}, issn = {1759-0914}, mesh = {Humans ; *Exosomes/metabolism/genetics ; *MicroRNAs/genetics/metabolism ; *Central Nervous System Diseases/genetics/metabolism/diagnosis ; Animals ; Biomarkers/metabolism ; }, abstract = {Neurological diseases present a wide range of conditions, intricate diagnosis and treatment processes, and complex prognostic considerations. Therefore, research focusing on the diagnosis and treatment of these diseases is crucial. Exosomal miRNAs are small RNA molecules enclosed in membrane vesicles, released by cells and known to play roles in the development of various neurological disorders. They also serve as specific biomarkers for these conditions. Drawing on extensive research on exosomal miRNAs in diseases like stroke, Alzheimer's, epilepsy, Parkinson's, and neuroregeneration, this paper provides a comprehensive review of the relationship between exosomal miRNAs and neurological diseases. We strive to offer current and detailed theoretical understandings to help with the diagnosis and treatment of these disorders.}, }
@article {pmid40165137, year = {2025}, author = {Yan, YJ and Lin, R and Luo, YT and Huang, CS and Cai, WC and Su, JW and Lin, SM and Lin, MJ and Li, H}, title = {Impact of combined art-based intervention on functional connectivity of multiple brain networks in older adults along the cognitive continuum: result from a parallel randomised controlled trial.}, journal = {BMC psychiatry}, volume = {25}, number = {1}, pages = {307}, pmid = {40165137}, issn = {1471-244X}, support = {2022QH1320//Fund for Scientific Research of Fujian Medical University/ ; 2023J05224//Natural Science Foundation of Fujian Province/ ; FJKX-2024XRHO4//Fujian Province Science and Technology-Economy Integration Service Platform/ ; }, mesh = {Humans ; Male ; Female ; Aged ; *Magnetic Resonance Imaging ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; *Cognition/physiology ; Art Therapy/methods ; Brain/diagnostic imaging/physiopathology ; Nerve Net/diagnostic imaging/physiopathology ; Neuropsychological Tests ; Memory/physiology ; Connectome/methods ; Middle Aged ; }, abstract = {BACKGROUND: Combined art-based interventions (CAIs) are considered effective treatment options for older adults along the cognitive continuum; however, the neural mechanisms underlying associated changes in neurocognitive performance remain unclear. Thus, we aimed to investigate the impact of a CAI programme in older adults along the cognitive continuum and to understand its mechanism.
METHODS: This parallel-arm randomised controlled trial was conducted between April 2021 and January 2023. Participants were randomised in a 1:1 ratio to either intervention group (IG) or waitlist control group (WG). The IG underwent a 16-week CAI programme. Neuropsychological assessments and magnetic resonance imaging were conducted before and after the intervention.
RESULTS: After the intervention, the IG showed greater improvement in general cognitive function, language, and memory than the WG. Significant differences were observed in the functional connectivity (FC) values in the temporal and cerebellar anterior lobes, fusiform, inferior occipital, and lingual gyri, and perirhinal and visual cortices between the groups. Further analyses showed that FC values were reduced in these regions in the IG. In addition, changes in FC values were positively correlated with those in neuropsychological test scores in the IG.
CONCLUSIONS: Our study suggests that the CAI programme can effectively improve general cognitive function, language, and memory in older adults along the cognitive continuum. These improvements may be changed due to decreases in FC in key brain regions, deepening the understanding of the neurocentral mechanisms that act as a tool for improving cognitive function.
TRIAL REGISTRATION: This trial was registered at ChiCTR.org. Identifier: ChiCTR2100044959, 03/04/2021.}, }
@article {pmid40164861, year = {2025}, author = {Bogdanovic, N and Smailovic, U and Jelic, V}, title = {Alzheimer mimicry: LATE and PART.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {40164861}, issn = {1435-1463}, abstract = {Alzheimer's disease (AD) is the main cause of dementia and accounts for 60% of dementia syndromes in people older than 75 years. The correct classification of AD and non-AD cases is mandatory to study disease mechanisms or new treatment possibilities. A typical clinical picture of AD consists of a progressive cognitive decline, with primary memory impairment. Structural, functional, and molecular brain imaging, along with CSF biomarkers of amyloid pathology, neurodegeneration, and the presence of a vulnerability-associated APOE genotype, support the diagnosis of AD. Use of biomarkers have led to the identification of individuals with mild cognitive impairment who are amyloid-negative addressing a conceptually separate clinical entity named suspected non-Alzheimer disease pathophysiology (SNAP). Clinical presentation and progression of SNAP can mimic AD which makes the final diagnosis and possible treatment uncertain in up to 30% of cases in clinical centers that are not using biomarkers. These non-AD pathologies are common with advancing age both in cognitively impaired and clinically normal elderly people and include Argyrophilic Grain Disease (ARG), Tangle Predominant Dementia and TDP-43 proteinopathy. The terms Primary age-related tauopathy (PART) and Limbic-dominant TDP-43 age-related encephalopathy (LATE) have been proposed as the most common and useful biological and emerging clinical construct to describe this phenomenon in > 80 years old individuals. Current evidence underlines the limitations of existing diagnostic tools, which remain inadequate for fully capturing the complexities of these conditions. Addressing these diagnostic ambiguities is crucial for assigning accurate diagnoses, reducing frequent misdiagnoses of AD, and implementing appropriate therapeutic strategies for elderly patients with mild cognitive impairment and dementia.}, }
@article {pmid40164781, year = {2025}, author = {Bassal, R and Rivkin-Natan, M and Rabinovich, A and Michaelson, DM and Frenkel, D and Pinkas-Kramarski, R}, title = {APOE4 impairs autophagy and Aβ clearance by microglial cells.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {74}, number = {1}, pages = {61}, pmid = {40164781}, issn = {1420-908X}, mesh = {Animals ; *Microglia/metabolism ; *Autophagy ; *Apolipoprotein E4/genetics/metabolism ; *Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; Mice ; Apolipoprotein E3/genetics/metabolism ; Sirolimus/pharmacology ; Alzheimer Disease/metabolism ; Mitochondria/metabolism ; Brain/metabolism ; Plaque, Amyloid/metabolism/pathology ; Humans ; Chloroquine/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a predominant form of dementia in elderly. In sporadic AD and in families with higher risk of AD, correlation with apolipoprotein E4 (APOE) allele expression has been found. How APOE4 induces its pathological effects is still unclear. Several studies indicate that autophagy, a major degradation pathway trough the lysosome, may be compromised in AD. Here we studied, the effects of APOE isoforms expression in microglia cells. By using an in-situ model, the clearance of Aβ plaques from brain sections of transgenic 5xFAD mice by the APOE expressing microglia was examined. The results show that APOE4 microglia has Impairment In clearance of insoluble Aβ plaques as compared to APOE3 and APOE2 microglia. Furthermore, APOE4 affect the uptake of soluble Aβ. We found that microglia expressing APOE4 exhibit reduced autophagic flux as compared to those expressing APOE3. The autophagy inhibitor chloroquine also blocked Aβ plaque uptake in APOE3 expressing cells. Furthermore, we found that APOE4 expressing microglia have altered mitochondrial dynamics protein expression, mitochondrial morphology and mitochondrial activity compared to those expressing APOE2, and APOE3. Rapamycin treatment corrected Mitochondrial Membrane Potential in APOE4-expressing cells. Taken together, these findings suggest that APOE4 impairs the activation of autophagy, mitophagy, and Aβ clearance and that autophagy-inducing treatments, such as rapamycin, can enhance autophagy and mitochondrial functions in APOE4 expressing microglia. Our results reveal a direct link between APOE4 to autophagy activity in microglia, suggesting that the pathological effects of APOE4 could be counteracted by pharmacological treatments inducing autophagy, such as rapamycin.}, }
@article {pmid40164726, year = {2025}, author = {Horie, K and Salvadó, G and Koppisetti, RK and Janelidze, S and Barthélemy, NR and He, Y and Sato, C and Gordon, BA and Jiang, H and Benzinger, TLS and Stomrud, E and Holtzman, DM and Mattsson-Carlgren, N and Morris, JC and Palmqvist, S and Ossenkoppele, R and Schindler, SE and Hansson, O and Bateman, RJ}, title = {Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer's disease.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {40164726}, issn = {1546-170X}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P01 AG03991//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P01 AG026276/AG/NIA NIH HHS/United States ; R01AG070941//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, abstract = {Insoluble tau aggregates within neurofibrillary tangles are a defining neuropathological feature of Alzheimer's disease (AD) and closely correlate with clinical symptoms. Although tau pathology can be assessed using tau positron emission tomography, a more accessible biomarker is needed for diagnosis, prognosis and tracking treatment effects. Here we present a new plasma tau species, the endogenously cleaved, microtubule-binding region containing residue 243 (eMTBR-tau243), which specifically reflects tau tangle pathology. Across the AD spectrum in three different cohorts (n = 108, 55 and 739), plasma eMTBR-tau243 levels were significantly elevated at the mild cognitive impairment stage and increased further in dementia. Plasma eMTBR-tau243 showed strong associations with tau positron emission tomography binding (β = 0.72, R[2] = 0.56) and cognitive performance (β = 0.60, R[2] = 0.40), outperforming other plasma tau (%p-tau217 and %p-tau205) biomarkers. These results suggest that plasma eMTBR-tau243 may be useful for estimating the tauopathy load in AD, thereby improving the diagnostic evaluation of AD in clinical practice and monitoring the efficacy of tau-targeted therapies in clinical trials.}, }
@article {pmid40164279, year = {2025}, author = {Shah, FA and Qadir, H and Khan, JZ and Faheem, M and Alanazi, FE and Khalid, T}, title = {A review: From old drugs to new solutions: The role of repositioning in alzheimer's disease treatment.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2025.03.064}, pmid = {40164279}, issn = {1873-7544}, abstract = {Drug repositioning or drug reprofiling, involves identifying novel indications for approved and previously abandoned drugs in the treatment of other diseases. The traditional drug discovery process is tedious, time-consuming, risky, and challenging. Fortunately, the inception of the drug repositioning concept has expedited the process by using compounds with established safety profiles in humans, and thereby significantly reducing costs. Alzheimer's disease (AD) is a severe neurological disorder characterized by progressive degeneration of the brain with limited and less effective therapeutic interventions. Researchers have attempted to identify potential treatment of AD from existing drug however, the success of drug repositioning strategy in AD remains uncertain. This article briefly discusses the importance and effectiveness of drug repositioning strategies, the major obstacles in the development of drugs for Alzheimer's disease (AD), approaches to address these challenges, and the role of machine learning in identifying early markers of AD for improved management.}, }
@article {pmid40164234, year = {2025}, author = {Yang, X and Yao, K and Zhang, M and Zhang, W and Zu, H}, title = {New insight into the role of altered brain cholesterol metabolism in the pathogenesis of AD: A unifying cholesterol hypothesis and new therapeutic approach for AD.}, journal = {Brain research bulletin}, volume = {224}, number = {}, pages = {111321}, doi = {10.1016/j.brainresbull.2025.111321}, pmid = {40164234}, issn = {1873-2747}, abstract = {The dysregulation of cholesterol metabolism homeostasis has been universally suggested in the aeotiology of Alzheimer's disease (AD). Initially, studies indicate that alteration of serum cholesterol level might contribute to AD. However, because blood-brain barrier impedes entry of plasma cholesterol, brain cells are not directly influenced by plasma cholesterol. Furthermore, mounting evidences suggest a link between alteration of brain cholesterol metabolism and AD. Interestingly, Amyloid-β proteins (Aβ) can markedly inhibit cellular cholesterol biosynthesis and lower cellular cholesterol content in cultured cells. And Aβ overproduction/overload induces a significant decrease of brain cellular cholesterol content in familial AD (FAD) animals. Importantly, mutations or polymorphisms of genes related to brain cholesterol transportation, such as ApoE4, ATP binding cassette (ABC) transporters, low-density lipoprotein receptor (LDLR) family and Niemann-Pick C disease 1 or 2 (NPC1/2), obviously lead to decreased brain cholesterol transport, resulting in brain cellular cholesterol loss, which could be tightly associated with AD pathological impairments. Additionally, accumulating data show that there are reduction of brain cholesterol biosynthesis and/or disorder of brain cholesterol trafficking in a variety of sporadic AD (SAD) animals and patients. Collectively, compelling evidences indicate that FAD and SAD could share one common and overlapping neurochemical mechanism: brain neuronal/cellular cholesterol deficiency. Therefore, accumulated evidences strongly support a novel hypothesis that deficiency of brain cholesterol contributes to the onset and progression of AD. This review highlights the pivotal role of brain cholesterol deficiency in the pathogenesis of AD. The hypothesis offers valuable insights for the future development of AD treatment.}, }
@article {pmid40163534, year = {2025}, author = {Tonegawa-Kuji, R and Hou, Y and Hu, B and Lorincz-Comi, N and Pieper, AA and Tousi, B and Leverenz, JB and Cheng, F}, title = {Efficacy and safety of passive immunotherapies targeting amyloid beta in Alzheimer's disease: A systematic review and meta-analysis.}, journal = {PLoS medicine}, volume = {22}, number = {3}, pages = {e1004568}, doi = {10.1371/journal.pmed.1004568}, pmid = {40163534}, issn = {1549-1676}, abstract = {BACKGROUND: While recently U.S. FDA-approved anti-amyloid beta (anti-Aβ) monoclonal antibodies (mAbs) offer new treatment approaches for patients suffering from Alzheimer's disease (AD), these medications also carry potential safety concerns and uncertainty about their efficacy for improving cognitive function. This study presents an updated meta-analysis of cognitive outcomes and side effects of anti-Aβ mAbs from phase III randomized controlled trials (RCTs) in patients with sporadic AD.
METHODS AND FINDINGS: Phase III randomized, placebo-controlled blinded trial evaluating the efficacy and safety of anti-Aβ mAbs in patients with AD were identified through a search in clinical trials.gov, PubMed and Embase on January 14th, 2024. The retrieved studies were further screened from January 15th, 2024, to February 14th, 2024. We included studies that had been published in any language. Quality of trials was assessed using the Jadad score and publication bias was assessed using Egger's test and Funnel plot. Primary outcomes were mean changes from baseline to post-treatment in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) and AD Assessment Scale-Cognitive Subscale (ADAS-Cog) scores, and secondary outcomes were adverse events including amyloid-related imaging abnormalities with edema (ARIA-E), and ARIA with hemorrhage (ARIA-H). Random-effects meta-analysis and meta-regression analyses were conducted. The literature search identified 13 phase III RCTs, which included 18,826 patients with mild cognitive impairment or dementia due to AD. Compared with placebo, treatment with mAbs significantly improved cognitive performance on CDR-SB (mean difference -0.25, 95% confidence interval [CI] [-0.38, -0.11]) and ADAS-Cog (standardized mean difference -0.09, 95% CI [-0.12, -0.06]), in which a negative change indicates improvement for both scores. Meta-regression analysis suggested that trials enrolling patients with early-stage AD were associated with better efficacy. Elevated risk of ARIA-E (risk ratio [RR] 9.79, 95% CI [5.32,18.01]), ARIA-H (RR 1.94, 95% CI [1.47,2.57]), and headaches (RR 1.21, 95% CI [1.10,1.32]) were noted. Statistical heterogeneity was relatively high for ARIA-E and ARIA-H, leading to wide confidence intervals and considerable variability in effect sizes, though meta-regression was conducted to address this. Furthermore, differences in trial designs introduce limitations in cross-trial comparisons.
CONCLUSIONS: Anti-Aβ mAb therapy slows cognitive decline, but with small effect sizes, and raises potential concerns about ARIA and headaches.}, }
@article {pmid40163151, year = {2025}, author = {Wadan, AS and Shaaban, AH and El-Sadek, MZ and Mostafa, SA and Moshref, AS and El-Hussein, A and Ellakwa, DE and Mehanny, SS}, title = {Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40163151}, issn = {1432-1912}, abstract = {Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.}, }
@article {pmid40162470, year = {2024}, author = {Fotovat, L and Wang, K and Chiappelli, F}, title = {Integrating MICRORNA941 and T cell subset research into public health strategies for managing inflammaging in elderly and immune-compromised patients.}, journal = {Bioinformation}, volume = {20}, number = {11}, pages = {1529-1531}, pmid = {40162470}, issn = {0973-2063}, abstract = {As of 2022, the Centers for Disease Control and Prevention (CDC) reported that the average life expectancy for both sexes in the United States is 77.5 years. While new advances in health have increased life expectancy, aging comes with complications that impact the development of diseases like cancer, senile dementia (non-Alzheimer), diabetes and Parkinson's. Through aging, the body's immune system declines, a process recognized as immunosenescence and which contributes to inflammaging, a state of chronic, though non-productive, inflammation that progresses with advancing age in the absence of overt infection and that contributes to the onset and progression of a spectrum of age-related pathologies. MicroRNAs are small forms of RNA that control gene expression by binding to messenger RNA (mRNA) in the cell cytoplasm. In particular, microRNA-941 (miR-941) has been found to play a critical role in the regulation of differentiation of cell populations, certain T cell subsets responsible for maintaining efficient immune surveillance in normal subjects, immune compromised individuals as well as the elderly. We propose that concerted research designed to define and characterize interventions targeting the regulatory effects of miRNA-941 specifically on T-cell subsets will benefit treatment of infectious (e.g., CoViD-19, H5N1 infection) and chronic illnesses (e.g., diabetes II, diabetes III, Long Covid [i.e., Post-Acute Covid-19 Syndrome, PACS], autoimmune disease), which are most common among the aging and the immune compromised population. It is possible and even probable that active research in this specific area will proffer new horizons for finding cures, aid in disease management and improved accessibility and affordability of public health services.}, }
@article {pmid40162198, year = {2025}, author = {Liu, X and Zhou, B and Chen, Y and Lin, J and Shao, C and Chen, L and Ruan, B and Zhang, X and Qian, Y}, title = {Design and synthesis of 2-phenyl-1H-benzo[d]imidazole derivatives as 17β-HSD10 inhibitors for the treatment of Alzheimer's disease.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {40162198}, issn = {2632-8682}, abstract = {It has been reported that 17β-HSD10 plays a key role in Alzheimer's disease. Here, a total of 44 2-phenyl-1H-benzo[d]imidazole derivatives were designed and synthesized as novel 17β-HSD10 inhibitors based on rational design and SAR studies. Among them, compound 33 (N-(4-(1,4,6-trimethyl-1H-benzo[d] imidazol-2-yl)phenyl)cyclohexanecarboxamide) showed high inhibitory efficacy (17β-HSD10 IC50 = 1.65 ± 0.55 μM) and low toxicity (HepaRG IC50 >100 μM). The Morris water maze experiment revealed that compound 33 could alleviate cognitive impairment induced by scopolamine in mice. This study facilitates the further development of more potent 17β-HSD10 inhibitors for the treatment of Alzheimer's disease.}, }
@article {pmid40160510, year = {2025}, author = {Hoang, MT and Zenker, A and Saha, S and Gerdtham, UG and Trepel, D}, title = {Economic evaluations of strategies targeting pre-diagnosis dementia populations: Protocol for a systematic review.}, journal = {HRB open research}, volume = {8}, number = {}, pages = {11}, pmid = {40160510}, issn = {2515-4826}, abstract = {INTRODUCTION: Dementia remains incurable, and treatment trials are typically conducted after the symptoms manifest, potentially too late in the disease process to alter its course. Early identification and intervention during the pre-diagnosis phase offer the potential to introduce more cost-effective strategies and enhance quality of life. This review aims to scrutinise emerging evidence and present a comprehensive summary of cost-effectiveness estimates of all strategies targeting the pre-diagnosis dementia population.
METHOD AND ANALYSIS: A systematic search will be conducted across six electronic databases. All articles will be assessed against pre-defined eligibility criteria through title and abstract screening, and full-text screening phases. Data from the included articles will be extracted using a standardized template. A newly established framework based on the CHEERS 2022 checklist will be applied to assess the reporting quality of the included articles. The entire review process, from screening to data extraction and quality assessment, will be a dual process conducted by two reviewers. Disagreements will be resolved by a third senior reviewer. The extracted data will be synthesised and presented in tables and figures.
CONCLUSION: This systematic review will present evidence of cost-effectiveness, along with the strengths and limitations of the existing literature. These findings aim to identify existing gaps, thereby informing and guiding the design of future studies in this domain.
ETHICS AND DISSEMINATION: Since this is a systematic review protocol, ethical approval is not required. The results will be published in a peer-reviewed journal, with both raw and summarised data shared through the journal or other open platforms.
PROSPERO - CRD42024521521.}, }
@article {pmid40160463, year = {2025}, author = {Cordeiro, GA and Faria, JA and Pavan, L and Garcia, IJP and Neves, EPFI and Lima, GFF and Campos, HM and Ferreira, PY and Ghedini, PC and Kawamoto, EM and Lima, MC and Villar, JAFP and Orellana, AMM and Barbosa, LA and Scavone, C and Leite, JA and Santos, HL}, title = {Evaluation of the neuroprotective potential of benzylidene digoxin 15 against oxidative stress in a neuroinflammation models induced by lipopolysaccharide and on neuronal differentiation of hippocampal neural precursor cells.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1537720}, pmid = {40160463}, issn = {1663-9812}, abstract = {Neuroinflammation, often driven by the overproduction of reactive oxygen species (ROS), plays a crucial role in the pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The susceptibility of the brain to oxidative stress is attributed to its high metabolic activity and limited antioxidant defense. This study aimed to evaluate the neuroprotective potential of Benzylidene Digoxin 15 (BD-15) following treatment and pretreatment in a lipopolysaccharide (LPS)-induced neuroinflammation model. Additionally, we examined whether BD-15 enhances the generation of neurons from neural progenitor cells (NPCs).Male Wistar rats were used for acute treatment studies and divided into four groups: control (saline), BD-15 (100 μg/kg), LPS (250 μg/kg), and LPS + BD-15 (250 μg/kg + 100 μg/kg). Swiss albino mice were used for chronic pretreatment studies and divided into the following groups: control (saline), BD-15 (0.56 mg/kg), LPS (1 mg/kg), and LPS + BD-15 (1 mg/kg + 0.56 mg/kg). Behavioral changes were assessed using the open field test, and brain tissues were analyzed for oxidative stress markers, including malondialdehyde (MDA), reduced glutathione (GSH), protein carbonylation, catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST). To assess neurogenesis, primary NPC cultures derived from the hippocampus of newborn Wistar rats were used, which led to reduced locomotor activity and increased oxidative stress, particularly in the cortex, as indicated by elevated MDA levels and reduced GSH levels. BD-15 treatment reversed these effects, notably by restoring GSH levels and reducing protein carbonylation in the cerebellum. Chronic BD-15 treatment in Swiss mice improved oxidative stress markers including MDA, SOD, CAT, and GST. Furthermore, BD-15 exhibits neuroprotective properties by alleviating oxidative stress and motor dysfunction, suggesting its potential as a therapeutic agent for neuroinflammatory disorders. However, BD-15 did not affect NPC cell proliferation, indicating that this cardiotonic steroid did not alter the cell cycle of these progenitor cells.}, }
@article {pmid40160278, year = {2025}, author = {Chen, X and Lv, Z and Xie, G and Zhao, C and Zhou, Y and Fu, F and Li, J and Zhang, X and Qi, F and Xu, Y and Chen, Y}, title = {Unleashing the potential: 40 Hz multisensory stimulation therapy for cognitive impairment.}, journal = {Journal of central nervous system disease}, volume = {17}, number = {}, pages = {11795735251328029}, pmid = {40160278}, issn = {1179-5735}, abstract = {Cognitive impairment encompasses a spectrum of disorders marked by acquired deficits in cognitive function, potentially leading to diminished daily functioning and work capacity, often accompanied by psychiatric and behavioral disturbances. Alzheimer's disease (AD) and Post-stroke cognitive impairment (PSCI) are significant causes of cognitive decline. With the global population getting older, AD and PSCI are becoming major health concerns, underscoring the critical necessity for successful treatment options. In recent years, various non-invasive biophysical stimulation techniques, including ultrasound, light, electric, and magnetic stimulation, have been developed for the treatment of central nervous system diseases. Preliminary clinical studies have demonstrated the feasibility and safety of these techniques. This review discuss the impact of 40 Hz multisensory stimulation on cerebral function, behavioral outcomes, and disease progression in both animal models and individuals exhibiting cognitive deficits, such as AD and PSCI. Furthermore, it summarizes the potential neural pathways involved in this therapeutic modality by synthesizing evidence from a variety of studies within the field. Subsequently, it evaluates the existing constraints of this technique and underscores the potential advantages of 40 Hz multisensory stimulation therapy for individuals with cognitive deficits, with the goal of enhancing the management and care of AD and PSCI.}, }
@article {pmid40159989, year = {2025}, author = {Han, X and Gong, S and Gong, J and Wang, P and Li, R and Chen, R and Xu, C and Sun, W and Li, S and Chen, Y and Yang, Y and Luan, H and Wen, B and Guo, J and Lv, S and Wei, C}, title = {Structural and metabolic topological alterations associated with butylphthalide treatment in mild cognitive impairment: Data from a randomized, double-blind, placebo-controlled trial.}, journal = {Psychiatry and clinical neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1111/pcn.13812}, pmid = {40159989}, issn = {1440-1819}, support = {82471450//the National Nature Science Foundation of China/ ; 2021ZD0201802//STI2030-Major Projects/ ; 2017YFC1310103//the National Key R&D Program of China/ ; }, abstract = {AIMS: Effective intervention for mild cognitive impairment (MCI) is key for preventing dementia. As a neuroprotective agent, butylphthalide has the potential to treat MCI due to Alzheimer disease (AD). However, the pharmacological mechanism of butylphthalide from the brain network perspective is not clear. Therefore, we aimed to investigate the multimodal brain network changes associated with butylphthalide treatment in MCI due to AD.
METHODS: A total of 270 patients with MCI due to AD received either butylphthalide or placebo at a ratio of 1:1 for 1 year. Effective treatment was defined as a decrease in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) > 2.5. Brain networks were constructed using T1-magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. A support vector machine was applied to develop predictive models.
RESULTS: Both treatment (drug vs. placebo)-time interactions and efficacy (effective vs. ineffective)-time interactions were detected on some overlapping structural network metrics. Simple effects analyses revealed a significantly increased global efficiency in the structural network under both treatment and effective treatment of butylphthalide. Among the overlapping metrics, an increased degree centrality of left paracentral lobule was significantly related to poorer cognitive improvement. The predictive model based on baseline multimodal network metrics exhibited high accuracy (88.93%) of predicting butylphthalide's efficacy.
CONCLUSION: Butylphthalide may restore abnormal organization in structural networks of patients with MCI due to AD, and baseline network metrics could be predictive markers for therapeutic efficacy of butylphthalide.
CLINICAL TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (Registration Number: ChiCTR1800018362, Registration Date: 2018-09-13).}, }
@article {pmid40159850, year = {2025}, author = {Lu, J and Yu, P and Wang, Y and Dai, Y and Wang, W and Liu, C and Dong, L and Lei, H and Yang, Y and Wang, L and Zou, F and Deng, X and Wang, B and Wei, S and Ma, M and Wang, H and Ye, L and Zhang, J and Tian, J}, title = {Rational Design of the First Dual Agonist at Trace Amine-Associated Receptor 1 and 5-HT2C Receptors Based on Binding Pocket Similarity for the Treatment of Schizophrenia and Alzheimer's Disease-Related Psychosis.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {7}, pages = {7082-7105}, doi = {10.1021/acs.jmedchem.4c02291}, pmid = {40159850}, issn = {1520-4804}, mesh = {Animals ; *Schizophrenia/drug therapy ; *Alzheimer Disease/drug therapy/complications ; *Receptors, G-Protein-Coupled/agonists/metabolism/genetics ; Humans ; *Drug Design ; Dogs ; *Receptor, Serotonin, 5-HT2C/metabolism/chemistry ; Mice ; Rats ; *Psychotic Disorders/drug therapy ; *Antipsychotic Agents/pharmacology/therapeutic use/chemistry ; Structure-Activity Relationship ; Male ; Binding Sites ; *Serotonin 5-HT2 Receptor Agonists/pharmacology/therapeutic use/chemistry ; Disease Models, Animal ; Rats, Sprague-Dawley ; }, abstract = {The clinical-stage agonists for trace amine-associated receptor 1 (TAAR1) show insufficient clinical efficacy, requiring the design of new compounds beyond the TAAR1 receptor alone. Here, we provide evidence for the feasibility of designing TAAR1/5-HT2CR dual agonists based on structural basis of these two targets and similarities of their agonists. Three series of novel agonists were discovered, leading to a potent compound named 21b. 21b exhibits submicromolar potency on both TAAR1 and 5-HT2CR targets with high specificity confirmed by site-directed mutagenesis. Preclinical proof-of-concept studies showed that 21b was highly efficacious against the positive and negative symptoms of schizophrenia in mice models. 21b also alleviated cognitive deficits and psychoactive symptoms in Alzheimer's disease (AD) model mice. Four week repeated dosing of 21b is exceptionally well tolerated in rats and beagle dogs without hyperglycemia commonly seen with antipsychotics. Thus, the favorable druggability of compound 21b warrants further clinical development for the treatment of schizophrenia and AD-related psychosis.}, }
@article {pmid40158900, year = {2025}, author = {Wang, MT and Hu, ZC and Xiang, Y and Zeng, XQ and Fei, ZC and Chen, J and Li, XP and Zhu, YP and Wang, J and Wang, YJ and Xu, ZQ and Liu, YH}, title = {Fingolimod ameliorates amyloid deposition and neurodegeneration in APP/PS1 mouse model of Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100131}, doi = {10.1016/j.tjpad.2025.100131}, pmid = {40158900}, issn = {2426-0266}, abstract = {INTRODUCTION: The immune system plays a critical role in regulating amyloid-beta (Aβ) metabolism in Alzheimer's Disease (AD). Both T and B lymphocytes are involved in the pathogenesis of AD. The sphingosine-1-phosphate (S1P) receptor modulator fingolimod used in the treatment of multiple sclerosis, can promote lymphocyte homing, potentially reducing the infiltration of peripheral lymphocytes into the brain.
METHODS: In this study, 8-month-old APP/PS1 mice were orally administered fingolimod at a dose of 1 mg/kg/day or saline as a control for 2 months. After treatment, the mice were subjected to behavioral tests, pathological examinations, and biochemical analyses to evaluate behavioral deficits and AD-type pathologies.
RESULTS: Fingolimod inhibits the infiltration of peripheral lymphocytes into the brain and reduces neuroinflammation. Fingolimod enhances cognitive function and alleviates brain Aβ deposition. Additionally, fingolimod treatment mitigates other AD-related pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Proteomic analysis further confirms the therapeutic effects of fingolimod in AD, reflected by the downregulation of proteins involved in multiple AD-associated pathways.
DISCUSSION: This study illustrates that fingolimod effectively ameliorates multiple pathological features of AD, highlighting its potential as a promising therapeutic candidate for the disease.}, }
@article {pmid40158867, year = {2025}, author = {Kshirsagar, S and Alvir, RV and Pradeepkiran, JA and Reddy, AP and Reddy, PH}, title = {Therapeutic potential of DDQ in enhancing mitochondrial health and cognitive function in Late-Onset Alzheimer's disease.}, journal = {Mitochondrion}, volume = {83}, number = {}, pages = {102036}, doi = {10.1016/j.mito.2025.102036}, pmid = {40158867}, issn = {1872-8278}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, mitochondrial dysfunction, and neuroinflammation. This study evaluates the therapeutic potential of DDQ, a small molecule in the humanized Abeta knockin (hAbKI) mice that represents late-onset AD. Our findings demonstrate that DDQ treatment significantly improves cognitive performance as assessed through behavioral tests, including the rotarod, open field, Y-maze, and Morris water maze, compared to untreated hAbKI mice. At the molecular level, DDQ promoted mitochondrial biogenesis, as evidenced by enhanced expression of key proteins like PGC1α, NRF1, and TFAM. Additionally, DDQ treatment facilitated mitophagy, as indicated by elevated levels of PINK1 and Parkin, and reduced neuroinflammation, reflected by decreased Iba1 and GFAP levels. Transmission electron microscopy analysis revealed a marked improvement in mitochondrial morphology, with increased mitochondrial length and reduced mitochondrial numbers in DDQ-treated mice. Furthermore, DDQ treatment led to an increase in mitophagic vacuoles, suggesting that it effectively removes dysfunctional mitochondria. Taken together, for the first time, our study results support the potential of DDQ as a promising neuroprotective agent for late-onset AD, addressing mitochondrial dysfunction, neuroinflammation, and cognitive decline. Our study focused on developing small molecules that modulate mitophagy, mitochondrial dynamics and neuroinflammatory pathways for aging, AD and other neurodegenerative disorders.}, }
@article {pmid40158246, year = {2025}, author = {Wang, W and Liu, Z and Cheng, H and Xu, M and Du, Z and Liu, W and Zhang, C}, title = {Cerium-doped carbon dots as dual-target agents against Alzheimer's β-amyloid fibrillogenesis and reactive oxygen species.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {252}, number = {}, pages = {114655}, doi = {10.1016/j.colsurfb.2025.114655}, pmid = {40158246}, issn = {1873-4367}, abstract = {Both fibrillogenesis of amyloid β-protein (Aβ) and elevated levels of reactive oxygen species (ROS) contribute to the pathogenesis of Alzheimer's disease (AD). Beyond Aβ aggregation inhibition, the complexity necessitates the development of comprehensive therapeutic interventions for halting AD progression. Herein, a dual-target agent capable of Aβ aggregation inhibition and ROS scavenging was synthesized by doping cerium into carbon dots (Ce CDs). Ce CDs with a high Ce (III)/Ce (IV) ratio of 0.67 can scavenge various ROS, including superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and Aβ40-induced ROS, thus mitigating cellular oxidative damage and rescuing cell viability. Additionally, Ce CDs present potent inhibition on Aβ40 on-pathway fibrillization, disrupting the formation of highly ordered β-sheet structures and increasing cell viability from 50.2 % to 91.9 %. It is validated that the electrostatic interactions between Ce CDs and Aβ40 are primarily responsible for preventing the conformational transition of Aβ40 monomers. In vivo experiments with the transgenic Caenorhabditis elegans strain further validate the bifunctionality of Ce CDs in suppression of Aβ fibrillogenesis and attenuation of oxidative stress, thereby demonstrating the potential of combination therapy for AD. This finding highlights the important role of electrostatic interactions between Aβ and inhibitors in regulating Aβ aggregation, and provides new insights into the development of multifunctional agents for AD treatment.}, }
@article {pmid40157622, year = {2025}, author = {Kshirsagar, S and Reddy, AP and Reddy, PH}, title = {Beneficial effects of mitophagy enhancers on amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer's disease.}, journal = {Mitochondrion}, volume = {83}, number = {}, pages = {102038}, doi = {10.1016/j.mito.2025.102038}, pmid = {40157622}, issn = {1872-8278}, abstract = {The purpose of our study is to investigate the beneficial effects of mitophagy enhancers against mutant amyloid precursor protein (APP) and amyloid beta (Aβ) induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD). Research spanning over two decades highlights the critical role of mitochondrial dysfunction and synaptic damage in the pathogenesis of both early-onset and late-onset AD. Emerging evidence suggests impaired clearance of damaged mitochondria is an early pathological event in AD, positioning mitophagy enhancers as potential therapeutic candidates. This study determined the optimal doses of four mitophagy enhancers-Urolithin A (UA), actinonin, tomatidine, and nicotinamide riboside (NR)-using immortalized mouse hippocampal (HT22) neurons. HT22 cells were transfected with mutant APP (mAPP) cDNA and treated with the enhancers. The effects were assessed by evaluating mRNA and protein expression levels of genes involved in mitochondrial dynamics, biogenesis, mitophagy, and synaptic function, alongside cell survival and mitochondrial respiration. Mitochondrial morphology was also examined in treated and untreated mAPP-HT22 cells. Results showed that mAPP-HT22 cells exhibited increased mitochondrial fission, reduced fusion, downregulated synaptic and mitophagy-related genes, diminished cell survival, impaired mitochondrial respiration, and excessively fragmented, shortened mitochondria. Treatment with mitophagy enhancers reversed these deficits, restoring mitochondrial and synaptic health. Enhanced cell survival, upregulation of mitochondrial fusion, synaptic, and mitophagy genes, improved mitochondrial structure, and reduced fragmentation were observed. Notably, UA demonstrated the most robust mitigating effects. These findings underscore the therapeutic potential of mitophagy enhancers, particularly UA, as promising candidates to treat mitochondrial and synaptic dysfunctions in AD.}, }
@article {pmid40156795, year = {2024}, author = {Odu, P and Odu, VK and Oyebanjo, OT and Benneth, BA and Onasanwo, SA}, title = {Cognitive And Neuroprotective Effects of Vernonia amygdalina in scopolamine-induced Memory impaired Rats.}, journal = {Nigerian journal of physiological sciences : official publication of the Physiological Society of Nigeria}, volume = {39}, number = {2}, pages = {233-240}, doi = {10.54548/njps.v39i2.9}, pmid = {40156795}, issn = {0794-859X}, mesh = {Animals ; *Scopolamine ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Vernonia ; Male ; Rats ; *Plant Extracts/pharmacology/isolation & purification/therapeutic use ; *Memory Disorders/chemically induced/drug therapy/prevention & control ; Oxidative Stress/drug effects ; Disease Models, Animal ; Cognition/drug effects ; Maze Learning/drug effects ; Rats, Wistar ; Cognitive Dysfunction/chemically induced/prevention & control/drug therapy ; Antioxidants/pharmacology ; }, abstract = {Cognitive impairment is largely associated with functional and structural loss in the brain of Alzheimer's disease (AD) models, and scopolamine has been successfully used to mimic these deficits in rodents. The cost and side effects of drugs presently used for the treatment of AD-related cognitive impairment have prompted research into alternative products, especially natural ones with high antioxidant capacity, since oxidative stress is a major pathophysiology associated with AD. The current study evaluated the cognitive and neuroprotective effects of Vernonia amygdalina (VA) on scopolamine-induced cognitive impairment in rats. Thirty-five male rats, randomly divided into seven groups (n = 5), were used. Group 1 served as the control and received distilled water. Groups 2 and 3 received Vernonia amygdalina, VA (50 and 100 mg/kg, respectively) per orally (p.o.). Group 4 received 1 mg/kg scopolamine SC (i.p.). Groups 5, 6, and 7 received pretreatment with either VA 50 mg/kg, VA 100 mg/kg, or Donepezil, DP (1 mg/kg), and then in combination with SC (1 mg/kg). The animals were subjected to memory tasks using the Morris water maze (MWM) and novel object recognition tasks (NORT) and sacrificed on day 14, after which their brains were isolated for biochemical and histological studies. The study showed that during MWM and NORT, spatial and non-spatial recognition memories, which were respectively impaired in the SC group compared to the control group, were reversed in the VA pretreatment groups. Scopolamine injection caused significant decreases in superoxide dismutase and catalase levels and an increase in malonaldehyde (MDA) levels in group 4 compared with the control group. Pretreatments with either VA or DP, however, caused a significant increase in the SOD and catalase levels and a decrease in the MDA level compared with the SC group. Histological studies revealed that VA was more potent in protecting the brain against SC-induced neurodegeneration and morphological alterations in the hippocampus and prefrontal cortex. Findings of this study suggest that VA attenuates scopolamine-induced cognitive deficits via inhibition of oxidative stress and neuronal degeneration and enhancement of cognition in the brains of rats.}, }
@article {pmid40156325, year = {2025}, author = {Donaghy, PC and Hasoon, J and Hamilton, CA and Ciafone, J and Durcan, R and Barnett, N and Olsen, K and Lawley, S and Greenfinch, G and Firbank, M and Heslegrave, A and Zetterberg, H and Allan, L and O'Brien, JT and Taylor, JP and Thomas, AJ}, title = {Plasma Biomarkers and Disease Prognosis in Mild Cognitive Impairment with Lewy Bodies.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {}, number = {}, pages = {}, doi = {10.1002/mds.30181}, pmid = {40156325}, issn = {1531-8257}, support = {//University College London Hospitals Biomedical Research Centre/ ; //NIHR Cambridge Biomedical Research Centre/ ; //NIHR Exeter Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute/ ; //Weston Family Foundation/ ; //GE Healthcare/ ; //NIHR Newcastle Biomedical Research Centre/ ; ARUK-PG3026-13//Alzheimer's Research UK/ ; AS-CTP-23-003/ALZS_/Alzheimer's Society/United Kingdom ; MR/W000229/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {BACKGROUND: Little is known about the prognostic value of plasma biomarkers in mild cognitive impairment with Lewy bodies (MCI-LB).
OBJECTIVES: To investigate the association of four plasma biomarkers with disease progression in MCI.
METHODS: Plasma amyloid-beta (Aβ)42/40, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 181 (pTau181) were measured at baseline in a longitudinal MCI cohort (n = 131).
RESULTS: Baseline plasma NfL was associated with increased risk of dementia/death in the entire cohort. In MCI-LB, baseline plasma NfL, GFAP, and pTau181 were associated with increased risk of dementia/death and increased cognitive decline measured by the Addenbrooke's Cognitive Examination-Revised.
CONCLUSIONS: pTau181, GFAP, and NfL are associated with more rapid disease progression in MCI-LB and, with further validation, could be useful to support prognosis and stratification for clinical practice and treatment trials. Further work, including clinicopathological studies, is needed to understand the biological correlates of these markers in MCI-LB. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.}, }
@article {pmid40155644, year = {2025}, author = {Jahng, GH and Lee, MB and Kwon, OI}, title = {Gadolinium based contrast agent induced electrical conductivity heterogeneity analysis in the brain of Alzheimer's disease.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {10832}, pmid = {40155644}, issn = {2045-2322}, support = {RS-2024-00335770//National Research Foundation of Korea/ ; RS-2023-00250977//National Research Foundation of Korea/ ; 2019R1A2C1004660//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology ; *Contrast Media ; *Electric Conductivity ; *Gadolinium ; *Brain/diagnostic imaging/physiopathology ; Aged ; *Magnetic Resonance Imaging/methods ; Female ; Male ; Cognitive Dysfunction/diagnostic imaging/diagnosis ; Aged, 80 and over ; Middle Aged ; }, abstract = {Magnetic resonance imaging (MRI) often uses gadolinium-based contrast agents (GBCAs) to improve the characterization of imaging contrast, owing to their strong paramagnetic properties. Magnetic resonance electrical properties tomography (MREPT) visualizes the conductivity distribution of biological tissues at the Larmor frequency using the [Formula: see text] field phase signal. In this paper, we investigate the effect of GBCA on brain conductivity. To compare the differences of reconstructed noisy conductivity maps before and after the GBCA injection, we propose a method to remove the background low-frequency noise artifact based on an elliptic partial differential equation. By analyzing the relationship between electrical conductivity and magnetic permeability, the objective of this study is to develop a cost-effective and accessible initial screening imaging tool for diagnosing and monitoring the treatment of Alzheimer's disease (AD) pathophysiology. To investigate vascular damage in AD, we define a conductivity heterogeneity volume fraction (CHVF) caused by GBCA leakage. Using CHVF, we develop three indices to characterize mild cognitive impairment (MCI) and AD. To verify the proposed method, we studied a total of 42 participants, including 14 individuals diagnosed with AD, 18 participants with MCI, and 10 cognitively normal (CN) participants. Finally, we designed a radar chart informed by the CHVF analysis, to exhibit the pertinent parameters for MCI and AD patients, facilitating the evaluation and ongoing monitoring of each patient's diagnosis and treatment regimen.}, }
@article {pmid40155270, year = {2025}, author = {Rabinovici, GD and Selkoe, DJ and Schindler, SE and Aisen, P and Apostolova, LG and Atri, A and Greenberg, SM and Hendrix, SB and Petersen, RC and Weiner, M and Salloway, S and Cummings, J}, title = {Donanemab: Appropriate use recommendations.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100150}, doi = {10.1016/j.tjpad.2025.100150}, pmid = {40155270}, issn = {2426-0266}, abstract = {Donanemab (Kisunla®), an IgG1 monoclonal antibody targeting N-terminal pyroglutamate-modified forms of amyloid-β, is approved in the United States for treatment of early symptomatic Alzheimer's disease (AD). Appropriate Use Recommendations (AUR) were developed to guide the implementation of donanemab in real-world practice, prioritizing safety considerations and opportunity for effectiveness. The AUR were developed by the AD and Related Disorders Therapeutic Workgroup by consensus, integrating available data and expert opinion. Appropriate candidates for donanemab treatment include persons with mild cognitive impairment or mild dementia due to AD (Clinical Stages 3-4, MMSE 20-30) who have biomarker confirmation of AD pathology by PET or CSF. Tau PET is not required for eligibility. Apolipoprotein E (APOE) genotyping should be performed prior to treatment to inform an individual's risk of developing Amyloid-Related Imaging Abnormalities (ARIA). Pre-treatment MRI should be obtained no more than 12 months prior to treatment. Patients with findings of >4 cerebral microbleeds, cortical superficial siderosis or a major vascular contribution to cognitive impairment should be excluded from treatment. The decision to initiate therapy should be grounded in a shared decision-making process that emphasizes the patient's values and goals of care. Donanemab is administered as a monthly intravenous infusion. Surveillance MRIs to evaluate for ARIA should be performed prior to the 2nd, 3rd, 4th and 7th infusions, prior to the 12th dose in higher risk individuals, and at any time ARIA is suspected clinically. Clinicians may consider discontinuing treatment if amyloid clearance is demonstrated by amyloid PET, typically obtained 12-18 months after initiating treatment.}, }
@article {pmid40155166, year = {2025}, author = {Chen, Y and Cheng, H and Tao, H and Liu, J and Li, Y and Li, QX and Yang, T and Meng, S and Yang, Y and Hu, R}, title = {Dual-mode sensing platform based on an iodide ion synergistic covalent triazine frameworks (CTFs) for point-of-care testing (POCT) of acetylcholinesterase.}, journal = {Analytica chimica acta}, volume = {1350}, number = {}, pages = {343836}, doi = {10.1016/j.aca.2025.343836}, pmid = {40155166}, issn = {1873-4324}, mesh = {*Acetylcholinesterase/chemistry/metabolism ; *Iodides/chemistry ; Humans ; *Point-of-Care Testing ; *Colorimetry/methods ; *Triazines/chemistry ; *Metal-Organic Frameworks/chemistry ; Limit of Detection ; Biosensing Techniques/methods ; }, abstract = {Acetylcholinesterase (AChE) plays a critical role in maintaining nervous system homeostasis and coordinating essential biological reactions. AChE is an important biomarker for early diagnosis and treatment, including Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Therefore, developing efficient and immediate sensing platforms for AChE detection is crucial for advancing early diagnostic tools. In this study, we developed a dual-mode colorimetric/photothermal sensing platform based on iodide ion-synergized covalent porphyrin-triazine backbone nanozymes (Zn-CTF/I) to detect AChE with high sensitivity and reliability. The synergistic interaction between iodide ions and zinc atoms effectively modulated the electronic structure of the catalytic active site, significantly enhancing the peroxidase-like (POD-like) activity of Zn-CTF/I. This enhancement led to a 10-fold reduction in the AChE detection limit compared to controls, with a minimum detection limit of 0.003 U L[-1], outperforming other reported assays. The integration of temperature-based photothermal signals with colorimetric detection improved the platform's accuracy and reliability. The system also demonstrated excellent recovery performance in detecting AChE in complex serum samples. The proposed dual-mode sensing platform provides a sensitive, reliable, and robust tool for AChE detection, with promising applications in early diagnosis and treatment monitoring of neurodegenerative diseases.}, }
@article {pmid40154898, year = {2025}, author = {Wang, Y and Lei, X and Zhao, D and Xue, A and Zhu, Z and Jin, M and Zhang, N and Li, X}, title = {Revealing the effective components and mechanism of Zhimu-Huangbai herb-pair in the treatment of Alzheimer's disease.}, journal = {Journal of ethnopharmacology}, volume = {}, number = {}, pages = {119699}, doi = {10.1016/j.jep.2025.119699}, pmid = {40154898}, issn = {1872-7573}, abstract = {The Zhimu-Huangbai herb-pair (ZB) is one of the most widely accepted prescriptions for treating Alzheimer's disease (AD) in traditional Chinese medicine. However, the effective components and mechanism of ZB for treating AD have not been fully understood.
AIM OF THE STUDY: This study aims to reveal the active components of ZB in the treatment of AD through serum pharmacochemistry, identify the potential targets and pathways of ZB in treating AD through metabolomics, and subsequently verify its mechanism through in vivo experiments.
MATERIALS AND METHODS: The components of ZB in both blood and cerebrospinal fluid were determined by using UPLC-Q-TOF-MS. The efficacy of ZB was assessed in a mouse model of AD induced by D-galactose. Metabolomics methods were used for screening and identification of differential metabolites and enrichment analysis of metabolic pathways. The enzyme-linked immunosorbent assay (ELISA) was used to detect the activities of enzyme complexes I-IV, as well as the levels of ATP and ROS in hippocampal mitochondria of mice. Additionally, the expression of key genes and proteins in the signaling pathway was examined by utilizing immunohistochemistry, real-time quantitative PCR, and Western blot.
RESULTS: A total of 27 prototype components were identified from the serum of rats given ZB, of which 8 components were simultaneously detected in the cerebrospinal fluid. A total of 20 different metabolites were identified from mouse plasma using a metabolomics technique. The enrichment analysis results revealed that the pathway of ZB treatment for AD mainly involves glycerophospholipid metabolism, arachidonic acid metabolism, and unsaturated fatty acid biosynthesis. In vivo experiments have shown that ZB can improve the energy metabolism of the brain and increase the production of ATP by improving mitochondrial dysfunction. In addition, ZB could promote the release of brain-derived neurotrophic factor (BDNF), increase the density of postsynaptic density protein (PSD95), and enhance the expression of synaptophysin (SYN).
CONCLUSION: Our study demonstrates that ZB can improve mitochondrial and synaptic function in AD mice induced by D-gal, providing experimental support for the clinical application and drug development for the prevention and treatment of AD.}, }
@article {pmid40154861, year = {2025}, author = {Hida, M and Yasuda, K and Toyokawa, M and Asada-Utsugi, M and Toda, S and Yanagida, N and Takahashi, R and Kinoshita, A and Maki, T}, title = {Amyloidogenic and non-amyloidogenic pathways of amyloid precursor protein processing in oligodendrocytes.}, journal = {Brain research}, volume = {1855}, number = {}, pages = {149601}, doi = {10.1016/j.brainres.2025.149601}, pmid = {40154861}, issn = {1872-6240}, mesh = {*Oligodendroglia/metabolism ; Animals ; *Amyloid beta-Protein Precursor/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; *Amyloid beta-Peptides/metabolism ; Cells, Cultured ; ADAM10 Protein/metabolism ; Peptide Fragments/metabolism ; Cell Differentiation/physiology ; Neurons/metabolism ; Rats ; Aspartic Acid Endopeptidases/metabolism ; Rats, Sprague-Dawley ; Cell Survival/physiology ; Oxidative Stress/physiology ; }, abstract = {Excessive accumulation of toxic amyloid-β (Aβ) species in the brain is a major pathological process triggering neurodegeneration in Alzheimer's disease (AD). Recent studies indicate that both neurons and glial cells, including oligodendrocyte lineages (OLs), contribute to brain homeostasis and affect AD pathology; however, the roles of oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLGs) in AD remain to be fully elucidated. This study examined Aβ production and related protein expression in primary cultured OLs. Primary cultured OLs produced Aβ40 and Aβ42 and expressed amyloid precursor protein (APP), β-secretase (BACE1) and γ-secretase (PS1) as well as α-secretase (ADAM10). OLGs express APP770 in addition to APP695. Treatment with a γ-secretase inhibitor reduced Aβ40 and Aβ42 production levels derived from OPCs/OLGs and suppressed OPC differentiation. Additionally, conditioned media from OLGs improved neuronal cell viability under oxidative stress and contained higher levels of sAPPα compared to OPCs. The neuroprotective effect of OLG was diminished by a sAPPα inhibitor, suggesting that OLG-derived sAPPα protects neurons under oxidative stress. These findings revealed that OLs produce pathogenic Aβ40/42 via the amyloidogenic pathway and secrete neuroprotective sAPPα via the non-amyloidogenic pathway. Elucidating the pathological shift from beneficial non-amyloidogenic to harmful amyloidogenic processes in OLs during AD onset and progression would provide crucial insights into novel therapeutic approaches.}, }
@article {pmid40153837, year = {2025}, author = {Costa, ML and Casanova-Martinez, D and Chen, H and Colasurdo, M and Kan, P}, title = {Implications of the glymphatic system in the pathogenesis of normal pressure hydrocephalus: an illustrated scoping review.}, journal = {Journal of neurosurgery}, volume = {}, number = {}, pages = {1-11}, doi = {10.3171/2024.12.JNS2420}, pmid = {40153837}, issn = {1933-0693}, abstract = {Idiopathic normal pressure hydrocephalus (iNPH) is characterized by the clinical triad of cognitive impairment, gait disturbances, and urinary incontinence, coupled with ventricular enlargement on brain imaging. The pathophysiology of iNPH remains complex, with varied patient responses to CSF diversion and a generally progressive nature of the disease. This scoping review aimed to provide an overview of the glymphatic system (GS) and its role in the development of iNPH. The review highlights the crucial function of the GS in maintaining brain homeostasis by clearing waste products from the interstitial space. Dysfunction in this system leads to impaired CSF clearance, resulting in the accumulation of neurotoxic substances that contribute to the symptoms of iNPH. Additionally, potential shared pathophysiological pathways between iNPH and other conditions affecting the GS such as aging, diabetes mellitus, hypertension, and sleep disorders are discussed. The findings suggest that GS dysfunction is a key factor in iNPH pathogenesis and may also be linked to the disease's poor responsiveness to shunt treatment. By enhancing understanding of these mechanisms, there is potential to develop targeted therapies aimed at restoring glymphatic function, thereby improving outcomes for patients with iNPH.}, }
@article {pmid40153582, year = {2025}, author = {Norata, D and Capone, F and Motolese, F and Marano, M and Rossi, M and Calandrelli, R and Sacchetti, M and Mantelli, F and Di Lazzaro, V and Pilato, F}, title = {1953-2023. Seventy Years of the Nerve Growth Factor: A Potential Novel Treatment in Neurological Diseases?.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.0573}, pmid = {40153582}, issn = {2152-5250}, abstract = {Rita Levi-Montalcini's 1953 discovery of nerve growth factor (NGF) in mouse sarcoma tumors marked a groundbreaking moment in neuroscience. NGF, a key signaling molecule, became the first identified neurotrophic factor, influencing the growth, differentiation, and survival of neurons in both peripheral and central nervous systems. NGF and related neurotrophic factors hold therapeutic potential for various neurological disorders, such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal cord injuries, neuropathies, traumatic brain injuries, and stroke. However, despite promising in vitro studies and animal models findings, NGF efficacy in patients remains unproven. Indeed, its use as a therapeutic agent faces challenges in delivery and clinical translation. This review delves into these challenges, exploring ongoing research on refined delivery methods, dosages, and safety profiles. Innovative strategies, including molecular mimicking, combination therapies, gene therapy, and coupling with neuromodulation techniques like transcranial magnetic stimulation and vagal nerve stimulation, are discussed. Incorporating nerve growth factor (NGF) into a comprehensive strategy may prove beneficial, particularly in non-neurodegenerative conditions such as stroke, trauma, and neuropathies. In these instances, NGF holds promise for promoting tissue regeneration and repair. Challenges persist in addressing the complexity of neurodegenerative pathologies for a combined therapeutic approach.}, }
@article {pmid40153090, year = {2025}, author = {Dantas, LP and Carneiro de Vasconcelos, E and da Silva Cunha, C and Batista, PVC and Torres, MCS and de Sousa, CNS and de Aquino, GA and Dos Santos Junior, MA and Freitas de Rezende, PH and Silva de Vasconcelos, W and Patrocinio, MCA and Vasconcelos, SMM}, title = {Protective effects of alpha-lipoic acid on memory deficit induced by repeated doses of solifenacin in mice: the role of nitro-oxidative stress.}, journal = {Metabolic brain disease}, volume = {40}, number = {4}, pages = {165}, pmid = {40153090}, issn = {1573-7365}, support = {312036/2021-3//CNPq/ ; }, mesh = {Animals ; *Thioctic Acid/pharmacology ; Mice ; *Oxidative Stress/drug effects ; *Memory Disorders/drug therapy/chemically induced/prevention & control/metabolism ; *Solifenacin Succinate/pharmacology ; Male ; *Antioxidants/pharmacology ; Lipid Peroxidation/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Muscarinic Antagonists/pharmacology ; Hippocampus/drug effects/metabolism ; Brain/drug effects/metabolism ; }, abstract = {Solifenacin (Sol) is one of the most used antimuscarinics for the treatment of bladder dysfunction and there are no conclusive studies on its effects on learning and memory after long-term use. Since substances with antioxidant action, such as alpha-lipoic acid (ALA), have shown protective action in memory deficit and Alzheimer's disease, we decided to study the effects of Sol alone or associated with ALA in behavioral tests of memory and its relation to nitro-oxidative stress in different brain areas. Mice received saline or Sol p.o. for 14 or 28 days. ALA groups received: (a) saline + ALA, (b) Sol for 14 days and Sol + ALA from the 15th to the 28th days and, (c) Sol + ALA for 28 days. Behavioral tests were performed and oxidative changes (lipid peroxidation) and nitrite in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) were also determined. Sol produced memory alterations in the mice, reducing the step-down latency and the recognition index in the novel object recognition test. Sol also increased lipid peroxidation in PFC, HC and ST and nitrite levels in the HC. On the other hand, ALA associated with Sol was able to restrict the effects caused by Sol alone, both in relation to nitro-oxidative parameters and in relation to behavioral tests. Taken together, our data suggest that ALA can be administered as an adjunctive drug in patients requiring prolonged use of Sol to mitigate these adverse central nervous system effects. However, clinical studies need to be performed to corroborate preclinical research.}, }
@article {pmid40153089, year = {2025}, author = {Awad, SM and Attia, YA and ElSayed, H and Abdelhafez, SH and Keshta, AT and Rashad, E and Khalil, HMA and Fathy, AT}, title = {Efficacy of curcumin-selenium nanoemulsion in alleviating oxidative damage induced by aluminum chloride in a rat model of Alzheimer's disease.}, journal = {Journal of molecular histology}, volume = {56}, number = {2}, pages = {122}, pmid = {40153089}, issn = {1567-2387}, mesh = {Animals ; *Curcumin/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/chemically induced/pathology ; *Aluminum Chloride/toxicity ; *Oxidative Stress/drug effects ; *Emulsions ; *Disease Models, Animal ; Rats ; *Selenium/pharmacology/therapeutic use/administration & dosage ; Male ; Antioxidants/pharmacology ; Brain/drug effects/metabolism/pathology ; Nanoparticles/chemistry ; Rats, Wistar ; Acetylcholinesterase/metabolism ; }, abstract = {Alzheimer's disease (AD) is a common neurological disorder primarily affecting older adults. A hallmark of this condition is the generation of reactive oxygen species (ROS), leading to increased oxidative stress and cellular damage. Treatment with a curcumin-selenium nanoemulsion has been shown to enhance behavioural performance and mitigate degenerative changes induced by aluminium chloride (AlCl3). This nanoemulsion also reduced the activity of acetylcholinesterase (AChE) and lowered levels of key proteins, including Aβ, p53, tau, nuclear factor erythroid 2-related factor 2 (Nrf2), and tumour necrosis factor-alpha (TNF-α). Additionally, it significantly decreased nitric oxide (NO) levels in the brain while enhancing the activity of catalase (CAT) and superoxide dismutase (SOD). The study highlights the antioxidant and anti-inflammatory properties of the curcumin-selenium nanoemulsion, suggesting its potential as a therapeutic option for alleviating AD induced by AlCl3. These results are further supported by improvements in the histological structure of the cortex and hippocampus, as well as enhanced immunohistochmical assessment of glial fibrillary acidic protein (GFAP). Cur- Se-nanoemulsion, the current drug delivery technology, may lower the amount of amyloid-β in AD rat brain and considerably ameliorate the memory deficit that improve therapy efficacy in AD lesions.}, }
@article {pmid40152120, year = {2025}, author = {Issa, EHB and Alghazo, EM and Gharaibeh, R and Momani, NB and Taha, DZ and Jaradat, RJ and Alzu'bi, A and Almahasneh, FA and Abu-El-Rub, E and Al-Zoubi, RM}, title = {Therapeutic potential and challenges of mesenchymal stem cells in neurological disorders: A concise analysis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnen/nlaf021}, pmid = {40152120}, issn = {1554-6578}, support = {//Qatar National Library/ ; }, abstract = {Neurological diseases comprise a wide array of conditions affecting both the central and peripheral nervous systems. Neurodegenerative diseases encompass a group of debilitating and often fatal neurological disorders for which effective treatments are currently lacking. Stem cells are recognized for their remarkable capacity for proliferation, multilineage differentiation, and self-renewal. The transplantation of stem cells represents a significant advancement in therapeutic strategies for neurological disorders, with applications in both preclinical and clinical settings. Mesenchymal stem cells (MSCs), in particular, have garnered substantial interest due to their unique properties, making them a highly sought-after source of therapeutic cells. Although the efficacy of MSCs in treating neurological disorders is well documented, further research is needed to elucidate the underlying mechanisms and to assess their in vivo applications more comprehensively. This article summarizes current research on the use of MSCs in the treatment of various neurological disorders, including Parkinson disease, stroke, multiple sclerosis, and Alzheimer disease.}, }
@article {pmid40152071, year = {2025}, author = {Yadav, M and Singh, VP}, title = {A review on benzoselenazoles: synthetic methodologies and potential biological applications.}, journal = {Organic & biomolecular chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1039/d4ob01897d}, pmid = {40152071}, issn = {1477-0539}, abstract = {Among the various heterocyclic organoselenium compounds, a new class of benzoselenazoles has received great attention due to their chemical properties and biological applications. The ever-growing interest in the five-membered benzoselenazole heterocycles amongst chemists has made commendable impact. These heterocycles are a prominent class of organic molecules that have emerged as potential therapeutic agents for the treatment of a wide range of diseases. Substantial progress has been made in elucidating the complex chemical properties of these heterocycles. Moreover, they have garnered significant importance in a wide range of biological applications. However, despite their biological activities, research on benzoselenazoles remains relatively limited, emphasising the need for further exploration in this area. Hence, considering the importance of benzoselenazoles, this comprehensive review compiles various synthetic procedures, highlighting the recent advances in their synthesis that have been disclosed in the literature. This review would offer chemists an array of information that will assist them in the development of more affordable and effective synthesis processes for benzoselenazoles. Therefore, it is believed that this review would provide relevant context on these achievements and will inspire synthetic organic chemists to use these effective technologies of such heterocycles for the future treatment of diseases caused by oxidative stress. The biological and pharmacological properties of these organoselenium heterocycles, which include their antioxidant, antitumor, and antibacterial activities and their application in Alzheimer's disease treatment and as pancreatic lipase inhibitors, are thoroughly summarized. Finally, this review provides some perspectives on the challenges and future directions in the development of benzoselenazoles as heterocyclic organoselenium compounds.}, }
@article {pmid40151913, year = {2025}, author = {Zhai, Y and Lu, K and Yuan, Y and Zhang, Z and Xue, L and Zhao, F and Xu, X and Wang, H}, title = {Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251329439}, doi = {10.1177/13872877251329439}, pmid = {40151913}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting the cognitive function. However, research about the mechanism of semaglutide as a therapeutic intervention in AD is sparse.ObjectiveThis study was to investigate the therapeutic efficacy of semaglutide in a transgenic mouse model of AD pathology and explored the detailed mechanism by semaglutide modulated neuroinflammatory processes.MethodsMale amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide or vehicle for 8 weeks. Morris water maze test was used to assess the therapeutic efficacy of semaglutide on recognition function. Pathology analysis was performed to detect the deposition of amyloid plaques. High-throughput sequencing analysis was applied to specify the mechanism. Microglia and astrocyte activation were assessed with immunofluorescent staining. Inflammation cytokine levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Related proteins and pathway were evaluated with western blot.ResultsSemaglutide treatment attenuated Aβ accumulation and enhanced cognitive function in APP/PS1 transgenic mice. Through transcriptomic profiling, immunohistochemical staining, and ELISA, semaglutide was substantiated to inhibit the overactivation of microglia and astrocytes, as well as to curtail the secretion of inflammatory mediators. Furthermore, semaglutide robustly activated AMP-activated protein kinase (AMPK) and suppressed the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing the Aβ deposition and dampening the inflammatory cascade.ConclusionsThe results demonstrated that semaglutide mitigated neuroinflammation and decelerated the advance of AD in APP/PS1 transgenic mice.}, }
@article {pmid40151908, year = {2025}, author = {Bartolini, E and Di Crosta, A and La Malva, P and Marin, A and Ceccato, I and Prete, G and Mammarella, N and Di Domenico, A and Palumbo, R}, title = {Gamma oscillation modulation for cognitive impairment: A systematic review.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251328698}, doi = {10.1177/13872877251328698}, pmid = {40151908}, issn = {1875-8908}, abstract = {BackgroundGamma oscillation modulation has emerged as a potential non-invasive treatment to counteract cognitive impairment in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Non-invasive brain stimulation techniques like transcranial alternating current stimulation (tACS), gamma sensory stimulation (GSS), and transcranial magnetic stimulation (TMS) show promise in supporting specific cognitive functions.ObjectiveTo review and evaluate the efficacy of gamma oscillation modulation techniques in benefiting cognitive functions among individuals with AD and MCI.MethodsA systematic review was conducted, analyzing studies from 2015 to 2023 across databases such as PubMed, Web of Science, and Scopus. Inclusion criteria focused on studies involving tACS, GSS, or TMS applied to older adults with MCI or AD. A total of 438 articles were screened, of which 10 met the eligibility criteria.ResultsFindings suggest that gamma tACS, especially targeting the precuneus and dorsolateral prefrontal cortex, benefits episodic memory and cognitive performance. GSS also showed potential in supporting memory and attention, while TMS exhibited inconsistent but promising results when applied to the angular gyrus. However, heterogeneity in study designs and small sample sizes limit the generalizability of these outcomes.ConclusionsGamma oscillation modulation offers potential cognitive benefits for patients with AD and MCI, particularly in memory support. Further studies with larger samples and well-designed protocols are needed to confirm its therapeutic efficacy and optimize intervention parameters.}, }
@article {pmid40151570, year = {2025}, author = {Grant, KL and Long, SN}, title = {Extended release huperzine for the treatment of idiopathic epilepsy in dogs - a Case Report.}, journal = {Frontiers in veterinary science}, volume = {12}, number = {}, pages = {1518379}, pmid = {40151570}, issn = {2297-1769}, abstract = {Huperzine is a naturally occurring alkaloid derived from the Chinese clubmoss Huperzia serrata. It is a potent acetylcholinesterase inhibitor, among other properties, and has demonstrated protection against induced seizures in a mouse model of Dravet's syndrome as well as nerve-agent induced seizures and is being explored as a novel anticonvulsant in a human clinical trial for focal impaired awareness seizures. It is also being explored as a treatment for Alzheimer's, via neuroprotective effects and an ability to ameliorate neuroinflammation. Here we present a case series of 6 dogs with idiopathic epilepsy treated with huperzine to investigate this potential novel anticonvulsant. Despite a 50% drop out rate over the course of the study due to various causes including unexplained death, humane euthanasia and systemic disease, huperzine was generally well tolerated and showed some positive effects on demeanor. This study highlights the need for more research to investigate its efficacy as a novel antiepileptic medication in dogs.}, }
@article {pmid40151398, year = {2025}, author = {Roy, SM and Acquarone, E and Argyrousi, EK and Zhang, H and Staniszewski, A and Inoue, A and Ziarek, JJ and Arancio, O and Watterson, DM}, title = {Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70073}, pmid = {40151398}, issn = {2352-8737}, abstract = {INTRODUCTION: Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non-pharmacological treatments. Cognitive or behavioral disturbances occur at early disease stages and increase with disease progression. Coincident pathologies include the loss of serotonin (5-HT) neurons and appearance of neurofibrillary tangles in the raphe nucleus. Brain 5-HT2b receptor (5-HT2bR) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post-stroke morbidity. HTR2B gene variants are implicated in psychiatric disorders. 5-HTRs are associated with atypical neurotropic drug mechanisms and behavioral dysfunction in drug abuse. The accumulating body of evidence suggests that selective 5-HT2bR inhibition might mitigate neuropsychiatric syndromes and the associated cognitive dysfunction. Atypical neurotropic drugs interact with a variety of monoamine receptors and outcomes are viewed as a combination of 5-HT and dopamine D2 receptor mediated actions. Clearly, there is a need for insight into precision 5-HT2bR inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.
METHODS: Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5-HT2bR activity and β-arrestin-1 recruitment that is devoid of dopamine receptor recognition and risk of 5-HT2bR agonist activity.
RESULTS: MW073 ameliorates amyloid and tau induction of behavioral dysfunction in preventive or disease stage intervention paradigms. Using MW073 as a standard of comparison, risperidone was shown to be a dose-dependent inhibitor 5-HT2bR activity and β-arrestin-1 recruitment.
DISCUSSION: Selective inhibition of 5-HT2bR activity is a viable mechanism for the treatment of neuropsychiatric syndromes with synaptic dysfunction as a root cause and is a previously unrealized pharmacodynamic mechanism potentially embedded in current neurotherapeutics.
HIGHLIGHTS: A new highly selective 5-HT2bR antagonist, MW073, is described and used as a reference standard.MW073 attenuates synaptic and behavioral dysfunctions an animal models of neuropsychatric syndromes.Risperidone is a dose dependent inhibitor of 5-HT2bR activity and arrestin recruitment.}, }
@article {pmid40151396, year = {2025}, author = {Hermans, AMM and Bakker, E and Starokozhko, V and den Otter, L and Elferink, AJA and Bradshaw, A and Guizzaro, L and Mol, PGM and Pasmooij, AMG}, title = {Biomarkers for neurodegenerative diseases in regulatory decision-making by the European Medicines Agency.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70072}, pmid = {40151396}, issn = {2352-8737}, abstract = {INTRODUCTION: Biomarkers (BMs) are valuable tools to facilitate early diagnosis of (subtypes of) diseases, improve patient selection and stratification, and detect therapeutic effects or safety concerns. This study explores the extent to which BMs are utilized in the development of treatments for neurodegenerative diseases (NDDs), as well as topics of discussion regarding BMs in regulatory advice- and decision-making processes and sharing of BM-related data.
METHODS: The European Medicines Agency's marketing authorization application (MAA), qualification (QA/QO), and scientific advice (SA) procedures regarding NDDs were screened, and those that mention BMs were analyzed. Data were extracted on the intended disease, BM type, and context of use proposed by applicants. BMs were categorized based on both nature and function.
RESULTS: In total, 105 procedures that discussed BMs were analyzed, 57 SAs (January 2020 to December 2022), 19 QAs/QOs (January 2008 to December 2023), and 29 MAAs (January 1995 to December 2023). The majority involved Alzheimer's disease (AD; n = 30), Parkinson's disease (PD; n = 9), and multiple sclerosis (MS; n = 33). Imaging BMs were the most common type of BMs discussed, and most BMs were used as pharmacodynamic/response measures. The acceptance and role of BMs differed between AD, PD, MS, and other NDDs. In regulatory procedures for AD, for example, diagnostic BMs guiding patient selection were commonly discussed, whereas in MAAs for MS, imaging BMs (particularly lesions) were generally accepted as supportive/secondary endpoints.
DISCUSSION: Despite the established role of certain BMs, mainly imaging BMs for MS, there remains a major need for more precise and reliable BMs to improve diagnostic accuracy and treatment monitoring for NDDs. To implement novel BMs and facilitate development of new treatments and to eventually improve clinical practice, robust evidence bases showcasing biological plausibility or clear clinical benefits are essential. Collaboration and data-sharing among stakeholders is vital in generating this evidence and enhancing the understanding and management of NDDs.
HIGHLIGHTS: The European Medicines Agency's marketing authorization applications and qualification and scientific advice procedures.One hundred five procedures were analyzed regarding neurodegenerative diseases that discuss biomarkers.We found that acceptance and role of biomarkers differ per disease.Biological plausibility/clinical benefits are essential for biomarker implementation.}, }
@article {pmid40151077, year = {2025}, author = {Nawaz, A and Sadiq, A and Bashir, N and Rashid, U and Ullah, F and Khan, S and Ullah, F and Khan, MI and Ayaz, M}, title = {Synthetic Derivates of Progesterone Ameliorate Scopolamine-Induced Cognitive Deficits in Animal Models: Antioxidant, Enzyme Inhibitory, Molecular Docking and Behavioral Correlates.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X357722250212094900}, pmid = {40151077}, issn = {1875-6190}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurological disorder characterized by cognitive decline and behavioral turbulence and is anticipated to badly affect the patient's quality of life. Previous studies revealed the neuroprotective effects of progesterone, so this study aimed to appraise the neuroprotective potentials of new derivatives of progesterone (AN-1 to AN-5).
METHODS: Subsequent to compound synthesis and structure elucidation, the in-vitro antioxidant (DPPH), acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory and molecular docking studies were performed following standard procedures. The most potent compound was subjected to more detailed behavioral studies, including Y-Maze, Elevated Plus Maze (EPM), and open field tests in scopolamine-induced amnesic animals.
RESULTS: In the DPPH assay, the AN-1 compound at 1000 μg/ml concentration exhibited 83.37 ± 2.03% inhibition of DPPH free radicals and an IC50 value of 24.81 μg/ml. Likewise, the compound AN-1 demonstrated 88.94 ± 1.20% inhibition against AChE and 86.78 ± 1.24% inhibition against BChE enzymes at 1000 μg/ml with IC50 values of 24.51 and 18.79 μg/ml, correspondingly. In behavioral studies, compound AN-1 demonstrated a significant decline in cognitive impairments and improved working memory as well as locomotor activities of the amnesic animals. Molecular docking studies also demonstrated that the compound AN-1 has promising inhibitory potentials against AChE and BChE enzymes by binding to their active sites. The binding energies of AN-1 with both enzymes were -7.6 Kcal/mol for AChE and -8.1 Kcal/mol for BChE.
CONCLUSION: Based on our findings, it is concluded that the derivatives of progesterone exhibit neuroprotective potential, and further research is needed to extend their neuroprotective role in the treatment of AD.}, }
@article {pmid40150858, year = {2025}, author = {Verwaerde, P and Defert, O}, title = {AZP2006 (Ezeprogind[®]): a Promising New Drug Candidate in the Battle Against Neurodegenerative Diseases.}, journal = {ChemMedChem}, volume = {}, number = {}, pages = {e202400891}, doi = {10.1002/cmdc.202400891}, pmid = {40150858}, issn = {1860-7187}, abstract = {Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disorder characterized by abnormal tau protein accumulation. This perspective article explores AZP2006 (INN: Ezeprogind), a novel small molecule targeting the Progranulin (PGRN) and Prosaposin (PSAP) axis to enhance lysosomal health in PSP treatment. AZP2006 stabilizes the PGRN-PSAP complex, improving lysosomal function and reducing tau pathology. Preclinical studies in tauopathy models demonstrated AZP2006's ability to decrease tau hyperphosphorylation, enhance neuronal survival, mitigate neuroinflammation and promote synaptogenesis. Clinical trials have shown AZP2006 to be well-tolerated in healthy volunteers and PSP patients. A Phase 2a study met its primary endpoints, as it provided valuable safety data and even encouraged further investigation of its efficacy in a larger clinical study. An upcoming Phase 2b/3 trial aims to assess long-term safety and efficacy in a larger PSP cohort. AZP2006's mechanism of action strongly suggests potential applications in other tauopathies, including Alzheimer's and Parkinson's diseases. By addressing lysosomal dysfunction and tau pathology, AZP2006 represents a promising disease-modifying approach for PSP and other neurodegenerative disorders.}, }
@article {pmid40150060, year = {2025}, author = {Muksimova, S and Umirzakova, S and Baltayev, J and Cho, YI}, title = {Multi-Modal Fusion and Longitudinal Analysis for Alzheimer's Disease Classification Using Deep Learning.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {6}, pages = {}, pmid = {40150060}, issn = {2075-4418}, abstract = {Background: Addressing the complex diagnostic challenges of Alzheimer's disease (AD), this study introduces FusionNet, a groundbreaking framework designed to enhance AD classification through the integration of multi-modal and longitudinal imaging data. Methods: FusionNet synthesizes inputs from Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), and Computed Tomography (CT) scans, harnessing advanced machine learning strategies such as generative adversarial networks (GANs) for robust data augmentation, lightweight neural architectures for efficient computation, and deep metric learning for precise feature extraction. The model uniquely combines cross-sectional and temporal data, significantly enhancing diagnostic accuracy and enabling the early detection and ongoing monitoring of AD. The FusionNet architecture incorporates specialized feature extraction pathways for each imaging modality, a fusion layer to integrate diverse data sources effectively, and attention mechanisms to focus on salient diagnostic features. Results: Demonstrating superior performance, FusionNet achieves an accuracy of 94%, with precision and recall rates of 92% and 93%, respectively. Conclusions: These results underscore its potential as a highly reliable diagnostic tool for AD, facilitating early intervention and tailored treatment strategies. FusionNet's innovative approach not only improves diagnostic precision but also offers new insights into the progression of Alzheimer's disease, supporting personalized patient care and advancing our understanding of this debilitating condition.}, }
@article {pmid40149815, year = {2025}, author = {Chen, Y and Xiao, D and Li, X}, title = {Lactylation and Central Nervous System Diseases.}, journal = {Brain sciences}, volume = {15}, number = {3}, pages = {}, pmid = {40149815}, issn = {2076-3425}, support = {2025ZNSFSC0674//the Natural Science Foundation Project of Sichuan Province/ ; 82071353 and 82001593//the National Natural Science Foundation of China/ ; 2021YFS0029 and 2020YFS0104//the key R&D projects of Science and Technology Department of Sichuan Province/ ; }, abstract = {As the final product of glycolysis, lactate serves as an energy substrate, metabolite, and signaling molecule in various diseases and mediates lactylation, an epigenetic modification that occurs under both physiological and pathological conditions. Lactylation is a crucial mechanism by which lactate exerts its functions, participating in vital biological activities such as glycolysis-related cellular functions, macrophage polarization, and nervous system regulation. Lactylation links metabolic regulation to central nervous system (CNS) diseases, such as traumatic brain injury, Alzheimer's disease, acute ischemic stroke, and schizophrenia, revealing the diverse functions of lactylation in the CNS. In the future, further exploration of lactylation-associated enzymes and proteins is needed to develop specific lactylation inhibitors or activators, which could provide new tools and strategies for the treatment of CNS diseases.}, }
@article {pmid40149774, year = {2025}, author = {Singh, AA and Katiyar, S and Song, M}, title = {Phytochemicals Targeting BDNF Signaling for Treating Neurological Disorders.}, journal = {Brain sciences}, volume = {15}, number = {3}, pages = {}, pmid = {40149774}, issn = {2076-3425}, abstract = {Neurological disorders are defined by a deterioration or disruption of the nervous system's structure and function. These diseases, which include multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and schizophrenia, are caused by intricate pathological processes that include excitotoxicity, neuroinflammation, oxidative stress, genetic mutations, and compromised neurotrophic signaling. Although current pharmaceutical treatments relieve symptoms, their long-term efficacy is limited due to adverse side effects and weak neuroprotective properties. However, when combined with other neuroprotective drugs or adjunct therapy, they may offer additional benefits and improve treatment outcomes. Phytochemicals have emerged as attractive therapeutic agents due to their ability to regulate essential neurotrophic pathways, especially the brain-derived neurotrophic factor (BDNF) signaling cascade. BDNF is an important target for neurodegenerative disease (ND) treatment since it regulates neuronal survival, synaptic plasticity, neurogenesis, and neuroprotection. This review emphasizes the molecular pathways through which various phytochemicals-such as flavonoids, terpenoids, alkaloids, and phenolic compounds-stimulate BDNF expression and modulate its downstream signaling pathways, including GSK-3β, MAPK/ERK, PI3K/Akt/mTOR, CREB, and Wnt/β-catenin. This paper also highlights how phytochemical combinations may interact to enhance BDNF activity, offering new therapeutic options for ND treatment. Despite their potential for neuroprotection, phytochemicals face challenges related to pharmacokinetics, blood-brain barrier (BBB) permeability, and absorption, highlighting the need for further research into combination therapies and improved formulations. Clinical assessment and mechanistic understanding of BDNF-targeted phytotherapy should be the main goals of future studies. The therapeutic efficacy of natural compounds in regulating neurotrophic signaling is highlighted in this review, providing a viable approach to the prevention and treatment of NDs.}, }
@article {pmid40149767, year = {2025}, author = {Ortiz, GG and González-Usigli, H and Nava-Escobar, ER and Ramírez-Jirano, J and Mireles-Ramírez, MA and Orozco-Barajas, M and Becerra-Solano, LE and Sánchez-González, VJ}, title = {Primary Progressive Aphasias: Diagnosis and Treatment.}, journal = {Brain sciences}, volume = {15}, number = {3}, pages = {}, pmid = {40149767}, issn = {2076-3425}, abstract = {Background and Objective: Primary Progressive Aphasias (PPAs) are rare neurodegenerative disorders classified within frontotemporal lobar degeneration (FTLD) and typically manifest between 45 and 70 years of age. In Mexico-and many other countries-reliable epidemiological data are lacking; however, estimates suggest that PPA accounts for 0.5-2.5% of neurodegenerative disease cases in Memory Clinics, with an incidence of approximately 1 per 100,000 and an average survival of 8 years. This review aims to provide clinicians with an overview of PPA's epidemiology, clinical features, and classification, thereby enhancing understanding of its subtypes and distinguishing characteristics from other aphasic conditions, such as vascular aphasia. Methods: This narrative review was conducted through a literature search using databases such as PubMed and Scopus. Relevant studies addressing the epidemiology, clinical presentation, and classification of PPA were identified, selected, and synthesized to offer a broad, clinically oriented overview of the condition. This approach was chosen to inform clinical practice and highlight the need for further targeted investigations, such as future systematic reviews focusing on specific aspects like therapeutic strategies. Key Contents and Findings: (a) Epidemiology: PPA is estimated to affect 0.5-2.5% of patients with neurodegenerative diseases in Memory Clinics, with an incidence of roughly 1 per 100,000. Average survival time is around 8 years (ranging from 3 to 17 years), with a generally balanced gender ratio, though some studies indicate a predominance of men. A positive family history is observed in 20-40% of cases, with about 10% following an autosomal dominant inheritance pattern. (b) Clinical Characteristics and Classification: PPA is marked by a gradual decline in language abilities, differentiating it from vascular aphasias. Subtypes include non-fluent forms (non-fluent progressive aphasia [nfPPA] and logopenic progressive aphasia [lPPA]), fluent forms (progressive fluent aphasia [PFA] and semantic dementia [SD]), and mixed forms (progressive mixed aphasia [PMA]). The neurodegenerative process in PPA extends beyond vascular boundaries, often resulting in presentations that deviate from classical Broca's and Wernicke's aphasias. Common symptoms include difficulties in word finding and naming, sometimes mistaken for memory loss, and, in the case of semantic dementia, personality changes that may go unnoticed by the patient. Conclusions: PPA is a heterogeneous and complex group of neurodegenerative disorders with significant clinical variability and a profound impact on patients and their families. While current epidemiological data are limited, this review emphasizes the need for further research to better delineate disease progression and refine diagnostic and therapeutic approaches. Future systematic reviews will be essential to address specific aspects of PPA, such as treatment strategies, to further improve patient care.}, }
@article {pmid40149580, year = {2025}, author = {Weidauer, S and Hattingen, E}, title = {Cerebral Amyloid Angiopathy: Clinical Presentation, Sequelae and Neuroimaging Features-An Update.}, journal = {Biomedicines}, volume = {13}, number = {3}, pages = {}, pmid = {40149580}, issn = {2227-9059}, abstract = {The prevalence of cerebral amyloid angiopathy (CAA) has been shown to increase with age, with rates reported to be around 50-60% in individuals over 80 years old who have cognitive impairment. The disease often presents as spontaneous lobar intracerebral hemorrhage (ICH), which carries a high risk of recurrence, along with transient focal neurologic episodes (TFNE) and progressive cognitive decline, potentially leading to Alzheimer's disease (AD). In addition to ICH, neuroradiologic findings of CAA include cortical and subcortical microbleeds (MB), cortical subarachnoid hemorrhage (cSAH) and cortical superficial siderosis (cSS). Non-hemorrhagic pathologies include dilated perivascular spaces in the centrum semiovale and multiple hyperintense lesions on T2-weighted magnetic resonance imaging (MRI). A definitive diagnosis of CAA still requires histological confirmation. The Boston criteria allow for the diagnosis of a probable or possible CAA by considering specific neurological and MRI findings. The recent version, 2.0, which includes additional non-hemorrhagic MRI findings, increases sensitivity while maintaining the same specificity. The characteristic MRI findings of autoantibody-related CAA-related inflammation (CAA-ri) are similar to the so-called "amyloid related imaging abnormalities" (ARIA) observed with amyloid antibody therapies, presenting in two variants: (a) vasogenic edema and leptomeningeal effusions (ARIA-E) and (b) hemorrhagic lesions (ARIA-H). Clinical and MRI findings enable the diagnosis of a probable or possible CAA-ri, with biopsy remaining the gold standard for confirmation. In contrast to spontaneous CAA-ri, only about 20% of patients treated with monoclonal antibodies who show proven ARIA on MRI also experience clinical symptoms, including headache, confusion, other psychopathological abnormalities, visual disturbances, nausea and vomiting. Recent findings indicate that treatment should be continued in cases of mild ARIA, with ongoing MRI and clinical monitoring. This review offers a concise update on CAA and its associated consequences.}, }
@article {pmid40149496, year = {2025}, author = {Poniah, P and Abdul Rashed, A and Abdul Jalil, J and Ali, EZ}, title = {Clinical Significance of Early-Onset Alzheimer's Mutations in Asian and Western Populations: A Scoping Review.}, journal = {Genes}, volume = {16}, number = {3}, pages = {}, pmid = {40149496}, issn = {2073-4425}, mesh = {Humans ; *Alzheimer Disease/genetics ; *Mutation ; *Asian People/genetics ; *Amyloid beta-Protein Precursor/genetics ; *Presenilin-2/genetics ; *Presenilin-1/genetics ; Age of Onset ; White People/genetics ; Genetic Predisposition to Disease ; Clinical Relevance ; }, abstract = {BACKGROUND/OBJECTIVES: Background: Early-onset Alzheimer's disease (EOAD) is primarily inherited in an autosomal dominant pattern, with mutations in the APP, PSEN1, and PSEN2 genes being central contributors. Diagnosing Alzheimer's poses challenges due to the coexistence of various co-pathologies, and treatment options remain limited for most patients, apart from familial cases linked to specific genetic mutations. While significant research on Alzheimer's genetics has been conducted in both Asian and Caucasian populations, the specific mutations and their clinical impacts in EOAD are still inadequately explored. This review aims to provide a detailed analysis of commonly reported genetic mutations and associated clinical features in EOAD patients from Asian and Western populations.
METHODS: Following the PRISMA-ScR guidelines, a systematic database search was conducted for studies published between 2016 and 2023. After screening 491 records, 36 studies from Asian cohorts and 40 from Western cohorts met the inclusion criteria.
RESULTS: The analysis revealed 127 unique mutations in the Asian population and 190 in the Western population. About 16.7% of Asian and 21.9% of Western studies covered both familial and sporadic AD, with consistent patterns across groups. Some mutations were shared between the populations and displayed similar clinical features, while others were population-specific.
CONCLUSIONS: These findings underscore the considerable variability in EOAD mutations and phenotypes, emphasizing the importance of genetic testing in younger patients to enhance diagnostic accuracy and guide treatment strategies effectively.}, }
@article {pmid40148951, year = {2025}, author = {Simonyan, K and Darbinyan, L and Hambardzumyan, L and Manukyan, L and Chavushyan, V}, title = {Teucrium Polium ameliorates amyloid β-induced brain network disorders in rats: electrophysiological and behavioral studies.}, journal = {BMC complementary medicine and therapies}, volume = {25}, number = {1}, pages = {116}, pmid = {40148951}, issn = {2662-7671}, mesh = {Animals ; *Amyloid beta-Peptides ; Rats ; Male ; *Teucrium/chemistry ; Plant Extracts/pharmacology ; Alzheimer Disease/drug therapy ; Neuronal Plasticity/drug effects ; Hippocampus/drug effects ; Rats, Sprague-Dawley ; Behavior, Animal/drug effects ; Peptide Fragments/pharmacology ; Synaptic Transmission/drug effects ; }, abstract = {Synaptic failure in specific cholinergic networks in rat brains has been implicated in amyloid β-induced neurodegeneration. Teucrium polium is a promising candidate for drug development against Alzheimer's disease (AD) and similar disorders. However, the protective effect of Teucrium polium against amyloid β-induced impairment of short-term synaptic plasticity is still poorly understood. In this study, we used in vivo extracellular single-unit recordings to investigate the preventive efficacy of Teucrium polium on Aβ(25-35)-induced aberrant neuronal activity in the hippocampus and basolateral amygdala of rats, in response to high-frequency stimulation of the cholinergic nucleus basalis magnocellularis (NBM). After 12 weeks of intracerebroventricular administration of Aβ(25-35), alterations such as decreased excitatory responses and increased inhibitory synaptic activity were observed in the NBM-hippocampus and NBM-basolateral amygdala cholinergic circuits. Treatment with Teucrium polium improved the balance of excitatory and inhibitory responses by modulating synaptic transmission strength and restoring short-term plasticity. Acute injection of a therapeutic dose of Teucrium temporarily inhibited spiking activity in single NBM neurons. Open field tests revealed that amyloid-injected rats displayed anxiety and reduced exploratory drive. Treatment with Teucrium polium improved these behaviors, reducing anxiety and increasing exploration. Teucrium polium mitigated amyloid β-induced alterations in cholinergic circuits by enhancing the adaptive capacity of short-term synaptic plasticity. These findings suggest that Teucrium polium could serve as a preventive strategy to delay the progression of cholinergic neurodegeneration.}, }
@article {pmid40148430, year = {2025}, author = {Liu, J and Yan, M and Chen, L and Yu, W and Lü, Y}, title = {Construction and evaluation of a diagnostic model for Alzheimer's disease based on mitophagy-related genes.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {10632}, pmid = {40148430}, issn = {2045-2322}, mesh = {*Alzheimer Disease/genetics/diagnosis/pathology ; Humans ; *Mitophagy/genetics ; *Gene Regulatory Networks ; Gene Expression Profiling ; ROC Curve ; Transcription Factors/genetics/metabolism ; Computational Biology/methods ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia. Mitophagy fulfills crucial functions in neurodegenerative disorders and neuronal survival but the relationship between mitophagy and AD is unclear. Mitophagy correlation scores between AD samples and control samples were calculated using single-sample GSEA (ssGSEA) based on two datasets from gene expression omnibus (GEO) database. Mitophagy-related genes (MRGs) and differentially expressed genes (DEGs) in AD screened by WGCNA and "limma" package were intersected to take common genes. These overlapping genes were further compressed and used for diagnostic modeling by adopting the recursive feature elimination (RFE) and LASSO analysis. The reliability of the diagnostic model was verified based on the receiver operating characteristic (ROC) curve. Then, a transcription factor (TF)-mRNA regulatory network of these key genes was established. Lastly, ssGSEA was employed to examine the relationship between the identified genes and cellular pathways and immune cell infiltration. AD samples had notably lower mitophagy correlation scores than control samples. A total of 12 MRGs in the module with the greatest mitophagy connection with AD patients were identified. Functional enrichment analysis revealed that the DEGs were significantly enriched in synaptic function-related pathways. Based on GSE122063, a diagnostic prediction model was created and validated using two mitophagy-related genes (YWHAZ and NDE1), showing an area under ROC curve (AUC) greater than 0.7. This confirmed that the diagnostic model had a high predictive value. The TF-mRNA network showed that four TFs, namely, FOXC1, FOXL1, HOXA5 and GATA2, were regulated by both YWHAZ and NDE1 genes. Immune infiltration analysis revealed that NDE1 promoted the infiltration of most immune cells, while YWHAZ mainly inhibited the infiltration of most immune cells. The current findings improved our understanding of mitophagy in AD, contributing to future research and treatment development in AD.}, }
@article {pmid40147827, year = {2025}, author = {Lee, SK and Han, M and Park, S and Park, SJ and Song, J and Kim, HJ and Kim, J and Lee, H and Shin, HY and Kim, KH and Park, SM}, title = {Association of Physical Activity with Dementia Risk in Cancer Survivors: A Korean Nationwide Cohort Study.}, journal = {Cancer research and treatment}, volume = {}, number = {}, pages = {}, doi = {10.4143/crt.2024.901}, pmid = {40147827}, issn = {2005-9256}, abstract = {PURPOSE: This study aimed to investigate the impact of physical activity on dementia risk among cancer survivors in South Korea.
MATERIALS AND METHODS: This retrospective, population-based cohort study included 344,152 cancer survivors identified from the National Health Insurance Service database in South Korea. The mean follow-up time was 5.81 years. Different levels of physical activity post-cancer diagnosis, ranging from inactive to highly active, were assessed. The primary outcome was the incidence of overall dementia, Alzheimer's disease (AD), and vascular dementia (VaD). Secondary outcomes included dementia risk stratified by cancer type and treatment (chemotherapy and radiation).
RESULTS: Of the total participants, 24,363 (7.08%) developed dementia. The risk of overall dementia decreased sequentially across the exercise groups compared to the inactive group: insufficiently active (adjusted HR, 0.89; 95% CI, 0.86-0.92), active (adjusted HR, 0.85; 95% CI, 0.83-0.88), and highly active (adjusted HR, 0.79; 95% CI, 0.76-0.82). This inverse relationship between exercise and dementia risk was statistically significant across various cancer types and was consistent regardless of age, comorbidities, and whether or not excluding the first 1, 2 years.
CONCLUSION: Among cancer survivors in South Korea, increased physical activity post-diagnosis was associated with a significantly lower risk of dementia. These findings underscore the importance of promoting physical activity in cancer survivors for cognitive health.}, }
@article {pmid40147601, year = {2025}, author = {Li, C and Gao, Z and Chen, X and Zheng, X and Zhang, X and Lin, CY and , }, title = {Ensemble network using oblique coronal MRI for Alzheimer's disease diagnosis.}, journal = {NeuroImage}, volume = {310}, number = {}, pages = {121151}, doi = {10.1016/j.neuroimage.2025.121151}, pmid = {40147601}, issn = {1095-9572}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Aged ; *Cognitive Dysfunction/diagnostic imaging ; Male ; Female ; *Deep Learning ; Aged, 80 and over ; *Brain/diagnostic imaging ; *Image Interpretation, Computer-Assisted/methods ; *Neuroimaging/methods ; Algorithms ; }, abstract = {Alzheimer's disease (AD) is a primary degenerative brain disorder commonly found in the elderly, Mild cognitive impairment (MCI) can be considered a transitional stage from normal aging to Alzheimer's disease. Therefore, distinguishing between normal aging and disease-induced neurofunctional impairments is crucial in clinical treatment. Although deep learning methods have been widely applied in Alzheimer's diagnosis, the varying data formats used by different methods limited their clinical applicability. In this study, based on the ADNI dataset and previous clinical diagnostic experience, we propose a method using oblique coronal MRI to assist in diagnosis. We developed an algorithm to extract oblique coronal slices from 3D MRI data and used these slices to train classification networks. To achieve subject-wise classification based on 2D slices, rather than image-wise classification, we employed ensemble learning methods. This approach fused classification results from different modality images or different positions of the same modality images, constructing a more reliable ensemble classification model. The experiments introduced various decision fusion and feature fusion schemes, demonstrating the potential of oblique coronal MRI slices in assisting diagnosis. Notably, the weighted voting from decision fusion strategy trained on oblique coronal slices achieved accuracy rates of 97.5% for CN vs. AD, 100% for CN vs. MCI, and 94.83% for MCI vs. AD across the three classification tasks.}, }
@article {pmid40147226, year = {2025}, author = {Sharma, V and Reang, J and Yadav, V and Sharma, PC and Majeed, J and Sharma, K}, title = {Discovery of 6-amino pyridine clubbed heterocycles as potent dual GSK-3β/CK-1δ inhibitors for the treatment of Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {159}, number = {}, pages = {108409}, doi = {10.1016/j.bioorg.2025.108409}, pmid = {40147226}, issn = {1090-2120}, abstract = {Alzheimer's disease (AD) is a progressive and chronic neurodegenerative disorder progression through various kinases. Glycogen synthase kinase 3β (GSK-3β) and Casein Kinase-1δ (CK-1δ) have gained a lot of attention for its role in tau pathology. Utilizing a multitarget strategy, a series of 6-amino pyridine derivatives were developed as promising dual GSK-3β/CK-1δ inhibitors for the treatment of AD. This study involved the design, synthesis, and evaluation of novel 6-amino pyridine derivatives as dual GSK-3β/CK-1δ inhibitors exhibiting excellent biological activities. The in-vitro results indicated that most of compounds displayed promising activity against GSK-3β/CK-1δ. Among the tested compounds, 8d exhibited strong inhibitory activity against GSK-3β and CK-1δ, with IC50 values of 0.77 ± 0.01 μM and 0.57 ± 0.12 μM, respectively. Notably, compound 8d significantly reduced tau hyperphosphorylated aggregates while demonstrating safety in SH-SY5Y neuroblastoma cell lines. ADME prediction results indicated that compound 8d adhered to Lipinski's rule of five and exhibited potential to permeate the blood-brain barrier (BBB). Molecular docking analysis revealed that this compound fits well within the ATP binding site, forming hydrogen bonds between its 6-amino pyridine ring with key amino acids, including Asp133 and Val135 in the hinge region of GSK-3β, as well as Leu85 of CK-1δ. These findings indicate that 6-amino pyridine derivatives have the potential to be effective dual-target candidates for AD.}, }
@article {pmid40145977, year = {2025}, author = {Zhao, W and Liu, Z and Wu, J and Liu, A and Yan, J}, title = {Potential targets of microglia in the treatment of neurodegenerative diseases: mechanism and therapeutic implications.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01343}, pmid = {40145977}, issn = {1673-5374}, abstract = {For diverse neurodegenerative disorders, microglial cells are activated. Furthermore, dysfunctional and hyperactivated microglia initiate mitochondrial autophagy, oxidative stress, and pathological protein accumulation, ending with neuroinflammation that exacerbates damage to dopaminergic neurons and contributes significantly to the pathology of neurodegenerative disorder. Microglial overactivation is closely associated with the secretion of pro-inflammatory cytokines, the phagocytosis of injured neurons, and the modulation of neurotoxic environments. This review summarizes the role of microglia neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, cortical degeneration, Lewy body dementia, and Huntington's disease. It also discusses novel forms of cell death such as ferroptosis, cuproptosis, disulfidptosis, and parthanatos (poly(adenosine diphosphate ribose) polymerase 1-dependent cell death), as well as the impact of regulatory factors related to microglial inflammation on microglial activation and neuroinflammation. The aim is to identify potential targets for microglial cell therapy in neurodegenerative diseases.}, }
@article {pmid40145329, year = {2025}, author = {Ruthirakuhan, M and Guan, DX and Mortby, M and Gatchel, J and Babulal, GM}, title = {Updates and future perspectives on neuropsychiatric symptoms in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e70079}, pmid = {40145329}, issn = {1552-5279}, mesh = {Humans ; *Alzheimer Disease ; *COVID-19/epidemiology ; SARS-CoV-2 ; Quality of Life ; }, abstract = {Neuropsychiatric symptoms (NPS) are common throughout the Alzheimer's disease (AD) continuum and profoundly affect patients, caregivers, and health-care systems. This review synthesizes key research presented in the 2022 and 2023 Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment Neuropsychiatric Syndromes-Professional Interest Area (NPS-PIA) Year-In-Reviews, emphasizing six critical areas: (1) diversity and disparities, (2) diagnostic frameworks, (3) neurobiology of NPS, (4) NPS as a disease marker, (5) the impact of COVID-19, and (6) interventions. NPS accelerates AD progression, increases functional decline, diminishes quality of life, and heightens caregiver burden and institutionalization rates. Current treatments primarily rely on psychotropics, which offer limited efficacy and raise safety concerns. This review aims to inform clinicians and researchers about recent NPS advancements while identifying gaps for future studies to improve outcomes for individuals with AD. HIGHLIGHTS: Research in Alzheimer's disease-related neuropsychiatric symptoms has rapidly increased, indicating heightened interest. Key areas include: diversity, diagnostics, markers, COVID-19 impact, and treatments. A road map for future studies, based on the key areas of research, is provided. This road map includes considerations to improve study applicability and validity.}, }
@article {pmid40145267, year = {2025}, author = {Hazan, J and Liu, KY and Isaacs, JD and Howard, R}, title = {Cut-points and gray zones: The challenges of integrating Alzheimer's disease plasma biomarkers into clinical practice.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e70113}, pmid = {40145267}, issn = {1552-5279}, support = {CRTF2023B-003//Alzheimer's Research UK/ ; //University College London Hospitals' National Institute for Health Research (NIHR) Biomedical Research Centre/ ; MR/S021418/1/MRC_/Medical Research Council/United Kingdom ; //National Institute for Health and Care Research/ ; }, mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *Biomarkers/blood/cerebrospinal fluid ; *tau Proteins/blood/cerebrospinal fluid ; *Positron-Emission Tomography ; Amyloid beta-Peptides/blood/cerebrospinal fluid ; }, abstract = {Plasma biomarkers for Alzheimer's disease (AD), such as plasma phosphorylated (p)-tau217, offer a more accessible means of testing for the presence of AD pathology compared to cerebrospinal fluid (CSF) or positron emission tomography (PET) methods. They can support diagnostic assessment and determine patient eligibility for treatment with amyloid beta-lowering drugs in community settings where access to CSF examination and amyloid-PET are limited. However, there are important challenges associated with interpreting and integrating plasma biomarker results in clinical practice. This article explores different approaches to interpreting plasma biomarker results in secondary care, important potential sources of uncertainty, and considerations for their clinical application. HIGHLIGHTS: Plasma biomarkers such as phosphorylated tau-217 (p-tau217) offer a promising, accessible alternative to cerebrospinal fluid (CSF) and positron emission tomography (PET) for detecting Alzheimer's disease pathology, especially in settings with limited diagnostic resources. Clinical integration of plasma biomarker testing presents challenges, particularly in interpreting results. This includes uncertainties around intermediate results and their role in patient management. Clear frameworks and guidelines are essential to optimize the use of plasma biomarkers, supported by further research and education to ensure effective application in clinical practice.}, }
@article {pmid40145080, year = {2025}, author = {Han, L}, title = {AD-Diff: enhancing Alzheimer's disease prediction accuracy through multimodal fusion.}, journal = {Frontiers in computational neuroscience}, volume = {19}, number = {}, pages = {1484540}, pmid = {40145080}, issn = {1662-5188}, abstract = {Early prediction of Alzheimer's disease (AD) is crucial to improving patient quality of life and treatment outcomes. However, current predictive methods face challenges such as insufficient multimodal information integration and the high cost of PET image acquisition, which limit their effectiveness in practical applications. To address these issues, this paper proposes an innovative model, AD-Diff. This model significantly improves AD prediction accuracy by integrating PET images generated through a diffusion process with cognitive scale data and other modalities. Specifically, the AD-Diff model consists of two core components: the ADdiffusion module and the multimodal Mamba Classifier. The ADdiffusion module uses a 3D diffusion process to generate high-quality PET images, which are then fused with MRI images and tabular data to provide input for the Multimodal Mamba Classifier. Experimental results on the OASIS and ADNI datasets demonstrate that the AD-Diff model performs exceptionally well in both long-term and short-term AD prediction tasks, significantly improving prediction accuracy and reliability. These results highlight the significant advantages of the AD-Diff model in handling complex medical image data and multimodal information, providing an effective tool for the early diagnosis and personalized treatment of Alzheimer's disease.}, }
@article {pmid40144920, year = {2025}, author = {Wang, W and Ye, J and Wei, Y and Huang, J and Wang, H and Liu, F and Wu, S and Wu, J and Li, Z and Guo, J and Xiao, A}, title = {Clinical characteristics of schizophrenia, depression, and Alzheimer's diseases among older adults: a retrospective study of 271 consecutive admissions.}, journal = {Frontiers in psychiatry}, volume = {16}, number = {}, pages = {1486626}, pmid = {40144920}, issn = {1664-0640}, abstract = {OBJECTIVE: This study aims to identify the clinical characteristics of schizophrenia, depression, and AD among older adults.
METHODS: General information of patients was collected, including diagnosis, age, gender, level of education, marital status, drinking behavior, smoking behavior, course of mental disorder, type of admission, history of modified electroconvulsive therapy (MECT) and hospitalization period. The Brief Psychiatric Rating Scale (BPRS), Geriatric Depression Scale (GDS), Generalized Anxiety Disorder 7-Item Scale (GAD-7), Insight and Treatment Attitudes Questionnaire (ITAQ), and Mini-Mental State Examination (MMSE) were employed to evaluate the participants' mental status. The Functional Activities Questionnaire (FAQ), Social Support Rating Scale (SSRS), Barthel ADL Index, Standardized Swallowing Assessment (SSA), and Mini-Nutritional Assessment (MNA) were applied to measure social and daily living function. The Nurses' Global Assessment of Suicide Risk (NGASR) and The Brøset Violence Checklist (BVC) were used to assess the patients' risk of suicide.
RESULTS: Totally 271 participants were recruited, the numbers of participants with schizophrenia, depression, and Alzheimer's diseases (AD), were 81 (29.9%), 85 (31.4%), and 105 (38.7%), respectively. One-way ANOVA was used to compare the variance of the crude score results among three groups of subjects. The results showed that patients with depression had the highest GDS total score, followed by patients with AD, and patients with schizophrenia had the lowest score (P < 0.001). The total scores of GAD-7 and ITAQ in patients with depression were higher than those in patients with AD and schizophrenia (P < 0.001). The total score of MMSE in patients with schizophrenia and depression was higher than that in patients with AD (P < 0.001). The incidence of circulatory system diseases in patients with depression and AD was higher than that in patients with schizophrenia (P < 0.05). The incidence of respiratory system diseases in patients with AD was highest, followed by patients with schizophrenia, and patients with depression had the lowest incidence (P < 0.05). The incidence of nervous system diseases in patients with AD was highest, followed by patients with depression, and patients with schizophrenia had the lowest incidence (P < 0.05). The total scores of FAQ and SSA in patients with AD were higher than those in patients with schizophrenia and depression (P < 0.001), while patients with depression had statistically lower SSRS scores than patients with schizophrenia and patients with AD (P < 0.05). Furthermore, patients with AD had lower Barthel ADL Index scores and water-swallowing test (P < 0.001). MNA scores of patients with schizophrenia were higher than those of patients with depression and AD, with statistical significance (P < 0.05). The NGASR scores of patients with depression were higher than those of patients with schizophrenia and AD, which was statistically significant (P < 0.001). Patients with AD had the highest BVC total score, followed by that of patients with schizophrenia and patients with depression had lowest score, and the difference was statistically significant (P < 0.05).
CONCLUSIONS: Patients with geriatric psychosis may experience abnormalities in various aspects that influenced daily living, including disorders of thinking, cognition, emotion, and behavior. Patients with schizophrenia have cognitive impairment. Cognitive training and medication are important. Patients with depression were considered to be at a greater risk for suicide compared to those with schizophrenia and AD. Active clinical measures must be adopted to improve patients' depressive symptoms, change their suicidal attitudes, and enhance their self-confidence. Patients with AD were prone to respiratory and neurological diseases. Treatment of respiratory infections and hypoxia and other respiratory diseases would be necessary, and cognitive function training should be conducted. In addition, regarding to high risk of swallowing disorders and malnutrition, swallowing function training should be carried out to ensure food intake and prevent malnutrition. Driven by psychiatric symptoms, violent behavior was prevalent, thus effective communication and de-escalation techniques are needed. Although the symptoms of these three diseases are different, timely professional intervention and support from family members are urgently needed.}, }
@article {pmid40144670, year = {2025}, author = {Évora, A and Garcia, G and Rubi, A and De Vitis, E and Matos, AT and Vaz, AR and Gervaso, F and Gigli, G and Polini, A and Brites, D}, title = {Exosomes enriched with miR-124-3p show therapeutic potential in a new microfluidic triculture model that recapitulates neuron-glia crosstalk in Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1474012}, pmid = {40144670}, issn = {1663-9812}, abstract = {BACKGROUND: Alzheimer's disease (AD), a complex neurodegenerative disease associated with ageing, is the leading cause of dementia. Few people with early AD are eligible for the novel Food and Drug Administration (FDA)-approved drug treatments. Accordingly, new tools and early diagnosis markers are required to predict subtypes, individual stages, and the most suitable personalized treatment. We previously demonstrated that the regulation of microRNA (miR)-124 is crucial for proper neuronal function and microglia reshaping in human AD cell models.
OBJECTIVE: The aim of this study was to develop an efficient miR-124-3p-loaded exosome strategy and validate its therapeutic potential in using a multi-compartment microfluidic device of neuron-glia that recapitulates age-AD pathological features.
METHODS AND RESULTS: Using cortical microglia from mouse pups, separated from glial mixed cultures and maintained for 2 days in vitro (stressed microglia), we tested the effects of SH-SY5Y-derived exosomes loaded with miR-124-3p mimic either by their direct transfection with Exo-Fect™ (ET124) or by their isolation from the secretome of miR-124 transfected cells (CT124). ET124 revealed better delivery effciency and higher potent effects in improving the stressed microglia status than CT124. Tricultures of human SH-SY5Y neuroblastoma cells (SH-WT) were established in the presence of the human microglia cell line (HMC3) and immortalized human astrocytes (IM-HA) in tricompartmentalized microfluidic devices. Replacement of SH-WT cells with those transfected with APP695 (SH-SWE) in the tricultures and addition of low doses of hydrogen peroxide were used to simulate late-onset AD. The system mimicked AD-associated neurodegeneration and neuroinflammation processes. Notably, ET124 exhibited neuroprotective properties across the three cell types in the AD model by preventing neuronal apoptosis and neurite deficits, redirecting microglial profiles towards a steady state, and attenuating the inflammatory and miRNA fingerprints associated with astrocyte reactivity.
CONCLUSION: To the best of our knowledge, this is the first study supporting the neuro- and immunoprotective properties of miR-124-engineered exosomes in a microfluidic triculture platform, recapitulating age-related susceptibility to AD. Our system offers potential to develop personalized medicines in AD patient subtypes.}, }
@article {pmid40144618, year = {2025}, author = {Zeng, R and Yang, B and Wu, F and Liu, H and Wu, X and Tang, L and Song, R and Zheng, Q and Wang, X and Guo, D}, title = {Early prediction of Alzheimer's disease using artificial intelligence and cortical features on T1WI sequences.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1552940}, pmid = {40144618}, issn = {1664-2295}, abstract = {BACKGROUND: Accurately predicting the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) is a challenging task, which is crucial for helping develop personalized treatment plans to improve prognosis.
PURPOSE: To develop new technology for the early prediction of AD using artificial intelligence and cortical features on MRI.
METHODS: A total of 162 MCI patients were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. By using a 3D-MPRAGE sequence, T1W images for each patient were acquired. All patients were randomly divided into a training set (n = 112) and a validation set (n = 50) at a ratio of 7:3. Morphological features of the cerebral cortex were extracted with FreeSurfer software. Network features were extracted from gray matter with the GRETNA toolbox. The network, morphology, network-clinical, morphology-clinical, morphology-network and morphology-network-clinical models were developed by multivariate Cox proportional hazard model. The performance of each model was assessed by the concordance index (C-index).
RESULTS: In the training group, the C-indexes of the network, morphology, network-clinical, morphology-clinical, morphology-network and morphology-network-clinical models were 0.834, 0.926, 0.915, 0.949, 0.928, and 0.951, respectively. The C-indexes of those models in the validation group were 0.765, 0.784, 0.849, 0.877, 0.884, and 0.880, respectively. The morphology-network-clinical model performed the best. A multi-predictor nomogram with high accuracy for individual AD prediction (C-index = 0.951) was established.
CONCLUSION: The early occurrence of AD could be accurately predicted using our morphology-network-clinical model and the multi-predictor nomogram. This could help doctors make early and personalized treatment decisions in clinical practice, which showed important clinical significance.}, }
@article {pmid40144496, year = {2025}, author = {Zhang, H and Ya, J and Sun, M and Du, X and Ren, J and Qu, X}, title = {Inhibition of the cGAS-STING pathway via an endogenous copper ion-responsive covalent organic framework nanozyme for Alzheimer's disease treatment.}, journal = {Chemical science}, volume = {}, number = {}, pages = {}, pmid = {40144496}, issn = {2041-6520}, abstract = {Inhibition of cGAS-STING overactivation has recently emerged as a promising strategy to counteract Alzheimer's disease (AD). However, current cGAS-STING inhibitors as immunosuppressants suffer from instability, non-specific targeting, and innate immune disruption. Here, an endogenous AD brain copper ion-responsive covalent organic framework (COF)-based nanozyme (denoted as TP@PB-COF@NADH) has been designed for targeted inhibition of the cGAS-STING pathway for AD treatment. The effective trapping of excess brain endogenous copper ions by TP@PB-COF@NADH not only inhibits the Cu[2+]-induced harmful reactive oxygen species (ROS) production which is one of the mediators of cGAS-STING activation, but also activates the nanozyme activity of TP@PB-COF@NADH. Furthermore, the well-prepared nanozyme catalytically generates NAD[+] and consumes hydrogen peroxide (H2O2) through second near-infrared (NIR-II) enhanced nicotinamide adenine dinucleotide (NADH) peroxidase (NPX)-like activity, realizing the efficient inhibition of the cGAS-STING pathway and associated neuroinflammation. Moreover, replenishing NAD[+] levels efficiently restores mitochondrial function and ATP supply. In vivo studies demonstrate that TP@PB-COF@NADH with NIR-II irradiation significantly improves cognitive function in 3× Tg-AD mice, with a reduction in amyloid-β (Aβ) plaque, neuroinflammation and neuronal damage. Collectively, this work presents a promising approach for AD treatment by using an AD brain harmful excess endogenous copper ion-responsive and efficient nanozyme.}, }
@article {pmid40144222, year = {2025}, author = {Pradeep, S and Sai Chakith, MR and Sindhushree, SR and Reddy, P and Sushmitha, E and Purohit, MN and Suresh, D and Swamy Shivananju, N and Silina, E and Manturova, N and Stupin, V and Kollur, SP and Shivamallu, C and Achar, RR}, title = {Exploring shared therapeutic targets for Alzheimer's disease and glioblastoma using network pharmacology and protein-protein interaction approach.}, journal = {Frontiers in chemistry}, volume = {13}, number = {}, pages = {1549186}, pmid = {40144222}, issn = {2296-2646}, abstract = {BACKGROUND: Alzheimer's disease (AD) and glioblastoma (GBM) are complex neurological disorders with distinct pathologies but overlapping molecular mechanisms, including neuroinflammation, oxidative stress, and dysregulated signaling pathways. Despite significant advancements in research, effective therapies targeting both conditions remain elusive. Identifying shared molecular targets and potential therapeutic agents could offer novel treatment strategies for these disorders.
METHODOLOGY: The study employs an integrative network pharmacology approach to explore the therapeutic potential of bioactive compounds from Eclipta alba, a medicinal herb known for its neuroprotective and anti-inflammatory properties. A systematic methodology was adopted, starting with network pharmacology analysis using STRING and DisGeNET databases, which identified 617 common genes associated with AD and GBM. Among these, key hub genes-TP53, STAT3, AKT1, and IL6-were prioritized using Cytoscape for network visualization and analysis.
RESULTS: Molecular docking studies were conducted using PyRx software to assess the binding interactions of 26 phytochemicals from Eclipta alba against the identified target genes. Luteolin exhibited the highest binding affinity to IL6 (-7.8 kcal/mol), forming stable hydrogen bonds and hydrophobic interactions. To further validate this interaction, molecular dynamics simulations (MDS) were performed using GROMACS, confirming the stability of the Luteolin-IL6 complex. Additionally, MM-PBSA binding energy calculations using AmberTools (-145.44 kJ/mol) provided further evidence of a strong and stable interaction. Pharmacokinetic and toxicity evaluations, conducted using SwissADME and pkCSM, highlighted luteolin's favorable drug-like properties, including good bioavailability and low toxicity. These findings suggest that luteolin may serve as a promising multi-target therapeutic agent for AD and GBM by modulating key pathological pathways.
CONCLUSION: The present study provides a strong computational foundation for further in vitro and in vivo validation. The results highlight the potential of luteolin in developing dual-target treatment strategies for neurodegenerative and oncological disorders, offering new avenues for therapeutic advancements.}, }
@article {pmid40143889, year = {2025}, author = {Lithgow, BJ and Saha, C and Dastgheib, Z and Moussavi, Z}, title = {Surface Versus Penetrative rTMS Stimulation May Be More Effective for AD Patients with Cerebrovascular Disease.}, journal = {Neuroscience insights}, volume = {20}, number = {}, pages = {26331055251328355}, pmid = {40143889}, issn = {2633-1055}, abstract = {Repetitive Transcranial Magnetic Stimulation (rTMS) has been applied as an investigational therapy for Alzheimer's Disease (AD). The recent largest (N = 135) double-blind study with 6 months post-treatment follow-up investigating rTMS efficacy as a treatment for AD found about 72% of participants in each group of active and sham were positively responsive to rTMS (using Magstim AirFilm active and sham coils). Since the used sham coil produced about 25.3% of the peak active stimulus, it was hypothesized it could evoke a measurable response in AD patients. This study looks at the details of the above study's sham responses to determine why and how such a response might occur and how cerebrovascular symptomatology may have impacted that response. In the above-mentioned study, 90 and 45 patients were randomly assigned to active and sham groups, respectively. Those with modified Hachinski Ischemic Scores (HIS) below and above 2 were labeled AD2 and ADcvd2, respectively. Analysis of the primary outcome measure ADAS-Cog score change from baseline to post-treatment and follow-ups showed the ADcvd2 in the sham group had a significantly (p = .034) greater improvement or less decline at post-treatment and follow-up sessions compared to the ADcvd2 in the active group. Additionally, the improvement of the ADcvd2 sham compared to those in the active group persisted longer. Also, there was a significant (p = .036) improvement for AD2 individuals in the active compared to AD2 sham stimulation group at 2-months post-treatment. Overall, the sham rTMS stimulus did evoke a measurable response which was more effective for ADcvd2 in sham than ADcvd2 in active support of a vascular mechanism likely linked to the shallower sham stimulus penetration.}, }
@article {pmid40143166, year = {2025}, author = {Alanazi, MM and Albaker, AB and Alzaagi, LA and Alsabhan, JF and Alasmari, F and Almutairi, MM and Alharbi, MS and Alasmari, AF and Alqahtani, F and Alsanea, S}, title = {Oxytocin Protects PC12 Cells Against β-Amyloid-Induced Cell Injury.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {3}, pages = {}, pmid = {40143166}, issn = {1424-8247}, support = {RSPD2025R657//King Saud University/ ; }, abstract = {Background/Objectives: Neurodegenerative diseases, particularly Alzheimer's disease (AD), are characterized by progressive cognitive decline and non-cognitive symptoms that significantly affect health and quality of life. Beta-amyloid (Aβ) protein accumulation is a key factor in AD pathology, leading to neuronal damage. Oxytocin (OXT), a neuropeptide with neuroprotective potential, has garnered interest owing to its ability to mitigate neurotoxicity. We hypothesized that oxytocin could protect PC12 cells from Aβ-induced cytotoxicity through antioxidant effects and modulation of apoptotic pathways (i.e., mitochondrial and MAPK pathways). In this study, we aim to assess oxytocin's protective effects on cell viability, oxidative stress, mitochondrial function, and apoptotic signaling. Methods: PC12 cells were treated with Aβ25-35 and pre-treated with varying oxytocin concentrations to assess cell viability, reactive oxygen species (ROS) generation, and mitochondrial membrane potential. Western blotting was performed to analyze the effects on mitochondrial apoptosis and MAPK pathways. Results: Oxytocin treatment significantly improved cell viability in a dose-dependent manner and reduced Aβ-induced oxidative stress and mitochondrial dysfunction. Oxytocin-treated groups exhibited decreased ROS levels, increased mitochondrial membrane potential, and modulation of apoptosis-related proteins. Oxytocin upregulated phosphorylated ERK1/2 and Bcl-2 while downregulating BAX and caspase-3, reducing the BAX/Bcl-2 ratio. Conclusions: Oxytocin effectively protects PC12 cells from Aβ-induced neurotoxicity, highlighting its potential as a therapeutic agent for AD. Further research is needed to clarify oxytocin's mechanisms and clinical implications in AD treatment.}, }
@article {pmid40143159, year = {2025}, author = {Pérez Aguilar, RDC and Rodríguez Salgado, T and Cruz-Miranda, OL and Soto Díaz, AU and Zenil Rodríguez, A and Bensaddek, L and Carreño-Campos, C and Villarreal, ML and Ortiz-Caltempa, A and Cardoso-Taketa, AT}, title = {Huperzine A Production and Acetylcholinesterase Inhibition by Phlegmariurus taxifolius Cell Suspension Culture: A Comparative Study in Flasks and an Airlift Bioreactor.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {3}, pages = {}, pmid = {40143159}, issn = {1424-8247}, support = {91040//CONAHCYT (years 2011-2014)/ ; }, abstract = {Background: The callus cultures from the fronds of the lycophyte Phlegmariurus taxifolius produce the huperzine A (HupA) alkaloid, which is used in Alzheimer's disease treatment. This study aimed to establish the growth kinetics and HupA production by the newly HupS21 cell line grown in 250 mL flasks and in a 2 L airlift bioreactor. Methods: Batch-type kinetics were carried out for 60 days in 250 mL flasks and for 20 days in a 2 L airlift bioreactor. Measurements of dry weight (DW), specific growth rate (μ), doubling time (dt), pH, carbohydrate consumption, and HupA quantification were performed. The acetylcholinesterase (AChE) inhibitory assay of the HupS21 alkaloidal extract was determined. Results: The 250 mL flasks kinetic reached a maximum cell growth of 8.17 g/L DW, with a μ of 0.045 day[-1] and a dt of 15.40 days. The maximum HupA production was of 2.03 μg/g DW at day 45. In the 2 L airlift reactor, a maximum growth of 16.70 g/L DW, a μ of 0.062 day[-1], a dt of 11.20 days, and HupA production of 2.48 μg/g DW at day 15 were obtained. The alkaloidal extract from the HupS21 cell line at 100 μg/mL showed an AChE inhibitory activity of 85.6 ± 1.27%. Conclusions: The airlift reactor outperformed the flask cultures in maximum cell growth, specific growth rate, doubling time, and HupA production. To our knowledge, this research is the first report on the establishment of suspension cell cultures of P. taxifolius in shaken flasks and in an airlift bioreactor, providing a foundation for scaling up HupA production for pharmaceutical use.}, }
@article {pmid40143145, year = {2025}, author = {Tsimpili, H and Zoidis, G}, title = {A New Era of Muscarinic Acetylcholine Receptor Modulators in Neurological Diseases, Cancer and Drug Abuse.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {3}, pages = {}, pmid = {40143145}, issn = {1424-8247}, support = {Miltiades Empirikos Grant//Empirikion Foundation/ ; }, abstract = {The cholinergic pathways in the central nervous system (CNS) play a pivotal role in different cognitive functions of the brain, such as memory and learning. This review takes a dive into the pharmacological side of this important part of CNS function, taking into consideration muscarinic receptors and cholinesterase enzymes. Targeting a specific subtype of five primary muscarinic receptor subtypes (M1-M5) through agonism or antagonism may benefit patients; thus, there is a great pharmaceutical research interest. Inhibition of AChE and BChE, orthosteric or allosteric, or partial agonism of M1 mAChR are correlated with Alzheimer's disease (AD) symptoms improvement. Agonism or antagonism on different muscarinic receptor subunits may lessen schizophrenia symptoms (especially positive allosteric modulation of M4 mAChR). Selective antagonism of M4 mAChR is a promising treatment for Parkinson's disease and dystonia, and the adverse effects are limited compared to inhibition of all five mAChR. Additionally, selective M5 antagonism plays a role in drug independence behavior. M3 mAChR overexpression is associated with malignancies, and M3R antagonists seem to have a therapeutic potential in cancer, while M1R and M2R inhibition leads to reduction of neoangiogenesis. Depending on the type of cancer, agonism of mAChR may promote cancer cell proliferation (as M3R agonism does) or protection against further tumor development (M1R agonism). Thus, there is an intense need to discover new potent compounds with specific action on muscarinic receptor subtypes. Chemical structures, chemical modification of function groups aiming at action enhancement, reduction of adverse effects, and optimization of Drug Metabolism and Pharmacokinetics (DMPK) will be further discussed, as well as protein-ligand docking.}, }
@article {pmid40143051, year = {2025}, author = {Zou, Y and Zhang, J and Chen, L and Xu, Q and Yao, S and Chen, H}, title = {Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles.}, journal = {Pharmaceutics}, volume = {17}, number = {3}, pages = {}, pmid = {40143051}, issn = {1999-4923}, support = {82100892//Hong Chen/ ; 82300929//Jing Zhang/ ; }, abstract = {Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson's disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently induce neuronal death and accelerate the progression of neurodegeneration. Therefore, mitigating excessive neuroinflammation has emerged as a promising strategy for the treatment of CNS diseases. Despite advancements in drug discovery and the development of novel therapeutics, the effective delivery of these agents to the CNS remains a serious challenge due to the restrictive nature of the blood-brain barrier (BBB). This underscores the need to develop a novel drug delivery system. Recent studies have identified oral lipid nanoparticles (LNPs) as a promising approach to efficiently deliver drugs across the BBB and treat neurological diseases. This review aims to comprehensively summarize the recent advancements in the development of LNPs designed for the controlled delivery and therapeutic modulation of CNS diseases through oral administration. Furthermore, this review addresses the mechanisms by which these LNPs overcome biological barriers and evaluate their clinical implications and therapeutic efficacy in the context of oral drug delivery systems. Specifically, it focuses on LNP formulations that facilitate oral administration, exploring their potential to enhance bioavailability, improve targeting precision, and alleviate or manage the symptoms associated with a range of CNS diseases.}, }
@article {pmid40142948, year = {2025}, author = {Tew, VK and Barathan, M and Nordin, F and Law, JX and Ng, MH}, title = {Emerging Role of Mesenchymal Stromal Cell and Exosome Therapies in Treating Cognitive Impairment.}, journal = {Pharmaceutics}, volume = {17}, number = {3}, pages = {}, pmid = {40142948}, issn = {1999-4923}, abstract = {Cognitive aging, characterized by the gradual decline in cognitive functions such as memory, attention, and problem-solving, significantly impacts daily life. This decline is often accelerated by neurodegenerative diseases, particularly Alzheimer's Disease (AD) and Parkinson's Disease (PD). AD is marked by the accumulation of amyloid-beta plaques and tau tangles, whereas PD involves the degeneration of dopaminergic neurons. Both conditions lead to severe cognitive impairment, greatly diminishing the quality of life for affected individuals. Recent advancements in regenerative medicine have highlighted mesenchymal stromal cells (MSCs) and their derived exosomes as promising therapeutic options. MSCs possess regenerative, neuroprotective, and immunomodulatory properties, which can promote neurogenesis, reduce inflammation, and support neuronal health. Exosomes, nanosized vesicles derived from MSCs, provide an efficient means for delivering bioactive molecules across the blood-brain barrier, targeting the underlying pathologies of AD and PD. While these therapies hold great promise, challenges such as variability in MSC sources, optimal dosing, and effective delivery methods need to be addressed for clinical application. The development of robust protocols, along with rigorous clinical trials, is crucial for validating the safety and efficacy of MSC and exosome therapies. Future research should focus on overcoming these barriers, optimizing treatment strategies, and exploring the integration of MSC and exosome therapies with lifestyle interventions. By addressing these challenges, MSC- and exosome-based therapies could offer transformative solutions for improving outcomes and enhancing the quality of life for individuals affected by cognitive aging and neurodegenerative diseases.}, }
@article {pmid40142943, year = {2025}, author = {Lei, K and Zhou, L and Dan, M and Yang, F and Jian, T and Xin, J and Yu, Z and Wang, Y}, title = {Trojan Horse Delivery Strategies of Natural Medicine Monomers: Challenges and Limitations in Improving Brain Targeting.}, journal = {Pharmaceutics}, volume = {17}, number = {3}, pages = {}, pmid = {40142943}, issn = {1999-4923}, abstract = {Central nervous system (CNS) diseases, such as brain tumors, Alzheimer's disease, and Parkinson's disease, significantly impact patients' quality of life and impose substantial economic burdens on society. The blood-brain barrier (BBB) limits the effective delivery of most therapeutic drugs, especially natural products, despite their potential therapeutic effects. The Trojan Horse strategy, using nanotechnology to disguise drugs as "cargo", enables them to bypass the BBB, enhancing targeting and therapeutic efficacy. This review explores the applications of natural products in the treatment of CNS diseases, discusses the challenges posed by the BBB, and analyzes the advantages and limitations of the Trojan Horse strategy. Despite the existing technical challenges, future research is expected to enhance the application of natural drugs in CNS treatment by integrating nanotechnology, improving delivery mechanisms, and optimizing targeting characteristics.}, }
@article {pmid40142784, year = {2025}, author = {Sundararaman, L and Gouda, D and Kumar, A and Sundararaman, S and Goudra, B}, title = {Glucagon-like Peptide-1 Receptor Agonists: Exciting Avenues Beyond Weight Loss.}, journal = {Journal of clinical medicine}, volume = {14}, number = {6}, pages = {}, pmid = {40142784}, issn = {2077-0383}, abstract = {The last two decades have proffered many remarkable choices in managing type 1 and type 2 diabetes mellitus. Leading the list are glucagon-like peptide-1 receptor agonists (GLP1RAs), the first of which, exenatide, was approved by the FDA in 2005. Two other major classes of drugs have also entered the market: dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly known as gliptins and approved in 2006, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, with the first approval occurring in 2013. These drugs have revolutionized the treatment of diabetes. Additionally, on the horizon, the once-weekly basal insulin analog insulin icodec and the once-weekly combination of insulin icodec and semaglutide are expected to be available in the future. Beyond glycemic control, GLP1RAs have exhibited benefits in conditions associated with diabetes, including hypertension, dyslipidemia, non-alcoholic steatohepatitis, as well as in neurodegenerative diseases such as Alzheimer's disease. Additionally, emerging research suggests potential roles in certain types of cancer, infertility, and associative learning. Major cardiovascular events seem to be lower in patients on GLP1RAs. While some evidence is robust, other findings remain tenuous. It is important that clinicians are familiar with current research in order to provide optimal evidence-based care to patients. In the not-too-distant future, there may be a case to prescribe these drugs for benefits outside diabetes.}, }
@article {pmid40142358, year = {2025}, author = {Palacino, F and Manganotti, P and Benussi, A}, title = {Targeting Neural Oscillations for Cognitive Enhancement in Alzheimer's Disease.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {61}, number = {3}, pages = {}, pmid = {40142358}, issn = {1648-9144}, mesh = {Humans ; *Alzheimer Disease/physiopathology/therapy ; *Transcranial Magnetic Stimulation/methods ; *Transcranial Direct Current Stimulation/methods ; Cognition/physiology ; Deep Brain Stimulation/methods ; Animals ; }, abstract = {Alzheimer's disease (AD), the most prevalent form of dementia, is marked by progressive cognitive decline, affecting memory, language, orientation, and behavior. Pathological hallmarks include extracellular amyloid plaques and intracellular tau tangles, which disrupt synaptic function and connectivity. Neural oscillations, the rhythmic synchronization of neuronal activity across frequency bands, are integral to cognitive processes but become dysregulated in AD, contributing to network dysfunction and memory impairments. Targeting these oscillations has emerged as a promising therapeutic strategy. Preclinical studies have demonstrated that specific frequency modulations can restore oscillatory balance, improve synaptic plasticity, and reduce amyloid and tau pathology. In animal models, interventions, such as gamma entrainment using sensory stimulation and transcranial alternating current stimulation (tACS), have shown efficacy in enhancing memory function and modulating neuroinflammatory responses. Clinical trials have reported promising cognitive improvements with repetitive transcranial magnetic stimulation (rTMS) and deep brain stimulation (DBS), particularly when targeting key hubs in memory-related networks, such as the default mode network (DMN) and frontal-parietal network. Moreover, gamma-tACS has been linked to increased cholinergic activity and enhanced network connectivity, which are correlated with improved cognitive outcomes in AD patients. Despite these advancements, challenges remain in optimizing stimulation parameters, individualizing treatment protocols, and understanding long-term effects. Emerging approaches, including transcranial pulse stimulation (TPS) and closed-loop adaptive neuromodulation, hold promise for refining therapeutic strategies. Integrating neuromodulation with pharmacological and lifestyle interventions may maximize cognitive benefits. Continued interdisciplinary efforts are essential to refine these approaches and translate them into clinical practice, advancing the potential for neural oscillation-based therapies in AD.}, }
@article {pmid40141340, year = {2025}, author = {Singh, AA and Khan, F and Song, M}, title = {Biofilm-Associated Amyloid Proteins Linked with the Progression of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {6}, pages = {}, pmid = {40141340}, issn = {1422-0067}, support = {RS-2023-00241461//This research was supported by the Basic Science Research Program through the National Research Foundation (NRF) of Korea, funded by the Ministry of Education (RS-2023-00241461)./ ; }, mesh = {Humans ; *Biofilms/growth & development ; *Neurodegenerative Diseases/metabolism/microbiology ; *Amyloidogenic Proteins/metabolism ; Disease Progression ; Animals ; Gastrointestinal Microbiome ; Blood-Brain Barrier/metabolism ; Amyloid/metabolism ; }, abstract = {Biofilm-associated amyloid proteins have emerged as significant contributors to the progression of neurodegenerative diseases, representing a complex intersection of microorganisms and human health. The cross-beta sheet structure characteristic of amyloids produced by gut-colonizing bacteria remains intact, crucial for the resilience of biofilms. These amyloids exacerbate neurodegenerative disorders such as Alzheimer's and Parkinson's by cross-seeding human amyloidogenic proteins like amyloid-beta and α-synuclein, accelerating their misfolding and aggregation. Despite molecular chaperones and heat shock proteins maintaining protein homeostasis, bacterial amyloids can overwhelm them, worsening neuronal damage. Genetic variations in chaperone genes further influence amyloidogenesis and neurodegeneration. Persistent bacterial infections and inflammation compromise the blood-brain barrier, allowing inflammatory molecules and amyloids to enter the brain, perpetuating the cycle of neurodegeneration. The gut-brain axis underscores the impact of dysbiosis and gut microbiota on brain function, potentially contributing to neurodegeneration. The enhancement of biofilm resilience and antibiotic resistance by functional amyloid fibrils complicates the treatment landscape. The interplay among chaperone systems, microbial amyloids, and neurodegenerative diseases underscores the urgent need for advanced treatment strategies targeting these pathways to attenuate disease progression. Understanding the processes that relate biofilm-associated amyloids to the onset of neurological disorders is critical for diagnosing and developing novel treatment strategies.}, }
@article {pmid40141302, year = {2025}, author = {Muramoto, S and Shimizu, S and Shirakawa, S and Ikeda, H and Miyamoto, S and Jo, M and Takemori, U and Morimoto, C and Wu, Z and Tozaki-Saitoh, H and Oda, K and Inoue, E and Nonaka, S and Nakanishi, H}, title = {Noradrenaline Synergistically Enhances Porphyromonas gingivalis LPS and OMV-Induced Interleukin-1β Production in BV-2 Microglia Through Differential Mechanisms.}, journal = {International journal of molecular sciences}, volume = {26}, number = {6}, pages = {}, pmid = {40141302}, issn = {1422-0067}, support = {JP21K06383//JSPS KAKENHI/ ; }, mesh = {*Porphyromonas gingivalis ; *Microglia/metabolism/drug effects ; *Interleukin-1beta/metabolism ; *Lipopolysaccharides/pharmacology ; Animals ; *Norepinephrine/pharmacology/metabolism ; Mice ; Cell Line ; Drug Synergism ; Signal Transduction/drug effects ; NF-kappa B/metabolism ; Transcription Factor AP-1/metabolism ; }, abstract = {Infection with Porphyromonas gingivalis (Pg), which is a major periodontal pathogen, causes a large number of systemic diseases based on chronic inflammation such as diabetes and Alzheimer's disease (AD). However, it is not yet fully understood how Pg can augment local systemic immune and inflammatory responses during progression of AD. There is a strong association between depression and elevated levels of inflammation. Noradrenaline (NA) is a key neurotransmitter that modulates microglial activation during stress conditions. In this study, we have thus investigated the regulatory mechanisms of NA on the production of interleukin-1β (IL-1β) by microglia following stimulation with Pg virulence factors, lipopolysaccharide (LPS), and outer membrane vesicles (OMVs). NA (30-1000 nM) significantly enhanced the mRNA level, promoter activity, and protein level of IL-1β up to 20-fold in BV-2 microglia following treatment with Pg LPS (10 μg/mL) and OMVs (150 μg of protein/mL) in a dose-dependent manner. Pharmacological studies have suggested that NA synergistically augments the responses induced by Pg LPS and OMVs through different mechanisms. AP-1 is activated by the β2 adrenergic receptor (Aβ2R)-mediated pathway. NF-κB, which is activated by the Pg LPS/toll-like receptor 2-mediated pathway, is required for the synergistic effect of NA on the Pg LPS-induced IL-1β production by BV-2 microglia. Co-immunoprecipitation combined with Western blotting and the structural models generated by AlphaFold2 suggested that cross-coupling of NF-κB p65 and AP-1 c-Fos transcription factors enhances the binding of NF-κB p65 to the IκB site, resulting in the synergistic augmentation of the IL-1β promoter activity. In contrast, OMVs were phagocytosed by BV-2 microglia and then activated the TLR9/p52/RelB-mediated pathway. The Aβ2R/Epac-mediated pathway, which promotes phagosome maturation, may be responsible for the synergistic effect of NA on the OMV-induced production of IL-1β in BV-2 microglia. Our study provides the first evidence that NA synergistically enhances the production of IL-1β in response to Pg LPS and OMVs through distinct mechanisms.}, }
@article {pmid40141075, year = {2025}, author = {Fang, X and Border, JJ and Zhang, H and Challagundla, L and Kaur, J and Hwang, SH and Hammock, BD and Fan, F and Roman, RJ}, title = {A Soluble Epoxide Hydrolase Inhibitor Improves Cerebrovascular Dysfunction, Neuroinflammation, Amyloid Burden, and Cognitive Impairments in the hAPP/PS1 TgF344-AD Rat Model of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {6}, pages = {}, pmid = {40141075}, issn = {1422-0067}, support = {AG079336/NH/NIH HHS/United States ; DK109737/NH/NIH HHS/United States ; HL170622-01/NH/NIH HHS/United States ; 23PRE1018124//American Heart Association/ ; }, mesh = {Animals ; *Epoxide Hydrolases/antagonists & inhibitors/metabolism ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Rats ; *Disease Models, Animal ; *Cognitive Dysfunction/drug therapy/metabolism/etiology ; *Phenylurea Compounds/pharmacology/therapeutic use ; Neuroinflammatory Diseases/drug therapy/metabolism/etiology ; Male ; Blood-Brain Barrier/metabolism/drug effects ; Piperidines/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; Humans ; Rats, Transgenic ; Brain/metabolism/drug effects/pathology ; Enzyme Inhibitors/pharmacology/therapeutic use ; Cerebrovascular Disorders/drug therapy/metabolism ; Rats, Inbred F344 ; Neurovascular Coupling/drug effects ; }, abstract = {Alzheimer's disease (AD) is an increasing global healthcare crisis with few effective treatments. The accumulation of amyloid plaques and hyper-phosphorylated tau are thought to underlie the pathogenesis of AD. However, current studies have recognized a prominent role of cerebrovascular dysfunction in AD. We recently reported that SNPs in soluble epoxide hydrolase (sEH) are linked to AD in human genetic studies and that long-term administration of an sEH inhibitor attenuated cerebral vascular and cognitive dysfunction in a rat model of AD. However, the mechanisms linking changes in cerebral vascular function and neuroprotective actions of sEH inhibitors in AD remain to be determined. This study investigated the effects of administration of an sEH inhibitor, 1-(1-Propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), on neurovascular coupling, blood-brain barrier (BBB) function, neuroinflammation, and cognitive dysfunction in an hAPP/PS1 TgF344-AD rat model of AD. We observed predominant β-amyloid accumulation in the brains of 9-10-month-old AD rats and that TPPU treatment for three months reduced amyloid burden. The functional hyperemic response to whisker stimulation was attenuated in AD rats, and TPPU normalized the response. The sEH inhibitor, TPPU, mitigated capillary rarefaction, BBB leakage, and activation of astrocytes and microglia in AD rats. TPPU increased the expression of pre- and post-synaptic proteins and reduced loss of hippocampal neurons and cognitive impairments in the AD rats, which was confirmed in a transcriptome and GO analysis. These results suggest that sEH inhibitors could be a novel therapeutic strategy for AD.}, }
@article {pmid40141072, year = {2025}, author = {Wang, K and Adjeroh, DA and Fang, W and Walter, SM and Xiao, D and Piamjariyakul, U and Xu, C}, title = {Comparison of Deep Learning and Traditional Machine Learning Models for Predicting Mild Cognitive Impairment Using Plasma Proteomic Biomarkers.}, journal = {International journal of molecular sciences}, volume = {26}, number = {6}, pages = {}, pmid = {40141072}, issn = {1422-0067}, mesh = {Humans ; *Cognitive Dysfunction/blood/diagnosis/genetics ; *Biomarkers/blood ; *Deep Learning ; *Proteomics/methods ; Female ; Male ; Aged ; *Machine Learning ; Support Vector Machine ; Middle Aged ; Aged, 80 and over ; }, abstract = {Mild cognitive impairment (MCI) is a clinical condition characterized by a decline in cognitive ability and progression of cognitive impairment. It is often considered a transitional stage between normal aging and Alzheimer's disease (AD). This study aimed to compare deep learning (DL) and traditional machine learning (ML) methods in predicting MCI using plasma proteomic biomarkers. A total of 239 adults were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort along with a pool of 146 plasma proteomic biomarkers. We evaluated seven traditional ML models (support vector machines (SVMs), logistic regression (LR), naïve Bayes (NB), random forest (RF), k-nearest neighbor (KNN), gradient boosting machine (GBM), and extreme gradient boosting (XGBoost)) and six variations of a deep neural network (DNN) model-the DL model in the H2O package. Least Absolute Shrinkage and Selection Operator (LASSO) selected 35 proteomic biomarkers from the pool. Based on grid search, the DNN model with an activation function of "Rectifier With Dropout" with 2 layers and 32 of 35 selected proteomic biomarkers revealed the best model with the highest accuracy of 0.995 and an F1 Score of 0.996, while among seven traditional ML methods, XGBoost was the best with an accuracy of 0.986 and an F1 Score of 0.985. Several biomarkers were correlated with the APOE-ε4 genotype, polygenic hazard score (PHS), and three clinical cerebrospinal fluid biomarkers (Aβ42, tTau, and pTau). Bioinformatics analysis using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed several molecular functions and pathways associated with the selected biomarkers, including cytokine-cytokine receptor interaction, cholesterol metabolism, and regulation of lipid localization. The results showed that the DL model may represent a promising tool in the prediction of MCI. These plasma proteomic biomarkers may help with early diagnosis, prognostic risk stratification, and early treatment interventions for individuals at risk for MCI.}, }
@article {pmid40141040, year = {2025}, author = {Pilotto, A and Carini, M and Bresciani, R and Monti, E and Ferrari, F and De Francesco, MA and Padovani, A and Biasiotto, G}, title = {Next Generation Sequencing Analysis in Patients Affected by Parkinson's Disease and Correlation Between Genotype and Phenotype in Selected Clinical Cases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {6}, pages = {}, pmid = {40141040}, issn = {1422-0067}, support = {Ex 60% Biasiotto//University of Brescia/ ; }, mesh = {Humans ; *Parkinson Disease/genetics ; Female ; Male ; Middle Aged ; *High-Throughput Nucleotide Sequencing/methods ; Aged ; *Mutation ; Phenotype ; Genotype ; Genetic Predisposition to Disease ; C9orf72 Protein/genetics ; Adult ; Genetic Association Studies/methods ; Hemochromatosis Protein/genetics ; alpha-Synuclein/genetics ; }, abstract = {Parkinson's Disease (PD) is the most frequent movement disorder and is second only to Alzheimer's Disease as the most frequent neurodegenerative pathology. Early onset Parkinson's disease (EOPD) is less common and may be characterized by genetic predisposition. NGS testing might be useful in the diagnostic assessment of these patients. A panel of eight genes (SNCA, PRKN, PINK1, DJ1, LRRK2, FBXO7, GBA1 and HFE) was validated and used as a diagnostic tool. A total of 38 in sequence EOPD patients of the Parkinson's Disease Unit of our Hospital Institution were tested. In addition, the number of the hexanucleotide repeats of the C9ORF72 gene and the frequency of main HFE mutations were evaluated. Six patients were carriers of likely pathogenic mutations in heterozygosity in the analyzed genes, one of them presented mutations in association and another had a complex genetic background. Their clinical symptoms were correlated with their genotypes. In the cohort of patients, only the p.Cys282Tyr of HFE was significantly decreased in the dominant model and allele contrast comparison. Only one patient with one allele of C9ORF72 containing 10 repeats was identified and clinically described. The clinical signs of sporadic and monogenic PD are often very similar; for this reason, it is fundamental to correlate genotypes and phenotypes, as we tried to describe here, to better classify PD patients with the aim to deepen our knowledge in the molecular mechanisms involved and collaborate in reaching a personalized management and treatment.}, }
@article {pmid40140971, year = {2025}, author = {Azarfar, K and Decourt, B and Sanchez Camacho, B and Lawrence, JJ and Omondi, TR and Sabbagh, MN}, title = {Cholesterol-modifying strategies for Alzheimer disease: promise or fallacy?.}, journal = {Expert review of neurotherapeutics}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/14737175.2025.2483928}, pmid = {40140971}, issn = {1744-8360}, support = {R01 AG059008/AG/NIA NIH HHS/United States ; R01 AG073212/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: As the world population ages, Alzheimer disease (AD) prevalence increases. However, understanding of AD etiology continues to evolve, and the pathophysiological processes involved are only partially elucidated. One compound suspected to play a role in the development and progression of AD is cholesterol. Several lines of evidence support this connection, yet it remains unclear whether cholesterol-modifying strategies have potential applications in the clinical management of AD.
AREAS COVERED: A deep literature search using PubMed was performed to prepare this narrative review. The literature search, performed in early 2024, was inclusive of literature from 1990 to 2024. After providing an overview of cholesterol metabolism, this study summarizes key preclinical studies that have investigated cholesterol-modifying therapies in laboratory models of AD. It also summarizes past and current clinical trials testing specific targets modulated by anti-cholesterol therapies in AD patients.
EXPERT OPINION: Based on current epidemiological and mechanistic studies, cholesterol likely plays a role in AD etiology. The use of cholesterol-modifying therapies could be a promising treatment approach if administered at presymptomatic to early AD phases, but it is unlikely to be efficient in mild, moderate, and late AD stages. Several recommendations are provided for hypercholesterolemia management in AD patients.}, }
@article {pmid40140189, year = {2025}, author = {Kalokhe, VM and Simran, S and Ahmad, A and Musthafa, F and Gangawane, VS and Raghuvanshi, RS and Srivastava, S}, title = {Unveiling Gaps and Demographic Influences in Alzheimer's Therapy: A Data-Centric Study of FDA-Approved Late-Phase Clinical Trials.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {40140189}, issn = {1590-3478}, abstract = {BACKGROUND: Alzheimer's disease is more prevalent in women than in men. In this study, the author examined the U.S. Food and Drug Administration (FDA) completed phase 4 clinical trials associated with Alzheimer's. The research aims to evaluate the women's participation-to-prevalence ratio (PPR) for Alzheimer's disease.
METHOD: Using the FDA's publicly available clinical trial database, 45 Phase 4 Alzheimer's trials from 2003 to 2019 were assessed. Further, the total PPR and yearly PPR value are calculated by dividing the percentage of women in clinical trials by the total percentage of women affected by Alzheimer's disease. The PPR value equal to 1 showcases the balanced participation of females in the Phase 4 clinical trial and the diseased affected population.
RESULT: Out of 45 trials, 41 were completed and four were terminated. The gender data was unavailable for three trials. In 38 clinical trials associated with Alzheimer's disease, 4502 participants were enrolled. Among 4502, 2604 (57.84%) were found to be female and 1898 (42.15%) were male. The PPR for women was 0.80, reflecting an adequate representation of women participants in late-phase clinical trials. The yearly PPR reduction has been seen in female participants.
CONCLUSION: In the year-based PPR, the range was from 0.72-1.0. In the initial year, the range was 1, which was reduced to 0.72 in 2007. In total, 38 completed clinical trials, 18 trials used placebo treatment, and the gender ratio in placebo was adequate. More transparency is essential in gender concerning SAE in publicly available databases.}, }
@article {pmid40138854, year = {2025}, author = {Koyama, G and Nakano, M and Takata, T and Kuramochi, S and Koreki, A and Ishida, T and Uchida, H and Funayama, M}, title = {Reversible dementia due to hyperthyroidism: Cognitive impairment, delusions, and agitation resolved with antithyroid treatment.}, journal = {Journal of the neurological sciences}, volume = {472}, number = {}, pages = {123474}, doi = {10.1016/j.jns.2025.123474}, pmid = {40138854}, issn = {1878-5883}, }
@article {pmid40138777, year = {2025}, author = {Yu, T and Wei, Z and Wang, J and Song, C and Huang, W and Zhang, P and Shi, J and Zhang, R and Jiang, M and Wang, D and Zhang, Y and Chen, H and Wang, H}, title = {Ginkgo biloba Extract GBE50 ameliorates cerebrovascular dysfunction and cognitive impairment in a mouse model of Alzheimer's disease.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {141}, number = {}, pages = {156646}, doi = {10.1016/j.phymed.2025.156646}, pmid = {40138777}, issn = {1618-095X}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder in which neurovascular unit (NVU) dysfunction plays a critical role. GBE50, a refined extract of Ginkgo biloba containing over 50 % total flavonoids and terpene lactones, is widely used in the clinical prevention and treatment of cardiovascular and cerebrovascular diseases due to its anti-platelet aggregation, anti-inflammatory, and antioxidant properties. However, its specific effects on NVU integrity and cerebrovascular function in AD remain unclear.
PURPOSE: This study aims to investigate the therapeutic effects of GBE50 on NVU integrity and cognitive impairment in an AD mouse model.
METHODS: APP/PS1 transgenic mice were treated with GBE50 via intragastric administration for 10 weeks. Cognitive performance was assessed through behavioral tests, while the structural and functional integrity of the NVU was evaluated using immunofluorescence, laser speckle imaging, and in vivo multi-photon imaging. Furthermore, target prediction and transcriptomic analyses were conducted to uncover potential molecular mechanisms and identify specific targets of GBE50.
RESULTS: GBE50 treatment significantly alleviated cognitive deficits in APP/PS1 mice. It enhanced cerebrovascular structure and function by increasing vessel density, diameter, and branching, leading to improved cerebral blood flow (CBF). GBE50 also restored NVU components such as endothelial cells, astrocytes, and pericytes, promoted parenchyma and perivascular Aβ clearance, and reduced neuroinflammation. Bioinformatics and transcriptomic analyses revealed that GBE50 exerted its effects by regulating pathways related to vascular repair, neuroprotection, and Aβ clearance.
CONCLUSION: The findings demonstrate that GBE50 improves cognitive dysfunction in AD by restoring NVU integrity and cerebrovascular function through multi-target mechanisms. This study highlights the potential of GBE50 as a promising therapeutic approach for AD and other neurodegenerative diseases involved in cerebrovascular dysfunction.}, }
@article {pmid40138748, year = {2025}, author = {Walsh, AE and Lukens, JR}, title = {Harnessing microglia-based cell therapies for the treatment of neurodegenerative diseases.}, journal = {Current opinion in immunology}, volume = {94}, number = {}, pages = {102552}, doi = {10.1016/j.coi.2025.102552}, pmid = {40138748}, issn = {1879-0372}, abstract = {Given the growing evidence linking microglia to the onset and progression of various neurodegenerative diseases, these brain-resident macrophages have emerged as a promising cell type for targeted therapeutic interventions. This review highlights recent studies that utilized innovative, microglia-focused strategies for the treatment of diverse neurodegenerative disorders including lysosomal storage disorders, granulin frontotemporal dementia, and Alzheimer's disease. Cutting-edge therapeutic strategies range from replacing faulty microglia with peripheral macrophage precursors or induced human pluripotent stem cell-derived microglia to engineering microglia that target toxic aggregates or deliver remediating payloads. We also examine the potential limitations as well as the clinical benefits of these strategies.}, }
@article {pmid40138382, year = {2025}, author = {Sillapakong, P and Wakabayashi, T and Suzuki, K}, title = {Naturido alleviates amyloid β1-42-induced adverse effects in a transgenic Caenorhabditis elegans model of Alzheimer's disease.}, journal = {PloS one}, volume = {20}, number = {3}, pages = {e0320636}, pmid = {40138382}, issn = {1932-6203}, mesh = {Animals ; *Caenorhabditis elegans/drug effects ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; *Animals, Genetically Modified ; *Disease Models, Animal ; Humans ; *Peptide Fragments/toxicity ; Serotonin/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily associated with aging. While the amyloid hypothesis is not the only explanation for AD pathogenesis, it is widely recognized that the accumulation of amyloid β (Aβ) protein triggers pathological changes in the brains of patients. In a previous study, we showed that Naturido, a cyclic peptide derived from the medicinal fungus (Isaria japonica) grown on domestic silkworms (Bombyx mori), could reverse several age-related deficits in senescence-accelerated mice. In this study, we explored the potential of Naturido to reduce Aβ-related toxicity in transgenic Caenorhabditis elegans models of AD, where human Aβ1-42 protein is overexpressed in neurons. Our results demonstrated that Naturido administration alleviated various phenotypes, including Aβ-induced impairment in associative learning, serotonin hypersensitivity, and locomotion in the transgenic C. elegans. These findings suggest the potential of Naturido as a candidate molecule for the prevention and/or treatment of AD.}, }
@article {pmid40137847, year = {2025}, author = {Liu, H and Zhou, J and Yang, WW}, title = {Etomidate ameliorates Alzheimer-like neuropathology and cognitive impairment in APP/PS1 mice.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {76}, number = {1}, pages = {}, doi = {10.26402/jpp.2025.1.04}, pmid = {40137847}, issn = {1899-1505}, mesh = {Animals ; *Etomidate/pharmacology ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Cognitive Dysfunction/drug therapy/metabolism ; *Hippocampus/drug effects/metabolism/pathology ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Amyloid beta-Peptides/metabolism ; *Mice, Transgenic ; Mice ; Male ; Presenilin-1/genetics ; Disease Models, Animal ; Neurons/drug effects/metabolism/pathology ; Cell Line ; Cognition/drug effects ; }, abstract = {To investigate the effect and mechanism of etomidate on attenuating Alzheimer-like neuropathology and cognitive impairment in mice with Alzheimer's disease (AD). AD was modeled in vivo using amyloid precursor protein/presenilin 1 (APP/PS1) mice. After etomidate treatment, behavioral experiments and histopathological observation of hippocampus were performed. Hippocampal Aβ deposition was detected using immunofluorescence. AD was modeled in vitro using a HT22 cells which are an immortalized cell line derived from primary mouse hippocampal neurons induced by Aβ1-42. Cell viability, apoptosis rate and LDH release were detected after etomidate intervention. Synaptic proteins were detected by mmunofluorescence or Western blot, and neurotransmitters and inflammatory factors were detected by ELISA. Etomidate improved the memory ability, novel object cognition ability, and spatial learning of APP/PS1 mice. The improvement of cognitive function and memory ability may be due to the recovery effect of etomidate on hippocampal pathological changes in APP/PS1 mice, including reducing Aβ deposition, neuron and synaptic loss. Etomidate also regulated neuroinflammation and the release of neurotransmitters GABA and 5-HT in APP/PS1 mice. Etomidate effectively reversed Aβ1-42-induced hippocampal neuronal damage, which was reflected in the improvement of cell viability and the inhibition of cytotoxicity, apoptosis and pro-inflammatory factors. Etomidate reversed the inhibition of the expression of synaptophysin (SYP) and postsynaptic density protein-95 (PSD-95) induced by Aβ1-42 in vitro. After etomidate intervention, the expression of serotonin 1A receptor (5HT1A) and gamma-aminobutyric acid type A receptor subunit alpha1 (GABRA1) in Aβ1-42-injured HT22 cells were up-regulated, and free calcium ion was increased. In conclusion, etomidate ameliorates Alzheimer-like neuropathology and cognitive impairment in APP/PS1 mice, indicating that etomidate may be a potentially useful drug for the treatment of AD.}, }
@article {pmid40137520, year = {2025}, author = {Ene, M and Savuca, A and Ciobica, AS and Jijie, R and Gurzu, IL and Hritcu, LD and Chelaru, IA and Plavan, GI and Nicoara, MN and Gurzu, B}, title = {The Neurobehavioral Impact of Zinc Chloride Exposure in Zebrafish: Evaluating Cognitive Deficits and Probiotic Modulation.}, journal = {Toxics}, volume = {13}, number = {3}, pages = {}, pmid = {40137520}, issn = {2305-6304}, abstract = {Zinc contamination in aquatic environments has become a growing concern due to its potential to bioaccumulate and induce neurotoxic effects in aquatic organisms. As an essential trace element, zinc plays a crucial role in various physiological processes, but excessive exposure can disrupt the gut-brain axis, leading to cognitive and behavioral impairments. Recent studies have suggested that probiotics may offer protective effects against environmental neurotoxins by modulating the gut microbiota and associated neurological functions. The zebrafish (Danio rerio) has emerged as a valuable model organism for studying the biological mechanisms underlying neurotoxicity and potential therapeutic interventions. This study aimed to assess the effects of probiotics on cognitive impairments induced by zinc chloride (ZnCl2) exposure in zebrafish. Specifically, zebrafish were exposed to ZnCl2 at concentrations of 0.5 mg/L and 1.0 mg/L for 96 h, followed by a 7-day post-exposure period to probiotics (Bifidobacterium longum, Bifidobacterium animalis lactis, Lactobacillus rhamnosus). ZnCl2 exposure at these concentrations is already known to induce behavioral and neuromotor deficits resembling Alzheimer's disease-like symptoms in zebrafish models, making it a suitable model for evaluating the neuroprotective potential of probiotics. Behavioral assessments including sociability tests along with short- and long-term memory evaluations were conducted using EthoVision XT 16 software. Memory tests demonstrated that ZnCl2 exposure impaired cognitive functions, while probiotic treatment did not significantly ameliorate these deficits. In the social behavior test, ZnCl2 at 0.5 mg/L resulted in a marked decrease in sociability, whereas exposure to 1.0 mg/L did not induce significant changes. However, post-exposure probiotic administration following ZnCl2 intoxication at 1.0 mg/L exhibited an anxiolytic effect on zebrafish. These findings suggest that probiotics may exhibit partial neurobehavioral benefits following zinc chloride-induced toxicity, particularly in mitigating anxiety-like behaviors rather than cognitive deficits. Further investigations are needed to elucidate the precise mechanisms by which probiotics interact with the gut-brain axis in the context of heavy metal neurotoxicity.}, }
@article {pmid40137398, year = {2025}, author = {Yang, Y and Huh, K and Kwak, YT}, title = {The Influence of a Specialized Dementia Ward on the Treatment of Alzheimer's Disease Patients.}, journal = {Journal of personalized medicine}, volume = {15}, number = {3}, pages = {}, pmid = {40137398}, issn = {2075-4426}, support = {grant number: HI22C0667//the Ministry of Health & Welfare, Republic of Korea/ ; }, abstract = {Background: Hospitalization for severe neuropsychiatric symptoms in Alzheimer's disease (AD) presents challenges, often requiring environments that ensure safety while addressing therapeutic needs. Traditional closed wards, originally designed for psychiatric conditions like schizophrenia, may not fully address the unique needs of AD patients. This study evaluates the effectiveness of a Specialized Dementia Ward (SDW) tailored for AD patients compared to a General Ward (GW). Methods: A retrospective study compared 51 AD patients in an SDW (February 2018-January 2019) and 40 AD patients in a GW (December 2017-January 2018). Patients met NINCDS-ADRDA criteria, with a Clinical Dementia Rating (CDR) ≤ 2 and a Korean Mini-Mental State Examination (K-MMSE) ≤ 20. Clinical assessments at admission and four weeks included K-MMSE, Resident Assessment Instrument Minimum Data Set Version 2.0 (RAI-MDS), and Neuropsychiatric Inventory Questionnaire (NPI-Q). Psychotropic medication use, length of stay, and discharge destination were also analyzed. Results: No statistically significant differences emerged between SDW and GW groups regarding baseline demographics, cognitive function, ADL, or neuropsychiatric symptoms. At four weeks, both groups exhibited trends toward improved K-MMSE, RAI-MDS, and NPI-Q scores and reduced psychotropic usage, but these did not reach statistical significance. Although mean length of stay was shorter for SDW patients (3.2 vs. 4.9 months; p = 0.078), the difference was not significant. Notably, a significantly higher proportion of SDW patients were discharged home (58.8% vs. 37.5%; p = 0.049). Conclusions: Although clinical outcomes were comparable, the SDW demonstrated advantages in facilitating discharge to home, suggesting that tailored ward environments may better support AD patients. These findings underscore the importance of therapeutic environments in dementia care and highlight the need for further research on specialized dementia ward designs to improve outcomes and patient satisfaction.}, }
@article {pmid40137277, year = {2025}, author = {Jia, C and Chai, J and Zhang, S and Sun, Y and He, L and Sang, Z and Chen, D and Zheng, X}, title = {The Advancements of Marine Natural Products in the Treatment of Alzheimer's Disease: A Study Based on Cell and Animal Experiments.}, journal = {Marine drugs}, volume = {23}, number = {3}, pages = {}, pmid = {40137277}, issn = {1660-3397}, support = {22367007//National Natural Science Foundation of China/ ; 824RC500//Hainan Provincial Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/drug therapy ; Animals ; *Biological Products/pharmacology/therapeutic use/chemistry ; Humans ; *Aquatic Organisms ; *Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Blood-Brain Barrier/metabolism/drug effects ; Disease Models, Animal ; }, abstract = {As life expectancy rises and the aging population grows, Alzheimer's disease (AD) has become a significant global health concern. AD is a complex neurodegenerative disorder with an unclear etiology. Current hypotheses primarily focus on β-amyloid (Aβ) aggregation, tau protein hyperphosphorylation, and neuroinflammation as key pathological processes. Given the limited efficacy of existing therapeutic strategies, there is an urgent need to explore novel treatment options. Marine natural products have garnered significant attention due to their unique chemical structures and diverse bioactivities, demonstrating potential for multi-target interventions in AD. This review systematically summarizes the roles of marine-derived compounds, including polysaccharides, carotenoids, and polyphenols, in modulating Aβ aggregation, mitigating tau protein pathology, and regulating gut-brain axis dysfunction. Furthermore, the challenges of current research are discussed, with an emphasis on improving blood-brain barrier permeability and optimizing drug delivery systems to facilitate clinical translation.}, }
@article {pmid40137226, year = {2025}, author = {Stella, R and Bertoli, A and Lopreiato, R and Peggion, C}, title = {A Twist in Yeast: New Perspectives for Studying TDP-43 Proteinopathies in S. cerevisiae.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {40137226}, issn = {2309-608X}, abstract = {TAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer's disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases.}, }
@article {pmid40137159, year = {2025}, author = {Shen, X and Feng, R and Zhou, R and Zhang, Z and Liu, K and Wang, S}, title = {Ceramide as a Promising Tool for Diagnosis and Treatment of Clinical Diseases: A Review of Recent Advances.}, journal = {Metabolites}, volume = {15}, number = {3}, pages = {}, pmid = {40137159}, issn = {2218-1989}, support = {S202410366117//Rui Zhou/ ; KJ2021A0268//Wang Sheng/ ; 82073558//Kaiyong Liu/ ; 2022xkjT007//Kaiyong Liu/ ; JK20215//Wang Sheng/ ; JKS2023018//Kaiyong Liu/ ; }, abstract = {Background/Objectives: Ceramide, a sphingolipid metabolite, has emerged as a key player in various physiological and pathological processes. Changes in ceramide levels are associated with the occurrence and development of various diseases, highlighting its potential as a biomarker of various clinical diseases. Methods: The biosynthesis and metabolism of ceramide are discussed, along with its functions in cell signaling, apoptosis, and inflammation. This study further examines the potential of ceramide as a biomarker for disease diagnosis and treatment. Results: This article highlights the involvement of ceramide in several diseases, including cardiovascular diseases, dermatosis, cancer, neurodegenerative disorders and metabolic syndromes. For each disease, the potential of ceramide as a biomarker for disease diagnosis and prognosis is explored, and the feasibility of therapeutic strategies targeting ceramide metabolism are reviewed. Additionally, the challenges and future directions in the field of ceramide research are addressed. Conclusions: This review article provides an overview of the recent advances in understanding the role of ceramide in clinical diseases and its potential as a diagnostic and therapeutic tool.}, }
@article {pmid40137124, year = {2025}, author = {Ceccarelli Ceccarelli, D and Solerte, SB}, title = {Unravelling Shared Pathways Linking Metabolic Syndrome, Mild Cognitive Impairment, Dementia, and Sarcopenia.}, journal = {Metabolites}, volume = {15}, number = {3}, pages = {}, pmid = {40137124}, issn = {2218-1989}, abstract = {Background: Aging is characterized by shared cellular and molecular processes, and aging-related diseases might co-exist in a cluster of comorbidities, particularly in vulnerable individuals whose phenotype meets the criteria for frailty. Whilst the multidimensional definition of frailty is still controversial, there is an increasing understanding of the common pathways linking metabolic syndrome, cognitive decline, and sarcopenia, frequent conditions in frail elderly patients. Methods: We performed a systematic search in the electronic databases Cochrane Library and PubMed and included preclinical studies, cohort and observational studies, and trials. Discussion: Metabolic syndrome markers, such as insulin resistance and the triglyceride/HDL C ratio, correlate with early cognitive impairment. Insulin resistance is a cause of synaptic dysfunction and neurodegeneration. Conversely, fasting and fasting-mimicking agents promote neuronal resilience by enhancing mitochondrial efficiency, autophagy, and neurogenesis. Proteins acting as cellular metabolic sensors, such as SIRT1, play a pivotal role in aging, neuroprotection, and metabolic health. In AD, β-amyloid accumulation and hyperphosphorylated tau in neurofibrillary tangles can cause metabolic reprogramming in brain cells, shifting from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect in cancer. The interrelation of metabolic syndrome, sarcopenia, and cognitive decline suggests that targeting these shared metabolic pathways could mitigate all the conditions. Pharmacological interventions, including GLP-1 receptor agonists, metformin, and SIRT 1 inducers, demonstrated neuroprotective effects in animals and some preliminary clinical models. Conclusions: These findings encourage further research on the prevention and treatment of neurodegenerative diseases as well as the drug-repurposing potential of molecules currently approved for diabetes, dyslipidemia, and metabolic syndrome.}, }
@article {pmid40135690, year = {2025}, author = {Harding, CD and Holloway, BM and DeYoung, PN and Kwan, C and Djonlagic, I and Ancoli-Israel, S and Banks, SJ and Malhotra, A}, title = {Subjective daytime sleepiness, not sleep quality or hypoxia, predicts sleep-dependent memory consolidation in a cohort of older adults.}, journal = {Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine}, volume = {}, number = {}, pages = {}, doi = {10.5664/jcsm.11648}, pmid = {40135690}, issn = {1550-9397}, support = {R01 HL157985/HL/NHLBI NIH HHS/United States ; T32 HL166127/HL/NHLBI NIH HHS/United States ; }, abstract = {STUDY OBJECTIVES: Aging markedly increases the risk of both Alzheimer's disease (AD) and obstructive sleep apnea (OSA). Memory deficits, an early indicator of AD, can be reduced in middle-aged OSA sufferers through treatment, with positive-airway pressure being the first line treatment standard. Here, we utilize natural variation in the OSA severity of an older-aged cohort to investigate whether hypoxia or sleep quality predict sleep-dependent memory consolidation (SDMC).
METHODS: Participants aged 65-85 years not currently receiving OSA treatment were recruited from the San Diego community via advertisement and referrals from other sleep studies. Participants undertook a computerized neurocognitive battery and overnight polysomnography. SDMC was measured using a word-pair associates task. Two linear regression analyses assessed associations between 1) SDMC and hypoxia metrics and 2) SDMC and sleep quality metrics.
RESULTS: The study included 67 participants (36 women, 31 men) most of whom presented with moderate or severe OSA. No significant associations were present in the hypoxia model. A negative association between Epworth Sleepiness Scale (ESS) score and SDMC was the only significant relationship in the sleep quality model. There was also a mild univariate correlation between ESS score and a second daytime function measure; the psychomotor vigilance task.
CONCLUSIONS: Objective measures of OSA pathology including hypoxia and sleep fragmentation were not associated with memory however ESS score, a subjective measure of daytime sleepiness, was associated with poorer memory task performance. This highlights the importance of considering subjective perceptions of sleep quality and daytime function in cognitive health outcomes of patients with OSA, particularly in older adults where they may integrate the myriad comorbidities that contribute to memory deficits in this group.
CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Identifier: NCT05094271; Title: Is Obstructive Sleep Apnea Important in the Development of Alzheimer's Disease?; URL: https://clinicaltrials.gov/study/NCT05094271.}, }
@article {pmid40135660, year = {2025}, author = {Ogunyemi, OM and Macaulay, OS and Gyebi, GA and Ogunyemi, MM and Agunloye, MO and Olaiya, CO}, title = {Binding interaction of acetylcholinesterase with steroidal pregnanes: insight from machine learning and atomistic simulation.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-27}, doi = {10.1080/07391102.2025.2480262}, pmid = {40135660}, issn = {1538-0254}, abstract = {Acetylcholinesterase (AChE) inhibition is a key strategy in the treatment of Alzheimer's disease and other neurodegenerative disorders. While pregnane-based compounds have been suggested as AChE inhibitors, their mechanism of action remains unclear. This study employed machine learning (ML) and molecular modeling to probe the molecular interaction of AChE with steroidal pregnanes. The ML models were trained and validated on AChE bioactivity datasets to predict pIC50 and pKi values of small-molecule compounds. Among the models tested, the Random Forest Regressor demonstrated superior performance and was used to identify pregnanes with pIC50 ≥ 5 and pKi ≥ 7 as promising inhibitors. Molecular docking revealed strong molecular interactions between AChE and several pregnanes, particularly 21-[(3-Hydroxy-2-naphthyl)oxy]pregnane-2-one. This compound interacted with critical sub-sites within the AChE binding gorge, including the catalytic active site, peripheral anionic site, oxyanion hole, and anionic sub-site, through multiple hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations over 100 ns indicated structural stability and conformational flexibility of representative AChE-pregnane complexes as indicated by the dynamic parameters and cluster patterns. The Molecular Mechanics with Generalized Born Surface Area free energy analysis confirmed strong binding affinities, while residual energy decomposition provided insights into key residue contributions. Additionally, the pregnanes demonstrated favorable blood-brain barrier permeability and other drug-like properties, suggesting their potential as neurotherapeutic agents. Given their predicted bioactivity, strong interactions with AChE, and drug-like properties, the identified pregnanes warrant further optimization and experimental evaluation for the development of safe and effective AChE inhibitors.}, }
@article {pmid40134954, year = {2025}, author = {Qin, G and Song, R and Sun, J and Dai, J and Wang, W and Meng, F and Wang, D and Liu, Z and Sun, B and Li, C}, title = {Unveiling the Therapeutic Potential of Banxia Xiexin Decoction in Alzheimer's Disease: Insights From Network Pharmacology and Experimental Validation.}, journal = {Drug design, development and therapy}, volume = {19}, number = {}, pages = {2133-2155}, pmid = {40134954}, issn = {1177-8881}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Drugs, Chinese Herbal/pharmacology/chemistry ; *Network Pharmacology ; Animals ; Mice ; Humans ; Male ; Mice, Transgenic ; Disease Models, Animal ; Metabolomics ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is associated with various pathological states for which there is no effective treatment. First documented in the Eastern Han Dynasty's medical classic, "Treatise on Febrile and Miscellaneous Diseases" (200-210 Anno Domini), Banxia Xiexin Decoction (BXD) stands as a quintessential approach to treating spleen ailments. Recent studies have shown BXD's effectiveness in mitigating memory impairment associated with AD. Yet, the precise mechanisms underlying BXD's action against AD require further exploration.
AIM OF THE STUDY: To explore the important components of BXD in exerting anti-AD effects and the underlying molecular mechanisms using network pharmacology, metabolomics analysis, and in vitro and in vivo validation strategies. Initially, candidates for BXD's application in AD therapy were identified through extensive database searches, followed by an analysis of protein-protein interactions (PPI). To elucidate BXD's therapeutic pathways in AD, we engaged in Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) assessments. Further, we delved into BXD's primary constituents through ultra-high-pressure liquid chromatography coupled with Q Exactive mass spectrometry and molecular docking techniques. Finally, AD-associated Aβ42-SY5Y cells and APPswe/PS1dE9 (APP/PS1) transgenic mice models were utilized to further determine the activity and mechanisms of BXD through various molecular or phenotypic assays and metabolomics analysis.
RESULTS: Our findings identified the PI3K/Akt signaling pathways as central to BXD's effects. Using in vitro and in vivo models, we found the activity of BXD against AD to be mediated by the suppression of neuroinflammation and apoptosis, accompanied by activation of the PI3K/Akt pathway. Finally, we observed robust changes in metabolite levels in the plasma of BXD-treated APP/PS1 mice.
CONCLUSION: Through systematic data analysis and experimental validation, the therapeutic advantages and fundamental molecular mechanisms of BXD in treating AD were revealed. These findings underscore the promising prospects and compelling potential of BXD, which targets the PI3K/Akt signaling pathway and inflammation, apoptosis, as a therapeutic strategy for improving AD.}, }
@article {pmid40134937, year = {2025}, author = {Simon, C and Graves, OK and Akeju, O and McKay, TB}, title = {Elevated TDP-43 serum levels associated with postoperative delirium following major cardiac surgery.}, journal = {Brain, behavior, & immunity - health}, volume = {45}, number = {}, pages = {100974}, pmid = {40134937}, issn = {2666-3546}, abstract = {BACKGROUND: Postoperative delirium is a recurring complication among vulnerable patients undergoing major cardiac surgery. While delirium has been associated with prodromal dementia, there is minimal evidence to support the causality of this nuanced relationship. Clarification as to how postoperative delirium might lead to neurodegenerative dementias, perhaps through evidence of contemporaneous biomarkers, would heighten the plausibility of a causal correlation. TAR DNA-binding protein 43 (TDP-43), a nuclear protein essential for transcriptional events, has been linked to pathological aggregation in Alzheimer's disease (AD) and AD-related dementias (ADRD).
METHODS: Circulating TDP-43 levels in cardiac surgical patients aged 60 years and older were evaluated in a biobank derived from the Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS) clinical trial. Serum total TDP-43 levels, measured with a single molecule array (Simoa), were compared across preoperative and postoperative day one timepoints according to delirium status assessed using the Confusion Assessment Method (CAM). To investigate the temporal changes in serum TDP-43, an independent validation cohort of 25 patients aged 60 years and older undergoing major cardiac surgery was analyzed.
RESULTS: Total serum TDP-43 levels increased by 16.5% (95% CI: 5.9%-27.9%, p = 0.0021) on postoperative day one compared to baseline levels. This increase was more pronounced in patients who experienced delirium (median increase of 55.1%, 95% CI: 22.9%-96.4%, p = 0.0002). Further, these findings were conserved in multiple logistic regression models adjusting for treatment, age, sex, and baseline cognitive scores. In the validation cohort, TDP-43 levels were found to be significantly elevated immediately following cardiopulmonary bypass from the baseline, with a gradual decrease by postoperative day one.
CONCLUSIONS: Our findings demonstrate that post-cardiac surgery delirium among vulnerable patients is associated with significant elevations in circulating TDP-43. This relationship suggests that TDP-43 may serve as a prognostic biomarker for acute neurological insults and blood-brain barrier integrity following cardiac surgery. Overall, our results provide mechanistic insights into the inter-relationship between postoperative delirium and subsequent cognitive impairment, potentially offering new avenues for early intervention in at-risk surgical patients.}, }
@article {pmid40134734, year = {2025}, author = {Doğancı, O and Sertel, M}, title = {Determination of balance, fall risk, and kinesiophobia in individuals with Alzheimer's Dementia.}, journal = {Frontiers in psychology}, volume = {16}, number = {}, pages = {1535440}, pmid = {40134734}, issn = {1664-1078}, abstract = {OBJECTIVE: This study aimed to determine balance, fall risk, and kinesiophobia in individuals with Alzheimer's Dementia (AD).
METHODS: The study was completed with 18 AD and 18 healthy AD-free control group with early or moderate-stage AD diagnosed by a neurologist. Socio-demographic characteristics of the individuals were assessed using an evaluation form, and their balance was evaluated using the Tinetti Balance and Gait Assessment Test, Timed Up and Go Test, and Single Leg Standing Test. The Falls Risk Self-Assessment Scale (FRSAS) was used to assess the risk of falls. Kinesiophobia was assessed using the Tampa Scale for Kinesiophobia (TKS). Additionally, participants underwent the Mini-Mental State Examination (MMSE).
RESULT: The mean age of individuals with AD was lower than that of healthy individuals, with means of 69 ± 3.66 years and 65.4 ± 4.10 years, respectively (p = 0.012). The Tinetti balance (p = 0.005), Tinetti gait (p < 0.001), Tinetti total (p < 0.001), and the Mini-Mental State Examination (MMSE) (p < 0,001) scores were lower in AD individuals relative to controls. The FRSAS (p < 0.001) scores were higher in AD individuals relative to controls. The TKS scores were found to be similar between individuals with AD and the control group (p = 0.860).
CONCLUSION: It was found that individuals with Alzheimer's disease (AD) have poorer balance and a higher risk of falls compared to healthy individuals. In light of these results, balance assessments should be included when developing rehabilitation protocols for individuals with AD. Treatment protocols designed for this patient group must incorporate balance-specific exercise and training programs. Additionally, individual and environmental preventive measures should be implemented to reduce the risk of falls in individuals with AD.
CLINICAL TRIAL REGISTRATION: Clinical Trial Number: NCT05201768.}, }
@article {pmid40134421, year = {2025}, author = {Sun, H and Hao, Y and Liu, H and Gao, F}, title = {The immunomodulatory effects of GLP-1 receptor agonists in neurogenerative diseases and ischemic stroke treatment.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1525623}, pmid = {40134421}, issn = {1664-3224}, mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor ; *Ischemic Stroke/drug therapy/immunology ; Animals ; Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/therapeutic use/pharmacology ; Immunomodulation/drug effects ; Glucagon-Like Peptide-1 Receptor Agonists ; }, abstract = {Glucagon-like peptide-1 (GLP-1) receptor is widely distributed in the digestive system, cardiovascular system, adipose tissue and central nervous system. Numerous GLP-1 receptor-targeting drugs have been investigated in clinical studies for various indications, including type 2 diabetes and obesity (accounts for 70% of the total studies), non-alcoholic steatohepatitis, Alzheimer's disease, and Parkinson's disease. This review presented fundamental information regarding two categories of GLP-1 receptor agonists (GLP-1RAs): peptide-based and small molecule compounds, and elaborated their potential neuroprotective effects by inhibiting neuroinflammation, reducing neuronal apoptosis, and ultimately improving cognitive function in various neurodegenerative diseases. As a new hypoglycemic drug, GLP-1RA has a unique role in reducing the concurrent risk of stroke in T2D patients. Given the infiltration of various peripheral immune cells into brain tissue, particularly in the areas surrounding the infarct lesion, we further investigated the potential immune regulatory mechanisms. GLP-1RA could not only facilitate the M2 polarization of microglia through both direct and indirect pathways, but also modulate the quantity and function of T cell subtypes, including CD4, CD8, and regulatory T cells, resulting into the inhibition of inflammatory responses and the promotion of neuronal regeneration through interleukin-10 secretion. Therefore, we believe that the "Tregs-microglia-neuron/neural precursor cells" axis is instrumental in mediating immune suppression and neuroprotection in the context of ischemic stroke. Given the benefits of rapid diffusion, favorable blood-brain barrier permeability and versatile administration routes, these small molecule compounds will be one of the important candidates of GLP-1RA. We look forward to the further clinical evidence of small molecule GLP-1RA intervention in ischemic stroke or T2D complicated by ischemic stroke.}, }
@article {pmid40133924, year = {2025}, author = {Nam, Y and Shin, SJ and Kumar, V and Won, J and Kim, S and Moon, M}, title = {Dual modulation of amyloid beta and tau aggregation and dissociation in Alzheimer's disease: a comprehensive review of the characteristics and therapeutic strategies.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {15}, pmid = {40133924}, issn = {2047-9158}, support = {RS-2023-00240010//National Research Foundation of Korea/ ; RS-2024-00450135//National Research Foundation of Korea/ ; RS-2023-00212388//National Research Foundation of Korea/ ; RS-2023-KH138733//Korea Health Industry Development Institute/Republic of Korea ; }, mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *tau Proteins/metabolism/antagonists & inhibitors ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Protein Aggregation, Pathological/metabolism ; Animals ; Protein Aggregates/drug effects/physiology ; }, abstract = {Alzheimer's disease (AD) is not a single-cause disease; rather, it is a complex neurodegenerative disease involving multiple pathological pathways influenced by various risk factors. Aggregation and accumulation of amyloid beta (Aβ) and tau are the most prominent features in the brains of AD patients. Aggregated Aβ and tau exert neurotoxic effects in the central nervous system, contributing to the pathogenesis and progression of AD. They also act synergistically to cause neurodegeneration, resulting in memory loss. In this context, dual inhibition of Aβ and tau aggregation, or dissociation of these two aggregates, is considered promising for AD treatment. Recently, dual inhibitors capable of simultaneously targeting the aggregation and dissociation of both Aβ and tau have been investigated. Specific amino acid domains of Aβ and tau associated with their aggregation/dissociation have been identified. Subsequently, therapeutic agents that prevent aggregation or promote disaggregation by targeting these domains have been identified/developed. In this review, we summarize the major domains and properties involved in Aβ and tau aggregation, as well as the therapeutic effects and mechanisms of agents that simultaneously regulate their aggregation and dissociation. This comprehensive review may contribute to the design and discovery of next-generation dual-targeting drugs for Aβ and tau, potentially leading to the development of more effective therapeutic strategies for AD.}, }
@article {pmid40133753, year = {2025}, author = {Zhou, Q and Wang, W and Deng, C}, title = {Advancements in Proteolysis Targeting Chimeras for Targeted Therapeutic Strategies in Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40133753}, issn = {1559-1182}, support = {82301620//National Natural Science Foundation of China/ ; 82302108//National Natural Science Foundation of China/ ; }, abstract = {The presence of hyperphosphorylated Tau proteins, which mislocalize and form neurofibrillary tangles, and the accumulation of amyloid-β plaques are hallmark features of Alzheimer's disease (AD). These toxic protein aggregates contribute to synaptic impairment and neuronal dysfunction, underscoring the need for strategies aimed at effectively clearing or reducing these aggregates in the treatment of AD. In recent years, proteolysis targeting chimera (PROTAC) technology has emerged as a promising approach for selectively degrading dysfunctional proteins rather than merely inhibiting their function. This approach holds great potential for developing more effective interventions that could slow AD progression and improve patient outcomes. In this review, we first examine the pathological mechanisms underlying AD, focusing on abnormal protein degradation and accumulation. We then explore the evolution of PROTAC technology, its mechanisms of action, and the current status of drug development. Finally, we discuss the latest findings regarding the application of PROTACs in AD therapy, highlighting the potential benefits and limitations of this technology. Although promising, further clinical research is necessary to fully assess the safety and efficacy of PROTAC-based therapies for AD treatment.}, }
@article {pmid40133608, year = {2025}, author = {Burns, AP and Fortel, I and Zhan, L and Lazarov, O and Mackin, RS and Demos, AP and Bendlin, B and Leow, A}, title = {Longitudinal excitation-inhibition balance altered by sex and APOE-ε4.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {488}, pmid = {40133608}, issn = {2399-3642}, support = {RF1MH125928//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01AG068057//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; IIS 2045848//National Science Foundation (NSF)/ ; IIS 2319450//National Science Foundation (NSF)/ ; }, mesh = {Humans ; Female ; Male ; Aged ; *Apolipoprotein E4/genetics ; Longitudinal Studies ; *Magnetic Resonance Imaging ; *Cognitive Dysfunction/physiopathology/genetics ; Middle Aged ; Brain/diagnostic imaging/physiopathology ; Sex Factors ; Alzheimer Disease/genetics/physiopathology ; Diffusion Tensor Imaging ; Sex Characteristics ; }, abstract = {Neuronal hyperexcitation affects memory and neural processing across the Alzheimer's disease (AD) cognitive continuum. Levetiracetam, an antiepileptic, shows promise in improving cognitive impairment by restoring the neural excitation/inhibition balance in AD patients. We previously identified a hyper-excitable phenotype in cognitively unimpaired female APOE-ε4 carriers relative to male counterparts cross-sectionally. This sex difference lacks longitudinal validation; however, clarifying the vulnerability of female ε4-carriers could better inform antiepileptic treatment efficacy. Here, we investigated this sex-by-ε4 interaction using a longitudinal design. We used resting-state fMRI and diffusion tensor imaging collected longitudinally from 106 participants who were cognitively unimpaired for at least one scan event but may have been assessed to have clinical dementia ratings corresponding to early mild cognitive impairment over time. By including scan events where participants transitioned to mild cognitive impairment, we modeled the trajectory of the whole-brain excitation-inhibition ratio throughout the preclinical cognitively healthy continuum and extended to early impairment. A linear mixed model revealed a significant three-way interaction among sex, ε4-status, and time, with female ε4-carriers showing a significant hyper-excitable trajectory. These findings suggest a possible pathway for preventative therapy targeting preclinical hyperexcitation in female ε4-carriers.}, }
@article {pmid40133283, year = {2025}, author = {Tang, H and Andrikopoulos, N and Li, Y and Ke, S and Sun, Y and Ding, F and Ke, PC}, title = {Emerging biophysical origins and pathogenic implications of amyloid oligomers.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2937}, pmid = {40133283}, issn = {2041-1723}, support = {R01 CA243001/CA/NCI NIH HHS/United States ; R35 GM145409/GM/NIGMS NIH HHS/United States ; R35GM145409, R01CA243001//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; 12402237//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *Amyloid/metabolism/chemistry ; *Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; Parkinson Disease/metabolism/pathology ; Animals ; Protein Multimerization ; Protein Aggregates ; }, abstract = {The amyloid hypothesis has been a leading narrative concerning the pathophysiological foundation of Alzheimer's and Parkinson's disease. At the two ends of the hypothesis lie the functional protein monomers and the pathology-defining amyloid fibrils, while the early stages of protein aggregation are populated by polymorphic, transient and neurotoxic oligomers. As the structure and activity of oligomers are intertwined, here we show oligomers arising from liquid-liquid phase separation and β-barrel formation, their routes to neurodegeneration, and their role in cerebrovascular perturbation. Together, this Perspective converges on the multifaceted oligomer-axis central to the pathological origin and, hence, the treatment of amyloid diseases.}, }
@article {pmid40133235, year = {2025}, author = {Gutiérrez-Jiménez, E and Rasmussen, PM and Mikkelsen, IK and Kura, S and Fruekilde, SK and Hansen, B and Bordoni, L and Carlsen, J and Palmfeldt, J and Boas, DA and Sakadžić, S and Vinogradov, S and Khatib, ME and Ramos-Cejudo, J and Wied, B and Leduc-Galindo, D and Canepa, E and Mar, AC and Gamallo-Lana, B and Fossati, S and Østergaard, L}, title = {Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e70023}, pmid = {40133235}, issn = {1552-5279}, support = {R310-2018-3455//Lundbeck Foundation/ ; R01 AG062572/AG/NIA NIH HHS/United States ; R01AG062572/GF/NIH HHS/United States ; U24EB028941//NIH USA/ ; R01 NS104127/NS/NINDS NIH HHS/United States ; 0026167//VELUX Foundation/ ; R01NS104127/GF/NIH HHS/United States ; //Karen Toffler Charitable Trust/ ; AARF-18-564411/ALZ/Alzheimer's Association/United States ; U24 EB028941/EB/NIBIB NIH HHS/United States ; }, mesh = {Animals ; *Carbonic Anhydrase Inhibitors/pharmacology/therapeutic use ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *Alzheimer Disease/drug therapy ; *Mice, Inbred C57BL ; Capillaries/drug effects ; Magnetic Resonance Imaging ; Amyloid beta-Peptides/metabolism ; Brain/drug effects ; Amyloidosis/drug therapy ; Cerebrovascular Circulation/drug effects/physiology ; }, abstract = {INTRODUCTION: Disturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimer's disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes.
METHODS: We employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo magnetic resonance imaging, to investigate early capillary dysfunction in C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax (Tg-SwDI) mice without memory impairment. We also assessed the efficacy of carbonic anhydrase inhibitors (CAIs) in preventing capillary flow disturbances.
RESULTS: Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and amyloid beta (Aβ) load in 9- to 10-month-old Tg-SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced Aβ load.
DISCUSSION: These findings underscore the importance of capillary flow disturbances as early biomarkers in presymptomatic AD and highlight the potential of CAIs for preserving vascular integrity in the early stages of AD.
HIGHLIGHTS: Uncovered early capillary dysfunction in a presymptomatic Alzheimer's disease (AD) mouse model. Evidence linking capillary stalls and capillary dysfunction with oxygen delivery issues in AD. Novel use of carbonic anhydrase inhibitors to prevent early capillary flow disturbances in AD.}, }
@article {pmid40133202, year = {2025}, author = {Guo, LL and Zhang, C and Huang, YJ and Liu, XY and Liu, DS and Long, T and Sun, JH and Liu, SF and Li, ZH and Wang, JZ and Mao, J}, title = {[Effects of nicotine exposure on endogenous metabolites in mouse brain based on metabolomics and mass spectrometry imaging].}, journal = {Se pu = Chinese journal of chromatography}, volume = {43}, number = {4}, pages = {363-371}, pmid = {40133202}, issn = {1872-2059}, mesh = {*Nicotine ; Animals ; Mice ; *Brain/metabolism/drug effects ; *Metabolomics ; Tandem Mass Spectrometry ; Male ; Chromatography, High Pressure Liquid ; }, abstract = {Nicotine, the principal alkaloid in tobacco, exhibits significant central nervous system activity and induces a wide array of physiological effects. In addition to its well-documented role in tobacco dependence, previous studies have suggested that nicotine also has diverse pharmacological properties. These include alleviating symptoms associated with Parkinson's disease, potentially reducing the risk of Alzheimer's disease, mitigating oxidative stress, as well as anti-inflammatory and anxiolytic effects. Neuroscientists frequently use an array of molecular biology techniques to elucidate the mechanisms responsible for the effects of nicotine on the central nervous system. However, disease onset is invariably accompanied by metabolic dysfunction, and organisms often exhibit complex and unpredictable responses to pharmacological stimuli. As a bioactive alkaloid with potent pharmacological properties, nicotine is able to cross the blood-brain barrier and induce brain-compound changes, which serves as the basis for its effects on the central nervous system. Consequently, examining the extensive impact of nicotine exposure on endogenous metabolites and metabolic pathways in the brain is an indispensable step toward providing a more robust foundation for understanding the complex physiological effects of nicotine. In this study, an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) metabolomic-analysis method was established to systematically examine the effects of repeated nicotine exposure on endogenous metabolites in mouse brains. Two chromatographic systems fitted with Acquity UPLC BEH HILIC (150 mm×2.1 mm, 1.7 μm) and BEH C18 (150 mm×2.1 mm, 1.7 μm) columns were used to determine the nicotine present in samples. As a result, the established UHPLC-MS/MS method identified a total of 759 endogenous metabolites. Compared with the saline group, nicotine exposure resulted in 575 significantly different metabolites, with 434 metabolites down-regulated and 141 up-regulated. Further pathway-enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that nicotine exposure primarily affects essential-amino-acid, lipid, nucleotide, carbohydrate, cofactor, and vitamin metabolism, as well as other amino-acid metabolic pathways in the brain. Although non-targeted metabolomics can simultaneously detect and analyze all small-molecule metabolites in an unbiased manner, accurately capturing metabolite changes in specific brain regions is challenging when dealing with complex brain-tissue systems. Targeting the aggregation of material bases and the delivery of precision treatment to certain brain regions is expected to be significant for the targeted therapy of central nervous system diseases. Airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) was further used to directly visualize the nicotine-induced distributions and variations of differentially expressed metabolites in various brain regions, which revealed that nicotine exposure leads to the significant downregulation of choline, serine, aspartate, and malate levels throughout the brain. Specifically, taurine, acetylcholine, and adenosine levels were notably affected in the cortical, hippocampal, and striatal regions, respectively. Essential-amino-acid metabolism was most affected by nicotine, with lipid metabolism found to be the next-most affected pathway. These metabolic pathways predominantly affected the cortical region, whereas the striatum, hippocampus, thalamus, and cerebellum were affected to varying degrees. These findings provide novel experimental evidence that enhances our understanding of metabolic biomarkers associated with nicotine exposure.}, }
@article {pmid40133008, year = {2025}, author = {Bakhdil, N}, title = {A kinetic theory approach for modeling Alzheimer's disease: Insights and challenges: Comment on "Mathematical models on Alzheimer's disease and its treatment: A review" by M. Maji and S. Khajanchi.}, journal = {Physics of life reviews}, volume = {53}, number = {}, pages = {221-222}, doi = {10.1016/j.plrev.2025.03.019}, pmid = {40133008}, issn = {1873-1457}, }
@article {pmid40132750, year = {2025}, author = {Liu, W and Chen, X and Yang, C and Lin, Z and Huang, X and Zhang, Z and Liu, J}, title = {Preventive effects of xanthohumol in APP/PS1 mice based on multi-omics atlas.}, journal = {Brain research bulletin}, volume = {224}, number = {}, pages = {111316}, doi = {10.1016/j.brainresbull.2025.111316}, pmid = {40132750}, issn = {1873-2747}, abstract = {Alzheimer's disease (AD) is a complex disease with unknown etiology and pathogenesis. We described a combined analysis of murine proteomics and microbiomics to find potential therapeutic targets of different doses of xanthohumol (Xn), with the goal of providing a biological basis for the treatment of early AD. Xn improved the spatial learning and memory ability of APP/PS1 mice; this was associated with an increased number of newborn neurons in the subgranular zone (SGZ) and dentate gyrus (DG) and a decreased inflammatory response. 108 proteins were significantly changed after 0.5 mg/kg Xn treatment while only 72 proteins changed by 5 mg/kg Xn. Eight significant microbiota were modulated by different doses of Xn at line discriminant analysis (LDA) score 3.0, but only three of which were regulated by 0.5 mg/kg Xn at LDA score 4.0. In addition, Xn treatment could significantly regulate the pathways of neurodegeneration- multiple diseases in the hippocampus and the penicillin and cephalosporin biosynthesis and atrazine degradation pathways in the gut. Interestingly, Nefl protein validated by correlation analysis was found in the common signaling pathway. 0.5 mg/kg Xn was able to reverse the correlation between hippocampal proteins and gut microbiota. Xn treatment significantly improved cognitive function in AD transgenic mice. Different doses of Xn caused significant differences in protein expression and flora composition and abundance, suggesting that the doses of Xn should be selected with caution, and low dose may be better in the prevention of AD.}, }
@article {pmid40132722, year = {2025}, author = {Kazemi, M and Sanati, M and Shekari Khaniani, M and Ghafouri-Fard, S}, title = {A review on the lncRNA-miRNA-mRNA regulatory networks involved in inflammatory processes in Alzheimer's disease.}, journal = {Brain research}, volume = {1856}, number = {}, pages = {149595}, doi = {10.1016/j.brainres.2025.149595}, pmid = {40132722}, issn = {1872-6240}, abstract = {Alzheimer's disease is a progressive neurodegenerative condition that is the most frequent reason for dementia. Due to the increasing trend of aging in societies, it will place a large social and financial burden on society. Although beta amyloid plaques and the formation of neurofibrillary tangles are mentioned as the main events in this disorder, the exact molecular pathology and inflammatory regulatory networks involved in neuroinflammatory events, as a fundamental pathogenic mechanism remain unknown. Understanding these molecular network pathways in addition to helping to understand the pathogenesis of Alzheimer's disease, can also help in the early diagnosis as well as the control of inflammatory processes that are involved in its progression. So, in this study, we intend to have an overview on the regulatory lncRNAs of Alzheimer's disease and their related miRNA and mRNAs, as well as the relationship of these regulatory pathways with inflammatory processes, so that we can provide a perspective for future studies in the field of diagnosis and possibly treatment of this disorder.}, }
@article {pmid40132562, year = {2025}, author = {Simon, PYR and David, R}, title = {Alzheimer's disease, β-amyloid peptides and ubiquitin-proteasome system: nutritherapeutic insights.}, journal = {Neuro-degenerative diseases}, volume = {}, number = {}, pages = {1-23}, doi = {10.1159/000545170}, pmid = {40132562}, issn = {1660-2862}, abstract = {BACKGROUND: The Alzheimer's disease - an age-related neurodegenerative disorder leading to a progressive cognitive impairment - is characterized by an intracerebral accumulation of soluble β-amyloid (Aβ) oligomers, followed by the appearance of abnormally ubiquitinylated neurofibrillary tangles - a process associated with a chronic inflammation. The systematic presence of ubiquitinylated inclusions reflects a decrease in the proteasome activity due to (and contributing to) the presence of Aβ oligomers - a central dysfunction in the etiology of the disease.
SUMMARY: The involvement of the ubiquitin-proteasome system opens new therapeutic perspectives for both prevention and treatment. In particular, the potential for synergistic strategies combining diet-derived proteasome activators, immunoproteasome inhibitors and modulators of β-amyloid peptide aggregation to prevent delay or even reverse the disease progression over time is currently arousing growing interest.
KEY MESSAGES: In that perspective, and in the light of the recent advances in the understanding of the key molecular and cellular mechanisms underlying the Alzheimer's disease pathogenesis, the present review highlights the mechanisms of action and the preventive and therapeutic potential of some diet-derived bioactive compounds and other natural substances of interest. This article is a translated, updated and expanded version of an article originally published in French in Médecine/Sciences, August/September 2023 (https://doi.org/10.1051/medsci/2023094).}, }
@article {pmid40132145, year = {2025}, author = {Nallapu, BT and Petersen, KK and Qian, T and Demirsoy, I and Ghanbarian, E and Davatzikos, C and Lipton, RB and Ezzati, A and , }, title = {A Machine Learning Approach to Predict Cognitive Decline in Alzheimer Disease Clinical Trials.}, journal = {Neurology}, volume = {104}, number = {8}, pages = {e213490}, doi = {10.1212/WNL.0000000000213490}, pmid = {40132145}, issn = {1526-632X}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Machine Learning ; Female ; Male ; Aged ; *Cognitive Dysfunction/etiology ; Neuropsychological Tests ; Aged, 80 and over ; Magnetic Resonance Imaging ; Biomarkers ; Predictive Value of Tests ; Middle Aged ; Clinical Trials as Topic/methods ; }, abstract = {BACKGROUND AND OBJECTIVES: Among the participants of Alzheimer disease (AD) treatment trials, 40% do not show cognitive decline over 80 weeks of follow-up. Identifying and excluding these individuals can increase power to detect treatment effects. We aimed to develop machine learning-based predictive models to identify persons unlikely to show decline on placebo treatment over 80 weeks.
METHODS: We used the data from the placebo arm of EXPEDITION3 AD clinical trial and a subpopulation from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants in the EXPEDITION3 trial were patients with mild dementia and biomarker evidence of amyloid burden. For this study, participants were identified as those who demonstrated clinically meaningful cognitive decline (CMCD) or cognitively stable (CS) at final visit of the trial (week 80). Machine learning-based classifiers were trained to classify participants into CMCD vs CS groups using combinations of demographics, APOE genotype, neuropsychological tests, and biomarkers (volumetric MRI). The results were developed in 70% of the EXPEDITION3 placebo sample using 5-fold cross-validation. Trained models were then used to classify the participants in an internal validation sample and an external matched sample ADNIAD.
RESULTS: Eight hundred ninety-four of the 1,072 participants in the placebo arm of the EXPEDITION3 trial had necessary follow-up data, who were on average aged 72.7 (±7.7) years and 59% female. 55.8% of those participants showed CMCD (∼2 years younger than those without) at the final visit. In the independent validation sample within the EXPEDITION3 data, all the models showed high sensitivity and modest specificity. Positive predictive values (PPVs) of models were at least 11% higher than base prevalence of CMCD observed at the end of the trial. The subset of matched ADNI participants (ADNIAD, N = 105) were aged 74.5 (±6.4) years and 46% female. The models that were validated in ADNIAD also showed high sensitivity, modest specificity, and PPVs of at least 15% higher than the base prevalence in ADNIAD.
DISCUSSION: Our results indicate that predictive models have the potential to improve the design of AD trials through selective inclusion and exclusion criteria based on expected cognitive decline. Such predictive models need further validation across data from different AD clinical trials.}, }
@article {pmid40131695, year = {2025}, author = {Wang, J and Liao, M and Tong, Z and Yuan, S and Hu, Z and Chen, Z and Zeng, F and Zou, R and Chen, D and Chen, G and Wang, Z and Liu, W}, title = {Treadmill Exercise Modulates the Leptin/LepR/GSK-3β Signalling Pathway to Improve Leptin Sensitivity and Alleviate Neuroinflammation in High-Fat Diet-Fed APP/PS1 Mice.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40131695}, issn = {1559-1182}, abstract = {Neuroinflammation plays a critical role in the development of Alzheimer's disease (AD) and is closely associated with obesity. In AD, the fat cell-secreted protein leptin crosses the blood-brain barrier and protects against nerve damage. However, obesity may induce leptin resistance, reduce leptin sensitivity, stimulate excessive glial cell activation, promote inflammatory factor production and exacerbate brain inflammation. Unfortunately, the mechanism of interaction among high-fat diets, obesity, neuroinflammation and neurodegenerative diseases remains unclear. We investigated the changes in neuroinflammation and leptin sensitivity in the brains of wild-type and high-fat-diet-fed APP/PS1 transgenic mice. We explored the effects of treadmill exercise for 12 weeks on the leptin/LepR/GSK-3β signalling pathway and memory. The body weights of the high-fat-diet-fed mice increased, and elevated levels of markers for leptin resistance, including suppressor of signalling 3 (SOCS3), protein tyrosine phosphatase 1B (PTP1B) and proinflammatory factors such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were observed. After 12 weeks of aerobic exercise, the leptin mRNA and protein levels increased, GSK-3β protein expression decreased and the mean fluorescence intensities of brain microglial (IBA-1) and neuron markers (NeuN) decreased, indicating that exercise may activate the leptin/LepR/GSK-3β signalling pathway, reducing glial cell activation and inflammation. Our study revealed that obesity induces and exacerbates the AD-related neuroinflammatory response. Aerobic exercise activates the leptin/LepR/GSK-3β pathway to relieve neuroinflammation and protect nerve cells, alleviating AD-associated memory loss. These promising outcomes could inform the development of nondrug-based aerobic exercise interventions for the treatment of AD and associated cognitive disorders.}, }
@article {pmid40131549, year = {2025}, author = {Firoozi, A and Shadi, M and Rezagholizadeh, A}, title = {The role of low-level laser therapy in Alzheimer's disease: a review of the potential benefits of vitamin D enhancement.}, journal = {Lasers in medical science}, volume = {40}, number = {1}, pages = {159}, pmid = {40131549}, issn = {1435-604X}, mesh = {*Low-Level Light Therapy/methods ; *Alzheimer Disease/radiotherapy ; Humans ; *Vitamin D/therapeutic use ; *Oxidative Stress/radiation effects ; Animals ; Mitochondria/radiation effects/metabolism ; Antioxidants/therapeutic use ; }, abstract = {As the global population ages, neurodegenerative diseases, particularly Alzheimer's disease (AD), have become a major public health concern. AD is the most prevalent neurodegenerative disorder, accounting for 60-80% of cases, and is characterized by progressive cognitive and memory decline due to neuronal loss. Current pharmacological treatments primarily offer symptomatic relief rather than a cure. Recent research has highlighted the role of vitamin D in neuroprotection, owing to its antioxidant, anti-inflammatory, and neuroprotective properties, as well as its ability to maintain blood-brain barrier integrity and regulate amyloid-beta (Aβ) clearance. Another emerging noninvasive therapeutic approach is Low-Level Laser Therapy (LLLT), a form of photobiomodulation (PBM) that has been shown to enhance neuronal function, reduce oxidative stress, inflammation, and Aβ deposition, and potentially increase vitamin D levels. This review examines the interplay between LLLT, vitamin D, and oxidative stress in AD pathophysiology. Findings suggest that LLLT can stimulate mitochondrial function, enhance synaptic plasticity, and improve cognitive performance in preclinical and clinical studies. Furthermore, LLLT has been reported to modulate immune responses, promote neurogenesis, and facilitate vitamin D synthesis by activating cytochrome c oxidase (CCO), which plays a crucial role in mitochondrial energy production. However, while promising, further in vivo and clinical trials are required to optimize treatment protocols and establish standardized guidelines for LLLT application, particularly in enhancing vitamin D levels, in AD patients. CLINICAL TRIAL NUMBER: Not applicable.}, }
@article {pmid40130456, year = {2025}, author = {Bilginer-Kartal, R and Arslan-Yildiz, A}, title = {Magnetic Levitational Assembly of Differentiated SH-SY5Y Cells for Aβ-Induced 3D Alzheimer's Disease Modeling and Curcumin Screening.}, journal = {Macromolecular bioscience}, volume = {}, number = {}, pages = {e2400658}, doi = {10.1002/mabi.202400658}, pmid = {40130456}, issn = {1616-5195}, support = {//İzmir Institute of Technology Biotechnology and Bioengineering Research and Application Center/ ; TÜBA-GEBİP/2019//Young Scientist Award Program, Turkish Academy of Sciences (TUBA)/ ; 2022IYTE-1-0058//IZTECH-Scientific Research Project/ ; }, abstract = {Alzheimer's disease is one of the prevalent neurodegenerative diseases and is characterized by amyloid beta aggregate (Aβ) accumulation. This study reports an Aβ 1-42 induced 3D Alzheimer's disease modeling utilizing differentiated SH-SY5Y spheroids, which is carried out by Magnetic levitation approach, and the neuroprotective effect of Curcumin is further investigated on this model. For this purpose, SH-SY5Y spheroids are differentiated using Retinoic acid-Brain-derived neurotrophic factor sequentially during 3D cell culture. Differentiated spheroids maintained high viability and exhibited significant neuronal characteristics, as evidenced by increasing β-III tubulin and NeuN expressions. 3D Alzheimer's disease model formation and neurotoxicity of Aβ 1-42 aggregates are investigated on un-/differentiated spheroids, resulting in 65% and 51% cell viability, respectively. Characterization of the 3D Alzheimer's disease model is done by immunostaining of Choline acetyltransferase to investigate cholinergic neuron activity loss, showing a 2.2 decrease in fluorescence intensity. Further, Curcumin treatment on the 3D Alzheimer's disease model resulted in augmenting cell viability, confirming neuroprotective effect of Curcumin on Aβ 1-42 induced Alzheimer's disease model. This study highlighted the magnetic levitation-based fabrication of Aβ 1-42-induced 3D Alzheimer's disease model successfully, offering a promising experimental platform for other neurodegenerative disease research and potential clinical applications.}, }
@article {pmid40129145, year = {2025}, author = {Yang, Q and Qiu, Y and Ni, J and Li, H and Qing, H}, title = {Deciphering T Cell Dynamics in Alzheimer's Disease Pathogenesis: Insights and Implications.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X350611250303044527}, pmid = {40129145}, issn = {1875-6190}, abstract = {Neuroinflammation has emerged as a crucial factor in the pathogenesis of Alzheimer's disease (AD), paving the way for promising therapeutic interventions. Increasing evidence highlights the interplay between the peripheral immune system and the central nervous system (CNS) in driving neuroinflammation, with T lymphocytes playing a vital role in both regulatory and effector functions. Aberrant activation of T cells during the early stages of neuroinflammation perpetuates inflammatory responses by interacting with CNS glial cells and releasing pro-inflammatory mediators, such as IFN-γ, TNF-α, and IL-17. Studies have documented significant T cell activation and infiltration into the brain parenchyma in AD, contributing to disease progression. However, the specific mechanisms by which T cells mediate AD pathogenesis remain unclear. This comprehensive review synthesizes the current understanding of T cell involvement in AD pathology, emphasizing their aberrant activation, interactions with microglia, tau protein pathology, and the influence of gut microbiota. Finally, we propose potential treatment modalities for AD, highlighting the promise of T cellbased therapies currently under investigation in clinical trials. Understanding the critical role of T cells in intercellular communication and disease progression may enhance our comprehension of the pathophysiology of AD.}, }
@article {pmid40129107, year = {2025}, author = {Lolak, N and Akocak, S and Topal, M and Koçyiğit, ÜM and Işık, M and Türkeş, C and Topal, F and Durgun, M and Beydemir, Ş}, title = {Sulfonamide-Bearing Pyrazolone Derivatives as Multitarget Therapeutic Agents: Design, Synthesis, Characterization, Biological Evaluation, In Silico ADME/T Profiling and Molecular Docking Study.}, journal = {Pharmacology research & perspectives}, volume = {13}, number = {2}, pages = {e70088}, pmid = {40129107}, issn = {2052-1707}, support = {ECZMAP/2023-001//Adıyaman University/ ; 2102S003//Anadolu University/ ; }, mesh = {*Molecular Docking Simulation ; *Carbonic Anhydrase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Pyrazolones/pharmacology/chemistry/chemical synthesis ; *Drug Design ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Acetylcholinesterase/metabolism ; Humans ; *Sulfonamides/pharmacology/chemistry/chemical synthesis ; *Carbonic Anhydrase II/antagonists & inhibitors/metabolism ; *Carbonic Anhydrase I/antagonists & inhibitors/metabolism ; Structure-Activity Relationship ; Butyrylcholinesterase/metabolism ; Computer Simulation ; }, abstract = {The research and design of new inhibitors for the treatment of diseases such as Alzheimer's disease and glaucoma through inhibition of cholinesterases (ChEs; acetylcholinesterase, AChE and butyrylcholinesterase, BChE) and carbonic anhydrase enzymes are among the important targets. Here, a series of novel sulfonamide-bearing pyrazolone derivatives (1a-f and 2a-f) were successfully synthesized and characterized by using spectroscopic and analytical methods. The inhibitory activities of these newly synthesized compounds were evaluated both in vitro and in silico for their effect on carbonic anhydrases (hCA I and hCA II isoenzymes) and ChEs. The in vitro studies showed that these novel compounds demonstrated potential inhibitory activity, with KI values covering the following ranges: 18.03 ± 2.86-75.54 ± 4.91 nM for hCA I, 24.84 ± 1.57-85.42 ± 6.60 nM for hCA II, 7.45 ± 0.98-16.04 ± 1.60 nM for AChE, and 34.78 ± 5.88-135.70 ± 17.39 nM for BChE. Additionally, many of these compounds showed promising inhibitory activity, and some showed higher potency than reference compounds. While the in silico studies have also identified the potential binding positions of these compounds, using the crystal structures of hCA I, II, AChE and BChE receptors. The varying affinities demonstrated by these designed compounds for ChEs and hCA isoenzymes show that these compounds could hold promise as potential alternative agents for selectively inhibiting ChEs and hCAs in the treatment of diseases such as Alzheimer's disease and glaucoma.}, }
@article {pmid40128823, year = {2025}, author = {Zhang, W and Huang, C and Yao, H and Yang, S and Jiapaer, Z and Song, J and Wang, X}, title = {Retrotransposon: an insight into neurological disorders from perspectives of neurodevelopment and aging.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {14}, pmid = {40128823}, issn = {2047-9158}, support = {2023TSYCCX0051//Tianshan Talent Training Program/ ; }, mesh = {Humans ; *Retroelements/genetics ; *Aging/genetics ; *Nervous System Diseases/genetics ; Animals ; }, abstract = {Neurological disorders present considerable challenges in diagnosis and treatment due to their complex and diverse etiology. Retrotransposons are a type of mobile genetic element that are increasingly revealed to play a role in these diseases. This review provides a detailed overview of recent developments in the study of retrotransposons in neurodevelopment, neuroaging, and neurological diseases. Retrotransposons, including long interspersed nuclear elements-1, Alu, SINE-VNTR-Alu, and endogenous retrovirus, play important regulatory roles in the development and aging of the nervous system. They have also been implicated in the pathological processes of several neurological diseases, including Alzheimer's disease, X-linked dystonia-parkinsonism, amyotrophic lateral sclerosis, autism spectrum disorder, and schizophrenia. Retrotransposons provide a new perspective for understanding the molecular mechanisms underlying neurological diseases and provide insights into diagnostic and therapeutic strategies of these diseases.}, }
@article {pmid40128806, year = {2025}, author = {Xu, H and Mu, S and Bao, J and Davatzikos, C and Shou, H and Shen, L}, title = {High-dimensional mediation analysis reveals the mediating role of physical activity patterns in genetic pathways leading to AD-like brain atrophy.}, journal = {BioData mining}, volume = {18}, number = {1}, pages = {24}, pmid = {40128806}, issn = {1756-0381}, support = {U01 AG068057/NH/NIH HHS/United States ; RF1 AG054409/NH/NIH HHS/United States ; U01 AG068057/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a complex disorder that affects multiple biological systems including cognition, behavior and physical health. Unfortunately, the pathogenic mechanisms behind AD are not yet clear and the treatment options are still limited. Despite the increasing number of studies examining the pairwise relationships between genetic factors, physical activity (PA), and AD, few have successfully integrated all three domains of data, which may help reveal mechanisms and impact of these genomic and phenomic factors on AD. We use high-dimensional mediation analysis as an integrative framework to study the relationships among genetic factors, PA and AD-like brain atrophy quantified by spatial patterns of brain atrophy.
RESULTS: We integrate data from genetics, PA and neuroimaging measures collected from 13,425 UK Biobank samples to unveil the complex relationship among genetic risk factors, behavior and brain signatures in the contexts of aging and AD. Specifically, we used a composite imaging marker, Spatial Pattern of Abnormality for Recognition of Early AD (SPARE-AD) that characterizes AD-like brain atrophy, as an outcome variable to represent AD risk. Through GWAS, we identified single nucleotide polymorphisms (SNPs) that are significantly associated with SPARE-AD as exposure variables. We employed conventional summary statistics and functional principal component analysis to extract patterns of PA as mediators. After constructing these variables, we utilized a high-dimensional mediation analysis method, Bayesian Mediation Analysis (BAMA), to estimate potential mediating pathways between SNPs, multivariate PA signatures and SPARE-AD. BAMA incorporates Bayesian continuous shrinkage prior to select the active mediators from a large pool of candidates. We identified a total of 22 mediation pathways, indicating how genetic variants can influence SPARE-AD by altering physical activity. By comparing the results with those obtained using univariate mediation analysis, we demonstrate the advantages of high-dimensional mediation analysis methods over univariate mediation analysis.
CONCLUSION: Through integrative analysis of multi-omics data, we identified several mediation pathways of physical activity between genetic factors and SPARE-AD. These findings contribute to a better understanding of the pathogenic mechanisms of AD. Moreover, our research demonstrates the potential of the high-dimensional mediation analysis method in revealing the mechanisms of disease.}, }
@article {pmid40128515, year = {2025}, author = {Tian, N and Li, J and Shi, X and Xu, M and Xiao, Q and Tian, Q and Chen, M and Song, W and Du, Y and Dong, Z}, title = {GALM Alleviates Aβ Pathology and Cognitive Deficit Through Increasing ADAM10 Maturation in a Mouse Model of Alzheimer's Disease.}, journal = {Neuroscience bulletin}, volume = {}, number = {}, pages = {}, pmid = {40128515}, issn = {1995-8218}, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, causing dementia and affecting millions of individuals. One prominent characteristic in the brains of AD patients is glucose hypometabolism. In the context of galactose metabolism, intracellular glucose levels are heightened. Galactose mutarotase (GALM) plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion of β-D-galactose into α-D-galactose (α-D-G). The latter is then converted into glucose-6-phosphate, improving glucose metabolism levels. However, the involvement of GALM in AD progression is still unclear. In the present study, we found that the expression of GALM was significantly increased in AD patients and model mice. Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein (APP) and APP-cleaving enzymes including a disintegrin and metalloprotease 10 (ADAM10), β-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PS1). Interestingly, genetic overexpression of GALM reduced APP and Aβ deposition by increasing the maturation of ADAM10, although it did not alter the expression of BACE1 and PS1. Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory in AD model mice. Importantly, direct α-D-G (20 mg/kg, i.p.) also inhibited Aβ deposition by increasing the maturation of ADAM10, thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, our results indicate that GALM shifts APP processing towards α-cleavage, preventing Aβ generation by increasing the level of mature ADAM10. These findings indicate that GALM may be a potential therapeutic target for AD, and α-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD.}, }
@article {pmid40128501, year = {2025}, author = {Sabat, SR and Warren, A}, title = {Death in advance or people living with dementia? Extending the philosophical discourse of Schweda and Jongsma through the persistence of self and other strengths.}, journal = {History and philosophy of the life sciences}, volume = {47}, number = {2}, pages = {21}, pmid = {40128501}, issn = {1742-6316}, mesh = {Humans ; *Dementia/psychology ; Philosophy ; Death ; }, abstract = {This article presents an extension of an article previously featured in History and Philosophy of the Life Sciences by Schweda and Jongsma (History and Philosophy of the Life Sciences, 2022), who aptly (1) critiqued the "Zombification" of people living with dementia by reviewing the historic and philosophic origins of this damaging metaphor and (2) offered a life course perspective to highlight the ethical implications related to biomedicine and the life sciences. Herein, we aim to build upon and constructively critique the important discourse offered by Schweda and Jongsma by (1) presenting a transdisciplinary perspective highlighting many important remaining social and cognitive abilities of people living with dementia that (2) further informs philosophical discussion and (3) provides ways of helping people diagnosed as well as formal and informal caregivers to live with dementia rather than enduring the damaging and incorrect "living death" notion, and its ramifications, of the syndrome. In the process, we will explore many inherent harms associated with the "zombie-like" construction of the syndrome: harms that entail dysfunctional treatment of people living with dementia. Specifically, we will draw upon evidence from psychology, sociology, philosophy, neurology, and neuroscience, to provide an integrated, whole-person perspective that adds specific dimensions to the life-course perspective and support the necessary multifaceted interdisciplinary and transdisciplinary research and clinical collaborations for this complex issue.}, }
@article {pmid40127855, year = {2025}, author = {Liu, TT and Yang, X and Lei, HP and Hu, YT and Wu, LN and Wei, AH and Ji, XH and Liu, J and Jin, H and Shi, JS and Zhou, SY and Jin, F}, title = {Gastrodin alleviates Aβ25-35-induced glycolytic dysfunction via activating PI3K/AKT/BACH1 signaling in Alzheimer's disease models.}, journal = {Experimental neurology}, volume = {389}, number = {}, pages = {115225}, doi = {10.1016/j.expneurol.2025.115225}, pmid = {40127855}, issn = {1090-2430}, abstract = {Cerebral glycolytic alteration has been identified as an important contributor to the pathological progress of Alzheimer's disease (AD). Research has shown that gastrodin (GAS) possesses neuroprotection in various experimental models of AD, but its specific mechanism remains unclear. In this study, we determined whether GAS exerted neuroprotective effects on AD models through regulating PI3K/AKT/BACH1 signaling axis. Eight-week-old C57BL/6 J male mice were intracerebroventricularly injected with Aβ25-35, to establish an AD model, followed by the administration of GAS (30, 60 mg·kg[-1]·d[-1], i.g.) for 21 days. Treatment of GAS markedly alleviated the downregulation of p-PI3K Tyr199/458, p-AKT Ser473, BACH1 and HK1 in the hippocampus of the Aβ25-35-induced AD mice. To further explore the mechanism of GAS-mediated neuroprotection, an in vitro AD cellular model was established by challenging HT22 cells with Aβ25-35. In the Aβ25-35 induced cells, the expression of BACH1, p-PI3K Tyr199/458 and p-AKT Ser473 was reduced, the mRNA and protein levels of HK1 were decreased, and the levels of pyruvate and ATP were reduced. After treatment of GAS, the decline of these indicators was reversed. In addition, overexpression of BACH1 by lentivirus transfection significantly upregulated the mRNA and protein levels of HK1, thereby enhancing glycolytic function and protecting HT22 cells from Aβ25-35-induced injury. The results of chromatin immunoprecipitation assay-real-time quantitative PCR revealed that BACH1 directly bound to the HK1 promoter region. Collectively, these findings suggest that GAS can play a protective role in Aβ25-35-induced experimental AD models by increasing HK1 expression and ameliorating glycolytic dysfunction through activation of the PI3K/AKT/BACH1 signaling axis.}, }
@article {pmid40126739, year = {2025}, author = {Arora, P and Swati, and Rani, S and Jha, S and Gupta, S and Kumar, S}, title = {Innovative approaches in acetylcholinesterase inhibition: a pathway to effective Alzheimer's disease treatment.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {40126739}, issn = {1573-501X}, abstract = {Acetylcholinesterase inhibitors (AChEIs) are essential in the treatment of neurodegenerative disorders like Alzheimer's disease, as they prevent the breakdown of acetylcholine, thereby enhancing cognitive function. This review provides a comprehensive analysis of the structural motifs and mechanisms governing AChEI pharmacological activity, with a focus on medicinal chemistry strategies to enhance potency, selectivity, and pharmacokinetic properties. Beginning with the physiological role of acetylcholinesterase in neurological disorders, the review explores the historical evolution of AChEIs and highlights key structural interactions with catalytic, peripheral anionic, and allosteric binding sites. Advances in computational modeling, virtual screening, and structure-based drug design are discussed, alongside emerging approaches, such as multi-target-directed ligands and prodrugs. Additionally, the significance of natural products and drug repurposing in identifying novel AChEI scaffolds is emphasized, contributing to chemical diversity and innovation in drug discovery. By integrating computational tools, expansive chemical libraries, and innovative design strategies, this review identifies promising directions for developing effective AChEIs. These advancements hold great potential in addressing the multifaceted nature of neurodegenerative diseases and improving therapeutic interventions.}, }
@article {pmid40126600, year = {2025}, author = {Alves, SS and Rossi, L and de Oliveira, JAC and Servilha-Menezes, G and Grigorio-de-Sant'Ana, M and Mazzei, RF and Almeida, SS and Sebollela, A and da Silva Junior, RMP and Garcia-Cairasco, N}, title = {Metformin Improves Spatial Memory and Reduces Seizure Severity in a Rat Model of Epilepsy and Alzheimer's Disease comorbidity via PI3K/Akt Signaling Pathway.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40126600}, issn = {1559-1182}, abstract = {Emerging evidence suggests a bidirectional relationship between Alzheimer's disease (AD) and epilepsy. In our previous studies, we identified a partial AD-like phenotype associated with central insulin resistance in the Wistar audiogenic rat (WAR), a genetic model of epilepsy. We also found that intracerebroventricular administration of streptozotocin, a compound used to model diabetes and AD, exacerbates seizure susceptibility. Given the role of insulin signaling in both AD and epilepsy, we hypothesized that metformin (MET), an anti-diabetic drug known for enhancing insulin sensitivity, could be a potential therapeutic agent for both conditions. Our objective was to investigate MET's effects on brain insulin signaling, seizure activity, and AD-like pathology in WARs. Adult male WARs received oral MET (250 mg/kg) for 21 days. Audiogenic seizures were assessed using the Categorized Severity Index and Racine's scale. Spatial memory was tested with the Morris water maze (MWM), followed by Western blot analysis of hippocampal proteins. MET significantly reduced seizure severity and improved MWM performance. Although MET did not affect insulin receptor levels or activation, it increased phosphoinositide 3-kinase (PI3K), activated Akt, and increased glycogen synthase kinase-3α/β (GSK-3α/β) levels. MET also decreased amyloid β precursor protein (AβPP) levels but did not affect Tau phosphorylation. These results suggest that chronic MET treatment alleviates behaviors related to both AD and epilepsy in WARs and modulates insulin signaling independently of insulin receptor activation. Our findings highlight MET's potential as a therapeutic agent for managing comorbid AD and epilepsy, warranting further investigation into its mechanisms of action.}, }
@article {pmid40126150, year = {2025}, author = {Li, B and Li, H and Chen, H and Sui, Y and Zeng, J and Lin, X and Fan, Q and Song, Z}, title = {Utilizing Hyperbaric Oxygen Therapy to Improve Cognitive Function in Patients With Alzheimer's Disease by Activating Autophagy-Related Signaling Pathways.}, journal = {Physiological research}, volume = {74}, number = {1}, pages = {141-147}, pmid = {40126150}, issn = {1802-9973}, mesh = {Animals ; *Alzheimer Disease/therapy/metabolism/genetics/psychology ; *Hyperbaric Oxygenation ; *Autophagy/physiology ; *Mice, Transgenic ; Mice ; *Mice, Inbred C57BL ; *Signal Transduction ; *Cognition/physiology ; Male ; Hippocampus/metabolism/pathology ; Humans ; Disease Models, Animal ; }, abstract = {To investigate the impact of hyperbaric oxygen therapy (HBOT) on the cognitive function of mice with Alzheimer's disease (AD), while also identifying the cellular pathways associated with autophagy involved in the treatment. Twenty-four APP/PSl double transgenic mice were randomly assigned to either Group A or Group B, while another 24 C57 mice were randomly allocated to Group C or Group D. HBOT was administered to mice in Group B and Group D, and the Morris water maze test was used to assess changes in mice behavior. Histological examination using hematoxylin and eosin staining was conducted to observe pathological alterations in the hippocampus of the mice brain tissue. Polymerase chain reaction (PCR) was employed to analyze autophagy-related gene pathways in the hippocampus of the mice. Following HBOT, mice in Group B exhibited a significant reduction in escape latency and a notable increase in residence time within the target quadrant compared with Group A (P<0.05), as well as Group C and Group D (P<0.01). The hippocampal neurons in Group A and Group B mice exhibited disorganized arrangements, characterized by pyknosis and margination. Conversely, neurons in Group C displayed orderly arrangements, retaining intact structures with round nuclei demonstrating clear nuclear staining and normal morphology. The cellular morphology of mice in Group D remained unaffected. PCR analysis revealed no notable disparity in autophagy-related gene expression between Group A and Group C. However, the expression levels of five genes including Tgfb1, Mapk14, Bid, Atg7, and Akt1, were significantly elevated in Group B compared to Group A. HBOT has the potential to improve the cognitive function in mice modeled with AD. This improvement of cognitive function appears to be mediated by the up-regulation of autophagy-related genes, specifically Tgfb1, Mapk14, Bid, Atg7, and Akt1. These results indicate that HBOT may offer a therapeutic strategy for treating AD by enhancing autophagy mechanisms. Key words Alzheimer's disease, Autophagy, Hyperbaric oxygen, Morris water maze, PCR.}, }
@article {pmid40125338, year = {2025}, author = {Funayama, M and Kurose, S and Takata, T and Sato, H and Izawa, N and Isozumi, K and Abe, Y}, title = {Identifying reversible psychiatric dementia mimics in new memory clinic outpatients.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251329804}, pmid = {40125338}, issn = {2542-4823}, abstract = {BACKGROUND: Timely identification of reversible conditions that mimic dementia is critical in memory clinic practice. However, psychiatric conditions as potential dementia mimics have not been studied as thoroughly as neurological ones, and detailed data on their reversibility remain limited.
OBJECTIVE: To identify reversible psychiatric dementia mimics.
METHODS: A retrospective chart review was conducted on 749 new outpatients to investigate etiologies, progression rates, a neuropsychological assessment, cognitive and functional levels, and potential reversibility, categorized by psychiatric and neurological conditions. Cases showing cognitive reversibility following treatment were also identified. Comparisons were made based on the presence or absence of potential reversibility, as well as actual reversibility.
RESULTS: Among the 749 individuals, 121 (16.2%) had potentially reversible conditions: 75 psychiatric and 46 neurological. Psychiatric conditions included depression, schizophrenia and delusional disorders, developmental disorders, alcohol use disorder, and dissociative and anxiety disorders. Compared to individuals without potentially reversible conditions, individuals with psychiatric conditions were younger, had a faster progression rate, and demonstrated higher cognitive function. Of the individuals who had mild cognitive impairment or dementia mimic, 6 (0.9%) showed complete cognitive resolution (3 cases) or partial cognitive improvement (3 cases). These 6 cases included two individuals with psychiatric conditions manifesting psychotic features.
CONCLUSIONS: While rare, reversible psychiatric dementia mimics highlight the importance of comprehensive evaluations in memory clinics, particularly for younger individuals experiencing rapid cognitive decline. The infrequency of reversibility may reflect a strong association between these potentially reversible conditions and dementia risk factors, or their role as prodromes of dementia itself.}, }
@article {pmid40125336, year = {2025}, author = {Shi, W and Lu, J and Wei, P and Ning, P and Fan, J and Huang, S and Guo, X and Li, R}, title = {The effects of coagulation factors on the risk of Alzheimer's disease: A Mendelian randomization study.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251327674}, pmid = {40125336}, issn = {2542-4823}, abstract = {BACKGROUND: Observational studies indicate a complex relationship between coagulation factors and Alzheimer's disease (AD). However, the current findings are inconsistent, and it remains uncertain whether a causal relationship exists.
OBJECTIVE: This study utilizes a Mendelian randomization analysis to investigate the causal relationships between blood levels of coagulation factors and AD risk.
METHODS: Eleven coagulation factors with valid instrumental variables available were evaluated. Two independent cohorts of European ancestry with AD genome-wide association study (GWAS) summary statistics were used: UK Biobank (UKB, N = 472,868) and the International Genomics of Alzheimer's Project (IGAP, N = 63,926). We primarily conducted Mendelian randomization (MR) analyses using the Inverse variance weighted (IVW). Meanwhile, the MR-Egger intercept test is used to detect horizontal pleiotropy, the Residual Sum of Squares observed (RSSobs) is used to assess the model's goodness of fit, and the leave-one-out analysis is employed for sensitivity analysis.
RESULTS: Using IVW analysis, the UKB database shows positive correlations of Protein C (PC, p = 0.002), Activated Partial Thromboplastin Time (aPTT, p = 0.019), and coagulation factor X (FX, p = 0.032) with AD, and a negative association for coagulation factor XI (FXI, p = 0.021). The IGAP database mirrors these findings for PC and FXI but not for the others. Leave-one-out analysis showed an anomaly after a single single nucleotide polymorphism (SNP) driving, yet the overall results remained stable.
CONCLUSIONS: This study demonstrates that elevated levels of PC, FX, and aPTT, along with reduced levels of FXI, are causally associated with an increased risk of AD. These findings might pave the way for the diagnosis and treatment of AD.}, }
@article {pmid40125270, year = {2025}, author = {Qian, Y and Liu, C and Zeng, X and Li, LC}, title = {RNAa: Mechanisms, therapeutic potential, and clinical progress.}, journal = {Molecular therapy. Nucleic acids}, volume = {36}, number = {2}, pages = {102494}, pmid = {40125270}, issn = {2162-2531}, abstract = {RNA activation (RNAa), a gene regulatory mechanism mediated by small activating RNAs (saRNAs) and microRNAs (miRNAs), has significant implications for therapeutic applications. Unlike small interfering RNA (siRNA), which is known for gene silencing in RNA interference (RNAi), synthetic saRNAs can stably upregulate target gene expression at the transcriptional level through the assembly of the RNA-induced transcriptional activation (RITA) complex. Moreover, the dual functionality of endogenous miRNAs in RNAa (hereafter referred to as mi-RNAa) reveals their complex role in cellular processes and disease pathology. Emerging studies suggest saRNAs' potential as a novel therapeutic modality for diseases such as metabolic disorders, hearing loss, tumors, and Alzheimer's. Notably, MTL-CEBPA, the first saRNA drug candidate, shows promise in hepatocellular carcinoma treatment, while RAG-01 is being explored for non-muscle-invasive bladder cancer, highlighting clinical advancements in RNAa. This review synthesizes our current understanding of the mechanisms of RNAa and highlights recent advancements in the study of mi-RNAa and the therapeutic development of saRNAs.}, }
@article {pmid40124420, year = {2025}, author = {Mehmood, T and Nasir, Q and Younis, I and Muanprasat, C}, title = {Inhibition of Mitochondrial Dynamics by Mitochondrial Division Inhibitor-1 Suppresses Cell Migration and Metastatic Markers in Colorectal Cancer HCT116 Cells.}, journal = {Journal of experimental pharmacology}, volume = {17}, number = {}, pages = {143-157}, pmid = {40124420}, issn = {1179-1454}, abstract = {INTRODUCTION: The mitochondria are highly dynamic organelles. The mitochondrial morphology and spatial distribution within the cell is determined by fusion and fission processes of mitochondria. Several studies have used mitochondrial division inhibitor-1 (Mdivi.1) to explore the roles of mitochondrial dynamics in various pathological conditions, including diabetic cardiomyopathy, myocardial infarction, cardiac hypertrophy, Alzheimer's disease, Huntington's disease and cancers.
PURPOSE: The objective of the study was to investigate the role of mitochondrial dynamics in the invasiveness of HCT116 colorectal cancer cells.
MATERIAL AND METHODS: MTT assay was used to determine the Mdivi.1-induced toxicity in HCT116 cells. Wound healing, cell migration and colony forming assays were adopted to measure the migration and invasion activity of HCT116 cells. Furthermore, flow cytometry was used to determine the Mdivi.1-induced mitochondrial mass quantification, mitochondrial membrane potential and reactive oxygen species generation in HCT116 cells. Additionally, Western Blot analysis was used to determine the expression level of Drp1, p-Drp1, Mnf2, AMPK-α, p-AMPK-α, Cox-2, iNos and MMP9 in HCT116 cells.
RESULTS: We found that Mdivi.1 induced toxicity and altered the morphology of HCT116 cells in concentration- and time-dependent manners. Mdivi.1 significantly increased mitochondrial mass and dissipated the mitochondrial membrane potential. Furthermore, Mdivi.1 induced reactive oxygen species (ROS) generation and mitochondrial superoxide production, leading to AMPK activation. Moreover, Mdivi.1 decreased dynamin-related protein-1 (Drp1) and phosphorylated-Drp1 expression and increased mitofusin-2 (Mfn2) expression in a concentration-dependent manner at 48 and 72 h post-treatment. Notably, Mdivi.1 induced inhibition of translocation of Drp1 from the cytosol to the outer mitochondrial membrane. Mdivi.1 significantly suppressed the invasion and migration of HCT116 cells and inhibited the formation of HCT116 cell colonies. In addition, Mdivi.1 significantly decreased the expression of metastatic markers including Cox-2, iNos, and MMP-9 in HCT116 cells.
CONCLUSION: Collectively, this study revealed that Mdivi.1 downregulates Drp1, upregulates Mfn2, and increases mitochondrial mass with attenuated oxidative metabolism, leading to the inhibition of cell invasion and metastasis in colorectal cancer HCT116 cells. Mitochondrial dynamics are regarded as possible drug targets for interrupting colorectal cancer cell migration and metastasis.}, }
@article {pmid40124351, year = {2025}, author = {Riahi, F and Fesharaki, S}, title = {The role of nuclear medicine in neurodegenerative diseases: a narrative review.}, journal = {American journal of neurodegenerative disease}, volume = {14}, number = {1}, pages = {34-41}, pmid = {40124351}, issn = {2165-591X}, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Lewy body dementia, are associated with the accumulation of brain proteins, leading to neuroinflammation, disruption of cellular clearance mechanisms, and neuronal death. Nuclear medicine, utilizing technologies like PET and SPECT, plays a crucial role in diagnosing and managing these disorders. Recent advancements in nuclear medicine have enhanced the understanding of disease pathophysiology and facilitated the development of tailored therapeutics. This study aims to address gaps in understanding nuclear medicine's potential to improve early diagnosis, monitor disease progression, and evaluate therapeutic effectiveness. In this review, we analyzed 28 papers and summarized their findings. PET radioligands have revolutionized the in vivo measurement of pathological targets in neurological diseases, offering new insights into the pathophysiology of neurodegenerative conditions. Amyloid PET has emerged as a reliable diagnostic imaging tool, accurately identifying cerebral amyloid-beta accumulation and enabling early differential diagnosis in clinical settings. Furthermore, radiopharmaceuticals such as [18F]Flortaucipir, [18F]FDOPA, and TSPO ligands provide significant advancements in the diagnosis and treatment of neurodegenerative disorders.}, }
@article {pmid40124279, year = {2025}, author = {Jiang, GH and Li, HY and Xie, LJ and Fan, JY and Li, SY and Yu, WQ and Xu, YT and He, ML and Jiang, Y and Bai, X and Zhou, J and Wang, X}, title = {Intestinal flora was associated with occurrence risk of chronic non-communicable diseases.}, journal = {World journal of gastroenterology}, volume = {31}, number = {11}, pages = {103507}, pmid = {40124279}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Noncommunicable Diseases/epidemiology ; Chronic Disease ; Risk Factors ; Bifidobacterium/isolation & purification ; Ruminococcus/isolation & purification ; Mendelian Randomization Analysis ; Aging ; }, abstract = {BACKGROUND: The intestinal flora (IF) has been linked to risks of non-communicable diseases, especially various cancers, stroke, and Alzheimer's disease. However, many uncertainties of these associations during different stages of growth, development, and aging still exist. Therefore, further in-depth explorations are warranted.
AIM: To explore the associations of the human IF with disease risks during different stages of growth, development, and aging to achieve more accurate and convincing conclusions.
METHODS: Cohort, cross-sectional, case-control, and Mendelian randomization studies published in the PubMed and Web of Science databases until December 31, 2023 were systematically reviewed to clarify the associations of the IF at the genus level with the risks of various non-communicable diseases, which were grouped in accordance with the 10[th] revision of the International Classification of Diseases.
RESULTS: In total, 57 studies were included to quantitatively examine the influence of the IF on the risks of 30 non-communicable diseases during different stages of growth, development, and aging. Population studies and Mendelian randomization studies confirmed positive associations of the abundances of Bifidobacterium and Ruminococcus with multiple sclerosis.
CONCLUSION: These findings contribute to a deeper understanding of the roles of the IF and provide novel evidence for effective strategies for the prevention and treatment of non-communicable diseases. In the future, it will be necessary to explore a greater variety of research techniques to uncover the specific mechanisms by which gut microbiota trigger diseases and conduct in-depth studies on the temporal relationship between microbiota alterations and diseases, so as to clarify the causal relationship more accurately.}, }
@article {pmid40124046, year = {2025}, author = {Abdullah, N and Hussain, F and Ullah, N and Fatima, H and Tahir, MA and Rashid, U and Hassan, A}, title = {Synthesis, Pharmacological Evaluation, and Molecular Modeling of Phthalimide Derivatives as Monoamine Oxidase and Cholinesterase Dual Inhibitors.}, journal = {ACS omega}, volume = {10}, number = {10}, pages = {10385-10400}, pmid = {40124046}, issn = {2470-1343}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and cognitive decline, associated with synaptic loss and degeneration of cholinergic neurons. New multitarget inhibitors for monoamine oxidase (MAO) and cholinesterase (ChE) enzymes are emerging as a potential treatment strategy for AD. Herein, we synthesized a series of N-benzyl-substituted biaryl phthalimide derivatives (3a-3m) encompassing potentially therapeutically active arenes/heteroarenes to serve as multitarget compounds for treating AD. To improve their binding affinity as well as inhibitory activity against ChE and MAO target proteins, comparable molecular structures were synthesized bearing electron-donating, electron-withdrawing, heterocyclic, and fluorinated moieties for a comprehensive SAR. In vitro evaluation of synthesized compounds against cholinesterases (AChE/BChE) and monoamine oxidases (MAO-A/MAO-B) revealed that compound 3e had good potency against AChE (IC50 = 0.24 μM) and BChE (IC50 = 6.29 μM), while compound 3f had the highest inhibition of MAO-B (IC50 = 0.09 μM). Selected compounds (3e,f) showed no cytotoxicity against the neuroblastoma cell line (SH-SY5Y) and normal human embryonic HEK-293 cells. Moreover, they showed high blood-brain barrier penetration (PAMPA assay) and reversible MAO-B inhibitory activity (ex vivo). In molecular docking studies, compounds 3e and 3f displayed the highest binding affinity with ChEs and MAO-B, respectively. In silico ADMET studies and MD simulation studies were also carried out for the most potent derivatives (3e and 3f), suggesting their strong potential as anti-Alzheimer agents.}, }
@article {pmid40123238, year = {2025}, author = {Shi, X and Zheng, WA and Hou, XL and Chen, Y and Chen, HF and Yao, WN and Lv, TY and Bai, F}, title = {Differential effects of 2 and 4 weeks repetitive transcranial magnetic stimulation inducing neuroplasticity on cognitive improvement.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251320124}, doi = {10.1177/13872877251320124}, pmid = {40123238}, issn = {1875-8908}, abstract = {BackgroundRepetitive transcranial magnetic stimulation (rTMS) is an efficient intervention for alleviating cognitive symptoms in Alzheimer's disease (AD), but the optimal treatment duration for high efficacy remains unclear.ObjectiveThis study investigates the effects of 2-week and 4-week rTMS on neural network plasticity and cognitive improvement, aiming to identify the optimal treatment duration for cognitive impairment.MethodsrTMS was administered to cognitively impaired patients over 2-week and 4-week periods, exploring its effects on cognitive improvement and induced neural circuits. The study also examines the predictive value of these neural circuits for individual treatment responses.ResultsThe 4-week rTMS treatment significantly outperformed the 2-week course in improving cognitive function. Neural activity analysis identified the precuneus as a key region for episodic memory. Changes in brain regions, particularly within the default mode network (DMN), visual network (VN), and motor network (MN), were associated with cognitive improvements. Baseline functional connectivity in these regions predicted changes in general cognition (r = 0.724, p < 0.001) and episodic memory (r = 0.447, p = 0.022) after rTMS.ConclusionsExtended rTMS treatment enhances cognitive performance in cognitive impairment patients, with the 4-week course showing superior effects. Reduced connectivity in the DMN following rTMS was linked to cognitive improvements. The neural network baseline can predict patients' treatment responses.}, }
@article {pmid40122980, year = {2025}, author = {Claus, JJ and Vom Hofe, I and van Ijlzinga Veenstra, A and Licher, S and Seelaar, H and de Jong, FJ and Neitzel, J and Vernooij, MW and Ikram, MA and Wolters, FJ}, title = {Generalizability of trial criteria on amyloid-lowering therapy against Alzheimer's disease to individuals with mild cognitive impairment or early Alzheimer's disease in the general population.}, journal = {European journal of epidemiology}, volume = {}, number = {}, pages = {}, pmid = {40122980}, issn = {1573-7284}, support = {Veni-09150162010108 and BIRD-NL-10510032120005/ZONMW_/ZonMw/Netherlands ; #10510032120003/ZONMW_/ZonMw/Netherlands ; CVON2018-28//Hartstichting/ ; AARF-22-924982/ALZ/Alzheimer's Association/United States ; }, abstract = {Treatment with anti-amyloid-β monoclonal antibodies slowed cognitive decline in recent RCTs in patients with mild cognitive impairment (MCI) and early dementia due to Alzheimer's disease (AD). However, stringent trial eligibility criteria may affect generalisability to clinical practice. We extracted eligibility criteria for trials of aducanumab, lecanemab and donanemab, and applied these to participants with MCI and early clinical AD dementia from the population-based Rotterdam Study. Participants underwent questionnaires, genotyping, brain-MRI, cognitive testing, and cardiovascular assessment. We determined amyloid status using a validated prediction model based on age and APOE-genotype. Of 968 participants (mean age: 75 years, 56% women), 779 had MCI and 189 dementia. Across trials, around 40% of participants would be ineligible because of predicted amyloid negativity. At least one clinical exclusion criterion was present in 76.3% of participants for aducanumab, 75.8% for lecanemab, and 59.8% for donanemab. Common criteria were cardiovascular disease (35.2%), anticoagulant (31.2%), psychotropic or immunological medication use (20.4%), anxiety or depression (15.9%), or lack of social support (15.6%). One-third were ineligible based on brain-MRI findings alone, similar across trials and predominantly due to cerebral small-vessel disease. Combining amyloid, clinical, and imaging criteria, eligibility ranged from 9% (95% CI:7.0-11.1) for aducanumab, 8% (6.2-9.9) lecanemab to 15% (12.4-17.5) for donanemab. Findings from recent RCTs reporting protective effects of monoclonal antibodies against amyloid-β are applicable to less than 15% of community-dwelling individuals with MCI or early AD. These findings underline that evidence for drug efficacy and safety is lacking for the vast majority of patients with MCI/AD in routine clinical practice.}, }
@article {pmid40122399, year = {2025}, author = {Afrin, MR and Upadhyaya, PG and Hashim, A and Bhattacharya, K and Chanu, NR and Das, D and Khanal, P and Deka, S}, title = {Advanced biomarkers: Beyond amyloid and tau: Emerging non-traditional biomarkers for alzheimer`s diagnosis and progression.}, journal = {Ageing research reviews}, volume = {108}, number = {}, pages = {102736}, doi = {10.1016/j.arr.2025.102736}, pmid = {40122399}, issn = {1872-9649}, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder that leads to progressive cognitive decline and imposes a significant socio-economic burden. Traditional diagnostic methods, primarily based on amyloid-beta (Aβ) and tau biomarkers, often identify the disease at late stages, highlighting the need for more sensitive and accessible early detection tools. This review explores emerging non-traditional biomarkers, including salivary, lipid, urinary, synaptic, blood-based, microRNA (miRNA), cerebrospinal fluid (CSF), fecal, and inflammatory markers, which provide deeper insights into AD pathophysiology. These biomarkers reflect key pathological processes such as neuroinflammation, mitochondrial dysfunction, oxidative stress, synaptic damage, lipid dysregulation, and genetic factors. Non-invasive biomarkers, such as those found in saliva and urine, present promising avenues for large-scale screening, while advanced blood-based markers like neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) offer precise monitoring of neurodegeneration and inflammation. Additionally, miRNAs and lipid biomarkers shed light on molecular alterations in neuronal health and signaling. Integrating these biomarkers with imaging techniques, proteomics, and genetic profiling enhances diagnostic accuracy and enables personalized treatment approaches. This shift toward multi-dimensional biomarker assessment not only improves early detection but also aids in tailoring therapeutic strategies to individual disease profiles. By reviewing recent advancements, this article highlights the transformative potential of emerging biomarkers in overcoming the limitations of conventional diagnostics. Standardization and validation across diverse populations will be crucial in expanding their clinical applicability, ultimately improving disease management, reducing societal burden, and enhancing the quality of life for individuals affected by AD.}, }
@article {pmid40122398, year = {2025}, author = {Skawratananond, S and Xiong, DX and Zhang, C and Tonk, S and Pinili, A and Delacruz, B and Pham, P and Smith, SC and Navab, R and Reddy, PH}, title = {Mitophagy in Alzheimer's disease and other metabolic disorders: A focus on mitochondrial-targeted therapeutics.}, journal = {Ageing research reviews}, volume = {108}, number = {}, pages = {102732}, doi = {10.1016/j.arr.2025.102732}, pmid = {40122398}, issn = {1872-9649}, abstract = {Mitochondria, as central regulators of cellular processes such as energy production, apoptosis, and metabolic homeostasis, are essential to cellular function and health. The maintenance of mitochondrial integrity, especially through mitophagy-the selective removal of impaired mitochondria-is crucial for cellular homeostasis. Dysregulation of mitochondrial function, dynamics, and biogenesis is linked to neurodegenerative and metabolic diseases, notably Alzheimer's disease (AD), which is increasingly recognized as a metabolic disorder due to its shared pathophysiologic features: insulin resistance, oxidative stress, and chronic inflammation. In this review, we highlight recent advancements in pharmacological interventions, focusing on agents that modulate mitophagy, mitochondrial uncouplers that reduce oxidative phosphorylation, compounds that directly scavenge reactive oxygen species to alleviate oxidative stress, and molecules that ameliorate amyloid beta plaque accumulation and phosphorylated tau pathology. Additionally, we explore dietary and lifestyle interventions-MIND and ketogenic diets, caloric restriction, physical activity, hormone modulation, and stress management-that complement pharmacological approaches and support mitochondrial health. Our review underscores mitochondria's central role in the pathogenesis and potential treatment of neurodegenerative and metabolic diseases, particularly AD. By advocating for an integrated therapeutic model that combines pharmacological and lifestyle interventions, we propose a comprehensive approach aimed at mitigating mitochondrial dysfunction and improving clinical outcomes in these complex, interrelated diseases.}, }
@article {pmid40122152, year = {2025}, author = {Yang, R and Deng, MY and Yang, LK and Wang, GZ and Ma, J and Wen, Q and Gao, N and Qiao, HL}, title = {Identification of Cytochrome P450 2E1 as a Novel Target in Neuroinflammation and Development of Its Inhibitor Q11 as a Treatment Strategy.}, journal = {Free radical biology & medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.freeradbiomed.2025.03.032}, pmid = {40122152}, issn = {1873-4596}, abstract = {Neuroinflammation is implicated in nearly all pathological processes of central nervous system (CNS) diseases. However, no medications specifically targeting neuroinflammation are clinically available, and conventional anti-inflammatory drugs exhibit limited efficacy. Here, we identified cytochrome P450 2E1 (CYP2E1) as a novel therapeutic target in neuroinflammation. Elevated CYP2E1 levels were observed in hippocampal tissues of mouse and rat neuroinflammation models, as well as in LPS-stimulated primary microglia. Genetic ablation of Cyp2e1 improved spatial learning and memory in neuroinflammatory rats and reduced pro-inflammatory cytokine levels in Cyp2e1-deficient microglia. Furthermore, Q11 (1-(4-methyl-5-thiazolyl) ethenone), a novel CYP2E1 inhibitor developed and synthesized in our laboratory, effectively ameliorated Alzheimer's disease-related spatial learning and memory functions and depression-related anxiety-like behaviors in mice/rats. Mechanistically, Q11 attenuated microglial activation, neuronal damage, oxidative stress, and neuroinflammation by suppressing the PI3K/Akt, STAT1/3, and NF-κB signaling pathways. These findings establish CYP2E1 as a druggable target for neuroinflammation and propose Q11 as a promising candidate for treating neuroinflammation-related diseases.}, }
@article {pmid40121956, year = {2025}, author = {Ji, D and Zhang, J and Liang, J and Huang, ZS and Shu, B and Li, D}, title = {Efficient strategy for alleviating neuronal apoptosis and oxidative stress damage of Alzheimer's disease through dual targeting BCL-2 gene promoter i-motif and β-amyloid.}, journal = {Redox biology}, volume = {82}, number = {}, pages = {103600}, doi = {10.1016/j.redox.2025.103600}, pmid = {40121956}, issn = {2213-2317}, abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by abnormal metabolism of β-amyloid (Aβ) precursor proteins and neuronal apoptosis, ultimately leading to cognitive dysfunction. The pathogenesis of AD is complex, and current single-target therapies are not effective in preventing the rapid progression of AD, which highlights the urgent need for developing multi-target drugs. In this study, a series of compounds were synthesized through a multi-targeting ligand strategy. After extensive screening and evaluation, we found a lead compound B14, which showed excellent dual targeting ability for effectively alleviating neuronal apoptosis and oxidative stress damage of AD. In our molecular and cellular level experiments, B14 could target and stabilize the i-motif structure formed on the BCL-2 promoter to upregulate BCL-2 expression, which could also bind to Aβ and inhibit its deposition. In the Aβ1-42-induced cell model, B14 could maintain mitochondrial function and number, regulate intracellular reactive oxygen species (ROS) and Ca[2+] metabolism disorders, and effectively reduce Aβ1-42-induced apoptosis. Further studies showed that B14 also exhibited good ability to cross the blood-brain barrier (BBB), which significantly improved learning memory and cognitive deficits, reduced brain Aβ plaques, alleviated inflammation and restored oxidative stress markers in APP/PS1 mice. Our findings provide an innovative strategy of dual targeting BCL-2 promoter i-motif for transcriptional regulation and Aβ aggregation synergistically for mitigating AD pathologies. B14 represents a promising multi-target lead compound with a good potential for further development for AD treatment.}, }
@article {pmid40120712, year = {2025}, author = {Galal, A and Moustafa, A and Salama, M}, title = {Transforming neurodegenerative disorder care with machine learning: Strategies and applications.}, journal = {Neuroscience}, volume = {573}, number = {}, pages = {272-285}, doi = {10.1016/j.neuroscience.2025.03.036}, pmid = {40120712}, issn = {1873-7544}, abstract = {Neurodegenerative diseases (NDs), characterized by progressive neuronal degeneration and manifesting in diverse forms such as memory loss and movement disorders, pose significant challenges due to their complex molecular mechanisms and heterogeneous patient presentations. Diagnosis often relies heavily on clinical assessments and neuroimaging, with definitive confirmation frequently requiring post-mortem autopsy. However, the emergence of Artificial Intelligence (AI) and Machine Learning (ML) offers a transformative potential. These technologies can enable the development of non-invasive tools for early diagnosis, biomarker identification, personalized treatment strategies, patient subtyping and stratification, and disease risk prediction. This review aims to provide a starting point for researchers, both with and without clinical backgrounds, who are interested in applying ML to NDs. We will discuss available data resources for key diseases like Alzheimer's and Parkinson's, explore how ML can revolutionize neurodegenerative care, and emphasize the importance of integrating multiple high-dimensional data sources to gain deeper insights and inform effective therapeutic strategies.}, }
@article {pmid40120708, year = {2025}, author = {Jain, S and Murmu, A and Chauhan, A}, title = {Advancing Alzheimer's disease therapy through engineered exosomal Macromolecules.}, journal = {Brain research}, volume = {1855}, number = {}, pages = {149590}, doi = {10.1016/j.brainres.2025.149590}, pmid = {40120708}, issn = {1872-6240}, mesh = {*Alzheimer Disease/therapy/drug therapy/metabolism/diagnosis ; Humans ; *Exosomes/metabolism ; Animals ; *Drug Delivery Systems/methods ; }, abstract = {Exosomes are a subject of continuous investigation due to their function as extracellular vesicles (EVs) that significantly contribute to the pathophysiology of certain neurodegenerative disorders (NDD), including Alzheimer's disease (AD). Exosomes have shown the potential to carry both therapeutic and pathogenic materials; hence, researchers have used exosomes for medication delivery applications. Exosomes have reduced immunogenicity when used as natural drug delivery vehicles. This guarantees the efficient delivery of the medication without causing significant side reactions. Exosomes have lately enabled the potential for drug delivery in AD, along with promising future therapeutic uses for the detection of neurodegenerative disorders. Furthermore, exosomes have been examined for their prospective use in illness diagnosis and prediction before the manifestation of symptoms. This review will document prior studies and will concentrate on the rationale behind the substantial potential of exosomes in the treatment of AD and their prospective use as a diagnostic and predictive tool for this condition.}, }
@article {pmid40120689, year = {2025}, author = {Moosavi, SG and Rahiman, N and Jaafari, MR and Arabi, L}, title = {Lipid nanoparticle (LNP) mediated mRNA delivery in neurodegenerative diseases.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {381}, number = {}, pages = {113641}, doi = {10.1016/j.jconrel.2025.113641}, pmid = {40120689}, issn = {1873-4995}, abstract = {Neurodegenerative diseases (NDD) are characterized by the progressive loss of neurons and the impairment of cellular functions. Messenger RNA (mRNA) has emerged as a promising therapy for treating NDD, as it can encode missing or dysfunctional proteins and anti-inflammatory cytokines or neuroprotective proteins to halt the progression of these diseases. However, effective mRNA delivery to the central nervous system (CNS) remains a significant challenge due to the limited penetration of the blood-brain barrier (BBB). Lipid nanoparticles (LNPs) offer an efficient solution by encapsulating and protecting mRNA, facilitating transfection and intracellular delivery. This review discusses the pathophysiological mechanisms of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), Huntington's disease (HD), ischemic stroke, spinal cord injury, and Friedreich's ataxia. Additionally, it explores the potential of LNP-mediated mRNA delivery as a therapeutic strategy for these diseases. Various approaches to overcoming BBB-related challenges and enhancing the delivery and efficacy of mRNA-LNPs are discussed, including non-invasive methods with strong potential for clinical translation. With advancements in artificial intelligence (AI)-guided mRNA and LNP design, targeted delivery, gene editing, and CAR-T cell therapy, mRNA-LNPs could significantly transform the treatment landscape for NDD, paving the way for future clinical applications.}, }
@article {pmid40120616, year = {2025}, author = {Bateman, RJ and Li, Y and McDade, EM and Llibre-Guerra, JJ and Clifford, DB and Atri, A and Mills, SL and Santacruz, AM and Wang, G and Supnet, C and Benzinger, TLS and Gordon, BA and Ibanez, L and Klein, G and Baudler, M and Doody, RS and Delmar, P and Kerchner, GA and Bittner, T and Wojtowicz, J and Bonni, A and Fontoura, P and Hofmann, C and Kulic, L and Hassenstab, J and Aschenbrenner, AJ and Perrin, RJ and Cruchaga, C and Renton, AE and Xiong, C and Goate, AA and Morris, JC and Holtzman, DM and Snider, BJ and Mummery, C and Brooks, WS and Wallon, D and Berman, SB and Roberson, E and Masters, CL and Galasko, DR and Jayadev, S and Sanchez-Valle, R and Pariente, J and Kinsella, J and van Dyck, CH and Gauthier, S and Hsiung, GR and Masellis, M and Dubois, B and Honig, LS and Jack, CR and Daniels, A and Aguillón, D and Allegri, R and Chhatwal, J and Day, G and Fox, NC and Huey, E and Ikeuchi, T and Jucker, M and Lee, JH and Levey, AI and Levin, J and Lopera, F and Roh, J and Rosa-Neto, P and Schofield, PR and , }, title = {Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer's disease: an open-label extension of the phase 2/3 multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU trial.}, journal = {The Lancet. Neurology}, volume = {24}, number = {4}, pages = {316-330}, doi = {10.1016/S1474-4422(25)00024-9}, pmid = {40120616}, issn = {1474-4465}, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology/administration & dosage ; Double-Blind Method ; Male ; Female ; *Alzheimer Disease/drug therapy/genetics ; Middle Aged ; Treatment Outcome ; Adult ; Aged ; }, abstract = {BACKGROUND: Amyloid plaque removal by monoclonal antibody therapies slows clinical progression in symptomatic Alzheimer's disease; however, the potential for delaying the onset of clinical symptoms in asymptomatic people is unknown. The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) is an ongoing platform trial assessing the safety and efficacy of multiple investigational products in participants with dominantly inherited Alzheimer's disease (DIAD). Based on findings of amyloid removal and downstream biological effects from the gantenerumab group of the platform trial, we continued a 3-year open-label extension (OLE) study to assess the safety and efficacy of long-term treatment with high doses of gantenerumab.
METHODS: The randomised, placebo-controlled, double-blind, phase 2/3 multi-arm trial (DIAN-TU-001) assessed solanezumab or gantenerumab versus placebo in participants who were between 15 years before and 10 years after their estimated years to symptom onset and who had a Clinical Dementia Rating (CDR) global score of 0 (cognitively normal) to 1 (mild dementia). This study was followed by an OLE study of gantenerumab treatment, conducted at 18 study sites in Australia, Canada, France, Ireland, Puerto Rico, Spain, the UK, and the USA. For inclusion in the OLE, participants at risk for DIAD had participated in the double-blind period of DIAN-TU-001 and were required to know their mutation status. We investigated increasing doses of subcutaneous gantenerumab up to 1500 mg every 2 weeks. Due to the lack of a regulatory path for gantenerumab, the study was stopped early after a prespecified interim analysis (when most participants had completed 2 years of treatment) of the clinical measure CDR-Sum of Boxes (CDR-SB). The primary outcome for the final analysis was the amyloid plaque measure [11]C-Pittsburgh compound-B positron emission tomography (PiB-PET) standardised uptake value ratio (SUVR [PiB-PET SUVR]) at 3 years, assessed in the modified intention-to-treat group (mITT; defined as participants who received any gantenerumab treatment post-OLE baseline, had at least one PiB-PET SUVR assessment before gantenerumab treatment, and a post-baseline assessment). All participants who received at least one dose of study drug in the OLE were included in the safety analysis. DIAN-TU-001 (NCT01760005) and the OLE (NCT06424236) are registered with ClinicalTrials.gov.
FINDINGS: Of 74 participants who were recruited into the OLE study between June 3, 2020, and April 22, 2021, 73 were enrolled and received gantenerumab treatment. 47 (64%) stopped dosing due to early termination of the study by the sponsor, and 13 (18%) prematurely discontinued the study for other reasons; 13 people completed 3 years of treatment. The mITT group for the primary analysis comprised 55 participants. At the interim analysis, the hazard ratio for clinical decline of CDR-SB in asymptomatic mutation carriers was 0·79 (n=53 [95% CI 0·47 to 1·32]) for participants who were treated with gantenerumab in either the double-blind or OLE period (Any Gant), and 0·53 (n=22 [0·27 to 1·03]) for participants who were treated with gantenerumab the longest (Longest Gant). At the final analysis, the adjusted mean change from OLE baseline to year 3 in PiB-PET SUVR was -0·71 SUVR (95% CI -0·88 to -0·53, p<0·0001). Amyloid-related imaging abnormalities occurred in 53% (39 of 73) of participants: 47% (34 of 73) with microhaemorrhages, 30% (22 of 73) with oedema, and 6% (five of 73) were associated with superficial siderosis. No treatment-associated macrohaemorrhages or deaths occurred.
INTERPRETATION: Partial or short-term amyloid removal did not show significant clinical effects. However, long-term full amyloid removal potentially delayed symptom onset and dementia progression. Our conclusions are limited due to the OLE design and use of external controls and need to be confirmed in long-term trials.
FUNDING: National Institute on Aging, Alzheimer's Association, GHR Foundation, and F Hoffmann-La Roche/Genentech.}, }
@article {pmid40120485, year = {2025}, author = {Wang, W and Sun, Y and Cao, R and Luo, W and Beng, S and Zhang, J and Wang, X and Peng, C}, title = {Illustrate the metabolic regulatory effects of Ganoderma Lucidum polysaccharides on cognitive dysfunction in formaldehyde-exposed mouse brain by mass spectrometry imaging.}, journal = {Ecotoxicology and environmental safety}, volume = {294}, number = {}, pages = {118060}, doi = {10.1016/j.ecoenv.2025.118060}, pmid = {40120485}, issn = {1090-2414}, mesh = {Animals ; *Formaldehyde/toxicity ; Mice ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Brain/drug effects/metabolism ; *Reishi/chemistry ; Male ; *Polysaccharides/pharmacology ; }, abstract = {Long-term formaldehyde (FA) exposure causes cognitive dysfunction, often associated with metabolic disorders. While some studies suggest Ganoderma lucidum polysaccharides (GLP) can improve cognitive function, such as Alzheimer's disease. However, the effects of GLP on FA-exposed cognitive dysfunction and the regulation of GLP on brain metabolic disturbances caused by FA remain unclear. In our study, we revealed that GLP significantly reversed FA-exposed spatial cognitive deficits in mice by using Morris Water Maze and Histological analysis. Furthermore, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) found that exposure of FA can caused dysregulated expression of 35 metabolites. Following GLP treatment, there was a significant restoration of the imbalance of choline and acetylcholine, carnitine and acetylcarnitine, and spermidine and spermine, which were all involved in choline metabolism, carnitine metabolism, and polyamine metabolism. Our results suggested that GLP alleviated FA-exposed cognitive dysfunction, likely through modulation of metabolic pathways, providing a potential therapeutic approach for FA-related cognitive dysfunction.}, }
@article {pmid40120042, year = {2025}, author = {Zhong, R and Chernick, D and Hottman, D and Tan, Y and Kim, M and Narayanan, M and Li, L}, title = {The HDL-Mimetic Peptide 4F Mitigates Vascular and Cortical Amyloid Pathology and Associated Neuroinflammation in a Transgenic Mouse Model of Cerebral Amyloid Angiopathy and Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40120042}, issn = {1559-1182}, support = {Cloyd Neuropharmacology Fellowship//University of Minnesota College of Pharmacy/ ; SURRGE award program//University of Minnesota College of Pharmacy/ ; RF1AG058081, RF1AG077772, and R01AG081426//National Institutes of Health/National Institute on Aging (NIH/NIA)/ ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia worldwide. Despite recent advances, more effective and safer treatment options for AD are needed. Cerebral amyloid angiopathy (CAA) is one of the key pathological hallmarks of AD characterized by amyloid-β (Aβ) deposition in the cerebral vasculature and is associated with intracerebral hemorrhage, cerebrovascular dysfunction, and cognitive impairment. CAA is also considered to underlie the main adverse effect of recently FDA-approved anti-Aβ immunotherapies, namely the amyloid-related imaging abnormalities (ARIA). Substantial evidence has shown that elevated levels of high-density lipoprotein (HDL) and its main protein component, APOA-I, are associated with reduced CAA and superior cognitive function. 4F is an APOA-I/HDL-mimetic peptide and its clinical safety and activity have been demonstrated in human trials for cardiovascular diseases. The present study investigates whether treatment with 4F modulates CAA and associated cognitive deficits and neuropathologies in the well-established Tg-SwDI mouse model of CAA/AD. Age/sex-matched Tg-SwDI mice received daily treatments of 4F or vehicle (PBS), respectively, by intraperitoneal injections for 12 weeks. The results showed that 4F treatment reduced overall Aβ plaque deposition and CAA, and attenuated CAA-associated microgliosis, without significantly affecting total levels of Aβ, astrocytosis, and behavioral function. Unbiased transcriptomic analysis revealed a heightened inflammatory state in the brain of SwDI mice and that 4F treatment reversed the overactivation of vascular cells, in particular vascular smooth muscle cells, relieving cerebrovascular inflammation in CAA/AD mice. Our study provides experimental evidence for the therapeutic potential of 4F to mitigate CAA and associated pathologies in AD.}, }
@article {pmid40119889, year = {2025}, author = {Ben Zaken, K and Bouhnik, R and Omer, N and Bloch, N and Samson, AO}, title = {Polyoxometalates bind multiple targets involved in Alzheimer's disease.}, journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry}, volume = {30}, number = {3}, pages = {299-309}, pmid = {40119889}, issn = {1432-1327}, mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *Molecular Docking Simulation ; *Acetylcholinesterase/metabolism/chemistry ; *Amyloid beta-Peptides/metabolism/chemistry ; *Tungsten Compounds/chemistry/metabolism ; *Butyrylcholinesterase/metabolism/chemistry ; Amyloid Precursor Protein Secretases/metabolism/chemistry ; Protein Binding ; alpha-Synuclein/metabolism/chemistry ; Binding Sites ; Aspartic Acid Endopeptidases/metabolism/chemistry ; Presenilin-2/metabolism/chemistry/genetics ; tau Proteins/metabolism/chemistry ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by brain aggregates of amyloid-β (Aβ) plaques and Tau tangles. Despite extensive research, effective therapy for AD remains elusive. Polyoxometalates (POMs), a class of inorganic compounds with diverse chemical structures and properties, are emerging as potential candidates for AD treatment due to their ability to target key molecular players implicated in disease pathogenesis, such as Aβ, acetylcholinesterase (AChE) and butyryl acetylcholinesterase (BChE). Here, we use molecular docking to predict the binding pose and affinities of POMs to 10 top targets associated with AD. First, we validate our method by replicating experimentally known binding of POMs to Aβ (ΔG = - 9.67 kcal/mol), AChE (ΔG = - 9.39 kcal/mol) and BChE (ΔG = - 10.86 kcal/mol). Then, using this method, we show that POM can also bind β-secretase 1 (BACE1, ΔG = - 10.14 kcal/mol), presenilin 1 (PSEN1, ΔG = - 10.65 kcal/mol), presenilin 2 (PSEN2, ΔG = - 7.94 kcal/mol), Amyloid Precursor Protein (APP, ΔG = - 7.26 kcal/mol), Apolipoprotein E (APOE4, ΔG = - 10.05 kcal/mol), Microtubule-Associated Protein Tau (MAPT, ΔG = - 5.28 kcal/mol) depending on phosphorylation, and α-synuclein (SNCA, ΔG = - 7.64 kcal/mol). Through such binding, POMs offer the potential to mitigate APP cleavage, Aβ oligomer neurotoxicity, Aβ aggregation, thereby attenuating disease progression. Overall, our molecular docking study represents a powerful tool in the discovery of POM-based therapeutics for AD, facilitating the development of novel treatments for AD.}, }
@article {pmid40119801, year = {2025}, author = {Wang, M and Li, M and Jiang, Y and Wang, S and Yang, X and Naseem, A and Algradi, AM and Hao, Z and Guan, W and Chen, Q and Zhang, L and Kuang, H and Yang, B and Liu, Y}, title = {Saponins from Astragalus membranaceus (Fisch.) Bge Alleviated Neuronal Ferroptosis in Alzheimer's Disease by Regulating the NOX4/Nrf2 Signaling Pathway.}, journal = {Journal of agricultural and food chemistry}, volume = {73}, number = {13}, pages = {7725-7740}, doi = {10.1021/acs.jafc.4c10497}, pmid = {40119801}, issn = {1520-5118}, mesh = {*Ferroptosis/drug effects ; Animals ; *NF-E2-Related Factor 2/metabolism/genetics ; *Saponins/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; *Astragalus propinquus/chemistry ; *Signal Transduction/drug effects ; Humans ; *Neurons/drug effects/metabolism ; *NADPH Oxidase 4/metabolism/genetics ; Male ; Plant Extracts/pharmacology/chemistry ; Neuroprotective Agents/pharmacology/chemistry ; }, abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disease of the central nervous system caused by loss of neuronal or myelin function, accompanied by ferroptosis. Astragalus membranaceus (Fisch.) Bge. (A. membranaceus) is one of China's homologous lists of medicines and food, and its active component saponins have neuroprotective effects. This study examines the mechanism of saponins from A. membranaceus (AS) in treating AD. UPLC-Q-TOF-MS analyzed the composition of AS. Ferroptosis models were established to evaluate the anti-AD efficacy. As a result, AS treatment inhibited ferroptosis in SAMP8 mice by restoring iron homeostasis and lipid peroxidation (LPO) balance in the brain, thereby improving cognitive impairment and pathological damage. Mechanistically, AS treatment reduced Fe[2+], MDA, and ROS levels and enhanced protein levels of SLC7A11, GPX4, FTH1, and FPN1. NADPH oxidase 4 (NOX4) overexpression revealed that AS treatment inhibited NOX4, thereby reducing NOX4 stability and regulating the NOX4/Nrf2 pathway in erastin-injured HT22 cells and significantly alleviating ferroptosis. Therefore, AS inhibited ferroptosis and improved AD by rebuilding iron homeostasis and LPO balance in the brain. AS has the potential to be a promising candidate medicine for AD.}, }
@article {pmid40119586, year = {2025}, author = {Wang, L and Li, B and Tang, Z and Wang, Y and Peng, Y and Sun, T and Zhang, A and Qi, X}, title = {Gastrodin Alleviates Tau Pathology by Targeting the Alzheimer's Risk Gene FERMT2, Reversing the Reduction in Brain Viscoelasticity.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {3}, pages = {e70283}, pmid = {40119586}, issn = {1755-5949}, support = {8226026//National Natural Science Foundation of China:/ ; QianJiaoji[2024]92//Guizhou Provincial Department of Education Youth Science and Technology Talent Project/ ; QiankehePlatformTalents-GCC[2023]035;QiankehePlatformTalents-CXTD[2023]003；QiankeheSupport[2023]General232;QiankeheBasic-[2024]Youth228//Guizhou Provincial Science and Technology Program Project/ ; gzwkj2023-461;gzwkj2022-187//Science and Technology Fund Project of the Guizhou Provincial Health Commission/ ; }, mesh = {*Glucosides/pharmacology ; *Benzyl Alcohols/pharmacology ; Animals ; Mice ; *tau Proteins/metabolism/genetics ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Maze Learning/drug effects/physiology ; Male ; Brain/drug effects/metabolism/pathology ; Elasticity/drug effects ; Membrane Proteins/metabolism ; Mice, Transgenic ; Viscosity ; Mice, Inbred C57BL ; Molecular Docking Simulation ; Humans ; }, abstract = {BACKGROUND: The pathogenesis of Alzheimer's disease (AD) remains incompletely elucidated, and there is a notable deficiency in effective and safe therapeutic interventions. The influence of brain matrix viscoelasticity on the progression of AD has frequently been underestimated. It is imperative to elucidate these overlooked pathogenic factors and to innovate novel therapeutic strategies for AD. Gastrodin, a bioactive constituent derived from the traditional Chinese medicinal herb Gastrodia elata, exhibits a range of pharmacological properties, notably in the enhancement of neural function. Nevertheless, the underlying mechanisms of its action remain insufficiently elucidated. Consequently, this study seeks to examine the therapeutic effects and underlying mechanisms of gastrodin in the context of AD, with particular emphasis on its potential influence on the viscoelastic properties of the brain matrix.
METHODS: This study employs a range of methodologies, including the Morris water maze test, Y-maze spontaneous alternation test, atomic force microscopy (AFM), immunofluorescence, transmission electron microscopy, molecular docking, and Cellular Thermal Shift Assay (CETSA), to demonstrate that gastrodin mitigates tau pathology by modulating FERMT2, thereby reversing the deterioration of mechanical viscoelasticity in the brain.
RESULTS: Gastrodin administration via gavage has been demonstrated to mitigate cognitive decline associated with AD, attenuate the hyperphosphorylation of tau protein in the hippocampus and cortex, and ameliorate synaptic damage. Additionally, gastrodin was observed to counteract the reduction in brain matrix viscoelasticity in 3xTg-AD mice, as evidenced by the upregulation of extracellular matrix components pertinent to viscoelasticity, notably collagen types I and IV. Furthermore, molecular docking and CETSA revealed a strong binding affinity between gastrodin and FERMT2. Gastrodin treatment resulted in a reduction of FERMT2 fluorescence intensity, which is selectively expressed in astrocytes. Additionally, gastrodin contributed to the restoration of the blood-brain barrier (BBB) and modulated the expression levels of inflammatory mediators interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and matrix metallopeptidase 8 (MMP8).
CONCLUSION: Gastrodin treatment has the potential to mitigate tau pathology, thereby enhancing learning and memory in AD mouse models. This effect may be mediated through the modulation of cerebral mechanical viscoelasticity via the mechanosensor FERMT2, which facilitates the restoration of synaptic structure and function. This process is potentially linked to the maintenance of BBB integrity and the modulation of inflammatory factor release.}, }
@article {pmid40119098, year = {2025}, author = {Hajare, AD and Dagar, N and Gaikwad, AB}, title = {Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases.}, journal = {Molecular biomedicine}, volume = {6}, number = {1}, pages = {19}, pmid = {40119098}, issn = {2662-8651}, mesh = {*Klotho Proteins ; Humans ; Animals ; *Glucuronidase/metabolism ; Fibroblast Growth Factor-23 ; Aging/metabolism ; Diabetic Nephropathies/metabolism/therapy ; Neoplasms/metabolism/therapy ; Signal Transduction ; Fibroblast Growth Factors/metabolism ; Oxidative Stress/drug effects ; }, abstract = {Klotho, initially introduced as an anti-aging protein, is expressed in the brain, pancreas, and most prominently in the kidney. The two forms of Klotho (membrane-bound and soluble form) have diverse pharmacological functions such as anti-inflammatory, anti-oxidative, anti-fibrotic, tumour-suppressive etc. The membrane-bound form plays a pivotal role in maintaining kidney homeostasis by regulating fibroblast growth factor 23 (FGF 23) signalling, vitamin D metabolism and phosphate balance. Klotho deficiency has been linked with significantly reduced protection against various kidney pathological phenotypes, including diabetic kidney disease (DKD), which is a major cause of chronic kidney disease leading to end-stage kidney disease. Owing to the pleiotropic actions of klotho, it has shown beneficial effects in DKD by tackling the complex pathophysiology and reducing kidney inflammation, oxidative stress, as well as fibrosis. Moreover, the protective effect of klotho extends beyond DKD in other pathological conditions, including cardiovascular diseases, alzheimer's disease, cancer, inflammatory bowel disease, and liver disease. Therefore, this review summarizes the relationship between Klotho expression and various diseases with a special emphasis on DKD, the distinct mechanisms and the potential of exogenous Klotho supplementation as a therapeutic strategy. Future research into exogenous Klotho could unravel novel treatment avenues for DKD and other diseases.}, }
@article {pmid40118731, year = {2025}, author = {Cash, DM and Morgan, KE and O'Connor, A and Veale, TD and Malone, IB and Poole, T and Benzinger, TL and Gordon, BA and Ibanez, L and Li, Y and Llibre-Guerra, JJ and McDade, E and Wang, G and Chhatwal, JP and Day, GS and Huey, E and Jucker, M and Levin, J and Niimi, Y and Noble, JM and Roh, JH and Sánchez-Valle, R and Schofield, PR and Bateman, RJ and Frost, C and Fox, NC and , }, title = {Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100133}, doi = {10.1016/j.tjpad.2025.100133}, pmid = {40118731}, issn = {2426-0266}, support = {U19 AG032438/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.
METHODS: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. Sample sizes were computed for detecting a reduction of either absolute levels of AD-related pathology (amyloid, tau) or change over time in neurodegeneration (atrophy, hypometabolism, cognitive change).
RESULTS: Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 47[95 %CI 25,104], cortical PIB 49[28,99], CSF p-tau181 74[48,125]) for a four-year trial in presymptomatic individuals (CDR=0) to have 80 % power (5 % statistical significance) to detect a 25 % reduction in absolute levels of pathology, allowing 40 % dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50 % reduction in rate of change. Sample sizes ranged from 250 to 900 (examples hippocampal volume: 338[131,2096], cognitive composite: 326[157,1074]). MRI, FDG and cognitive outcomes had lower sample sizes when including indivduals with mild impairment (CDR=0.5 and 1) as well as presymptomatic individuals (CDR=0).
DISCUSSION: Despite the rarity of ADAD, presymptomatic clinical trials with feasible sample sizes given the number of cases appear possible.}, }
@article {pmid40118333, year = {2025}, author = {Cho, W and Choi, SW and Lim, DS and Gwon, HJ and Abd El-Aty, AM and Ahmet Aydemir, H and Hong, SA and Jeong, JH and Jung, TW}, title = {Donepezil alleviates hepatic steatosis by mitigating ER stress via the AMPK/autophagy pathway.}, journal = {Molecular and cellular endocrinology}, volume = {601}, number = {}, pages = {112523}, doi = {10.1016/j.mce.2025.112523}, pmid = {40118333}, issn = {1872-8057}, mesh = {Animals ; *Autophagy/drug effects ; *Endoplasmic Reticulum Stress/drug effects ; *Donepezil/pharmacology/therapeutic use ; Male ; *AMP-Activated Protein Kinases/metabolism ; *Fatty Liver/drug therapy/metabolism/pathology ; Mice ; *Lipid Metabolism/drug effects ; *Mice, Inbred C57BL ; Signal Transduction/drug effects ; Humans ; Hepatocytes/drug effects/metabolism ; Liver/drug effects/metabolism/pathology ; Apoptosis/drug effects ; Lipogenesis/drug effects/genetics ; }, abstract = {Donepezil (Do), a drug known for its ability to reduce neuronal inflammation and for its use in the treatment of Alzheimer's disease, has shown promise in combating hepatic lipid accumulation in hyperlipidemic conditions and endoplasmic reticulum (ER) stress, a factor associated with alterations in hepatic lipid metabolism. However, the mechanisms by which these problems are alleviated have not been fully elucidated. In this study, we investigated the effects of Do on hepatic lipid metabolism through both in vitro and in vivo studies. We examined the expression of proteins associated with lipogenesis and ER stress via immunoblot analysis, and hepatic lipid accumulation was assessed via oil red O staining. In addition, autophagosome formation was analyzed by counting MDC-positive cells. Our results demonstrated that Do treatment improved hepatic lipid metabolism and reduced the expression of ER stress markers, resulting in decreased lipogenic lipid deposition and apoptosis in the hepatocytes and livers of hyperlipidemic mice. Mechanistically, knocking down AMPK or inhibiting autophagy with 3-methyladenine (3 MA) attenuated the effects of Do on palmitate-exposed hepatocytes. These results suggest that Do alleviates hepatic ER stress via the AMPK/autophagy pathway and AMPK-mediated fatty acid oxidation, resulting in improved hepatic lipid metabolism and reduced hepatic steatosis and apoptosis. Our study provides evidence that Do may be a promising therapeutic approach for Alzheimer's disease patients with metabolic dysfunction-associated steatotic liver disease (MASLD).}, }
@article {pmid40117490, year = {2025}, author = {Fuller, JL and Shi, K and Pockes, S and Finzel, BC and Ashe, KH and Walters, MA}, title = {Reengineering of Circularly Permuted Caspase-2 to Enhance Enzyme Stability and Enable Crystallographic Studies.}, journal = {ACS chemical biology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschembio.4c00795}, pmid = {40117490}, issn = {1554-8937}, abstract = {Caspase activation has been linked to several diseases, including cancer, neurodegeneration, and inflammatory conditions, generating interest in targeting this family of proteases for drug development. Caspase-2 (Casp2) in particular has been implicated in Alzheimer's Disease (AD) by cleaving tau protein into fragment Δtau314, which reversibly impairs cognitive and synaptic function. Thus, Casp2 inhibition could be a useful strategy for therapeutic treatment of AD. To that end, we have previously synthesized and characterized various series of peptide and peptidomimetic inhibitors that demonstrate potency and selectivity for Casp2 over caspase-3 (Casp3). Despite promising developments in the design of selective Casp2 inhibitors, low expression yields of Casp2 hinder crystallographic experiments and make structure-based design challenging. The design of circularly permuted (cp) Casp2 increased protein yields considerably; however, this protein could not be crystallized. This article describes the characterization of ten novel cpCasp2 mutants, designed with the goal of increasing stability and facilitating crystallization. Gratifyingly, engineered mutant JF1cpCasp2 displayed high relative stability and was readily crystallizable with the canonical Casp2 inhibitor AcVDVAD-CHO, leading to what we believe to be the first crystal structures of any reverse caspase in the PDB. Moreover, we have reported the structure of JF1cpCasp2 with our recently described Casp2-selective inhibitor MUR-65, which revealed a unique interaction with Arg417 in the binding pocket. Overall, JF1cpCasp2 has proven valuable for structure-based design and expanding understanding of Casp2 inhibition, with potential implications for drug discovery and the development of more selective compounds.}, }
@article {pmid40117001, year = {2025}, author = {Aghdam, MA and Bozdag, S and Saeed, F and , }, title = {Machine-learning models for Alzheimer's disease diagnosis using neuroimaging data: survey, reproducibility, and generalizability evaluation.}, journal = {Brain informatics}, volume = {12}, number = {1}, pages = {8}, pmid = {40117001}, issn = {2198-4018}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; R01 AG043434/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; R35 GM153434/GM/NIGMS NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; R35GM153434/NH/NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; OAC-2312599//Division of Computing and Communication Foundations/ ; }, abstract = {Clinical diagnosis of Alzheimer's disease (AD) is usually made after symptoms such as short-term memory loss are exhibited, which minimizes the intervention and treatment options. The existing screening techniques cannot distinguish between stable MCI (sMCI) cases (i.e., patients who do not convert to AD for at least three years) and progressive MCI (pMCI) cases (i.e., patients who convert to AD in three years or sooner). Delayed diagnosis of AD also disproportionately affects underrepresented and socioeconomically disadvantaged populations. The significant positive impact of an early diagnosis solution for AD across diverse ethno-racial and demographic groups is well-known and recognized. While advancements in high-throughput technologies have enabled the generation of vast amounts of multimodal clinical, and neuroimaging datasets related to AD, most methods utilizing these data sets for diagnostic purposes have not found their way in clinical settings. To better understand the landscape, we surveyed the major preprocessing, data management, traditional machine-learning (ML), and deep learning (DL) techniques used for diagnosing AD using neuroimaging data such as structural magnetic resonance imaging (sMRI), functional magnetic resonance imaging (fMRI), and positron emission tomography (PET). Once we had a good understanding of the methods available, we conducted a study to assess the reproducibility and generalizability of open-source ML models. Our evaluation shows that existing models show reduced generalizability when different cohorts of the data modality are used while controlling other computational factors. The paper concludes with a discussion of major challenges that plague ML models for AD diagnosis and biomarker discovery.}, }
@article {pmid40116675, year = {2025}, author = {Monteiro-Junior, RS}, title = {Virtual reality-based interventions for individuals with dementia: A potential further treatment and new perspectives.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251328723}, doi = {10.1177/13872877251328723}, pmid = {40116675}, issn = {1875-8908}, abstract = {This commentary highlights issues regarding virtual reality (VR)-based interventions for individuals with Alzheimer's disease, emphasizing their potential to improve cognitive function and delay decline. The aim of this manuscript is to present current findings and critically synthesize the practical applications of VR interventions. A recent meta-analysis demonstrates promising results, with VR interventions enhancing memory, executive functions, and overall cognition. Despite the limited number of studies and small sample sizes, findings suggest that engaging VR environments can motivate patients, fostering adherence to treatment. This commentary underscores the need for further research to validate these results and establish standardized methodologies for the effective use of VR in dementia care. Several methodological aspects and new perspectives are highlighted herein.}, }
@article {pmid40116674, year = {2025}, author = {Richter, N and Breidenbach, L and Schmieschek, MH and Heiss, WD and Fink, GR and Onur, OA}, title = {Alzheimer-typical temporo-parietal atrophy and hypoperfusion are associated with a more significant cholinergic impairment in amnestic neurodegenerative syndromes.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251324080}, doi = {10.1177/13872877251324080}, pmid = {40116674}, issn = {1875-8908}, abstract = {BackgroundTo date, cholinomimetics remain central in the pharmacotherapy of Alzheimer's disease (AD) dementia. However, postmortem investigations indicate that the AD-typical progressive amnestic syndrome may also result from predominantly limbic non-AD neuropathology such as TDP-43 proteinopathy and argyrophilic grain disease. Experimental evidence links a beneficial response to cholinomimetics in early AD to reduced markers of cholinergic neurotransmission. However, the cholinergic impairment varies among patients with a clinical AD presentation, likely due to non-AD (co)-pathologies.ObjectiveThis study examines whether AD-typical atrophy and hypoperfusion can provide information about the cholinergic system in clinically diagnosed AD.MethodsThirty-two patients with amnestic mild cognitive impairment or mild dementia due to AD underwent positron emission tomography (PET) with the tracer N-methyl-4-piperidyl-acetate (MP4A) to estimate acetylcholinesterase (AChE) activity, neurological examinations, cerebral magnetic resonance imaging (MRI) and neuropsychological assessment. The 'cholinergic deficit' was computed as the deviation of AChE activity from cognitively normal controls across the cerebral cortex and correlated gray matter (GM) and perfusion of temporo-parietal cortices typically affected by AD and basal forebrain (BF) GM.ResultsTemporo-parietal perfusion and GM, as well as the inferior temporal to medial temporal ratio of perfusion correlated negatively with the 'cholinergic deficit'. A smaller Ch4p area of the BF was associated with a more significant 'cholinergic deficit', albeit to a lesser degree than cortical measures.ConclusionsIn clinically diagnosed AD, temporo-parietal GM and perfusion are more closely associated with the 'cholinergic deficit' than BF volumes, making them possible markers for cholinergic treatment response in amnestic neurodegeneration.}, }
@article {pmid40115072, year = {2025}, author = {Li, J and Hu, X and Tao, X and Li, Y and Jiang, W and Zhao, M and Ma, Z and Chen, B and Sheng, S and Tong, J and Zhang, H and Shen, B and Gao, X}, title = {Deconstruct the link between gut microbiota and neurological diseases: application of Mendelian randomization analysis.}, journal = {Frontiers in cellular and infection microbiology}, volume = {15}, number = {}, pages = {1433131}, pmid = {40115072}, issn = {2235-2988}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Gastrointestinal Microbiome/genetics ; *Nervous System Diseases/genetics/microbiology ; Brain-Gut Axis ; Genome-Wide Association Study ; }, abstract = {BACKGROUND: Recent research on the gut-brain axis has deepened our understanding of the correlation between gut bacteria and the neurological system. The inflammatory response triggered by gut microbiota may be associated with neurodegenerative diseases. Additionally, the impact of gut microbiota on emotional state, known as the "Gut-mood" relationship, could play a role in depression and anxiety disorders.
RESULTS: This review summarizes recent data on the role of gut-brain axis in the pathophysiology of neuropsychiatric and neurological disorders including epilepsy, schizophrenia, Alzheimer's disease, brain cancer, Parkinson's disease, bipolar disorder and stroke. Also, we conducted a Mendelian randomization study on seven neurological disorders (Epilepsy, schizophrenia, Alzheimer's disease, brain cancer, Parkinson's disease, bipolar disorder and stroke). MR-Egger and MR-PRESSO tests confirmed the robustness of analysis against horizontal pleiotropy.
CONCLUSIONS: By comparing the protective and risk factors for neurological disorders found in our research and other researches, we can furtherly determine valuable indicators for disease evolution tracking and potential treatment targets. Future research should explore extensive microbiome genome-wide association study datasets using metagenomics sequencing techniques to deepen our understanding of connections and causality between neurological disorders.}, }
@article {pmid40114925, year = {2025}, author = {Ullah, S and Park, TJ and Park, JS and Atiq, A and Ali, J and Kang, MH and Ali, W and Choe, K and Kim, MO}, title = {Ambroxol attenuates detrimental effect of LPS-induced glia-mediated neuroinflammation, oxidative stress, and cognitive dysfunction in mice brain.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1494114}, pmid = {40114925}, issn = {1664-3224}, mesh = {Animals ; *Oxidative Stress/drug effects ; *Lipopolysaccharides ; *Ambroxol/pharmacology/therapeutic use ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Neuroglia/drug effects/metabolism ; *Brain/metabolism/drug effects/pathology ; Male ; *Neuroprotective Agents/pharmacology/therapeutic use ; Disease Models, Animal ; Antioxidants/pharmacology ; Mice, Inbred C57BL ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are multifactorial. Among various factors, lipopolysaccharides (LPSs) from Gram-negative bacteria, such as E. coli, are considered potential causative agents. Despite significant advancements in the field, there is still no cure. In this study, we investigated the neuroprotective effects of ambroxol against LPS-induced neuroinflammation, oxidative stress, neurodegeneration, and the associated cognitive dysfunction. Intraperitoneal injection of LPS (250 µg/kg every alternative day for a total of seven doses over 14 days) triggered glial cell activation, neuroinflammation, oxidative stress, and neurodegeneration in the mouse brain. Ambroxol treatment (30 mg/kg/day for 14 days) significantly reduced neuroinflammation and oxidative stress compared to LPS-treated mice. Immunoblotting and immunofluorescence results showed that ambroxol reduced levels of Toll-like receptor 4 (TLR4) and oxidative stress kinase phospho-c-Jun N-terminal Kinase 1 (p-JNK). It also decreased astrocyte and microglia activation in the cortex and hippocampus of LPS+ Amb-treated mice, as indicated by the downregulation of GFAP and Iba-1. Furthermore, ambroxol-reversed LPS-induced neuroinflammation by inhibiting inflammatory mediators, such as IL-1β and TNF-α, through regulation of the transcription factor p-NFkB. Persistent neuroinflammation disrupted the natural antioxidant mechanisms, leading to oxidative stress. Ambroxol treatment upregulated antioxidant markers, including Nrf-2, HO-1, and SOD, which were downregulated in the LPS-treated group. Additionally, ambroxol-inhibited lipid peroxidation, maintaining malondialdehyde levels in the mouse brain. Ambroxol also improves synaptic integrity by upregulating synaptic biomarkers, including PSD-95 and SNAP-23. Overall, ambroxol demonstrated anti-inflammatory, antioxidant, and neuroprotective effects in LPS-treated mice, highlighting its potential benefits in neurological disorders.}, }
@article {pmid40114707, year = {2025}, author = {Kumari, A and Rahaman, A and Zeng, XA and Baloch, Z}, title = {Therapeutic potential and microRNA regulating properties of phytochemicals in Alzheimer's disease.}, journal = {Molecular therapy. Nucleic acids}, volume = {36}, number = {1}, pages = {102439}, pmid = {40114707}, issn = {2162-2531}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia in the elderly and is characterized by the aggregation of Aβ (peptide) and neurofibrillary tangles along with inflammatory processes. Aging is a significant driver of these alterations, and dementia is a major cause of disability and mortality. Despite extensive clinical trials over the past two decades, no effective drug has been developed to improve AD symptoms or slow its progression, indicating the inefficiency of current treatment targets. In AD development, the molecular microenvironment plays a significant role. MicroRNAs (miRNAs) are a key component of this microenvironment, regulate post-transcriptional gene expression, and are expressed more abundantly in the brain than in other tissues. Several dysregulated miRNAs in AD have been linked to neuropathological changes, such as plaque and tangle accrual, as well as altered expression of notorious molecules. Preclinical studies have confirmed the efficacy of phytochemicals/food bioactive compounds (PCs/FBCs) in regulating miRNA expression, which makes them immensely beneficial for targeting miRNA-altered expression patterns in neuronal diseases. This review highlights the potential of miRNAs in driving AD pathology and its development. Furthermore, it discusses the therapeutic efficacy of PCs/FBCs and their miRNA-regulatory properties, especially focusing on antiinflammatory and antioxidant capacities for their development as effective AD agents.}, }
@article {pmid40114579, year = {2025}, author = {Ahmad, F}, title = {Nano-healing: Exploring the Therapeutic Potentials of Nanomedicine for CNS Disorders.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128362577250227081919}, pmid = {40114579}, issn = {1873-4286}, abstract = {INTRODUCTION: Nanomedicine offers immense potential in the field of Central Nervous System (CNS) disorder treatment, encompassing conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and stroke.
METHOD: Through the utilization of nanotechnology-driven drug delivery systems, the efficacy of drugs can be amplified, their toxicity minimized, and their bioavailability increased, enabling them to effectively reach the intended site within the CNS. This review aims to examine the therapeutic possibilities that nanomedicine presents in addressing these debilitating disorders. This exploration entails an analysis of diverse nanotechnology- based approaches for CNS drug delivery, including polymeric nanoparticles, liposomes, dendrimers, and carbon nanotubes. Moreover, notable advancements in nanotechnology-based therapeutics for CNS disorders are highlighted, such as the application of nanoparticles for delivering curcumin in Alzheimer's disease, liposomes for delivering L-DOPA in Parkinson's disease, and dendrimers for delivering interferon-beta in multiple sclerosis.
RESULTS: Additionally, the potential of nanotechnology-based approaches in the treatment of epilepsy and stroke is discussed. The review concludes by addressing the challenges faced and emphasizes the significant potential of clinical trials in enhancing drug delivery and future prospects in the development of nanotechnology- based therapeutics for CNS disorders.
CONCLUSION: Overall, the therapeutic potential of nanomedicine in CNS disorder treatment is vast, instilling optimism for the creation of safe and effective therapies for these devastating conditions.}, }
@article {pmid40114255, year = {2025}, author = {Pu, Y and Beck, D and Verspoor, K}, title = {Enriched knowledge representation in biological fields: a case study of literature-based discovery in Alzheimer's disease.}, journal = {Journal of biomedical semantics}, volume = {16}, number = {1}, pages = {3}, pmid = {40114255}, issn = {2041-1480}, support = {CI70200030//Australian Research Council/ ; }, mesh = {*Alzheimer Disease ; Humans ; Knowledge Discovery/methods ; }, abstract = {BACKGROUND: In Literature-based Discovery (LBD), Swanson's original ABC model brought together isolated public knowledge statements and assembled them to infer putative hypotheses via logical connections. Modern LBD studies that scale up this approach through automation typically rely on a simple entity-based knowledge graph with co-occurrences and/or semantic triples as basic building blocks. However, our analysis of a knowledge graph constructed for a recent LBD system reveals limitations arising from such pairwise representations, which further negatively impact knowledge inference. Using LBD as the context and motivation in this work, we explore limitations of using pairwise relationships only as knowledge representation in knowledge graphs, and we identify impacts of these limitations on knowledge inference. We argue that enhanced knowledge representation is beneficial for biological knowledge representation in general, as well as for both the quality and the specificity of hypotheses proposed with LBD.
RESULTS: Based on a systematic analysis of one co-occurrence-based LBD system focusing on Alzheimer's Disease, we identify 7 types of limitations arising from the exclusive use of pairwise relationships in a standard knowledge graph-including the need to capture more than two entities interacting together in a single event-and 3 types of negative impacts on knowledge inferred with the graph-Experimentally infeasible hypotheses, Literature-inconsistent hypotheses, and Oversimplified hypotheses explanations. We also present an indicative distribution of different types of relationships. Pairwise relationships are an essential component in representation frameworks for knowledge discovery. However, only 20% of discoveries are perfectly represented with pairwise relationships alone. 73% require a combination of pairwise relationships and nested relationships. The remaining 7% are represented with pairwise relationships, nested relationships, and hypergraphs.
CONCLUSION: We argue that the standard entity pair-based knowledge graph, while essential for representing basic binary relations, results in important limitations for comprehensive biological knowledge representation and impacts downstream tasks such as proposing meaningful discoveries in LBD. These limitations can be mitigated by integrating more semantically complex knowledge representation strategies, including capturing collective interactions and allowing for nested entities. The use of more sophisticated knowledge representation will benefit biological fields with more expressive knowledge graphs. Downstream tasks, such as LBD, can benefit from richer representations as well, allowing for generation of implicit knowledge discoveries and explanations for disease diagnosis, treatment, and mechanism that are more biologically meaningful.}, }
@article {pmid40112330, year = {2025}, author = {Vasileva-Metodiev, SZ and Spargo, D and Klein, EG and Quevenco, FC and Cotton, S and Sanchez-Juan, P and Niimi, Y and Fowler, NR}, title = {Diagnostic journey and management of patients with mild cognitive impairment and Alzheimer's disease dementia: A multinational, real-world survey.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251322978}, doi = {10.1177/13872877251322978}, pmid = {40112330}, issn = {1875-8908}, abstract = {BackgroundAn Alzheimer's disease (AD) diagnosis made in the earliest symptomatic stages substantially benefits patients and their care partners. However, little is known regarding the clinical, healthcare system-level, and patient-specific barriers that hinder timely diagnosis and treatment.ObjectiveTo explore real-world practices surrounding the diagnostic journey and management of mild cognitive impairment (MCI)/AD dementia patients.MethodsData were drawn from Adelphi Real World Dementia Disease Specific Programme™, a cross-sectional survey of physicians treating MCI/AD dementia patients in France, Germany, Italy, Spain, the United Kingdom, the United States, and Japan between 2022 and 2024.ResultsOverall, 779 physicians reported data on 5551 patients. Physicians indicated current disease severity for 5421 patients; 37.2% had MCI (87.3% with suspected prodromal AD and 12.7% undetermined etiology), 17.2% AD with mild dementia, 31.1% AD with moderate dementia, and 14.5% AD with severe dementia. When not immediately diagnosed, the median time from first consultation to initial diagnosis was 8.9 and 12.6 weeks when patients first consulted and were diagnosed by either a primary care practitioner (PCP) or a specialist, respectively, compared with 21.6 weeks when a PCP referred to a specialist for diagnosis. Diagnostic delays were predominantly due to specialist wait times. Few patients had diagnostic AD biomarker tests (cerebrospinal fluid testing 9.5%, amyloid positron emission tomography 3.7%, AD-blood tests 5.3%).ConclusionsTimely MCI and AD diagnosis is impeded by referral delays and limited use of biomarker testing. Addressing these critical care gaps requires enhanced physician training, reduced wait times and increased biomarker utilization for early management.}, }
@article {pmid40112319, year = {2025}, author = {Fuseya, K and Mimura, Y and Nakajima, S and Mimura, M and Kasanuki, K and Noda, Y}, title = {A systematic review and meta-analysis on the characteristics of transcranial magnetic stimulation treatment protocols for patients with Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251325887}, doi = {10.1177/13872877251325887}, pmid = {40112319}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) is the most common neurodegenerative condition causing dementia. Currently, there has been no established non-pharmacological treatment for cognitive decline in patients with AD. Recent evidence suggests that repetitive transcranial magnetic stimulation (rTMS) may be effective as a non-invasive treatment for improving cognitive function in AD.ObjectiveThis study aimed to examine the characteristics of rTMS treatment protocols for patients with ADMethodsWe conducted a systematic literature search on clinical trials on rTMS for improving cognitive decline in patients with AD, using the PubMed, PsycINFO, and Scopus databases and performed a meta-analysis according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. To clarify which cognitive domains in AD are improved by rTMS, meta-analyses were conducted on both global cognitive function and on each cognitive domain including verbal memory, processing speed, and executive function. In addition, sub-analyses of the treatment details of rTMS parameters including stimulation sites, stimulation frequency, stimulation intensity, and with/without the neuro-navigation technique and meta-regression analyses adjusting for gender, education, and the number of rTMS pulses were performed.ResultsThe results showed significant improvements in global cognitive function, while no significant findings in verbal memory, processing speed and executive function. No significant results were found in subgroup analysis or meta-regression.ConclusionsTo enrich the evidence for cognitive enhancement in AD with rTMS, the randomized controlled trials using a unified rTMS protocol with a larger sample size are warranted.}, }
@article {pmid40111937, year = {2025}, author = {Wimo, A and Handels, R and Blennow, K and Kirsebom, KB and Selnes, P and Bon, J and Emersic, A and Gonzalez-Ortiz, F and Gregoric Kramberger, M and Sköldunger, A and Speh, A and Timón-Reina, S and Vromen, E and Jelle Visser, P and Winblad, B and Fladby, T}, title = {Cost-effectiveness of diagnosing and treating patients with early Alzheimer's disease with anti-amyloid treatment in a clinical setting.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251323231}, doi = {10.1177/13872877251323231}, pmid = {40111937}, issn = {1875-8908}, abstract = {BackgroundThe introduction of anti-amyloid treatments (AAT) for Alzheimer's disease (AD) has put the cost-effectiveness into focus.ObjectiveEstimate the potential cost-effectiveness of diagnostic pathways combined with AAT for early AD.MethodsDiagnostic accuracy of blood-based (BBM) and cerebrospinal fluid (CSF) biomarkers was obtained from Norwegian memory clinics using positron emission tomography (PET) as reference standard. In a health-economic model, the cost-effectiveness of three diagnostic strategies was estimated relying either on BBM (p-tau 217), CSF (Aβ42/40 ratio), and BBM with CSF confirmatory testing and compared with standard of care (SoC) and compared with CSF-AAT. The model consisted of a decision tree reflecting the diagnostic process and a subsequent Markov cohort model starting at mild cognitive impairment due to AD. All strategies except SoC were combined with AAT including costs of treatment (assumed €5000/year), infusions and monitoring.ResultsCompared with SoC all three strategies (CSF-AAT, BBM-AAT, and BBM-CSF-AAT) resulted in QALY gains at higher costs, with an incremental cost-effectiveness ratio (ICER) of 110k€, 141k€ and 110k€ respectively. Compared with CSF-AAT both BBM-AAT and BBM-CSF-AAT strategies resulted in QALYs lost at lower costs, with an ICER of 27k€ and 109k€ respectively. Results were particularly sensitive to the price of AAT and possible subcutaneous administration.ConclusionsCompared with SoC all three strategies are potentially not cost-effective as they exceeded the Swedish maximum willingness to pay threshold of €94,800 per QALY gained. BBM-CSF-AAT versus CSF-AAT is potentially cost-effective if willing to accept its QALY loss. Discussions on budget impact on different payers are needed after introducing AAT.}, }
@article {pmid40111934, year = {2025}, author = {Gui, S and Zeng, F and Wu, Z and Nonaka, S and Sano, T and Ni, J and Nakanishi, H and Moriyama, M and Kanematsu, T}, title = {Lipopolysaccharides from Porphyromonas gingivalis indirectly induce neuronal GSK3β-dependent synaptic defects and cause cognitive decline in a low-amyloid-β-concentration environment in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251326879}, doi = {10.1177/13872877251326879}, pmid = {40111934}, issn = {1875-8908}, abstract = {BackgroundLipopolysaccharides from Porphyromonas gingivalis (P.gLPS) are involved in the pathology of Alzheimer's disease (AD). However, the effect of P.gLPS on synaptic defects remains unclear.ObjectiveIn this study, we tested our hypothesis that P.gLPS induces synaptic defects in a low-amyloid-beta (Aβ)-concentration environment.MethodsMG6 microglia or N2a neurons was treated with P.gLPS (0.1 μg/mL), soluble Aβ42 (0.1 μM) or AL (combined P.gLPS and soluble Aβ42 at 0.1 μM).ResultsIn cultured MG6 microglia, increased the mRNA expression of TNF-α, IL-1β and IL-6 and the TNF-α release in parallel with increased NF-κB activation. In cultured N2a neurons, treatment with Aβ42, P.gLPS, and AL did not affect the mRNA expression of synapsin1 (SYN1) or post-synaptic density protein-95 (PSD-95). However, the treatment with conditioned medium from AL-exposed MG6 microglia (AL-MCM) significantly reduced the mRNA and protein expression of SYN1, PSD-95, and nuclear translocation of repressor element-1 silencing transcription factor (REST) but significantly increased the mRNA expression of TNF receptor type I (at 48 h) and glycogen synthase kinase (GSK)3β (at 24 h). TWS119 pretreatment (5 μM), a GSK3β specific inhibitor, significantly reversed the AL-MCM-induced reduction in the mRNA expression of SYN1 and PSD-95 and nuclear translocation of REST in cultured N2a neurons. In APP[NL-F/NL-F] mice, the immunofluorescence intensity of SYN1 and PSD-95 in cortical neurons was positively correlated with the index of the memory test but negatively correlated with that of TNF-α-positive microglia.ConclusionsThese observations demonstrate that P.gLPS induces neuronal GSK3β-dependent synaptic defects in a low-Aβ concentration environment via microglial activation.}, }
@article {pmid40111696, year = {2025}, author = {Zeng, Y and Lin, D and Chen, A and Ning, Y and Li, X}, title = {Periodontal Treatment to Improve General Health and Manage Systemic Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {1472}, number = {}, pages = {245-260}, pmid = {40111696}, issn = {0065-2598}, mesh = {Humans ; *Periodontitis/microbiology/therapy/immunology ; Dysbiosis/therapy/microbiology ; Microbiota ; Cardiovascular Diseases/therapy/microbiology/immunology ; }, abstract = {Periodontitis is increasingly recognized for its role in overall health and its associations with systemic conditions. Shared etiological factors, including microbiological, immunological, genetic, and environmental influences, have prompted interest in the potential impact of periodontal therapy on broader health outcomes. The oral microbiome plays a key role in the pathogenesis of periodontitis, with microbial imbalances (dysbiosis) contributing to inflammation and systemic disease progression. Additionally, immune responses to periodontal infection, such as chronic inflammation and dysregulated immune activity, are central to linking periodontitis with conditions like diabetes, cardiovascular disease, and autoimmune disorders. This chapter explores the connections between periodontal treatment and systemic diseases, such as diabetes, rheumatoid arthritis, cardiovascular disease, chronic kidney disease, Alzheimer's disease, digestive disorders, and respiratory disease. It also reviews the current research on the mechanisms, including microbial and immune factors, that underlie these associations. By emphasizing the role of periodontal health, the oral microbiome, and immune regulation in disease prevention and management, this chapter underscores the importance of integrated healthcare approaches to improve patient outcomes.}, }
@article {pmid40111689, year = {2025}, author = {Mattos, MCO and Vivacqua, A and Carneiro, VMA and Grisi, DC and Guimarães, MDCM}, title = {Interaction of the Systemic Inflammatory State, Inflammatory Mediators, and the Oral Microbiome.}, journal = {Advances in experimental medicine and biology}, volume = {1472}, number = {}, pages = {121-132}, pmid = {40111689}, issn = {0065-2598}, mesh = {Humans ; *Microbiota/immunology ; *Mouth/microbiology/immunology ; *Inflammation Mediators/metabolism ; *Inflammation/microbiology/immunology ; *Periodontitis/microbiology/immunology ; Dysbiosis/microbiology/immunology ; Animals ; }, abstract = {Humans are biological units that host numerous microbial symbionts and their genomes, which together form a superorganism or holobiont. Changes in the balance of the oral ecosystem can have consequences for both general and oral health, such as cavities, gingivitis, and periodontitis. Periodontitis is initiated by a synergistic and dysbiotic microbial community that causes local inflammation and destruction of the tooth's supporting tissues, potentially leading to systemic inflammation. This inflammation caused by periodontal disease has been associated with various systemic alterations, and the immune system is largely responsible for the body's exacerbated response, which can induce and exacerbate chronic conditions. Studies indicate that subgingival microorganisms found in periodontitis reach the bloodstream and are distributed throughout the body and, therefore, can be found in distant tissues and organs. Among all diseases associated with periodontal disease, diabetes mellitus presents the strongest and most elucidated link, and its bidirectional relationship has already been demonstrated. Chronic hyperglycemia favors the worsening of periodontal parameters, while the aggravation of periodontal parameters can promote an increase in glycemic indexes. Other systemic diseases have been related to periodontitis, such as Alzheimer's, chronic kidney disease, atherosclerosis, and respiratory diseases. The importance of periodontal control may suggest a reduction in the chances of developing chronic inflammatory diseases because these two alterations often share inflammatory pathways and, for this reason, may influence each other.}, }
@article {pmid40111567, year = {2025}, author = {Bhratee, A and Chatterjee, D and Kaur, R and Singh, S}, title = {Protective mechanism of apigenin in proton pump inhibitor-associated progressive cognitive impairment in adult zebrafish via targeting GSK-3β pathway.}, journal = {Metabolic brain disease}, volume = {40}, number = {4}, pages = {155}, pmid = {40111567}, issn = {1573-7365}, mesh = {Animals ; *Zebrafish ; *Apigenin/pharmacology/therapeutic use ; *Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism/prevention & control ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Proton Pump Inhibitors/pharmacology ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Male ; }, abstract = {Cognitive impairment is characterized by memory loss and difficulty in focusing, remembering, adhering to directions, and solving problems; commonly seen in an elderly population. Apigenin (APG) (4', 5, 7-trihydroxyflavone) is a flavonoid with several positive health benefits, including chemoprevention, antioxidant and can suppress inflammatory responses by inhibiting TNF-α and IL-1β levels. In this experimental study, we observed the possible neuroprotective effects of APG in the zebrafish model exposed to Lansoprazole (LPZ), a proton pump inhibitor known to induce cognitive impairment through hyperactivation of GSK-3β pathway. This experiment involves 12 adult zebrafish per group, where one group received LPZ (100 mg) as a toxin for 7 days and APG (25, 50, and 100 mg/kg) as treatment, while DPZ (5 mg/kg) served as a standard comparison over the same period. Neurobehavioral tests such as T-Maze, Novel Tank Test (NTT), and Novel Object Recognition (NOR) were performed. Several biochemical assessments were also performed to evaluate the level of lipid peroxidation (LPO), glutathione (GSH), nitrite (NO), acetylcholinesterase activity (AChEs), catalase activity, neurotransmitters (GABA and glutamate), neuroinflammatory markers (IL-1β, TNF-α, and IL-10), and histopathological analysis. The results showed that apigenin enhanced memory function, improved neurotransmitter balance, decreased oxidative stress markers, regulated the production of proinflammatory cytokines, and inhibited GSK-3β activity. Additionally, the co-administration of a GSK-3β inhibitor further promoted neuroprotection and cognitive enhancement facilitated by apigenin, highlighting the importance of the GSK-3β signaling pathway. These findings highlight the potential of apigenin as a natural compound for mitigating cognitive dysfunction. However, this study should also include long-term toxicity assessments and deeper molecular analysis to elucidate Apigenin's mechanism of action fully. Future research should address these gaps to validate its therapeutic potential.}, }
@article {pmid40110667, year = {2025}, author = {Pini, L and Imbimbo, BP}, title = {Rethinking biological biomarkers to track treatment efficacy in Alzheimer's disease: Focus on brain connectivity.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e70083}, pmid = {40110667}, issn = {1552-5279}, }
@article {pmid40110649, year = {2025}, author = {Liu, S and Maruff, P and Saint-Jalmes, M and Bourgeat, P and Masters, CL and Goudey, B and , }, title = {Predicting amyloid beta accumulation in cognitively unimpaired older adults: Cognitive assessments provide no additional utility beyond demographic and genetic factors.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e70036}, pmid = {40110649}, issn = {1552-5279}, support = {U19 AG024904/AG/NIA NIH HHS/United States ; IC170100030//Australian Research Council Training Centre in Cognitive Computing for Medical Technologies/ ; }, mesh = {Humans ; *Amyloid beta-Peptides/metabolism ; Female ; Aged ; Male ; *Alzheimer Disease/genetics ; *Neuropsychological Tests/statistics & numerical data ; *Machine Learning ; Biomarkers ; Cognition/physiology ; Aged, 80 and over ; Cohort Studies ; Positron-Emission Tomography ; Neuroimaging ; Risk Factors ; }, abstract = {BACKGROUND: Integrating non-invasive measures to estimate abnormal amyloid beta accumulation (Aβ+) is key to developing a screening tool for preclinical Alzheimer's disease (AD). The predictive capability of standard neuropsychological tests in estimating Aβ+ has not been quantified.
METHODS: We constructed machine learning models using six cognitive measurements alongside demographic and genetic risk factors to predict Aβ status. Data were drawn from three cohorts: Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Australian Imaging, Biomarker & Lifestyle (AIBL) study. Internal validation was conducted within A4 with external validations in ADNI and AIBL to assess model generalizability.
RESULTS: The highest area under the curve (AUC) for predicting Aβ+ was observed with demographic, genetic, and cognitive variables in A4 (median AUC = 0.745), but this was not significantly different from models without cognitive variables. External validation showed no improvement in ADNI and a slight decrease in AIBL.
DISCUSSION: Standard neuropsychological tests do not significantly enhance Aβ+ prediction in cognitively unimpaired adults beyond demographic and genetic information.
HIGHLIGHTS: Standard neuropsychological tests do not significantly improve the prediction of amyloid beta positivity (Aβ+) in cognitively unimpaired older adults beyond demographic and genetic information alone. Across three well-characterized cohorts, machine learning models incorporating cognitive measures failed to significantly improve Aβ+ prediction, indicating the limited relationship between cognitive performance on these tests and the risk of pre-clinical Alzheimer's disease (AD). These findings challenge assumptions about cognitive symptoms preceding Aβ+ screening and emphasize the need for developing more sensitive cognitive tests for early AD detection.}, }
@article {pmid40110480, year = {2025}, author = {Wu, J and Teng, Y and Xie, Y and Xing, S and Zhi, S}, title = {Comparing the efficacy of physical therapy interventions in Alzheimer's disease: a network meta-analysis.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1541287}, pmid = {40110480}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a progressive and debilitating neurodegenerative disorder that significantly impairs cognitive function and daily living abilities, representing a major public health challenge. Given the multifactorial nature of AD, effective therapeutic interventions targeting both cognitive and functional decline are critical. This study aimed to conduct a comprehensive comparison of the therapeutic effects of music therapy, acupuncture therapy, game therapy, cognitive training therapy, and exercise therapy on AD patients through a network meta-analysis. Randomized controlled trials (RCTs) published up until 2024 were systematically retrieved from multiple databases. Data were extracted, including the first author, publication year, country, total sample size, mean participant age, type and duration of intervention, and outcome measures such as the Mini-Mental State Examination, Activities of Daily Living, and Alzheimer's Disease Assessment Scale-Cognitive Subscale. Statistical analyses were performed using the RevMan 5.3 and Stata 17 software. The analysis included 52 RCTs with a total of 3,409 participants, offering a strong dataset. The results indicated that game therapy produced statistically significant improvements in mental state and daily living abilities, while acupuncture therapy yielded the most pronounced improvements in cognitive function among AD patients. Notably, the comparative efficacy of these interventions suggests that game therapy may offer short-term benefits, particularly for mental health and functional abilities, whereas acupuncture therapy demonstrated superior long-term cognitive enhancements. In conclusion, tailored physical and cognitive interventions such as game therapy and acupuncture therapy may hold significant potential in optimizing treatment outcomes for AD patients, with implications for both clinical practice and future research.}, }
@article {pmid40109740, year = {2025}, author = {Schäker-Hübner, L and Toledano-Pinedo, M and Eimermacher, S and Krasniqi, V and Porro-Pérez, A and Tan, K and Horn, G and Stegen, P and Elsinghorst, PW and Wille, T and Pietsch, M and Gütschow, M and Marco-Contelles, J and Hansen, FK}, title = {Contilisant-Belinostat Hybrids: Polyfunctionalized Indole Derivatives as Multineurotarget Drugs for the Potential Treatment of Alzheimer's Disease.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {3}, pages = {831-840}, pmid = {40109740}, issn = {2575-9108}, abstract = {In this work, we designed, synthesized, and evaluated two types of multineurotargeting compounds using a pharmacophore merging strategy, aiming to develop potential treatments for Alzheimer's disease. We combined belinostat, an FDA-approved unselective histone deacetylase (HDAC) inhibitor, with the 5-substituted indole core of contilisant, known for its antioxidant and neuroprotective properties as well as its potent inhibitory activity against monoamine oxidases (MAOs), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Among these, compounds 8c (HDAC1, IC50 = 0.019 μM; HDAC6, IC50 = 0.040 μM; AChE, IC50 = 20.06 μM; BChE, IC50 = 17.10 μM; MAO-B, IC50 = 2.14 μM), and 9c (HDAC1, IC50 = 0.126 μM; HDAC6, IC50 = 0.020 μM; AChE, IC50 = 2.73 μM; BChE, IC50 = 4.03 μM; MAO-B, IC50 = 1.18 μM) emerged as the most promising candidates. These compounds warrant further investigation as potential treatments for Alzheimer's disease due to their unique inhibition profiles and favorable mode of inhibition.}, }
@article {pmid40109529, year = {2025}, author = {Zhou, T and Zhang, R and Ohulchanskyy, TY and Qu, J}, title = {Monitoring photobiomodulation of amyloid-β aggregation in 3D cultured cells using label-free nonlinear optical imaging.}, journal = {Biomedical optics express}, volume = {16}, number = {3}, pages = {1143-1155}, pmid = {40109529}, issn = {2156-7085}, abstract = {The accumulation of beta-amyloid (Aβ) peptide aggregates, commonly known as plaques, is considered a key hallmark in the development of Alzheimer's disease (AD). Recently, low-level light therapy (LLLT), also referred to as photobiomodulation (PBM), has emerged as a promising treatment approach for AD. Previous studies have shown that PBM reduces Aβ load primarily by enhancing the clearance capabilities of glia cells. However, it remains unclear whether PBM can directly reduce the formation of Aβ plaques in neuronal cells independent of the glia cell effect. In this study, we employed three-dimensional (3D) cultured HEK 293 APPsw cells as an AD model to investigate the impact of PBM on Aβ aggregation. We demonstrated that label-free two-photon excited fluorescence (TPEF) imaging and second harmonic generation (SHG) imaging are effective tools for monitoring Aβ aggregation in 3D cell models. The TPEF imaging results and subsequent quantification revealed that PBM, particularly with low-level near-infrared light from an 808 nm laser (compared to 1064, 1210, and 1470 nm lasers), significantly reduced Aβ aggregation, specifically plaques formation, in the 3D cultured cells, with the effect found to be dose-dependent. Moreover, a comprehensive analysis of protein expression in the 3D cultured cells revealed that PBM induces overexpression of the LRP1 receptor, which mediates Aβ degradation and thus leads to the reduction of Aβ aggregation. This study highlights the use of label-free nonlinear optical imaging to monitor Aβ aggregation in AD progression and provides novel insights into the effects of PBM on Aβ plaque formation in AD models.}, }
@article {pmid40109054, year = {2025}, author = {Tuan, PM and Vu, DC and Van, SV and Thuy, NT and Tham, VM and Ngan, N}, title = {Phytochemical composition, antioxidant and enzyme inhibitory effects of Stahlianthus thorelii Gagnep. rhizomes.}, journal = {Acta chimica Slovenica}, volume = {72}, number = {1}, pages = {63-70}, doi = {10.17344/acsi.2024.9043}, pmid = {40109054}, issn = {1580-3155}, mesh = {*Rhizome/chemistry ; *Antioxidants/pharmacology/chemistry/isolation & purification ; *Plant Extracts/pharmacology/chemistry ; *Enzyme Inhibitors/pharmacology/chemistry/isolation & purification ; alpha-Amylases/antagonists & inhibitors/metabolism ; Acetylcholinesterase/metabolism ; Phytochemicals/pharmacology/chemistry/isolation & purification ; Monophenol Monooxygenase/antagonists & inhibitors/metabolism ; Cholinesterase Inhibitors/pharmacology/chemistry ; alpha-Glucosidases/metabolism ; }, abstract = {Stahlianthus thorelii Gagnep. is used in traditional medicine to treat various diseases. In this study, ethyl acetate (EtOAc) extract of S. thorelii rhizomes was analyzed for its phychemicals, antioxidant activity and inhibition against enzymes (acetylcholinesterase, α-amylase, α-glucosidase, and tyrosinase). The EtOAc extract showed the presence of ferulic acid, catechin, epicatechin, epigallocatechin gallate, quercetin, and kaempferol, with average levels ranging from 169.29 to 2449.60 μg/g. Analysis of the volatile components of the extract revealed that β-patchoulene (23.1%), (E)-nerolidyl isobutyrate (11.9%), and aristolene (10.8%) were the major compounds. The antioxidant potential of the extract measured by DPPH (IC50 = 86.94 ± 2.87 μg/mL) and ABTS (IC50 = 743.60 ± 56.52 μg/mL) assays showed promising results. The inhibitory effects against acetylcholinesterase and α-amylase demonstrated potential with IC50 values of 246.43 ± 11.39 and 789.84 ± 8.27 µg/mL, respectively. The findings above suggest that the EtOAc extract of S. thorelii could contribute to supporting the treatment of certain diseases such as diabetes and Alzheimer's.}, }
@article {pmid40109019, year = {2025}, author = {Wang, L and Sooram, B and Kumar, R and Schedin-Weiss, S and Tjernberg, LO and Winblad, B}, title = {Tau degradation in Alzheimer's disease: Mechanisms and therapeutic opportunities.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e70048}, pmid = {40109019}, issn = {1552-5279}, support = {//Private Initiative "Innovative ways to fight Alzheimer´s disease Leif Lundblad Family and others"/ ; //Strategic Research Program in Neuroscience (StratNeuro) funding for postdoctoral researchers at Karolinska Institutet/ ; //Stiftelsen för Gamla Tjänarinnor/ ; //Gun och Bertil Stohnes Stiftelse/ ; //Åhlén-stiftelsen/ ; //Tore Nilsons Stiftelse för Medicinsk Forskning/ ; FO2024-0287-HK-66//Hjärnfonden/ ; 2024-03573//Vetenskapsrådet/ ; //Margaretha af Ugglas Foundation/ ; //Foundation for Geriatric Diseases at Karolinska Institutet/ ; //Karolinska Institutet Research Grants/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism ; *tau Proteins/metabolism ; *Proteolysis ; Autophagy/physiology ; Protein Processing, Post-Translational ; Animals ; Proteasome Endopeptidase Complex/metabolism ; Lysosomes/metabolism ; Ubiquitin/metabolism ; }, abstract = {In Alzheimer's disease (AD), tau undergoes abnormal post-translational modifications and aggregations. Impaired intracellular degradation pathways further exacerbate the accumulation of pathological tau. A new strategy - targeted protein degradation - recently emerged as a modality in drug discovery where bifunctional molecules bring the target protein close to the degradation machinery to promote clearance. Since 2016, this strategy has been applied to tau pathologies and attracted broad interest in academia and the pharmaceutical industry. However, a systematic review of recent studies on tau degradation mechanisms is lacking. Here we review tau degradation mechanisms (the ubiquitin-proteasome system and the autophagy-lysosome pathway), their dysfunction in AD, and tau-targeted degraders, such as proteolysis-targeting chimeras and autophagy-targeting chimeras. We emphasize the need for a continuous exploration of tau degradation mechanisms and provide a future perspective for developing tau-targeted degraders, encouraging researchers to work on new treatment options for AD patients. HIGHLIGHTS: Post-translational modifications, aggregation, and mutations affect tau degradation. A vicious circle exists between impaired degradation pathways and tau pathologies. Ubiquitin plays an important role in complex degradation pathways. Tau-targeted degraders provide promising strategies for novel AD treatment.}, }
@article {pmid40109001, year = {2025}, author = {Bai, P and Mondal, P and Liu, Y and Gomm, A and Suen, C and Yang, L and Zhu, B and Sun, H and Ran, C and Shen, S and Tanzi, RE and Zhang, C and Wang, C}, title = {HDAC11 displays neuropathological alterations and offers as a novel drug target for Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e14616}, pmid = {40109001}, issn = {1552-5279}, support = {1R01AG086433/GF/NIH HHS/United States ; //Cure Alzheimer's Fund/ ; //Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital/ ; 1P30AG062421-01//MADRC/ ; }, mesh = {*Alzheimer Disease/drug therapy/pathology ; Animals ; *Mice, Transgenic ; Mice ; Humans ; *Histone Deacetylases/metabolism/drug effects ; *Brain/drug effects/pathology/metabolism ; *Disease Models, Animal ; Male ; Histone Deacetylase Inhibitors/pharmacology ; Female ; Aged ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by amyloid pathology and neuroinflammation, leading to cognitive decline. Targeting histone deacetylase-11 (HDAC11) offers a novel therapeutic strategy due to its role in immune regulation.
METHODS: We conducted neuropathological analyses on human AD post mortem brain tissues and 5xFAD transgenic mice. We developed PB94, a brain-permeable HDAC11-selective inhibitor, and assessed its effects using live-animal imaging and behavioral studies.
RESULTS: HDAC11 was significantly upregulated in AD brains, correlating with amyloid pathology and neuroinflammatory markers. PB94 treatment reduced amyloid burden and neuroinflammation, improving cognitive function in 5xFAD mice.
DISCUSSION: Our findings highlight HDAC11 as a promising drug target for AD. PB94's ability to reduce amyloid pathology and neuroinflammation suggests its potential as an effective therapeutic. This study supports further exploration of HDAC11 inhibition as a treatment strategy for AD.
HIGHLIGHTS: Histone deacetylase-11 (HDAC11) is significantly upregulated in Alzheimer's disease (AD) brains and colocalizes with amyloid pathology and neuroinflammatory markers. Novel brain-permeable HDAC11-selective inhibitor PB94 demonstrates promising therapeutic potential for AD treatment. PB94 treatment reduces amyloid burden and neuroinflammation in AD mouse models, confirmed by live imaging studies. HDAC11 inhibition enhances microglial phagocytosis of amyloid beta proteins and modulates inflammatory cytokine levels. PB94 treatment improves cognitive function in AD mouse models while showing favorable brain penetration and selectivity.}, }
@article {pmid40108882, year = {2025}, author = {Davidson, M and Stanciu, GD and Rabinowitz, J and Untu, I and Dobrin, RP and Tamba, BI}, title = {Exploring novel therapeutic strategies: Could psychedelic perspectives offer promising solutions for Alzheimer's disease comorbidities?.}, journal = {Dialogues in clinical neuroscience}, volume = {27}, number = {1}, pages = {1-12}, pmid = {40108882}, issn = {1958-5969}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Comorbidity ; *Hallucinogens/therapeutic use ; }, abstract = {The increasing prevalence of dementia within an ageing global population, combined with prolonged life expectancy, accentuates Alzheimer's disease (AD) as a multifaceted healthcare challenge. This challenge is further compounded by the limited therapeutic options currently available. Addressing the intricacies of AD management, the mitigation of comorbidities has emerged as a pivotal facet of treatment. Comorbid conditions, such as neurobehavioral symptoms, play a role in shaping the clinical course, management, and outcomes of this pathology; highlighting the importance of comprehensive care approaches for affected individuals. Exploration of psychedelic compounds in psychiatric and palliative care settings has recently uncovered promising therapeutic potential, enhancing neuroplasticity, emotional processing and connection. These effects are particularly relevant in the context of AD, where psychedelic therapy offers hope not only for mitigating core symptoms but also for addressing the array of comorbidities associated with this condition. The integration of this comprehensive method offers a chance to significantly enhance the care provided to those navigating the intricate landscape of AD. Therefore, the current paper reviews the intricate link between more frequent additional health conditions that may coexist with dementia, particularly in the context of AD, and explores the therapeutic potential of psychedelic compounds in addressing these concurrent conditions.}, }
@article {pmid40107930, year = {2025}, author = {Hendrix, SB and Sano, M and Lyketsos, C and Rosenberg, PB and Porsteinsson, AP and Brown, BL and Hedges, D and Cummings, JL}, title = {Cohen-mansfield agitation inventory total score as a measure of agitation and aggression in Alzheimer's disease: A factor analysis.}, journal = {International psychogeriatrics}, volume = {}, number = {}, pages = {100056}, doi = {10.1016/j.inpsyc.2025.100056}, pmid = {40107930}, issn = {1741-203X}, abstract = {BACKGROUND: Alzheimer's disease (AD) is often associated with agitation and aggression, which may impair function, impede care, and be a major source of stress for caregivers. The Cohen-Mansfield Agitation Inventory (CMAI) is often used to assess agitation and aggression. In its original, nursing-home version, it is a 29-item, caregiver-informed, clinician-administered 7-point scale that assesses the frequency of various agitation or aggressive behaviors. However, the instruction manual advises against the use of the total score in favor of a domain-based analysis. This recommendation has been followed in both clinical trials and practice. Because the CMAI is comprehensive and easy to administer, we sought to determine the validity of its total score as a single construct for assessing agitation and aggression in patients with AD.
METHODS: We used a previously conducted factor analysis of the CMAI scores from two risperidone trials in patients with dementia (N = 648), and a follow-up analysis of the subset of patients with psychosis of AD (N = 479), to examine, using vector analysis and an effect-size-versus-signal-to-noise ratio analysis, whether the total CMAI score could confidently be used as a global measure of agitation and aggression in AD.
RESULTS: Our findings suggest that the CMAI items from the dataset analyzed load into 4 clusters, which cover about 50 % of the total data variance. Surprisingly, items with the lowest signal-to-noise ratio (hitting, performing repetitious mannerisms, aimless pacing or wandering) had the strongest response to treatment (and vice versa), and belonged to different factors. The further observation that many items were spread among the factors, instead of primarily measuring a single factor or domain, suggests that there is a continuum of symptoms, and separating them into domains requires separating very similar items that measure two or more domains.
CONCLUSIONS: These findings suggest that assessing agitation and aggression via CMAI domains instead of the total score is likely to miss important behavioral signals. Using total CMAI score in clinical trials and practice, along with the assessment of individual items, is warranted.}, }
@article {pmid40107763, year = {2025}, author = {, and , }, title = {[Expert consensus on disease-modifying therapy for Alzheimer's disease].}, journal = {Zhonghua yi xue za zhi}, volume = {105}, number = {}, pages = {1-11}, doi = {10.3760/cma.j.cn112137-20250304-00512}, pmid = {40107763}, issn = {0376-2491}, support = {2021ZD0201801//Science and Technology Innovation 2030-Major Project on "Brain Science and Brain-Like Research"/ ; 2022YFC3602600//National Key Research and Development Program of China/ ; }, abstract = {Alzheimer's disease (AD) poses a significant challenge to China's aging population, and treatment is now comprehensively shifting toward disease-modifying therapy (DMT). By targeting core pathophysiological mechanisms, DMT seeks to alter the natural progression of AD. As an emerging therapeutic paradigm, there is an urgent need for expert consensus to standardize the clinical use of DMT drugs in AD. This consensus systematically reviews both clinical practice and research advancements related to DMT for AD, including its target populations, contraindications and high-risk groups, pre-treatment evaluation procedures, administration methods and durations, efficacy assessments, and adverse event monitoring. It presents 17 recommendations to guide the clinical application of DMT in AD.}, }
@article {pmid40107503, year = {2025}, author = {Zhu, L and Liu, C and Wang, Y and Zhu, X and Wu, L and Chen, L and Zhou, J and Wang, F}, title = {METTL3/IGF2BP2/IκBα axis participates in neuroinflammation in Alzheimer's disease by regulating M1/M2 polarization of microglia.}, journal = {Neurochemistry international}, volume = {186}, number = {}, pages = {105964}, doi = {10.1016/j.neuint.2025.105964}, pmid = {40107503}, issn = {1872-9754}, abstract = {BACKGROUND: Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD.
METHOD: Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N[6]-methyladenosine (m[6]A) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF.
RESULTS: Stimulation with Aβ1-42 led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα m[6]A modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα.
CONCLUSION: Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.}, }
@article {pmid40107427, year = {2025}, author = {Oh, JM and Kim, SH and Pandey, BP and Shin, WH and Son, HJ and Kwon, YJ and Kim, H}, title = {A stilbenoid, rhapontigenin, isolated from the root of Rheum palmatum L. acts as a potent BACE1 inhibitor.}, journal = {Fitoterapia}, volume = {182}, number = {}, pages = {106484}, doi = {10.1016/j.fitote.2025.106484}, pmid = {40107427}, issn = {1873-6971}, mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors ; *Stilbenes/pharmacology/isolation & purification/chemistry ; *Aspartic Acid Endopeptidases/antagonists & inhibitors ; *Rheum/chemistry ; *Plant Roots/chemistry ; Molecular Structure ; Phytochemicals/pharmacology/isolation & purification ; Humans ; China ; Anthraquinones/pharmacology/isolation & purification/chemistry ; Molecular Docking Simulation ; }, abstract = {Seven compounds, comprising three anthraquinones and four stilbenoids, were isolated from the roots of Rheum palmatum L. These compounds include chrysophanol (1), aloe-emodin (2), aloe-emodin 8-O-β-D-glucopyranoside (3), desoxyrhapontigenin (4), rhapontigenin (5), desoxyrhaponticin (6), and piceatannol 3'-O-β-D-glucopyranoside (7). Among these, compound 5 showed potent β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitory activity with an IC50 value of 0.256 ± 0.008 μM, making it the most effective inhibitor obtained from herbal extracts to date, followed by compounds 3 (1.164 ± 0.108 μM), 6 (1.213 ± 0.193 μM), 7 (1.270 ± 0.130 μM), and 4 (2.028 ± 0.108 μM). Furthermore, kinetic analysis revealed that compound 5 acted as a mixed type-I inhibitor with an inhibition constant Ki value of 0.28 ± 0.07 μM. Notably, compound 2 exhibited potent Aβ aggregation inhibition with an IC50 value of 3.56 ± 0.19 μM, whereas compound 5 showed low Aβ aggregation inhibition with an IC50 value of >40 μM. The docking simulations revealed that compound 5 had a high binding affinity and interacted with TYR132, predicting it as a key residue for inhibition via hydrophobic interaction, and with THR133 via hydrogen bonding, in the flap region of BACE1. These results suggest that stilbenoids generally exhibit higher BACE1 inhibitory activity than that of anthraquinones, and that compound 5 (rhapontigenin) could be a promising candidate for the treatment of Alzheimer's disease as a potent BACE1 inhibitor.}, }
@article {pmid40107366, year = {2025}, author = {Qin, W and He, J and Zhou, Y}, title = {Potential mechanism and efficacy evaluation of transcranial focused ultrasound therapy for Alzheimer's disease.}, journal = {Journal of neuroscience methods}, volume = {418}, number = {}, pages = {110428}, doi = {10.1016/j.jneumeth.2025.110428}, pmid = {40107366}, issn = {1872-678X}, abstract = {BACKGROUND: Transcranial focused ultrasound (TFU) is emerging as a promising non-invasive therapy capable of blood-brain barrier (BBB) opening. TFU potentially allows the transfer of therapeutic agents to targeted brain areas for patients affected with Alzheimer's disease (AD).
NEW METHOD: The efficacy and mechanism of TFU in modulating BBB permeability in key brain regions, including the hippocampus and frontal lobe, are investigated in this research. A total of 20 participants aged 60-85 years were involved with AD. The treatment protocol involved three TFU sessions, spaced three weeks apart. The research encompasses pre-assessment and post-assessment of treatment with follow-up ranging from 5 to 12 months.
RESULTS: Statistical analysis involved paired t-tests to compare pre- and post-treatment cognitive scores, and ANOVA to predict significant differences in amyloid reduction across different brain regions, with the high decrease observed in the hippocampus. Multivariate Analysis (MANOVA) to explore the combined effect of cognitive and amyloid data. Linear Regression Analysis to predict cognitive improvement from amyloid plaque reduction. Longitudinal analysis for time-to-event analysis assessing the durability of effects over time.
Florbetaben Positron Emission Tomography (PET) scans demonstrated a reduction in β-amyloid plaque burden, with a 15 % average decrease in the treated brain regions. No adverse effects on disease progression were observed up to 1 year after treatment.
CONCLUSION: This analysis presents the largest cohort of AD patients treated with TFU, with the longest follow-up to date. The treatment demonstrated safety and feasibility, with reversible BBB opening in multiple brain regions.}, }
@article {pmid40107340, year = {2025}, author = {Tozihi, M and Nourazarian, A and Yousefi, H and Dehghan, G}, title = {Methylglyoxal-induced neuronal dysfunction: Linking diabetes to Alzheimer's disease through cytoskeletal disruption.}, journal = {European journal of pharmacology}, volume = {998}, number = {}, pages = {177526}, doi = {10.1016/j.ejphar.2025.177526}, pmid = {40107340}, issn = {1879-0712}, abstract = {This study investigates how methylglyoxal affects Alzheimer's disease, which is common in patients with diabetes mellitus. Using SH-SY5Y cells as a model of AD, we investigated the effects of MGO on cell viability, morphology, inflammation, and stress responses. Exposure to MGO induces cytotoxicity, inflammation and oxidative stress that contribute to AD in diabetic patients. We analyzed how MGO (150-900 μM) affects SH-SY5Y cells and its effects on cell survival, gene expression, cytoskeletal integrity, stress indicators, and Aβ42 accumulation (dose- and time-dependent). MGO dramatically affected cell viability depending on the dose and exposure time. Cell death occurred via intrinsic (BAX, CASP9) and extrinsic (FAS, FASLG) apoptotic pathways. Markers related to insulin signaling such as INSR, IRS1, IRS2, SLC2A4, etc. were downregulated, whereas markers of inflammation such as TNF-α, IL-6 and oxidative markers such as HMOX1, G6PD, etc. were upregulated with MGO (P < 0.001). Changes in MAP2 and TUBB3 expression were associated with cytoskeletal damage (P < 0.01). High levels of Aβ42 and low SOD activity confirmed that oxidative stress was induced. LPS treatment exacerbated these effects (P < 0.01). The results highlight the possible role of MGO in cognitive decline associated with diabetes and suggest the need for novel treatment against MGO-related neurotoxicity.}, }
@article {pmid40105503, year = {2025}, author = {Chen, YH and Wang, ZB and Liu, XP and Mao, ZQ and , }, title = {Cerebrospinal fluid LMO4 as a synaptic biomarker linked to Alzheimer's disease pathology and cognitive decline.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251326286}, doi = {10.1177/13872877251326286}, pmid = {40105503}, issn = {1875-8908}, abstract = {BackgroundLIM-domain-only 4 (LMO4) is involved in neurodevelopment and synaptic plasticity, but its role in the pathogenesis of Alzheimer's disease (AD) remains unclear.ObjectiveTo investigate the association between cerebrospinal fluid (CSF) LMO4 levels and core AD biomarkers, neurodegeneration, and cognitive decline.MethodsWe included 703 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Associations between CSF LMO4 and AD biomarkers (Aβ42, Ptau181, amyloid PET) and postmortem neuropathology were evaluated. We also explored cross-sectional and longitudinal associations between CSF LMO4 and neurodegeneration and cognitive function. Receiver operating characteristic (ROC) analysis assessed the diagnostic accuracy of CSF LMO4 in distinguishing Aβ-positive from Aβ-negative participants and amyloid PET-confirmed AD cases. Mediation analysis explored the potential mediating role of CSF LMO4 between Aβ pathology and tau pathology.ResultsLMO4 levels were decreased in participants with abnormal Aβ levels and cognitive impairment. Lower CSF LMO4 levels were associated with increased Aβ and tau pathology, brain atrophy, cognitive decline, and postmortem neuropathology. CSF LMO4 partially mediated the relationship between Aβ and tau pathology and demonstrated acceptable discriminative ability in distinguishing Aβ-positive from Aβ-negative participants and amyloid PET-confirmed AD from non-AD cases.ConclusionsCSF LMO4 plays a crucial role in the pathogenesis and progression of AD and may represent a potential therapeutic target for AD treatment.}, }
@article {pmid40105173, year = {2025}, author = {Deng, H and Wang, Y and Dai, Y and Wang, Q and Lu, H and Wang, Q}, title = {Unraveling the genetic mysteries of sarcopenia: A bioinformatics approach.}, journal = {Technology and health care : official journal of the European Society for Engineering and Medicine}, volume = {33}, number = {2}, pages = {1140-1153}, doi = {10.1177/09287329241291323}, pmid = {40105173}, issn = {1878-7401}, mesh = {*Sarcopenia/genetics ; Humans ; *Computational Biology/methods ; *Protein Interaction Maps/genetics ; Gene Regulatory Networks ; Gene Expression Profiling ; Gene Ontology ; Biomarkers/metabolism ; }, abstract = {Background As life expectancy increases and the global population ages, the incidence of sarcopenia is also increasing, highlighting the need for better diagnosis and treatment methods.ObjectiveTo study the genetic expression of sarcopenia using bioinformatics methods.MethodsA Weighted Gene Coexpression Network Analysis (WGCNA) was conducted to construct coexpression networks, along with protein-protein interaction networks. Diagnostic biomarker potential was evaluated using receiver operating characteristic curves. An analysis of Single-Sample Gene Set Enrichment Analysis (ssGSEA) was performed in order to determine the amount of immune cell infiltration. We analyzed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) enrichment using the KEGG.ResultsWGCNA identified modules linked to bone metabolism, ssGSEA showed unique gene enrichment patterns, and 268 genes were found to be differentially expressed in sarcopenia. Fourteen co-expression modules related to bone metabolism were identified, with one showing a strong positive correlation. KEGG pathway analysis indicated downregulation of the renin-angiotensin system and Alzheimer's disease pathways. The differentially expressed genes were primarily involved in adipocyte differentiation.ConclusionThis study analyzes genetic changes and immune cell patterns in sarcopenia, providing insights into its causes and potential diagnostic markers for future research on treatments.}, }
@article {pmid40104800, year = {2025}, author = {Wang, SQ and Wang, X and Guo, L and Chen, XX and Huang, XJ and Zhang, S and Ye, WC and Zhang, XQ and Shi, L and Wang, Y and Hu, LJ}, title = {In-Silico Screening-Based Discovery of New Natural eEF2K Inhibitors with Neuritogenic Activity.}, journal = {ACS medicinal chemistry letters}, volume = {16}, number = {3}, pages = {475-482}, pmid = {40104800}, issn = {1948-5875}, abstract = {Eukaryotic elongation factor 2 kinase (eEF2K), an atypical Ser/Thr-protein kinase that regulates neuronal protein synthesis homeostasis via an inhibitory phosphorylation of eEF2, has emerged as a promising therapeutic target for several diseases, including Alzheimer's disease (AD). In this study, we employed molecular docking with an in-house natural product library of 4270 compounds, containing 2177 novel compounds and 603 new structural frameworks, to identify eEF2K inhibitors. Following virtual screening, 25 natural products were selected for in-vitro evaluation of eEF2 phosphorylation inhibition as well as protein synthesis promotion. Our findings identified that compounds 17 and 23 potently suppress eEF2K activity, increase protein synthesis, and concurrently induce neuritogenesis. Molecular dynamics simulations suggest that 17 and 23 may stably bind to the eEF2K protein. Our findings highlighted 17 and 23 as new natural eEF2K inhibitors and promising candidates for promoting neural differentiation, providing potential therapeutic leads for the treatment of AD.}, }
@article {pmid40104794, year = {2025}, author = {Feng, S and Liang, SH}, title = {Identification of Indazole- and Azaindazole-Substituted Cyclopentapyrroles as G2019S Leucine-Rich Repeat Kinase 2 Inhibitors for the Treatment of CNS Disorders.}, journal = {ACS medicinal chemistry letters}, volume = {16}, number = {3}, pages = {368-370}, pmid = {40104794}, issn = {1948-5875}, abstract = {This patent describes a novel class of novel indazole/azaindazole-substituted cyclopentapyrroles, which selectively inhibit the Leucine-Rich Repeat Kinase 2 (LRRK2) with G2019S mutation. These LRRK2 inhibitors are proposed for treating Parkinson's diseases, Alzheimer's disease, and other central nervous system (CNS) disorders.}, }
@article {pmid40104524, year = {2025}, author = {Sullivan, AC and Zuniga, G and Ramirez, P and Fernandez, R and Wang, CP and Li, J and Davila, L and Pelton, K and Gomez, S and Sohn, C and Gonzalez, E and Lopez-Cruzan, M and Gonzalez, DA and Parker, A and Zilli, E and de Erausquin, GA and Seshadri, S and Espinoza, S and Musi, N and Frost, B}, title = {A Phase IIa clinical trial to evaluate the effects of anti-retroviral therapy in Alzheimer's disease (ART-AD).}, journal = {NPJ dementia}, volume = {1}, number = {1}, pages = {2}, pmid = {40104524}, issn = {3005-1940}, support = {RF1 NS112391/NS/NINDS NIH HHS/United States ; }, abstract = {Retrotransposons constitute over 40% of the human genome. Studies in Drosophila, mice, cultured cells, and human brain show that retrotransposons are activated in tauopathies, including Alzheimer's disease, and causally drive neurodegeneration. The reverse transcriptase inhibitor 3TC (lamivudine) reduces retrotransposon activation and suppresses tau neurotoxicity among model systems. This phase 2a open-label trial (Pilot Study to Investigate the Safety and Feasibility of Anti-Retroviral Therapy for Alzheimer's Disease, NCT04552795, registered 09/10/2020) followed 12 participants with early Alzheimer's disease (MMSE > 24, CDR = 0.5) over 24 weeks to assess safety, tolerability, and feasibility of daily 300 mg 3TC treatment. The sample was well-educated (12-20 years) and culturally diverse (25% from underrepresented groups). In addition to a favorable safety profile and stable cognitive measures, notable significant changes in fluid-based biomarkers include reduction of glial fibrillary acidic protein (GFAP) (P = 0.03) in CSF, suggestive of reduced neuroinflammation, and elevation of Aβ42/40 (P = 0.009) in plasma, suggestive of reduced plaque load in the brain. These results warrant further exploration in a larger, placebo-controlled trial.}, }
@article {pmid40102464, year = {2025}, author = {Ur Rahman, J and Hanif, M and Ur Rehman, O and Haider, U and Mian Qaisar, S and Pławiak, P}, title = {Stages prediction of Alzheimer's disease with shallow 2D and 3D CNNs from intelligently selected neuroimaging data.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {9238}, pmid = {40102464}, issn = {2045-2322}, mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; *Neuroimaging/methods ; *Magnetic Resonance Imaging/methods ; *Neural Networks, Computer ; *Deep Learning ; Aged ; Female ; Brain/diagnostic imaging/pathology ; Male ; Cognitive Dysfunction/diagnostic imaging ; Positron-Emission Tomography/methods ; }, abstract = {Detection of Alzheimer's Disease (AD) is critical for successful diagnosis and treatment, involving the common practice of screening for Mild Cognitive Impairment (MCI). However, the progressive nature of AD makes it challenging to identify its causal factors. Modern diagnostic workflows for AD use cognitive tests, neurological examinations, and biomarker-based methods, e.g., cerebrospinal fluid (CSF) analysis and positron emission tomography (PET) imaging. While these methods are effective, non-invasive imaging techniques like Magnetic Resonance Imaging (MRI) are gaining importance. Deep Learning (DL) approaches for evaluating alterations in brain structure have focused on combining MRI and Convolutional Neural Networks (CNNs) within the spatial architecture of DL. This combination has garnered significant research interest due to its remarkable effectiveness in automating feature extraction across various multilayer perceptron models. Despite this, MRI's noisy and multidimensional nature requires an intelligent preprocessing pipeline for effective disease prediction. Our study aims to detect different stages of AD from the multidimensional neuroimaging data obtained through MRI scans using 2D and 3D CNN architectures. The proposed preprocessing pipeline comprises skull stripping, spatial normalization, and smoothing. It is followed by a novel and efficient pixel count-based frame selection and cropping approach, which renders a notable dimension reduction. Furthermore, the learnable resizer method is applied to enhance the image quality while resizing the data. Finally, the proposed shallow 2D and 3D CNN architectures extract spatio-temporal attributes from the segmented MRI data. Furthermore, we merged both the CNNs for further comparative analysis. Notably, 2D CNN achieved a maximum accuracy of 93%, while 3D CNN reported the highest accuracy of 96.5%.}, }
@article {pmid40102200, year = {2025}, author = {Wang, M and Jin, B and Jo, J}, title = {Acute Restraint Stress Induces Long-Lasting Synaptic Enhancement by Inhibiting AMPK Activation in AD Model Mice.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {3}, pages = {e70335}, pmid = {40102200}, issn = {1755-5949}, support = {23YR1600//the Korean government (MSIP)/ ; 24-BR-03-05//KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT/ ; 10.13039/501100003725//Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education/ ; 10.13039/100020206//Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; LQ24H310001//Natural Science Foundation of Zhejiang Province/ ; }, mesh = {Animals ; *Disease Models, Animal ; *Long-Term Potentiation/drug effects/physiology ; *Restraint, Physical ; *Stress, Psychological/psychology/metabolism ; *Alzheimer Disease/metabolism ; *Mice, Transgenic ; Mice ; AMP-Activated Protein Kinases/metabolism ; Male ; Hippocampus/drug effects/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Humans ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by a gradual synaptic loss. The progression of AD severely affects late-phase long-term potentiation (L-LTP), which is essential for long-term memory consolidation.
AIM: We have previously demonstrated the beneficial effects of acute restraint stress (ARS) on hippocampal LTP in AD mouse models. This study aimed to verify the effects and potential mechanisms of ARS on the maintenance of hippocampal L-LTP in two AD mouse models.
MATERIALS AND METHODS: 5xFAD and Tg2576 mice underwent a 30-min body immobilization protocol to induce ARS, followed by electrophysiological recordings of L-LTP (> 3 h) in the CA1 region of thehippocampus.
RESULTS: The ARS-exposed group exhibited significantly enhanced L-LTP compared to the control group. Maintenance of L-LTP requires new protein synthesis and signaling via the mammalian target of rapamycin (mTOR) pathway. Our findings revealed that ARS increased hippocampal adenosine triphosphate (ATP) production and reduced AMPK activity. Inactivation of AMPK and subsequent activation of the mTOR pathway were strongly associated with the ARS-facilitated enhancement of L-LTP. Furthermore, our experiments using the mTOR inhibitor rapamycin demonstrated that it effectively prevented the enhancement of L-LTP following ARS, underscoring the pivotal role of mTOR in this process.
CONCLUSION: ARS may significantly modify AMPK activation and mTOR regulation in L-LTP, potentially triggering the mechanisms of long-term memory consolidation in AD mouse model mice. Identifying these underlying mechanisms could help promote the development of novel pharmaceutical agents for the treatment of AD.}, }
@article {pmid40102146, year = {2025}, author = {Aho, E and Religa, D and Ding, M and Winblad, B and Jönsson, L and Modig, K}, title = {Patient management pathways in dementia - Resource utilisation, diagnosis and drug treatment in the Stockholm region, Sweden.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100132}, doi = {10.1016/j.tjpad.2025.100132}, pmid = {40102146}, issn = {2426-0266}, abstract = {BACKGROUND: New diagnostic and therapeutic options for Alzheimer's disease are beginning to be introduced and expected igto become more widely available in the coming years. Improved understanding of current pathways in diagnosis and initial care of patients with dementia can help inform choices around how best to integrate new technologies in existing care structures.
OBJECTIVES: The aim of this study is to describe the care management pathways defined by the involvement of specialist and primary care for individuals with newly diagnosed dementia. It also seeks to characterise individuals in different management pathways based on resource use prior to diagnosis, the type of dementia diagnosis received, and the proportion who receive symptomatic anti-dementia drug treatment.
DESIGN: Observational cohort study SETTING: Stockholm region, Sweden.
PARTICIPANTS: All newly diagnosed dementia cases between 1st January 2018 to 30th June 2020 (n = 9,781). Dementia diagnoses in primary care were based on Regional Stockholm health care database and diagnoses in specialist care were based on the National Patient Register in Sweden.
MEASUREMENTS: Care management pathways were categorized into three groups: primary care only (diagnosed and followed up in primary care), specialist, no follow-up (diagnosed in specialist care but not followed up in specialist care), and specialist with follow-up (diagnosed and followed up in specialist care). These classifications were based on patients' care episodes from the date of diagnosis and the subsequent 18 months. age at diagnosis, resource utilisation one-year prior diagnosis and diagnosis given and symptomatic anti-dementia treatment 18 months after initial diagnosis.
RESULTS: A total of 9,781 newly diagnosed dementia cases were identified. In the 18 months following diagnosis, 63 % of patients were diagnosed either partly or fully in specialist care, while 37 % were diagnosed solely in primary care. Patients diagnosed and managed only in primary care were older, spent more days in hospital, and received more social care in the year preceding their diagnosis. Their total care costs were also the highest. Alzheimer's disease was the most common diagnosis (48 %), while 27 % had an unspecified dementia diagnosis, varying by care setting (61 % for patients managed in primary care only and 6 % for patients diagnosed and followed up in specialist care). Overall, 47 % of patients received symptomatic anti-dementia treatment, with the highest share for patients diagnosed and followed up in specialist care (73 %) and the lowest in primary care only (19 %). Diagnosis varied by age and care setting Alzheimer's was most common in settings involving specialist care, whereas unspecified dementia was more common in primary care only regardless of age.
CONCLUSION: The findings that patients managed exclusively in primary care were older, had higher pre-diagnosis resource utilisation, and were less likely to receive specific diagnoses or anti-dementia treatments highlight the crucial role of primary care in diagnosing and managing dementia among older individuals with complex needs. Further research is needed to explore primary care's role in diagnosis and treatment across diverse healthcare systems. Future research is needed to explore whether and how new diagnostic tools and treatment for AD could facilitate timely diagnosis and care for older individuals with dementia in primary care.}, }
@article {pmid40101857, year = {2025}, author = {Wang, J and Pan, H and Tang, H and Zhang, J and Li, T and Liu, Y and Huang, Y and Fei, Z and Wang, Y}, title = {Shuangxia Decoction attenuates sleep disruption in 5×FAD mice through neuroinflammation inhibition: An integrative analysis of transcriptomic and molecular biology investigations.}, journal = {Journal of ethnopharmacology}, volume = {345}, number = {}, pages = {119642}, doi = {10.1016/j.jep.2025.119642}, pmid = {40101857}, issn = {1872-7573}, mesh = {Animals ; Mice ; Male ; *Transcriptome/drug effects ; *Alzheimer Disease/drug therapy ; Mice, Inbred C57BL ; Neuroinflammatory Diseases/drug therapy ; Mice, Transgenic ; Sleep Wake Disorders/drug therapy ; Disease Models, Animal ; Drugs, Chinese Herbal/pharmacology/chemistry ; Pinellia/chemistry ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory and learning deficits. Circadian rhythm disruption-induced sleep disruption is frequently observed in AD patients. The Shuangxia Decoction (SXD) comprising Pinellia ternata (Thunb.) Breit. (Banxia) and Prunella vulgaris L. (Xiakucao), has been effectively used to treate sleep disruption for thousands of years. However, the mechanisms by which SXD treated AD through circadian rhythm-related pathways remain unexplored.
AIMS OF THE STUDY: This research sought to determine the efficacy, mechanisms, and active compounds of SXD in AD treatment via an integrative approach.
MATERIALS AND METHODS: We conducted a chronic jet lag (CJL) protocol in wild-type (WT) mice and monitored their rest/activity to compare their rest/activity period among WT, CJL, and CJD + SXD groups. In addition, we evaluated the impact of SXD on the cognitive and Aβ burden of 5 × FAD mice by behavioral tests and Thioflavin staining. The underlying pathway analysis of SXD was revealed through transcriptomic and biology experimental validation. The active compounds of SXD were further analyzed using the UPLC-MS, molecular docking, and cellular thermal shift assay (CESTA).
RESULTS: Our study demonstrated a rapid recovery of rest/activity period in CJL mice following SXD treatment. Additionally, SXD treatment alleviated Aβ plaque accumulation, subsequently preserving cognitive behavior and motor ability in 5 × FAD mice. Moreover, SXD significantly enhanced neuronal synaptic plasticity dendritic plasticity in CA1 neurons of 5 × FAD mice. Transcriptomic analysis showed upregulation of the neuroinflammation-related pathway in 5 × FAD mice. Subsequent heatmap analysis indicated a suppression of inflammatory factor secretion (Cd68, Trem2, IL-6, IL-1β, Cxc3r1, Tnf et al.) and an increase of anti-inflammatory factor secretion (IL4, Ccl19, Ccl21a et al.) following SXD treatment in the 5 × FAD mice. Meanwhile, SXD upregulated positive regulators involved in the circadian rhythm like Bmal1 and Clock, and downregulated negative regulators like Nr1d1. Moreover, microglia exhibited an amoeboid morphology characterized by few processes and rounded cell bodies in 5 × FAD mice, whereas the age-matched SXD group maintained microglia with a ramified appearance. Additionally, our study identified 20 major components of SXD and identified 3-(3,4-Dihydroxyphenyl) lactic acid, Salviaflaside, and Ilexhainanoside D for further molecular docking with REV-ERBα (NR1D1), a commonly used circadian target. Salviaflaside further showed a strong bind with REV-ERBα via CESTA.
CONCLUSIONS: Our findings indicate that SXD may rescue circadian rhythm in 5 × FAD mice through specifically binding to REV-ERBα in microglia to activate the BMAL1/CLOCK pathway, thus inhibiting transcription of inflammatory factors, contributing to alleviating neuroinflammation and impeding AD progression. Our results offer a scientific foundation for developing SXD-based therapies in the early stage of AD, where sleep disruption precedes cognitive decline, offering potential leads for clinical trials to improve sleep quality thus delaying neurodegeneration in AD patients.}, }
@article {pmid40101674, year = {2025}, author = {Iaccarino, L and Burnham, SC and Tunali, I and Wang, J and Navitsky, M and Arora, AK and Pontecorvo, MJ}, title = {A practical overview of the use of amyloid-PET Centiloid values in clinical trials and research.}, journal = {NeuroImage. Clinical}, volume = {46}, number = {}, pages = {103765}, pmid = {40101674}, issn = {2213-1582}, abstract = {The density of brain amyloid-beta neuritic plaque accumulation, a marker of Alzheimer's disease (AD), can be visualized and quantified using amyloid-positron emission tomography (PET). Amyloid-PET data can be obtained using different tracers and methodologies; therefore, comparison across studies can be difficult. The introduction of Centiloids in 2015 allowed for the transformation of amyloid-PET quantitative data to a common scale, enhancing comparability across studies and potentially enabling pooled analysis. Since then, Centiloid values have been used increasingly in research and clinical trials for multiple purposes, being tested and validated with a variety of clinical, biomarker and pathological standards of truth. In clinical trials, Centiloid values have been used for patient selection, to confirm the presence of AD pathology, as well as for treatment monitoring, especially in trials of disease-modifying treatments such as amyloid-targeting therapies. Building on their widespread adoption, Centiloid values are increasingly being integrated into commercially available software solutions for quantifying amyloid-PET, paving the way for real-world applications at the community level. This article addresses frequently asked questions about Centiloid definition, implementation, interpretation, and caveats, and also summarizes the available literature on published thresholds, ultimately supporting wider access and informed use of Centiloid values in Alzheimer's disease research.}, }
@article {pmid40101029, year = {2025}, author = {Liu, D and Zhao, Y and Liu, R and Qiao, B and Lu, X and Bei, Y and Niu, Y and Yang, X}, title = {Traditional Chinese medicine as a viable option for managing vascular cognitive impairment: A ray of hope.}, journal = {Medicine}, volume = {104}, number = {11}, pages = {e41694}, pmid = {40101029}, issn = {1536-5964}, mesh = {Humans ; *Medicine, Chinese Traditional/methods ; *Dementia, Vascular/drug therapy ; *Cognitive Dysfunction/drug therapy/etiology ; *Drugs, Chinese Herbal/therapeutic use ; }, abstract = {Vascular cognitive impairment (VCI) is a prevalent cognitive disorder resulting from cerebrovascular disease and encompasses a spectrum of cognitive deficits, ranging from mild impairment to vascular dementia (VD). VCI is responsible for a minimum of 20% to 40% of all cases of dementia, with its prevalence ranking second only to Alzheimer's disease on a global scale. The pathogenesis of VCI is complex and includes a lack of cholinergic nerve cells, inflammation, oxidative stress, alterations in the blood-brain barrier, and cell apoptosis. Current guideline-recommended drugs have unsatisfactory therapeutic effects. However, traditional Chinese medicine (TCM) has long been associated with treating dementia, and numerous studies regarding treating dementia with TCM have been conducted. The etiology and pathogenesis of VaD are linked to deficiencies in the spleen and kidney, as well as phlegm turbidity. Treatment involves benefiting the spleen and kidney, improving blood circulation, removing blood stasis, and dispelling phlegm. Moreover, TCM presents benefits such as few adverse effects, low cost, long-term use suitability, and preventive effects. This review outlines the pathogenesis of VCI in both modern medicine and TCM, examines traditional prescriptions and single-agent ingredients with their pharmacological effects, emphasizes TCM's unique features, and explores its multi-targeted approach to treating VCI.}, }
@article {pmid40100917, year = {2025}, author = {Thau-Habermann, N and Gschwendtberger, T and Bodemer, C and Petri, S}, title = {Parthenolide regulates microglial and astrocyte function in primary cultures from ALS mice and has neuroprotective effects on primary motor neurons.}, journal = {PloS one}, volume = {20}, number = {3}, pages = {e0319866}, pmid = {40100917}, issn = {1932-6203}, mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Sesquiterpenes/pharmacology ; *Motor Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; Mice ; *Astrocytes/drug effects/metabolism ; Cells, Cultured ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; }, abstract = {Over the last twenty years, the role of microgliosis and astrocytosis in the pathophysiology of neurodegenerative diseases has increasingly been recognized. Dysregulation of microglial and astrocyte properties and function has been described also in the fatal degenerative motor neuron disease amyotrophic lateral sclerosis (ALS). Microglia cells, the immune cells of the nervous system, can either have an immunonegative neurotoxic or immunopositive neuroprotective phenotype. The feverfew plant (Tanacetum parthenium) derived compound parthenolide has been found to be capable of interfering with microglial phenotype and properties. Positive treatment effects were shown in animal models of neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Now we were able to show that PTL has a modulating effect on primary mouse microglia cells, both wild type and SOD1, causing them to adopt a more neuroprotective potential. Furthermore, we were able to show that PTL, through its positive effect on microglia, also has an indirect positive impact on motor neurons, although PTL itself has no direct effect on these primary motor neurons. The results of our study give reason to consider PTL as a drug candidate for ALS.}, }
@article {pmid40100148, year = {2025}, author = {Kawaguchi, K and Maeda, M and Murata, F and Nakashima, Y and Fukuda, H}, title = {Association of low bone mineral density and dementia in older women: insights from the Longevity Improvement and Fair Evidence Study.}, journal = {Age and ageing}, volume = {54}, number = {3}, pages = {}, doi = {10.1093/ageing/afaf058}, pmid = {40100148}, issn = {1468-2834}, support = {JPMJFR205J//Japan Science and Technology Agency's FOREST Program/ ; }, mesh = {Humans ; Female ; Aged ; *Bone Density ; *Dementia/epidemiology/diagnosis ; Japan/epidemiology ; Aged, 80 and over ; Risk Factors ; Osteoporosis/epidemiology/diagnosis ; Risk Assessment ; Longevity ; Alzheimer Disease/epidemiology/diagnosis ; }, abstract = {BACKGROUND: Both osteoporosis and dementia have emerged as important public health challenges in Japan's aging population. This study aimed to investigate the impact of low bone mineral density (BMD) on the subsequent risk of dementia in older Japanese women aged ≥65 years, given the overlapping demographics of individuals affected by these two conditions.
METHODS: This cohort study was conducted using osteoporosis screening data and insurance claims data from a municipality. We identified 8618 women (median age: 73 years) who underwent osteoporosis screening between April 2019 and March 2021. Participants with a BMD <80% of the young adult mean were assigned to a low-BMD group (n = 2297), whereas those with a BMD ≥80% were assigned to a control group (n = 6321). The study outcomes were new-onset all-cause dementia and Alzheimer's disease (AD). To estimate the risk of low BMD on these outcomes, we constructed Cox proportional hazards models that adjusted for covariates (age, care needs, year of cohort entry, comorbidities and medications) using inverse probability of treatment weighting.
RESULTS: The low-BMD group had a significantly higher risk of developing both all-cause dementia (adjusted hazard ratio: 1.58, 95% confidence interval: 1.20-2.08) and AD (1.61, 1.11-2.36) than the control group over approximately 30 months of follow-up.
CONCLUSION: These findings suggest that low BMD is associated with medium-term onset of dementia. Osteoporosis screenings could be useful not only for the secondary prevention of osteoporosis, but also for the primary prevention of dementia.}, }
@article {pmid40099247, year = {2025}, author = {Mujib, MD and Rao, AZ and Haque, MFU and Alokaily, AO and Hussain, SS and Aldohbayb, AA and Qazi, SA and Hasan, MA}, title = {Modulated theta band frequency with binaural beat stimulation correlates with improved cognitive scores in Alzheimer's patients.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1543282}, pmid = {40099247}, issn = {1663-4365}, abstract = {INTRODUCTION: Alzheimer's disease (AD) affects 50 million individuals worldwide, a number projected to triple by 2050. Due to discomfort through electrical and magnetic neuromodulation technologies, this is the first study to propose the potential of auditory binaural beat (BB) stimulation at an alpha frequency (10 Hz) for enhancing cognitive and neurological outcomes in AD patients.
METHODS: Twenty-five patients were divided into the experimental-Group (n = 15) and control-Group (n = 10). Psychometric and neurological assessments were conducted Pre-Treatment (Day 1) and Post-Treatment (Day 14) following consecutive days of binaural beats (BB) or auditory tone stimulation administered from Day 2 to Day 13.
RESULTS: A two-way ANOVA revealed a significant main effect of group (F = 6.087, p = 0.016) and session (F = 3.859, p = 0.024) on MMSE scores, with the experimental group showing significant improvement in MMSE scores (t = 7.33, p = 0.00000012) compared to the control group (p = 0.2306). Paired t-tests revealed a significant reduction in depression scores (DASS-21, t = 1.701, p = 0.0253) in the experimental group, while no significant improvements were noted in the control group. EEG recordings revealed significant changes in α-band, β-band, and γ-band power (p < 0.05). Moreover, The correlation between EEG bands and MMSE subparts showed that increased θ-band power in the experimental group was positively correlated (p < 0.05) with the frontal region during language tasks and in the frontal and central regions during registration and orientation tasks, indicating potential neurocognitive benefits.
DISCUSSION: The results of this research imply that BB stimulation has untapped potential as a non-invasive therapy for patients with AD, hence there is the need for further studies to manage the dementia epidemic.}, }
@article {pmid40098618, year = {2025}, author = {Ye, CQ and Leng, J and Jin, MY and Meng, YD and Zhao, ZY and Meng, FX and Xu, X and Fan, SS and Luo, HB and Meng, XY}, title = {SysNatMed: rational natural medicine discovery by systems genetics.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1496061}, pmid = {40098618}, issn = {1663-9812}, abstract = {BACKGROUND: Although acknowledged as an important complement to modern medicine, the utility of natural medicine (NM) remains under-exploited. We aimed to develop a novel data-driven approach for natural medicine discovery.
METHODS: GWAS summary statistics of disease (Alzheimer's disease, i.e., AD, for the case study) and quantitative trait loci were collected from public sources. The ranking of disease-gene associations was established using summary-based Mendelian randomization. The comprehensive hierarchical relationships among ingredients, natural products, and target genes were compiled from the BATMAN-TCM v2.0 database. Based on the ranking of disease-gene associations and the comprehensive hierarchical relationships among ingredients, natural products, and target genes, we prioritized NM ingredients as potential candidates for AD management and examined the efficacy for AD prevention using rat AD models.
RESULTS: We developed a non-trivial transparent data-driven framework for systems genetics-based NM discovery. Among the 139 prioritized candidates for AD management, we demonstrated the efficacy of Dang Gui (Angelicae Sinensis Radix, ASR) and Dang Shen (Codonopsis Pilosula, CP) for AD prevention using rat models. Mechanistically, we showed that ASR may prevent AD-related damage through protection of neural cells, as well as inhibition of microglia, angiogenesis, inflammation, and extracellular matrices.
CONCLUSION: Our method holds potential for the development of new strategies of complementary medicine for disease treatment and prevention, especially for complex conditions involving a number of genes.}, }
@article {pmid40098612, year = {2025}, author = {Zhang, W and Wang, R and Guo, R and Yi, Z and Wang, Y and Wang, H and Li, Y and Li, X and Song, J}, title = {The multiple biological activities of hyperoside: from molecular mechanisms to therapeutic perspectives in neoplastic and non-neoplastic diseases.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1538601}, pmid = {40098612}, issn = {1663-9812}, abstract = {In recent years, hyperoside (quercetin 3-O-β-D-galactopyranoside) has garnered significant attention due to its diverse biological effects, which include vasoprotective, antioxidant, anti-inflammatory, and anti-tumor properties. Notably, hyperoside has shown remarkable potential in cancer therapy by targeting multiple mechanisms; it induces apoptosis, inhibits proliferation, blocks angiogenesis, and reduces the metastatic potential of cancer cells. Furthermore, hyperoside enhances the sensitivity of cancer cells to chemotherapy by modulating key signaling pathways. Beyond neoplastic diseases, hyperoside also presents promising therapeutic applications in managing non-cancerous conditions such as diabetes, Alzheimer's disease, and pulmonary fibrosis. This review comprehensively examines the molecular mechanisms underlying hyperoside's anti-cancer effects and highlights its role in the treatment of cancers, including lung and colorectal cancers. Additionally, it explores the latest research on hyperoside's potential in addressing non-neoplastic conditions, such as pulmonary fibrosis, diabetes, and Parkinson's disease. By summarizing current findings, this review underscores the unique therapeutic value of hyperoside and its potential as a multifunctional treatment in both neoplastic and non-neoplastic contexts.}, }
@article {pmid40098057, year = {2025}, author = {Franzmeier, N and Roemer-Cassiano, SN and Bernhardt, AM and Dehsarvi, A and Dewenter, A and Steward, A and Biel, D and Frontzkowski, L and Zhu, Z and Gnörich, J and Pescoller, J and Wagner, F and Hirsch, F and de Bruin, H and Ossenkoppele, R and Palleis, C and Strübing, F and Schöll, M and Levin, J and Brendel, M and Höglinger, GU}, title = {Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer's disease.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {31}, pmid = {40098057}, issn = {1750-1326}, support = {A2021026S//BrightFocus Foundation/ ; AARG-22-973496/ALZ/Alzheimer's Association/United States ; NA//Gerhard und Ilse Schick Stiftung/ ; }, mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism/pathology ; Female ; Male ; *alpha-Synuclein/metabolism ; Aged ; *Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; Middle Aged ; Aged, 80 and over ; Biomarkers/metabolism/cerebrospinal fluid ; Cognitive Dysfunction/metabolism/pathology ; Amyloid/metabolism ; }, abstract = {BACKGROUND: Aggregated alpha-Synuclein (αSyn) is a hallmark pathology in Parkinson's disease but also one of the most common co-pathologies in Alzheimer's disease (AD). Preclinical studies suggest that αSyn can exacerbate tau aggregation, implying that αSyn co-pathology may specifically contribute to the Aβ-induced aggregation of tau that drives neurodegeneration and cognitive decline in AD. To investigate this, we combined a novel CSF-based seed-amplification assay (SAA) to determine αSyn positivity with amyloid- and tau-PET neuroimaging in a large cohort ranging from cognitively normal individuals to those with dementia, examining whether αSyn co-pathology accelerates Aβ-driven tau accumulation and cognitive decline.
METHODS: In 284 Aβ-positive and 308 Aβ-negative subjects, we employed amyloid-PET, Flortaucipir tau-PET, and a CSF-based αSyn seed-amplification assay (SAA) to detect in vivo αSyn aggregation. CSF p-tau181 measures were available for 384 subjects to assess earliest tau abnormalities. A subset of 155 Aβ-positive and 135 Aβ-negative subjects underwent longitudinal tau-PET over approximately 2.5 years. Using linear regression models, we analyzed whether αSyn SAA positivity was linked to stronger Aβ-related increases in baseline fluid and PET tau biomarkers, faster Aβ-driven tau-PET increase, and more rapid cognitive decline.
RESULTS: αSyn SAA positivity was more common in Aβ + vs. Aβ- subjects and increased with clinical severity (p < 0.001). Most importantly, αSyn positivity was also associated with greater amyloid-associated CSF p-tau181 increases (p = 0.005) and higher tau-PET levels in AD-typical brain regions (p = 0.006). Longitudinal analyses confirmed further that αSyn positivity was associated with faster amyloid-related tau accumulation (p = 0.029) and accelerated amyloid-related cognitive decline, potentially driven driven by stronger tau pathology.
CONCLUSIONS: Our findings suggest that αSyn co-pathology, detectable via CSF-based SAAs, is more prevalent in advanced AD and contributes to the development of aggregated tau pathology thereby driving faster cognitive decline. This highlights that a-Syn co-pathology may specifically accelerate amyloid-driven tau pathophysiology in AD, underscoring the need to consider αSyn in AD research and treatment strategies.}, }
@article {pmid40097723, year = {2025}, author = {Fantini, J and Azzaz, F and Aulas, A and Chahinian, H and Yahi, N}, title = {Preclinical assessment of a ganglioside-targeted therapy for Parkinson's disease with the first-in-class adaptive peptide AmyP53.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {9144}, pmid = {40097723}, issn = {2045-2322}, support = {Private funding//AmyPore/ ; }, mesh = {*alpha-Synuclein/metabolism ; *Parkinson Disease/drug therapy/metabolism ; *Gangliosides/metabolism ; Animals ; Humans ; Peptides/pharmacology/chemistry/therapeutic use ; Disease Models, Animal ; Mice ; Drug Evaluation, Preclinical ; }, abstract = {We propose a new concept for the treatment of Parkinson's disease (PD), which considers that its root cause, α-synuclein, is an intrinsically disordered protein (IDP) difficult to target by classic approaches. Upon binding to lipid raft gangliosides, α-synuclein shifts from random coil to α-helix, forming Ca[2+]-permeable oligomeric pores triggering a neurotoxicity cascade. We used the α-synuclein-ganglioside interaction as guideline to design a therapeutic peptide (AmyP53) that combines the respective flexible ganglioside-binding domains of α-synuclein and Alzheimer's β-amyloid protein. AmyP53 is an adaptive peptide, the first representant of a new therapeutic class. It acts as a competitive inhibitor of α-synuclein oligomer formation in brain cell membranes and prevents subsequent downstream synaptotoxicity, including the loss of dopaminergic neurons in an animal α-synuclein injection model of PD. It is active against both wild-type and mutant forms of α-synuclein. AmyP53 is administered intranasally without side effects. This new concept "target the target (gangliosides), not the arrow (IDP)" is distinct from classic α-synuclein centric approaches that did not cure PD so far.}, }
@article {pmid40097131, year = {2025}, author = {Soni, U and Singh, K and Jain, D and Pujari, R}, title = {Exploring Alzheimer's disease treatment: Established therapies and novel strategies for future care.}, journal = {European journal of pharmacology}, volume = {998}, number = {}, pages = {177520}, doi = {10.1016/j.ejphar.2025.177520}, pmid = {40097131}, issn = {1879-0712}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a gradual decline in cognitive function, memory impairment, and alterations in behavior. As the predominant etiology of dementia, AD affects millions of individuals worldwide, with its hallmark pathological feature being the accumulation of amyloid beta (Aβ) plaques, which disrupt neuronal function and progressively compromise brain structure. Early clinical manifestations often include forgetfulness, disorientation, and social withdrawal. Primarily impacting the elderly population, AD significantly impairs daily functioning and diminishes overall quality of life. Current therapeutic approaches for AD mainly focus on symptomatic relief and decelerating the disease's progression. Cholinesterase inhibitors, such as donepezil and rivastigmine, increase acetylcholine (ACh) levels to enhance cognitive function in individuals with mild to moderate AD. For individuals in more advanced stages of the disease, NMDA receptor antagonists modulate glutamate activity to mitigate excitotoxicity. In addition to pharmacological interventions, lifestyle modifications such as adherence to a balanced diet, regular physical activity, and cognitive engagement are advocated to support brain health. Novel therapeutic avenues are being explored to address underlying pathophysiological mechanisms, such as metal ion dysregulation within the brain. Furthermore, non-pharmacological approaches, including cognitive-behavioral therapy and patient support groups, provide essential behavioral and emotional support. Cutting-edge research continues to investigate innovative treatments, such as immunotherapies targeting amyloid plaques and tau tangles and neuroprotective compounds derived from natural sources. The goal of these multifaceted strategies is to alleviate symptoms, enhance quality of life, and offer hope for individuals and families affected by AD. This review provides a comprehensive summary of both established and emerging therapeutic interventions for the management of AD.}, }
@article {pmid40096973, year = {2025}, author = {Alqudah, AS and Abaalkhail, NS and Alturki, AS and Naseer, YS and Almansour, SK}, title = {The prevalence of Alzheimer's disease among diabetic patients in Saudi Arabia.}, journal = {Saudi medical journal}, volume = {46}, number = {3}, pages = {244-253}, pmid = {40096973}, issn = {1658-3175}, mesh = {Humans ; Saudi Arabia/epidemiology ; Female ; *Alzheimer Disease/epidemiology ; Male ; Middle Aged ; Prevalence ; *Health Knowledge, Attitudes, Practice ; Surveys and Questionnaires ; Aged ; Adult ; Diabetes Mellitus/epidemiology ; Risk Factors ; }, abstract = {OBJECTIVES: To investigate the knowledge of Alzheimer's disease (AD) among 228 Saudi adults with diabetes, aiming to assess cognitive awareness through a questionnaire. It explores risk factors, symptoms, prevention strategies, and attitudes towards dementia, while integrating demographic data to illuminate cognitive landscapes and correlations between diabetes and cognitive health.
METHODS: Trained dietitians administered questionnaires to 228 adult Saudi diabetic participants, focusing on their understanding of AD across various domains. The study employed validated tools for data collection and amalgamated responses with demographic and medical details.
RESULTS: Of the 228 participants, 56.6% were female. Findings revealed a high acknowledgment of 3 subdomains of the Alzheimer's disease knowledge scale (ADKS) - risk factors, course, and diagnosis - with 75% agreement. However, lower acknowledgment rates with agreements were observed in the domains of life impact (71%), symptoms (71%), caregiving (72%), and treatment management (69%). Statistical analysis indicated significant differences in knowledge based on education levels (p≤0.05), with university-educated individuals demonstrating greater agreement across all ADKS subdomains.
CONCLUSION: The research highlights the need for enhanced awareness of AD among Saudi diabetic individuals. By integrating healthcare, education, and culturally sensitive interventions, the study advocates for targeted education to improve understanding of cognitive health and effective management strategies in this demographic, emphasizing the role of educational background in shaping perceptions.}, }
@article {pmid40096963, year = {2025}, author = {Li, Y and Yang, C and Liu, X and Shu, J and Zhao, N and Sun, Z and Tabish, MS and Hong, Y and Liu, E and Wei, N and Sun, M}, title = {Potential therapeutic targets for Alzheimer's disease: Fibroblast growth factors and their regulation of ferroptosis, pyroptosis and autophagy.}, journal = {Neuroscience}, volume = {573}, number = {}, pages = {42-51}, doi = {10.1016/j.neuroscience.2025.03.009}, pmid = {40096963}, issn = {1873-7544}, abstract = {Alzheimer's disease (AD) is a progressively worsening neurodegenerative disorder characterized primarily by the deposition of amyloid beta (Aβ) plaques in the brain and the abnormal aggregation of tau protein forming neurofibrillary tangles. These pathological changes lead to impaired neuronal function and cell death, subsequently affecting the structure and function of the brain. Fibroblast growth factors (FGFs) are a group of proteins that play crucial roles in various biological processes, including cell proliferation, differentiation, and survival. This article reviews the expression and regulation of FGFs in the central nervous system and how they affect neuronal survival, as well as the changes in FGF signaling pathways and its regulation of programmed cell death in AD. It particularly focuses on the impact of FGF1, FGF2, FGF21, other members of the FGF family, and FGFR on the pathophysiological mechanisms of AD. The potential of the PI3K/AKT/GSK-3β, Wnt/β-catenin, and NF-κB signaling pathways as targets for AD treatment is also discussed. Furthermore, the relationship between FGF-regulated ferroptosis, Pyroptosis and Autophagy and AD is explored, along with the role of these mechanisms in improving the progression of AD.}, }
@article {pmid40096940, year = {2025}, author = {Abdel-Aal, RA and Meligy, FY and Maghraby, N and Sayed, N and Mohamed Ashry, IE}, title = {Comparing levetiracetam and zonisamide effects on rivastigmine anti-Alzheimer's activity in aluminum chloride-induced Alzheimer's-like disease in rats: Impact on α7 nicotinic acetylcholine receptors and amyloid β.}, journal = {Brain research}, volume = {1855}, number = {}, pages = {149573}, doi = {10.1016/j.brainres.2025.149573}, pmid = {40096940}, issn = {1872-6240}, mesh = {Animals ; *Rivastigmine/pharmacology ; *Levetiracetam/pharmacology ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; *alpha7 Nicotinic Acetylcholine Receptor/metabolism/drug effects ; Aluminum Chloride ; Rats ; Male ; *Zonisamide/pharmacology ; Amyloid beta-Peptides/metabolism ; Hippocampus/metabolism/drug effects ; Cholinesterase Inhibitors/pharmacology ; Anticonvulsants/pharmacology ; Disease Models, Animal ; Rats, Wistar ; Neuroprotective Agents/pharmacology ; }, abstract = {BACKGROUND AND AIM: Alzheimer's disease (AD) is the most progressive form of neurodegenerative disease, which severely impairs cognitive function. The leading class of drugs used to treat AD is acetylcholinesterase inhibitors (AChE-Is) as Rivastigmine (RIVA), partially ameliorate its cognitive symptoms. Since epilepsy is a common comorbidity with AD, we explored the potential that new the antiepileptic drugs; Levetiracetam (LEV) and Zonisamide (ZNS) may possess an additional therapeutic benefit to RIVA in AlCl3-induced AD rat model.
MATERIALS AND METHODS: AlCl3 was used to provoke AD in rats which were then supplemented with treatment drugs for 2 weeks. Treated groups were: Control, AlCl3, RIVA, LEV, RIVA + LEV, ZNS and RIVA + ZNS. Then, the behavioral tests; passive avoidance (PA), Morris water maze (MWM) and novel object recognition (NOR) were conducted to assess cognitive behavior and memory. The Hippocampal Aβ assembly was thoroughly examined by histopathology and ELISA. α7 Nicotinic ACh receptors' (α7nAChRs) expression was assessed immunohistochemically and by real-time quantitative polymerase chain reaction (qPCR). Caspase 3 expression was also assessed by real-time qPCR in hippocampal tissues.
RESULTS: AlCl3 administration impaired memory and cognitive functions in rats, augmented hippocampal Aβ deposition, with subsequent neurodegeneration and α7nAChRs down-regulation. LEV, but not ZNS, administration significantly mitigated AlCl3-induced cognitive impairment probably through suppression of amyloid β (Aβ) deposition, enhancement of neurogenesis and α7nAChRs expression. When combined to RIVA, ZNS treatment negatively affected cognition possibly through its impact on hippocampal Aβ and subsequent neuronal damage.
CONCLUSION: Although our results indicated that neither LEV nor ZNS provided any extra benefit to cognitive enhancements in AD rats receiving rivastigmine, LEV demonstrated positive effects individually while ZNS had negative effects when combined with RIVA. As a result, this study suggests the use of LEV rather than ZNS for managing epilepsy in patients with AD given that Alzheimer's and epilepsy can coexist.}, }
@article {pmid40096820, year = {2025}, author = {Rust, R and Sagare, AP and Zhang, M and Zlokovic, BV and Kisler, K}, title = {The blood-brain barrier as a treatment target for neurodegenerative disorders.}, journal = {Expert opinion on drug delivery}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/17425247.2025.2480654}, pmid = {40096820}, issn = {1744-7593}, abstract = {INTRODUCTION: The blood-brain barrier (BBB) is a vascular endothelial membrane which restricts entry of toxins, cells, and microorganisms into the brain. At the same time, the BBB supplies the brain with nutrients, key substrates for DNA and RNA synthesis, and regulatory molecules, and removes metabolic waste products from brain to blood. BBB breakdown and/or dysfunction have been shown in neurogenerative disorders including Alzheimer's disease (AD). Current data suggests that these BBB changes may initiate and/or contribute to neuronal, synaptic, and cognitive dysfunction, and possibly other aspects of neurodegenerative processes.
AREAS COVERED: We first briefly review recent studies uncovering molecular composition of brain microvasculature and examine the BBB as a possible therapeutic target in neurodegenerative disorders with a focus on AD. Current strategies aimed at protecting and/or restoring altered BBB functions are considered. The relevance of BBB-directed approaches to improve neuronal and synaptic function, and to slow progression of neurodegenerative processes are also discussed. Lastly, we review recent advancements in drug delivery across the BBB.
EXPERT OPINION: BBB breakdown and/or dysfunction can significantly affect neuronal and synaptic function and neurodegenerative processes. More attention should focus on therapeutics to preserve or restore BBB functions when considering treatments of neurodegenerative diseases and AD.}, }
@article {pmid40095667, year = {2025}, author = {Lu, Y and Li, D and Yu, Y and Wang, Q and Li, A and Quan, Y and Xing, Y and , }, title = {Cerebrospinal fluid VGF is associated with the onset and progression of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251323002}, doi = {10.1177/13872877251323002}, pmid = {40095667}, issn = {1875-8908}, abstract = {BackgroundIt remains unclear whether cerebrospinal fluid (CSF) VGF (non-acronymic) is associated with the onset and progression of Alzheimer's disease (AD).ObjectiveTo assess the levels of CSF VGF throughout the AD continuum, and its association with primary AD pathology, cognition, brain atrophy, and brain metabolism.MethodsWe studied a total of 526 individuals including 377 amyloid-positive individuals (76 preclinical AD, 200 prodromal AD, and 101 AD dementia) and 149 amyloid-negative cognitively normal individuals. VGF peptide in CSF was analyzed using mass spectrometry.ResultsWe observed decreased CSF VGF in preclinical, prodromal, and AD dementia individuals than amyloid-negative cognitively normal individuals. Reduced CSF VGF was associated with cognitive decline, hippocampal atrophy, ventricle enlargement, and glucose hypometabolism at baseline, and it predicted a more marked deterioration over time.ConclusionsOur findings support the important contributions of VGF to disease pathogenesis and progression in the early stages of AD. Exploring the biologics modulating VGF might be a promising approach for AD prevention and early treatment.}, }
@article {pmid40095493, year = {2025}, author = {Bhardwaj, S and Jindal, A and Singh, S and Kaur, R and Kaur Grewal, A}, title = {Pharmacological Evaluation of Aescin for Neuroprotection in Intracerebroventricular Streptozotocin Model of Alzheimer's Disease in Experimental Rats.}, journal = {Assay and drug development technologies}, volume = {}, number = {}, pages = {}, doi = {10.1089/adt.2024.130}, pmid = {40095493}, issn = {1557-8127}, abstract = {Alzheimer's disease (AD) is a neurological disorder that results in the loss of memory and cognitive functions linked to redox disbalance, neuroinflammation, neurotransmitters changes, and the accumulation of amyloid-beta (1-42) plaques in AD. In this study, rats were administered with intracerebroventricular (ICV) streptozotocin (STZ) to produce AD-like symptoms in rats. ICV-STZ bilaterally, 3 mg/kg, was infused on days 1 and 3 with the help of Hamilton syringe by fixing cannula at the target position of rat brain using coordinates -2 mm (anteriposterior), 1.6 mm Mediolateral (ML), and 1.5 mm (dorsoventral). Learning and spatial memory were checked using Morris water maze and elevated plus maze apparatus. In ICV-STZ, rats lost their spatial and learning memory, increased level of prooxidant like Lipid peroxidation (LPO), nitrite and reduced glutathione (GSH), catalase, and superoxide dismutase (SOD) level. The increased level acetylcholinesterase (AChE) catalyzed acetylcholine (ACh) concentration indicates cholinergic neuron degeneration. Furthermore, we found raised inflammatory markers and altered neurotransmitters level after ICV-STZ. Administration of aescin (10, 20, and 30 mg/kg, p.o.) dose-dependently ameliorated the behavioral alteration and inhibited inflammatory markers like tumor necrosis factor-alpha, interleukin-6 (IL-6), and IL-1β. Furthermore, aescin restored antioxidants like GSH, SOD, and catalase and reduced the nitrite and lipid peroxidation level. AChE enzyme causes degradation of ACh, and its level was declined after treatment with aescin. Aescin also restored GABA, norepinephrine, and serotonin level in the brain with prevention of raised glutamate level. Moreover, the histopathological study confirmed neuronal pathogenesis, and aescin significantly achieved neuroprotective effect via preventing neuroinflammation, balancing redox potential, and inhibiting AChE enzyme.}, }
@article {pmid40095481, year = {2025}, author = {Becker, C and Herschung, L and Gomm, W and Haenisch, B}, title = {Dementia diagnosis and prescription of antidementia drugs: An analysis of German claims data (2006-2016).}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251319468}, doi = {10.1177/13872877251319468}, pmid = {40095481}, issn = {1875-8908}, abstract = {BackgroundUse of claims data allows to analyze health service characteristics of dementia, which is one of the most frequent cognitive disorders in Germany and worldwide.ObjectiveThe study aimed at describing the variability in dementia diagnoses and in antidementia drug prescription pattern.MethodsWe analyzed data from a population-based sample of one of the largest German statutory health insurances. The cohort included 30,403 patients with incident dementia diagnosis from 2006-2016. We described frequencies, patterns, and interrelations of diagnoses (Alzheimer's disease (AD), vascular dementia, other specific dementia, unspecified dementia (UD), antidementia drugs (ADD), and professional groups. We described switches in diagnostic and medication patterns between index quarter and following quarters, and evaluated the prescriptions in relation to national guidelines.ResultsA total of 87% of patients received a diagnosis of UD in at least one quarter of insurance. In the quarter of incident diagnosis, 14% of patients received more than one diagnostic code of dementia, whereas over the course of observation, the majority of patients received more than one diagnostic code (61%). Most patients were diagnosed by a general practitioner without involving a specialist. All professional groups primarily made UD diagnoses except specialists who mainly diagnosed AD. Thirty-five percent of all patients and 67% of AD patients were prescribed an ADD at least once.ConclusionsSpecialists made the most specific diagnoses and prescribed most ADDs. A specialist consultation may be advisable, but only 34% of patients visited one. Many AD patients might be left untreated due to underdiagnosis or -treatment.}, }
@article {pmid40095345, year = {2025}, author = {Dehghani, S and Ocakcı, O and Hatipoglu, PT and Özalp, VC and Tevlek, A}, title = {Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40095345}, issn = {1559-1182}, abstract = {Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.}, }
@article {pmid40095208, year = {2025}, author = {Bhuiyan, P and Zhang, W and Liang, G and Jiang, B and Vera, R and Chae, R and Kim, K and Louis, LS and Wang, Y and Liu, J and Chuang, DM and Wei, H}, title = {Intranasal Delivery of Lithium Salt Suppresses Inflammatory Pyroptosis in the Brain and Ameliorates Memory Loss and Depression-like Behavior in 5XFAD Mice.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {20}, number = {1}, pages = {26}, pmid = {40095208}, issn = {1557-1904}, support = {R01 AG061447/AG/NIA NIH HHS/United States ; R01AG061447/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Administration, Intranasal ; Mice ; *Brain/drug effects/metabolism ; *Lithium Chloride/administration & dosage/toxicity ; *Depression/drug therapy ; *Alzheimer Disease/drug therapy/metabolism ; *Mice, Transgenic ; *Pyroptosis/drug effects/physiology ; Memory Disorders/drug therapy ; Male ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disease (AD) and has no treatment that can cure or halt the disease progression. This study explored the therapeutic potential of lithium salt dissolved in Ryanodex formulation vehicle (RFV) and delivered to the brain by intranasal application. We first compared lithium concentrations in the brain and blood of wild-type mice following intranasal or oral administration of lithium chloride (LiCl) dissolved in either RFV or water. The beneficial and side effects of intranasal versus oral LiCl in RFV in these mice were assessed and potential mechanisms underlying the efficacy of anti-inflammation and anti-pyroptosis in the brains were also investigated in both wild-type and 5XFAD Alzheimer's Disease (AD) mice brains.
METHODS: For the study of brain versus blood lithium concentrations, wild-type (WT) B6SJLF1/J mice at 2 months of age were treated with intranasal or oral LiCl (3 mmol/kg) dissolved in RFV or in water. Brain and blood lithium concentrations were measured at various times after drugs administration. Brain/blood lithium concentration ratios were then determined. For studying therapeutic efficacy versus side effects and their underlying mechanisms, 5XFAD and WT B6SJLF1/J mice were treated with intranasal LiCl (3 mmol/kg) daily, Monday to Friday each week, in RFV beginning at 2 or 9 months of age with a 12-week treatment duration. Animal behaviors were assessed for depression (tail suspension), cognition (fear conditioning and Y maze), olfaction (buried food test), and motor functions (rotarod) at the age of 5 and 12 months. Blood and brain tissue were harvested from these mice at 13 months. Blood biomarkers for the functions of thyroid (thyroid stimulating hormone, TSH) and kidney (creatinine) were measured using ELISA. Changes in protein expression levels of the endoplasmic reticulum Ca[2+] release channels type 1 InsP3 receptors (InsP3R-1), malondialdehyde (MDA)-modified proteins and 4-hydroxy-2-nonenal (4-HNE), pyroptosis regulatory proteins (NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, N-terminal of Gasdermin D (GSDMD)), cytotoxic (IL-1β, IL-18, IL-6, TNF-α) and cytoprotective (IL-10) cytokines and synapse proteins (PSD-95, synapsin-1) were determined using immunoblotting. Mouse body weights were monitored regularly.
RESULTS: Compared to oral LiCl in RFV nanoparticles, intranasal treatment of WT mice with LiCl in RFV markedly decreased blood concentrations at the time range of 30-120 min. The ratio of brain/blood lithium concentration after intranasal lithium chloride in RFV significantly increased, in comparison to those after oral administration lithium chloride in RFV or intranasal administration of lithium chloride in water. Intranasal lithium chloride in RFV inhibited both memory loss and depressive behavior in adult and aged 5XFAD mice. Additionally intranasal treatment of aged 5XFAD mice with LiCl in RFV effectively suppressed the increases in InsP3R-1, intracellular oxidative stress markers (4-HNE-bound and MDA-modified proteins), pyroptosis activation proteins (NLRP3, cleaved caspase-1, N-terminal GSDMD) and cytotoxic cytokines (IL-1β, IL-6, TNF-α), but reversed the down-regulation of cytoprotective cytokine IL-10. Intranasal LiCl in RFV also alleviated the loss of the postsynaptic synapse proteins PSD-95, but not synapsin-1, in aged 5XFAD mice. Blood level of the kidney function marker creatinine was significantly increased in 5XFAD than in WT mice in an age-dependent manner and this elevation was abolished by intranasal delivery of LiCl in RFV. Intranasal LiCl in RFV for 12 weeks in both WT or 5XFAD mice did not affect blood biomarkers for thyroid function, nor did it affect smell or muscle function or body weight.
CONCLUSION: Intranasal administration of LiCl in RFV significantly decreased lithium blood concentrations and increased brain/blood lithium concentration ratio, in comparison to its oral administration. Intranasal administration of LiCl in RFV robustly protected against both memory loss and depressive-like behavior, while had no side effects concerning thyroid and kidney toxicity in 5XFAD mice. These lithium-induced beneficial effects were strongly associated with lithium's suppression of InsP3R-1 Ca[2+] channel receptor increase, pathological neuroinflammation and activation of the pyroptosis pathway, as well as the loss of the synaptic protein PSD-95. Intranasal delivery of lithium salt in RFV could become an effective and potent inhibitor of pathological inflammation/pyroptosis in the CNS and serve as a new treatment for both AD-associated dementia and depression with minimal unwanted side effects including peripheral organ toxicity.}, }
@article {pmid40094842, year = {2025}, author = {Aghasizadeh Sherbaf, R and Kaposvári, GM and Nagy, K and Pakáski, M and Gajdács, M and Matusovits, D and Baráth, Z}, title = {Oral Health Status and Factors Associated with Oral Health in Patients with Alzheimer's Disease: A Matched Case-Control Observational Study.}, journal = {Journal of clinical medicine}, volume = {14}, number = {5}, pages = {}, pmid = {40094842}, issn = {2077-0383}, abstract = {Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease, ranking as the seventh leading cause of death in both sexes. There is increasing awareness of the role of chronic periodontal disease and severe tooth loss as a modifiable risk factor for developing AD. The aim of the present observational study was to assess AD patients with non-affected healthy controls in the context of their dental and periodontal health outcomes; additionally, the potential impact of anamnestic factors and lifestyle habits on oral health outcomes was also studied. Methods: A total of n = 41 AD patients receiving treatment at the Department of Psychiatry, University of Szeged, were compared with n = 41 age- and gender-matched controls from individuals seeking dental treatment and from retirement homes (mean age was 83.32 ± 7.82 years). Dental and periodontal status indices were assessed according to World Health Organization (WHO) criteria. Results: Overall, 51.2%, 68.3%, and 87.8% of AD patients received mood stabilizers, drugs for their non-cognitive symptoms and cognitive symptoms, respectively. Severe tooth loss was observed in 43.9% of AD patients and 56.1% of controls, respectively. There were no significant differences among AD patients and controls regarding the dental status indices studied (p > 0.05 for all indicators). AD patients had significantly higher plaque indices (%) (59.06 ± 15.45 vs. 41.35 ± 7.97; p < 0.001), bleeding on probing (BOP%) (62.65 ± 12.00 vs. 40.12 ± 10.86; p < 0.001), pocket depth [PD] (2.63 ± 0.56 vs. 2.29 ± 0.13; p = 0.002) and attachment loss [AL] (2.85 ± 0.79 vs. 2.39 ± 0.41; p = 0.026) values, compared to controls. Smoking (vs. non-smokers; 56.28 ± 12.36 vs. 51.40 ± 13.23, p = 0.038) and consumption of alcohol (vs. non-drinkers; 58.68 ± 9.86 vs. 54.78 ± 14.86, p = 0.040) were associated with higher plaque indices [%], while no similar effects were shown for dental status parameters (p > 0.05). In contrast, coffee intake and vitamin supplement use had no significant effect on dental or periodontal status parameters (p > 0.05 in all cases). Conclusions: The results of our study underscore the substantial treatment needs of AD patients, calling for heightened awareness among dental healthcare professionals.}, }
@article {pmid40093888, year = {2025}, author = {Pees, A and Morrone, CD and Tong, J and Rong, J and Shao, T and Wear, D and Liang, SH and Yu, WH and Vasdev, N}, title = {Sex- and age-specific sensitivities of the endocannabinoid system in Alzheimer's disease revealed by PET imaging with [[18]F]FMPEP-d 2 and [[18]F]MAGL-2102.}, journal = {Theranostics}, volume = {15}, number = {8}, pages = {3368-3385}, pmid = {40093888}, issn = {1838-7640}, mesh = {Animals ; *Alzheimer Disease/diagnostic imaging/metabolism ; Female ; Male ; Mice ; *Brain/diagnostic imaging/metabolism ; *Endocannabinoids/metabolism ; *Disease Models, Animal ; *Positron-Emission Tomography/methods ; Monoacylglycerol Lipases/metabolism/genetics/antagonists & inhibitors ; Mice, Transgenic ; Fluorine Radioisotopes ; Positron Emission Tomography Computed Tomography/methods ; Receptor, Cannabinoid, CB1/metabolism/genetics ; Humans ; Sex Factors ; Age Factors ; Radiopharmaceuticals ; Amyloid beta-Protein Precursor/metabolism/genetics ; Autoradiography ; }, abstract = {The endocannabinoid system is a critical brain signaling pathway that is dysregulated in various brain disorders, including Alzheimer's disease (AD). Cannabinoid-targeted therapies and imaging approaches have gained increasing interest; however, the biological impact of the endocannabinoid system in disease needs further validation. We aimed to study changes in cannabinoid receptor 1 (CB1) and monoacylglycerol lipase (MAGL), components of endocannabinoid signaling and degradation, in a mouse model of AD by PET imaging. Methods: [[18]F]FMPEP-d 2 and [[18]F]MAGL-2102 were produced on a commercial radiosynthesis module. PET-CT images with both tracers were acquired in a knock-in mouse model of AD bearing mutated human amyloid precursor protein (App[NL-G-F]) at 3 ages, and compared to wild-type mice. Excised brains were used for in vitro autoradiography with [[18]F]FMPEP-d 2 and [[18]F]MAGL-2102, immunofluorescence, and western blotting. Male wild-type and 5xFAD mice were chronically treated with MAGL inhibitor JZL184 and imaged with [[18]F]MAGL-2102 two days after ending treatment. Results: PET imaging showed sex-, age- and genotype-dependent changes in CB1 and MAGL availability. At 4-months (early-stage β-amyloid pathology), female App[NL-G-F] mice had lower CB1 availability, and MAGL availability was increased in male App[NL-G-F] , compared to wild-types. At 8-months, no genotype differences in CB1 were observed, yet MAGL availability was reduced in App[NL-G-F] frontal cortex, and male App[NL-G-F] mice exhibited higher MAGL than transgenic females brain-wide. At 12-months (late-stage β-amyloid pathology), significantly lower uptake of [[18]F]FMPEP-d 2 was observed in App[NL-G-F] compared to wild-type, with no changes in [[18]F]MAGL-2102 binding. App[NL-G-F] plaque staging was confirmed by Thioflavin-S staining. Imaging findings were supplemented by autoradiography, immunofluorescence, and western blots. [[18]F]MAGL-2102 availability was responsive to target engagement of the MAGL inhibitor JZL184 in wild-type and 5xFAD mice. Conclusions: The present study showed dynamic age-, sex- and pathology-related changes in CB1 and MAGL availability from early-stage β-amyloid pathology, suggesting that the endocannabinoid system is a useful target for diagnostics and treatment of AD. Finally, these results highlight that endocannabinoid sex differences should be considered in diagnostics and drug development.}, }
@article {pmid40093519, year = {2025}, author = {Atta, AM and Rihan, N and Abdelwaly, AM and Nafie, MS and Elgawish, MS and Moustafa, SM and Helal, MA and Darwish, KM}, title = {Development, biological evaluation, and molecular modelling of novel isocytosine and guanidine derivatives as BACE1 inhibitors using a fragment growing strategy.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {40093519}, issn = {2632-8682}, abstract = {Alzheimer's disease (AD) is a neurodegenerative condition characterized by significant synaptic loss and neuronal death in brain regions critical for cognitive functions. The disease is characterized by the formation of amyloid plaques, which are extracellular constructs consisting mainly of aggregated Aβ42. The latter is a peptide formed by the proteolytic cleavage of β-amyloid precursor protein (APP) by two enzymes, β- and γ-secretase. Therefore, inhibition of the aspartic protease β-secretase (BACE1) is considered a promising therapeutic approach for the treatment and prevention of Alzheimer's disease. Unfortunately, a limited number of β-secretase inhibitors have reached human trials and eventually failed due to inconclusive therapeutic and/or safety profiles. In this study, we developed drug-like molecules with a β-secretase inhibitory activity using a fragment growing strategy on isocytosine and acyl guanidine warheads. Our approach is based on optimizing the hydrophobic part of the molecules to obtain a conformationally restrained scaffold complementary to the hydrophobic pockets within the enzyme active site. We developed 32 compounds with promising in vitro inhibitory activity against BACE1 down to sub-micromolar IC50. Docking simulation studies were performed to understand the mode of binding of the prepared compounds. We demonstrated that compounds with superior activities, such as 16b and 16g, are able to provide the best balance between the steric shape and position of the polar substituent for achieving preferential anchoring into the S1, S3, S1', and S2' sub-pockets. Further, in vivo characterization of selected drug-like candidates of the benzimidazole series AMK-IV, namely 16a and 16k, demonstrated their ability to reduce oxidation stress and their safety within brain and liver tissues.}, }
@article {pmid40093146, year = {2025}, author = {Wu, P and Chen, D and Wang, F and Lu, K and Sigurdsson, EM and Jin, C}, title = {Formaldehyde induces and promotes Alzheimer's disease pathologies in a 3D human neural cell culture system.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.02.27.640690}, pmid = {40093146}, issn = {2692-8205}, abstract = {Alzheimer's disease (AD) arises from complex multilevel interactions between genetic, epigenetic, and environmental factors. Recent studies suggest that exposure to the environmental and occupational toxicant formaldehyde (FA) may play a significant role in AD development. However, the effects of FA exposure on Aβ and tau pathologies in human neural cell 3D culture systems remain unexplored. To investigate FA's role in AD initiation, we differentiated 3D-cultured immortalized human neural progenitor ReN cells (ReNcell VM) into neurons and glial cells, followed by FA treatment. FA exposure for 12 weeks resulted in a dose-dependent increase in Aβ40, Aβ42, and phosphorylated tau levels. To further examine FA's role in AD progression, we established a 3D human neural cell culture AD model by transfecting ReN cells with AD-related mutant genes, including mutant APP and PSEN1, which recapitulate key AD pathological events. Our findings demonstrate that FA exposure significantly elevated Aβ40, Aβ42, and phosphorylated tau levels in this 3D-cultured AD model. These results suggest that FA exposure contributes to the initiation and progression of AD pathology in 3D-cultured human neural cells.}, }
@article {pmid40092207, year = {2025}, author = {Wihadmadyatami, H and Zulfikar, MA and Herawati, H and Karnati, S and Saragih, GR and Aliffia, D and Pratama, DAOA and Handayani, N and Kustiati, U and Tirtosari, DR and Tjahjono, Y}, title = {Neuroprotection effect of bovine umbilical mesenchymal stem cell-conditioned medium on the rat model of Alzheimer's disease mediated by upregulation of BDNF and NGF and downregulation of TNF-α and IL-1β.}, journal = {Open veterinary journal}, volume = {15}, number = {1}, pages = {151-161}, pmid = {40092207}, issn = {2218-6050}, mesh = {Animals ; *Alzheimer Disease/metabolism/veterinary/therapy ; Rats ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; Male ; *Nerve Growth Factor/metabolism/genetics ; *Interleukin-1beta/metabolism ; *Tumor Necrosis Factor-alpha/metabolism/genetics ; *Mesenchymal Stem Cells ; Culture Media, Conditioned/pharmacology ; *Disease Models, Animal ; Cattle ; *Up-Regulation/drug effects ; Down-Regulation/drug effects ; Neuroprotective Agents/pharmacology ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) are distinguished by impairment and depletion of nerve cells; one of the most common NDDs is Alzheimer's disease (AD), which can appear in early onset or late onset. In recent years, the secretome or conditioned medium of mesenchymal stem cells has provided new hope for improving conditions and preventing AD. One of the secretomes is bovine umbilical mesenchymal stem cells-conditioned medium (BUMSC-CM), where BUMSC is predicted to promote neuronal proliferation potentially.
AIM: This study analyzes the therapeutic efficiency of conditioned medium or secretome produced from BUMSC-CM in treating neurodegeneration in animal models of AD.
METHODS: Five groups consisting of 12 male rats were assigned: untreated (Group A, n = 5), positive control group given normal saline 1 ml/100 g BW (Group B, n = 5), AD rats model followed by Donepezil treatment (Group C, n = 5), AD rats model with BUMSC-CM 0.2 ml/kg BW post-trimethyltin (TMT) induction (Group D, n = 5), and AD rats model with BUMSC-CM 0.5 ml/kg BW post-TMT induction (Group E, n = 5). The brain samples were analyzed for neuronal density using cresyl violet staining. The expression and activity of brain-derived neurotrophic factor (BDNF) were analyzed by ELISA; in addition, interleukin 1beta (IL-1β), tumor necrotic factor-alpha (TNF-α), and neural growth factor (NGF) were analyzed by quantitative polymerase chain reaction. Interactions between the main substances of BUMSC-CM and beta-amyloid protein were visualized using in silico molecular docking.
RESULTS: Our result demonstrated that BUMSC-CM with the dosage of 0.5 ml/kg BW significantly increased BDNF concentration. We also found that BUMSC-CM with dosage 0.2 ml/kg BW and 0.5 ml/kg BW down-regulated IL-1β and TNF-α and upregulated NGF expression. Additionally, the number of neurons in AD rats post-treated with BUMSC-CM was significantly increasing. Furthermore, the amino acids in BUMSC-CM, including isoleucine, leucine, and valine, bind to the amyloid beta protein via interactions that are hydrophobic and hydrogen-bonded.
CONCLUSION: In this study, the neuroprotective potential of BUMSC-CM was demonstrated by its ability to upregulate BDNF and NGF while downregulating IL-1β and TNF-α. Additionally, BUMSC-CM showed potential to promote neuron proliferation in the hippocampus regions of a rat AD model. The main constituents in BUMSC-CM adhere to amyloid beta protein, hence diminishing the likelihood of ND disorders, specifically AD.}, }
@article {pmid40092057, year = {2025}, author = {Reddy, NK}, title = {Redefining disease in the age of blood-based biomarkers.}, journal = {Frontiers in sociology}, volume = {10}, number = {}, pages = {1533429}, pmid = {40092057}, issn = {2297-7775}, abstract = {This article explores the sociological and ethical implications of redefining disease in the era of advanced diagnostic technologies, with a focus on blood-based biomarkers. Drawing from Foucault's concept of medicalization and Illich's critique of disease mongering, it highlights how diagnostic expansions, driven by corporate and institutional influences, are reshaping the boundaries of health and disease. Advances such as blood assays for Alzheimer's and Parkinson's diseases, liquid biopsies in oncology, and biomarkers for depression and diabetes, while promising, raise concerns about premature diagnoses and overtreatment. The influence of pharmaceutical and insurance industries on diagnostic criteria, as seen in the ICD updates, underscores the need to address conflicts of interest and regulatory gaps. Case studies on Alzheimer's and Parkinson's reveal how these changes could benefit stakeholders at the expense of patient welfare. The article calls for ethical oversight, stricter regulation, and research into the population-level efficacy of diagnostic and treatment protocols.}, }
@article {pmid40091636, year = {2025}, author = {Lee, EH and Kwon, H and Park, SY and Park, JY and Hong, JH and Paeng, JW and Kim, YK and Han, PL}, title = {Sphingomonas Paucimobilis-derived Extracellular Vesicles Reverse Aβ-induced Dysregulation of Neurotrophic Factors, Mitochondrial Function, and Inflammatory Factors through MeCP2-mediated Mechanism.}, journal = {Experimental neurobiology}, volume = {34}, number = {1}, pages = {20-33}, pmid = {40091636}, issn = {1226-2560}, abstract = {Recent studies have shown an increased abundance of Sphingomonas paucimobilis, an aerobic, Gram-negative bacterium with a distinctive cell envelope rich in glycosphingolipids, within the gut microbiome of individuals with Alzheimer Disease (AD). However, the fact that S. paucimobilis is a well-known pathogen associated with nosocomial infections presents a significant challenge in investigating whether its presence in the gut microbiome is detrimental or beneficial, particularly in the context of AD. This study examines the impact of S. paucimobilis-derived extracellular vesicles (Spa-EV) on Aβ-induced pathology in cellular and animal models of AD. Microarray analysis reveals that Spa-EV treatment modulates Aβ42-induced alterations in gene expression in both HT22 neuronal cells and BV2 microglia cells. Among the genes significantly affected by Spa-EV, notable examples include Bdnf, Nt3/4, and Trkb, which are key players of neurotrophic signaling; Pgc1α, an upstream regulator of mitochondrial biogenesis; Mecp2 and Sirt1, epigenetic factors that regulate numerous gene expressions; and Il1β, Tnfα, and Nfκb-p65, which are associated with neuroinflammation. Remarkably, Spa-EV effectively reverses Aβ42-induced alteration in the expression of these genes through the upregulation of Mecp2. Furthermore, administration of Spa-EV in Tg-APP/PS1 mice restores the reduced expression of neurotrophic factors, Pgc1α, MeCP2, and Sirt1, while suppressing the increased expression of proinflammatory genes in the brain. Our results indicate that Spa-EV has the potential to reverse Aβ-induced dysregulation of gene expression in neuronal and microglial cells. These alterations encompass those essential for neurotrophic signaling and neuronal plasticity, mitochondrial function, and the regulation of inflammatory processes.}, }
@article {pmid40090653, year = {2025}, author = {Zaater, MA and El Kerdawy, AM and Mahmoud, WR and Abou-Seri, SM}, title = {Going beyond ATP binding site as a novel inhibitor design strategy for tau protein kinases in the treatment of Alzheimer's disease: A review.}, journal = {International journal of biological macromolecules}, volume = {307}, number = {Pt 3}, pages = {142141}, doi = {10.1016/j.ijbiomac.2025.142141}, pmid = {40090653}, issn = {1879-0003}, abstract = {Alzheimer's disease (AD) is among the top mortality causing diseases worldwide. The presence of extracellular β-amyloidosis, as well as intraneuronal neurofibrillary aggregates of the abnormally hyperphosphorylated tau protein are two major characteristics of AD. Targeting protein kinases that are involved in the disease pathways has been a common approach in the fight against AD. Unfortunately, most kinase inhibitors currently available target the adenosine triphosphate (ATP)- binding site, which has proven unsuccessful due to issues with selectivity and resistance. As a result, a pressing need to find other alternative sites beyond the ATP- binding site has profoundly evolved. In this review, we will showcase some case studies of inhibitors of tau protein kinases acting beyond ATP binding site which have shown promising results in alleviating AD.}, }
@article {pmid40090428, year = {2025}, author = {Shete, P and Misar, A and Ugale, V and Suryavanshi, K and Ghatpande, N and Waghole, R and Datar, M and Shravage, B and Kulkarni, P}, title = {Multi-target activity of ethanolic extract of Crinum woodrowii Baker for the treatment of Alzheimer's disease.}, journal = {Journal of ethnopharmacology}, volume = {345}, number = {}, pages = {119622}, doi = {10.1016/j.jep.2025.119622}, pmid = {40090428}, issn = {1872-7573}, mesh = {Animals ; *Plant Extracts/pharmacology/chemistry/therapeutic use ; *Alzheimer Disease/drug therapy ; Mice ; RAW 264.7 Cells ; *Ethanol/chemistry ; Male ; *Neuroprotective Agents/pharmacology/isolation & purification/therapeutic use ; *Cholinesterase Inhibitors/pharmacology/isolation & purification ; Rats ; Drosophila ; Disease Models, Animal ; Anti-Inflammatory Agents/pharmacology/isolation & purification/therapeutic use ; Rats, Wistar ; Acetylcholinesterase/metabolism ; Rats, Sprague-Dawley ; Brain/drug effects/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease affecting mental ability and neurocognitive functions. Crinum woodrowii Baker (C. woodrowii) is an endemic plant with significant ethnobotanical potential against neurological and inflammatory conditions with a characteristic improvement of cognitive functions.
AIM OF THE STUDY: To assess the anti-AD potential of C. woodrowii extract through in-vitro assays and preclinical in-vivo screening and to validate its neuroprotective effect by biochemical and histopathological analysis.
MATERIALS AND METHODS: Herein, galantamine contents of the ethanolic extract of C. woodrowii were quantified using HPLC and LCMS. Further, the extract was examined for in-vitro cytotoxicity, anti-inflammatory, anti-cholinesterase activities, and in-vivo neuropharmacological studies.
RESULTS: The extract exhibited low cytotoxicity on RAW 264.7 cells and the inhibition of LPS-induced nitric oxide production. The extract also showed anti-cholinesterase activities. The treatment with extract significantly rescued the rough eye phenotype in the Drosophila model of AD. In neuropharmacological screening, the extract showed no symptoms of acute oral toxicity in rats. The extract significantly reversed scopolamine-induced memory deficit in mice and improved their learning ability with memory retention in exteroceptive behavioral models. The pretreatment of mice with extract reinstated the elevated brain acetylcholinesterase, lipid peroxidation, and reduced glutathione levels due to scopolamine and aging. The extract also restored the altered superoxide dismutase and catalase levels. The extract alleviated neuronal tissue damage caused by the scopolamine, as indicated by the histological analyses of the brain.
CONCLUSION: Our findings suggested that the C. woodrowii extract has neuroprotective properties and ameliorates cognitive dysfunction and hence could be explored further as a potential neurotherapeutics for treating AD.}, }
@article {pmid40090398, year = {2025}, author = {Wang, A and Zhang, F and Zhang, W and Gong, J and Sun, X}, title = {PPM1D ameliorates Alzheimer's disease by promoting mitophagy.}, journal = {Experimental neurology}, volume = {388}, number = {}, pages = {115218}, doi = {10.1016/j.expneurol.2025.115218}, pmid = {40090398}, issn = {1090-2430}, abstract = {Mitochondrial autophagy (mitophagy) plays an essential role in the maintenance of mitochondrial homeostasis. Defective mitophagy triggered by amyloid beta (Aβ) is linked to neuronal deterioration and neurodegeneration in Alzheimer's disease (AD). However, the molecular mechanism underlying the defective mitophagy in AD is still not fully illustrated. Protein phosphatase Mn[2+]/Mg[2+]-dependent 1D (PPM1D) triggers autophagy in mouse embryonic fibroblasts. Downregulated PPM1D was shown in the hippocampus of APP/PS1 mice. This study aims to investigate the role of PPM1D in the progression of AD. Here, APP/PS1 mice were used to mimic AD, and rAAV2 vectors expressing PPM1D were injected into the bilateral hippocampus. In vitro, the mouse hippocampal neuron cell line HT22 was stimulated by Aβ1-42 to trigger neuronal damage. High PPM1D expression alleviated the impairments of spatial cognition and memory in APP/PS1 mice. Additionally, PPM1D enhanced autophagosome formation, lysosomal degradation of impaired mitochondria, amyloid plaque deposition, and neuronal degeneration and apoptosis in the hippocampus of APP/PS1 mice. Similar effects of PPM1D on neuronal apoptosis and mitophagy were observed in Aβ1-42-treated HT22 cells, and the effects could be reversed by the mitophagy inhibitor cyclosporine A. In conclusion, PPM1D facilitates mitophagy to inhibit the progression of AD-like disease. Taken together, the present work uncovers defective mitophagy in AD may be associated with down-regulated PPM1D, and PPM1D may be a potential therapeutic target for AD treatment.}, }
@article {pmid40089260, year = {2025}, author = {Singh, R and Prerna, and Bansal, R}, title = {Neuroprotective potential of 17-oximino-16-arylidene steroids: In vivo and in silico investigations.}, journal = {European journal of pharmacology}, volume = {998}, number = {}, pages = {177467}, doi = {10.1016/j.ejphar.2025.177467}, pmid = {40089260}, issn = {1879-0712}, abstract = {Several recent literature reports indicate the strong neuroprotective potential of synthetic heterosteroids, still search for potent, safer and effective neuroprotective steroidal molecules continues. In the current study, a new series of 17-oximino-16-substituted steroids (1-8) has been evaluated in MPTP-induced Parkinson's disease in mice and amyloid-β induced Alzheimer's disease in rats with an intention to discover an effective and efficient neuroprotective molecule. Behavioural studies followed by histopathological and estimation of the several neuroinflammatory biochemical parameters such as acetylcholinesterase, lipid peroxide, reactive oxygen, and nitric oxide species were carried out. A significant improvement in cognitive and locomotive dysfunctions was observed after treatment with these compounds. In silico molecular docking and simulation studies also correlated with the neuroprotective effects of the steroidal oximes 1-8 as strong binding affinities for TNF-α, IL-1β, AChE and β-secretase were seen. Among all the compounds, 4-pyridylidene (3) and 2-pyridylidene (1) substituted steroids displayed maximum neuroprotective efficacy in animal models of Parkinson's disease and Alzheimer's disease, respectively, and produced effects better than standard drugs. Hence, a new series of 16-arylideno-17-oximino steroids has been identified as potent neuroprotective agents which could be further explored structurally and clinically to discover and develop lead drug molecules useful for the treatment of Parkinson's and Alzheimer's disease.}, }
@article {pmid40089090, year = {2025}, author = {Men, J and Wang, X and Zhou, Y and Huang, Y and Zheng, Y and Wang, Y and Yang, S and Chen, N and Yan, N and Duan, X}, title = {Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential.}, journal = {Cellular signalling}, volume = {131}, number = {}, pages = {111715}, doi = {10.1016/j.cellsig.2025.111715}, pmid = {40089090}, issn = {1873-3913}, abstract = {Neurodegenerative diseases (NDDs) are a class of diseases in which the progressive loss of subtype-specific neurons leads to dysfunction. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Previous studies have demonstrated that the pathogenesis of NDDs involves various mechanisms, including genetic factors, oxidative stress, apoptosis, and the immune response. Recent studies have shown that epigenetic regulation mediates the interactions between DNA methylation, chromatin remodeling, histone modification, and non-coding RNAs, thus affecting gene transcription. A growing body of research links epigenetic modifications to crucial pathways involved in the occurrence and development of NDDs. Epigenetics has also been found to regulate and maintain nervous system function, and its imbalance is closely related to the occurrence and development of NDDs. The present review summarizes focuses on the role of epigenetic modifications in the pathogenesis of NDDs and provides an overview of the key genes regulated by DNA methylation, histone modification, and non-coding RNAs in NDDs. Further, the current research status of epigenetics in NDDs is summarized and the potential application of epigenetics in the clinical diagnosis and treatment of NDDs is discussed.}, }
@article {pmid40089052, year = {2025}, author = {Pedrinolla, A and Dorelli, G and Porcelli, S and Burleigh, M and Mendo, M and Martignon, C and Fonte, C and Dalle Carbonare, LG and Easton, C and Muti, E and Schena, F and Venturelli, M}, title = {Increasing nitric oxide availability via ingestion of nitrate-rich beetroot juice improves vascular responsiveness in individuals with Alzheimer's Disease.}, journal = {Nitric oxide : biology and chemistry}, volume = {156}, number = {}, pages = {50-56}, doi = {10.1016/j.niox.2025.03.001}, pmid = {40089052}, issn = {1089-8611}, abstract = {Poor vascular function and reduced nitric oxide (NO)-bioavailability have been recognized to be involved in aging and Alzheimer's Disease (AD). A non-pharmacological treatment that is gaining clinical interest in the context of vascular function is dietary inorganic nitrate (NO3[-]) supplementation which increases NO-bioavailability through the NO3[-] -nitrite (NO2[-]) - NO pathway. This treatment has been demonstrated to improve vascular function in several clinical populations, but no study has investigated the effects in individuals with AD. Therefore, changes in plasma NO3[-] and NO2[-] and vascular responsiveness (hyperemic response to single-passive leg movement (ΔPLM)) were measured in individuals with AD (n = 10, 76 ± 9 years), healthy elderly (OLD, n = 10, 75 ± 6 years), and young individuals (YN, n = 10, 25 ± 4 years) before (T0) and hourly for 4 h (T1, T2, T3, and T4) after ingestion of either NO3[-]-rich beetroot juice (BR) or a placebo (PLA). No changes in NO3[-] and NO2[-], nor ΔPLM were detected in any group following PLA intake. Plasma NO3[-] and NO2[-] increased significantly in all three groups at T1 (p < 0.001) and remained elevated for the rest of the trial. The same trend was found in ΔPLM, which significantly increased in all three groups over the time (p < 0.001). However, AD exhibited significantly lower ΔPLM values at any time point compared to YN (p < 0.001) and OLD (p < 0.001). These data suggest that AD-individuals included in this study were able to reduce NO3[-] to NO2[-] and to increase NO-mediated vascular responsiveness as non-AD-individuals. Other mechanisms, beyond NO-bioavailability, may be involved in vascular dysfunction in patients with AD. This research suggests that an acute administration of inorganic nitrate is not enough to revert chronically adapted vascular properties and completely restore vascular responsiveness in AD.}, }
@article {pmid40089002, year = {2025}, author = {da Silva, EA and Faber, J and Penitente, AR and Fernandes, J and Bertolucci, PHF and Longo, BM and Arida, RM}, title = {Effects of resistance exercise on behavioral and molecular changes in transgenic female mice for Alzheimer's disease in early and advanced stages.}, journal = {Experimental neurology}, volume = {388}, number = {}, pages = {115217}, doi = {10.1016/j.expneurol.2025.115217}, pmid = {40089002}, issn = {1090-2430}, abstract = {UNLABELLED: Alzheimer's disease (AD) is a neurodegenerative condition that affects memory and cognition, with a higher prevalence in women. Given the lack of effective treatment, physical activity stands out as a complementary approach to prevent or delay disease progression. While numerous studies on humans and animals indicate that aerobic exercise induces brain changes, the impact of resistance exercise (RE) on AD is not fully understood.
OBJECTIVE: This study aimed to investigate the behavioral and molecular changes induced by RE in female transgenic mice with AD at the early and advanced stages of the disease.
MATERIALS AND METHODS: Adult (initial phase - 7 to 8 months of age, n = 32) and adult/elderly (advanced phase - 22 to 23 months of age, n = 32) female mice (2xTg-AD) for the APPSWE/PS1dE9 mutation were subjected to a four-week RE protocol. Mobility, anxiety-like behavior, long-term memory (LTM), and depressive-like behavior were assessed. Beta-amyloid (βA) and cytokines were quantified using the ELISA technique.
RESULTS: There was a progressive increase in strength in both trained groups at different ages. RE reversed memory deficits only in adult AD animals and the anxiety-like behavior only in adult/elderly AD animals. RE reversed depressive-like behavior in adult and adult/elderly AD animals. RE reduced βA only in adult AD animals. RE modified the expression of several cytokines in animals in the early and advanced stage of AD.
CONCLUSION: RE can be a promising strategy to minimize the deleterious effects of AD; however, its effectiveness may be more limited to the early stages of the disease.}, }
@article {pmid40088370, year = {2025}, author = {Bhatia, V and Vikram, V and Chandel, A and Rattan, A}, title = {Interplay between PI3k/AKT signaling and caspase pathway in Alzheimer disease: mechanism and therapeutic implications.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {40088370}, issn = {1568-5608}, abstract = {Alzheimer's disease, a neurodegenerative disorder, is characterized by cognitive impairment, neuronal loss, and synaptic dysfunction. The interplay between the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and the caspase-mediated apoptotic cascade plays a pivotal role in its progression. The signaling pathway responsible for neuronal survival also regulates synaptic plasticity and resistance to oxidative stress, whereas caspase activation accelerates neurodegeneration by triggering cell death and inflammation. Dysregulation of these pathways leads to amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, and mitochondrial dysfunction, creating a negative feedback loop and accelerating disease progression. Emerging treatment methods that target PI3K/AKT activation and caspase inhibition have showed promise in preclinical models, preventing neuronal apoptosis while retaining cognitive function. This review investigates the molecular processes driving PI3K/AKT and caspase crosstalk, their significance in Alzheimer's disease, and prospective therapeutic strategies aiming at regulating these pathways to improve disease outcomes.}, }
@article {pmid40087862, year = {2025}, author = {Balantzategi, U and Gaminde-Blasco, A and Kearns, CA and Bayón-Cordero, L and Sánchez-Gómez, MV and Zugaza, JL and Appel, B and Alberdi, E}, title = {Amyloid-β Dysregulates Oligodendroglial Lineage Cell Dynamics and Myelination via PKC in the Zebrafish Spinal Cord.}, journal = {Glia}, volume = {}, number = {}, pages = {}, doi = {10.1002/glia.70015}, pmid = {40087862}, issn = {1098-1136}, support = {FPU17/04891//Ministerio de Ciencia, Innovación y Universidades/ ; PID2019-108465RB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2022-140236OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; IT1551-22//Eusko Jaurlaritza/ ; PIBA_2020_1_0012//Eusko Jaurlaritza/ ; PRE_2019_1_0132//Eusko Jaurlaritza/ ; PRE_2019_1_0317//Eusko Jaurlaritza/ ; BIO22/ALZ/014//Berrikuntza + Ikerketa + Osasuna Eusko Fundazioa/ ; NS095679/NH/NIH HHS/United States ; R35NS122191/NH/NIH HHS/United States ; }, abstract = {Soluble forms of amyloid-β (Aβ) peptide have been proposed as candidates to induce oligodendrocyte (OL) and myelin dysfunctions in the early stages of Alzheimer's disease (AD) pathology. Nevertheless, little is known about how Aβ affects OL differentiation and myelination in vivo, and the underlying molecular mechanisms. In this study, we explored the effects of a brain intraventricular injection of Aβ on OLs and myelin in the developing spinal cord of zebrafish larvae. Using quantitative fluorescent in situ RNA hybridization assays, we demonstrated that Aβ altered myrf and mbp mRNA levels and the regional distribution of mbp during larval development, suggesting an early differentiation of OLs. Through live imaging of Tg(myrf:mScarlet) and Tg(mbpa:tagRFP) zebrafish lines, both crossed with Tg(olig2:EGFP), we found that Aβ increased the number of myrf[+] and mbp[+] OLs in the dorsal spinal cord at 72 hpf and 5 dpf, respectively, without affecting total cell numbers. Furthermore, Aβ also increased the number of Sox10[+]cells, myelin sheaths per OL, and the number of myelinated axons in the dorsal spinal cord at 8 dpf compared to vehicle-injected control animals. Interestingly, the treatment of Aβ-injected zebrafish with the pan-PKC inhibitor Gö6983 restored the aforementioned alterations in OLs and myelin to control levels. Altogether, not only do we demonstrate that Aβ induces a precocious oligodendroglial differentiation leading to dysregulated myelination, but we also identified PKC as a key player in Aβ-induced pathology.}, }
@article {pmid40087766, year = {2025}, author = {Tocci, D and Fogel, M and Gupta, V and Kim, P and Latimer, J and Adlimoghaddam, A and Robison, LS and Albensi, BC}, title = {Beyond expectations: investigating nilotinib's potential in attenuating neurodegeneration in alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {60}, pmid = {40087766}, issn = {1758-9193}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Pyrimidines/therapeutic use/pharmacology ; Animals ; *Protein Kinase Inhibitors/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), pose a formidable global challenge. While therapeutic options are available, their limitations are significant, necessitating the development of innovative treatment approaches. Here, we highlight the importance of repurposing drugs and discuss the future of drug treatments for AD. We review the potential of tyrosine kinase inhibitors (TKI) for mitigating AD pathology and symptoms, as well as neurodegenerative processes more broadly. We focus on nilotinib, a selective BCR-ABL tyrosine kinase inhibitor, which has unique mechanisms of action involving the modulation of cell responses and removal of toxic proteins associated with AD pathogenesis. Encouraging studies have demonstrated its efficacy, calling for further investigation through clinical trials to assess its potential in various neurodegenerative conditions. However, despite these promising preclinical findings, no clinical studies have yet conclusively demonstrated its efficacy in treating AD. Considering the future directions in AD research, personalized medicine approaches hold promise by incorporating patient-specific factors, including sex and gender differences, to tailor nilotinib treatment for improved efficacy and safety profiles.}, }
@article {pmid40087204, year = {2025}, author = {Lin, D and Howard, A and Raihane, AS and Di Napoli, M and Cáceres, E and Ortiz, M and Davis, J and Abdelrahman, AN and Divani, AA}, title = {Traumatic Brain Injury and Gut Microbiome: The Role of the Gut-Brain Axis in Neurodegenerative Processes.}, journal = {Current neurology and neuroscience reports}, volume = {25}, number = {1}, pages = {23}, pmid = {40087204}, issn = {1534-6293}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/microbiology/physiopathology ; *Brain Injuries, Traumatic/microbiology/physiopathology/complications ; *Brain-Gut Axis/physiology ; Animals ; Dysbiosis ; Brain/physiopathology ; }, abstract = {PURPOSE OF REVIEW: A deeper understanding of the communication network between the gut microbiome and the central nervous system, termed the gut-brain axis (GBA), has revealed new potential targets for intervention to prevent the development of neurodegenerative disease associated with tramatic brain injury (TBI). This review aims to comprehensively examine the role of GBA post-traumatic brain injury (TBI).
RECENT FINDINGS: The GBA functions through neural, metabolic, immune, and endocrine systems, creating bidirectional signaling pathways that modulate brain and gastrointestinal (GI) tract physiology. TBI perturbs these signaling pathways, producing pathophysiological feedback loops in the GBA leading to dysbiosis (i.e., a perturbed gut microbiome, impaired brain-blood barrier, impaired intestinal epithelial barrier (i.e., "leaky gut"), and a maladaptive, systemic inflammatory response. Damage to the CNS associated with TBI leads to GI dysmotility, which promotes small intestinal bacterial overgrowth (SIBO). SIBO has been associated with the early stages of neurodegenerative conditions such as Parkinson's and Alzheimer's disease. Many of the bacteria associated with this overgrowth promote inflammation and, in rodent models, have been shown to compromise the structural integrity of the intestinal mucosal barrier, causing malabsorption of essential nutrients and further exacerbating dysbiosis. TBI-induced pathophysiology is strongly associated with an increased risk of neurodegenerative diseases, including Parkinson's and Alzheimer's diseases, which represents a significant public health burden and challenge for patients and their families. A healthy gut microbiome has been shown to promote improved recovery from TBI and prevent the development of neurodegenerative disease, as well as other chronic complications. The role of the gut microbiome in brain health post-TBI demonstrates the potential for microbiome-targeted interventions to mitigate TBI-associated comorbidities. Promising new evidence on prebiotics, probiotics, diet, and fecal microbiota transplantation may lead to new therapeutic options for improving the quality of life for patients with TBI. Still, many of these preliminary findings must be explored further in clinical settings. This review covers the current understanding of the GBA in the setting of TBI and how the gut microbiome may provide a novel therapeutic target for treatment in this patient population.}, }
@article {pmid40086955, year = {2025}, author = {Chin, WL and Lee, BH and Hsu, QY and Hou, CY and Pai, MC and Lin, CW and Hsu, WH}, title = {Small intestine-residing probiotics suppress neurotoxic bile acid production via extracellular vesicle-mediated inhibition of Clostridium scindens.}, journal = {Food research international (Ottawa, Ont.)}, volume = {207}, number = {}, pages = {116049}, doi = {10.1016/j.foodres.2025.116049}, pmid = {40086955}, issn = {1873-7145}, mesh = {Animals ; *Probiotics/pharmacology ; *Clostridium/metabolism ; *Intestine, Small/microbiology/metabolism ; *Gastrointestinal Microbiome ; *Bile Acids and Salts/metabolism ; Mice ; *Extracellular Vesicles/metabolism ; *Mice, Transgenic ; Lactobacillus johnsonii/metabolism ; Lithocholic Acid/metabolism ; Humans ; Alzheimer Disease/metabolism/microbiology ; }, abstract = {Dysbiosis in gut microbiota and abnormalities in bile acids have been linked to neurodegenerative diseases. While many studies have focused on the relationship between colonic bacteria and Alzheimer's disease (AD), this study propose that alterations in the small intestine microbiota may play a more critical role. This is because the small intestine is pivotal in recycling bile acids through enterohepatic circulation. This study uses amyloid precursor protein knock-in (APP[NL-G-F/NL-G-F]) transgenic mice to investigate the association between intestinal microbiota and bile acid metabolism. The results showed that the accumulation of beta-amyloid (Aβ) leads to a significant decrease in Lactobacillus johnsonii and a notable increase in bacteria of the genus Clostridium in the small intestine, which are important microorganisms for producing toxic bile acids. Extracellular vesicles (EVs) involved in bacterial interactions and bacteria-host interactions are currently a focus of research. Treatment with L. johnsonii-derived EVs at concentrations of 10[10] and 10[12]/mL) inhibited the growth of Clostridium scindens and suppressed the production of toxic secondary lithocholic acid (TLA) at non-cytotoxic concentrations (10[8]/mL). Furthermore, the removal of small RNA from L. johnsonii-derived EVs resulted in the loss of their ability to suppress TLA production. These results suggest that the small intestine microbiota may play a more critical role than the colonic microbiota in AD. Deterioration of small intestine microbiota led to the metabolism disruption of certain secondary bile acids, which have been reported to exacerbate AD pathology. The EVs released by L. johnsonii, which is abundant in the small intestine, can suppress toxic TLA and have the potential to be developed into health-promoting probiotics.}, }
@article {pmid40086910, year = {2025}, author = {Sankhe, K and Tumati, S and Perin, J and Rivet, L and Vieira, D and Rosenberg, PB and Herrmann, N and Shade, D and Lerner, AJ and Padala, PR and Brawman-Mintzer, O and van Dyck, CH and Porsteinsson, AP and Craft, S and Levey, AI and Mintzer, J and Lanctôt, KL}, title = {Correlation between changes in apathy and cognition in Alzheimer's disease associated apathy: Analysis of the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).}, journal = {International psychogeriatrics}, volume = {37}, number = {2}, pages = {100012}, doi = {10.1016/j.inpsyc.2024.100012}, pmid = {40086910}, issn = {1741-203X}, mesh = {Humans ; *Apathy/drug effects ; *Methylphenidate/therapeutic use/pharmacology ; Male ; Female ; Aged ; *Alzheimer Disease/drug therapy/psychology ; *Cognition/drug effects ; *Neuropsychological Tests ; *Central Nervous System Stimulants/therapeutic use ; Aged, 80 and over ; Treatment Outcome ; Double-Blind Method ; }, abstract = {BACKGROUND: Previous trials have shown improvements in both apathy and cognition with methylphenidate (MPH).
OBJECTIVES: To assess whether changes in apathy correlated with changes in cognition in the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).
PARTICIPANTS: Mild to moderate AD patients with clinically significant apathy randomized to MPH (20 mg/day) or placebo for 6 months.
MEASUREMENTS: Apathy was measured with the Neuropsychiatric Inventory-apathy (NPI-A) domain. Cognition was measured using the Mini-Mental State Exam (MMSE), Hopkins Verbal Learning (immediate [HVLT-I], delayed [HVLT-D] recall), Digit Span (Forward [DF], Backward [DB]), Trail Making (TMT-A, TMT-B), Action Verbal Fluency (AV), Category Fluency (CF), and the Short Boston Naming Test (BNT).
DESIGN: Linear mixed models included cognitive change scores as dependent variables and time, treatment, change in NPI-A and the interaction between treatment and change in NPI-A as independent variables, which were additionally adjusted for baseline NPI-A and cognitive scores, age, sex, level of education and presence of diabetes.
RESULTS: 199 participants (66 % male) were included (98-MPH, 101-placebo). Among all participants, worsening CF was associated with worsening apathy (-0.15 (0.05), p = .003). In addition, change in HVLT-I was associated with the interaction between changes in apathy and treatment (-0.31 (0.07), p = 0.0000158).
CONCLUSION: Changes in apathy are mostly independent of cognitive changes and apathy response to MPH may be independent from cognition. These results are consistent with the view that apathy as a syndrome is related to but distinct from cognition.}, }
@article {pmid40086116, year = {2025}, author = {Lin, G and Liang, W and He, Q and Wang, Y and Yang, X}, title = {Dual single nucleotide polymorphisms typing of apolipoprotein E gene based on double restriction endonuclease with lambda exonuclease and triple helix molecular switch assistance.}, journal = {Biosensors & bioelectronics}, volume = {278}, number = {}, pages = {117365}, doi = {10.1016/j.bios.2025.117365}, pmid = {40086116}, issn = {1873-4235}, mesh = {Humans ; *Alzheimer Disease/diagnosis/genetics/therapy ; Early Diagnosis ; Feasibility Studies ; *Genotyping Techniques/methods ; Polymorphism, Restriction Fragment Length ; Polymorphism, Single Nucleotide ; Precision Medicine/methods ; Sensitivity and Specificity ; Limit of Detection ; }, abstract = {Single nucleotide polymorphisms (SNPs) are critical determinants of disease susceptibility, pathogenesis, and drug response, underscoring the need for their accurate monitoring in clinical practice. In this study, we propose a novel apolipoprotein E (APOE) genotyping method for the rapid and precise identification of six genotypes (ε2/ε2, ε3/ε3, ε4/ε4, ε2/ε3, ε2/ε4, and ε3/ε4). The method utilizes restriction endonucleases AflIII and HaeII to selectively cleave the rs429358 and rs7412 sites, thereby generating distinct double-stranded DNA fragments. These fragments are subsequently processed by Lambda exonuclease to produce single-stranded DNA, which binds to a triple-helix molecular switch (THMS) and induces its conformational transition into a hairpin structure, resulting in a fluorescence change. The optimized assay exhibits a linear detection range of 5-1000 copies with a minimum detection limit of 2 copies for the rs429358 site, and a range of 10-1000 copies with a minimum detection limit of 6 copies for the rs7412 site. Furthermore, the method was validated using clinical samples from 10 Alzheimer's disease patients, achieving complete concordance with sequencing results, which underlines the high specificity and sensitivity of the method and demonstrates its potential as a valuable tool for the early diagnosis and personalized treatment of Alzheimer's disease.}, }
@article {pmid40084546, year = {2025}, author = {Magnussen, JH}, title = {Advances in PET Imaging of α7 Nicotinic Receptors: From Radioligand Development to CNS Applications.}, journal = {Basic & clinical pharmacology & toxicology}, volume = {136}, number = {4}, pages = {e70025}, pmid = {40084546}, issn = {1742-7843}, mesh = {*alpha7 Nicotinic Acetylcholine Receptor/metabolism ; *Positron-Emission Tomography/methods ; Humans ; Animals ; *Radiopharmaceuticals/pharmacokinetics ; *Central Nervous System Diseases/drug therapy/diagnostic imaging/metabolism ; Brain/metabolism/diagnostic imaging ; Drug Development/methods ; Ligands ; Blood-Brain Barrier/metabolism ; }, abstract = {Positron emission tomography (PET) has significantly advanced our understanding of the brain by enabling non-invasive imaging and quantification of molecular processes, including receptor binding. In this review, we explore the development and application of PET radioligands targeting the α7 nicotinic acetylcholine receptor (α7 nAChR), a receptor implicated in various central nervous system (CNS) diseases, such as Alzheimer's disease, schizophrenia and cognitive disorders. Despite challenges associated with the low density of α7 nAChRs and difficulties in achieving adequate brain penetration, several promising radioligands have been developed, including [11]C-(R)-MeQAA, [11]C-NS14492 and [18]F-ASEM. These radioligands facilitate the evaluation of the 'three pillars of survival' in drug development: tissue accessibility, target engagement and downstream pharmacology. PET imaging offers critical insights into drug distribution across the blood-brain barrier, receptor occupancy and the pharmacodynamic effects of α7 nAChR-targeted therapies. By reviewing current radioligands and their applications, we highlight the potential of PET imaging to deepen our understanding of α7 nAChR-mediated signalling pathways and its implications for CNS drug discovery. Future innovations in radioligand development, including more selective and brain-penetrant compounds, will be key to fully realizing the potential of PET imaging in α7 nAChR-targeted research and treatment.}, }
@article {pmid40084342, year = {2025}, author = {Perez, FP and Walker, B and Morisaki, J and Kanakri, H and Rizkalla, M}, title = {Neurostimulation devices to treat Alzheimer's disease.}, journal = {Exploration of neuroscience}, volume = {4}, number = {}, pages = {}, pmid = {40084342}, issn = {2834-5347}, support = {UL1 TR000006/TR/NCATS NIH HHS/United States ; }, abstract = {The use of neurostimulation devices for the treatment of Alzheimer's disease (AD) is a growing field. In this review, we examine the mechanism of action and therapeutic indications of these neurostimulation devices in the AD process. Rapid advancements in neurostimulation technologies are providing non-pharmacological relief to patients affected by AD pathology. Neurostimulation therapies include electrical stimulation that targets the circuitry-level connection in important brain areas such as the hippocampus to induce therapeutic neuromodulation of dysfunctional neural circuitry and electromagnetic field (EMF) stimulation that targets anti-amyloid molecular pathways to promote the degradation of beta-amyloid (Aβ). These devices target specific or diffuse cortical and subcortical brain areas to modulate neuronal activity at the electrophysiological or molecular pathway level, providing therapeutic effects for AD. This review attempts to determine the most effective and safe neurostimulation device for AD and provides an overview of potential and current clinical indications. Several EMF devices have shown a beneficial or harmful effect in cell cultures and animal models but not in AD human studies. These contradictory results may be related to the stimulation parameters of these devices, such as frequency, penetration depth, power deposition measured by specific absorption rate, time of exposure, type of cell, and tissue dielectric properties. Based on this, determining the optimal stimulation parameters for EMF devices in AD and understanding their mechanism of action is essential to promote their clinical application, our review suggests that repeated EMF stimulation (REMFS) is the most appropriate device for human AD treatments. Before its clinical application, it is necessary to consider the complicated and interconnected genetic and epigenetic effects of REMFS-biological system interaction. This will move forward the urgently needed therapy of EMF in human AD.}, }
@article {pmid40083619, year = {2025}, author = {Hong, JP and Chen, WF and Nguyen, DH and Xie, Q}, title = {A Proposed Role for Lymphatic Supermicrosurgery in the Management of Alzheimer's Disease: A Primer for Reconstructive Microsurgeons.}, journal = {Archives of plastic surgery}, volume = {52}, number = {2}, pages = {96-103}, pmid = {40083619}, issn = {2234-6163}, abstract = {The relatively recent discovery of a novel lymphatic system within the brain meninges has spurred interest in how waste products generated by neurons and glial cells-including proteins associated with Alzheimer's disease (AD) pathology such as amyloid beta (Aβ) and tau-are disposed of. Evidence is building that suggests disease progression in AD and other cognitive impairments could be explained by dysfunction in the brain's lymphatic system or obstruction of drainage. An interesting implication of this hypothesis is that, by relieving the obstruction of flow, lymphatic reconstruction along the drainage pathway could serve as a potential novel treatment. Should this concept prove true, it could represent a surgical solution to a problem for which only medical solutions have thus far been considered. This study is meant to serve as a primer for reconstructive microsurgeons, introducing the topic and current hypotheses about the potential role of lymphatic drainage in AD. A preview of current research evaluating the feasibility of lymphatic reconstruction as a surgical approach to improving Aβ clearance is provided, with the aim of inspiring others to design robust preclinical and clinical investigations into this intriguing hypothesis.}, }
@article {pmid40083584, year = {2024}, author = {Pandey, S and Danielsen, MB and Xiang, Y and Zhang, Z and Sharma, G and Jeon, BT and Song, S and Hao, Y and Zhang, G and Christensen, NJ and Sørensen, KK and Harris, P and Pokhrel, P and Cunningham, R and Kim, MH and Leng, Y and Lou, C and Mao, H}, title = {De novo design of a mechano-pharmaceutical screening platform against formation of individual beta-amyloid oligomers.}, journal = {Cell reports. Physical science}, volume = {5}, number = {12}, pages = {}, pmid = {40083584}, issn = {2666-3864}, support = {R01 CA252827/CA/NCI NIH HHS/United States ; }, abstract = {Small molecules that can reduce the neurotoxic beta-amyloid (Aβ) aggregates in the brain provide a potential treatment for Alzheimer disease (AD). Most screening methods for small-molecule hits focus on the overall Aβ aggregations without a specific target, such as the very first association step (i.e., nucleation) en route to the Aβ oligomers. Located in the middle of a full-length Aβ peptide, Aβ19-20 (diphenylalanine or FF) nucleates the neurotoxic Aβ oligomer formation. Here, we innovate a single-molecule screen method in optical tweezers by targeting the nucleation process in Aβ aggregation, namely FF-dimerization. With a 121-compound National Institutes of Health (NIH) library, we identify 12 inhibitors and 8 stimulants that can inhibit/promote Aβ19-20 dimerization significantly. The representative hits are subjected to the thioflavin T and cell toxicity assays to confirm their inhibiting or stimulating activities. By replacing FF with longer Aβ sequences, our single-molecule platform may identify more specific and potent small molecules to fight AD.}, }
@article {pmid40083386, year = {2025}, author = {Wang, S and Yang, J and Zheng, W and Zhang, S and Zhong, D}, title = {The effect of tanshinones on cognitive impairments in animal models of Alzheimer's disease: a systematic review and meta-analysis.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1529327}, pmid = {40083386}, issn = {1663-9812}, abstract = {BACKGROUND: Alzheimer's disease (AD) is an age-related neurological illness that poses a significant hazard to human health. A fat-soluble compound called tanshinones was isolated from Danshen, a traditional Chinese herb. Recent years have seen reports of clinical trials examining the effects of tanshinones on cognitive impairment among individuals with AD, as well as the publication of pertinent basic research. Tanshinones are not yet commonly utilized in the therapeutic treatment of AD, and the effectiveness of tanshinones as a treatment program for AD is not yet adequately supported by evidence. To assess the impact of tanshinones on cognitive impairment in experimental rodent models of AD, we carried out a systematic review in this work.
METHOD: All relevant studies on the usage of tanshinones in AD model animals published in PubMed, Cochrane Library, Web of Science, EMBASE, Chinese Biomedicine Database, and China National Knowledge Infrastructure before 8 September 2024, were systematically retrieved. To assess the methodological quality, the CAMARADES checklist was used. Meta-analysis was calculated and graphed in the Stata 14.0 software. For each outcome in every study, the standard mean difference (SMD) and the 95% confidence interval (CI) of each effect size were calculated.
RESULTS: Fourteen studies were included in this study. Compared with the AD model group without tanshinones intervention, tanshinones significantly reduced the number of escape latency [SMD = -2.082, 95% CI = (-2.481, -1.683), p < 0.001]. Tanshinones also increased the times of platform crossing [SMD = 1.464, 95% CI = (1.183, 1.744), p < 0.001] and time in target quadrants [SMD = 2.703, 95% CI = (2.132, 3.275), p < 0.001].
CONCLUSION: Tanshinones are thought to have positive effects on cognitive impairment in rodent models of AD, according to the findings of this study. However, the level of quality of the included research may have an impact on the accuracy of positive outcomes. Thus, more high-quality randomized controlled animal studies are required to guide future scientific and clinical research.
identifier CRD42024557980.}, }
@article {pmid40083013, year = {2025}, author = {Jiang, Y and Guo, Z and Zhou, X and Jiang, N and He, J}, title = {Exploration of working memory retrieval stage for mild cognitive impairment: time-varying causality analysis of electroencephalogram based on dynamic brain networks.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {22}, number = {1}, pages = {58}, pmid = {40083013}, issn = {1743-0003}, support = {ZYYC22001//the 1.3.5 Project for Disciplines of 1435 Excellence Grant from the West China Hospital/ ; Z2024YY002//National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/ ; YJ202373//the Fundamental Research Funds for the Central Universities/ ; XZ202201ZD0001G//the Science and Technology Major Project of Tibetan Autonomous Region of China/ ; }, mesh = {Humans ; *Cognitive Dysfunction/physiopathology/diagnosis ; *Electroencephalography/methods ; *Memory, Short-Term/physiology ; Female ; Male ; Aged ; *Brain/physiopathology ; Nerve Net/physiopathology ; Middle Aged ; Mental Recall/physiology ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Mild Cognitive Impairment (MCI) is an intermediate stage between the expected cognitive decline of normal aging and Alzheimer's disease (AD). Its management is crucial for it helps intervene and slow the progression of cognitive decline to AD. However, the understanding of the MCI mechanism is not completely clear. As working memory (WM) damage is a common symptom of MCI, this study focused on the core stage of WM, i.e., the memory retrieval stage, to investigate information processing and the causality relationships among brain regions based on electroencephalogram (EEG) signals.
METHOD: 21 MCI and 20 normal cognitive control (NC) participants were recruited. The delayed matching sample paradigm with two different loads was employed to evaluate their WM functions. A time-varying network based on the Adaptive transfer function (ADTF) was constructed on the EEG of the memory retrieval trials.to perform the dynamic brain network analysis.
RESULTS: Our results showed that: (a) Behavioral data analysis: there were significant differences in accuracy and accuracy / reaction time between MCI and NC in tasks with memory load capacity of low load-four and high load-six, especially in tasks with memory load capacity of four. (b) Dynamic brain network analysis: there were significant differences in the dynamic changes of brain network patterns between the two groups during the memory retrieval stage of the WM task. Specifically, in low load WM tasks, the dynamic brain network changes of NC were more regular to accommodate for efficient information processing, with important core nodes showing a transition from bottom to up, while MCI did not display a regular dynamic brain network pattern. Further, the brain functional areas associated with low load WM disorders were mainly located in the left prefrontal lobe (FC1) and right occipital lobe (PO8). Compared with low load WM task, during the high load WM task, the dynamic brain network changes of NC during the memory retrieval stage were regular, and the core nodes exhibited a consistent transition phenomenon from up to bottom to up, which were not observed in MCI.
CONCLUSIONS: Behavioral data in the low load WM task paradigm and abnormal electrophysiological signals in the left prefrontal (FC1) and right occipital lobes (PO8) could be used for MCI diagnosis. This is the first time based on large-scale dynamic network methods to investigate the dynamic network patterns of MCI memory retrieval stages under different load WM tasks, providing a new perspective on the neural mechanisms of WM deficits in MCI patients and providing some reference for the clinical intervention treatment of MCI-WM memory disorders.}, }
@article {pmid40082927, year = {2025}, author = {Meng, X and Li, X and Cao, M and Dong, J and Wang, H and Cao, W and Liu, D and Wang, Y}, title = {Summarizing attributable factors and evaluating risk of bias of Mendelian randomization studies for Alzheimer's dementia and cognitive status: a systematic review and meta-analysis.}, journal = {Systematic reviews}, volume = {14}, number = {1}, pages = {61}, pmid = {40082927}, issn = {2046-4053}, support = {2017YFE0118800-779238//National Key R&D Program of China-European Commission Horizon 2020/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics ; *Mendelian Randomization Analysis ; *Cognitive Dysfunction ; Risk Factors ; Bias ; Cognition ; }, abstract = {BACKGROUND: No effective treatment is available to delay or reverse the onset and progression of Alzheimer's dementia (AD). Mild cognitive impairment, a clinical state between normal aging and AD, may offer the proper window for AD intervention and treatment. This systematic review aimed to summarize evidence from Mendelian randomization (MR) studies exploring factors attributable to AD and related cognitive status and to assess its credibility.
METHODS: We searched PubMed, Embase, MEDLINE, and the Cochrane Library to identify MR studies investigating the associations between any factor and AD and related cognitive status. The risk of bias in MR studies was evaluated using nine signaling questions tailored to identify potential biases based on the STROBE-MR guidelines.
RESULTS: A total of 125 eligible publications were examined, including 106 AD-related MR studies reporting 674 records and 28 cognition-related MR studies reporting 141 records. We identified 185 unique causal risk factors for AD and 49 for cognitive status. More than half of the MR studies reporting AD or cognitive status outcomes exhibited poor methodological quality, with a high risk of bias observed in 59% of the AD-related studies and 64% of the cognitive-related studies.
CONCLUSIONS: This systematic review summarized modifiable factors and omics signatures, providing a database of MR studies on AD and related cognitive status. The evaluation of bias risk in MR studies serves to raise awareness and improve overall quality. A critical appraisal checklist for assessing the risk of bias may pave the way for the development of a standardized tool.
The review protocol was registered with the Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42023213990.}, }
@article {pmid40081955, year = {2025}, author = {Tunali, I and Wang, J and Arora, AK and Kim, MJ and Shcherbinin, S and Pontecorvo, M and Iaccarino, L}, title = {Development and Validation of a [18]F-Flortaucipir PET Visual Stratification Method.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {66}, number = {4}, pages = {612-619}, pmid = {40081955}, issn = {1535-5667}, abstract = {Tau PET quantitation methods have been used in research settings and clinical trials to measure tau burden for diagnostic, staging, and prognostic purposes. However, these methods require specialized software, skilled analysts, and advanced image processing. We developed a novel [18]F-flortaucipir PET (FTP, or Tauvid) visual read method enabling stratification of patients with Alzheimer disease (AD) according to the tau level without the need for quantitation. An independent reader study (I7E-AV-A26) was conducted to test this method against a quantitation-based high-tau standard of truth. Methods: A total of 140 baseline or screening FTP scans were randomly selected from the TRAILBLAZER-ALZ 2 phase 3 trial (NCT04437511). Five qualified imaging physicians were trained for the FTP visual stratification method, using previously identified thresholds and cortical regions of interest thought to optimally stratify high-tau and non-high-tau scans. Positive and negative percent agreement (PPA and NPA, respectively) between visual stratifications and quantitation-based high tau (AD-signature SUV ratio > 1.46) were calculated. Predefined success criteria were met if the lower bounds of a 2-sided 95% CI for PPA and NPA were 50% or greater for at least 3 of the 5 readers. Inter- and intrareader reliability were assessed using Fleiss κ (n = 140) and Cohen κ (n = 20 test-retest scans) metrics. Results: The median PPA and NPA were 83.4% and 88.9%, respectively, with lower bounds of 2-sided 95% CIs being 50% or greater for all readers. The Fleiss κ-point estimate was 0.8882 (95% CI, 0.8356-0.9409) and the Cohen κ-point estimate was 0.9599 (95% CI, 0.9049-1.000) for all readers, indicating almost perfect inter- and intrareader agreement. Study I7E-AV-A26 successfully validated the feasibility of the FTP visual stratification method, possibly supporting AD staging and prognosis with high inter- and intrareader agreements, confirming the reliability of the method. Conclusion: Future investigations may include expanding the validation dataset, including real-world clinical data from diverse populations, using autopsy confirmation, exploring alternative regions and thresholds for other tau PET stratifications, and assessing differences in treatment response among visually stratified participants enrolled in disease-modifying therapy trials.}, }
@article {pmid40081796, year = {2025}, author = {Chen, G and Zhang, K and Sun, M and Xie, N and Wu, L and Zhang, G and Guo, B and Huang, C and Man Hoi, MP and Zhang, G and Shi, C and Sun, Y and Zhang, Z and Wang, Y}, title = {Multi-functional memantine nitrate attenuated cognitive impairment in models of vascular dementia and Alzheimer's disease through neuroprotection and increased cerebral blood flow.}, journal = {Neuropharmacology}, volume = {272}, number = {}, pages = {110410}, doi = {10.1016/j.neuropharm.2025.110410}, pmid = {40081796}, issn = {1873-7064}, mesh = {Animals ; *Memantine/pharmacology/therapeutic use/analogs & derivatives ; *Alzheimer Disease/drug therapy/pathology/physiopathology/complications ; *Dementia, Vascular/drug therapy/physiopathology/pathology/complications ; *Cerebrovascular Circulation/drug effects/physiology ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Cognitive Dysfunction/drug therapy ; Mice ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Mice, Transgenic ; Amyloid beta-Peptides ; *Nitrates/pharmacology/therapeutic use ; }, abstract = {Alzheimer's disease (AD) and vascular dementia (VaD) are two prevalent forms of dementia. VaD is linked to cerebrovascular lesions, such as those from white matter ischemia and chronic cerebral hypoperfusion, which can also occur in AD. Nitric oxide (NO) regulates cerebral blood flow (CBF) in the central nervous system. Memantine is an NMDA receptor antagonist approved for AD treatment. This study investigated the efficacy and molecular mechanism of MN-08, a novel memantine nitrate, in one VaD model (2VO) and two AD models (APP/PS1 mice and Aβ1-42-induced mice). MN-08 increased CBF, ameliorated cognitive and memory functions in VaD and AD, and was more effective than memantine. MN-08 increased the survival rate of CA1 neurons and mitigated white matter lesions and axonal damage. Moreover, MN-08 protected neurons from OGD-induced loss and promoted axonal outgrowth in the hippocampus by upregulating phosphorylated Akt (p-Akt), glycogen synthase kinase-3β (p-GSK3β), and high-molecular-weight neurofilaments (p-NFH). The beneficial effects of MN-08 were attenuated by carboxy-PTIO, a potent NO scavenger, suggesting that MN-08-derived NO may alleviate cognitive impairment from cerebral hypoperfusion. Taken together, our studies demonstrate that MN-08 is a promising therapeutic agent for the treatment of dementia including VaD and AD.}, }
@article {pmid40081504, year = {2025}, author = {Guo, Y and Liu, T and Chen, H and Zhou, L and Huang, W and Zhang, K and Wang, X and Wang, Y and Zhou, JH and Chen, F and , }, title = {Decreased brain interstitial fluid dynamics is associated with risk of Alzheimer's disease-related cognitive decline.}, journal = {Brain research bulletin}, volume = {224}, number = {}, pages = {111295}, doi = {10.1016/j.brainresbull.2025.111295}, pmid = {40081504}, issn = {1873-2747}, abstract = {BACKGROUND: Diffusion-tensor image analysis along the perivascular space (ALPS) index that has the potential to reflect brain interstitial fluid (ISF) dynamics may predict the development of Alzheimer's Disease (AD). We aimed to study whether brain ISF dynamics indicated by the ALPS index relate to AD dementia diagnosis and AD-related changes.
METHODS: This study included a discovery cohort (n = 180) and a validation cohort (n = 127), which were composed of cognitively normal, subjective memory concern, mild cognitive impairment, and AD dementia subjects. All participants underwent brain magnetic resonance imaging examination and neuropsychological evaluation. The diffusivities and diffusion-tensor image analysis along the perivascular space (ALPS) were calculated. The support vector machine (SVM) model for AD dementia diagnosis was built in the discovery cohort and validated in the validation cohort. Linear mixed-effects models were used to evaluate the association between the ALPS and cognitive decline. Cox regression models were used to evaluate the association between the ALPS and the risk of AD dementia.
RESULTS: There was a lower median ALPS index in the AD dementia group compared to other groups (all P < 0.05) for both cohorts. The SVM model for AD dementia diagnosis produced an AUC of 0.802 in the discovery cohort (P < 0.001) and 0.783 in the external validation cohort (P < 0.001). Higher ALPS levels were associated with less cognitive decline (P < 0.001). Moreover, lower baseline ALPS had a greater risk of converting to AD dementia (P = 0.014).
CONCLUSIONS: The SVM model based on diffusivities and ALPS was effective for AD dementia diagnosis, and higher ALPS levels are associated with a lower risk of AD-related changes. These findings suggest that ALPS may provide a useful AD progression or treatment biomarker.}, }
@article {pmid40081261, year = {2025}, author = {Yang, R and Meng, X and Zhao, W and Xu, SQ and Wang, SY and Li, MM and Guan, W and Chen, QS and Zhang, LL and Kuang, HX and Li, H and Yang, BY and Liu, Y}, title = {Phenylpropanoids of Eleutherococcus senticosus (Rupr. & maxim.) maxim. Alleviate oxidative stress in Alzheimer's disease in vitro and in vivo models by regulating Mst1 and affecting the Nrf2/Sirt3 pathway.}, journal = {Bioorganic chemistry}, volume = {159}, number = {}, pages = {108347}, doi = {10.1016/j.bioorg.2025.108347}, pmid = {40081261}, issn = {1090-2120}, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder, and oxidative stress plays a significant role in its progression. Owing to its nourishing effects, Eleutherococcus senticosus (Rupr. & maxim.) maxim. (ES) has gained widespread popularity globally as a functional food and long-term consumption has been shown to enhance memory. The phenylpropanoid components extracted from Eleutherococcus senticosus (Rupr. & maxim.) maxim. (ESP) exhibit a diverse array of bioactivities and are commonly employed in the treatment of central nervous system (CNS) disorders. Nonetheless, the exact mechanisms by which ESP alleviates oxidative stress in AD models require further investigation. Therefore, this study utilized SAMP8 mice as models for AD and employed L-glutamate (L-Glu)-induced HT22 cells to establish an in vitro AD model. The effects of ESP on cognitive function were evaluated using the Morris water maze (MWM) test. Additionally, various techniques such as pathology, immunofluorescence staining (IF), ROS staining, cellular thermal shift assay (CETSA), Mst1 inhibitor analysis, and western blotting (WB) were conducted to further investigate the pharmacological efficacy and potential molecular mechanisms of ESP. In vivo, ESP was found to improve cognitive function in SAMP8 mice and alleviate AD-like pathological features. In vitro, ESP reduced intracellular ROS levels. Mechanistically, CETSA analysis confirmed the binding affinity between ESP and Mst1, demonstrated that ESP modulated the Mst1 signaling pathway to mitigate oxidative stress and decrease ROS levels. These findings suggested that ESP holded significant potential for developing therapeutic strategies for AD.}, }
@article {pmid40081008, year = {2025}, author = {Lin, M and Tang, K and Zheng, W and Zheng, S and Hu, K}, title = {Curcumin delivery system based on a chitosan-liposome encapsulated zeolitic imidazolate framework-8: a potential treatment antioxidant and antibacterial treatment after phacoemulsification.}, journal = {Biomedical materials (Bristol, England)}, volume = {20}, number = {3}, pages = {}, doi = {10.1088/1748-605X/adc05c}, pmid = {40081008}, issn = {1748-605X}, mesh = {*Chitosan/chemistry ; *Curcumin/chemistry/administration & dosage ; *Antioxidants/chemistry/administration & dosage ; Liposomes/chemistry ; *Anti-Bacterial Agents/chemistry/administration & dosage/pharmacology ; *Zeolites/chemistry ; *Phacoemulsification/methods ; Animals ; Drug Delivery Systems ; Oxidative Stress/drug effects ; Imidazoles/chemistry ; Humans ; Ophthalmic Solutions/chemistry ; Rabbits ; }, abstract = {Curcumin is a natural polyphenol extracted from plants that can interact with various molecular targets, including antioxidant, antibacterial, anticancer, and anti-aging activities. Due to its variety of pharmacological activities and large margin pf safety, curcumin has been used in the prevention and treatment of various diseases, such as Alzheimer's, heart, and rheumatic immune diseases. To develop curcumin eye drops that can be used as antioxidant and antibacterial agents after phacoemulsification, we have designed a nano-based drug delivery system to improve curcumin bioavailability and duration of action. We successfully prepared zeolitic imidazolate framework-8 (ZIF-8) coated with chitosan-liposome (Cur@ZIF-8/CS-Lip) for curcumin delivery. It can release curcumin for over 20 hin vitroand exhibits excellent biosafety, antioxidant, and antibacterial activities. Therefore, we hypothesized that Cur@ZIF-8/CS-Lip could reduce the incidence of oxidative stress and infection after cataract surgery.}, }
@article {pmid40080205, year = {2025}, author = {Nadais, A and Martins, I and Henriques, AG and Trigo, D and da Cruz E Silva, OAB}, title = {Comparing In vitro Protein Aggregation Modelling Using Strategies Relevant to Neuropathologies.}, journal = {Cellular and molecular neurobiology}, volume = {45}, number = {1}, pages = {24}, pmid = {40080205}, issn = {1573-6830}, support = {SFRH/BD/121289/2016//Fundação para a Ciência e a Tecnologia/ ; EXPL/BTM-SAL/0902/2021//Fundação para a Ciência e a Tecnologia/ ; PTDC/DTPPIC/5587/2014//Fundação para a Ciência e a Tecnologia/ ; CI21-00276//'la Caixa' Foundation/ ; CENTRO-01-0145-FEDER-000003//CCDRC/ ; CENTRO-01-0145-FEDER-000003//CCDRC/ ; POCI-01-0145-FEDER-016904//COMPETE 2020/ ; }, mesh = {Humans ; Cell Line, Tumor ; *Amyloid beta-Peptides/metabolism ; *Rotenone/pharmacology ; Protein Aggregates/drug effects ; Peptide Fragments/metabolism ; Protein Aggregation, Pathological/metabolism/pathology ; Models, Biological ; Leupeptins/pharmacology ; tau Proteins/metabolism ; Oligomycins/pharmacology ; }, abstract = {Protein aggregation is remarkably associated with several neuropathologies, including Alzheimer´s (AD) and Parkinson´s disease (PD). The first is characterized by hyperphosphorylated tau protein and Aβ peptide deposition, thus forming intracellular neurofibrillary tangles and extracellular senile plaques, respectively; while, in PD, α-synuclein aggregates and deposits as Lewy bodies. Considerable research has focused on developing protein aggregation models to be explored as research tools. In the present work, four in vitro models for studying protein aggregation were studied and compared, namely treatment with: the toxic Aβ1-42 peptide, the isoflavone rotenone, the ATP synthase inhibitor oligomycin, and the proteosome inhibitor MG-132. All treatments result in aggregation-relevant events in the human neural SH-SY5Y cell line, but significant model-dependent differences were observed. In terms of promoting aggregate formation, Aβ and MG-132 provoked the greatest effect, but only MG-132 was associated with an increase in HSP-70 chaperone expression. In fact, the type of aggregates formed appear to be dependent on the treatment employed, and supports the hypothesis that Aβ exposure is a relevant AD model, and rotenone is a valid model for PD. Furthermore, the results revealed that protein phosphorylation is relevant to aggregate formation and as expected, tau co-localized to the deposits formed in the Aβ peptide aggregate induction cell model. In summary, different molecular processes, from overall and specific protein aggregation to proteostatic modulation, can be induced by using distinct aggregation modelling strategies, and these can be used to study different protein-aggregation-related processes associated with distinct neuropathologies.}, }
@article {pmid40079275, year = {2025}, author = {Pang, S and Li, Z and Liu, A and Luo, ZH and Yin, H and Fan, S and Shi, J and Liu, N and Pan, S and Yang, YJ and Zhang, GJ and Chen, J}, title = {A Novel Oxo-Palmatine Derivative 2q as Potent Reversal Agents Against Alzheimer's Disease.}, journal = {Drug development research}, volume = {86}, number = {2}, pages = {e70073}, doi = {10.1002/ddr.70073}, pmid = {40079275}, issn = {1098-2299}, support = {//This study was supported by the Beijing Natural Science Foundation (grant no. 7244343), National Natural Science Foundation of China (grant no. 82401383, 82471472), Joint Basic-Clinical Laboratory of Pediatric Epilepsy and Cognitive Developmental (grant no. 3-1-013-03), and the Drug Innovation Major Project (2018ZX09711-001-005)./ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Berberine Alkaloids/pharmacology/therapeutic use/chemistry ; Mice ; Humans ; Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Male ; Blood-Brain Barrier/metabolism/drug effects ; Disease Models, Animal ; Phosphorylation/drug effects ; }, abstract = {Palmatine (PAL), as an active ingredient in traditional Chinese medicine, had been demonstrated efficacy in ameliorating the manifestations of AD. Our research group has previously designed and synthesized the novel oxo-PAL derivative 2q and found that it has exhibited notable neuroprotective properties. However, compound 2q therapeutic impact on AD remains uncertain. In the current investigation, our findings demonstrated that compound 2q displayed significant anti-AβOs activity in vitro by using xCELLigence analysis, and showed a high likelihood of crossing the blood-brain barrier. Furthermore, administration of compound 2q yielded a notable amelioration in Aβ accumulation and hyperphosphorylation of Tau in 3×Tg mice. Additionally, it was observed that compound 2q potentially enhanced the pathological characteristics of AD by targeting Potassium/Sodium Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 2 (HCN2). In conclusion, compound 2q emerged as a promising candidate for AD treatment, as it effectively restored AD-associated pathological impairments. Furthermore, it has been identified as a potential target of HCN2, thereby offering novel avenues for the development of treatments for AD.}, }
@article {pmid40077790, year = {2025}, author = {Gualtieri, P and Frank, G and Cianci, R and Ciancarella, L and Romano, L and Ortoman, M and Bigioni, G and Nicoletti, F and Falco, MI and La Placa, G and Di Renzo, L}, title = {Exploring the Efficacy and Safety of Nutritional Supplements in Alzheimer's Disease.}, journal = {Nutrients}, volume = {17}, number = {5}, pages = {}, pmid = {40077790}, issn = {2072-6643}, support = {PNRR-MAD-2022-12376383, CIMA//Ministero della Salute/ ; }, mesh = {*Alzheimer Disease ; Humans ; *Dietary Supplements ; Fatty Acids, Omega-3/administration & dosage ; Curcumin/therapeutic use/administration & dosage ; Probiotics/therapeutic use/administration & dosage ; Vitamin E/administration & dosage ; Resveratrol ; Melatonin/administration & dosage/therapeutic use ; Treatment Outcome ; }, abstract = {Background: Alzheimer's disease (AD) represents one of the major challenges of modern medicine, with a growing impact on public health and healthcare systems. In recent years, dietary supplements use has been the subject of increasing interest as a complementary strategy for the prevention and treatment of the disease. Materials and Methods: A Review of reviews was conducted following PRISMA guidelines and REAPPRAISED checklist to evaluate the efficacy and safety of supplement use in AD. The search, performed across major scientific databases, identified 54 relevant articles, including 53 reviews and one mini-review, after applying specific inclusion criteria and removing duplicates. Results: The growing body of evidence suggests that some supplements may help reduce cognitive decline, inflammation, and target mechanisms behind AD. However, many of these supplements are still under investigation, with mixed results highlighting the need for high-quality research. A key challenge is the lack of data on optimal dosages, administration duration, and long-term safety, which limits clinical guidelines. Some studies have reported positive effects from specific regimens, such as curcumin (800 mg/day), omega-3 fatty acids (2 g/day), and resveratrol (600 mg/day). Other supplements, like phosphatidylserine (300 mg/day), multinutrient formulations, probiotics, vitamin E (2000 IU/day), and melatonin (3-10 mg/day), also show benefits, though study variability makes conclusions uncertain. Conclusions: While certain supplements show potential in mitigating cognitive decline in AD, inconsistent findings and gaps in dosage and safety data highlight the need for rigorous, large-scale trials. Future research should focus on personalized, multimodal strategies integrating targeted supplementation, dietary patterns, and microbiota-gut-brain interactions for enhanced neuroprotection.}, }
@article {pmid40076984, year = {2025}, author = {Li, J and Wang, M and Wang, Y and Peng, X and Lv, G and Zheng, T and Peng, Y and Li, J}, title = {Revealing Lingonberry's Neuroprotective Potential in Alzheimer's Disease Through Network Pharmacology and Molecular Docking.}, journal = {International journal of molecular sciences}, volume = {26}, number = {5}, pages = {}, pmid = {40076984}, issn = {1422-0067}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Molecular Docking Simulation ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Humans ; *Vaccinium vitis-idaea/chemistry ; Network Pharmacology ; Molecular Dynamics Simulation ; Coumaric Acids/chemistry/pharmacology/therapeutic use ; Monoamine Oxidase/metabolism/chemistry ; Plant Extracts/chemistry/pharmacology/therapeutic use ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disorder with limited treatment options. Lingonberry (Vaccinium vitis-idaea L.) has demonstrated neuroprotective and anti-inflammatory properties, yet the underlying mechanisms remain unclear. This study employed network pharmacology, molecular docking, and molecular dynamics simulations to explore the therapeutic potential in Alzheimer's disease. Pathway analysis identified monoamine oxidase B as a key target involved in serotonergic synapse dysfunction related to Alzheimer's disease. Molecular docking revealed that ferulic acid, a major bioactive compound in lingonberry, exhibits strong binding affinity to monoamine oxidase B. Further molecular dynamics simulations confirmed the stability of this interaction, highlighting the potential inhibitory effect of ferulic acid on monoamine oxidase B. These findings provide novel insights into the neuroprotective mechanisms of lingonberry and suggest its potential as a natural therapeutic intervention for Alzheimer's disease.}, }
@article {pmid40076831, year = {2025}, author = {Wang, S and Xiao, L}, title = {Progress in AAV-Mediated In Vivo Gene Therapy and Its Applications in Central Nervous System Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {5}, pages = {}, pmid = {40076831}, issn = {1422-0067}, support = {2021ZD0201703//STI 2030-Major Project/ ; 32170957//National Natural Science Foundation of China/ ; 31970913//National Natural Science Foundation of China/ ; 2021A1515012156//Guangdong Basic and Applied Basic Research Foundation/ ; 2019B030335001//Key-Area Research and Development Program of Guang-dong Province/ ; }, mesh = {*Dependovirus/genetics ; Humans ; *Genetic Therapy/methods ; *Genetic Vectors/genetics ; Animals ; *Central Nervous System Diseases/therapy/genetics ; Blood-Brain Barrier/metabolism ; Gene Transfer Techniques ; }, abstract = {As the blood-brain barrier (BBB) prevents molecules from accessing the central nervous system (CNS), the traditional systemic delivery of chemical drugs limits the development of neurological drugs. However, in recent years, innovative therapeutic strategies have tried to bypass the restriction of traditional drug delivery methods. In vivo gene therapy refers to emerging biopharma vectors that carry the specific genes and target and infect specific tissues; these infected cells and tissues then undergo fundamental changes at the genetic level and produce therapeutic proteins or substances, thus providing therapeutic benefits. Clinical and preclinical trials mainly utilize adeno-associated viruses (AAVs), lentiviruses (LVs), and other viruses as gene vectors for disease investigation. Although LVs have a higher gene-carrying capacity, the vector of choice for many neurological diseases is the AAV vector due to its safety and long-term transgene expression in neurons. Here, we review the basic biology of AAVs and summarize some key issues in recombinant AAV (rAAV) engineering in gene therapy research; then, we summarize recent clinical trials using rAAV treatment for neurological diseases and provide translational perspectives and future challenges on target selection.}, }
@article {pmid40076742, year = {2025}, author = {Wen, S and Han, Y and Li, Y and Zhan, D}, title = {Therapeutic Mechanisms of Medicine Food Homology Plants in Alzheimer's Disease: Insights from Network Pharmacology, Machine Learning, and Molecular Docking.}, journal = {International journal of molecular sciences}, volume = {26}, number = {5}, pages = {}, pmid = {40076742}, issn = {1422-0067}, support = {20210202109NC//Key R&D Project of the Jilin Province Science and Technology Development Plan/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Molecular Docking Simulation ; Humans ; *Machine Learning ; *Network Pharmacology ; Plants, Medicinal/chemistry ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a gradual decline in cognitive function. Currently, there are no effective treatments for this condition. Medicine food homology plants have gained increasing attention as potential natural treatments for AD because of their nutritional value and therapeutic benefits. In this work, we aimed to provide a deeper understanding of how medicine food homology plants may help alleviate or potentially treat AD by identifying key targets, pathways, and small molecule compounds from 10 medicine food homology plants that play an important role in this process. Using network pharmacology, we identified 623 common targets between AD and the compounds from the selected 10 plants, including crucial proteins such as STAT3, IL6, TNF, and IL1B. Additionally, the small molecules from the selected plants were grouped into four clusters using hierarchical clustering. The ConPlex algorithm was then applied to predict the binding capabilities of these small molecules to the key protein targets. Cluster 3 showed superior predicted binding capabilities to STAT3, TNF, and IL1B, which was further validated by molecular docking. Scaffold analysis of small molecules in Cluster 3 revealed that those with a steroid-like core-comprising three fused six-membered rings and one five-membered ring with a carbon-carbon double bond-exhibited better predicted binding affinities and were potential triple-target inhibitors. Among them, MOL005439, MOL000953, and MOL005438 were identified as the top-performing compounds. This study highlights the potential of medicine food homology plants as a source of active compounds that could be developed into new drugs for AD treatment. However, further pharmacokinetic studies are essential to assess their efficacy and minimize side effects.}, }
@article {pmid40076682, year = {2025}, author = {Guo, H and Yang, R and Cheng, W and Li, Q and Du, M}, title = {An Update of Salivary Biomarkers for the Diagnosis of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {5}, pages = {}, pmid = {40076682}, issn = {1422-0067}, support = {82301091//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/diagnosis/metabolism/cerebrospinal fluid ; Humans ; *Biomarkers/cerebrospinal fluid ; *Saliva/metabolism ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid/analysis ; tau Proteins/metabolism/cerebrospinal fluid ; }, abstract = {Alzheimer's disease (AD) is characterized by progressive cognition and behavior impairments. Diagnosing AD early is important for clinicians to slow down AD progression and preserve brain function. Biomarkers such as tau protein and amyloid-β peptide (Aβ) are used to aid diagnosis as clinical diagnosis often lags. Additionally, biomarkers can be used to monitor AD status and evaluate AD treatment. Clinicians detect these AD biomarkers in the brain using positron emission tomography/computed tomography or in the cerebrospinal fluid using a lumbar puncture. However, these methods are expensive and invasive. In contrast, saliva collection is simple, inexpensive, non-invasive, stress-free, and repeatable. Moreover, damage to the brain parenchyma can impact the oral cavity and some pathogenic molecules could travel back and forth from the brain to the mouth. This has prompted researchers to explore biomarkers in the saliva. Therefore, this study provides an overview of the main finding of salivary biomarkers for AD diagnosis. Based on these available studies, Aβ, tau, cholinesterase enzyme activity, lactoferrin, melatonin, cortisol, proteomics, metabolomics, exosomes, and the microbiome were changed in AD patients' saliva when compared to controls. However, well-designed studies are essential to confirm the reliability and validity of these biomarkers in diagnosing and monitoring AD.}, }
@article {pmid40076562, year = {2025}, author = {Pokrzyk, J and Kulczyńska-Przybik, A and Guzik-Makaruk, E and Winkel, I and Mroczko, B}, title = {Clinical Importance of Amyloid Beta Implication in the Detection and Treatment of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {5}, pages = {}, pmid = {40076562}, issn = {1422-0067}, support = {SUB.B24.559.01.S//Medical Univerity of Białystok/ ; }, mesh = {*Alzheimer Disease/diagnosis/metabolism/therapy ; Humans ; *Amyloid beta-Peptides/metabolism ; Animals ; Brain/metabolism/diagnostic imaging/pathology ; Positron-Emission Tomography/methods ; Biomarkers ; Clinical Relevance ; }, abstract = {The role of amyloid beta peptide (Aβ) in memory regulation has been a subject of substantial interest and debate in neuroscience, because of both physiological and clinical issues. Understanding the dual nature of Aβ in memory regulation is crucial for developing effective treatments for Alzheimer's disease (AD). Moreover, accurate detection and quantification methods of Aβ isoforms have been tested for diagnostic purposes and therapeutic interventions. This review provides insight into the current knowledge about the methods of amyloid beta detection in vivo and in vitro by fluid tests and brain imaging methods (PET), which allow for preclinical recognition of the disease. Currently, the priority in the development of new therapies for Alzheimer's disease has been given to potential changes in the progression of the disease. In light of increasing amounts of data, this review was focused on the diagnostic and therapeutic employment of amyloid beta in Alzheimer's disease.}, }
@article {pmid40076550, year = {2025}, author = {Zhang, D and He, X and Wang, Y and Wang, X and Han, X and Liu, H and Xing, Y and Jiang, B and Xiu, Z and Bao, Y and Dong, Y}, title = {Hesperetin-Enhanced Metformin to Alleviate Cognitive Impairment via Gut-Brain Axis in Type 2 Diabetes Rats.}, journal = {International journal of molecular sciences}, volume = {26}, number = {5}, pages = {}, pmid = {40076550}, issn = {1422-0067}, support = {202202AE090075//Yunnan Talent Support Plan for Industrial Innovation Talents, Major Science and Technology Projects in Yunnan Province/ ; 202205AF15007//Academician (Expert) Workstation Construction Project of Yunnan Province/ ; H2020206616//Natural Science Foundation of Hebei Province/ ; }, mesh = {Animals ; *Hesperidin/pharmacology/therapeutic use ; *Metformin/pharmacology/therapeutic use ; *Cognitive Dysfunction/drug therapy/etiology/metabolism ; Rats ; *Diabetes Mellitus, Type 2/drug therapy/complications/metabolism ; Male ; *Diabetes Mellitus, Experimental/drug therapy/complications ; *Brain-Gut Axis/drug effects ; Gastrointestinal Microbiome/drug effects ; Hypoglycemic Agents/pharmacology/therapeutic use ; Rats, Sprague-Dawley ; Brain-Derived Neurotrophic Factor/metabolism/genetics ; Insulin Resistance ; Brain/metabolism/drug effects ; }, abstract = {Diabetes constitutes a risk factor for cognitive impairment, whereas insulin resistance serves as the shared pathogenesis underlying both diabetes and cognitive decline. The use of metformin for treating cognitive impairment remains controversial. The present study found that hesperetin, a flavanone derived from citrus peel, enhanced metformin's efficacy in reducing blood sugar levels, improving insulin sensitivity, and ameliorating cognitive impairment in diabetic rats. Additionally, it reduced the required dosage of metformin to one-third of its conventional dose. Transcriptome analysis and 16S rRNA sequencing revealed that the activation of insulin and cyclic-adenosine monophosphate response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathways benefited from the regulation of gut microbiota and the promotion of short-chain fatty acid (SCFA) producers such as Romboutsia. Furthermore, this study demonstrated that hesperetin supplementation counteracted the upregulation of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a pathological factor of Alzheimer's disease (AD) that was induced by metformin. Our findings reveal that hesperetin can be used in supplementary treatment for cognitive impairment associated with diabetes.}, }
@article {pmid40076425, year = {2025}, author = {Silva, J and Tumurbaatar, B and Guptarak, J and Zhang, WR and Fracassi, A and Taglialatela, G}, title = {Sub-Immunosuppressive Tacrolimus Ameliorates Amyloid-Beta and Tau Pathology in 3xTg-AD Mice.}, journal = {International journal of molecular sciences}, volume = {26}, number = {5}, pages = {}, pmid = {40076425}, issn = {1422-0067}, support = {R01 AG060718/AG/NIA NIH HHS/United States ; R01-AG060718/AG/NIA NIH HHS/United States ; 1R01AG060718-04A1/NH/NIH HHS/United States ; }, mesh = {Animals ; *tau Proteins/metabolism ; *Tacrolimus/pharmacology ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Mice ; *Mice, Transgenic ; *Immunosuppressive Agents/pharmacology/therapeutic use ; *Hippocampus/metabolism/drug effects/pathology ; *Disease Models, Animal ; Mice, Inbred C57BL ; Male ; }, abstract = {Tacrolimus (TAC) has emerged as a potential therapy for Alzheimer's disease (AD), with the challenge of balancing its therapeutic benefits against its immunosuppressive effects. This study explores the efficacy of a sub-immunosuppressive TAC dosing regimen to ameliorate AD-related pathologies. TAC was administered daily for 14 days, with drug concentrations measured via liquid chromatography tandem mass spectrometry (LC-MS/MS) in whole blood and hippocampal tissue from C57BL6J mice, while immunofluorescence analyses and Western blotting (performed on hippocampal extracts) were conducted in 10-12 month old 3xTg-AD mice to evaluate levels of tau and amyloid-beta (Aβ) proteins. The results from LC-MS/MS revealed that lower TAC doses resulted in sub-immunosuppressive blood levels, while still penetrating the hippocampi. Immunofluorescence showed reductions in tau and Aβ proteins in 3xTg-AD mice. Additionally, Western blot analyses revealed reductions in tau and Aβ, along with increases in synaptic and autophagy-related proteins. These findings highlight the potential of sub-immunosuppressive TAC doses in effectively targeting AD pathology while minimizing the risk of chronic systemic immunosuppression. Further research and clinical trials are warranted to establish the optimal TAC dosing regimen for AD treatment.}, }
@article {pmid40075859, year = {2025}, author = {Taiyeb Khosroshahi, M and Morsali, S and Gharakhanlou, S and Motamedi, A and Hassanbaghlou, S and Vahedi, H and Pedrammehr, S and Kabir, HMD and Jafarizadeh, A}, title = {Explainable Artificial Intelligence in Neuroimaging of Alzheimer's Disease.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {5}, pages = {}, pmid = {40075859}, issn = {2075-4418}, abstract = {Alzheimer's disease (AD) remains a significant global health challenge, affecting millions worldwide and imposing substantial burdens on healthcare systems. Advances in artificial intelligence (AI), particularly in deep learning and machine learning, have revolutionized neuroimaging-based AD diagnosis. However, the complexity and lack of interpretability of these models limit their clinical applicability. Explainable Artificial Intelligence (XAI) addresses this challenge by providing insights into model decision-making, enhancing transparency, and fostering trust in AI-driven diagnostics. This review explores the role of XAI in AD neuroimaging, highlighting key techniques such as SHAP, LIME, Grad-CAM, and Layer-wise Relevance Propagation (LRP). We examine their applications in identifying critical biomarkers, tracking disease progression, and distinguishing AD stages using various imaging modalities, including MRI and PET. Additionally, we discuss current challenges, including dataset limitations, regulatory concerns, and standardization issues, and propose future research directions to improve XAI's integration into clinical practice. By bridging the gap between AI and clinical interpretability, XAI holds the potential to refine AD diagnostics, personalize treatment strategies, and advance neuroimaging-based research.}, }
@article {pmid40075143, year = {2025}, author = {Xu, W and Huang, Y and Zhou, R}, title = {NLRP3 inflammasome in neuroinflammation and central nervous system diseases.}, journal = {Cellular & molecular immunology}, volume = {22}, number = {4}, pages = {341-355}, pmid = {40075143}, issn = {2042-0226}, support = {81821001, 82130107, 82330052, 82202038, U20A20359//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Humans ; *Inflammasomes/metabolism ; Animals ; *Central Nervous System Diseases/immunology/pathology ; *Neuroinflammatory Diseases/immunology/pathology/metabolism ; Inflammation/immunology/pathology ; }, abstract = {Neuroinflammation plays an important role in the pathogenesis of various central nervous system (CNS) diseases. The NLRP3 inflammasome is an important intracellular multiprotein complex composed of the innate immune receptor NLRP3, the adaptor protein ASC, and the protease caspase-1. The activation of the NLRP3 inflammasome can induce pyroptosis and the release of the proinflammatory cytokines IL-1β and IL-18, thus playing a central role in immune and inflammatory responses. Recent studies have revealed that the NLRP3 inflammasome is activated in the brain to induce neuroinflammation, leading to further neuronal damage and functional impairment, and contributes to the pathological process of various neurological diseases, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, and stroke. In this review, we summarize the important role of the NLRP3 inflammasome in the pathogenesis of neuroinflammation and the pathological course of CNS diseases and discuss potential approaches to target the NLRP3 inflammasome for the treatment of CNS diseases.}, }
@article {pmid40074652, year = {2025}, author = {Hu, J and Luo, Y and Wang, X}, title = {Multi-omics analysis of druggable genes to facilitate Alzheimer's disease therapy: A multi-cohort machine learning study.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100128}, doi = {10.1016/j.tjpad.2025.100128}, pmid = {40074652}, issn = {2426-0266}, abstract = {BACKGROUND: The swift rise in the prevalence of Alzheimer's disease (AD) alongside its significant societal and economic impact has created a pressing demand for effective interventions and treatments. However, there are no available treatments that can modify the progression of the disease.
METHODS: Eight AD brain tissues datasets and three blood datasets were obtained. Consensus clustering was utilized as a method to discern the various subtypes of AD. Then, module genes were screened using weighted correlation network analysis (WGCNA). Furthermore, screening hub genes was conducted through machine-learning analyses. Finally, A comprehensive analysis using a systematic approach to druggable genome-wide Mendelian randomization (MR) was conducted.
RESULTS: Two AD subclasses were identified, namely cluster.A and cluster.B. The levels of gamma secretase activity, beta secretase activity, and amyloid-beta 42 were found to be significantly elevated in patients classified within cluster A when compared to those in cluster B. Furthermore, by utilizing the differentially expressed genes shared among these clusters, along with identifying druggable genes and applying WGCNA to these subtypes, we were able to develop a scoring system referred to as DG.score. This scoring system has demonstrated remarkable predictive capability for AD when evaluated against multiple datasets. Besides, A total of 30 distinct genes that may serve as potential drug targets for AD were identified across at least one of the datasets investigated, whether derived from brain samples or blood analyses. Among the identified genes, three specific candidates that are considered druggable (LIMK2, MAPK8, and NDUFV2) demonstrated significant expression levels in both blood and brain tissues. Furthermore, our research also revealed a potential association between the levels of LIMK2 and concentrations of CSF Aβ (OR 1.526 (1.155-2.018)), CSF p-tau (OR 1.106 (1.024-01.196)), and hippocampal size (OR 0.831 (0.702-0.948)).
CONCLUSIONS: This study provides a notable advancement to the existing literature by offering genetic evidence that underscores the potential therapeutic advantages of focusing on the druggable gene LIMK2 in the treatment of AD. This insight not only contributes to our understanding of AD but also guides future drug discovery efforts.}, }
@article {pmid40074096, year = {2025}, author = {Wu, L and Sun, Y and Zhao, L and Xing, S and Liu, R and Wong, NL and Lin, Y and Song, C and Lu, C and Zhang, H}, title = {Lancao decoction alleviates Alzheimer's disease: Depending on activating CaMKII to protect neuronal refunction by reducing β-amyloid in the hippocampus.}, journal = {Journal of ethnopharmacology}, volume = {345}, number = {}, pages = {119619}, doi = {10.1016/j.jep.2025.119619}, pmid = {40074096}, issn = {1872-7573}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Hippocampus/drug effects/metabolism ; *Amyloid beta-Peptides/metabolism ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Mice ; Male ; *Drugs, Chinese Herbal/pharmacology ; Maze Learning/drug effects ; Neurogenesis/drug effects ; Mice, Inbred C57BL ; Neurons/drug effects/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Neuroprotective Agents/pharmacology ; }, abstract = {Lancao decoction (LC) is a traditional Chinese medicine (TCM) formulation mentioned in the "Huangdineijing", known for its ability to dispel turbidity and eliminate heat. TCM believes that the etiology of Alzheimer's disease (AD) is phlegm turbidity, and the fiery internal obstruction of the gods, which suggests that LC has the possibility of treating.
AIM OF THE STUDY: This investigation will examine the possibilities of LC to improve AD and uncover the underlying mechanisms.
MATERIALS AND METHODS: Gas chromatography (GC) and HPLC-MS were used to identify the content of the primary elements in LC and test the stability of its extraction. The function of LC in ameliorating AD was characterized by utilizing behavioral assessments such as the Morris water maze (MWM) and the Y-maze in AD modeling mice. Levels of molecular signaling and neurogenesis within the hippocampus was assessed using Western blot and immunostaining. Pharmacological interventions were used to explore the association of specific targets with neurogenesis and synaptic proteins and their contributions in LC improvement of AD.
RESULTS: The main components of LC include p-Cymene, 3-Methoxy-p-cymene, neryl acetate, gallic acid, protocatechuic acid and euparin. APP/PS1 mice displayed behavioral characteristics indicative of memory and learning deficits, such as a notably longer time taken to reach the platform and reduced time spent in the area without the platform in the Morris Water Maze (MWM), as well as a longer delay in exploring the new arm and less time spent in the new arm in the Y-maze, when compared to C57BL6/J mice. However, these impairments were alleviated by chronic treatment with either LC or donepezil (DON) over a period of 14 days. Additionally, the phosphorylated levels of CaMKII and the amounts of synaptic proteins (synapsin1 and PSD95) were greatly diminished within the hippocampal region of APP/PS1 mice, which were also reversed by LC or DON. In addition, Aβ area was obviously increased in the hippocampus of the APP/PS1 murine model, which was also reversed by LC or DON. Inhibition of CaMKII activities not only blunted LC's therapeutic actions of AD, but also blocked the enhancements of LC on synaptic proteins in the hippocampus, the quantity of cells that are co-stained with BrdU and DCX, and Ki67-positive cells located in the dentate gyrus (DG) of the hippocampus.
CONCLUSION: The results indicated that LC activated CaMKII to relieve Aβ formation, thereby enhancing neuronal functions in the hippocampus, and thus alleviated AD, which provided a theoretical basis for a deeper understanding of the mechanism, clinical application, and subsequent research of LC in alleviating AD.}, }
@article {pmid40073978, year = {2025}, author = {Mukherjee, AG and Mishra, S and Gopalakrishnan, AV and Kannampuzha, S and Murali, R and Wanjari, UR and B, S and Vellingiri, B and Madhyastha, H and Kanagavel, D and Vijayan, M}, title = {Unraveling the mystery of citrate transporters in Alzheimer's disease: An updated review.}, journal = {Ageing research reviews}, volume = {107}, number = {}, pages = {102726}, doi = {10.1016/j.arr.2025.102726}, pmid = {40073978}, issn = {1872-9649}, abstract = {A key molecule in cellular metabolism, citrate is essential for lipid biosynthesis, energy production, and epigenetic control. The etiology of Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive decline, may be linked to dysregulated citrate transport, according to recent research. Citrate transporters, which help citrate flow both inside and outside of cells, are becoming more and more recognized as possible participants in the molecular processes underlying AD. Citrate synthase (CS), a key enzyme in the tricarboxylic acid (TCA) cycle, supports mitochondrial function and neurotransmitter synthesis, particularly acetylcholine (ACh), essential for cognition. Changes in CS activity affect citrate availability, influencing energy metabolism and neurotransmitter production. Choline, a precursor for ACh, is crucial for neuronal function. Lipid metabolism, oxidative stress reactions, and mitochondrial function can all be affected by aberrant citrate transport, and these changes are linked to dementia. Furthermore, the two main pathogenic characteristics of AD, tau hyperphosphorylation and amyloid-beta (Aβ) aggregation, may be impacted by disturbances in citrate homeostasis. The goal of this review is to clarify the complex function of citrate transporters in AD and provide insight into how they contribute to the development and course of the illness. We aim to provide an in-depth idea of which particular transporters are dysregulated in AD and clarify the functional implications of these dysregulated transporters in brain cells. To reduce neurodegenerative processes and restore metabolic equilibrium, we have also discussed the therapeutic potential of regulating citrate transport. Gaining insight into the relationship between citrate transporters and the pathogenesis of AD may help identify new indicators for early detection and creative targets for treatment. This study offers hope for more potent ways to fight this debilitating illness and is a crucial step in understanding the metabolic foundations of AD.}, }
@article {pmid40073745, year = {2025}, author = {Radermacher, J and Erhardt, VKJ and Walzer, O and Haas, EC and Kuppler, KN and Zügner, JSR and Lauer, AA and Hartmann, T and Grimm, HS and Grimm, MOW}, title = {Influence of Ibuprofen on glycerophospholipids and sphingolipids in context of Alzheimer´s Disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {185}, number = {}, pages = {117969}, doi = {10.1016/j.biopha.2025.117969}, pmid = {40073745}, issn = {1950-6007}, mesh = {*Ibuprofen/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; *Sphingolipids/metabolism ; Humans ; *Glycerophospholipids/metabolism ; Plasmalogens/metabolism ; Male ; Brain/drug effects/metabolism/pathology ; Female ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; Aged ; }, abstract = {Alzheimer's disease (AD) is a multifactorial disorder associated with neuroinflammation, elevated oxidative stress, lipid alterations as well as amyloid-deposits and the formation of neurofibrillary tangles. Ibuprofen, a globally used analgesic, is discussed to influence disease progression due to its anti-inflammatory effect. However, changes in lipid-homeostasis induced by Ibuprofen have not yet been analyzed. Here we investigate the effect of Ibuprofen on lipid classes known to be associated with AD. Ibuprofen treatment leads to a significant increase in phosphatidylcholine, sphingomyelin and triacylglyceride (TAG) species whereas plasmalogens, which are highly susceptible for oxidation, were significantly decreased. The observed alterations in phosphatidylcholine and sphingomyelin levels in presence of Ibuprofen might counteract the reduced phosphatidylcholine- and sphingomyelin-levels found in AD brain tissue with potential positive aspects on synaptic plasticity and ceramide-induced apoptotic effects. On the other hand, Ibuprofen leads to elevated TAG-level resulting in the formation of lipid droplets which are associated with neuroinflammation. Reduction of plasmalogen-levels might accelerate decreased plasmalogen-levels found in AD brains. Treatment of Ibuprofen in terms of lipid-homeostasis reveals both potentially positive and negative changes relevant to AD. Therefore, understanding the influence of Ibuprofen on lipid-homeostasis may help to understand the heterogeneous results of studies treating AD with Ibuprofen.}, }
@article {pmid40072050, year = {2025}, author = {Auer, S and Schicht, M and Hoffmann, L and Budday, S and Frischknecht, R and Blümcke, I and Paulsen, F}, title = {The Role of Perineuronal Nets in Physiology and Disease: Insights from Recent Studies.}, journal = {Cells}, volume = {14}, number = {5}, pages = {}, pmid = {40072050}, issn = {2073-4409}, support = {460333672//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Extracellular Matrix/metabolism ; Animals ; Neurons/metabolism/physiology ; Central Nervous System/physiology/pathology ; Neuronal Plasticity/physiology ; Nervous System Diseases/physiopathology ; Nerve Net/physiology ; }, abstract = {Perineuronal nets (PNNs) are specialized extracellular matrix structures that predominantly surround inhibitory neurons in the central nervous system (CNS). They have been identified as crucial regulators of synaptic plasticity and neuronal excitability. This literature review aims to summarize the current state of knowledge about PNNs, their molecular composition and structure, as well as their functional roles and involvement in neurological diseases. Furthermore, future directions in PNN research are proposed, and the therapeutic potential of targeting PNNs to develop novel treatment options for various neurological disorders is explored. This review emphasizes the importance of PNNs in CNS physiology and pathology and underscores the need for further research in this area.}, }
@article {pmid40071886, year = {2024}, author = {Mehnaz, D and Shamsi, Y and Akhtar, MW and Rahman, Y}, title = {Therapeutics for Dementia and Alzheimer's Disease in Unani Medicine.}, journal = {Alternative therapies in health and medicine}, volume = {}, number = {}, pages = {}, pmid = {40071886}, issn = {1078-6791}, abstract = {Alzheimer's disease refers to a neurological disorder marked by memory loss and cognitive dysfunction caused by the death of brain cells. It is a progressive, devitalizing disease of aging that has skyrocketed in recent years. The disease progresses gradually, with symptoms including forgetfulness, difficulty with language or communication, disorientation, mood swings, and changes in behaviour. Unani medicine, being an older system of medicine, does not mention Alzheimer's disease as such since the name was coined only in 1907 AD. The Unani medical literature has, however, described the existence of Nisyān with signs and symptoms similar to those of Alzheimer's disease. The renowned Unani scholars have not only mentioned the aetiology and pathogenesis of Nisyān but also designed a specific line of treatment. This study attempts to present the pathophysiology of Alzheimer's disease and Nisyān, along with an exploration of potential treatment options available in Unani medicine.}, }
@article {pmid40071123, year = {2025}, author = {Liu, FX and Yang, SZ and Shi, KK and Li, DM and Song, JB and Sun, L and Dang, X and Li, JY and Deng, ZQ and Zhao, M and Feng, YC}, title = {The role of protein phosphorylation modifications mediated by iron metabolism regulatory networks in the pathogenesis of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1540019}, pmid = {40071123}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disease characterized mainly by the formation of amyloid beta (Aβ) plaques and abnormal phosphorylation of tau. In recent years, an imbalance in iron homeostasis has been recognized to play a key role in the pathological process of AD. Abnormal iron accumulation can activate various kinases such as glycogen synthase kinase-3β, cyclin-dependent kinase 5, and mitogen-activated protein kinase, leading to abnormal phosphorylation of tau and amyloid precursor protein, and accelerating the formation of Aβ plaques and neurofibrillary tangles. In addition, iron-mediated oxidative stress not only triggers neuronal damage, but also exacerbates neuronal dysfunction by altering the phosphorylation of N-methyl-D-aspartate receptors and γ-aminobutyric acid type A receptors. Iron accumulation also affects the phosphorylation status of tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, interfering with the dopamine signaling pathway. On the other hand, iron affects iron transport and metabolism in the brain by regulating the phosphorylation of transferrin, further disrupting iron homeostasis. Therapeutic strategies targeting iron metabolism show promise by reducing iron accumulation, inhibiting oxidative stress, and reducing abnormal phosphorylation of key proteins. This article reviews the molecular mechanisms of phosphorylation modifications mediated by iron homeostasis imbalance in AD, and discusses the potential of interventions that regulate iron metabolism and related signaling pathways, providing a new theoretical basis for the treatment of AD.}, }
@article {pmid40070544, year = {2025}, author = {Jiao, D}, title = {Advancing personalized digital therapeutics: integrating music therapy, brainwave entrainment methods, and AI-driven biofeedback.}, journal = {Frontiers in digital health}, volume = {7}, number = {}, pages = {1552396}, pmid = {40070544}, issn = {2673-253X}, abstract = {Mental health disorders and cognitive decline are pressing global concerns, increasing the demand for non-pharmacological interventions targeting emotional dysregulation, memory deficits, and neural dysfunction. This review systematically examines three promising methodologies-music therapy, brainwave entrainment (binaural beats, isochronic tones, multisensory stimulation), and their integration into a unified therapeutic paradigm. Emerging evidence indicates that music therapy modulates affect, reduces stress, and enhances cognition by engaging limbic, prefrontal, and reward circuits. Brainwave entrainment, particularly within the gamma frequency range (30-100 Hz), facilitates neural oscillatory patterns linked to relaxation, concentration, and memory, with 40 Hz showing promise for cognitive enhancement, albeit with individual variability. Synchronized multisensory stimulation, combining auditory and visual inputs at gamma frequencies, has demonstrated potential in enhancing memory and supporting neural integrity, particularly in Alzheimer's disease. However, challenges such as patient response variability, lack of standardization, and scalability hinder widespread implementation. Recent research suggests that a synergistic application of these modalities may optimize therapeutic outcomes by leveraging complementary mechanisms. To actualize this, AI-driven biofeedback, enabling real-time physiological assessment and individualized adjustments-such as tailoring musical complexity, entrainment frequencies, and multisensory components-emerges as a promising solution. This adaptive model enhances treatment accessibility and consistency while maximizing long-term efficacy. Although in early stages, preliminary evidence highlights its transformative potential in reshaping non-pharmacological therapeutic strategies. Advancing this field requires interdisciplinary research, rigorous evaluation, and ethical data stewardship to develop innovative, patient-centered solutions for mental health and cognitive rehabilitation.}, }
@article {pmid40069789, year = {2025}, author = {Ketron, GL and Grun, F and Grill, JD and Feldman, HH and Rissman, RA and Brewer, GJ}, title = {Pharmacokinetic and pharmacodynamic assessment of oral nicotinamide in the NEAT clinical trial for early Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {59}, pmid = {40069789}, issn = {1758-9193}, support = {BRD-16-501530//UC Cures/ ; BRD-16-501530//UC Cures/ ; BRD-16-501530//UC Cures/ ; #1066394//Alzheimer's Association Zenith Award ./ ; }, mesh = {Humans ; *Niacinamide/pharmacokinetics/administration & dosage/cerebrospinal fluid/blood/therapeutic use ; *Alzheimer Disease/drug therapy/cerebrospinal fluid/blood ; Administration, Oral ; Male ; Female ; Aged ; Biomarkers/blood/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Double-Blind Method ; Middle Aged ; }, abstract = {BACKGROUND: Nicotinamide, a form of B3 vitamin, is an NAD[+] precursor that reduces pTau231 levels via histone deacetylase inhibition in murine models of Alzheimer's disease (AD). A recent phase 2a randomized placebo-controlled trial tested high-dose oral nicotinamide for the treatment of early AD. While nicotinamide demonstrated good safety and tolerability, it did not significantly lower CSF pTau231, the primary biomarker endpoint of the study. Characterization of nicotinamide's pharmacokinetics and metabolites in the blood and CSF is needed.
METHODS: In these post hoc, blinded analyses of plasma and CSF samples from the completed two-site placebo controlled randomized trial testing of 1500 mg PO BID oral nicotinamide, we used mass spectroscopy to measure nicotinamide and its inactive metabolite 1-methyl-nicotinamide in plasma at baseline, 6, and 12 months and in CSF at baseline and 12 months from 23 participants on drug and 24 on placebo.
RESULTS: Pharmacokinetic analysis found mean 12 month plasma nicotinamide increased > 130-fold to 52 μM while mean methyl-nicotinamide increased > 600-fold to 91 μM in individuals receiving nicotinamide compared to those receiving placebo, whose levels were unchanged from baseline. However, CSF nicotinamide was only measurable in 6 of the 19 available participants (32%) (mean increase of at least 147-fold to 18 μM). These CSF nicotinamide concentrations were 66% of their plasma levels, indicating good CNS bioavailability in only some participants. In contrast to CSF nicotinamide, more treated participants had higher CSF methyl-nicotinamide (n = 9, 43 μM), suggesting high-dosage nicotinamide was sufficient to pass the blood-brain barrier, but 13 of 19 were metabolically inactivated. Treatment favorably decreased mean pTau231 levels by 34% in those six participants with elevated CSF levels of nicotinamide, compared to 3% elevation in participants who did not have elevated CSF nicotinamide, and a 3% decrease for placebo. No such relationships were observed for total tau, pTau181, or amyloid beta biomarkers.
CONCLUSIONS: Our findings suggest that oral administration markedly increased mean plasma nicotinamide levels, however CSF levels were below quantitation in a majority of participants and there was extensive metabolic inactivation to methyl-nicotinamide. Both the bioavailability and rapid metabolic methylation need to be addressed if nicotinamide is further developed as a potential intervention for AD.
TRIAL REGISTRATION: NCT03061474, last updated 2023-10-17. https://clinicaltrials.gov/study/NCT03061474 .}, }
@article {pmid40068133, year = {2025}, author = {Angehrn, FN and Duan, P and Zhang, JY and Hong, M}, title = {Binding Sites of a PET Ligand in Tau Fibrils with the Alzheimer's Disease Fold from [19]F and [13]C Solid-State NMR.}, journal = {Biochemistry}, volume = {64}, number = {7}, pages = {1624-1635}, doi = {10.1021/acs.biochem.5c00016}, pmid = {40068133}, issn = {1520-4995}, mesh = {*tau Proteins/chemistry/metabolism ; *Alzheimer Disease/metabolism ; Humans ; *Positron-Emission Tomography/methods ; Ligands ; Binding Sites ; Molecular Docking Simulation ; Amyloid/chemistry/metabolism ; Nuclear Magnetic Resonance, Biomolecular/methods ; Carbon Isotopes ; Fluorine/chemistry ; Protein Folding ; Carbolines ; }, abstract = {Aggregation of the tau protein into cross-β amyloid fibrils is a hallmark of Alzheimer's disease (AD) and many other neurodegenerative disorders. Developing small molecules that bind these tau fibrils is important for the diagnosis and treatment of tauopathies. Here, we report the binding sites of a positron emission tomography (PET) ligand, PI-2620, to a recombinant tau construct that adopts the C-shaped AD fold. Using solid-state NMR [13]C-[19]F rotational-echo double-resonance (REDOR) experiments, we measured the proximity of protein residues to the fluorine atom of the ligand. These data indicate that PI-2620 binds at two main locations in the concave interior of the C-shaped structure. Molecular docking simulations constrained by these REDOR data identified five binding poses at these two locations. In addition, 2D [13]C-[13]C correlation NMR spectra indicate that PI-2620 decreased the intensities of residues at the protofilament interfaces, indicating that the ligand disordered the filament packing. Quantitative analysis of the [19]F NMR spectra indicates that PI-2620 binds these AD-fold tau fibrils with a stoichiometry of ∼20 mol %, in which 10 mol % are immobilized and the rest are mobile. These results provide experimental constraints to the interaction of this second-generation PET tracer with tau fibrils adopting the AD fold and should be useful for the development of future imaging agents with improved stoichiometry and specificity for AD tau.}, }
@article {pmid40067678, year = {2025}, author = {Banu, Z and Poduri, RR and Bhattamisra, SK}, title = {Phytochemical profiling, in silico molecular docking and ADMET prediction of alkaloid rich fraction of Elaeocarpus angustifolius blume seeds against Alzheimer's disease.}, journal = {Natural product research}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/14786419.2025.2477211}, pmid = {40067678}, issn = {1478-6427}, abstract = {The limitations of current Alzheimer's disease (AD) therapies necessitate novel treatment approaches. Elaeocarpus angustifolius Blume, a plant traditionally used in India for neurological disorders, was investigated for its therapeutic potential in AD. E. angustifolius alkaloid-rich fraction (EAF) was analysed using LCMS and GCMS, identifying 66 phytochemicals. Compounds were evaluated using Schrodinger software against key AD targets obtained from Protein Data Bank (PDB), including recombinant human acetylcholinesterase (PDB ID: 4EY7), β-secretase (PDB ID: 6C2I), TNF-α converting enzyme (PDB ID: 2FV5), glycogen synthase kinase 3 (PDB ID: 1Q5K), and amyloid-β precursor protein (PDB ID: 1AAP). Among the identified compounds, (+)-Elaeocarpine, Genistein, Caffeic acid, Avenalumic acid, Verimol A, Apigenin 7-glucoside, and (1xi,3xi)-1,2,3,4-Tetrahydro-1-methyl-β-carboline-3-carboxylic acid exhibited the highest binding affinities. ADMET analysis confirmed favourable profiles for these phytochemicals. The study suggests that these compounds present in EAF could be promising candidates for developing novel AD therapies.}, }
@article {pmid40067468, year = {2025}, author = {Hassanzadeh-Khanmiri, M and Moshari, A and Kheradmand, R and Haghgouei, T and Homaei, M and Charsouei, S and Mobed, A}, title = {Nanomedicine: a cost-effective and powerful platform for managing neurodegenerative diseases.}, journal = {Metabolic brain disease}, volume = {40}, number = {3}, pages = {142}, pmid = {40067468}, issn = {1573-7365}, mesh = {Humans ; *Nanomedicine/methods ; *Neurodegenerative Diseases/drug therapy ; *Drug Delivery Systems/methods/economics ; Animals ; Nanoparticles ; Blood-Brain Barrier/metabolism ; Cost-Benefit Analysis ; }, abstract = {Neurodegenerative diseases (NDDs) are characterized by the chronic and progressive deterioration of the structure and function of the nervous system, imposing a significant burden on patients, their families, and society. These diseases have a gradual onset and continually worsen, making early diagnosis challenging. Current drugs on the market struggle to effectively cross the blood-brain barrier (BBB), leading to poor outcomes and limited therapeutic success. Consequently, there is an urgent need for new diagnostic tools and treatment strategies. To address these challenges, nanotechnology-based drug delivery systems-such as liposomes, micelles, dendrimers, and solid lipid nanoparticles (SLNs)-have emerged as promising solutions. This study provides a comprehensive review of recent advances in nanomedicine and nanotechnology-based platforms, alongside an exploration of ND mechanisms. The authors conducted a systematic literature search across relevant databases such as PubMed, Scopus, and Web of Science, focusing on peer-reviewed articles, reviews, and clinical studies published within the last 5 to 10 years. Additionally, this paper addresses the challenges faced by nanomedicines and delivery systems, offering insights into future directions in the field and the need for further research to establish their clinical viability as alternatives to current therapies.}, }
@article {pmid40066595, year = {2025}, author = {Zarnowska, A and Milewska, M and Rokicka, G and Kacprzyk, K and Panczyk, M and Folwarski, M and Szostak-Węgierek, D}, title = {Prevalence of malnutrition in patients with Alzheimer's disease - A systematic review. The call for consistent nutritional assessment methods.}, journal = {Nutricion hospitalaria}, volume = {}, number = {}, pages = {}, doi = {10.20960/nh.05611}, pmid = {40066595}, issn = {1699-5198}, abstract = {OBJECTIVES: epidemiological data show growing numbers of patients with Alzheimer´s disease. Cognitive decline and progressive swallowing impairment lead to a significant deterioration of the nutrition status in this population. Early detection and treatment of malnutrition is important for the prognosis of the disease.
METHOD: a systematic review was conducted. Four databases such as Cochrane, PubMed, Embase and Web of Science were searched by two independent researchers. The inclusion criteria encompass adult patients with diagnosed Alzheimer's disease, studies with screening tools for nutritional assessment such as Mini-Nutritional Assessment and body mass index. Patients without diagnosis or with possible or probable Alzheimer's disease were excluded. Finally, 36 studies with 5293 participants were included to the systematic review. PRISMA protocol was followed when writing this article. Critical Appraisal tools for use in JBI Systematic Reviews were used for quality assessment.
RESULTS: 36 studies were included in this systematic review. More than half of the respondents were from Europe. According to MNA 33.97 % of participants were at risk of malnutrition, 3.74 % malnourished and more than 62 % had proper nutritional status. According to the BMI, nearly 50 % of patients were overweight or obese, 4.22 % had BMI < BMI < 18,49 kg/m2. Risk of malnutrition and malnutrition was diagnosed in 53.8 % and 8.2 % of patients assessed with Mini-Nutritional Assessment - Short Form.
CONCLUSION: the risk of malnutrition in AD is high, however, significant differences between studies can be observed due to methodological differences. Large epidemiological studies are needed with unified nutritional assessment methods for patients with Alzheimer's disease.}, }
@article {pmid40066331, year = {2025}, author = {Li, T and Chen, J and Xie, Z and Fang, J and Wu, Q and Cao, X and Chen, Z and Wang, Y and Fan, Q and Wang, Q and Liu, J}, title = {Ginsenoside Ro ameliorates cognitive impairment and neuroinflammation in APP/PS1 mice via the IBA1/GFAP-MAPK signaling pathway.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1528590}, pmid = {40066331}, issn = {1663-9812}, abstract = {INTRODUCTION: Ginseng, known as the "king of herbs," has long been used in traditional Chinese medicine due to its beneficial properties, including anti-aging, anti-inflammatory, and anti-apoptotic effects. Ginsenosides, the active compounds in ginseng, have shown promise in treating neurodegenerative diseases such as Alzheimer's disease (AD). This study investigates the therapeutic potential of Ginsenoside Ro and its underlying mechanisms in AD treatment.
METHODS: In this study, male APP/PS1 transgenic mice were divided into five groups and treated with Ginsenoside Ro or ginseng for one month. Cognitive function and anxiety were assessed through behavioral tests, including the open field test (OFT) and Morris water maze (MWM). To evaluate Aβ deposition, neuronal apoptosis, neuroinflammation, and the MAPK pathway, various techniques were employed: Thioflavin-T staining, Nissl staining, immunofluorescence, Western blot, and qRT-PCR analyses.
RESULTS: Ginsenoside Ro significantly improved cognitive function and reduced anxiety in APP/PS1 mice. It also decreased Aβ deposition and ameliorated neuronal apoptosis in the cerebral cortex. The treatment regulated the expression of pro-apoptotic proteins (Bax and Caspase3) and increased the anti-apoptotic protein Bcl-2. Additionally, Ginsenoside Ro reduced neuroinflammation by decreasing IBA1-positive microglia and GFAP-positive astrocytes and lowering pro-inflammatory cytokines while enhancing anti-inflammatory cytokine IL-10. Furthermore, the phosphorylation levels of p38 and JNK in the MAPK pathway were significantly reduced, suggesting a key mechanism for its therapeutic effects.
DISCUSSION: These findings provide strong evidence supporting Ginsenoside Ro as a potential therapeutic agent for Alzheimer's disease. Its effects appear to be mediated through the modulation of the IBA1/GFAP-MAPK pathway, which may offer new insights into AD treatment strategies.}, }
@article {pmid40065918, year = {2025}, author = {Cummings, J}, title = {Perspective: Minimal clinically important difference (MCID) and Alzheimer's disease clinical trials.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70059}, pmid = {40065918}, issn = {2352-8737}, abstract = {UNLABELLED: The minimum clinically important difference (MCID) is a measure of the minimal clinically relevant change. The MCID represents the smallest difference in score on the measure or domain of interest which patients or clinicians perceive as beneficial or as meaningful decline. The MCID is not an alternative clinical trial outcome; it does not apply to group measures and is used as a means of determining whether an individual patient has reached a threshold of change. MCIDs have been derived for symptomatic treatments and for disease targeted therapies. MCIDs have been derived for nearly all clinical trial instruments used in AD therapeutic research. Application of the MCID to patients on disease-targeted therapies requires awareness of the expected increasing treatment-no treatment difference exhibited by these agents. The MCID complements other strategies for assessing the meaningfulness of interventions including effect size, number needed to treat, responder analyses, time saved, quality of life, and quality-adjusted life years. MCID is not a required measure for regulatory approval of a therapeutic since it is applicable to individual patients and not to group outcomes or mean differences used to determine treatment benefit in clinical trials.
HIGHLIGHTS: MCID is a key measure of within-person change in cognition, function, or behavior when it is applied to metrics of Alzheimer's disease progression.In Alzheimer's disease, MCID or minimum within person change (MWPC) can function as useful means of determining if a patient has progressed to thresholds of detectable change.In Alzheimer's disease, MCID/MWPC can be used to determine the number or percent of individuals who have progressed to detectable levels of within-person change, with differences anticipated in active treatment and placebo groups.MCID/MWPC are not measures that are appropriately applied to group outcomes of clinical trials.}, }
@article {pmid40065917, year = {2025}, author = {Leuchter, MK and Oughli, HA and Durbin, KA and Jackson, NJ and Elashoff, D and Chang, TS and Corlier, J and Ngo, D and Matthews, C and Wong, D and Fogel, BL and Bitan, G and Leuchter, AF and Vossel, K and Suthana, N}, title = {Broad repetitive transcranial magnetic stimulation (rTMS) of the precuneus in Alzheimer's disease: A rationale and study design.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70043}, pmid = {40065917}, issn = {2352-8737}, abstract = {INTRODUCTION: Brain network dysfunction, particularly within the default mode network (DMN), is an increasingly apparent contributor to the clinical progression of Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) can target key DMN hubs, maintain signaling function, and delay or improve clinical outcomes in AD. Here, we present the rationale and design of a study using off-the-shelf equipment and the latest clinical evidence to expand on prior rTMS work and reduce participant burden in the process.
METHODS: We will conduct a two-stage trial of large-coil rTMS targeting the precuneus (a key hub in the DMN affected by AD) in 54 participants with mild to moderate Alzheimer's Clinical Syndrome focused primarily on determining tolerability and feasibility and secondarily focused on determining short-term efficacy for memory. The first stage will involve 5 to 10 participants receiving open-label active treatment to refine the protocol. The following second stage will consist of a 1:1 randomized, double-blind, sham-controlled clinical trial to study feasibility and tolerability while exploring target engagement and short-term efficacy for memory. Participants will undergo 16 total rTMS brain stimulation sessions over the course of 5 weeks. A full course of open-label active treatment will be offered as an extension to the sham group after unblinding. Outcomes will focus on completion rates and adverse events to demonstrate feasibility and tolerability. Further exploratory outcomes will include neuropsychological assessments, electroencephalography, neuroimaging, and blood biomarkers to demonstrate the feasibility of collection and explore preliminary changes in these measures.
RESULTS: We anticipate this treatment is feasible and tolerable and may show evidence of target engagement and clinical improvement.
DISCUSSION: Should we achieve expected positive outcomes in feasibility and tolerability, this will justify future work focusing on clear demonstrations of clinical efficacy and biomarker engagement, as well as enhancement of generalizability and scalability.
HIGHLIGHTS: Induction-to-maintenance repetitive transcranial magnetic stimulation (rTMS) of the precuneus is a promising treatment for Alzheimer's disease (AD), though recent methods require intensive personalization.We propose here a trial design of precuneus rTMS in mild-to-early-moderate AD dementia using exclusively off-the-shelf equipment and protocol modifications to reduce participant burden.Our two novel modifications from prior work are (1) using a larger rTMS coil, and (2) consolidating the induction phase of treatment.This trial focuses primarily on tolerability and feasibility while exploring clinical measures of efficacy and biomarkers of target engagement.Our trial is registered at ClinicalTrials.gov NCT06597942.}, }
@article {pmid40065171, year = {2025}, author = {Rash, BG and Ramdas, KN and Agafonova, N and Naioti, E and McClain-Moss, L and Zainul, Z and Varnado, B and Peterson, K and Brown, M and Leal, T and Kopcho, S and Carballosa, R and Patel, P and Brody, M and Herskowitz, B and Fuquay, A and Rodriguez, S and Jacobson, AF and Leon, R and Pfeffer, M and Schwartzbard, JB and Botbyl, J and Oliva, AA and Hare, JM}, title = {Allogeneic mesenchymal stem cell therapy with laromestrocel in mild Alzheimer's disease: a randomized controlled phase 2a trial.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {40065171}, issn = {1546-170X}, abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, severe brain atrophy and neuroinflammation. We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 2a clinical trial that tested the safety and efficacy of laromestrocel, a bone-marrow-derived, allogeneic mesenchymal stem-cell therapy, in slowing AD clinical progression, atrophy and neuroinflammation. Participants across ten centers in the United States were randomly assigned 1:1:1:1 to four infusion groups: group 1 (placebo; four monthly infusions, n = 12); group 2 (25 million cells, one infusion followed by three monthly infusions of placebo, n = 13); group 3 (25 million cells; four monthly doses, n = 13); and group 4 (100 million cells; four monthly doses, n = 11). The study met its primary end point of safety; the rate of treatment-emergent serious adverse events within 4 weeks of any infusion was similar in all four groups: group 1, 0% (95% CI 0-26.5%); group 2, 7.7% (95% CI 0.2-36%); group 3, 7.7% (95% CI 0.2-36%) and group 4, 9.1% (95% CI 0.2-41.3%). Additionally, there were no reported infusion-related reactions, hypersensitivities or amyloid-related imaging abnormalities. Laromestrocel improved clinical assessments at 39 weeks compared to placebo, as measured by a composite AD score (secondary end point was met: group 2 versus placebo change: 0.38; 95% CI -0.06-0.82), Montreal cognitive assessment and the Alzheimer's Disease Cooperative Study Activities of Daily Living. At 39 weeks, Laromestrocel slowed the decline of whole brain volume compared to placebo (n = 10) by 48.4% for all treatment groups combined (groups 2-4: P = 0.005; n = 32) and left hippocampal volume by 61.9% (groups 2-4, P = 0.021; n = 32), and reduced neuroinflammation as measured by diffusion tensor imaging. The change in bilateral hippocampal atrophy correlated with the change in mini-mental state exam scores (R = 0.41, P = 0.0075) in all study patients (N = 42). Collectively these results support safety of single and multiple doses of laromestrocel treatment for mild AD and provide indications of efficacy in combating decline of brain volume and potentially cognitive function. Larger-scale clinical trials of laromestrocel in AD are warranted. ClinicalTrials.gov registration: NCT05233774 .}, }
@article {pmid40064805, year = {2025}, author = {Dahiya, M and Yadav, M and Goyal, C and Kumar, A}, title = {Insulin resistance in Alzheimer's disease: signalling mechanisms and therapeutics strategies.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {40064805}, issn = {1568-5608}, abstract = {BACKGROUND: Alzheimer's disease (AD), one of the most common neurodegenerative disorders, is characterised by hallmark abnormalities such as amyloid-β plaques and neurofibrillary tangles (NFTs). Emerging evidence suggests that faulty insulin signalling contributes to these pathological features, impairing critical cellular and metabolic processes.
OBJECTIVE: This review aims to elucidate the role of insulin signalling in the central nervous system (CNS) under normal and pathological conditions and to explore therapeutic approaches targeting insulin pathways in AD and other neurodegenerative diseases.
METHODS: We reviewed studies highlighting the involvement of insulin-signalling pathways in neuronal health, with a particular focus on the key components-IRS, PI3K, Akt, and GSK-3β-predominantly expressed in cortical and hippocampal regions.
RESULTS: Insulin, an essential growth factor, regulates numerous cellular functions, including glucose metabolism, mitochondrial activity, oxidative stress response, autophagy, synaptic plasticity, and cognitive processes. Altered phosphorylation of signalling molecules in insulin pathways contributes to oxidative stress, inflammation, and the formation of AD hallmarks. Indirect modulators such as NF-κB and caspases further exacerbate neuronal damage, linking impaired insulin signalling to neurodegeneration.
CONCLUSION: Insulin signalling plays a crucial role in maintaining neuronal health and mitigating neurodegenerative processes. Targeting insulin pathways and associated molecules offers promising therapeutic avenues for AD and other neurodegenerative disorders.}, }
@article {pmid40064490, year = {2025}, author = {Wada, K}, title = {[Diagnostic Communication for Alzheimer's Disease].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {3}, pages = {251-257}, doi = {10.11477/mf.188160960770030251}, pmid = {40064490}, issn = {1881-6096}, mesh = {*Alzheimer Disease/diagnosis ; Humans ; *Biomarkers/cerebrospinal fluid/blood ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Positron-Emission Tomography ; Communication ; }, abstract = {The introduction of amyloid positron emission tomography and cerebrospinal fluid biomarkers, along with the advent of anti-amyloid β antibodies, has brought about significant changes in the diagnosis and treatment of dementia. Furthermore, new technologies, such as plasma biomarkers, are being developed. Therefore, it is increasingly important to accurately convey the latest and most appropriate information in daily clinical practice. This paper outlines the latest diagnostic criteria, advancements in diagnostic technology, and anti-amyloid β antibody therapy for Alzheimer's disease, and discusses important points in communicating diagnoses.}, }
@article {pmid40063015, year = {2025}, author = {Zimmer, JA and Ardayfio, P and Wang, H and Khanna, R and Evans, CD and Lu, M and Sparks, J and Andersen, S and Lauzon, S and Nery, ESM and Battioui, C and Engle, SE and Biffi, A and Svaldi, D and Salloway, S and Greenberg, SM and Sperling, RA and Mintun, M and Brooks, DA and Sims, JR}, title = {Amyloid-Related Imaging Abnormalities With Donanemab in Early Symptomatic Alzheimer Disease: Secondary Analysis of the TRAILBLAZER-ALZ and ALZ 2 Randomized Clinical Trials.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {40063015}, issn = {2168-6157}, abstract = {IMPORTANCE: Amyloid-related imaging abnormalities (ARIA) are the major adverse event associated with amyloid-targeting immunotherapy. Identifying clinical features and individual risk factors for ARIA could facilitate effective prediction and prevention strategies.
OBJECTIVE: To characterize ARIA in participants treated with donanemab.
These prespecified and post hoc exploratory analyses use data from the placebo-controlled portions of the TRAILBLAZER-ALZ and ALZ 2 randomized clinical trials, conducted from December 2017 to December 2020 and from June 2020 to April 2023, respectively. Additional analyses are included from a stand-alone open-label addendum conducted from August 2021 through August 2023. Participants in the placebo-controlled trials and the open-label addendum aged 60 to 85 years with early symptomatic Alzheimer disease and elevated amyloid levels were included. The placebo-controlled trials, but not the addendum, had tau inclusion criteria.
INTERVENTIONS: Placebo-controlled trial participants were randomized 1:1 to receive placebo or donanemab, and all open-label participants received donanemab. Donanemab was administered every 4 weeks for up to 72 weeks.
MAIN OUTCOMES AND MEASURES: The primary outcomes were the frequency, radiographic severity, seriousness, symptoms, timing relative to donanemab treatment, and risk factors for ARIA.
RESULTS: Across 3030 total participants (placebo-controlled trials: 999 placebo participants, 984 donanemab participants; open-label addendum: 1047 donanemab participants), mean (SD) age was approximately 73.7 (6.0) years and 1684 participants (55.6%) were female. Frequencies of ARIA-edema/effusions (ARIA-E) and ARIA-microhemorrhages and hemosiderin deposition (ARIA-H) were higher with donanemab (24.4% and 31.3% in placebo-controlled trials, respectively; 19.8% and 27.2% in open-label addendum, respectively) than with placebo (1.9% and 13.0%, respectively). ARIA-E was mostly mild or moderate in severity. Serious ARIA-E was reported in 1.5% and symptomatic ARIA-E in 5.8% of donanemab-treated participants in the placebo-controlled trials. Symptoms most frequently reported with ARIA-E were headache and confusional state. In 58.3% of donanemab-treated participants with ARIA-E, the first event occurred by the third infusion (approximately month 3). Risk analysis demonstrated independent associations between ARIA-E and 6 baseline variables, including increased risk with APOE ε4 allele number, greater number of microhemorrhages, presence of cortical superficial siderosis, higher amyloid plaque, and elevated mean arterial pressure, and decreased risk with antihypertensive use.
CONCLUSIONS AND RELEVANCE: ARIA is an adverse event associated with donanemab treatment that requires safety monitoring. Individual ARIA risk can be assessed by APOE ε4 status and baseline imaging findings.
TRIAL REGISTRATIONS: ClinicalTrials.gov Identifiers: NCT03367403 and NCT04437511.}, }
@article {pmid40061341, year = {2025}, author = {Barnett, EJ and Hess, JL and Hou, J and Escott-Price, V and Fennema-Notestine, C and Kremen, W and Lin, SJ and Zhang, C and Gaiteri, C and Elman, J and Holmans, P and Faraone, SV and Glatt, SJ}, title = {A Novel Method to Disentangle Tightly Linked Risk and Resilience Genes for Brain Disorders: Application to Alzheimer's Disease.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40061341}, support = {R01 AG061800/AG/NIA NIH HHS/United States ; R01 AG064955/AG/NIA NIH HHS/United States ; P01 AG055367/AG/NIA NIH HHS/United States ; R01 MH130899/MH/NIMH NIH HHS/United States ; R21 MH126494/MH/NIMH NIH HHS/United States ; R01 DA047879/DA/NIDA NIH HHS/United States ; R01 NS128535/NS/NINDS NIH HHS/United States ; K01 AG063805/AG/NIA NIH HHS/United States ; R01 MH116037/MH/NIMH NIH HHS/United States ; R01 MH131685/MH/NIMH NIH HHS/United States ; U01 AR076092/AR/NIAMS NIH HHS/United States ; R01 DK083345/DK/NIDDK NIH HHS/United States ; R01 MH125720/MH/NIMH NIH HHS/United States ; R01 AG050595/AG/NIA NIH HHS/United States ; R01 DA047906/DA/NIDA NIH HHS/United States ; R01 AG061798/AG/NIA NIH HHS/United States ; U01 AG079847/AG/NIA NIH HHS/United States ; R01 MH098742/MH/NIMH NIH HHS/United States ; U01 MH135970/MH/NIMH NIH HHS/United States ; R01 AG060470/AG/NIA NIH HHS/United States ; 75N95023C00013/DA/NIDA NIH HHS/United States ; R01 MH126459/MH/NIMH NIH HHS/United States ; R24 MH129166/MH/NIMH NIH HHS/United States ; R01 AG076838/AG/NIA NIH HHS/United States ; P30 MH062512/MH/NIMH NIH HHS/United States ; }, abstract = {BACKGROUND: Genetic risk factors for psychiatric and neurodegenerative disorders are well documented. However, some individuals with high genetic risk remain unaffected, and the mechanisms underlying such resilience remain poorly understood. The presence of protective resilience factors that mitigate risk could help explain the disconnect between predicted risk and reality, particularly for brain disorders, where genetic contributions are substantial but incompletely understood. Identifying and studying resilience factors could improve our understanding of pathology, enhance risk prediction, and inform preventive measures or treatment strategies. However, such efforts are complicated by the difficulty of identifying resilience that is separable from low risk.
METHODS: We developed a novel adversarial multi-task neural network model to detect genetic resilience markers. The model learns to separate high-risk unaffected individuals from affected individuals at similar risk while "unlearning" patterns found in low-risk groups using adversarial learning. In simulated and existing Alzheimer's disease (AD) datasets, we identified markers of resilience with a feature-importance-based approach that prioritized specificity, generated resilience scores, and analyzed associations with polygenic risk scores (PRS).
RESULTS: In simulations, our model had high specificity and moderate sensitivity in identifying resilience markers, outperforming traditional approaches. Applied to AD data, the model generated genetic resilience scores protective against AD and independent of PRS. We identified five resilience-associated SNPs, including known AD-associated variants, underscoring their potential involvement in risk/resilience interactions.
CONCLUSIONS: Our methods of modeling and evaluation of feature-importance successfully identified resilience markers that were obscured in previous work. The high specificity of our model provides high confidence that these markers reflect resilience and not simply low risk. Our findings support the utility of resilience scores in modifying risk predictions, particularly for high-risk groups. Expanding this method could aid in understanding resilience mechanisms, potentially improving diagnosis, prevention, and treatment strategies for AD and other complex brain disorders.}, }
@article {pmid40060520, year = {2025}, author = {Holmes, BB and Weigel, TK and Chung, JM and Kaufman, SK and Apresa, BI and Byrnes, JR and Kumru, KS and Vaquer-Alicea, J and Gupta, A and Rose, IVL and Zhang, Y and Nana, AL and Alter, D and Grinberg, LT and Spina, S and Leung, KK and Condello, C and Kampmann, M and Seeley, WW and Coutinho-Budd, JC and Wells, JA}, title = {β-Amyloid Induces Microglial Expression of GPC4 and APOE Leading to Increased Neuronal Tau Pathology and Toxicity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060520}, issn = {2692-8205}, support = {R35 GM122451/GM/NIGMS NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; K24 AG053435/AG/NIA NIH HHS/United States ; K08 NS133290/NS/NINDS NIH HHS/United States ; R01 NS121101/NS/NINDS NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; RF1 AG061874/AG/NIA NIH HHS/United States ; }, abstract = {To elucidate the impact of Aβ pathology on microglia in Alzheimer's disease pathogenesis, we profiled the microglia surfaceome following treatment with Aβ fibrils. Our findings reveal that Aβ-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). In a Drosophila amyloidosis model, glial GPC4 expression exacerbates motor deficits and reduces lifespan, indicating that glial GPC4 contributes to a toxic cellular program during neurodegeneration. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act in trans to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. These studies offer a mechanistic framework linking Aβ and tau pathology through microglial HSPGs and APOE.}, }
@article {pmid40060041, year = {2025}, author = {Wang, S and Qi, C and Rajpurohit, C and Ghosh, B and Xiong, W and Wang, B and Qi, Y and Hwang, SH and Hammock, BD and Li, H and Gan, L and Zheng, H}, title = {Inhibition of Soluble Epoxide Hydrolase Confers Neuroprotection and Restores Microglial Homeostasis in a Tauopathy Mouse Model.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40060041}, issn = {2693-5015}, support = {P01 AG066606/AG/NIA NIH HHS/United States ; RF1 AG020670/AG/NIA NIH HHS/United States ; R01 NS093652/NS/NINDS NIH HHS/United States ; RF1 NS093652/NS/NINDS NIH HHS/United States ; U01 AG068031/AG/NIA NIH HHS/United States ; R01 AG020670/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolasis by the soluble epoxide hydrolase (sEH). Accordingly, inhibition of sEH has been shown to stabilize the EETs and dampen neuroinflammation in Aβ mouse models of Alzheimer's disease (AD). However, the role of the sEH-EET signaling pathway in other cell types of the CNS and in other neurodegenerative conditions are less understood.
METHODS: Here we examined the mechanisms and the functional role of the sEH-EET axis in tauopathy by treating the PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the PS19 mice with Ephx2 (gene encoding sEH) knockout mice, followed by single-nucleus RNA-sequencing (snRNA-seq), biochemical and immunohistochemical characterization, and behavioral analysis. We also tested the effect of the sEH-EET pathway in primary microglia cultures and human induced pluripotent stem cell (iPSC)-derived neurons that develop seeding-induced Tau inclusions.
RESULTS: We show that sEH inhibition improved cognitive function, rescued neuronal cell loss, and reduced Tau pathology and microglia reactivity. snRNA-seq revealed that TPPU treatment resulted in the upregulation of actin cytoskeleton and excitatory synaptic pathway genes. Treating the human iPSC-derived neurons with TPPU led to enhanced synaptic density without affecting Tau accumulation, indicating a cell-autonomous effect of sEH blockade in neuroprotection. Further, sEH inhibition reversed disease-associated and interferon-response microglia states in PS19 mice and EET supplementation enhanced Tau phagocytosis and clearance in primary microglia cultures.
CONCLUSION: These findings demonstrate that sEH blockade or EET augmentation confer therapeutic benefit against neurodegenerative tauopathies through parallel targeting of neuronal and microglial pathways.}, }
@article {pmid40059628, year = {2025}, author = {Chen, Q and Li, X and Xiao, W and Sun, Y and Shen, R and Kou, X and Yang, A}, title = {Design, synthesis, biological evaluation, and X-ray single crystal structure of novel computer-aided-drug-designbased α-mangostin derivatives: Multifunctional ligands against Alzheimer's disease.}, journal = {Archiv der Pharmazie}, volume = {358}, number = {3}, pages = {e2400671}, doi = {10.1002/ardp.202400671}, pmid = {40059628}, issn = {1521-4184}, support = {2023029//Integrated Traditional Chinese and Western Medicine Project of Tianjin Municipal Health and Health Committee, China/ ; 2023031//Integrated Traditional Chinese and Western Medicine Project of Tianjin Municipal Health and Health Committee, China/ ; NSFC, 81503462//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/drug therapy ; *Drug Design ; *Xanthones/pharmacology/chemistry/chemical synthesis ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Animals ; Ligands ; Structure-Activity Relationship ; *Butyrylcholinesterase/metabolism ; *Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Crystallography, X-Ray ; Caenorhabditis elegans/drug effects ; Computer-Aided Design ; Molecular Structure ; Reactive Oxygen Species/metabolism ; Humans ; Copper/chemistry/pharmacology ; Dose-Response Relationship, Drug ; Molecular Docking Simulation ; }, abstract = {Multifunctional ligand design strategy may be a promising approach for the treatment of Alzheimer's disease (AD). α-Mangostin (α-M), a natural small molecule with anti-AD properties, was used as the lead compound for the design and synthesis of six α-M derivatives (1-6) with the help of computer-aided-drug-design (CADD). Both theoretical calculations and experimental results suggested that 1-6 might serve as promising selective butyrylcholinesterase (BuChE) inhibitors and amyloid-β (Aβ) aggregation inhibitors. Meanwhile, experimental results confirmed the high selectivity of the derivatives, in which 1 had the best inhibitory activity and selectivity on BuChE (IC50 = 0.016 µM, SI = 700.63). The experimental results also showed that 1-6 could act as copper chelators and reactive oxygen species (ROS) scavengers. Furthermore, in vivo experiments with Caenorhabditis elegans also showed that 1 could scavenge ROS and inhibit Aβ aggregation. Notably, single crystals of 1, 4, and the 4-Cu(II) complex were prepared for the first time, which provided a reliable structural basis for analyzing the structure-activity relationship. The dimethylamino derivatives (1, 4) of α-M showed the best activities and were expected to become promising candidate drugs for multifunctional anti-AD.}, }
@article {pmid40059298, year = {2025}, author = {Dindar, Z and Anbaraki, A and Hosseini, SS and Harati, Z and Bahrami, A and Balalaie, S and Ghobeh, M and Mahdavi, M and Seyedarabi, A}, title = {The Use of Natural Volatile Compounds on the Fibrillation Domain of Amyloid Beta (GSNKGAIIGLM)─Towards Promising Agents to Combat Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {6}, pages = {1086-1102}, doi = {10.1021/acschemneuro.4c00768}, pmid = {40059298}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; *Peptide Fragments/metabolism ; *Neuroprotective Agents/pharmacology/chemistry ; Volatile Organic Compounds/pharmacology ; Microscopy, Atomic Force ; }, abstract = {Alzheimer's disease (AD), which is caused by the accumulation of amyloid-beta, is a major medical concern today. Controlling these aggregates is critical to drug development, but delivering them effectively into the bloodstream poses significant challenges. In this context, aromatherapy has been proposed as an innovative and promising approach for AD disease. The volatile compounds cinnamaldehyde, phenylethyl alcohol, α-asarone, and β-caryophyllene have neuroprotective effects that can be effective in the treatment of neurodegenerative diseases like AD. The amyloid-beta (Aβ) fragment (25-35), which retains the properties of the full-length Aβ is used as a suitable model to evaluate the potential toxicity associated with AD. This study investigated the effects of the four mentioned volatile compounds at four different concentrations on the fibrillation process of the Aβ (25-35) peptide. Structural changes in the peptide have been analyzed using various techniques such as fluorescence probing, far-UV circular dichroism spectroscopy (CD), and atomic force microscopy (AFM). Fluorescence probing results showed that these compounds can effectively prevent the formation of amyloid fibrils by forming chemical bonds with the intermediate species. CD spectroscopy results indicated a decrease in β-sheet content of fibrils and confirmed the effect of pH on structural changes. AFM analysis revealed that volatile compounds effectively prevented the formation of amyloid fibrils at different concentrations and changed the average size of intermediates and oligomeric species. These findings show a promising future for AD patients and emphasize the importance of natural compounds in the treatment and prevention of neurodegenerative diseases.}, }
@article {pmid40059211, year = {2025}, author = {Jiang, Q and Liu, J and Huang, S and Wang, XY and Chen, X and Liu, GH and Ye, K and Song, W and Masters, CL and Wang, J and Wang, YJ}, title = {Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {76}, pmid = {40059211}, issn = {2059-3635}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Aging/genetics/drug effects ; Alzheimer Disease/genetics/pathology/therapy ; Brain/pathology/metabolism ; }, abstract = {In the context of global ageing, the prevalence of neurodegenerative diseases and dementia, such as Alzheimer's disease (AD), is increasing. However, the current symptomatic and disease-modifying therapies have achieved limited benefits for neurodegenerative diseases in clinical settings. Halting the progress of neurodegeneration and cognitive decline or even improving impaired cognition and function are the clinically meaningful goals of treatments for neurodegenerative diseases. Ageing is the primary risk factor for neurodegenerative diseases and their associated comorbidities, such as vascular pathologies, in elderly individuals. Thus, we aim to elucidate the role of ageing in neurodegenerative diseases from the perspective of a complex system, in which the brain is the core and peripheral organs and tissues form a holistic network to support brain functions. During ageing, the progressive deterioration of the structure and function of the entire body hampers its active and adaptive responses to various stimuli, thereby rendering individuals more vulnerable to neurodegenerative diseases. Consequently, we propose that the prevention and treatment of neurodegenerative diseases should be grounded in holistic antiageing and rejuvenation means complemented by interventions targeting disease-specific pathogenic events. This integrated approach is a promising strategy to effectively prevent, pause or slow down the progression of neurodegenerative diseases.}, }
@article {pmid40059056, year = {2025}, author = {Yuan, GM and Su, FY and Li, PY and Guo, YM and Zhang, J and Xu, Y and Lü, ZX and Zhao, JY and Gong, YN}, title = {[Cerebral protective effect of acupuncture based on its regulative effect on programmed cell death].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {50}, number = {2}, pages = {210-216}, doi = {10.13702/j.1000-0607.20230934}, pmid = {40059056}, issn = {1000-0607}, mesh = {*Acupuncture Therapy ; Humans ; Animals ; *Apoptosis ; Brain/metabolism ; Pyroptosis ; Autophagy ; Ferroptosis ; Brain Diseases/therapy/metabolism/genetics ; }, abstract = {Programmed cell death (PCD) in the brain occurs throughout the whole process of life, and abnormal PCD may be an important factor leading to encephalopathy. It has been demonstrated that acupuncture has a good cerebral protective effect in the treatment of epilepsy, Alzheimer's disease, Parkinson's disease, depression, anxiety, insomnia, migraine and other dozens of brain diseases, and possesses characteristics of multi-point, networking, two-way and holistic regulation. In the present paper, we sum up the protective effect of acupuncture therapy from 1) cell apoptosis (for example, improving post-surgery cognition impairment, traumatic brain injury and ischemic stroke by relieving mitochondrial damage, activating mitochondrial autophagy, increasing blood-brain barrier permeability, and thus reducing cell apoptosis), 2) cell autophagy (for example, improving post-surgery cognition impairment, traumatic brain injury and ischemic stroke by relieving mitochondrial damage, activating mitochondrial autophagy, and increasing blood-brain barrier permeability, and thus reducing cell apoptosis), 3) pyroptosis (for example, inhibiting abnormally-activated inflammasomes, and caspase and gasdermin D activity to remit pyroptosis in the treatment of stroke, depression, Parkinson's disease, and Alzheimer's disease animal models), 4) ferroptosis (for instance, regulating iron ion metabolism, relieving lipid peroxidation damage, and thus playing a brain protection role in the treatment of ischemic and hemorrhagic stroke animal models), 5) necroptosis (inhibiting necrotic apoptosis mediated by receptor-interacting protein kinase 1 in intracerebral hemorrhage rats), and so on. We believe that along with the continuous development of brain science, artificial intelligence, big data and other new concepts and new technologies, it is expected to expand and improve the research level and quality of acupuncture in the prevention and treatment of encephalopathy through faster, more accurate and more comprehensive methods, which will help promote the modern interpretation of the brain protective effect of traditional acupuncture from the perspective of acupuncture regulation of PCD.}, }
@article {pmid40058984, year = {2025}, author = {Weber, M and Roth, HL and Abramowitz, A and Johnson, KG}, title = {Developing Treatment Models for the Delivery of the Antiamyloid Therapy, Lecanemab: Considerations for Implementation of Lecanemab in Healthcare Systems.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jagp.2025.02.007}, pmid = {40058984}, issn = {1545-7214}, abstract = {We describe the model developed by two separate healthcare systems to deliver the antiamyloid therapy, lecanemab, to patients with mild cognitive impairment and mild dementia. Based on current guidelines, the experience of two separate healthcare systems that developed lecanemab clinical care delivery programs is described in detail including the development of patient eligibility criteria, cooperation with specialty services, patient monitoring, and practical steps required to safely implement lecanemab programs at a systems level. Geriatric psychiatrists have a prominent role in prescribing and monitoring antiamyloid therapy in both systems and we highlight the unique role of the geriatric psychiatrist in the future delivery of antiamyloid therapies as memory care specialists.}, }
@article {pmid40058974, year = {2025}, author = {Kitchigina, VF}, title = {Colocalization of Neurotransmitters in Hippocampus and Afferent Systems: Possible Functional Role.}, journal = {Biochemistry. Biokhimiia}, volume = {90}, number = {1}, pages = {61-78}, doi = {10.1134/S0006297924603915}, pmid = {40058974}, issn = {1608-3040}, mesh = {*Neurotransmitter Agents/metabolism ; Animals ; Humans ; *Hippocampus/metabolism ; Synaptic Transmission/physiology ; Neurons/metabolism ; }, abstract = {In neurophysiology, the transmitter phenotype is considered as an indicator of neuronal identity. It has become known at the end of last century that a nerve cell can produce and use several different molecules to communicate with other neurons. These could be "classical" transmitters: glutamate or gamma-aminobutyric acid (or acetylcholine, serotonin, norepinephrine), as well as secondary messengers, mainly neuropeptides released from the same neurons. In the case, when classical neurotransmitters are released together from the same nerve cell, this event is called cotransmission or corelease (release from the same vesicles). In this review article, the term "cotransmission" is used in a broad sense, denoting neurons that can release more than one classical mediator. Since transmitters are often intermediate products of metabolism and are found in many cells, the neuron classification is currently based on the carrier proteins (transporters) that "pack" neurotransmitters synthesized in the cytoplasm into vesicles. Here, we limit the issue of colocalization of the main neurotransmitters in mammals to the neurons of hippocampus and those structures that send their pathways to it. The review considers problems concerning the mechanisms of multitransmitter signaling, as well as probable functional role of mediator colocalization in the work of hippocampus, which yet has been poorly understood. It has been suggested that co-expression of different mediator phenotypes is involved in maintaining the balance of excitation and inhibition in different regions of hippocampus, facilitates rapid selection of information processing mode, induction of long-term potentiation, maintenance of spatial coding by place cells, as well as ensuring flexibility of learning and formation of working memory. However, the functional role of mediator colocalization, as well as the mechanisms of release of "dual" transmitters, have not been fully elucidated. The solution of these problems will advance some areas of fundamental neuroscience and help in the treatment of those diseases, where disruption of the balance between excitation and inhibition is detected, such as, for example, in epilepsy, Alzheimer's disease, and many others.}, }
@article {pmid40058668, year = {2025}, author = {Wang, YY and Zhou, YN and Wang, S and Liu, L and Jiang, L and Zhang, Y and Zhang, L and Zhou, CN and Luo, YM and Tang, J and Liang, X and Xiao, Q and Dou, XY and Zhou, JR and Chao, FL and Tang, Y}, title = {Voluntary wheel exercise improves learning and memory impairment caused by hippocampal Hb-α deficiency by reducing microglial activation and reversing synaptic damage.}, journal = {Brain, behavior, and immunity}, volume = {127}, number = {}, pages = {81-95}, doi = {10.1016/j.bbi.2025.03.010}, pmid = {40058668}, issn = {1090-2139}, abstract = {Decreased hemoglobin (Hb) levels in peripheral blood may be a risk factor for Alzheimer's disease (AD). Hb-α is a monomeric form of Hb that exists in the central nervous system. Our previous RNA sequencing results revealed a decrease in the expression of the Hb-α gene in the hippocampus of AD model mice. However, the effects of Hb-α deficiency in the hippocampus on cognitive function and the underlying mechanism are unclear. Running exercise has been shown to improve cognition, but whether it can reverse the damage caused by Hb-α deficiency in the hippocampus needs to be further researched. In the present study, Mendelian randomization (MR) analyses revealed that lower levels of mean corpuscular Hb and Hemoglobin alpha 1 (HBA1) increased the risk of developing AD. When an adeno-associated virus (AAV) was used to knock down hippocampal Hb-α, the learning and memory ability of the resulting model mice decreased, similar to that of AD model mice. Moreover, the expression levels of advanced glycation end products (AGE) and their receptor (RAGE) were upregulated, microglia were activated, and the number of engulfed synapses increased, which damaged the number and structure of hippocampal synapses in the model mice. However, four weeks of voluntary wheel exercise effectively improved these conditions. In addition, we found that voluntary wheel exercise may compensate for Hb-α protein deficiency in the hippocampus by increasing the expression levels of Hb-α protein in plasma, cerebrospinal fluid, and other brain regions without altering Hb-α mRNA in the hippocampus of model mice. These results highlight the key role of Hb-α in hippocampal synaptic damage, elucidate the mechanism by which running exercise improves cognition by connecting the peripheral circulation and central nervous system through Hb-α, and provide new ideas for the diagnosis and treatment of AD.}, }
@article {pmid40058463, year = {2025}, author = {Zhao, T and Cui, X and Zhang, X and Zhao, M and Rastegar-Kashkooli, Y and Wang, J and Li, Q and Jiang, C and Li, N and Xing, F and Han, X and Zhang, J and Xing, N and Wang, J and Wang, J}, title = {Hippocampal sclerosis: A review on current research status and its mechanisms.}, journal = {Ageing research reviews}, volume = {108}, number = {}, pages = {102716}, doi = {10.1016/j.arr.2025.102716}, pmid = {40058463}, issn = {1872-9649}, abstract = {Hippocampal sclerosis (HS) is a pathological condition characterized by significant loss of hippocampal neurons and gliosis. This condition represents the most common neuropathological change observed in patients with temporal lobe epilepsy (TLE) and is also found in aging individuals. TLE related to HS is the most prevalent type of drug-resistant epilepsy in adults, and its underlying mechanisms are not yet fully understood. Therefore, developing improved methods for predicting and treating drug-resistant patients with TLE-HS is crucial. Patients with TLE-HS often experience cognitive impairment and psychological comorbidities, significantly affecting their quality of life. Consequently, a thorough review of the current research status of TLE-HS is essential, focusing on its prediction, diagnosis, treatment, and underlying mechanisms. The hippocampus plays a pivotal role in memory and cognition. HS of aging (HS-Aging), a condition linked to dementia in the ultra-elderly, is marked by severe CA1 (cornu ammonis) neuronal loss and frequent transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy, often misdiagnosed as Alzheimer's disease (AD). Nonetheless, clinical characteristics and patterns of hippocampal atrophy can help differentiate between the two disorders. This review aims to provide a comprehensive overview of the pathological features of HS, the relevant mechanisms underlying TLE-HS and HS-Aging, current imaging diagnostic techniques, including machine learning, and available treatment modalities. It also explores the prognosis and comorbidities related to these conditions. Future research directions include establishing animal models to clarify the poorly understood mechanisms underlying HS, particularly those related to emotional processing. Investigating post-HS behavioral and cognitive changes in these models will lay the foundation for further advancements in this field. This review is a cornerstone for future investigations and suggests additional research endeavors.}, }
@article {pmid40057929, year = {2025}, author = {Sarkar, S and Porel, P and Kosey, S and Aran, KR}, title = {Diverse role of S100 calcium-binding protein B in alzheimer's disease: pathological mechanisms and therapeutic implications.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {40057929}, issn = {1568-5608}, abstract = {S100 calcium-binding protein B, a member of the S100 protein family, plays an important role in the pathogenesis of Alzheimer's disease. Alzheimer's disease, a neurodegenerative disorder, is characterized by amyloid-beta plaques, neurofibrillary tangles, progressive dementia, and severe neuroinflammation. S100 calcium-binding protein B, predominantly secreted by astrocytes, exhibits a dual role in Alzheimer's disease, where at low (nanomolar) concentrations, it exhibits neurotrophic and neuroprotective effects and enhances synaptic plasticity, while at higher concentrations, it contributes to neuroinflammation and neuronal damage. In addition to its pathological roles in Alzheimer's disease, S100 calcium-binding protein B is also considered a potential biomarker, as increased levels correlate with cognitive decline and disease progression in cerebrospinal fluid. Targeting S100 calcium-binding protein B and/or its interaction with the receptor for advanced glycation end-products seems to be a potential target for therapeutic intervention. The development of multiple treatment approaches, such as pharmacological inhibitors, immunotherapy, and modulation of S100 calcium-binding protein B / receptor for advanced glycation end-products signalling pathways, might help to reduce neuroinflammation and amyloid-beta deposition effectively. This review aims to provide an overview of the role of S100 calcium-binding protein B in Alzheimer's disease and to explore its potential as a treatment target, well-grounded in its dual nature. Understanding S100 calcium-binding protein B's involvement in the pathogenesis of Alzheimer's disease may advance its application as a biomarker and help in the development of new treatment strategies, ultimately improving patients' quality of life.}, }
@article {pmid40030015, year = {2025}, author = {Johnson, EA and Nowar, R and Viola, KL and Huang, W and Zhou, S and Bicca, MA and Zhu, W and Kranz, DL and Klein, WL and Silverman, RB}, title = {Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {10}, pages = {e2402117122}, pmid = {40030015}, issn = {1091-6490}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; R56 AG050492/AG/NIA NIH HHS/United States ; AG061708//HHS | National Institutes of Health (NIH)/ ; AG050492//HHS | National Institutes of Health (NIH)/ ; }, mesh = {*Amyloid beta-Peptides/metabolism ; Animals ; Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; Neurons/metabolism/drug effects ; Mice ; Hippocampus/metabolism/pathology ; Alzheimer Disease/metabolism/drug therapy/pathology ; Lysosomes/metabolism ; Protein Aggregation, Pathological/metabolism/drug therapy ; Autophagy/drug effects ; }, abstract = {Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin. Transl. Med. 11, e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer's disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22, 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.}, }
@article {pmid40057461, year = {2025}, author = {Wallensten, J and Wachtler, C and Bogdanovic, N and Olofsson, A and Kivipelto, M and Jönsson, L and Petrovic, P and Carlsson, AC}, title = {Machine learning to detect Alzheimer's disease with data on drugs and diagnoses.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100115}, doi = {10.1016/j.tjpad.2025.100115}, pmid = {40057461}, issn = {2426-0266}, abstract = {BACKGROUND: Integrating machine learning with medical records offers potential for early detection of Alzheimer's disease (AD), enabling timely interventions.
OBJECTIVES: This study aimed to evaluate the effectiveness of machine learning in constructing a predictive model for AD, designed to predict AD with data up to three years before diagnosis. Using clinical data, including prior diagnoses and medical treatments, we sought to enhance sensitivity and specificity in diagnostic procedures. A second aim was to identify the most important factors in the machine learning models, as these may be important predictors of AD.
DESIGN: The study employed Stochastic Gradient Boosting, a machine learning method, to identify diagnoses predictive of AD using primary healthcare data. The analyses were stratified by sex and age groups.
SETTING: The study included individuals within Region Stockholm, Sweden, using medical records from 2010 to 2022.
PARTICIPANTS: The study analyzed clinical data for individuals over the age of 40. Patients with an AD diagnosis (ICD-10-SE codes F00 or G30) during 2010-2012 were excluded to ensure prospective modeling. In total, AD was identified in 3,407 patients aged 41-69 years and 25,796 patients aged over 69.
MEASUREMENTS: The machine learning model ranked predictive diagnoses, with performance assessed by the area under the receiver operating characteristic curve (AUC). Known and novel predictors were evaluated for their contribution to AD risk.
RESULTS: AUC values ranged from 0.748 (women aged 41-69) to 0.816 (women over 69), with men across age groups falling within this range. Sensitivity and specificity ranged from 0.73 to 0.79 and 0.66 to 0.79, respectively, across age and gender groups. Negative predictive values were consistently high (≥0.954), while positive predictive values were lower (0.199-0.351). Additionally, we confirmed known risk factors as predictors and identified novel predictors that warrant further investigation. Key predictors included medical observations, cognitive symptoms, antidepressant treatment, visit frequency, and vitamin B12/folic acid treatment.
CONCLUSIONS: Machine learning applied to clinical data shows promise in predicting AD, with robust model performance across age and sex groups. The findings confirmed known risk factors, such as depression and vitamin B12 deficiency, while also identifying novel predictors that may guide future research. Clinically, this approach could enhance early detection and risk stratification, facilitating timely interventions and improving patient outcomes.}, }
@article {pmid40057172, year = {2025}, author = {Zhang, C and Xu, J and Xu, F and Xie, X and Ji, T and Wang, C and Du, J}, title = {1-Epilupinine enhances cognition and reduces inflammation in scopolamine-induced dementia model mice.}, journal = {Neuroscience letters}, volume = {852}, number = {}, pages = {138184}, doi = {10.1016/j.neulet.2025.138184}, pmid = {40057172}, issn = {1872-7972}, mesh = {Animals ; *Scopolamine/pharmacology ; *Dementia/drug therapy/chemically induced/metabolism ; Mice ; Male ; *Cognition/drug effects ; *Disease Models, Animal ; Inflammation/drug therapy/chemically induced/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Maze Learning/drug effects ; }, abstract = {Dementia is a growing global public health concern. The search for effective anti-dementia drugs with fewer side effects, particularly in the early stages of the disease, is a key focus of current research. Natural compounds like 1-Epilupinine (ELP) may offer therapeutic potential for cognitive improvement and neuroprotection. To assess the potential of ELP in improving dementia and neuroinflammation in a scopolamine-induced dementia model in mice, a mouse model was induced using scopolamine hydrobromide, with Donepezil as the positive control. After five days of treatment, cognitive performance was assessed using the Morris water maze test. Motor function and anxiety-related behaviors were evaluated through the open field test. An inflammatory factor array was employed to measure inflammatory markers in the prefrontal cortex. The Morris water maze showed that the model group treated with scopolamine hydrobromide (1 mg/kg) had significantly fewer platform crossings and longer latency (P < 0.001) while mice treated with ELP (5 mg/kg) exhibited improved performance, with more crossings and reduced latency (P < 0.01), suggesting ELP effectively reversed cognitive deficits. In the open field test, no significant difference of total movement distance was detected in ELP-treated groups, indicating it did not impair motor function. The result of the inflammation factors array detecting showed lower levels of GM-CSF, IFN-γ, IL-2, and IL-23 significantly in the ELP (5 mg/kg) group, suggesting its potential anti-inflammatory properties for the dementia treatment. Therefore, ELP may serve as a promising treatment for early-stage dementia, offering cognitive improvement alongside anti-inflammatory neuroprotection.}, }
@article {pmid40057157, year = {2025}, author = {Chen, H and Fang, Z and Lin, SL and Schachner, M}, title = {L1CAM mimetic compound duloxetine improves cognitive impairment in 5xFAD mice and protects Aβ1-42-damaged HT22 cells.}, journal = {European journal of pharmacology}, volume = {997}, number = {}, pages = {177476}, doi = {10.1016/j.ejphar.2025.177476}, pmid = {40057157}, issn = {1879-0712}, abstract = {BACKGROUND: Synapse loss and damage are underlying causes of Alzheimer's disease. Duloxetine has been identified as a mimetic of neural adhesion molecule L1CAM, a neuronal synapse component, suggesting duloxetine could be therapeutic for Alzheimer's disease.
METHODS: Cognitive function in 5xFAD mice was evaluated by open field, novel object recognition, and Morris water maze tests. Hippocampal and cortical Aβ1-40, Aβ1-42 and amyloid plaque deposition were quantified by ELISA and immunohistochemistry. RT-qPCR and western blotting quantified the effects of duloxetine treatment on L1CAM levels and PI3K/Akt/CREB signaling pathway activation. Apoptosis markers Bcl-2 and Bax were also measured by RT-qPCR and western blotting. HT22 cell survival was measured by CCK8 assay.
RESULTS: Duloxetine preserved learning and memory abilities, but had no effect on locomotor performance of 5xFAD mice. Duloxetine decreased Aβ1-42 expression levels, increased Aβ1-40 levels, reduced amyloid plaque formation, and activated the PI3K/Akt/CREB signaling pathway in both cortices and hippocampi of 5xFAD mice. Moreover, duloxetine increased the expression of L1CAM and Bcl-2, and inhibited the expression of Bax, as well as prevented Aβ1-42 cytotoxicity in wild-type, but not L1CAM-knockdown HT22 cells, suggesting a feed-forward mechanism for duloxetine-mediated neuroprotection, whereby duloxetine induces and activates L1CAM to exert neuroprotective effects.
CONCLUSIONS: Our findings demonstrate that duloxetine plays a neuroprotective role in 5xFAD mice and HT22 cells through activating L1CAM, likely by regulating the PI3K/Akt/CREB signaling pathway. These results suggest that duloxetine may be a potential reagent for the treatment of Alzheimer's disease.}, }
@article {pmid40056763, year = {2025}, author = {Mesias, A and Borges, S and Pintado, M and Baptista-Silva, S}, title = {Bioactive peptides as multipotent molecules bespoke and designed for Alzheimer's disease.}, journal = {Neuropeptides}, volume = {111}, number = {}, pages = {102515}, doi = {10.1016/j.npep.2025.102515}, pmid = {40056763}, issn = {1532-2785}, abstract = {In an increasingly aging world where neurodegenerative diseases (NDs) are exponentially rising, research into more effective and innovative treatments seems paramount. Bioactive peptides (BPs) emerge as promising compounds with revolutionary potential in the treatment of NDs, particularly in well-known conditions like Alzheimer's disease (AD). The biological potential of these compounds is primarily attributed to their drug development advantages such as enhanced penetration, low toxicity, and rapid clearance, as well as, their antioxidant, and anti-inflammatory properties bio-linked to the neuroprotective effect, able to attenuate the multifactorial pathologies of AD. BPs can be sourced from common dietary origins, like animals, plants, marine, and from emerging sources like edible insects. However, to isolate an active BP with beneficial biological effects it must first be released from its parent protein, followed by a synthesis-flow. While in silico approaches can predict a BP's potential bioactivity and structural characteristics, in vitro, cell-based, and in vivo assays should be conducted to ensure these properties. The blood-brain-barrier (BBB) microenvironment and permeability in health or disease state are key factors to consider since they can limit the ability of circulating therapeutical agents, including BPs, to reach the brain. This review focuses on the bioactivity properties of BPs from different dietary protein sources and explores their beneficial effect and neuroprotective activity in AD, unraveling new paths of treatment.}, }
@article {pmid40055645, year = {2025}, author = {Zhao, J and Li, Z and Zhang, R and Yu, H and Zhang, L}, title = {Network pharmacology mechanism of Rosmarinus officinalis L.(Rosemary) to improve cell viability and reduces apoptosis in treating Alzheimer's disease.}, journal = {BMC complementary medicine and therapies}, volume = {25}, number = {1}, pages = {94}, pmid = {40055645}, issn = {2662-7671}, support = {2017FE467(-024) and 202201AY070001-034//Applied Basic Research Programs of Yunnan Province associated with Kunming Medical University in China/ ; }, mesh = {*Alzheimer Disease/drug therapy ; *Rosmarinus/chemistry ; *Cell Survival/drug effects ; *Apoptosis/drug effects ; *Network Pharmacology ; *Molecular Docking Simulation ; *Plant Extracts/pharmacology/chemistry ; Humans ; Neuroprotective Agents/pharmacology ; Abietanes/pharmacology ; Animals ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neurodegeneration, nerve loss, neurofibrillary tangles and Aβ plaques. Different process of the AD pathology present more opportunities for treatment. In addition, the holistic approaches involving network pharmacology with traditional Chinese medicine (TCM) may be viable options for AD treatment, and lead to an effective cure for AD in the future. Therefore, this study explored the therapeutic effect and mechanism of Rosmarinus officinalis L(rosemary) in the treatment of Alzheimer's disease on basis of cell experiments, network pharmacology and molecular docking.
METHODS: We performed cell experiments, to investigate the therapeutic effects of Rosmarinus officinalis L on AD in vitro using CCK8 assay, flow cytometry and TMRE Kit. In addition, carnosic acid is a major antioxidant diterpenoid in Rosmarinus officinalis L. We performed cell experiments, to investigate the neuroprotective effects of carnosic acid on AD in virto using CCK8 assay and flow cytometry. Furthermore, the main antioxidant compounds of rosemary ware collected through literature reviews, PharmMapper and Swiss Target prediction ware used to identify their potential targets. Targets of AD were obtained from Genecards and OMIM. The intersection targets of the main active components of rosemary and the therapeutic targets of Alzheimer's disease were subsequently obtained by using online Venn diagram. Protein-protein interaction, Cytoscape, Gene Ontology, and Kyoto Encyclopedia of Genes were used to analyze potential targets and key pathways of rosemary in AD. Besides, through molecular docking, the interactions of the main active components of rosemary, and the predicted candidate targets were verified. Finally, quantitative Real-Time PCR (RT-qPCR) was performed to confirm the effectiveness of the genes.
RESULTS: It was found that rosemary could reversed Aβ25-35 induced damage to mouse hippocampal neuron HT22 cells, significantly improved the viability of damaged cells, and reduced apoptosis. The results of fluorescent staining with Hoechst 33,342 and TMRE suggested that rosemary inhibited the reduction of mitochondrial membrane potential levels induced by Aβ25-35, which had a specific protective effect on AD in vitro. Additionally, a main antioxidant compound in rosemary, carnosic acid, also has neuroprotective effects. Eight main antioxidant compounds of rosemary ware collected. Network pharmacology and molecular docking, revealed that rosemary plays a therapeutic role in the treatment of Alzheimer's disease through the main active carnosic acid, carnosol, rosmarinol, rosmadial, genkwanin, cirsimaritin, rosmarinic acid and caffeic acid in Rosmarinus officinalis L, which affects the gene regulation of HRAS, ESR1, RHOA, IGF1, SRC, ANXA5, MMP9, MAPK14, NOS3, and PIK3R1, and participates in the PI3K-Akt, Rap1, MAPK, and estrogen signaling pathways. RT-qPCR indicated that rosemary could elevated expression of IGF1, MMP9 and decreased mRNA levels of SRC, MAPK14, compared with the control group.
CONCLUSIONS: Rosemary is an important economic plant with multi-component, multi-target and multi-pathway synergistic effects.The findings highlight the effectiveness of rosemary in helping to increase cell viability and reduce apoptosis when treating mouse hippocampal neuron HT22 cells, thereby supporting its therapeutic potential in treating Alzheimer's disease.}, }
@article {pmid40055203, year = {2025}, author = {Soni, S and Kaur, G}, title = {Emerging therapeutic application of clemastine: a review of recent patents updates.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40055203}, issn = {1432-1912}, abstract = {Clemastine, a first-generation antihistamine traditionally used for treating allergic rhinitis and urticaria, has recently gathered interest due to its potential therapeutic applications beyond its antihistaminergic properties. This review examines recent patent filings (2015-2024) to elucidate the emerging therapeutic landscape for this compound. The analysis reveals various potential applications, including neurodegenerative disorders, cardiovascular diseases, and cancer treatment. Specifically, several studies focus on its ability to promote remyelination in multiple sclerosis and other demyelinating disorders, highlighting its potential neuroprotective effects. Recent findings suggest its efficacy in treating heart failure and arrhythmias, possibly through its action on cardiac ion channels. In oncology, patents propose this compound as an adjuvant therapy to enhance the efficacy of existing treatments and potentially overcome drug resistance. This review also explores combination therapies involving this drug, which aim to synergize its effects with other active compounds. The patent literature indicates a significant change in the therapeutic potential of ethanolamine derivatives, from a simple antihistamine to a multifaceted drug candidate with far-reaching implications across various medical fields. These developments emphasize the importance of repurposing existing drugs and highlight Clemastine as a promising candidate for further clinical investigation in multiple therapeutic areas.}, }
@article {pmid40054389, year = {2025}, author = {Nordvall, G and Yan, P and Agholme, L and Lundkvist, J and Sandin, J and Biverstål, H and Winblad, B and Zetterberg, H and Klintenberg, R and Ferm, M and Cirrito, JR and Lee, JM}, title = {γ-Secretase modulation inhibits amyloid plaque formation and growth and stimulates plaque regression in amyloid precursor protein/presenilin-1 mice.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {392}, number = {4}, pages = {103400}, doi = {10.1016/j.jpet.2025.103400}, pmid = {40054389}, issn = {1521-0103}, abstract = {γ-Secretase modulators (GSMs) represent an emerging oral therapy for preventing and targeting Aβ-amyloidosis in Alzheimer disease. Aβ is a family of peptides of varying lengths where both the total and relative amounts of the individual Aβ peptides affect the process of amyloidosis. In contrast to inhibitors of Aβ synthesis, GSMs do not affect the total amount of Aβ peptides generated but decrease longer more amyloidogenic Aβ species while increasing the production of shorter less amyloidogenic Aβ peptides. In this study, we investigated how this modulation of Aβ production affects Aβ plaque dynamics in the brains of APP/PS1dE9 transgenic mice. Similar to studies with different inhibitors of Aβ synthesis, we found that 28 days of once-daily oral treatment with the GSM AZ4126 (100 μmol/kg) resulted in a strong reduction in plaque formation and plaque growth. In addition, and in contrast to Aβ production inhibitors, the GSM AZ4126 caused a significant reduction in the size of established Aβ plaques. Moreover, the antiamyloidogenic activity was accompanied by a marked reduction in brain interstitial fluid Aβ40 and Aβ42 and an increase in Aβ37. Treatment of induced pluripotent stem cell-derived cortical neurons with the GSM AZ4126 reduced secreted Aβ40 and Aβ42 dose-dependently and with a complementary increase in Aβ37 and Aβ38. These studies unravel a previously unknown antiamyloidogenic effect of GSMs, suggesting that they promote the clearance of already established Aβ pathology in addition to their inhibition of Aβ amyloid formation. SIGNIFICANCE STATEMENT: Immunotherapies promoting Aβ-amyloid clearance have shown efficacy in early Alzheimer disease, but complementary Aβ targeting therapeutic approaches are needed. γ-Secretase modulators (GSMs) target Aβ production with an effective and tolerable mechanism. This study demonstrates that a GSM not only inhibits Aβ-amyloid formation but also promotes Aβ-plaque clearance in experiments conducted in an Aβ-amyloidosis mouse model and supports further development of GSMs as an effective oral treatment for Alzheimer disease.}, }
@article {pmid40052227, year = {2025}, author = {Davidowitz, EJ and Lopez, P and Patel, D and Jimenez, H and Wolin, A and Eun, J and Adrien, L and Koppel, J and Morgan, D and Davies, P and Moe, JG}, title = {Therapeutic Treatment With OLX-07010 Inhibited Tau Aggregation and Ameliorated Motor Deficits in an Aged Mouse Model of Tauopathy.}, journal = {Journal of neurochemistry}, volume = {169}, number = {3}, pages = {e70025}, pmid = {40052227}, issn = {1471-4159}, support = {R43 AG029777/AG/NIA NIH HHS/United States ; R44 AG053150/AG/NIA NIH HHS/United States ; R43AG029777/AG/NIA NIH HHS/United States ; R44AG053150/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Tauopathies/drug therapy/pathology/metabolism ; *tau Proteins/metabolism ; Mice ; *Mice, Transgenic ; *Disease Models, Animal ; Aging/drug effects ; Male ; Protein Aggregates/drug effects ; Humans ; Motor Disorders/drug therapy ; Female ; Dose-Response Relationship, Drug ; Motor Activity/drug effects ; }, abstract = {Targeting tau protein is a strategy for the development of disease-modifying therapeutics for Alzheimer's disease (AD) and numerous rare tauopathies. A small molecule approach targeting tau aggregation was used to select and optimize compounds inhibiting tau self-association in vitro that have translated in vivo in preventive studies in htau and P301L tau JNPL3 mouse models of tauopathy. In this therapeutic treatment study, aged JNPL3 mice with pre-existing tau aggregates were used to evaluate the therapeutic effect of OLX-07010. The study had a Baseline group of mice aged 7 months, a vehicle, and two dose groups treated until 12 months by administration in feed. The primary endpoint of the study was the reduction of insoluble tau aggregates with statistical significance. The secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of soluble tau, and improvement of motor behavior. ELISAs and immunoblots were used to determine the levels of tau and its aggregated forms including self-associated tau and Sarkosyl insoluble tau. Effect on motor behavior, as measured by Rotarod assay, was also assessed between the treatment groups. At the end of treatment, reduced levels of self-associated tau, Sarkosyl insoluble tau aggregates, and overall levels of tau in the heat-stable fraction with statistical significance in the cortex were observed. Treatment prevented the accumulation of tau aggregates above baseline, and in parallel, treatment groups had improved motor behavior in a Rotarod assay compared to baseline and vehicle control groups, suggesting that treatment was rescuing motor impairment in aged mice. The functional and biochemical readouts suggest that this small molecule has potential for treating neurodegenerative diseases characterized by tau aggregation such as AD and progressive supranuclear palsy.}, }
@article {pmid40052020, year = {2025}, author = {Nawar, NF and Beltagy, DM and Tousson, E and El-Keey, MM and Mohamed, TM}, title = {Coenzyme Q10 alleviates AlCl3 and D-galactose induced Alzheimer via modulating oxidative burden and TLR-4/MAPK pathways and regulation microRNA in rat brain.}, journal = {Toxicology research}, volume = {14}, number = {2}, pages = {tfaf031}, pmid = {40052020}, issn = {2045-452X}, abstract = {UNLABELLED: Alzheimer's disease (ad) is the most progressive form of neurodegenerative disease resulting in cognitive and non-cognitive deficits. Coenzyme Q10 (CoQ10) is an anti-inflammatory and anti-oxidative stress supplement that can improve inflammation and oxidative stress associated with ad. This study aimed to explore the protective potential of coenzyme Q10 (CoQ10). It also sought to uncover any synergistic effects when combined with donepezil, an acetylcholinesterase inhibitor, in treating Alzheimer's disease in rats, focusing on the modulation of the TLR-4/MAPK pathway and regulation of microRNA. The experiment involved seventy rats categorized into different groups: control, Reference group (donepezil 10 mg/kg/P.O.), CoQ10 alone (1,200 mg/kg/P.O.), ad-model (D-galactose (120 mg/kg/i.p) + Alcl3 (50 mg/kg/P.O.)), donepezil co-treatment, CoQ10 co-treatment, and CoQ10 + donepezil co-treatment. Behavioral parameter was defined using the Morris-Maze test (MMT) and various assessments, such as GABA, oxidative stress, Aβ1-42, ion homeostasis, toll-like receptor-4 (TLR-4), mitogen-activated protein kinase-1 (MAPK-1), micro-RNA (mir-106b, mir-107, and mir-9) were measured. Immunohistological staining was used to assess structural abnormalities in hippocampus. CoQ10 treatment demonstrated memory improvement, enhanced locomotion, and increased neuronal differentiation, mainly through the activation of the TLR-4/MAPK pathway and regulation of mir-106b, mir-107, and mir-9.
HIGHLIGHTS: Coenzyme Q10 (CoQ10) improved the rats' passive avoidance memory impairment caused by D-gal and AlCl3. ad led to the alteration of the TLR-4/MAPK pathways.CoQ10 as a protective agent, diminishes oxidative burden, improve ion homeostasis.CoQ10 counteracts Alzheimer's disease by enhancing neurotransmitter parameter and regulating the MicroRNA.CoQ10 lowered accumulation of Aβ plaque in the hippocampal neurons of D-Gal and AlCl3-treated rats.One promising therapeutic method was the combination of donepezil and CoQ10 therapy.}, }
@article {pmid40051562, year = {2025}, author = {Liu, JJ and Wei, F and Wang, YD and Liu, J and Xu, BL and Ma, SC and Yang, JB}, title = {Ginseng and Polygonum multiflorum formula protects brain function in Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1461177}, pmid = {40051562}, issn = {1663-9812}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no effective treatment currently available. The Panax ginseng C.A.Mey. and Polygonum multiflorum Thunb. formula (GSPM) has shown potential neuroprotective effects, but its therapeutic efficacy and underlying mechanisms in AD remain unclear and require further investigation.
METHODS: In this study, senescence-accelerated mouse prone 8 (SAMP8) mice, an AD model, were treated with GSPM (low: 117 mg/kg, high: 234 mg/kg) or donepezil (1.3 mg/kg) via gavage for 2 months. Cognitive function was assessed using the Morris water maze. Hippocampal morphology was evaluated by H&E staining, and neuronal apoptosis was detected by TUNEL assay. Microgliosis and astrogliosis were analyzed by Iba1 and GFAP immunohistochemistry. Levels of phosphorylated Tau, Aβ1-42, Aβ1-40, inflammatory cytokines, oxidative stress markers, and senescence markers were measured. Gut microbiota composition was analyzed by 16S rRNA sequencing. In vitro, the effects of GSPM were evaluated in Aβ1-42-stimulated HT22 hippocampal neurons. Cell viability was assessed via CCK-8, and apoptosis was detected by flow cytometry. The AMPK/Sirt1 pathway was investigated by Western blotting, and SIRT1-dependent effects were evaluated following EX527 treatment, a SIRT1 inhibitor.
RESULTS: GSPM treatment improved cognitive function, reduced hippocampal tissue damage, and decreased neuronal apoptosis in AD mice. It alleviated neuroinflammation by reducing microgliosis and astrogliosis and lowered the levels of p-Tau protein and Aβ accumulation in both the hippocampus and cerebrospinal fluid. Additionally, GSPM reversed the enhanced inflammation, oxidative stress, and neuronal senescence observed in AD mice. Furthermore, GSPM modulated gut microbiota composition by reducing microbial diversity and restoring the Firmicutes/Bacteroidetes ratio to levels similar to those in control mice. GSPM increased the abundance of Lactobacillus, which was negatively correlated with inflammation, Aβ1-42, p-Tau, and senescence markers. It also decreased the abundance of bacteria, such as Oscillibacter, Helicobacter, and Odoribacter, which are associated with inflammation, oxidative stress, and neuronal senescence. In line with in vivo findings, GSPM increased cell viability, reduced apoptosis, and alleviated oxidative stress in Aβ1-42-stimulated HT22 hippocampal neurons. It also decreased the production of pro-inflammatory cytokines and reduced expression of senescence markers in vitro. Furthermore, GSPM restored AMPK phosphorylation and Sirt1 expression in neurons. Notably, inhibition of Sirt1 by EX527 reversed the neuroprotective effects of GSPM.
CONCLUSION: Our data demonstrated that GSPM exhibits protective effects on AD via suppressing the inflammation, oxidation, and senescence, possibly through regulating the Sirt1 signaling. These findings provided a novel therapeutic approach for AD.}, }
@article {pmid40051287, year = {2025}, author = {Kadi, I and Seyhan, G and Zebbiche, Z and Sari, S and Barut, B and Boumoud, T and Mermer, A and Boulebd, H}, title = {Novel 2-Alkoxy-3-Cyanopyridine Derivatives as Cholinesterase Inhibitors: Synthesis, Biological Evaluation, and In Silico Investigations.}, journal = {Chemistry & biodiversity}, volume = {}, number = {}, pages = {e202402915}, doi = {10.1002/cbdv.202402915}, pmid = {40051287}, issn = {1612-1880}, abstract = {Alzheimer's disease remains a major challenge in neuroscience and medicine. Cholinesterase inhibitors provide symptomatic relief but do not alter disease progression. While significant progress has been made in understanding its biology, there is an urgent need for effective therapies. In this study, a series of 2-alkoxy-3-cyanopyridine derivatives (1-7) were prepared and evaluated as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among the compounds, 3 and 4 were identified as good inhibitors of AChE and BuChE with relatively low IC50 values. 3 inhibited AChE with an IC50 of 53.95 ± 4.29 µM, while 4 had a greater potency for BuChE with an IC50 of 31.79 ± 0.38 µM. Kinetic studies revealed that 3 and 4 are competitive inhibitors with Ki values of 14.23 ± 0.42 and 19.80 ± 3.38 µM for AChE and BuChE, respectively. In silico investigations, including docking studies, DFT calculations, and ADME/drug-likeness properties, were carried out to understand the mode of interaction of 3 and 4 toward the AChE and BuChE enzymes, as well as to determine their molecular geometry, chemical reactivity, and pharmacokinetic properties. This study highlights the potential of 3-cyanopyridine derivatives in the treatment of AD and provides a solid foundation for further optimization and exploration of their therapeutic applications.}, }
@article {pmid40051090, year = {2025}, author = {Bobbins, A and Davies, M and Lynn, E and Roy, D and Yeomans, A and Shakir, SAW}, title = {Safety and effectiveness of the anti-amyloid monoclonal antibody (mAb) drug lecanemab for early Alzheimer's disease: The pharmacovigilance perspective.}, journal = {British journal of clinical pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1002/bcp.70021}, pmid = {40051090}, issn = {1365-2125}, abstract = {The development of humanized IgG1 anti-amyloid monoclonal antibodies, such as lecanemab, provides a promising novel treatment pathway with potential disease-modifying effects for patients with early Alzheimer's disease (AD). Lecanemab, which gained marketing approval by the United States Food and Drug Administration (US FDA) in July 2023, has since been approved in multiple countries, including the United Kingdom (UK). The decision by the UK's Medicines and Healthcare products Regulatory Agency (MHRA) to approve lecanemab in August 2024 followed similar regulatory decisions in the US and Japan. However, at the time of approval, the decision contrasted with that of the European Medicine Agency (EMA) in July 2024. Subsequently, the EMA recommended the marketing approval of lecanemab in November 2024 following a re-examination of further data submitted by the Marketing Authorisation Holder. The UK's National Institute for Health and Care Excellence (NICE) has not recommended lecanemab for use in early AD amid concerns, including treatment cost and the translation of efficacy outcomes into clinically meaningful improvement. The risks of serious adverse events (SAEs), including amyloid-related imaging abnormalities (ARIA), have also emerged from clinical trial data with a concern for the potential for rare, life-threatening events. This narrative review discusses the requirement for a robust method of monitoring the safety and effectiveness of lecanemab in the real-world clinical setting considering recent regulatory decisions. Additionally, the need to evaluate proposed risk minimization measures (RMMs) is discussed considering the resource constraints of healthcare systems, such as those faced by the UK's National Health Service (NHS).}, }
@article {pmid40050982, year = {2025}, author = {Zhan, H and Cammann, D and Cummings, JL and Dong, X and Chen, J}, title = {Biomarker identification for Alzheimer's disease through integration of comprehensive Mendelian randomization and proteomics data.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {278}, pmid = {40050982}, issn = {1479-5876}, support = {70823173//IDSA Foundation/ ; U54GM104944//Mountain West Clinical and Translational Research Infrastructure Network Program/ ; R15AG083618-01A1/AG/NIA NIH HHS/United States ; R35AG71476/AG/NIA NIH HHS/United States ; R25AG083721-01/AG/NIA NIH HHS/United States ; P20GM109025/GM/NIGMS NIH HHS/United States ; RO1NS139383/NS/NINDS NIH HHS/United States ; Alzheimer's Drug Discovery Foundation//Alzheimer's Drug Discovery Foundation/ ; Ted and Maria Quirk Endowment//Ted and Maria Quirk Endowment/ ; Joy Chambers-Grundy Endowment//Joy Chambers-Grundy Endowment/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/blood ; *Mendelian Randomization Analysis ; *Proteomics ; *Biomarkers/blood/metabolism ; *Quantitative Trait Loci/genetics ; *Genome-Wide Association Study ; Bayes Theorem ; Genetic Predisposition to Disease ; White People/genetics ; White ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the main cause of dementia with few effective therapies. We aimed to identify potential plasma biomarkers or drug targets for AD by investigating the causal association between plasma proteins and AD by integrating comprehensive Mendelian randomization (MR) and multi-omics data.
METHODS: Using two-sample MR, cis protein quantitative trait loci (cis-pQTLs) for 1,916 plasma proteins were used as an exposure to infer their causal effect on AD liability in individuals of European ancestry, with two large-scale AD genome-wide association study (GWAS) datasets as the outcome for discovery and replication. Significant causal relationships were validated by sensitivity analyses, reverse MR analysis, and Bayesian colocalization analysis. Additionally, we investigated the causal associations at the transcriptional level with cis gene expression quantitative trait loci (cis-eQTLs) data across brain tissues and blood in European ancestry populations, as well as causal plasma proteins in African ancestry populations.
RESULTS: In those of European ancestry, the genetically predicted levels of five plasma proteins (BLNK, CD2AP, GRN, PILRA, and PILRB) were causally associated with AD. Among these five proteins, GRN was protective against AD, while the rest were risk factors. Consistent causal effects were found in the brain for cis-eQTLs of GRN, BLNK, and CD2AP, while the same was true for PILRA in the blood. None of the plasma proteins were significantly associated with AD in persons of African ancestry.
CONCLUSIONS: Comprehensive MR analyses with multi-omics data identified five plasma proteins that had causal effects on AD, highlighting potential biomarkers or drug targets for better diagnosis and treatment for AD.}, }
@article {pmid40050873, year = {2025}, author = {Ma, J and Tian, Y and Du, C and Zhu, Y and Huang, W and Ding, C and Wei, P and Yi, X and Lin, Z and Fang, W}, title = {Cerium-doped Prussian blue biomimetic nanozyme as an amplified pyroptosis inhibitor mitigate Aβ oligomer-induced neurotoxicity in Alzheimer's disease.}, journal = {Journal of nanobiotechnology}, volume = {23}, number = {1}, pages = {181}, pmid = {40050873}, issn = {1477-3155}, support = {2021Y2001//Technology Platform Construction Project of Fujian Province/ ; 2023J01664//Natural Science Foundation of Fujian Province/ ; 2023YSJYX-PD-4//Fujian Neurological Disease Medical Center - Neurosurgery "Double High Level" Construction Project/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism ; Mice ; Humans ; *Blood-Brain Barrier/metabolism/drug effects ; *Cerium/chemistry/pharmacology ; *Pyroptosis/drug effects ; *Ferrocyanides/chemistry/pharmacology ; Cell Line, Tumor ; Biomimetic Materials/chemistry/pharmacology ; Disease Models, Animal ; Nanoparticles/chemistry ; Male ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; }, abstract = {Antioxidant enzyme therapy shows promise for treating Alzheimer's disease (AD), but significant challenges remain in achieving effective blood-brain barrier (BBB) penetration and sustained therapeutic effects. We developed a novel neutrophil membrane (NM)-coated cerium-doped Prussian blue biomimetic nanozyme (NM@PB-Ce) that demonstrates outstanding enzymatic properties and targeted therapeutic efficacy. Extensive physicochemical characterization using transmission electron microscopy, X-ray photoelectron spectroscopy, and dynamic light scattering confirmed the successful synthesis of uniform nanoparticles (~ 142 nm) with preserved membrane protein functionality. In vitro studies utilizing SH-SY5Y neuroblastoma cells revealed that NM@PB-Ce effectively scavenged reactive oxygen species through multiple enzyme-mimetic activities (catalase, superoxide dismutase, and peroxidase). The nanozyme significantly suppressed NLRP3 inflammasome activation and subsequent pyroptosis, reducing inflammatory markers (IL-1β, IL-18) while attenuating Aβ aggregation. Using a sophisticated co-culture BBB model and real-time in vivo fluorescence imaging, we demonstrated NM@PB-Ce's ability to traverse the BBB and accumulate specifically in AD-affected regions. In an Aβ1-42 oligomer-induced AD mouse model, systematic administration of NM@PB-Ce (320 μg/mL, 0.01 mL/g/day for 14 days) significantly improved cognitive performance across multiple behavioral paradigms, including the Morris water maze, Y-maze, and open field tests. Molecular and histological analyses revealed decreased neuroinflammation markers (GFAP, Iba-1) in the hippocampus, reduced levels of NLRP3, caspase-1, and phosphorylated tau (demonstrated by Western blot and ELISA), and enhanced dendritic spine density (visualized through Golgi staining). This comprehensive study establishes NM@PB-Ce as a promising therapeutic platform for AD treatment, providing both mechanistic insights into its mode of action and robust evidence of its therapeutic efficacy in targeting neuroinflammation and cognitive decline.}, }
@article {pmid40050853, year = {2025}, author = {Ranjan, S and Tripathi, A and Shende, H and Badal, R and Kumar, A and Yadav, P and Joshi, D and Kumar, L}, title = {Deep learning-based classification of dementia using image representation of subcortical signals.}, journal = {BMC medical informatics and decision making}, volume = {25}, number = {1}, pages = {113}, pmid = {40050853}, issn = {1472-6947}, support = {RP04502G.//IIT Mandi iHub and HCI Foundation India/ ; RP04502G.//IIT Mandi iHub and HCI Foundation India/ ; RP04502G.//IIT Mandi iHub and HCI Foundation India/ ; }, mesh = {Humans ; *Deep Learning ; *Electroencephalography/methods ; Aged ; Alzheimer Disease/diagnostic imaging/classification ; Dementia/classification/diagnostic imaging ; Frontotemporal Dementia/diagnostic imaging/classification/physiopathology ; Female ; Middle Aged ; Male ; Cognitive Dysfunction/classification/diagnostic imaging/diagnosis ; Brain/diagnostic imaging/physiopathology ; Hippocampus/diagnostic imaging/physiopathology ; Amygdala/diagnostic imaging/physiopathology ; }, abstract = {BACKGROUND: Dementia is a neurological syndrome marked by cognitive decline. Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the common forms of dementia, each with distinct progression patterns. Early and accurate diagnosis of dementia cases (AD and FTD) is crucial for effective medical care, as both conditions have similar early-symptoms. EEG, a non-invasive tool for recording brain activity, has shown potential in distinguishing AD from FTD and mild cognitive impairment (MCI).
METHODS: This study aims to develop a deep learning-based classification system for dementia by analyzing EEG derived scout time-series signals from deep brain regions, specifically the hippocampus, amygdala, and thalamus. Scout time series extracted via the standardized low-resolution brain electromagnetic tomography (sLORETA) technique are utilized. The time series is converted to image representations using continuous wavelet transform (CWT) and fed as input to deep learning models. Two high-density EEG datasets are utilized to validate the efficacy of the proposed method: the online BrainLat dataset (128 channels, comprising 16 AD, 13 FTD, and 19 healthy controls (HC)) and the in-house IITD-AIIA dataset (64 channels, including subjects with 10 AD, 9 MCI, and 8 HC). Different classification strategies and classifier combinations have been utilized for the accurate mapping of classes in both data sets.
RESULTS: The best results were achieved using a product of probabilities from classifiers for left and right subcortical regions in conjunction with the DenseNet model architecture. It yield accuracies of 94.17 % and 77.72 % on the BrainLat and IITD-AIIA datasets, respectively.
CONCLUSIONS: The results highlight that the image representation-based deep learning approach has the potential to differentiate various stages of dementia. It pave the way for more accurate and early diagnosis, which is crucial for the effective treatment and management of debilitating conditions.}, }
@article {pmid40050704, year = {2025}, author = {van Olst, L and Simonton, B and Edwards, AJ and Forsyth, AV and Boles, J and Jamshidi, P and Watson, T and Shepard, N and Krainc, T and Argue, BM and Zhang, Z and Kuruvilla, J and Camp, L and Li, M and Xu, H and Norman, JL and Cahan, J and Vassar, R and Chen, J and Castellani, RJ and Nicoll, JA and Boche, D and Gate, D}, title = {Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer's disease.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {40050704}, issn = {1546-170X}, support = {WE.06-2023-03//Alzheimer Nederland (Alzheimer Netherlands)/ ; AG078713//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30 AG072977/AG/NIA NIH HHS/United States ; NS112458//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; A2023003S//BrightFocus Foundation (BrightFocus)/ ; 23AARG-1026607/ALZ/Alzheimer's Association/United States ; }, abstract = {Alzheimer's disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. We compare actively immunized patients with AD with nonimmunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aβ removal after lecanemab treatment. We uncover spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of the triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) in microglia across immunization approaches, which correlate positively with antibody responses and Aβ removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aβ clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aβ removal and shed light on the role of microglia in immune-mediated Aβ clearance. Importantly, our work uncovers potential molecular targets that could enhance Aβ-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD.}, }
@article {pmid40050677, year = {2025}, author = {Lee, WS and Kokubo, T and Choi, Y and Hamano, T and Zaboronok, A and Ishikawa, T and Kwon, OD and Kim, E and Kim, JK}, title = {Carbon ion stimulation therapy reverses iron deposits and microglia driven neuroinflammation and induces cognitive improvement in an Alzheimer's disease mouse model.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {7938}, pmid = {40050677}, issn = {2045-2322}, support = {2013M7A1A1075764//National Research Foundation of Korea/ ; 2013M7A1A1075764//National Research Foundation of Korea/ ; 2022R1F1A1073750//National Research Foundation of Korea/ ; 2013M7A1A1075764//National Research Foundation of Korea/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/therapy/drug therapy ; *Microglia/metabolism/drug effects ; *Disease Models, Animal ; Mice ; *Iron/metabolism ; Cognition/drug effects ; Neuroinflammatory Diseases/metabolism ; Carbon ; Mice, Transgenic ; Brain/metabolism/drug effects ; }, abstract = {Insoluble iron deposits often exist as iron oxide nanoparticles in protein aggregates, impaired ferritin, or activated microglia and have been implicated as major causes of neuroinflammation in Alzheimer's disease. However, no crucial evidence has been reported to support the therapeutic effects of current iron chelators on the deposition of various molecular forms of insoluble iron. We investigated the therapeutic effect of carbon ion stimulation (CIS) via a transmission beam on insoluble iron deposits, iron inclusion bodies, and the associated biological response in 5xFAD AD mouse brains. Compared with no treatment, CIS dose-dependently induced a 33-60% reduction in the amount of ferrous-containing iron species and associated inclusion bodies in the brains of AD mice. CIS induced considerable neuroinflammation downregulation and, conversely, anti-inflammatory upregulation, which was associated with improved memory and enhanced hippocampal neurogenesis. In conclusion, our results suggest that the effective degradation of insoluble iron deposits in combination with pathogenic inclusion bodies promotes AD-modifying properties and offers a potential CIS treatment option for AD.}, }
@article {pmid40049315, year = {2025}, author = {Peng, XQ and Guo, HS and Zhang, X and Wu, XY and Ruganzu, JB and Wu, SD and Zhao, MT and Li, L and Yang, Y and Ji, SF and Yang, WN and Ren, PY}, title = {TREM2 promotes hippocampal neurogenesis through regulating microglial M2 polarization in APP/PS1 mice.}, journal = {Experimental neurology}, volume = {388}, number = {}, pages = {115205}, doi = {10.1016/j.expneurol.2025.115205}, pmid = {40049315}, issn = {1090-2430}, abstract = {Triggering receptor expressed on myeloid cells-2 (TREM2) mainly expressed on microglia in the brain, and its mutations can increase the risk of Alzheimer's disease (AD). Upregulation or activation of TREM2 has been found to ameliorate several pathological features of AD, such as the reduction of amyloid beta (Aβ) plaques and tau hyperphosphorylation. However, the effects of TREM2 on neurogenesis are little understood. Here, we aimed to investigate the effects of TREM2 on hippocampal neurogenesis associated with microglial M2 polarization in APP/PS1 mice. Lentivirus vectors were used to interfere with the expression of TREM2 on microglia in the hippocampus of APP/PS1 mice and BV2 cells. The supernatant was collected from BV2 cells as a conditioned medium (CM) to culture neural stem cells (NSCs) in vitro. Upregulation of TREM2 partially salvaged the proliferation of NSCs and the decrease of the number of immature/mature neurons in the hippocampus of APP/PS1 mice, which was accompanied by an improvement in cognitive ability. Furthermore, upregulation of TREM2 increased the M2 microglia marker CD206, brain-derived neurotrophic factor (BDNF), and anti-inflammatory factors, while decreased the M1 microglia markers CD16/32 and CD86 and pro-inflammatory factors in vivo and in vitro. Importantly, the upregulation of TREM2 also led to a significant increase in the phosphorylation of PI3K and Akt. In vitro, treatment with LY294002, a PI3K inhibitor, abolished the beneficial effects of TREM2 on shifting microglia from M1 to M2 and the proliferation and differentiation of NSCs. Taken together, these findings indicated that upregulation of TREM2 activated the PI3K/Akt signaling pathway to promote microglial M2 polarization and led to the secretion of more BDNF, accompanied by an improved hippocampal neurogenesis and spatial cognitive function in APP/PS1 mice. Thus, TREM2 might be a promising target for the treatment of neurodegenerative disease.}, }
@article {pmid40049006, year = {2025}, author = {Upadhyay, RK and Pandey, V and Parshad, RD}, title = {From multi-scale to non-local models: Comment on "Mathematical models on Alzheimer's disease and its treatment: A review" by M. Maji & S. Khajanchi.}, journal = {Physics of life reviews}, volume = {53}, number = {}, pages = {125-127}, doi = {10.1016/j.plrev.2025.02.011}, pmid = {40049006}, issn = {1873-1457}, }
@article {pmid40047916, year = {2025}, author = {Chik, MW and Meor Mohd Affandi, MMR and Mohd Nor Hazalin, NA and Surindar Singh, GK}, title = {Astaxanthin nanoemulsion improves cognitive function and synaptic integrity in Streptozotocin-induced Alzheimer's disease model.}, journal = {Metabolic brain disease}, volume = {40}, number = {3}, pages = {136}, pmid = {40047916}, issn = {1573-7365}, support = {FRGS/1/2019/SKK08/UITM/02/5//Ministry of Higher Education, Malaysia/ ; FRGS/1/2019/SKK08/UITM/02/5//Ministry of Higher Education, Malaysia/ ; FRGS/1/2019/SKK08/UITM/02/5//Ministry of Higher Education, Malaysia/ ; FRGS/1/2019/SKK08/UITM/02/5//Ministry of Higher Education, Malaysia/ ; }, mesh = {Animals ; *Xanthophylls/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; Male ; *Streptozocin ; *Cognition/drug effects ; *Emulsions ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; Synapses/drug effects/metabolism ; Rats, Wistar ; Rats, Sprague-Dawley ; Hippocampus/drug effects/metabolism ; }, abstract = {Astaxanthin derived from natural sources has excellent antioxidant and anti-inflammatory effects, and it is currently being widely researched as a neuroprotectant. However, astaxanthin possesses low oral bioavailability, and thus, astaxanthin extract from Haematococcus pluvialis was formulated into a nanoemulsion to improve its bioavailability and administered to Alzheimer's disease (AD)-like rats to study its possible neuroprotective benefits. Astaxanthin nanoemulsion was administered orally once a day for 28 days to streptozotocin (STZ)-induced AD rats at concentrations of 160, 320, and 640 mg/kg of body weight (bw) and subsequently assessed for cognitive function using behavioral assessments. Brain samples were collected for the assessment of AD biomarkers. Astaxanthin nanoemulsion at a dosage of 640 mg/kg bw significantly improved spatial learning, spatial memory, and recognition memory against STZ-AD rats. At 320 and 640 mg/kg bw, astaxanthin nanoemulsion significantly reduced levels of hippocampus synaptosomal amyloid beta and paired-helical fibrillary tau protein while increasing neuron survival. Additionally, astaxanthin nanoemulsion at 640 mg/kg bw significantly increased acetylcholine levels in the hippocampus and cerebellum. Astaxanthin nanoemulsion at all treatment dosages significantly reduced malondialdehyde, a lipid peroxidation product, and neuroinflammatory mediators (GFAP and TNF-α). Astaxanthin nanoemulsion supplementation has the potential to improve cognitive function and synaptic function by lowering amyloid beta and tau levels, as well as preserve neuron integrity by reducing neuroinflammation and lipid peroxidation, indicating that it may be able to treat some of the underlying causes of AD.}, }
@article {pmid40047827, year = {2025}, author = {Berezutsky, MA and Durnova, NA and Kurchatova, MN and Matvienko, UA}, title = {[Neurobiological potential of astragaloside IV and prospects for its use in the treatment of Alzheimer's disease].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {125}, number = {2}, pages = {7-12}, doi = {10.17116/jnevro20251250217}, pmid = {40047827}, issn = {1997-7298}, mesh = {*Triterpenes/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy ; *Saponins/pharmacology/therapeutic use ; Humans ; Animals ; Rats ; Neuroprotective Agents/therapeutic use/pharmacology ; Neurons/drug effects ; PC12 Cells ; }, abstract = {The review presents an analysis of experimental data on the study of the neurobiological effects of astragaloside IV, which can be used in the treatment of Alzheimer's disease. Astragaloside IV is a cycloartan triterpene saponin, which is found in the roots of membranous milk vetch (Astragalus membranaceus (Fisch. ex Link) Bunge) and has a very wide range of pharmacological activity. In recent years, this compound has attracted attention due to its diverse neurobiological effects. Studies have shown the ability of astragaloside IV to modulate microglial activity. The protective effect of this saponin on neurons from the effects of glutamate-induced neurotoxicity has been demonstrated. In PC12 cells, astragaloside IV is shown to be able to resolve various types of mitochondrial dysfunction and inhibit endoplasmic reticulum stress. This compound is also a PPARγ agonist. In vivo experiments have shown that the test substance effectively protects synapses as well as improves cognitive functions, including memory and learning. It is concluded that astragaloside IV, apparently, may be used in the future as a multi-purpose complex therapy for Alzheimer's disease.}, }
@article {pmid40047257, year = {2025}, author = {Fioriti, L and Wijesekara, N and Argyrousi, EK and Matsuzaki, S and Takamura, H and Satoh, K and Han, K and Yamauchi, H and Staniszewski, A and Acquarone, E and Orsini, F and Martucci, A and Katayama, T and Arancio, O and Fraser, PE}, title = {Genetic and pharmacologic enhancement of SUMO2 conjugation prevents and reverses cognitive impairment and synaptotoxicity in a preclinical model of Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e70030}, pmid = {40047257}, issn = {1552-5279}, support = {NIH-NINDS R01NS110024/NH/NIH HHS/United States ; R01 NS110024/NS/NINDS NIH HHS/United States ; 17KK0197 to S.M//Fostering Joint International Research/ ; NIH R01NS134902 to L.F/NH/NIH HHS/United States ; R01NS049442 to O.A/NH/NIH HHS/United States ; R01 NS134902/NS/NINDS NIH HHS/United States ; AARG 17-505136 to L.F/ALZ/Alzheimer's Association/United States ; //Japanese Society for the Promotion of Science/ ; PJT-173497/CAPMC/CIHR/Canada ; TR192065//Weston Brain Institute/ ; 21K06759 to S.M//Grant-in-Aid for Scientific Research/ ; //Japanese Society for the Promotion of Science (JSPS)/ ; R01 NS049442/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Disease Models, Animal ; *Mice, Transgenic ; *Cognitive Dysfunction/drug therapy ; Mice ; Humans ; *Synapses/drug effects ; Amyloid beta-Peptides/metabolism ; Brain/drug effects/metabolism ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Amyloid beta-Protein Precursor/genetics ; }, abstract = {INTRODUCTION: Amyloid beta oligomers (Aβos) are toxic to synapses and key to the progression of Alzheimer's disease (AD) and amyloid pathology, representing a target for therapeutic strategies.
METHODS: Amyloid and small ubiquitin modifier 2 (SUMO2) transgenics were analyzed by electrophysiology and behavioral testing. A recombinant analogue of SUMO2, SBT02, was generated and assessed for brain penetration and the ability to mitigate amyloid pathology.
RESULTS: Elevated SUMO2 expression prevents cognitive and synaptic impairment in a mouse model of AD amyloid pathology. Systemic administration of SBT02 resulted in high brain bioavailability and prophylactically halted the progression of AD-associated deficits. SBT02 also restored cognition and synaptic function in late-stage amyloid load. Mechanistically, SUMO2 and SBT02 do not alter amyloid processing or clearance and mitigate synaptotoxicity in the presence of high amyloid loads.
DISCUSSION: SBT02 is a promising therapeutic strategy to counteract and reverse the toxic effects of Aβos in AD.
HIGHLIGHTS: Genetic overexpression of human SUMO2 prevents the long-term potentiation (LTP) impairments and cognitive deficits in amyloid precursor protein (APP) transgenics without affecting amyloid pathology. A recombinant analogue of human SUMO2, termed SBT02, when administered systemically, displays high brain bioavailability and has no adverse effects at high doses. Prophylactic treatment of APP transgenics with SBT02 prior to the development of amyloid pathology results in the prevention of synaptic and behavioral dysfunction. SBT02 also reverses pre-existing LTP and cognitive impairments when administered to APP transgenics with advanced and severe pathology. SBT02 has no impact on amyloid pathology, indicating a mechanism of action on synaptic resistance to Aβ toxicity.}, }
@article {pmid40047116, year = {2025}, author = {Posan, E}, title = {Sweet Solutions: Unlocking the Diabetes-Dementia Connection for Better Outcomes.}, journal = {Journal of insurance medicine (New York, N.Y.)}, volume = {52}, number = {1}, pages = {14-20}, doi = {10.17849/insm-52-1-14-20.1}, pmid = {40047116}, issn = {0743-6661}, mesh = {Humans ; *Diabetes Mellitus, Type 2/epidemiology ; *Alzheimer Disease ; Risk Factors ; Dementia ; }, abstract = {Type 2 diabetes and Alzheimer's dementia represent important health challenges in our society today. Understanding the relationship between these conditions is crucial. This article explores the research on whether they share common risk factors or if they may influence each other's development, which could lead to more effective prevention and treatment strategies.}, }
@article {pmid40046779, year = {2025}, author = {Fisher, RP and Matheny, L and Ankeny, S and Qin, L and Coleman, LG and Vetreno, RP}, title = {Adolescent binge alcohol exposure accelerates Alzheimer's disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1531628}, pmid = {40046779}, issn = {1663-4365}, support = {R01 AA028924/AA/NIAAA NIH HHS/United States ; U24 AA020024/AA/NIAAA NIH HHS/United States ; U01 AA020023/AA/NIAAA NIH HHS/United States ; U01 AA028710/AA/NIAAA NIH HHS/United States ; R01 AG072894/AG/NIA NIH HHS/United States ; }, abstract = {Human studies suggest that heavy alcohol use may be an etiological factor contributing to the development of Alzheimer's disease (AD) neuropathology. Both alcohol use disorder (AUD) and AD share common underlying neuropathology, including proinflammatory high-mobility group box 1 (HMGB1)-mediated neuroimmune signaling and basal forebrain cholinergic neuron degeneration. Adolescent onset of binge drinking represents a significant risk factor for later development of an AUD, and accumulating evidence suggests that adolescent initiation of heavy alcohol use induces HMGB1 signaling and causes degeneration of the basal forebrain cholinergic system that persists into adulthood. However, it is unknown whether adolescent binge drinking confers increased risk for later development of AD-associated neuropathology through persistent induction of proinflammatory HMGB1 neuroimmune signaling. To investigate this question, we first (Experiment 1) assessed AD-associated neuropathology in the post-mortem human basal forebrain of individuals with AUD and an adolescent age of drinking onset relative to age-matched moderate drinking controls (CONs). In Experiment 2, we treated non-transgenic and 5xFAD male and female mice, which overexpress both mutant human APP and PS1, with adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g. 2-days on/2-days off; postnatal day [P]30 - P55), and assessed AD-associated neuropathology in the adult (P100) basal forebrain. In Experiment 3, 5xFAD female mice received AIE treatment followed by glycyrrhizic acid (150 mg/L), an HMGB1 inhibitor, in drinking water from P56 to P100, and basal forebrain tissue was collected on P100 for assessment of AD-associated neuropathology. In the post-mortem human AUD basal forebrain (Experiment 1), we report upregulation of Hmgb1 and the HMGB1 receptors Rage and Tlr4 as well as microglial activation and increased intraneuronal Aβ1-42 accumulation in association with reduced cholinergic neuron marker expression (ChAT). In the 5xFAD mouse model (Experiment 2), AIE accelerated AD-associated induction of Hmgb1 proinflammatory neuroimmune genes, microglial activation, and reductions of ChAT+ basal forebrain cholinergic neurons in the adult female, but not male, basal forebrain. In Experiment 3, post-AIE treatment with glycyrrhizic acid rescued the AIE-induced acceleration of AD-associated increases in proinflammatory HMGB1 neuroimmune signaling, microglial activation, and persistent reductions of basal forebrain cholinergic neurons in adult 5xFAD female mice. Together, these findings suggest that adolescent binge ethanol exposure may represent an underappreciated etiological factor contributing to onset of AD-associated neuropathology in adulthood through HMGB1- mediated neuroimmune signaling.}, }
@article {pmid40046641, year = {2025}, author = {Dratva, MA and Diaz, JM and Thomas, ML and Shen, Q and Tsiknia, AA and Rostowsky, KA and Sundermann, EE and Banks, SJ}, title = {Is late-life vulnerability to cardiovascular disease risk associated with longitudinal tau accumulation in older adults with mild cognitive impairment?.}, journal = {JAR life}, volume = {14}, number = {}, pages = {100001}, pmid = {40046641}, issn = {2534-773X}, abstract = {BACKGROUND: Older females have higher Alzheimer's Disease (AD) risk and tau burden, especially in early disease stages, compared to males. Overlapping cardiovascular disease (CVD) and dementia risk factors, like the apolipoprotein (APOE)-ε4 allele, show mixed sex-specific results. We previously found that late-life CVD risk related more strongly to tau at a single timepoint in cognitively normal, older female APOE-ε4 carriers than in males.
OBJECTIVES: Do composite and component CVD risk factors explain sex differences in tau accumulation in older adults with mild cognitive impairment (MCI) and underlying amyloid-beta (Aβ) pathology?
DESIGN: Longitudinal analysis in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.
SETTING: ADNI is a multi-site longitudinal study across the United States and Canada.
PARTICIPANTS: n = 52 older adults (aged 60-90), designated as both Aβ-positive and MCI.
MEASUREMENTS: CVD risk was measured by body mass index (BMI) and FRS, which includes age, systolic blood pressure (BP), high-density lipoprotein (HDL), total cholesterol, hypertension treatment, smoking, and diabetes. Regional standardized uptake value ratios (SUVRs) were extracted at each tau-PET timepoint. Composite SUVRs for Braak34 and Braak56 were calculated. Statistical models examined the separate and interactive effects of sex and APOE-ε4 on tau accumulation, and moderating effects of FRS, its components, or BMI, on tau accumulation.
RESULTS: Females accumulated more tau than males in bilateral Braak34 and right Braak56, while APOE-ε4 carriers trended toward more tau accumulation in left Braak56. FRS and its components did not relate to tau accumulation, nor influence sex effects, although they attenuated APOE-ε4 effects. In left Braak56, higher baseline BMI in males showed a trend toward greater tau accumulation.
CONCLUSIONS: In MCI and Aβ-positive older adults, females accumulated more tau than males, and late-life vascular risk did not explain this relationship. Higher BMI related to more tau accumulation in males only, suggesting sex-specific vulnerability to BMI on brain health. Although replication in larger and more representative cohorts is needed, these findings corroborate accelerated tau progression in older females, independent of CVD risk, and suggest that vascular health has limited influence on tau progression once AD pathology is established in the brain.}, }
@article {pmid40046438, year = {2025}, author = {Lin, K and Lin, W and Guo, Z and Chen, C and Chen, L and Cai, X}, title = {Plasma exosomal miRNA expression and gut microbiota dysbiosis are associated with cognitive impairment in Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1545690}, pmid = {40046438}, issn = {1662-4548}, abstract = {INTRODUCTION: The gut microbiota composition and the expression profiles of microRNAs (miRNAs) in the brain tissue, cerebrospinal fluid, and blood of patients with Alzheimer's disease (AD) differ significantly from those with normal cognition function. The study aimed to initially explore the relationship between plasma exosomal microRNAs, gut microbiota, and cognitive impairment, providing insights into the pathogenesis and treatment of AD.
METHODS: The study enrolled 8 participants with AD and 8 participants with normal cognition. The Mini-Mental State Examination (MMSE) was utilized to evaluate cognitive function. High-throughput sequencing was used to identify differentially expressed miRNAs in plasma exosomes, while metagenomic sequencing was employed to detect differences in the abundance of gut microbiota. Furthermore, the associations among them were analyzed.
RESULTS: Four exosomal miRNAs and 14 microbiota taxa, which exhibited differential expression and abundance, respectively, in comparison between AD group and normal cognition group, were identified to be significantly associated with MMSE scores. Notably, the abundance of potential probiotics, including Faecalibacterium prausnitzii, Roseburia intestinalis and Roseburia inulinivorans, which was decreased in AD patients, exhibited positive correlations with specific exosomal miRNAs: Roseburia intestinalis correlated with miR-3120-3p and miR-6529-5p; Roseburia inulinivorans correlated with miR-3120-3p, miR-6529-5p and miR-124-3p; Faecalibacterium prausnitzii correlated with miR-3120-3p.
DISCUSSION: The study revealed a close association among gut microbiota, plasma exosomal miRNAs, and cognitive impairment in AD, and suggested that specific components of gut microbiota and exosomal miRNAs may serve as potential biomarkers and therapeutic targets for AD on the microbiota-gut-brain axis.}, }
@article {pmid40046339, year = {2025}, author = {Assogna, M and Di Lorenzo, F and Bonnì, S and Borghi, I and Cerulli Irelli, E and Mencarelli, L and Maiella, M and Minei, M and Esposito, R and Casula, EP and Pezzopane, V and D'Acunto, A and Porrazzini, F and Candeo, F and Ferraresi, M and Motta, C and Ferrari, C and Caltagirone, C and Martorana, A and Koch, G}, title = {Phase 2 study of palmitoylethanolamide combined with luteoline in frontotemporal dementia patients.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf080}, pmid = {40046339}, issn = {2632-1297}, abstract = {Frontotemporal dementia is a devastating neurodegenerative disorder for which no pharmacological treatments have been approved. Neuroinflammation plays a central role in driving the pathogenic mechanisms underlying frontotemporal dementia. In the last few years, co-ultramicronized palmitoylethanolamide combined with luteoline has emerged as a potential therapeutic molecule in neurodegenerative disorders pathogenically related to frontotemporal dementia, for its demonstrated strong anti-inflammatory and neuroprotective properties. Here we wanted to determine whether treatment with co-ultramicronized palmitoylethanolamide combined with luteoline may have a clinical impact in frontotemporal dementia patients. We performed a Phase 2, monocentric, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of co-ultramicronized palmitoylethanolamide combined with luteoline in frontotemporal dementia patients. Forty eight patients with a diagnosis of probable frontotemporal dementia were randomly assign in a 1:1 ratio to receive co-ultramicronized palmitoylethanolamide combined with luteoline oral suspension at the dosage of 700 mg + 70 mg twice/day (n = 25) or placebo twice/day (n = 23) for 24 weeks. The primary efficacy outcome measure was the change at 24-weeks in the Clinical Dementia Rating Dementia Staging Instrument from the National Alzheimer's Coordinating Center and frontotemporal lobar degeneration modules-sum of boxes (CDR plus NACC FTLD-SoB). Secondary outcome measures included the Frontal Assessment Battery, Screening for Aphasia in Neurodegeneration, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Neuropsychiatric Inventory, Mini-Mental State Examination and Addenbrooke's Cognitive Examination Revised. Among 48 patients randomized [mean (SD) age 63.2 (8.4), 23 (47.9%) female], 45 (93%) completed the study. Patients in the co-ultramicronized palmitoylethanolamide combined with luteoline group showed less decline for the primary outcome measure (CDR plus NACC FTLD) as compared with patients treated with placebo. The estimated mean change (W0-W24) in CDR plus NACC FTLD score was 0.53 for the co-ultramicronized palmitoylethanolamide combined with luteoline group [95% confidence interval (0.12-0.94)] and 1.39 for the placebo group [95% confidence interval (0.96-1.82)], with an estimated mean difference between of 0.86 [95% confidence interval (0.28-1.45), P = 0.005]. Estimated mean change in Alzheimer's Disease Cooperative Study-Activities of Daily Living score was -1.8 for co-ultramicronized palmitoylethanolamide combined with luteoline (95% confidence interval, -3.67 to 0.06) and -7.39 for placebo (95% confidence interval -9.34 to -5.45). Estimated mean change in screening for Aphasia in neurodegeneration scores was -3.987 for co-ultramicronized palmitoylethanolamide combined with luteoline (95% confidence interval, -7.75 to -0.22) and -10.35 for placebo (95% confidence interval, -14.33 to -6.37). No effect of treatment was found on other secondary outcome measures. Our results demonstrate that co-ultramicronized palmitoylethanolamide combined with luteoline shows promising efficacy in slowing down the progression of cognitive and functional symptoms in frontotemporal dementia patients. These findings warrant further investigation and offer potential for the development of effective therapeutic strategies for frontotemporal dementia.}, }
@article {pmid40045806, year = {2025}, author = {Schmidt, E and Krauss, JK}, title = {Treatment of iNPH: novel insights.}, journal = {Journal of neurosurgical sciences}, volume = {69}, number = {1}, pages = {79-91}, doi = {10.23736/S0390-5616.24.06360-4}, pmid = {40045806}, issn = {1827-1855}, mesh = {Humans ; *Hydrocephalus, Normal Pressure/diagnosis/surgery/therapy/physiopathology ; Cerebrospinal Fluid Shunts/methods ; }, abstract = {This review advocates for a shift from traditional symptom-based diagnosis of idiopathic normal pressure hydrocephalus (iNPH) to a deeper investigation into its underlying pathophysiological mechanisms, particularly the role of altered cerebral hydrodynamics as an important pathological hallmark. We explore the heterogeneity of iNPH, emphasizing its frequent overlap and cooccurrence with neurodegenerative conditions like Alzheimer and Parkinson disease, and subcortical vascular encephalopathy, complicating diagnosis and treatment strategies. The lumbar infusion test emerges as a useful diagnostic tool, offering quantitative insights into CSF outflow resistance that should be considered as a useful biomarker related to cerebral hydrodynamics and iNPH pathophysiology. Furthermore, we propose the hypothesis that shunt placement, by regulating brain fluid mechanics, may also serve as a form of neuromodulation, potentially enhancing neuronal function and mitigating clinical symptoms. This review advocates for an interdisciplinary, physics-based and patient-centered approach that emphasizes early detection, accurate diagnostics, and personalized treatment plans to enhance patient outcomes and quality of life, particularly in the aging population.}, }
@article {pmid40044513, year = {2025}, author = {Delbecque, L and Elliott, E and Cleanthous, S and Heinrich, P and Cano, S and Wessels, AM and Atkins, AS}, title = {Qualitative research and literature review support the integrated Alzheimer's Disease Rating Scale (iADRS) content validity in early symptomatic AD.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {4}, pages = {100101}, doi = {10.1016/j.tjpad.2025.100101}, pmid = {40044513}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis ; *Qualitative Research ; *Activities of Daily Living ; Female ; Aged ; Cognitive Dysfunction/diagnosis/psychology ; Male ; Reproducibility of Results ; Severity of Illness Index ; Neuropsychological Tests ; Caregivers/psychology ; }, abstract = {BACKGROUND AND OBJECTIVES: The integrated Alzheimer's Disease Rating Scale (iADRS) is a measure of cognition and daily function used to evaluate treatment effects in Alzheimer's disease (AD) clinical trials. This study aimed to assess the content validity of the iADRS in early symptomatic AD, and to determine whether integrating assessment of cognition and function into a single measure of global disease severity is supported by the patients' experience.
METHODS: A targeted literature review of qualitative research in AD and qualitative interviews with 25 care partners of individuals with early symptomatic AD were conducted. Interviews started with open-ended concept elicitation exploring the patient experience of AD from the care partner perspective, including how cognitive changes affect daily functioning. This was followed by cognitive debriefing of the ADCS-iADL items. Interview transcripts were analyzed thematically. Concepts extracted from the literature review and interviews were categorized into a conceptual model of patient experience of AD. A concept-to-item mapping exercise was conducted to assess the conceptual coverage of the iADRS.
RESULTS: The literature review comprised sixty articles. Interviews were conducted with care partners of 7 individuals with Mild Cognitive Impairment (MCI)-AD and care partners of 18 individuals with dementia due to AD. The resulting conceptual model incorporated 75 concepts related to AD experience categorized into three overarching domains: Cognition, Daily Function and Other Symptoms/Impacts. Interview findings endorsed the close link between cognition and daily function. Concept-to-item mapping demonstrated all Cognition and Daily function sub-domains within the model were assessed by at least one iADRS item, except Work/Professional, providing supportive evidence that the iADRS covers concepts that reflect the patient experience of early symptomatic AD.
CONCLUSIONS: This study offers a comprehensive conceptualisation of the patient experience of early symptomatic AD and highlights the intrinsic connection between cognition and daily function. The findings endorse the relevance of an integrated assessment of cognition and function and provide strong evidence for the content validity of the iADRS, highlighting its utility as a meaningful clinical outcome assessment (COA) for use as an endpoint in AD.}, }
@article {pmid40044002, year = {2025}, author = {Yang, S and Wang, L and Liang, X and Pei, T and Zeng, Y and Xie, B and Wang, Y and Yang, M and Wei, D and Cheng, W}, title = {Radix Hedysari Polysaccharides modulate the gut-brain axis and improve cognitive impairment in SAMP8 mice.}, journal = {International journal of biological macromolecules}, volume = {306}, number = {Pt 4}, pages = {141715}, doi = {10.1016/j.ijbiomac.2025.141715}, pmid = {40044002}, issn = {1879-0003}, abstract = {OBJECTIVE: Radix Hedysari Polysaccharides (RHP) are the principal bioactive constituents of the traditional Chinese medicinal herb Radix Hedysari. This study aims to evaluate the neuroprotective effects of RHP in both cellular and animal models of Alzheimer's disease (AD) and to elucidate the underlying molecular mechanisms.
METHODS: HT22 cells subjected to Aβ25-35-induced cytotoxicity were pretreated with RHP, followed by assessments of reactive oxygen species (ROS) generation, mitochondrial superoxide (mSOX) levels, and mitochondrial membrane potential (ΔΨm). Senescence-accelerated mouse-prone 8 (SAMP8) mice were orally administered RHP for 12 weeks. Behavioral assays were conducted to assess cognitive function, while metabolomic and proteomic analyses were performed to examine serum metabolic alterations and hippocampal protein expression profiles. Additionally, neuronal autophagy and gut barrier integrity were evaluated using immunohistochemistry, transmission electron microscopy, and biomarker quantification.
RESULTS: RHP treatment significantly attenuated Aβ25-35-induced oxidative stress in HT22 cells by reducing ROS and mSOX production while preserving ΔΨm. In SAMP8 mice, RHP improved cognitive performance, preserved hippocampal mitochondrial ultrastructure, and enhanced neuronal autophagic activity. Moreover, RHP modulated serum metabolic pathways and alleviated gut barrier dysfunction, suggesting a role in gut-brain axis regulation.
CONCLUSION: RHP ameliorates cognitive impairment in SAMP8 mice, potentially through its modulation of systemic metabolism, mitigation of neuronal mitochondrial damage, and restoration of gut barrier integrity. These findings highlight the therapeutic potential of RHP in AD intervention and warrant further investigation into its mechanistic underpinnings.}, }
@article {pmid40043915, year = {2025}, author = {Chen, Y and Yang, X and Li, J and Luo, H and Huang, Q and Yang, W and Lei, T and Lui, S and Gong, Q and Li, H and Wu, H and Gao, H}, title = {A nasally administrated reactive oxygen species-responsive carrier-free gene delivery nanosystem for Alzheimer's disease combination therapy.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {381}, number = {}, pages = {113604}, doi = {10.1016/j.jconrel.2025.113604}, pmid = {40043915}, issn = {1873-4995}, abstract = {Combination therapies targeting multiple pathways are needed in order to improve treatment outcomes in Alzheimer's disease (AD) due to its complex pathogenesis. Amyloid-β and microglia-mediated neuroinflammation significantly contribute to AD pathogenesis. Amyloid-β-related nucleic acid drugs have demonstrated considerable potential in AD treatment; however, their clinical translation is limited by complex synthesis processes and carrier toxicity. Herein, an intranasally administrated, reactive oxygen species (ROS)-responsive, carrier-free gene delivery nanosystem (FTBR-NAC) was constructed for re-polarizing microglia and decreasing amyloid-β expression. In this nanosystem, fingolimod was conjugated with biguanide via an ROS-responsive linker to form the carrier for β-secretase 1 siRNA (siBACE1) to form FTBR nanoparticles. The electropositivity of FTBR and mucolytic activity of N-acetylcysteine (NAC) together enhanced the brain entry of FTBR. Upon reaching the brain, FTBR responded to the elevated ROS at the pathological site, releasing siBACE1 and fingolimod. Administration of FTBR-NAC improved cognitive function in AD mice, demonstrating the high therapeutic efficacy of this relatively simple nanosystem.}, }
@article {pmid40043855, year = {2025}, author = {Al-Kuraishy, HM and Sulaiman, GM and Mohammed, HA and Al-Gareeb, AI and Albuhadily, AK and Mohammed, SG}, title = {Role of RhoA-ROCK signaling inhibitor fasudil in Alzheimer disease.}, journal = {Behavioural brain research}, volume = {484}, number = {}, pages = {115524}, doi = {10.1016/j.bbr.2025.115524}, pmid = {40043855}, issn = {1872-7549}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/pharmacology ; Humans ; *rho-Associated Kinases/metabolism/antagonists & inhibitors ; *Signal Transduction/drug effects/physiology ; Animals ; *rhoA GTP-Binding Protein/metabolism/antagonists & inhibitors ; Protein Kinase Inhibitors/pharmacology ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer disease (AD) is the most common neurodegenerative brain disease linked with the development of dementia. AD neuropathology is characterized by the progressive accumulation of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Different signaling pathways are involved in AD neuropathology through modulation of Aβ formation and tau protein hyperphosphorylation. One of these signaling is Rho-associated protein kinase (ROCK). RhoA-ROCK signaling boosts the production of Aβ through activation of β-secretase and augments the formation of NFTs. RhoA-ROCK signaling is also intricate in the development of oxidative stress and neuroinflammation. Consequently, targeting RhoA-ROCK signaling by specific inhibitors, such as fasudil, may decrease AD neuropathology. Therefore, this perspective aims to discuss the role of RhoA-ROCK signaling in the pathogenesis of AD and how fasudil could be effective in its treatment.}, }
@article {pmid40043785, year = {2025}, author = {Zheng, C and Zhao, Y and Hu, C and Zhang, L and Li, G and Yang, C}, title = {Transcriptomic and network analysis identifies shared pathways across Alzheimer's disease and vascular dementia.}, journal = {Brain research}, volume = {1854}, number = {}, pages = {149548}, doi = {10.1016/j.brainres.2025.149548}, pmid = {40043785}, issn = {1872-6240}, mesh = {*Alzheimer Disease/metabolism/genetics ; *Dementia, Vascular/genetics/metabolism ; Humans ; Animals ; *Transcriptome ; Mice ; Gene Expression Profiling/methods ; Protein Interaction Maps ; Gene Regulatory Networks ; Signal Transduction/physiology ; }, abstract = {Alzheimer's disease (AD) and vascular dementia (VaD) are often accompanied, but there are no effective differential diagnosis and treatment for VaD. The search for common pathogenic targets or pathways connecting the two diseases is helpful to the drug development and treatment of the disease. In this study, we used gene expression array data from the GEO database to analyze common differentially expressed genes (DEGs) in the temporal cortex of patients with AD and VaD. AD and VaD shared 143 DEGs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that the biological function of common DEGs was mainly related to chemical synaptic transmission, neuroactive ligand-receptor, and cytokine-cytokine receptor interaction pathway. The protein-protein interaction (PPI) analysis showed the interaction of down- and up-regulated DEGs. The mRNA expression levels of key proteins in neuroactive ligand-receptor and cytokine-cytokine receptor interaction pathway were verified in AD and VaD mice. The real-time quantitative polymerase chain reaction (RT-qPCR) test was used to detect the expression of DEGs. Data of RT-qPCR showed the mRNA level of γ-aminobutyric acid type B receptor subunit 1 (GABBR1) was decreased in both AD and VaD. In addition, the mRNA of interleukin-17 receptor A (IL-17RA), IL-17 and IL-18 were increased. In conclusion, the shared genes in AD and VaD were verified in our study. We identified the critical genes to offer a theoretical basis for understanding the linkage of AD and VaD, which provided potential drug targets against AD and VaD.}, }
@article {pmid40043618, year = {2025}, author = {Jannesar, K and Soraya, H}, title = {MPO and its role in cancer, cardiovascular and neurological disorders: An update.}, journal = {Biochemical and biophysical research communications}, volume = {755}, number = {}, pages = {151578}, doi = {10.1016/j.bbrc.2025.151578}, pmid = {40043618}, issn = {1090-2104}, mesh = {Humans ; *Peroxidase/metabolism ; *Neoplasms/metabolism/pathology/enzymology ; *Cardiovascular Diseases/metabolism/pathology/enzymology ; *Nervous System Diseases/metabolism/enzymology/pathology ; Animals ; }, abstract = {Myeloperoxidase (MPO) is an enzyme that contains a heme group, found mostly in neutrophils and in small amounts in monocytes and plays a major role in their anti-microbial activity. However, excessive levels of MPO have been linked to various disorders and identified as a major cause of tissue destruction. Inhibiting its activity can reduce the severity and extent of tissue damage. Over activity of MPO during chronic inflammation has been shown to be involved in tumorigenesis by inducing a hyper-mutagenic environment through oxidant interaction with DNA, causing DNA modification. Vascular endothelium is one of the most important targets of MPO and high levels have been associated with increased rates of cardiomyopathy, ischemic stroke, heart failure, myocardial infarction, and atrial fibrillation. Therefore, it may be considered a therapeutic target in the treatment of cardiovascular disorders. MPO also participates in the pathogenesis of neurodegenerative diseases. For example, an increase in MPO levels has been observed in the brain tissue of patients with Alzheimer's, Multiple sclerosis (MS), and Parkinson's diseases. In Alzheimer's disease, active MPO is mostly found in the location of beta amyloids and microglia. Therefore, targeting MPO may be a potential treatment and prevention strategy for neurological disorders. This review will discuss MPO's physiological and pathological role in cancer, cardiovascular, and neurological disorders.}, }
@article {pmid40043372, year = {2025}, author = {M, M and Sabavath, BTN and Gaddam, V and Paul, D}, title = {Transformative potentials, challenges and innovative solutions of lipidomics in multiple clinical applications.}, journal = {Talanta}, volume = {291}, number = {}, pages = {127855}, doi = {10.1016/j.talanta.2025.127855}, pmid = {40043372}, issn = {1873-3573}, mesh = {Humans ; *Lipidomics/methods ; *Biomarkers/analysis ; Mass Spectrometry/methods ; Lipids/analysis/chemistry ; Cardiovascular Diseases/diagnosis/metabolism ; Neoplasms/metabolism ; Neurodegenerative Diseases/metabolism/diagnosis ; Animals ; }, abstract = {Lipidomics, a rapidly evolving field within metabolomics, provides comprehensive insights into lipid profiles and their roles in health and disease. Advances in lipidomics have enabled the discovery of novel biomarkers with significant clinical applications, revolutionizing the diagnosis, prognosis, and therapeutic monitoring of various diseases. Emerging methodologies, including high-resolution mass spectrometry (HRMS), Ion mobility spectrometry (IMS), and Supercritical Fluid Chromatography (SFC) have enhanced lipid identification and quantification with remarkable analytical whip hands. These advancements are complemented by innovative sample preparation techniques ensuring the recovery of diverse lipid species with minimal degradation. Biomarker discovery with lipidomics has illuminated critical pathways in numerous diseases, including cardiovascular disorders, neurodegenerative conditions, metabolic syndromes, and cancers. Specific lipid classes, such as sphingolipids (SLs) and phospholipids (PLs) have been linked to Alzheimer's disease and diabetes, respectively, while oxylipins and eicosanoids are emerging as inflammatory biomarkers. Furthermore, lipidomic profiles have shown promise in personalized medicine, enabling the stratification of patient sub-populations and tailoring treatment strategies. This review emphasizes the latest innovative developments in analytical technologies, advanced sample preparation techniques and challenges for lipidomics research including bioinformatic tools on multiple clinical conditions. By exploring these cutting-edge developments, this review highlights the transformative potential of lipidomics in biomarker discovery across diverse clinical applications.}, }
@article {pmid40043125, year = {2025}, author = {Coughlan, GT and Rubinstein, Z and Klinger, H and Lopez, KA and Hsieh, S and Boyle, R and Seto, M and Townsend, D and Mayblyum, D and Thibault, E and Jacobs, HIL and Farrell, M and Rabin, JS and Papp, K and Amariglio, R and Baker, S and Lois, C and Rentz, D and Price, J and Schultz, A and Properzi, M and Johnson, K and Sperling, R and Buckley, RF}, title = {Associations between hormone therapy use and tau accumulation in brain regions vulnerable to Alzheimer's disease.}, journal = {Science advances}, volume = {11}, number = {10}, pages = {eadt1288}, pmid = {40043125}, issn = {2375-2548}, support = {DP2 AG082342/AG/NIA NIH HHS/United States ; K99 AG083063/AG/NIA NIH HHS/United States ; P01 AG036694/AG/NIA NIH HHS/United States ; R01 AG079142/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/etiology ; *tau Proteins/metabolism ; Female ; Middle Aged ; Aged ; Aged, 80 and over ; *Brain/metabolism/drug effects/diagnostic imaging ; *Amyloid beta-Peptides/metabolism ; *Positron-Emission Tomography ; Estrogen Replacement Therapy ; Hormone Replacement Therapy ; Menopause/metabolism ; }, abstract = {Elucidating the downstream impact of exogenous hormones on the aging brain will have far-reaching consequences for understanding why Alzheimer's disease (AD) predominates in women almost twofold over men. We tested the extent to which menopausal hormone therapy (HT) use is associated with later-life amyloid-β (Aβ) and tau accumulation using PET on N = 146 baseline clinically normal women, aged 51 to 89 years. Women were scanned over a 4.5-year (SD, 2.1; range, 1.3 to 10.4) and 3.5-year (SD, 1.5; range, 1.2 to 8.1) period for Aβ and tau, respectively, ~14 years after the initiation of HT. In older women (aged >70 years), HT users exhibited faster regional tau accumulation relative to non-users, localized to the entorhinal cortex and the inferior temporal and fusiform gyri, with an indirect effect of HT on cognitive decline through regional tau accumulation. In younger women (aged <70 years), HT associations with tau accumulation were negligible. Findings are relevant for optimizing menopausal treatment guidelines.}, }
@article {pmid40042687, year = {2025}, author = {Mashhadi-Sharif, N and Soodi, M and Mirnajafi-Zadeh, J and Shadboorestan, A and Ebadi-Ramsheh, H and Bakhtiarzadeh, F}, title = {Ferulago angulata Extract Protects against Beta-amyloid-induced Memory Impairment Through Modulation of Monoaminoxidase Enzymes in the Rat's Hippocampus.}, journal = {Neurochemical research}, volume = {50}, number = {2}, pages = {114}, pmid = {40042687}, issn = {1573-6903}, mesh = {Animals ; Male ; *Amyloid beta-Peptides/toxicity/metabolism ; *Rats, Wistar ; *Plant Extracts/pharmacology/therapeutic use ; *Memory Disorders/drug therapy/prevention & control/chemically induced ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Hippocampus/drug effects/metabolism ; Rats ; *Apiaceae/chemistry ; *Peptide Fragments/toxicity ; Monoamine Oxidase/metabolism ; Acetylcholinesterase/metabolism ; Maze Learning/drug effects ; }, abstract = {Ferulago angulata, a medicinal plant of the Apiaceae family, is known for its antioxidative, anti-inflammatory, anti-apoptotic, and neuroprotective effects. This study investigated the protective potential of F. angulata total extract against memory impairment induced by amyloid β-peptide (Aβ25-35) in rats. Aβ25-35 was bilaterally administered into the CA1 region of the hippocampus in male Wistar rats for four consecutive days. Starting from the first surgery day, rats received oral treatment with F. angulata extract (400 mg/kg) or Rivastigmine (1.5 mg/kg) for 16 consecutive days. Morris water maze tests conducted from days 14 to 17 evaluated the learning and memory performance, followed by biochemical and molecular assays on isolated hippocampi. F. angulata extract significantly reversed Aβ-induced deficits in learning and memory. In the Aβ group, monoamine oxidase A and B enzyme activities and gene expression increased, along with elevated acetylcholinesterase gene expression but decreased enzyme activity compared to the control group. Treatment with F. angulata extract mitigated all these abnormalities. Safety assessments revealed no alterations in blood biochemistry or histology following F. angulata extract treatment. In conclusion, our findings suggest that F. angulata extract possesses neuroprotective properties, and ameliorates Aβ-induced memory deficits by modulating monoamine oxidase enzyme activity and acetylcholinesterase levels without significant adverse effects. Thus, this safe herbal extract shows promise for further exploration in Alzheimer's disease research and potential therapeutic interventions.}, }
@article {pmid40042516, year = {2025}, author = {Dohl, J and Treadwell, Z and Norris, C and Head, E}, title = {Calcineurin inhibition may prevent Alzheimer disease in people with Down syndrome.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e70034}, pmid = {40042516}, issn = {1552-5279}, support = {DGE-1839285//NSF Graduate Research Fellowship/ ; U19 AG068054/AG/NIA NIH HHS/United States ; RF1AG056998//NIH National Institute on Aging/ ; U19AG068054//NIH National Institute on Aging/ ; RF1 AG056998/AG/NIA NIH HHS/United States ; }, mesh = {*Down Syndrome/complications/drug therapy ; Humans ; *Alzheimer Disease/drug therapy ; *Calcineurin Inhibitors/therapeutic use ; *Calcineurin/metabolism ; Tacrolimus/therapeutic use/pharmacology ; DNA-Binding Proteins ; Muscle Proteins ; }, abstract = {Virtually all people with Down syndrome will develop Alzheimer disease pathology during their lifetime. As Alzheimer disease is the third leading cause of death and a significant factor in end-of-life complications for adults with Down syndrome, identifying interventions is a medical necessity. Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, has recently been investigated as a possible Alzheimer treatment. This review explores the histories behind Down syndrome and Alzheimer disease, and their intersecting pathologies. This is followed by the role that calcineurin and its U.S. Food and Drug Administration-approved pharmacological inhibitor, tacrolimus, may play in the prevention or treatment of Alzheimer disease. Finally, this review discusses the gap in the literature surrounding the role of calcineurin, its regulators, and calcineurin inhibitors in the context of Down syndrome and comorbid Alzheimer disease. Future studies investigating the role that calcineurin plays in this pathology will be essential in determining the viability of calcineurin inhibitors to treat Alzheimer disease in people with Down syndrome. HIGHLIGHTS: Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, has become prominent as a possible therapeutic target to treat Alzheimer disease. People with Down syndrome develop Alzheimer pathology as they age, requiring novel therapeutics for treatment. People with Down syndrome may exhibit contraindications to calcineurin inhibition-based therapy, as they overexpress RCAN1 and DYRK1A, regulators of calcineurin. There is a significant gap in the literature involving the expression of calcineurin, RCAN1 and DYRK1A, in people with Down syndrome and Alzheimer disease, which must be addressed to determine the efficacy and safety of newly developed therapeutics.}, }
@article {pmid40042515, year = {2025}, author = {Ono, D and Sekiya, H and Maier, AR and Murray, ME and Koga, S and Dickson, DW}, title = {Parkinsonism in Alzheimer's disease without Lewy bodies in association with nigral neuron loss: A data-driven clinicopathologic study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e14628}, pmid = {40042515}, issn = {1552-5279}, support = {//Japan Society for the Promotion of Science Overseas Research Fellowships/ ; 24A08//State of Florida Ed and Ethel Moore Alzheimer 's Disease Research Program/ ; }, mesh = {Humans ; *Alzheimer Disease/pathology ; Female ; Male ; *Substantia Nigra/pathology ; Aged ; *Neurons/pathology ; Aged, 80 and over ; *Lewy Bodies/pathology ; *DNA-Binding Proteins/metabolism ; Parkinsonian Disorders/pathology ; tau Proteins/metabolism ; }, abstract = {INTRODUCTION: Parkinsonism in patients with Alzheimer's disease (AD) is often attributed to Lewy-related pathology, given its high comorbidity. In the era of anti-amyloid therapy, recognizing parkinsonism caused by AD pathology is needed to optimize the treatment.
METHODS: This study aimed to quantitatively characterize parkinsonism and nigral neuropathology in AD without Lewy bodies (LB). Nigral neurons were counted automatically. Fine-tuned ChatGPT collected structured clinical data.
RESULTS: Among 635 AD patients without LB, 62 (9.7%) presented parkinsonism, which correlated with reduced nigral neuron density (p < 0.01). Tau burden did not explain the nigral neuronal loss. TAR DNA-binding protein 43 (TDP-43) pathology correlated with reduced nigral pigmented neuron density (p = 0.03).
DISCUSSION: Our findings suggest that parkinsonism in AD without LB is related to nigral neuronal loss in association with TDP-43 pathology. Recognition of parkinsonism in AD without LB is crucial for appropriate therapy.
HIGHLIGHTS: One in 10 Alzheimer's disease (AD) patients without Lewy bodies had parkinsonism. Parkinsonism in AD was correlated with reduced nigral neuron density. TAR DNA-binding protein 43 pathology was associated with nigral degeneration in AD. AD should be included in the differential diagnosis of dementia with parkinsonism.}, }
@article {pmid40042496, year = {2025}, author = {Devanarayan, V and Ye, Y and Zhu, L and Tian, L and Kramer, L and Irizarry, M and Dhadda, S}, title = {Predicted natural progression as an Alzheimer's prognostic covariate improves the precision of lecanemab efficacy assessments and clinical trial efficiency.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e70045}, pmid = {40042496}, issn = {1552-5279}, support = {//Eisai Inc/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Disease Progression ; Prognosis ; Magnetic Resonance Imaging ; Female ; Male ; Aged ; Antibodies, Monoclonal, Humanized/therapeutic use ; Cognitive Dysfunction/drug therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Heterogeneity in Alzheimer's disease (AD) progression introduces variability in treatment effect assessments. Using predicted future progression as an AD prognostic covariate (APC) may reduce this variability. This study evaluates this strategy in lecanemab trials and its implications for AD trial design.
METHODS: Two APCs were derived at baseline for each trial participant from published models with historical controls: one with clinical features, the other adding structural MRI features. Their impact on estimating the difference in cognitive decline between the treatment and placebo arms and the time saved from delayed progression (TSDP) was assessed.
RESULTS: Incorporating either APC reduced variance estimates by up to 19.1% across phase II and phase III trials, increased power to 90.2%, and reduced sample size by 27.2%. These APCs improved treatment effect estimates and TSDP, demonstrating broad applicability across endpoints.
DISCUSSION: APCs enhance treatment effect evaluation, improve statistical power, and reduce required sample sizes in Alzheimer's trials.
GOV IDENTIFIERS: NCT01767311 (Lecanemab Study 201), NCT03887455 (Lecanemab Study 301; ClarityAD).
HIGHLIGHTS: Baseline prediction of future progression can serve as an APC for treatment effect assessments. These predictions can be derived from progression models developed using external controls. APC accounts for heterogeneity in progression among trial participants, improving treatment effect estimates. Enhanced accuracy and precision were observed across lecanemab phase II and phase III trials for various endpoints. This approach results in substantial increase in statistical power and reduced sample size for future AD trials.}, }
@article {pmid40042495, year = {2025}, author = {Mattke, S and Yue, S and Becker, A and Liu, Y}, title = {Demographic and clinical characteristics of initial patients receiving amyloid-targeting treatments in the United States after regulatory approval.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e70054}, pmid = {40042495}, issn = {1552-5279}, support = {R01AG083189//National Institute on Aging of the National Institutes of Health/ ; R01AG083189/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; United States ; Male ; *Alzheimer Disease ; Female ; Aged ; *Medicare/statistics & numerical data ; Aged, 80 and over ; Demography ; }, abstract = {INTRODUCTION: Three treatments for Alzheimer's disease have been approved in the United States. Data are lacking on the characteristics of the initial treatment recipients.
METHODS: We identified treatment recipients in the full Medicare fee-for-service data for 2021 to 2023. We compared their age, sex, race/ethnicity, dual eligibility, comorbidities, and median household income and educational attainment in their residence's ZIP Code Tabulation Area (ZCTA) to those of the overall Medicare population aged 65+.
RESULTS: Treated patients were more likely to be non-Hispanic White (89% vs 82%) and less likely to be dually eligible (1% vs 8.8%). Average median household income ($97,136 vs $84,449) and proportion of residents with at least a bachelor's degree (41% vs 31%) were higher in treated patients' ZCTAs.
DISCUSSION: The first patients receiving amyloid-targeting treatment represent a more privileged subset. While needing to be confirmed with more data, these results point to the need for efforts to make access more equitable.
HIGHLIGHTS: Little is known about the initial 924 patients receiving amyloid-targeting treatments in the United States from 2021 to 2023. They were more likely to be White and less likely to be dually eligible than the Medicare population. They resided in wealthier and more highly educated areas. Comorbidity burden was similar to that observed in clinical trials. Those initial results point to the need to improve equitable access to treatment.}, }
@article {pmid40042065, year = {2025}, author = {Yin, M and Peng, J and Chen, M and Zhan, Q and Zhong, H}, title = {Rosa Roxburghii Tratt Polysaccharides Prevent Alzheimer's Disease-Like Cognitive Dysfunctions and Pathology in Rats by Regulating the Microbiota-Gut-Brain Axis and Oxidative Stress.}, journal = {Journal of medicinal food}, volume = {28}, number = {3}, pages = {232-242}, doi = {10.1089/jmf.2024.k.0160}, pmid = {40042065}, issn = {1557-7600}, mesh = {Animals ; *Alzheimer Disease/metabolism ; *Oxidative Stress/drug effects ; *Gastrointestinal Microbiome/drug effects ; Rats ; *Polysaccharides/pharmacology ; Male ; *Rosa/chemistry ; *Cognitive Dysfunction ; *Brain-Gut Axis/drug effects ; Humans ; Rats, Sprague-Dawley ; Hippocampus/metabolism ; Plant Extracts/pharmacology ; Brain/metabolism/drug effects ; Cognition/drug effects ; Disease Models, Animal ; Antioxidants/pharmacology ; Superoxide Dismutase/metabolism ; Maze Learning ; Malondialdehyde/metabolism ; }, abstract = {The microbial-gut-brain axis and oxidative stress may be important to the pathogenesis of Alzheimer's disease (AD). Rosa roxburghii Tratt polysaccharides (RRTP) have a strong antioxidant effect and can affect the gut microbiota, and whether it can affect AD is unknown. So, AlCl3 and d-galactose were used to establish AD model rats, and RRTP was used as an intervention treatment. Morris water maze test was used to detect cognitive functions. The hippocampus was used to observe the pathological changes, and the cortex was used to measure antioxidant markers. The stool was collected for 16S rDNA sequencing. Morris water maze test showed that the learning ability and memory level of AD group rats were decreased, and RRTP intervention could mitigate the injury to a certain extent. In the AD group, hematoxylin-eosin staining revealed changes in the morphology of neurons, silver glycine staining revealed neurofibrillary tangles and Congo red staining revealed β-amyloid. RRTP could ameliorate the above changes to some extent. The results of superoxide dismutase, malondialdehyde, and glutathione peroxidase showed that the antioxidant capacity in the RRTP intervention group was significantly higher than that in the AD group. 16S rDNA sequencing results showed that there were differences in the species composition of gut microbiota, and the ratio of Firmicutes to Bacteroidetes in the AD group was decreased. After RRTP intervention, the proportion of Lactobacillus increased. In conclusion, RRTP may prevent AD pathology and cognitive functions in rats to a certain extent through the microbiota-gut-brain axis and oxidative stress.}, }
@article {pmid40041912, year = {2025}, author = {Dash, UC and Bhol, NK and Swain, SK and Samal, RR and Nayak, PK and Raina, V and Panda, SK and Kerry, RG and Duttaroy, AK and Jena, AB}, title = {Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {1}, pages = {15-34}, pmid = {40041912}, issn = {2211-3835}, abstract = {Neuroprotection is a proactive approach to safeguarding the nervous system, including the brain, spinal cord, and peripheral nerves, by preventing or limiting damage to nerve cells and other components. It primarily defends the central nervous system against injury from acute and progressive neurodegenerative disorders. Oxidative stress, an imbalance between the body's natural defense mechanisms and the generation of reactive oxygen species, is crucial in developing neurological disorders. Due to its high metabolic rate and oxygen consumption, the brain is particularly vulnerable to oxidative stress. Excessive ROS damages the essential biomolecules, leading to cellular malfunction and neurodegeneration. Several neurological disorders, including Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple sclerosis, and ischemic stroke, are associated with oxidative stress. Understanding the impact of oxidative stress in these conditions is crucial for developing new treatment methods. Researchers are exploring using antioxidants and other molecules to mitigate oxidative stress, aiming to prevent or slow down the progression of brain diseases. By understanding the intricate interplay between oxidative stress and neurological disorders, scientists hope to pave the way for innovative therapeutic and preventive approaches, ultimately improving individuals' living standards.}, }
@article {pmid40041886, year = {2025}, author = {Lu, J and Zhou, Q and Zhu, D and Song, H and Xie, G and Zhao, X and Huang, Y and Cao, P and Wang, J and Shen, X}, title = {Drofenine as a Kv2.1 inhibitor alleviated AD-like pathology in mice through Aβ/Kv2.1/microglial NLRP3/neuronal Tau axis.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {1}, pages = {371-391}, pmid = {40041886}, issn = {2211-3835}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the Aβ-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how Aβ mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric Aβ (o-Aβ) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown in vitro (si-Kv2.1) and in vivo (AAV-ePHP-si-Kv2.1). Dfe deprived o-Aβ of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-κB pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-Aβ-driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD.}, }
@article {pmid40041377, year = {2025}, author = {Hung, NV and Quoc Tien, L and Hai Linh, VN and Tran, H and Nguyen, TK and Pham, DV and Hoang, VH and Hien, TTT and Nguyen, TX and Thai, QM and Nguyen, TH and Ngo, ST and Tran, PT}, title = {Discovery of novel theophylline derivatives bearing tetrazole scaffold for the treatment of Alzheimer's disease.}, journal = {RSC advances}, volume = {15}, number = {9}, pages = {6994-7003}, pmid = {40041377}, issn = {2046-2069}, abstract = {Alzheimer's disease (AD) is associated with AChE and BACE1 enzymes. Designing inhibitors for preventing these enzymes can be benefit for AD treatment. In this context, theophylline derivatives were generated to prevent the biological activity of AChE and BACE1. In particular, the potential inhibitory of these compounds was rapidly and accurately estimated via knowledge-methods. The in vitro tests were then performed to validate the artificial intelligent approach. Among these, compound 12 exhibited the most potent AChE inhibition with an IC50 of 15.68 μM, while showing limited activity against BACE1. In addition, six compounds were indicated that are able to inhibit AChE, however, the theophylline derivatives play poor performance over the BACE1 target. Atomistic simulations were finally applied to clarify the ligand-binding mechanism to the biological target. The outcomes disclose that theophylline derivatives rigidly form van der Waals interactions to AChE via π-stacking and SC contacts. Overall, the theophylline derivatives may offer a potential scaffold for novel anti-AD agents.}, }
@article {pmid40040632, year = {2025}, author = {Khan, F and Rashan, L}, title = {Phytochemical Analysis and Pharmaceutical Applications of Monoterpenoids Present in the Essential Oil of Boswellia sacra (Omani Luban).}, journal = {Advances in pharmacological and pharmaceutical sciences}, volume = {2025}, number = {}, pages = {3536898}, pmid = {40040632}, issn = {2633-4690}, abstract = {Due to its intricacy and long-term usefulness, traditional medicine continues to be practiced in several nations. Among the many medicinal plants found in the Dhofar region of Oman, the aromatic oleo-gum resin generated by Boswellia sacra, commonly referred to as frankincense, stands out for its medical and commercial significance. Resin-carrying ducts are unique to members of the Boswellia family. Boswellia sacra Flueck is one of the 29 species in the genus Boswellia (Burseraceae) and has long been cultivated for its aromatic gums and resins for use as incense. In addition to the resins (60%-80% alcohol soluble), gums (15%-20% water soluble), and essential oil (5%-7%), other components, including polysaccharides and polymeric compounds, also exist in smaller amounts. Physiochemical analyses indicate that Boswellia resin oil is made up of 42.5% diterpenes, 13.1% monoterpenes, and 1% sesquiterpenes. Traditional medicine makes extensive use of frankincense for the treatment of stomach diseases, Alzheimer's disease, and hepatic illnesses. The bioactive chemicals present in frankincense, particularly boswellic acids, are plentiful. The current review examines various compounds present in different species of Boswellia, especially Boswellia sacra, along with their structure.}, }
@article {pmid40039841, year = {2024}, author = {Wei, Y and Abrol, A and Lah, J and Qiu, D and Calhoun, VD}, title = {A deep spatio-temporal attention model of dynamic functional network connectivity shows sensitivity to Alzheimer's in asymptomatic individuals.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10781740}, pmid = {40039841}, issn = {2694-0604}, mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; Brain/diagnostic imaging/physiopathology ; Female ; Aged ; Male ; Deep Learning ; Nerve Net/physiopathology/diagnostic imaging ; }, abstract = {Alzheimer's disease (AD) progresses from asymptomatic changes to clinical symptoms, emphasizing the importance of early detection for proper treatment. Functional magnetic resonance imaging (fMRI), particularly dynamic functional network connectivity (dFNC), has emerged as an important biomarker for AD. Nevertheless, studies probing at-risk subjects in the pre-symptomatic stage using dFNC are limited. To identify at-risk subjects and understand alterations of dFNC in different stages, we leverage deep learning advancements and introduce a transformer-convolution framework for predicting at-risk subjects based on dFNC, incorporating spatial-temporal self-attention to capture brain network dependencies and temporal dynamics. Our model significantly outperforms other popular machine learning methods. By analyzing individuals with diagnosed AD and mild cognitive impairment (MCI), we studied the AD progression and observed a higher similarity between MCI and asymptomatic AD. The interpretable analysis highlights the cognitive-control network's diagnostic importance, with the model focusing on intra-visual domain dFNC when predicting asymptomatic AD subjects.}, }
@article {pmid40039671, year = {2024}, author = {Lankenau, KM and Brause, E and Schill, J and Hirsch, JG and Schroder, J and Gunther, M and Schultz, T}, title = {Multimodal Dementia Screening from Brain Magnetic Resonance Imaging and Conversational Speech.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10781749}, pmid = {40039671}, issn = {2694-0604}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Speech ; *Brain/diagnostic imaging ; *Dementia/diagnostic imaging ; Aged ; Female ; Male ; Alzheimer Disease/diagnostic imaging ; Longitudinal Studies ; }, abstract = {Early detection of Alzheimer's dementia is crucial for effective symptomatic treatment. Herein, we explore the opportunities of dementia screening based on automatically derived biomarkers from Magnetic Resonance Imaging (MRI) and spoken communication. In particular, we compare the screening performance of unimodal MRI-based or speech-based markers with their multimodal counterparts. We use structural MRI data and interview recordings from the Interdisciplinary Longitudinal Study on Adult Development and Aging to analyze state and predictive screening between participants with and without cognitive impairment. We assess the effect of varying training set sizes on unimodal screening performance and compare screening performance of unimodal data with multimodal data, which are combined through Early, Late and Tensor Fusion. For both state and predictive screening, classifiers that combined both modalities with the Early Fusion method outperformed the single modalities, achieving an Unweighted Average Recall of 83.2% and 74.9%, respectively. On the evaluated dataset, markers derived from speech are just as useful for predictive screening as markers derived from MRI.}, }
@article {pmid40039646, year = {2024}, author = {Yao, M and Liu, J and Pu, Y and Katie Chan, KH}, title = {Multi-class Prediction of Cognitively Normal / Mild Cognitive Impairment / Alzheimer's Disease Status in Dementia Based on Convolutional Neural Networks with Attention Mechanism.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-7}, doi = {10.1109/EMBC53108.2024.10781557}, pmid = {40039646}, issn = {2694-0604}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology ; *Cognitive Dysfunction/diagnostic imaging/physiopathology/diagnosis ; *Neural Networks, Computer ; *Magnetic Resonance Imaging/methods ; Aged ; Deep Learning ; Female ; Male ; Aged, 80 and over ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with insidious onset and progressive development. AD is a health issue that is attracting attention as the world's populations get older. Although there is currently no effective treatment for this disease, early diagnosis is necessary to help people prevent it. Here, we developed an MRI-based deep learning and multi-class AD classification and prediction framework. Based on the traditional Visual Geometry Group 19 (VGG19) architecture, we embedded the Convolutional Block Attention Module Attention layer to build an Alzheimer's directional prediction 3D convolution model referred to as AD_Net in this paper. We used MRI images from the ADNI open data resource to train, classify, and predict three different conditions: AD, mild cognitive impairment (MCI), and cognitively normal (CN). Experimental results showed that the prediction accuracy and system robustness of AD_Net are superior to those of basic VGG19. To improve the accuracy of the prediction, we developed a multilayer perceptron (MLP)-based model to incorporate additional factors into the model, such as age, gender, and Mini-Mental State Examination score. We presented the model performance for groups with and without directional influence factors. Accuracy for the two groups was 51.2% and 89%, respectively. The latter group had a standard deviation as low as 1.8%, reflecting predictive performance that is both good and stable. Our model can be applied to the early diagnosis of Alzheimer's disease and other similar conditions that can be diagnosed by MRI and the patient's underlying factors.}, }
@article {pmid40039638, year = {2024}, author = {Poonam, K and Guha, R and Chakrabarti, PP}, title = {Artificial Intelligence Based Hierarchical Classification of Frontotemporal Dementia.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10782700}, pmid = {40039638}, issn = {2694-0604}, mesh = {Humans ; *Frontotemporal Dementia/diagnostic imaging/classification/pathology ; *Support Vector Machine ; *Magnetic Resonance Imaging/methods ; *Artificial Intelligence ; Aged ; Male ; Female ; Middle Aged ; Brain/diagnostic imaging/pathology ; }, abstract = {Frontotemporal dementia (FTD) is a typical kind of presenile dementia with three main subtypes: behavioral-variant FTD (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), and semantic variant primary progressive aphasia (svPPA). Our aim is to classify brain images of each subject into one of the spectrums of the FTD in a hierarchical order by applying data-driven techniques. Specifically, we took 300 subjects (30 bvFTD, 41 svPPA, 25 nfvPPA, 80 Alzheimer's Disease, and 124 cognitively normal) from the Frontotemporal Lobar Degeneration Neuroimaging Initiative archive to validate our approach. The cortical and subcortical measurements, e.g., cortical thickness and volumetric segmentation, were extracted from MRI images for the experiment. Our proposed model yielded classification accuracy of 87.42%, 83.23%, and 82.44% with Support Vector Machine (SVM), Linear Discriminant Analysis, and Naive Bayes methods, respectively, for five classes. We observed a significant improvement over the flat multi-class model, which has an accuracy of 82.80%, 81.27%, and 80.45%, respectively, for five classes. We also compared our proposed approach with a Convolutional Neural Networks model and ensemble with multi-layer perception as well. The results showed that the hierarchical approach performs almost equally well here as in the SVM model. Moreover, we also tested our hierarchical approach for three classes (CN, Non-FTD, FTD) to compare with state-of-the-art methods and obtained better results.Clinical relevance- This study provides a detailed understanding of the heterogeneity within the FTD subtypes; clinicians can better tailor diagnostic and treatment strategies to match each subtype's specific characteristics and progression patterns.}, }
@article {pmid40039434, year = {2024}, author = {Goerttler, S and He, F and Wu, M}, title = {Balancing Spectral, Temporal and Spatial Information for EEG-based Alzheimer's Disease Classification.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10782936}, pmid = {40039434}, issn = {2694-0604}, mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnosis/classification ; *Electroencephalography/methods ; Signal Processing, Computer-Assisted ; Algorithms ; }, abstract = {The prospect of future treatment warrants the development of cost-effective screening for Alzheimer's disease (AD). A promising candidate in this regard is electroencephalography (EEG), as it is one of the most economic imaging modalities. Recent efforts in EEG analysis have shifted towards leveraging spatial information, employing novel frameworks such as graph signal processing or graph neural networks. Here, we investigate the importance of spatial information relative to spectral or temporal information by varying the proportion of each dimension for AD classification. To do so, we systematically test various dimension resolution configurations on two routine EEG datasets. Our findings show that spatial information is more important than temporal information and equally valuable as spectral information. On the larger second dataset, substituting spectral with spatial information even led to an increase of 1.1% in accuracy, which emphasises the importance of spatial information for EEG-based AD classification. We argue that our resolution-based feature extraction has the potential to improve AD classification specifically, and multivariate signal classification generally.Clinical relevance- This study proposes balancing the spectral, temporal and spatial feature resolution to improve EEGbased diagnosis of neurodegenerative diseases.}, }
@article {pmid40038883, year = {2025}, author = {Añazco, T and Werner, T and Torres, MJ and Hornos-Carneiro, MF and Fernández, J and Zivkovic, A and Salas, CO and Castro-Álvarez, A and Gutiérrez, M and Stark, H and Espinosa-Bustos, C}, title = {First in class pyrrolo[2,3-d]pyrimidine derivatives fused to fluorobenzylpiperidines as dual ligands of acetylcholinesterase and histamine H3 receptor.}, journal = {Archiv der Pharmazie}, volume = {358}, number = {3}, pages = {e2400387}, doi = {10.1002/ardp.202400387}, pmid = {40038883}, issn = {1521-4184}, support = {//DFG/ ; //VRI-PUC/ ; //VRI-PUC Puente-2023-19/ ; //FONDEQUIP EQY220018/ ; //FONDEQUIP EQM210203/ ; //DFG GRK2158/ ; }, mesh = {Humans ; *Acetylcholinesterase/metabolism ; *Pyrimidines/pharmacology/chemical synthesis/chemistry ; Ligands ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Receptors, Histamine H3/metabolism ; Structure-Activity Relationship ; HEK293 Cells ; Piperidines/pharmacology/chemical synthesis/chemistry ; Molecular Structure ; Dose-Response Relationship, Drug ; Butyrylcholinesterase/metabolism ; Pyrroles/pharmacology/chemical synthesis/chemistry ; Alzheimer Disease/drug therapy ; Molecular Docking Simulation ; Cell Line, Tumor ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease with manifold underlying pathophysiological mechanisms. Therefore, multitarget-directed ligands potentially offer beneficial therapeutic effects compared with classical therapies. Dual targeting of the histamine H3 receptor (H3R) and acetylcholinesterase (AChE) is a valid strategy for the treatment of AD. In this work, a new series of pyrrolo[2,3-d]pyrimidines fused to fluorobenzylpiperidine derivatives was designed, synthesized, and pharmacologically evaluated. Among the 16 derivatives reported here, compounds 4a (IC50 = 2.19 µM for human acetylcholinesterase (hAChE) and Ki = 1.05 µM for H3R) and 4f (IC50 = 4.27 µM for hAChE and Ki = 1.31 µM for H3R) show the most balanced dual targeting behavior coupled with moderate affinities at both targets. Selected compounds showed medium inhibition of butyrylcholinesterase (BuChE). Moreover, these compounds did not show any toxicity in the SH-SY5Y or HEK-293 cell lines at pharmacologically relevant concentrations. In silico studies allowed the proposition of binding modes and the prediction of favorable absorption, distribution, metabolism and excretion properties. The cumulative results suggest compounds 4a and 4f as lead structures for the further development of novel dual-targeted ligands for AD therapy.}, }
@article {pmid40038765, year = {2025}, author = {Quan, S and Fu, X and Cai, H and Ren, Z and Xu, Y and Jia, L}, title = {The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer's disease.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {25}, pmid = {40038765}, issn = {1750-1326}, support = {Nos. 81870825//National Natural Science Foundation of China/ ; 82071194//National Natural Science Foundation of China/ ; No. Z201100005520016//Beijing Brain Initiative from the Beijing Municipal Science & Technology Commission/ ; No. 7202061//Beijing Municipal Natural Science Foundation/ ; No.2022-2-2017//Capital's Funds for Health Improvement and Research/ ; No. 2022ZD0211600//STI 2030-Major Projects/ ; 2022ZD0211605//STI 2030-Major Projects/ ; }, mesh = {*Alzheimer Disease/metabolism/immunology ; Humans ; *DNA, Mitochondrial/metabolism/genetics ; *Nucleotidyltransferases/metabolism ; *Signal Transduction/physiology ; *Membrane Proteins/metabolism ; Animals ; Mitochondria/metabolism ; }, abstract = {The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing cytosolic damage-associated molecular patterns (DAMPs), and inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation of this pathway culminates in AD-related neuroinflammation and neurodegeneration. A substantial body of evidence indicates that mitochondria are involved in the critical pathogenic mechanisms of AD, whose damage leads to the release of mitochondrial DNA (mtDNA) into the extramitochondrial space. This leaked mtDNA serves as a DAMP, activating various pattern recognition receptors and immune defense networks in the brain, including the cGAS-STING pathway, ultimately leading to an imbalance in immune homeostasis. Therefore, modulation of the mtDNA-cGAS-STING pathway to restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In this review, we focus on the mechanisms of mtDNA release during stress and the activation of the cGAS-STING pathway. Additionally, we delve into the research progress on this pathway in AD, and further discuss the primary directions and potential hurdles in developing targeted therapeutic drugs, to gain a deeper understanding of the pathogenesis of AD and provide new approaches for its therapy.}, }
@article {pmid40038143, year = {2025}, author = {Abaidullah, N and Muhammad, K and Waheed, Y}, title = {Delving Into Nanoparticle Systems for Enhanced Drug Delivery Technologies.}, journal = {AAPS PharmSciTech}, volume = {26}, number = {3}, pages = {74}, pmid = {40038143}, issn = {1530-9932}, mesh = {Humans ; *Drug Delivery Systems/methods ; *Nanoparticles/chemistry ; Animals ; Nanotechnology/methods ; Neoplasms/drug therapy ; Nanoparticle Drug Delivery System/chemistry ; Drug Carriers/chemistry ; }, abstract = {Nanotechnology, based on the utilization of nanoparticles, has revolutionized drug delivery techniques, offering groundbreaking methods for managing and diagnosing intricate ailments over the past four decades. This article aims to underscore how the use of these particles has been used to treat previously incurable diseases such as cancer, Alzheimer's, and Parkinson's disease. Recently, the integration of diagnostic imaging and targeted therapy using theranostic nanoparticles has improved cancer treatment precision. Moreover, exosome-based drug delivery has demonstrated high in vivo biocompatibility and antigen-carrying ability during vaccine development. The unique properties of these tiny particles enable their transport to specific locations inaccessible to large drug molecules. The development of these nanodrugs by either encapsulation or adsorption of drugs on particles has allowed the loading of both hydrophilic and hydrophobic drugs. Innovative engineering approaches have enabled the engineering of shear-sensitive nanoparticles for site-targeted drug release, which eliminates the requirement for frequent doses, which is common in conventional drug delivery. Factors such as size, shape as well as surface modification are considered during the top-down and bottom-up approaches for engineering nanoparticle-based systems. However, issues related to scaling up manufacturing, long-term safety, and regulatory approval for these techniques must be resolved. The use of these drug delivery systems offers many therapeutic advantages. This article examines the application of these systems across various medical domains including cancer treatment, infectious diseases, cardiovascular disorders, central nervous system ailments, and ophthalmic conditions. This fusion of nanotechnology with drug delivery has the potential to elevate healthcare standards in the future by introducing innovative frameworks for revolutionizing therapeutic practices.}, }
@article {pmid40037511, year = {2025}, author = {Du, J and Baranova, A and Cao, H and Zhang, F}, title = {Evaluating the causal effects of circulating metabolic biomarkers on Alzheimer's disease.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {138}, number = {}, pages = {111309}, doi = {10.1016/j.pnpbp.2025.111309}, pmid = {40037511}, issn = {1878-4216}, abstract = {BACKGROUND: The diagnosis and treatment of Alzheimer's disease (AD) is challenging due to the complexity of its pathogenesis. Although research suggests a link between circulating metabolites and AD, their causal relationship is not fully understood.
METHODS: Based on publicly available genome-wide association study data, we investigated the causative relationship between AD (7759 cases and 334,740 controls) and 233 traits describing circulating metabolites (136,016 participants) using a two-sample Mendelian randomization (MR) method. We adopted the inverse variance weighted approach as the priority and performed sensitivity analyses with MR-Egger intercept method and Cochran's Q test.
RESULTS: The overall causal effect of circulating metabolic traits on AD was significantly higher than the inverse effect (beta: 0.15 ± 0.42 vs. 0.04 ± 0.07; p < 0.05). A total of 72 circulating metabolic traits (odd ratio (OR): 1.16-2.48) had a significant positive causal effect on AD, while a total of 16 circulating metabolic traits with significant negative causal effects on AD were detected (OR: 0.38-0.88). AD had a significant positive causal effect (OR: 1.02-1.17) on 142 circulating metabolic traits and a negative causal effect (OR: 0.87-0.99) on 43 circulating metabolic traits. Circulating metabolites that have a bi-directional causative relationship with AD mainly include apolipoprotein B levels, total cholesterol levels, total triglycerides levels, and omega-6 fatty acids levels.
CONCLUSION: The causative relationship between AD and the circulating metabolic traits is complex and bidirectional. Analyzing metabolites causally involved in the development of AD may provide clues for identifying preventive and therapeutic targets for this disorder.}, }
@article {pmid40037055, year = {2025}, author = {Duenias, D and Nichyporuk, B and Arbel, T and Riklin Raviv, T and , }, title = {Hyperfusion: A hypernetwork approach to multimodal integration of tabular and medical imaging data for predictive modeling.}, journal = {Medical image analysis}, volume = {102}, number = {}, pages = {103503}, doi = {10.1016/j.media.2025.103503}, pmid = {40037055}, issn = {1361-8423}, abstract = {The integration of diverse clinical modalities such as medical imaging and the tabular data extracted from patients' Electronic Health Records (EHRs) is a crucial aspect of modern healthcare. Integrative analysis of multiple sources can provide a comprehensive understanding of the clinical condition of a patient, improving diagnosis and treatment decision. Deep Neural Networks (DNNs) consistently demonstrate outstanding performance in a wide range of multimodal tasks in the medical domain. However, the complex endeavor of effectively merging medical imaging with clinical, demographic and genetic information represented as numerical tabular data remains a highly active and ongoing research pursuit. We present a novel framework based on hypernetworks to fuse clinical imaging and tabular data by conditioning the image processing on the EHR's values and measurements. This approach aims to leverage the complementary information present in these modalities to enhance the accuracy of various medical applications. We demonstrate the strength and generality of our method on two different brain Magnetic Resonance Imaging (MRI) analysis tasks, namely, brain age prediction conditioned by subject's sex and multi-class Alzheimer's Disease (AD) classification conditioned by tabular data. We show that our framework outperforms both single-modality models and state-of-the-art MRI tabular data fusion methods. A link to our code can be found at https://github.com/daniel4725/HyperFusion.}, }
@article {pmid40036706, year = {2025}, author = {Wang, RZ and Chen, SF and Fei, CJ and Zhang, YR and Chen, KL and Zhang, W and Li, MM and Huang, YY and Xiang, ST and Wu, KM and Li, WH and Wu, BS and Cheng, W and Cui, M and Yu, JT}, title = {Clinical, radiological, pathological and prognostic features of general paresis: a cohort study.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awae389}, pmid = {40036706}, issn = {1460-2156}, abstract = {General paresis is a rare type of syphilis characterized by progressive cognitive impairment and psychiatric syndromes. It is often misdiagnosed because of its rarity and similarity with other diseases. We aimed to comprehensively investigate the clinical, radiological, pathological, and prognostic features of general paresis, and compare it with other dementias. Between August 2019 and January 2024, patients were recruited from a Memory Clinic Setting of National Center for Neurological Disorders in China. Participants underwent clinical evaluation, laboratory testing, and imaging, and were followed after treatment. Comparative analysis was conducted on clinical features and neuropsychiatric assessments, while brain image features were investigated using linear regression models and SuStaIn models. Seventy-eight patients were included, with 90% being male. The median duration from symptom onset to the first diagnostic visit was 15 months. Sixty-three patients were followed for an average of 1.4 years. Cognitive impairment emerged as the most common symptom, with half of the patients co-existed with motor symptoms. Impairment across all cognitive domains accompanied by positive psychiatric symptoms raised suspicion for general paresis, and distinguishing it from Alzheimer's disease, frontotemporal dementia, and anti-LGI1 encephalitis-related dementia. Common imaging abnormalities in general paresis included whole brain atrophy and cortical hypointensity. The hippocampal-predominant and hippocampal-sparing atrophy subtypes were identified. Autoimmune responses in general paresis were demonstrated through the detection of autoimmune encephalitis antibodies in 11% of patients. Pathological amyloid changes were observed in 26% of patients, while elevated total tau levels were found in 30%. Seventy percent of patients showed improvement following treatment, with a reduction in the number of symptoms observed across all cases. This study identifies specific clinical syndromes and radiological features of general paresis and refines the understanding of its prognosis. We provide clues to distinguish general paresis from other dementias, facilitating early diagnosis and treatment. The role of novel pathological changes in general paresis needs to be further studied.}, }
@article {pmid40036675, year = {2025}, author = {Stoeckel, LE and John, D and Sutterer, M}, title = {Towards AI-Driven Precision Measurement of Cognition, Behavior, and Psychological Function in Aging and AD/ADRD.}, journal = {The journals of gerontology. Series B, Psychological sciences and social sciences}, volume = {}, number = {}, pages = {}, doi = {10.1093/geronb/gbaf045}, pmid = {40036675}, issn = {1758-5368}, abstract = {The National Institute on Aging (NIA) is at the forefront of leveraging advances in artificial intelligence (AI) to better understanding of aging and the diagnosis and treatment of Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementias (ADRD). Recent NIA-supported projects have highlighted the transformative potential of AI, digital health, and computational approaches in improving the modeling, detection, and monitoring of changes in healthy aging and AD/ADRD. This perspective is forward looking, emphasizing key areas and efforts in AI-driven precision measurement in cognition, behavior, and psychological function.}, }
@article {pmid40036478, year = {2025}, author = {Vigne, MM and Kweon, J and Fukuda, AM and Brown, JC and Carpenter, LL}, title = {The Role of Brain Derived Neurotrophic Factor Polymorphism in Transcranial Magnetic Stimulation Response for Major Depressive Disorder.}, journal = {The journal of ECT}, volume = {}, number = {}, pages = {}, doi = {10.1097/YCT.0000000000001123}, pmid = {40036478}, issn = {1533-4112}, abstract = {OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective therapy for treatment-resistant depression (TRD). A crucial next step in improving rTMS therapy is to identify response predictors to inform patient selection criteria. Brain-derived neurotrophic factor (BDNF) exerts influence over TRD treatment modalities. BDNF polymorphism, Val66Met, has shown altered cortical plasticity after single-session rTMS in healthy subjects and clinical response in noninvasive brain stimulation methods in major depressive disorder, stroke, Alzheimer's, and cerebral palsy. We sought to evaluate the effect of this BDNF polymorphism on clinical response in a standard course of rTMS therapy for TRD.
METHODS: In this naturalistic study, 75 patients with TRD completed a standard course of rTMS with weekly clinical assessments via the Inventory of Depressive Symptomatology Self-Report (IDS-SR). BDNF polymorphisms were retrospectively compared in respect to treatment response and remission, baseline and final scores, percent change scores, and scores across the 6-week treatment course.
RESULTS: As expected, rTMS significantly decreased depressive symptoms as measured by IDS-SR scores. No difference was found in baseline, final, or percent change IDS-SR scores between polymorphism types. There was no difference between polymorphisms in IDS-SR scores across the treatment course. Response and remission rates did not differ between genotypes.
CONCLUSIONS: In contrast to previous research highlighting differential response between BDNF polymorphisms to motor plasticity and clinical rTMS outcomes, our data suggest that BDNF polymorphism status may not influence the response to a standard course of 10-Hz rTMS for major depressive disorder. Differences in TMS protocol, target, or BDNF serum levels may underlie our results.}, }
@article {pmid40035979, year = {2025}, author = {de Rezende, VL and de Aguiar da Costa, M and Martins, CD and Mathias, K and Gonçalves, CL and Barichello, T and Petronilho, F}, title = {Systemic Rejuvenating Interventions: Perspectives on Neuroinflammation and Blood-Brain Barrier Integrity.}, journal = {Neurochemical research}, volume = {50}, number = {2}, pages = {112}, pmid = {40035979}, issn = {1573-6903}, mesh = {*Blood-Brain Barrier/metabolism ; Humans ; Animals ; *Neuroinflammatory Diseases ; Aging/physiology ; Inflammation ; Neurodegenerative Diseases/therapy/metabolism ; }, abstract = {The aging process results in structural, functional, and immunological changes in the brain, which contribute to cognitive decline and increase vulnerability to neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke-related complications. Aging leads to cognitive changes and also affect executive functions. Additionally, it causes neurogenic and neurochemical alterations, such as a decline in dopamine and acetylcholine levels, which also impact cognitive performance. The chronic inflammation caused by aging contributes to the impairment of the blood-brain barrier (BBB), contributing to the infiltration of immune cells and exacerbating neuronal damage. Therefore, rejuvenating therapies such as heterochronic parabiosis, cerebrospinal fluid (CSF) administration, plasma, platelet-rich plasma (PRP), and stem cell therapy have shown potential to reverse these changes, offering new perspectives in the treatment of age-related neurological diseases. This review focuses on highlighting the effects of rejuvenating interventions on neuroinflammation and the BBB.}, }
@article {pmid40035974, year = {2025}, author = {Zhong, YY and Deng, JZ and Wang, Q and Chen, L and Yang, ZH and Zhang, YM and Zhou, LY and Li, YR and Wu, JQ and Wang, XQ}, title = {Development of novel melatonin-isatin hybrids as multifunctional agents for Alzheimer's disease.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {40035974}, issn = {1573-501X}, support = {GDMU2022167//the research funds of the Students' Innovative Program of Guangdong Medical University/ ; GDMU2023157//the research funds of the Students' Innovative Program of Guangdong Medical University/ ; GDMU2023328//the research funds of the Students' Innovative Program of Guangdong Medical University/ ; GDMU2023219//the research funds of the Students' Innovative Program of Guangdong Medical University/ ; B2016019//Guangdong Province Medical Research Foundation/ ; 2016B01019//Zhanjiang science and technology project/ ; B2017011//the research funds of the Doctoral Program of Guangdong Medical University/ ; 21502025//the National Natural Science Foundation of China/ ; }, abstract = {The development of multifunctional agents has been a heated area of research for AD treatment in recent years. In this work, a series of melatonin-isatin hybrids were designed, synthesized, and evaluated as multifunctional agents for treating AD. In vitro studies indicated that most of the synthesized compounds displayed moderate to good MAO-B inhibition activities and good antioxidant activities. In particular, compounds IM-5 and IM-10 exhibited the best inhibitory activities with IC50 value of 12.4 μM and 15.6 μM against MAO-B, and potent antioxidant activities with their ORAC-FL values of 4.6 and 5.2 at 5 μM, respectively. ThT assay revealed compounds IM-5 and IM-10 exhibited the optimal Aβ1-42 self-induced aggregation inhibitory activities with the inhibition ratio of 72.8% and 69.7% at 20 μM. In addition, compounds IM-5 and IM-10 exhibited low cytotoxicities and significant neuroprotective effects on Aβ1-42-induced and H2O2-induced SH-SY5Y cell injury. More importantly, compounds IM-5 and IM-10 could significantly ameliorate the memory impairment and cognition injury in scopolamine-induced mice. The SwissADME program was used to predict drug-like properties of compounds IM-5 and IM-10 which exhibited they had good pharmacokinetics and drug-likeness properties. Molecular docking study further manifested that compounds IM-5 and IM-10 showed high hMAO-B inhibitory potency. In summary, all above results revealed compounds IM-5 and IM-10 might be promising multifunctional agents for AD treatment.}, }
@article {pmid40035902, year = {2025}, author = {Li, N and Cui, N and Li, T and Zhao, P and Bakry, IA and Li, Q and Cheng, Y and Galaverna, G and Yang, H and Wang, F}, title = {Pea Peptides and Heavy Metal Neurotoxicity: Exploring Mechanisms and Mitigation Strategies in PC12 Cells.}, journal = {Plant foods for human nutrition (Dordrecht, Netherlands)}, volume = {80}, number = {1}, pages = {85}, pmid = {40035902}, issn = {1573-9104}, mesh = {PC12 Cells ; Animals ; Rats ; *Lead/toxicity ; Peptides/pharmacology ; Pea Proteins ; Pisum sativum/chemistry ; MAP Kinase Signaling System/drug effects ; Calcium-Binding Proteins/metabolism/genetics ; p38 Mitogen-Activated Protein Kinases/metabolism ; Neurotoxicity Syndromes/drug therapy ; Metals, Heavy ; }, abstract = {Calsyntenin-1 (Clst1) is a sensitive indicator of lead (Pb) toxicity in neural tissue. This study was designed to investigate the impact of lead exposure on Clst1 expression in PC12 cells and the mitigating effect of pea peptide 4 (PP4) on lead-induced neurotoxicity. Data showed that lead exposure, at varying doses and durations, disrupted the mRNA expression and protein levels of Clstn1 in PC12 cells. However, immunofluorescence results showed that treatment with PP4 significantly increased Clstn1 protein expression in the Pb + PP4 and PP4 groups compared to the Pb groups (P < 0.05). Lead exposure activates the JNK and p38 pathways; at the same time, PP4 treatment enhances ERK pathway activation and reduces JNK and p38 activation.}, }
@article {pmid40035705, year = {2025}, author = {Liu, H and Zhao, X and Chen, J and Win, YY and Cai, J}, title = {Unnatural foldamers as inhibitors of Aβ aggregation via stabilizing the Aβ helix.}, journal = {Chemical communications (Cambridge, England)}, volume = {61}, number = {24}, pages = {4586-4594}, pmid = {40035705}, issn = {1364-548X}, support = {R01 AG056569/AG/NIA NIH HHS/United States ; R01 GM150196/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyloid beta-Peptides/antagonists & inhibitors/metabolism/chemistry ; Humans ; *Protein Aggregates/drug effects ; Protein Conformation, alpha-Helical ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Protein aggregation is a critical factor in the development and progression of several human diseases, including Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, and type 2 diabetes. Among these conditions, AD is recognized as the most prevalent progressive neurodegenerative disorder, characterized by the accumulation of amyloid-beta (Aβ) peptides. Neuronal toxicity is likely driven by soluble oligomeric intermediates of the Aβ peptide, which are thought to play a central role in the cascade leading to neuronal dysfunction and cognitive decline. In response, numerous therapeutic strategies have been developed to inhibit Aβ oligomerization, as this is believed to delay the formation of Aβ protofibrils. Traditional research has focused on discovering small molecules or peptides that antagonize Aβ oligomerization. However, recent studies have explored an alternative approach-developing ligands that stabilize the Aβ peptide in its α-helical conformation. This stabilization is thought to alter the peptide's natural aggregation kinetics, shifting it away from toxic oligomer formation and toward less harmful states. Crucially, by maintaining Aβ in this α-helical form, these ligands have been shown to rescue the peptide's associated cytotoxicity, offering a promising mechanism to mitigate the detrimental effects of Aβ in AD. While challenges remain, including treatment costs and side effects like ARIA (amyloid-related imaging abnormalities), anti-Aβ drug development represents a major advancement in Alzheimer's research and therapeutic options. This brief review aims to highlight the development and potential of these α-helix-stabilizing ligands as antagonists of Aβ aggregation, focusing on their interactions with Aβ and how these compounds induce and maintain secondary structural changes in the Aβ peptide. Notably, this innovative strategy holds promise beyond Aβ-related pathology, as the fundamental principles could be applied to other amyloidogenic proteins implicated in various amyloid-related diseases, potentially broadening the scope of therapeutic intervention for multiple neurodegenerative conditions.}, }
@article {pmid40034790, year = {2025}, author = {Wang, G and Chen, T and O'Gorman, J and Li, Y and Li, C and Guizzetti, L and Mangal, B and Wang, W and Wu, S and Inman, D and McDade, E and Bateman, RJ}, title = {Harnessing Greater Statistical Power: Comprehensive Evaluation of Disease Modifying Treatment Effects Across All or Multiple Post-Baseline Visits Compared to the Last Visit for Alzheimer's Disease Clinical Trials.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40034790}, support = {R01 AG068319/AG/NIA NIH HHS/United States ; U01 AG059798/AG/NIA NIH HHS/United States ; R01 AG046179/AG/NIA NIH HHS/United States ; R01 AG053267/AG/NIA NIH HHS/United States ; U01 AG042791/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: In Alzheimer's disease (AD) clinical trials, efficacy inference is traditionally based on the last visit (e.g., 18 months). However, recent studies suggest that disease-modifying treatment effects may emerge as early as 3 months post-baseline.
OBJECTIVE: To explore this further, our study aimed to assess the increased statistical power achieved by incorporating all or multiple post-baseline visits to estimate treatment effect, compared to relying solely on the last visit.
METHODS: We developed explicit formulas for the base functions of the natural cubic spline model, ensuring compatibility with standard SAS procedures. Through simulations using disease progression trajectories from ClarityAD and TRAILBLAZER-ALZ2 trials, we comprehensively evaluated various models in terms of power and type I error. Additionally, we offer SAS codes that to facilitate seamless implementation of different modeling approaches.
RESULTS: Simulations based on ClarityAD and TRAILBLAZER-ALZ2 disease trajectories demonstrated that models incorporating multiple or all post-baseline visits yield greater power than those using only the last visit, while maintaining Type I error control. Furthermore, when three post-baseline visits were included, adding more visits resulted in minimal power gains.
CONCLUSIONS: Our findings support prioritizing statistical models that incorporate multiple or all post-baseline visits for treatment efficacy inference, as they offer greater efficiency than models relying solely on the last visit.}, }
@article {pmid40034778, year = {2025}, author = {Wang, G and Li, Y and McDade, E and Xiong, C and Hartz, SM and Bateman, RJ and Morris, JC and Schneider, LS}, title = {Clinical Progression on CDR-SB[©]: Progression Free Time at Each 0.5-unit Level in Dominantly Inherited and Sporadic Alzheimer's Disease Populations.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40034778}, support = {R01 AG063826/AG/NIA NIH HHS/United States ; R01 AG068319/AG/NIA NIH HHS/United States ; R01 AG055444/AG/NIA NIH HHS/United States ; U01 AG059798/AG/NIA NIH HHS/United States ; R01 AG046179/AG/NIA NIH HHS/United States ; U01 AG052564/AG/NIA NIH HHS/United States ; R01 AG053267/AG/NIA NIH HHS/United States ; R01 AG074983/AG/NIA NIH HHS/United States ; R01 AG051346/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; U01 AG042791/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; R01 AG062687/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; R01 AG054434/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: CDR-SB is a reliable and clinically meaningful composite for assessing treatment effects in Alzheimer's disease (AD) clinical trials. Small CDR-SB differences at the end of a trial often lead to controversy in deriving clinically meaningful interpretations.
METHODS: We estimated progression-free time participants remained at each 0.5-unit CDR-SB increment in dominantly inherited AD (DIAD) and sporadic AD populations, evaluating its potential as an alternative measure of treatment effects.
RESULTS: Progression-free time is longer at CDR-SB ≤ 2.0 (1-2 years) and shorter at CDR-SB ≥ 5 (0.33 or less) in the ADNI cohort. The DIAD cohort showed similar but shorter times. Using progression-free time, continuous lecanemab treatment for three years is estimated to delay disease progression by 0.7 years in the sporadic population.
DISCUSSION: Progression-free time provides a benchmark for expressing clinical progression and treatment effects and can be applied particularly during open-label extensions and single-arm trials without placebo comparisons.}, }
@article {pmid40034532, year = {2025}, author = {Lee, CY and Wang, WF and Hsu, JL and Yang, YH and Jhang, KM}, title = {A 52-week, open-label, observational study evaluating tolerability, efficacy and physicians satisfaction of rivastigmine oral solution in Alzheimer's disease in Taiwan.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823241311860}, pmid = {40034532}, issn = {2542-4823}, abstract = {BACKGROUND: There is limited data on the use of rivastigmine oral solution in patients with Alzheimer's disease (AD).
OBJECTIVE: To evaluate the tolerability, efficacy and physicians' satisfaction of Rivast[®] (rivastigmine oral solution 2 mg/ml) in Taiwanese patients with mild to moderate AD over a 52-week period.
METHODS: An open-label, non-comparative, observational study was conducted across four hospitals in Taiwan. 142 Patients with mild to moderate AD were enrolled. Adverse events and adherence rates were monitored throughout the 52-week study period, while cognitive (Mini-Mental State Examination (MMSE)) and global functional outcomes (Clinical Dementia Rating (CDR)-Sum of Boxes) were recorded at baseline and at week 52. Factors associated with discontinuation, adverse events, and declines in cognitive and global function were determined.
RESULTS: The study achieved a 92.3% adherence rate, with 19% experiencing adverse events. The optimal dose was 3.8 ml, reached within 8.3 weeks. 43.7% of the patients reached an optimal dose of 4 ml and 59.8% achieved optimal dose within 4 weeks. Age and clinically significant electrocardiogram (EKG) abnormalities were associated with a higher risk of discontinuation, while female patients exhibited a lower risk. Additionally, both a higher initial dose and a higher optimal dose were associated with a reduced risk of adverse effects. Abnormal EKG findings were significantly associated with cognitive decline. More time to optimal dose was significantly associated with worse global function. All physicians regarded the medication is ease of use and the administration schedule is simple.
CONCLUSIONS: This study provides valuable insights into the tolerability and efficacy of rivastigmine oral solution in Taiwanese patients with mild to moderate AD.}, }
@article {pmid40034524, year = {2025}, author = {Simpson, AJ and Wyman-Chick, KA and Daniel, MS}, title = {Neuropsychological and clinical indicators of Lewy body and Alzheimer's pathology.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823241304386}, pmid = {40034524}, issn = {2542-4823}, abstract = {BACKGROUND: Clinical distinction between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) poses significant challenges due to pathological comorbidity. Similar ages of onset and overlapping cognitive and psychiatric symptoms can lead to diagnostic inaccuracy and inappropriate treatment recommendations.
OBJECTIVE: Identify the best combination of clinical and neuropsychological predictors of AD, DLB, and mixed DLB/AD neuropathology in dementia patients.
METHODS: Using the National Alzheimer's Coordinating Center dataset, we selected either pure AD (n = 189), DLB (n = 21), or mixed DLB/AD (n = 42) patients on autopsy. Neuropsychological and clinical predictors, including core clinical features of DLB, were entered into multivariable logistic regressions.
RESULTS: Gait disturbances (odds ratio (OR) = 19.32; p = 0.01), visual-spatial complaints (OR = 6.06; p = 0.03), and visual hallucinations (OR = 31.06; p = 0.002) predicted DLB compared to AD, along with better memory (OR = 3.42; p = 0.003), naming (OR = 3.35; p = 0.002), and worse processing speed (OR = 0.51; p = 0.01). When comparing DLB to DLB/AD, gait disturbances (OR = 6.33; p = 0.01), increased depressive symptoms (OR = 1.44; p = 0.03), and better memory (OR = 3.01; p = 0.004) predicted DLB. Finally, rapid eye movement sleep behavior disorder (RBD) (OR = 6.44; p = 0.004), parkinsonism severity (OR = 1.07; p = 0.02), and lower depressive symptoms (OR = 0.70; p = 0.006) and memory impairment (OR = 0.57; p = 0.02) distinguished DLB/AD from AD.
CONCLUSIONS: Our study converges with prior research suggesting specific neuropsychological and clinical features can help distinguish DLB from AD. Neuropsychological differentiation becomes more challenging among mixed pathologies and in advanced cognitive impairment, although the presence of RBD and parkinsonism distinguished DLB. Earlier clinical assessment and incorporation of in vivo and postmortem biomarkers should enhance diagnostic accuracy and understanding of disease characteristics, offering significant relevance for disease-modifying treatments.}, }
@article {pmid40034522, year = {2025}, author = {Chaudhuri, I and Das, S}, title = {Heterogeneous treatment effects of BCG vaccine on Alzheimer's disease risk.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251317955}, pmid = {40034522}, issn = {2542-4823}, abstract = {BACKGROUND: This project has investigated the role of the Bacillus Calmette-Guérin (BCG) vaccine as a potential treatment against Alzheimer's disease (AD) and related dementias (ADRD).
OBJECTIVE: To further establish that BCG treatment results in lower risk of ADRD through novel machine learning methods and to analyze the heterogeneity of treatment effects.
METHODS: This retrospective cohort study was conducted from May 28, 1987 to May 6, 2021, in patients who were 50 years or older and were diagnosed with non-muscle-invasive bladder cancer (NMIBC). Follow-up duration was 15-years. Machine learning algorithms using survival analysis and the random forest algorithm were the primary methods of data analysis.
RESULTS: The research has found that on average, NMIBC patients who received BCG treatment had a 6.9% (95% CI: 0.43%, 13.4%) lower risk of developing ADRD compared to those who did not. Heterogeneous treatment effects were also detected for those with a history of mental health disorders and also for those with a history of respiratory diseases. Those with mental health disorders were at a 14.7% (95% CI: 0.6%, 28.9%) reduced risk of ADRD if they received BCG treatment compared to no BCG treatment. Additionally, those taking BCG with respiratory diseases increased risk of ADRD by 13.6% (95% CI: 1.1%, 26.1%) compared to those with no BCG treatment.
CONCLUSIONS: BCG is associated with a lower risk of ADRD through novel analysis methods and has detected heterogeneity of treatment effects. This presents BCG as a potential low-cost method, with few side-effects, to prevent ADRD.}, }
@article {pmid40034517, year = {2025}, author = {Ott, FW and Sichler, ME and Bouter, C and Enayati, M and Wiltfang, J and Bayer, TA and Beindorff, N and Löw, MJ and Bouter, Y}, title = {Chronic exposure to a synthetic cannabinoid improves cognition and increases locomotor activity in Tg4-42 Alzheimer's disease mice.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823241306770}, pmid = {40034517}, issn = {2542-4823}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and behavior impairments. Despite recent approvals of anti-amyloid antibodies, there remains a need for disease modifying and easily accessible therapies. Emerging evidence suggests that targeting the endocannabinoid system may hold promise for AD therapy as it plays a crucial role in different physiological processes, including learning, memory and anxiety, as well as inflammatory and immune responses.
OBJECTIVE: In this study, we investigated the therapeutic potential of the synthetic cannabinoid WIN 55,212-2 on memory deficits in Tg4-42 transgenic mice.
METHODS: Tg4-42 mice were assigned to two treatment groups to investigate the preventive effects of WIN 55,212-2 after a prolonged washout period, as well as the therapeutic effects of WIN 55,212-2 on behavior. Furthermore, the effects of WIN 55,212-2 treatment on AD pathology, including inflammation, amyloid-β load, neurogenesis, and brain glucose metabolism, were evaluated.
RESULTS: Therapeutic WIN 55,212-2 treatment rescued recognition memory and spatial reference deficits in Tg4-42 mice. Furthermore, therapeutic WIN 55,212-2 administration improved motor performance. In addition, preventative WIN 55,212-2 treatment rescued spatial learning and reference memory deficits. Importantly, WIN 55,212-2 treatment did not affect anxiety-like behavior. However, therapeutic and preventative WIN 55,212-2 treatment resulted in an increase locomotor activity and swimming speed in Tg4-42 mice. WIN-treatment reduced microgliosis in the hippocampus of preventively treated mice and rescued brain glucose metabolism in therapeutically treated Tg4-42 mice.
CONCLUSIONS: Our findings emphasize the therapeutic promise of the synthetic cannabinoid WIN 55,212-2 in alleviating behavioral and cognitive deficits linked to AD.}, }
@article {pmid40034512, year = {2025}, author = {Islam, B and Li, T and Ibrahim, TI and Yang, D and Lv, H and Zhang, Q and Xu, M and Gassara, G and Wang, J}, title = {The relationship between levels of physical activity, adherence to the MIND diet, and cognitive impairment in adults aged 65 years or older in Pakistan.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823241290132}, pmid = {40034512}, issn = {2542-4823}, abstract = {BACKGROUND: In contrast to existing evidence focusing on high-income countries, this study offers novel insights into the demographic and geographical context that have yet to be explored in the existing literature. Comparatively, in Pakistan, cognitive impairment is one of the neglected disorders that can develop into dementia and Alzheimer's disease. As no treatment is available, lifestyle modifications are a valid intervention for cognitive health.
OBJECTIVE: This study aimed to assess the relationship between physical functionality, adherence to the Mediterranean-DASH diet Intervention for Neurological Delay (MIND), and cognitive impairment among elderly individuals in Pakistan.
METHODS: From January to June 2023, this cross-sectional study recruited 462 participants aged 65 and above. We used proven tools in gerontological research, such as the MIND diet quiz and Quick Physical Activity Rating scale (QPAR), to evaluate diet and physical activity levels. Cognitive function was assessed using the Mini-Mental State Examination.
RESULTS: Our analysis revealed that 26.40% of the participants had mild cognitive impairment, whereas 48.50% demonstrated low adherence to the MIND diet. The mean QPAR score was 20.51 ± 18.77. A significant association was found between lower physical activity levels and increased cognitive impairment (adjusted odds ratio 9.94, confidence interval (CI): 6.07-16.27). Additionally, higher adherence to the MIND diet correlated with reduced cognitive impairment (odds ratio 0.29, CI: 0.18-0.46).
CONCLUSIONS: These findings highlight the critical role of diet and physical activity in cognitive health among the elderly population. The study emphasizes the need for targeted public health interventions and further longitudinal research to explore the long-term effects of these factors on cognitive health.}, }
@article {pmid40034511, year = {2025}, author = {Mohamed Amine, J and Mourad, M and , }, title = {Alzheimer's disease classification by supervised and intelligent techniques.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823241311838}, pmid = {40034511}, issn = {2542-4823}, abstract = {BACKGROUND: Significant advancements in neuroimaging have emerged over the past decade, notably through positron emission tomography (PET) and magnetic resonance imaging (MRI) for diagnosing Alzheimer's disease (AD) and its precursor, mild cognitive impairment (MCI). Combining imaging modalities with machine learning (ML) techniques enhances diagnostic accuracy.
OBJECTIVE: To develop predictive models using pre-treatment brain imaging data to distinguish between normal controls (NC), MCI, and AD stages, improving diagnostic precision.
METHODS: We utilized the Alzheimer's Disease Neuroimaging Initiative database, processing 3D MRI, PET Florbetaben, and PET Flortaucipir images. Techniques included convolutional neural networks (CNN), fuzzy logic, and multi-layer perceptron (MLP). Feature extraction involved amyloid-β volume, tau protein levels, and empty space volumes.
RESULTS: The fuzzy logic approach achieved a classification accuracy of 99.1%, outperforming CNN (90.67%) and MLP (94%). Integration of multimodal data significantly enhanced performance compared to single-modality approaches.
CONCLUSIONS: Our study demonstrates that integrating advanced ML techniques with multimodal neuroimaging can effectively classify AD stages. These findings address critical gaps in early detection and provide a foundation for future clinical applications.}, }
@article {pmid40034500, year = {2025}, author = {Sato, K and Niimi, Y and Ihara, R and Iwata, A and Nemoto, K and Arai, T and Higashi, S and Igarashi, A and Kasuga, K and Iwatsubo, T}, title = {Sentiment analysis of social media responses to the approval of lecanemab for the treatment of Alzheimer's disease in Japan.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823241307639}, pmid = {40034500}, issn = {2542-4823}, abstract = {Lecanemab, an anti-amyloid therapy for early Alzheimer's disease, received approval by the FDA and Japan in 2023. Public response on social media was scrutinized, aiming to obtain insights into communication and treatment development. For 478 posts from X and Facebook, their sentiments on efficacy, safety, societal significance, and overall lecanemab impression were assessed by GPT-4 and the authors. Results indicated impressions were 43.7% negative, 26.6% neutral, and 29.7% positive. Social significance concerns dominated negative views. Specific attitude patterns were observed in the overall impression to lecanemab's approval. These insights highlight the need for targeted communication and research on anti-amyloid therapies.}, }
@article {pmid40034447, year = {2025}, author = {Shah, R and Basapur, S and Hendrickson, K and Anderson, J and Plenge, J and Troutman, A and Ranjit, E and Banker, J}, title = {Does an Audio Wearable Lead to Agitation Reduction in Dementia: The Memesto AWARD Proof-of-Principle Clinical Research Study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40034447}, issn = {2693-5015}, support = {R43 AG074725/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Agitation is a common behavioral symptom in persons living with Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD), especially in the setting of residential care. Pharmacologic and non-pharmacologic interventions are limited. Memesto is a wearable audio device designed to provide messages and music that can be scheduled or played on demand. The objective of this proof-of-principle study was to quantify whether Memesto can reduce agitation in persons with AD/ADRD.
METHODS: Persons living with AD/ADRD with a Clinical Global Impressions-Severity (CGI-S) average score of 4 or greater, one informal caregiver, and one formal caregiver (triad) were recruited from residential care facilities in the Midwest region of the United States. After consent and a two-week training period, the triad was monitored every two weeks from Baseline to Week 10 with the Neuropsychiatric Inventory (NPI) agitation domain subscale (primary endpoint) and the CGI-S scale (secondary endpoint) with the last observation carried forward. The average score on the NPI agitation domain subscale and the CGI-S scale at Baseline and Week 10 as rated by the two caregivers were compared. A 30% drop in the NPI agitation domain subscale in 50% of the persons living with AD/ADRD was considered a clinically meaningful finding.
RESULTS: Over thirteen months of recruitment, 9 triads were identified in 6 residential care facilities in three Midwestern states. For the NPI agitation domain, 6 of 9 (67%) persons with AD/ADRD had a 30% reduction in the average caregiver ratings at Week 10. No adverse events were identified associated with the use of the device. Device usability was rated as positive based on a survey.
DISCUSSION: This study provided quantitative data on psychometrically sound agitation scales regarding a 10-week treatment course with Memesto after a two-week training period. The results were limited by the inability to recruit the desired set of 20 triads due to disruptions in care and staff at residential care facilities. Further effectiveness testing in a larger cohort with a sham control device is necessary.
TRIAL REGISTRATION: www.clinicaltrials.gov. NCT05153161. First posted December 10, 2021.}, }
@article {pmid40034367, year = {2024}, author = {Huang, YS and Kung, TJ and Chuang, YF}, title = {Intravenous thrombolysis therapy and dementia risk in acute ischemic stroke patients: A retrospective cohort study in Taiwan.}, journal = {Journal of Alzheimer's disease reports}, volume = {8}, number = {1}, pages = {1541-1548}, pmid = {40034367}, issn = {2542-4823}, abstract = {BACKGROUND: Intravenous thrombolysis (IVT) is the standard treatment for acute ischemic stroke (AIS) to improve functional outcomes. Furthermore, AIS is an important risk factor for dementia. Limited evidence has shown the long-term benefit of IVT on dementia in Western countries.
OBJECTIVE: We aim to investigate the association between IVT and the risk of dementia in acute ischemic stroke patients in Asian population.
METHODS: A retrospective cohort study using medical records from a medical center in Taiwan between 2017 and 2022 was conducted. We included acute ischemic stroke patients aged over 55 years old who had not previously been diagnosed with dementia. The primary outcome was incident dementia ascertained through dementia diagnosis in medical records. The inverse probability of treatment-weighted Cox proportional hazard models were used to estimate the association between IVT and incident dementia.
RESULTS: A total of 1471 patients with AIS were included. 939 (63.8%) were male, and the mean age was 70.7 ± 9.6 years. Among them, 19.1% of patients (n = 281) received IVT. The mean follow-up time was 2.6 ± 1.7 years. Although not statistically significant, the IVT was associated with a decreased risk of dementia (HR: 0.88 [95%CI 0.54-1.41)]).
CONCLUSIONS: The IVT was associated with lower risk of dementia, although not statistically significant, in reducing the incidence of dementia in Asian patients with ischemic stroke. Studies with larger sample sizes will be needed in the future.}, }
@article {pmid40034361, year = {2024}, author = {Xu, J and Liu, B and Shang, G and Liu, S and Feng, Z and Yang, H and Liu, D and Chang, Q and Chen, Y and Yu, X and Mao, Z}, title = {Deep brain stimulation of the nucleus basalis of Meynert in severe Alzheimer's disease.}, journal = {Journal of Alzheimer's disease reports}, volume = {8}, number = {1}, pages = {1573-1586}, pmid = {40034361}, issn = {2542-4823}, abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly prevalent, leading to severe cognitive decline and a diminished quality of life for patients. Nucleus basalis of Meynert deep brain stimulation (NBM-DBS) is a potential treatment approach.
OBJECTIVE: This study aims to assess the efficacy and safety of NBM-DBS for AD patients.
METHODS: We conducted a clinical study involving 6 patients with severe AD who received NBM-DBS. The treatment's safety and efficacy were evaluated using cognitive function tests (Mini-Mental State Examination, Montreal Cognitive Assessment, Alzheimer's Disease Rating Scale- cognitive subscale, Clinical Dementia Rating) and assessments of neuropsychiatric symptoms and sleep disorders (Functional Activity Questionnaire, Functional Independence Measure, Zarit Burden Interview, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, Neuropsychiatric Inventory, Pittsburgh Sleep Quality Index).
RESULTS: NBM-DBS was safe, with no severe adverse events. It improved cognitive functions and self-care abilities without altering the disease's progression. Notably, NBM-DBS significantly alleviated neuropsychiatric symptoms and sleep disturbances.
CONCLUSIONS: NBM-DBS could be a promising therapeutic approach for severe AD, particularly for managing neuropsychiatric symptoms and sleep disorders. Further research is warranted to confirm these preliminary findings.}, }
@article {pmid40034353, year = {2024}, author = {Don Bosco, RB and Selvan Christyraj, JRS and Yesudhason, BV}, title = {Synergistic activity of nootropic herbs as potent therapeutics for Alzheimer's disease: A cheminformatics, pharmacokinetics, and system pharmacology approach.}, journal = {Journal of Alzheimer's disease reports}, volume = {8}, number = {1}, pages = {1745-1762}, pmid = {40034353}, issn = {2542-4823}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which subdues over 55 million people and finding a cure, still remains disenchanting. Indian medicinal herbs notably, Withania somnifera, Bacopa monnieri, Curcuma longa, and Clitoria ternatea are traditionally utilized for their memory-enhancing properties.
OBJECTIVE: We computationally investigated the therapeutic potential of four nootropic herbs by uncovering the molecular mechanisms underlying their treatment for AD.
METHODS: Cheminformatics, pharmacokinetics, and system pharmacology studies were carried out to predict the phytocompounds drug-like properties, protein targets, targets functional association and enrichment analysis. A comparative study was performed with phytocompounds and FDA-approved drugs. Investigation on the expression of protein targets in the hippocampus and entorhinal cortex of the AD brain was performed. Network was constructed to depict the interaction between phytocompounds, drugs, and molecular targets.
RESULTS: Through comparative analysis, we found that the phytocompounds shared common targets with both FDA drugs and drugs under clinical trials. We identified potential active compounds notably, Withaferin A, Withanolide-D, Withanolide-E, Withanolide-G, and Humulene epoxide II, that can combat AD. Interestingly, the enzyme inhibition scores of the identified drugs were much higher than FDA-approved drugs. In addition, regulatory proteins such as AβPP, acetylcholinesterase, BACE1, and PTPN1 were the targets of 8, 16, 9, and 22 phytocompounds, respectively. Nonetheless, AR and CYP19A, were the primary targets of most phytocompounds.
CONCLUSIONS: Herbal medicines can synergistically stimulate multiple protein targets, rendering a holistic and integrative treatment, encouraging a promising avenue to treat AD.}, }
@article {pmid40034352, year = {2024}, author = {Matthews, DG and Khorani, M and Bobe, G and Caruso, M and Magana, AA and Gray, NE and Quinn, JF and Stevens, JF and Maier, CS and Soumyanath, A}, title = {Centella asiatica improves cognitive function and alters the hippocampal metabolome of aged Tg2576 and wild-type mice.}, journal = {Journal of Alzheimer's disease reports}, volume = {8}, number = {1}, pages = {1611-1638}, pmid = {40034352}, issn = {2542-4823}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a growing public health problem in the aging population, with limited treatment options. We previously reported that Centella asiatica herb water extract (CAW) attenuates cognitive decline in murine models of AD and aging.
OBJECTIVE: To explore changes in the hippocampal metabolome associated with CAW's modulation of cognitive function and amyloid-β (Aβ) plaque load in aged Tg2576 and wild-type (WT) mice.
METHODS: We compared cognitive function, hippocampal Aβ plaque burden, and hippocampal metabolite profile in 20-month-old Tg2576 female mice and their WT littermates following 3-5 weeks treatment with CAW (0, 200, or 1000 mg/kg/d p.o.). Cognitive testing included contextual fear response (CFR) and novel object recognition task (NORT). Aβ plaque burden was measured via immunohistochemistry. Metabolomic profiles of mouse hippocampi were obtained using liquid chromatography coupled with high resolution tandem mass spectrometry.
RESULTS: CAW treatment resulted in dose-related improvements in CFR and NORT performance of Tg2576 and WT mice. However, while CFR correlated with neurosignaling and glycosylated ceramide levels, NORT performance correlated with lysophosphatidylcholines and oxidized metabolites, and Aβ accumulation was linked to elevated excitatory and suppressed inhibitory neurotransmission. Only a subset of the metabolite changes induced by CAW in Tg2576 mice represented a reversal of metabolite differences between Tg2576 and WT mice, suggesting the involvement of other pathways in CAW's cognitive effects.
CONCLUSIONS: Mechanisms underlying CAW's cognitive effects extend beyond reversing metabolic effects of Aβ accumulation. The data support the potential use of CAW to manage memory challenges in aged individuals with or without AD.}, }
@article {pmid40034349, year = {2024}, author = {Xu, J and Liu, B and Feng, Z and Yu, X and Shang, G and Liu, Y and Sun, Y and Yang, H and Chen, Y and Zhang, Y and Mao, Z}, title = {Deep brain stimulation versus nonsurgical treatment for severe Alzheimer's disease: A long-term retrospective cohort study.}, journal = {Journal of Alzheimer's disease reports}, volume = {8}, number = {1}, pages = {1677-1689}, pmid = {40034349}, issn = {2542-4823}, abstract = {BACKGROUND: Severe Alzheimer's disease (AD) is characterized by significant neuropsychiatric symptoms and sleep disorders, with limited effectiveness of conservative drug treatments. Deep brain stimulation (DBS) offers a potential alternative.
OBJECTIVE: To evaluate the efficacy, safety, and long-term outcomes of DBS versus conservative treatment in patients with severe AD.
METHODS: We retrospectively analyzed 40 patients with severe AD diagnosed at the People's Liberation Army General Hospital from 2015 to 2022. Twenty patients received DBS, and twenty received conservative treatment. Treatment effects were assessed using standardized scales at three- and twelve-months post-treatment. Primary outcomes included changes in cognitive function [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Alzheimer's Disease Rating Scale-Cognitive subscale, Clinical Dementia Rating). Secondary outcomes included quality of life, sleep quality, neuropsychiatric symptoms, and caregiver burden (Barthel Index, Functional Activity Questionnaire, Functional Independence Measure (FIM), Neuropsychiatric Inventory (NPI), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), Pittsburgh Sleep Quality Index (PDQI), Zarit Burden Interview (ZBI)].
RESULTS: DBS patients showed significantly greater improvements in MMSE, MoCA, FIM, and ZBI scores than controls, suggesting improved cognitive function and quality of life, and reduced caregiver burden (p < 0.05). Notably, DBS significantly reduced HAM-A, HAM-D, and PSQI scores, and improved NPI scores more than controls, indicating significant amelioration of neuropsychiatric symptoms and sleep disorders (p < 0.05).
CONCLUSIONS: DBS is a safe and reversible treatment that potentially enhances cognitive function and quality of life in severe AD patients and alleviates caregiver burden. For the first time, we report that DBS also improves neuropsychiatric symptoms and sleep disorders, highlighting its clinical potential in AD.}, }
@article {pmid40034344, year = {2024}, author = {Fischer, MHF and Zibrandtsen, IC and Johannsen, P and Siersma, V and Rasmussen, JB and Larsen, JB and Høgh, P}, title = {Therapeutic drug monitoring for dose optimization in Alzheimer's disease and in dementia with Lewy bodies: A randomized single-blinded clinical trial.}, journal = {Journal of Alzheimer's disease reports}, volume = {8}, number = {1}, pages = {1516-1528}, pmid = {40034344}, issn = {2542-4823}, abstract = {BACKGROUND: Previous evidence suggests serum concentrations of donepezil varies in clinical populations and that a dose higher than standard may have additional positive effect on cognition. Therapeutic drug monitoring (TDM) is a tool for dose optimization (DO) whereby treatment is adjusted based on previous quantification of the prescribed drug.
OBJECTIVE: Investigate whether TDM-based DO of donepezil or memantine improves clinical outcomes and/or reduce the frequency of adverse reactions (ARs) in neurodegenerative conditions commonly treated with these two study drugs.
METHODS: Single-blinded 1:1 randomized controlled study in an outpatient memory clinic. Eligible participants either newly diagnosed with Alzheimer's disease dementia (AD), dementia with Lewy bodies (DLB), or Parkinson's disease dementia (PDD) scheduled for treatment with donepezil or memantine. The intervention group received TDM based DO. The control group received DO solely based on clinical assessment. Clinical outcomes were change in Mini-Mental State Examination, Addenbrooke's Cognitive Examination, Neuropsychiatric Inventory, and Disability Assessment in Dementia from baseline to 12 months. Additionally, data on incidence and severity of ARs and proportion of participants with a serum concentration within the therapeutic reference range were collected.
RESULTS: 132 participants recruited (125 AD, 7 DLB, none with PDD) of whom 107 completed the study (101 AD and 6 DLB), fewer in the control group than planned. Statistical analysis did not reveal significant differences between groups neither for clinical outcomes nor for frequency of ARs.
CONCLUSIONS: TDM based DO did not significantly improve clinical outcomes nor reduce the frequency of ARs albeit important caveats to the results apply.
CLINCIALTRIALSGOV IDENTIFIER: NCT04117178 (first posted October 7, 2019).}, }
@article {pmid40034321, year = {2025}, author = {Uthaman, SK and Kang, WS and Park, JY and Kim, S and Le, DD and Oh, SJ and Murugesh, K and Oh, LM and Lee, M and Park, JW}, title = {Endogenous extraction yielded high quality sulforaphane from broccoli sprouts unveils potent antioxidant and anti-Alzheimer's activities.}, journal = {Heliyon}, volume = {11}, number = {4}, pages = {e42673}, pmid = {40034321}, issn = {2405-8440}, abstract = {The extraction of sulforaphane (SFN) is challenging due to its instability and low water solubility, with existing methods often involving toxic solvents or yielding low SFN. We optimized an endogenous extraction protocol for high SFN content, characterized by HPLC and LC-MS analyses. SFN remained stable in refrigerated broccoli sprout extract powder (BSEP) for over a month. BSEP showed four times higher oxygen radical absorbance capacity (ORAC) than the SFN standard, indicating high antioxidant capacity. It also reduced inflammatory responses by down-regulating COX-2, IL-6, and TNF-α gene expression in LPS-induced RAW 264.7 macrophages. Additionally, BSEP exhibited neuroprotective properties in amyloid-beta (1-42) (Aβ1-42)-induced Alzheimer's disease (AD) mice, enhancing memory and learning retention in water maze and passive avoidance tests. BSEP mitigated spatial cognitive impairment and improved memory function in Aβ1-42-induced memory-deficient mice. While BSEP did not alter acetylcholine (ACh) concentration, it improved memory and learning by inhibiting acetylcholinesterase (AChE) activity. BSEP with SFN content exceeding 200 mg/kg ameliorated neurobehavioral deficits and protected the brain from amyloid deposition, suggesting its therapeutic potential in AD treatment. We propose an eco-friendly form of SFN-rich BSEP for daily intake and commercial therapeutics.}, }
@article {pmid40034281, year = {2025}, author = {Nour, H and Abchir, O and Mounadi, N and Samadi, A and Salah, B and Chtita, S}, title = {Exploration of natural products for the development of promising cholinesterase inhibitors in Alzheimer's disease treatment.}, journal = {Heliyon}, volume = {11}, number = {4}, pages = {e42479}, pmid = {40034281}, issn = {2405-8440}, abstract = {Cholinesterase enzymes (BuChE and AChE) are privileged biological targets for the symptomatic treatment of Alzheimer's disease. Indeed, inhibition of cholinesterase enzymes has been proven to improve the neurotransmission mechanisms in Alzheimer's disease patients. In this investigation, we attempt to highlight new cholinesterase inhibitors from natural products. For this purpose, secondary metabolites (299 phytoconstituents) of twenty-eight Medicinal plants were virtually screened using molecular docking, pharmacokinetic and toxicological analysis. Ten phytoconstituents (L82, L86, L92, L121, L148, L187, L211, L221, L228) exhibited their high binding affinity with BuChE, and five phytoconstituents, namely L119, L147, L149, L192 and L193, exhibited their strong binding ability with AChE. Subsequently, these phytoconstituents were evaluated for their ADMET properties. As result, L221 is predicted to be highly bioavailable and readily absorbed by the human intestinal tract without significant toxicity concerns, making it suitable for oral administration. Crucially, it can penetrate the blood-brain barrier (BBB), allowing it to effectively reach the central nervous system. Molecular dynamics simulations and MM-PBSA analysis revealed that the best-screened phytoconstituent form thermodynamically favorable and stable complex with the BuChE binding site. The conducted investigations highlighted promising outcomes that can orient towards the rational development of effective Cholinesterase inhibitors.}, }
@article {pmid40033867, year = {2025}, author = {Zhou, L and Zhang, M and Zheng, Q and Song, Y and Yan, Z and Wang, H and Xiong, Y and Chen, Y and Cai, Z and Yuan, J}, title = {Exploring the Mechanism of Kai-Xin-San to Improve Cognitive Deficits in AD Rats Induced by D-Gal and Aβ25-35 Based on Multi-Omics and Network Analysis.}, journal = {Biomedical chromatography : BMC}, volume = {39}, number = {4}, pages = {e70047}, doi = {10.1002/bmc.70047}, pmid = {40033867}, issn = {1099-0801}, support = {82060822//National Natural Science Foundation of China/ ; CXTD22003//Innovation Team of Processing Technique of Traditional Chinese Medicine/ ; GSJK202313//Science and Technology projects of Jiangxi Market Supervision Bureau/ ; 20202ACBL206030//Natural Science Foundation of Jiangxi Province/ ; }, mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology ; Rats ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism ; Male ; *Cognitive Dysfunction/drug therapy/metabolism ; *Proteomics/methods ; *Peptide Fragments/metabolism ; Rats, Sprague-Dawley ; Disease Models, Animal ; Metabolomics ; Metabolome/drug effects ; Hippocampus/drug effects/metabolism ; Multiomics ; }, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disease for which there are no effective drugs. Kai-Xin-San (KXS), with definite curative effects, is widely used for the prevention and treatment of AD in China. But its mechanism is not yet fully understood. Based on our established rat model and previous pharmacodynamics study, Multi-omics (metabolomics, proteomics) and network analysis were integrated to explore the holistic mechanism of anti-AD effects of KXS. The key pathways were validated with western blot and ELISA methods. Morris water maze and Nissl staining showed that KXS could ameliorate cognitive deficits and pathological morphology of the hippocampus in AD rats. A total of nine metabolites were identified, which were related to pyrimidine metabolism, riboflavin metabolism, tyrosine metabolism, tryptophan metabolism, and glycerophospholipid metabolism. Proteomics results indicated that the improvement of cognitive deficits by KXS was closely related to the regulation of oxidative phosphorylation in mitochondria. Western blotting results showed that KXS significantly inhibited the expression of Mt-nd2 and Ndufb6 in AD rats. Integrated analysis indicated that the anti-AD targets of KXS were interrelated and KXS could exert its anti-AD effect by reducing oxidative stress, neurotoxicity, and inflammation.}, }
@article {pmid40033713, year = {2025}, author = {Radjenovic, S and Bender, L and Gaal, M and Grigoryeva, D and Mitterwallner, M and Osou, S and Zettl, A and Plischek, N and Lachmair, P and Herzhauser, K and Matt, E and Beisteiner, R}, title = {A retrospective analysis of ultrasound neuromodulation therapy using transcranial pulse stimulation in 58 dementia patients.}, journal = {Psychological medicine}, volume = {55}, number = {}, pages = {e70}, doi = {10.1017/S0033291725000406}, pmid = {40033713}, issn = {1469-8978}, mesh = {Humans ; Female ; Male ; Retrospective Studies ; Aged ; *Cognitive Dysfunction/therapy ; *Dementia/therapy ; Aged, 80 and over ; Transcranial Direct Current Stimulation/methods ; Middle Aged ; Ultrasonic Therapy/methods ; Alzheimer Disease/therapy ; Treatment Outcome ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Novel ultrasound neuromodulation techniques allow therapeutic brain stimulation with unmet precision and non-invasive targeting of deep brain areas. Transcranial pulse stimulation (TPS), a multifrequency sonication technique, is approved for the clinical treatment of Alzheimer's disease (AD). Here, we present the largest real-world retrospective analysis of ultrasound neuromodulation therapy in dementia (AD, vascular, mixed) and mild cognitive impairment (MCI).
METHODS: The consecutive sample involved 58 patients already receiving state-of-the-art treatment in an open-label, uncontrolled, retrospective study. TPS therapy typically comprises 10 sessions (range 8-12) with individualized MRI-based target areas defined according to brain pathology and individual pathophysiology. We compared the CERAD-Plus neuropsychological test battery results before and after treatment, with the CERAD Corrected Total Score (CTS) as the primary outcome. Furthermore, we analyzed side effects reported by patients during the treatment period.
RESULTS: CERAD Corrected Total Score (CTS) significantly improved (p = .017, d = .32) after treatment (Baseline: M = 56.56, SD = 18.56; Post-treatment: M = 58.65, SD = 19.44). The group of top-responders (top quartile) improved even by 9.8 points. Fewer than one-third of all patients reported any sensation during treatment. Fatigue and transient headaches were the most common, with no severe adverse events.
CONCLUSIONS: The findings implicate TPS as a novel and safe add-on therapy for patients with dementia or MCI with the potential to further improve current state-of-the-art treatment results. Despite the individual benefits, further randomized, sham-controlled, longitudinal clinical trials are needed to differentiate the effects of verum and placebo.}, }
@article {pmid40033213, year = {2025}, author = {Qader, MA and Hosseini, L and Abolhasanpour, N and Oghbaei, F and Maghsoumi-Norouzabad, L and Salehi-Pourmehr, H and Fattahi, F and Sadeh, RN}, title = {A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models.}, journal = {BMC neuroscience}, volume = {26}, number = {1}, pages = {17}, pmid = {40033213}, issn = {1471-2202}, mesh = {Animals ; *NAD/metabolism ; Disease Models, Animal ; Cognitive Dysfunction/drug therapy ; Rats ; Mice ; }, abstract = {This systematic review sought to assess the impact of nicotinamide adenine dinucleotide (NAD[+]) precursors on cognitive impairments in several diseases in rat/mouse models. Accumulating evidence suggests that inflammation, apoptosis, oxidative stress responses, and mitochondrial dysfunction are potential factors of cognitive deficits in aging, Alzheimer's disease (AD), diabetes, traumatic brain injury (TBI), vascular dementia (VAD), and schizophrenia. NAD[+] precursors have received increased interest due to their unique molecular structure targets antioxidant and inflammatory pathways and mitochondrial function. The PubMed, Scopus, Google Scholar, Embase, and Web of Science databases were searched through May 30, 2024. Studies investigating the effect of NAD[+] precursors on cognitive impairments in rodent models were included. Two reviewers independently extracted and evaluated the data. The PRISMA guidelines for reporting systematic reviews were followed. Thirty preclinical studies were included in the review. Studies have revealed that treatment with NAD[+] rescues cognitive deficits by inhibiting inflammation, oxidative stress, and apoptosis and improving mitochondrial function. Preclinical evidence has demonstrated that treatment with NAD[+] precursors may be more effective in learning and memory recovery in AD, TBI, diabetes, aging, VAD, and schizophrenia. The outcomes of this investigation may lead to additional studies on the use of NAD[+] precursors for treating human cognitive decline.}, }
@article {pmid40032030, year = {2025}, author = {Wang, S and Yang, Y and Lin, J and Zhang, W and Yang, C and Zhang, R and Zhou, C and Zhang, L and Wang, X and Liu, J and Jin, X and Ma, Y}, title = {Astragalin actives autophagy and inhibits apoptosis of astrocytes in AD mice via down-regulating Fas/Fasl-VDAC1 pathway.}, journal = {Free radical biology & medicine}, volume = {232}, number = {}, pages = {72-85}, doi = {10.1016/j.freeradbiomed.2025.02.047}, pmid = {40032030}, issn = {1873-4596}, abstract = {Alzheimer's disease (AD) as a common neurodegenerative disease, which characterized by amyloid Aβ deposition and neurofibrillary tangles. Astragalin (AST), a natural flavonoid, has anti-inflammatory, antioxidant, anti-cancer, and other pharmacological effects. Astrocytes can phagocytize and degrade Aβ in their vicinity. In this study, we used the AD mice model established by injecting the mixture of Aβ1-42 and Aβ25-35 into the CA1 region of the hippocampus, and C8D1A cells injured by Aβ1-42 to explore the neuroprotective effects of AST. Our findings showed that AST enhances learning and cognitive ability of AD mice, reduces Aβ deposition and neurofibrillary tangles in the brain, and improves the structural morphology of hippocampal nerve cells. Furthermore, AST promoted autophagy and suppressed apoptosis of astrocytes in the AD model. Additionally, AST inhibited the expression of proteins associated with the Fas/Fasl-VDAC1 signaling pathway, while autophagy inhibitor chloroquine (CQ) or apoptosis agonist phenoxodiol reversed above change. Interestingly, consistent with the action of pathway Fas inhibitor KR-33493, AST could activate autophagy of Aβ1-42 injured C8D1A cells while inhibit their apoptosis. In conclusion, AST activated autophagy and inhibited apoptosis of hippocampal astrocytes in AD mice, ameliorating animal cognitive deficits by down-regulating Fas/Fasl-VDAC1 signaling pathway. Thus, this study provided a new perspective and experimental foundation for developing AD treatment drugs.}, }
@article {pmid40031897, year = {2025}, author = {Loupy, KM and Dawud, LM and Zambrano, CA and Lee, T and Heinze, JD and Elsayed, AI and Hassell, JE and D'Angelo, HM and Frank, MG and Maier, SF and Brenner, LA and Lowry, CA}, title = {Effects of Oral Administration of the Probiotic Lactobacillus rhamnosus GG on the Proteomic Profiles of Cerebrospinal Fluid and Immunoregulatory Signaling in the Hippocampus of Adult Male Rats.}, journal = {Neuroimmunomodulation}, volume = {32}, number = {1}, pages = {94-109}, doi = {10.1159/000544842}, pmid = {40031897}, issn = {1423-0216}, mesh = {Animals ; Male ; *Lacticaseibacillus rhamnosus ; Rats ; *Hippocampus/metabolism/drug effects ; *Probiotics/administration & dosage/pharmacology ; Administration, Oral ; *Signal Transduction/drug effects/physiology ; Proteomics ; Rats, Sprague-Dawley ; Proteome/metabolism ; }, abstract = {INTRODUCTION: The microbiome-gut-brain axis, by modulating bidirectional immune, metabolic, and neural signaling pathways in the host, has emerged as a target for the prevention and treatment of psychiatric and neurological disorders. Oral administration of the probiotic bacterium Lactobacillus rhamnosus GG (LGG; ATCC 53103) exhibits anti-inflammatory effects, although the precise mechanisms by which LGG benefits host physiology and behavior are not known. The goal of this study was to explore the general effects of LGG on the cerebrospinal fluid (CSF) proteome and a biological signature of anti-inflammatory signaling in the central nervous system (CNS) of undisturbed, adult male rats.
METHODS: Liquid chromatography-tandem mass spectrometry-based proteomics were conducted using CSF samples collected after 21 days of oral treatment with live LGG (3.34 × 107 colony-forming units (CFU)/mL in the drinking water (resulting in an estimated delivery of ∼1.17 × 109 CFU/day/rat) or water vehicle. Gene enrichment analysis (using DAVID, v. 6.8) and protein-protein interactions (using STRING, v. 11) were used to explore physiological network changes in CSF. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was performed to assess gene expression changes of anti-inflammatory cytokines in the hippocampus. Genes associated with anti-inflammatory signaling that were analyzed included Il10, Tgfb1, Il4, and IL-4-responsive genes, Cd200, Cd200r1, and Mrc1 (Cd206).
RESULTS: Oral LGG administration altered the abundance of CSF proteins, increasing the abundance of five proteins (cochlin, NPTXR, reelin, Sez6l, and VPS13C) and decreasing the abundance of two proteins (CPQ, IGFBP-7) in the CSF. Simultaneously, LGG increased the expression of Il10 mRNA, encoding the anti-inflammatory cytokine interleukin 10, in the hippocampus.
CONCLUSION: Oral LGG altered the abundance of CSF proteins associated with extracellular scaffolding, synaptic plasticity, and glutamatergic signaling. These data are consistent with the hypothesis that oral administration of LGG improves memory and cognition, and promotes a physiological resilience to neurodegenerative disease, by increasing glutamatergic signaling and promoting an anti-inflammatory environment in the brain.}, }
@article {pmid40031708, year = {2025}, author = {Dong, Z and Xu, W and Xu, X and Zhang, Z}, title = {Modality Imbalance? Dynamic Multi-Modal Knowledge Distillation in Automatic Alzheimer's Disease Recognition.}, journal = {IEEE journal of biomedical and health informatics}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/JBHI.2025.3546950}, pmid = {40031708}, issn = {2168-2208}, abstract = {Alzheimer's disease (AD), as the most prevalent form of dementia, necessitates early identification and treatment for the critical enhancement of patients' quality of life. Recent studies strive to explore advanced machine learning approaches with multiple information cues, such as speech and text, to automatically and precisely detect this disease from conversations. However, these multi-modality-based approaches often suffer from a modality- imbalance challenge that leads to performance degradation. That is, the multi-modal model performs worse than the best mono-modal model, although the former contains more information. To address this issue, we propose a Dynamic Multi-Modal Knowledge Distillation (DMMKD) approach, which dynamically identify the dominant modality and the weak modality, and opt to conduct an inter(cross)-modal or intra-modal knowledge distillation. The core idea is to balance the individual learning speed in the multi-modal learning process by boosting the weak modality with the dominant modality. To evaluate the effectiveness of the introduced DMMKD algorithm, we conducted extensive experiments on two publicly available and widely used AD datasets, i.e. ADReSSo and ADReSS-M. Compared to the multi-modal approaches without dealing with the modality imbalance issue, the introduced DMMKD indicates substantial performance improvements by 15.4% and 10.9% in terms of relative accuracy on the ADReSSo and ADReSS-M datasets, respectively. Moreover, when compared to the state-of-the-art models for automatic AD detection, the DMMKD achieves the best performance of 91.5% and 87.0% accuracies on the two datasets, respectively.}, }
@article {pmid40031545, year = {2025}, author = {Wang, Q and Xu, L and Shan, Y and Shen, W and Li, L and Bi, XA and Liu, Z}, title = {CPST-GAN: Conditional Probabilistic State Transition Generative Adversarial Network With the Biomedical Large Foundation Models.}, journal = {IEEE transactions on neural networks and learning systems}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TNNLS.2025.3539006}, pmid = {40031545}, issn = {2162-2388}, abstract = {The risk prediction of Alzheimer's disease (AD) is crucial for its early prevention and treatment. However, current risk prediction methods face challenges in effectively extracting and fusing multiomics features, particularly overlooking the multilevel evolutionary mechanisms of AD. This article combines biomedical large foundation models with the conditional generative adversarial network (GAN) to mine the evolutionary patterns of AD by considering the regulatory effect of genes on brain lesions. Specifically, we first use biomedical large foundation models to effectively construct high-quality imaging genetic features. Next, a conditional probabilistic state transition mathematical model is constructed to describe AD progression as state transitions of brain regions under genetic regulations. Based on the mathematical model, a conditional probabilistic state transition GAN (CPST-GAN) is proposed. This algorithm can mine the dynamic evolutionary patterns of AD by fusing brain imaging and genetic features to achieve risk prediction of AD. Finally, experiments on the public imaging genetics datasets validate the effectiveness and superiority of CPST-GAN in evolutionary pattern mining and risk prediction of AD. This article not only provides a reliable intelligence algorithm for early intervention of AD but also offers new insights for future research on AD pathogenesis. The code has been published at github.com/fmri123456/CPST-GAN.}, }
@article {pmid40030850, year = {2025}, author = {Hong, Z and Yi, S and Deng, M and Zhong, Y and Zhao, Y and Li, L and Zhou, H and Xiao, Y and Hu, X and Niu, L}, title = {Transcranial Focused Ultrasound Modifies Disease Progression in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on ultrasonics, ferroelectrics, and frequency control}, volume = {72}, number = {2}, pages = {191-201}, doi = {10.1109/TUFFC.2024.3525143}, pmid = {40030850}, issn = {1525-8955}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnostic imaging/genetics ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Ultrasonic Therapy/methods ; Superoxide Dismutase-1/genetics ; Disease Progression ; Muscle, Skeletal/physiopathology ; Male ; Motor Cortex ; Humans ; Elasticity Imaging Techniques ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressively worsening neurodegenerative condition with very few treatment options available. Ultrasound neuromodulation offers promising benefits for treating neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. However, the effects and underlying mechanisms of ultrasound neuromodulation on ALS remain unclear. A head-mounted ultrasound neuromodulation system was developed to noninvasively stimulate the motor cortex of symptomatic mice carrying the G93A human SOD1 mutation (SOD $1^{\text {G93A}}$) for four weeks. Motor performance was assessed through the rotarod locomotor test, grip strength test, and open field test. In addition, the effect of ultrasound stimulation on the elastic modulus of gastrocnemius muscle atrophy was measured using real-time shear wave elastography (SWE). Subsequently, the brain tissues of the mice were harvested. Gastrocnemius morphology was examined using hematoxylin-eosin and Gomori aldehyde-fuchsin (GAF) staining. The number of neurons and the phenotype of microglia in the motor cortex were observed by immunohistochemical analysis. Ultrasound therapy delayed disease onset by 10.7% and increased the lifespan by 6.7% in SOD $1^{\text {G93A}}$ mice by reduction of neuronal loss and enhancement of M2 microglia in the motor cortex. Furthermore, we found significant improvements in motor function for ultrasound-treated mice. More importantly, ultrasound stimulation ameliorated gastrocnemius muscle atrophy in the SOD $1^{\text {G93A}}$ mice. These results revealed the neuroprotective effects of ultrasound against the disease pathogenesis of SOD $1^{\text {G93A}}$ mice. Transcranial ultrasound neuromodulation provides an innovative tool for the intervention and treatment of neurodegenerative diseases.}, }
@article {pmid40028606, year = {2025}, author = {Nieves, J and Gil, G and Gonzalez, A}, title = {A bird's eye view to the homeostatic, Alzheimer and Glioblastoma attractors.}, journal = {Heliyon}, volume = {11}, number = {4}, pages = {e42445}, pmid = {40028606}, issn = {2405-8440}, abstract = {Dimensional reduction analysis of available data for white matter of the brain allows to locate the normal (homeostatic), Glioblastoma and Alzheimer's disease attractors in gene expression space and to identify paths related to transitions like carcinogenesis or Alzheimer's disease onset. A predefined path for aging is also apparent, which is consistent with the hypothesis of programmatic aging. In addition, reasonable assumptions about the relative strengths of attractors allow to draw a schematic landscape of fitness: a Wright's diagram. These simple diagrams reproduce known relations between aging, Glioblastoma and Alzheimer's disease, and rise interesting questions like the possible connection between programmatic aging and Glioblastoma in this tissue. We anticipate that similar multiple diagrams in other tissues could be useful in the understanding of the biology of apparently unrelated diseases or disorders, and in the discovery of unexpected clues for their treatment.}, }
@article {pmid40028337, year = {2025}, author = {Fu, J and Wang, R and He, J and Liu, X and Wang, X and Yao, J and Liu, Y and Ran, C and Ye, Q and He, Y}, title = {Pathogenesis and therapeutic applications of microglia receptors in Alzheimer's disease.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1508023}, pmid = {40028337}, issn = {1664-3224}, mesh = {Humans ; *Alzheimer Disease/metabolism/immunology/therapy/etiology ; *Microglia/metabolism/immunology ; Animals ; Receptors, Immunologic/metabolism ; Brain/metabolism/immunology/pathology ; }, abstract = {Microglia, the resident immune cells of the central nervous system, continuously monitor the brain's microenvironment through their array of specific receptors. Once brain function is altered, microglia are recruited to specific sites to perform their immune functions, including phagocytosis of misfolded proteins, cellular debris, and apoptotic cells to maintain homeostasis. When toxic substances are overproduced, microglia are over-activated to produce large amounts of pro-inflammatory cytokines, which induce chronic inflammatory responses and lead to neurotoxicity. Additionally, microglia can also monitor and protect neuronal function through microglia-neuron crosstalk. Microglia receptors are important mediators for microglia to receive external stimuli, regulate the functional state of microglia, and transmit signals between cells. In this paper, we first review the role of microglia-expressed receptors in the pathogenesis and treatment of Alzheimer's disease; moreover, we emphasize the complexity of targeting microglia for therapeutic interventions in neurodegenerative disorders to inform the discovery of new biomarkers and the development of innovative therapeutics.}, }
@article {pmid40027607, year = {2025}, author = {Katel, S and Cicalo, J and Vasciaveo, V and Carrion, J and Leann, M and Huerta, PT and Marambaud, P and Giliberto, L and d'Abramo, C}, title = {AAV-mediated peripheral single chain variable fragments' administration to reduce cerebral tau in adult P301S transgenic mice: mono- vs combination therapy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027607}, issn = {2692-8205}, support = {P01 AI073693/AI/NIAID NIH HHS/United States ; P01 AI102852/AI/NIAID NIH HHS/United States ; R01 AG061381/AG/NIA NIH HHS/United States ; }, abstract = {Tau is a primary target for immunotherapy in Alzheimer's disease. Recent studies have shown the potential of anti-tau fragment antibodies in lowering pathological tau levels in vitro and in vivo. Here, we compared the effects of single-chain variable fragments (scFv) derived from the well-characterized monoclonal antibodies PHF1 and MC1. We used adeno-associated virus 1 (AAV1) to deliver scFvs to skeletal muscle cells in eight-week-old P301S tau transgenic mice. We evaluated motor and behavioral functions at 16 and 23 weeks of age and measured misfolded, soluble, oligomeric and insoluble brain tau species. Monotherapy with scFv-MC1 improved motor and behavioral functions more effectively than scFv-PHF1 or combination therapy. Brain glucose metabolism also benefited from scFv-MC1 treatment. Surprisingly, combining scFvs targeting early (MC1) and late (PHF1) tau modifications did not produce additive or synergistic effects. These results confirm that intramuscular AAV1-mediated scFv-MC1 gene therapy holds promise as a potential treatment for Alzheimer's disease. Our findings also suggest that combining scFvs targeting different tau epitopes may not necessarily enhance efficacy if administered together in a prevention paradigm. Further research is needed to explore whether other antibodies' combinations and/or administration schedules could improve the efficacy of scFv-MC1 alone.}, }
@article {pmid40027342, year = {2025}, author = {Al-Karmalawy, AA and Mohamed, AF and Shalaby, HN and Elmaaty, AA and El-Shiekh, RA and Zeidan, MA and Alnajjar, R and Alzahrani, AYA and Al Mughram, MH and Shaldam, MA and Tawfik, HO}, title = {Donepezil-based rational design of N-substituted quinazolinthioacetamide candidates as potential acetylcholine esterase inhibitors for the treatment of Alzheimer's disease: in vitro and in vivo studies.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {40027342}, issn = {2632-8682}, abstract = {Alzheimer's disease (AD) stands as one of the most outstanding progressive neurodegenerative disorders. Obviously, acetylcholine esterase (AChE) is the primary enzyme responsible for breaking down acetylcholine (ACh) with a much more prominent effect than butyrylcholine esterase (BuChE). Hence, novel quinazoline derivatives (3a-p) were designed and synthesized as AChE inhibitors for AD treatment. The newly synthesized quinazoline derivatives (3a-p) were pursued for their inhibitory potential towards both AChE and BuChE. Notably, compound 3e displayed the highest inhibitory potential towards AChE (IC50 = 9.26 nM) surpassing donepezil (IC50 = 16.43 nM). On the other side, compound 3e effectively negated the decline in memory acquisition and retention instigated by ICV administration of streptozotocin (STZ) in mice, an effect that was comparable to that produced by donepezil. Moreover, compound 3e, reduced BACE1 by 51.08% (p < 0.0001), Aβ42 by 52.47% (p < 0.0001), and p(Ser199)-tau by 69.16% (p < 0.0001) compared to STZ mice. Such effects were similar to those of donepezil which reduced all 3 parameters by 57.53%, 58.5%, and 66.78%, respectively, compared to STZ mice. Furthermore, molecular docking studies showed that the superimposition view clarified the similar binding mode of both 3e and the co-crystallized donepezil at the AChE binding pocket. Moreover, the docked complexes (3e-AChE and 3e-BuChE) were further subject to molecular dynamics simulations for 100 ns. In addition, eligible pharmacokinetic profiles as well as feasible BBB penetration were anticipated for compound 3e using ADME and BBB permeation prediction studies. Accordingly, the synthesized compounds, in particular compound 3e, can be treated as promising lead compounds for AD treatment with future further optimization.}, }
@article {pmid40027104, year = {2025}, author = {Shah, AJ and Dar, MY and Adnan, M and Varma, T and Agarwal, D and Garg, P and Mir, RH and Meena, R and Masoodi, MH}, title = {Integration of phytochemical profiling and computational approaches to evaluate the neuroprotective potential of Nardostachys jatamansi in Alzheimer's disease.}, journal = {Biotechnology reports (Amsterdam, Netherlands)}, volume = {45}, number = {}, pages = {e00881}, pmid = {40027104}, issn = {2215-017X}, abstract = {Despite broad spectrum utility of Nardostachys jatamansi (D. Don) DC, little is known about the molecular processes that underlie its anti-Alzheimer action. To investigate the molecular targets and therapeutic potential of N. jatamansi for Alzheimer's disease (AD), we used Gas Chromatography-Mass Spectrometry (GC-MS), ADMET analysis, network pharmacology, differential gene expression analysis, molecular docking, and molecular dynamics (MD) simulations. The STITCH database was used for network creation and protein-protein interaction analysis, while Cytoscape was used for network visualization and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) for term enrichment. Additionally, to investigate the intermolecular interactions between the active chemicals and target proteins, molecular docking experiments were conducted using the Blind docking on the Achilles server. The stability of the PS1 gene complex with Spirojatamol, was further evaluated using MD simulations. With Spirojatamol showing the highest binding energy scores against PS1 (-6.9 kcal/mol), molecular docking confirmed the activity of this metabolite against AD targets PS1 and Spirojatamol formed a stable complex at 100 nanoseconds, according to additional investigation using MD simulations. Significant ligand-protein interactions were verified by binding free energy calculations using the MM/GBSA technique. The PS1-Spirojatamol complex had a binding energy of ΔG: -36.95 ± 5.00 kcal/mol. By focusing on several genes and pathways, involved in AD, this work reveals the molecular underpinnings behind N. jatamansi possible use in the treatment of AD.}, }
@article {pmid40026419, year = {2025}, author = {Marizzoni, M and Tournier, BB and Chevalier, C and Saleri, S and Lathuilière, A and Ceyzériat, K and Paquis, A and Park, R and Troesch, E and Cattaneo, A and Millet, P and Frisoni, GB}, title = {Stools from a human APOEe2 donor reduces amyloid and tau pathology and increases neuroinflammation in a 3xTg AD mouse model.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1539067}, pmid = {40026419}, issn = {1663-4365}, abstract = {BACKGROUND: The mechanisms underlying the protective effect of the e2 variant of the APOE gene (APOEe2) against Alzheimer's disease (AD) have not been elucidated. We altered the microbiota of 3xTgAD mice by fecal microbiota transplantation from a human APOEe2 donor (e2-FMT) and tested the effect of microbiota perturbations on brain AD pathology.
METHODS: FMT of bacteria isolated from stools of untreated 3xTgAD mice (M-FMT) or e2-FMT were transplanted in 15-month-old 3xTgAD mice. FMT was done alone or in combination with antibiotic and proton-pump inhibitor following the Microbiota Transfer Therapy protocol (MTT). The effect of donor (M or e2) and transplantation protocol (FMT or MTT) on hippocampal amyloid, tau pathology and neuroinflammation were assessed at the end of the treatment.
RESULTS: e2-FMT reduced amyloid, and tau pathology as well as increased neuroinflammation as compared with M-FMT. MTT was associated with reduced number of Aβ40+ plaques and tau pathology. Low levels of amyloid were associated with high levels of pro-inflammatory molecules in e2-FMT mice. These associations were partially attenuated by MTT.
CONCLUSION: Bacteria from a human APOEe2 donor reduced AD pathology and increased neuroinflammation in mice suggesting that the gut microbiota may be a mediator of the protective effect of APOEe2.}, }
@article {pmid40025713, year = {2025}, author = {Bosire, EN and Blackmon, K and Kamau, LW and Udeh-Momoh, C and Sokhi, D and Shah, J and Mbugua, S and Muchungi, K and Meier, I and Narayan, V and Nesic, O and Merali, Z}, title = {Healthcare providers perspectives and perceptions of dementia diagnosis and management at the Aga Khan University Hospital, Nairobi, Kenya.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251320411}, doi = {10.1177/13872877251320411}, pmid = {40025713}, issn = {1875-8908}, abstract = {BACKGROUND: The rising number of older people, including those living with Alzheimer's disease and related dementias (AD/ADRD) in sub-Saharan Africa (SSA) highlights the need for an improved clinical diagnosis and management of the diseases.
OBJECTIVE: To understand and describe healthcare providers' perceptions and practices regarding AD/ADRD diagnosis and care in Kenya, not previously reported.
METHODS: This was an ethnographic study involving observations and semi-structured interviews with healthcare providers working at the Aga Khan University Hospital, Nairobi (AKUHN) Kenya. Twenty-one healthcare providers were purposively recruited and interviewed in English, with the data transcribed verbatim and thematically analysed using Nvivo version 14.
RESULTS: Our findings reveal that AKUHN's dementia diagnostic pathway aligns with universal best practice models and involves multidisciplinary care. Yet, healthcare providers noted that this level of care is not representative of most public hospitals in Kenya, where a lack of diagnostic equipment and trained staff severely limits patient access to timely dementia care. In addition, new medications that can slow AD/ADRD progression, are not readily available in Africa, including Kenya. We also identified barriers to timely diagnosis and care such as: lack of dementia policy and guidelines, limited expertise of healthcare providers, high cost of care, and sociocultural factors, including stigma.
CONCLUSIONS: We emphasize the need for the Kenyan government and relevant stakeholders to develop social and healthcare policies and allocate resources to raise awareness about dementia and combat stigma; train healthcare providers; improve early detection and service delivery through access to diagnostic tools, and establish clear guidelines/protocols for AD/ADRD care.}, }
@article {pmid40024487, year = {2025}, author = {Roy, H and Maddiboyina, B and Nandi, S and Srungarapati, S and Nayak, BS and Gade, NJ and Anjana, TLNS and Vinayasri, KM and Gummadi, A and Haseena, S}, title = {Enhanced rivastigmine delivery through nanoemulsion and pyridoxine supplementation: An in-vivo study on Alzheimer's disease intervention.}, journal = {Nanomedicine : nanotechnology, biology, and medicine}, volume = {}, number = {}, pages = {102810}, doi = {10.1016/j.nano.2025.102810}, pmid = {40024487}, issn = {1549-9642}, abstract = {Nanoemulsions are nanostructured material and stabilized colloidal in nature evolved as a highly desirable mechanism for the delivery of drugs. Our objective of the study deals with a successful Rivastigmine (RSG) loaded nanoemulsion which can effectively progress the treatment of AD patients. We developed nanoemulsion containing RSG by combining pyridoxine, an essential vitamin supplement for central nervous system development, with linseed oil, which functioned as the lipophilic phase in the nanoemulsion formulation. The optimal formulation having globular size of 202.3 nm was further evaluated by various analytical techniques, including zeta potential analysis, ATR, DSC, and XRD study. The study utilized the Morris Water Maze (MWM) model to assess the cognitive abilities of Long-Evans rats. The current investigation establishes that the utilization of RSG nanoemulsion incorporating blend of linseed oil and pyridoxine which reduced travel distance in animal mode and can be successfully contribute to therapeutic advancements in patients with AD.}, }
@article {pmid40024279, year = {2025}, author = {López-García, P and Tejero-Ojeda, MM and Vaquero, ME and Carrión-Vázquez, M}, title = {Current amyloid inhibitors: Therapeutic applications and nanomaterial-based innovations.}, journal = {Progress in neurobiology}, volume = {247}, number = {}, pages = {102734}, doi = {10.1016/j.pneurobio.2025.102734}, pmid = {40024279}, issn = {1873-5118}, mesh = {Humans ; *Nanostructures ; Animals ; Amyloidogenic Proteins/metabolism/antagonists & inhibitors ; }, abstract = {Amyloid proteins have long been in the spotlight for being involved in many degenerative diseases including Alzheimer´s, Parkinson´s or type 2 diabetes, which currently cannot be prevented and for which there is no effective treatment or cure. Here we provide a comprehensive review of inhibitors that act directly on the amyloidogenic pathway (at the monomer, oligomer or fibril level) of key pathological amyloids, focusing on the most representative amyloid-related diseases. We discuss the latest advances in preclinical and clinical trials, focusing on cutting-edge developments, particularly on nanomaterials-based inhibitors, which offer unprecedented opportunities to address the complexity of protein misfolding disorders and are revolutionizing the landscape of anti-amyloid therapeutics. Notably, nanomaterials are impacting critical areas such as bioavailability, penetrability and functionality of compounds currently used in biomedicine, paving the way for more specific therapeutic solutions tailored to various amyloid-related diseases. Finally, we highlight the window of opportunity opened by comparative analysis with so-called functional amyloids for the development of innovative therapeutic approaches for these devastating diseases.}, }
@article {pmid40024051, year = {2025}, author = {Periyasamy, TS and Kasivishwanathan, A and Roy, G and Sekar, N and Lakshmanan, H}, title = {Phytocompounds of Senecio candicans as potential acetylcholinesterase inhibitors targeting Alzheimer's disease: A structure-based virtual screening and molecular dynamics simulation study.}, journal = {Computational biology and chemistry}, volume = {117}, number = {}, pages = {108396}, doi = {10.1016/j.compbiolchem.2025.108396}, pmid = {40024051}, issn = {1476-928X}, abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by cognitive decline due to the accumulation of amyloid-beta plaques, neurofibrillary tangles, and decreased acetylcholine levels caused by acetylcholinesterase (AChE) activity. Current treatments using synthetic acetylcholinesterase inhibitors (AChEIs) provide only symptomatic relief and are associated with adverse effects, highlighting the need for safer and more effective alternatives. This study investigates the potential of phytoconstituents from the plant Senecio candicans as natural AChE inhibitors for AD treatment. Using structure-based virtual screening, molecular docking, and molecular dynamics simulations, we evaluated several compounds from Senecio candicans for their binding affinity, stability, and inhibitory activity against AChE. The findings identified compounds such as Estra-135(10)-trien-17β-ol and Vulgarone A, which demonstrated strong binding affinities and stable interactions with AChE, comparable to or surpassing the clinically used drug Donepezil. These phytoconstituents exhibited potential as effective AChEIs with potentially fewer side effects. The results underscore the therapeutic potential of plant-based molecules for drug discovery, offering a promising avenue for developing new treatments for neurodegenerative diseases. Combining phytochemical studies with computational methods provides a powerful approach to identifying novel therapeutic agents. This study suggests that phytoconstituents from Senecio candicans could serve as safer alternatives for managing AD. Further experimental validation and clinical studies are necessary to confirm these compounds' efficacy and safety, paving the way for innovative, plant-derived treatments for Alzheimer's disease.}, }
@article {pmid40023730, year = {2025}, author = {Cai, Z and Zhong, J and Zhu, G and Zhang, J}, title = {Comparative efficacy and safety of antidiabetic agents in Alzheimer's disease: A network meta-analysis of randomized controlled trials.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100111}, doi = {10.1016/j.tjpad.2025.100111}, pmid = {40023730}, issn = {2426-0266}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Emerging evidence suggests that antidiabetic agents may offer neuroprotective effects by targeting shared pathophysiological mechanisms such as insulin resistance and neuroinflammation. However, the comparative efficacy, and safety of these agents in the treatment of AD remain unclear.
OBJECTIVES: This study aimed to systematically evaluate and compare the efficacy and safety of antidiabetic agents for improving cognitive outcomes, reducing amyloid-β (Aβ) deposition, and managing adverse effects in patients with AD, using a network meta-analysis of randomized controlled trials (RCTs).
METHODS: A comprehensive literature search was conducted across multiple databases to identify RCTs examining the effects of antidiabetic agents in patients with AD. The primary outcomes included cognitive performance (e.g., MMSE scores), Aβ deposition (measured via CSF biomarkers), and safety/adverse effects. A network meta-analysis was performed to integrate direct and indirect evidence, ranking interventions using Surface Under the Cumulative Ranking (SUCRA) probabilities. Risk of bias was assessed using the Cochrane risk-of-bias tool.
RESULTS: A total of 26 studies, involving 7,361 participants, were included in the analysis. The interventions evaluated included insulin detemir (both low-dose and high-dose), liraglutide, exenatide, metformin, and pioglitazone. Both low-dose insulin detemir (mean difference: 2.10, 95 % CI: 1.04 to 3.15), high-dose insulin detemir (mean difference: 1.40, 95 % CI: -0.07 to 2.88), exenatide (mean difference: 1.19, 95 % CI: 0.06 to 2.32), and metformin combined with exenatide (mean difference: 1.06, 95 % CI: -1.68 to 3.80) showed cognitive improvements compared to placebo. Among these, low-dose insulin detemir demonstrated the most significant improvement. In terms of reducing Aβ deposition, metformin ranked highest in effectiveness, with the highest SUCRA score (84.6), followed by high-dose insulin detemir (SUCRA: 54.1). Low-dose insulin detemir (SUCRA: 51.1) also demonstrated moderate efficacy. Low-dose insulin detemir showed some reduction in Aβ deposition (mean difference: -0.31, 95 % CI: -2.82 to 2.20), although statistical significance was limited. Liraglutide exhibited the highest rate of study treatment withdrawal (mean difference: 1.97, 95 % CI: -0.07 to 4.00), while pioglitazone demonstrated the lowest withdrawal rates (mean difference: 0.07, 95 % CI: -0.03 to 0.17).
CONCLUSIONS: This network meta-analysis provides valuable insights into the comparative efficacy and safety of antidiabetic agents in AD. Low-dose insulin detemir demonstrated the most significant cognitive improvement and a moderate effect on reducing Aβ deposition. Metformin emerged as the most effective agent for reducing Aβ levels, though its effects on cognitive function were less pronounced. Safety profiles varied, with liraglutide associated with the highest rate of treatment withdrawals, while pioglitazone demonstrated the lowest incidence of treatment-related discontinuations. These findings support the potential use of antidiabetic agents, particularly insulin detemir, as a therapeutic option for AD, although further studies are needed to confirm their long-term benefits and safety.}, }
@article {pmid40022853, year = {2025}, author = {Liu, S and Zhang, Z and Gu, Y and Hao, J and Liu, Y and Fu, H and Guo, X and Song, H and Zhang, S and Zhao, Y}, title = {Beyond the eye: A relational model for early dementia detection using retinal OCTA images.}, journal = {Medical image analysis}, volume = {102}, number = {}, pages = {103513}, doi = {10.1016/j.media.2025.103513}, pmid = {40022853}, issn = {1361-8423}, abstract = {Early detection of dementia, such as Alzheimer's disease (AD) or mild cognitive impairment (MCI), is essential to enable timely intervention and potential treatment. Accurate detection of AD/MCI is challenging due to the high complexity, cost, and often invasive nature of current diagnostic techniques, which limit their suitability for large-scale population screening. Given the shared embryological origins and physiological characteristics of the retina and brain, retinal imaging is emerging as a potentially rapid and cost-effective alternative for the identification of individuals with or at high risk of AD. In this paper, we present a novel PolarNet+ that uses retinal optical coherence tomography angiography (OCTA) to discriminate early-onset AD (EOAD) and MCI subjects from controls. Our method first maps OCTA images from Cartesian coordinates to polar coordinates, allowing approximate sub-region calculation to implement the clinician-friendly early treatment of diabetic retinopathy study (ETDRS) grid analysis. We then introduce a multi-view module to serialize and analyze the images along three dimensions for comprehensive, clinically useful information extraction. Finally, we abstract the sequence embedding into a graph, transforming the detection task into a general graph classification problem. A regional relationship module is applied after the multi-view module to explore the relationship between the sub-regions. Such regional relationship analyses validate known eye-brain links and reveal new discriminative patterns. The proposed model is trained, tested, and validated on four retinal OCTA datasets, including 1,671 participants with AD, MCI, and healthy controls. Experimental results demonstrate the performance of our model in detecting AD and MCI with an AUC of 88.69% and 88.02%, respectively. Our results provide evidence that retinal OCTA imaging, coupled with artificial intelligence, may serve as a rapid and non-invasive approach for large-scale screening of AD and MCI. The code is available at https://github.com/iMED-Lab/PolarNet-Plus-PyTorch, and the dataset is also available upon request.}, }
@article {pmid40022313, year = {2025}, author = {Liu, H and Zhang, Z and Li, X and Zhang, L and Zhao, A and Zheng, Z and Gao, H and You, S and Zhang, J and Sun, J}, title = {Depolymerized peanut skin-derived proanthocyanidins alleviate cognitive dysfunction by inhibiting Aβ42 aggregation in Alzheimer's disease.}, journal = {Food research international (Ottawa, Ont.)}, volume = {203}, number = {}, pages = {115747}, doi = {10.1016/j.foodres.2025.115747}, pmid = {40022313}, issn = {1873-7145}, mesh = {*Proanthocyanidins/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism ; Animals ; *Cognitive Dysfunction/drug therapy ; *Arachis/chemistry ; Rats ; *Peptide Fragments ; Male ; Antioxidants/pharmacology/chemistry ; Rats, Sprague-Dawley ; Disease Models, Animal ; Polymerization ; }, abstract = {Peanut skin proanthocyanidins (PSP) are natural polyphenols with antioxidant properties that mitigate Alzheimer's disease (AD), a complex progressive neurodegenerative disorder whose underlying biological mechanisms includes the aggregation of insoluble amyloid plaques. However, the high degree of polymerization of PSP, extracted using conventional methods, limits its bioavailability. This study established the optimal processes for ultrasound-assisted alkaline depolymerization to produce oligomeric proanthocyanidins (OPSP) from PSP content (2.7 mg/mL), depolymerization temperature (54.8 °C), ultrasonic power (480 W, 28 Hz), ultrasonic duration (28.7 min), and pH (12.1). Under these conditions, the degree of polymerization of the proanthocyanidins decreased from 6.74 to 2.87. Physicochemical characteristics of PSP and OPSP were analyzed. Both PSP and OPSP exhibited shared structural bonding and a repeating 288 Da unit, with Proanthocyanidin A identified as the predominant type. Furthermore, compared with PSP, OPSP demonstrated enhanced stability and antioxidant activity. Using in vitro detection of amyloid-beta (Aβ42) inhibition, this study demonstrated that OPSP exhibited greater inhibition of Aβ42 fibrillogenicity than underpolymerized PSP, and OPSP significantly inhibited Aβ42-induced cytotoxicity. In addition, the effect of OPSP was investigated in a rat model of Alzheimer's disease. The results indicated that OPSP improved the memory performance of AD rats in the water maze and decreased the levels of inflammatory factors IL-6, IL-1β, and TNF-α. Moreover, OPSP ameliorated histopathological changes and reduced Aβ42 plaque deposition in the brains of AD rats. These findings regarding OPSP are anticipated to facilitate high-value utilization of peanut by-products, expand their applications, and provide guidance for the use of OPSP in the development of natural healthcare pharmaceuticals and mitigation and treatment of Alzheimer's disease.}, }
@article {pmid40022172, year = {2025}, author = {Decaix, T and Bouaziz-Amar, E and Paquet, C and Lilamand, M}, title = {Revisiting ABCB1 polymorphism: a missing piece in Alzheimer's risk and treatment?.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {252}, pmid = {40022172}, issn = {1479-5876}, }
@article {pmid40021385, year = {2025}, author = {Zeng, J and Zhang, R and Xu, H and Zhang, C and Lu, L}, title = {Integrative single-cell RNA sequencing and mendelian randomization analysis reveal the potential role of synaptic vesicle cycling-related genes in Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100097}, doi = {10.1016/j.tjpad.2025.100097}, pmid = {40021385}, issn = {2426-0266}, abstract = {BACKGROUND: Alzheimer's disease (AD) involves alterations in synaptic vesicle cycling (SVC), which significantly affect neuronal communication and function. Therefore, a thorough investigation into the potential roles of SVC-related genes (SVCRGs) in AD can enhance the identification of critical biomarkers that may influence disease progression and treatment responses.
METHODS: The datasets used in this study were sourced exclusively from public databases. By integrating differential expression analysis with Mendelian randomization (MR), we identified SVCRGs as biomarkers for AD. Functional characterization of these biomarkers was performed, followed by integration into a nomogram. Further investigation of immune infiltration in AD patients and healthy individuals was carried out. Ultimately, the potential cellular mechanisms of AD were explored through single-cell RNA sequencing (scRNA-seq) analysis.
RESULTS: ATP6V1D, ATP6V1G2, CLTB, and NSF were identified as biomarkers, exhibiting a positive correlation with each other and a downregulated expression in AD. These markers were pinpointed as protective factors for AD [odds ratio (OR) < 1, P < 0.05], with potential to reduce the risk of the disease. Integrated into a nomogram, they demonstrated satisfactory diagnostic performance and clinical utility, surpassing the use of single gene. They were collectively enriched in pathways related to "interferon gamma response", "inflammatory response", and "TNFα signaling via NFκB". Additionally, an increase in infiltration of 17 immune cell types in AD was noted, particularly cells associated with neuroinflammation such as activated CD8 T cells and various dendritic cells (DCs), suggesting an inflammatory milieu in AD while also displaying a negative correlation with the biomarkers. The cell types were further annotated, revealing specific expressions of biomarkers and uncovering the heterogeneity of excitatory neurons. A significant reduction in the overall number of excitatory neurons under AD conditions was observed, alongside consistent expression of biomarkers during the developmental stages of excitatory neurons.
CONCLUSION: By using MR, we firstly identified four SVCRGs as protective factors for AD, functioning through pathways associated with mitochondrial dysfunction, chronic inflammation, immune dysregulation, and neuronal damage. These genes had the potential to modulate immune cell infiltration activated in AD patients and exhibited cell-type-specific expression profiles within AD-related cellular contexts. Their findings provide novel insights and valuable references for future research on AD pathogenesis and therapeutic strategies.}, }
@article {pmid40021093, year = {2025}, author = {Jia, B and Xu, Y and Zhu, X}, title = {Cognitive resilience in Alzheimer's disease: Mechanism and potential clinical intervention.}, journal = {Ageing research reviews}, volume = {106}, number = {}, pages = {102711}, doi = {10.1016/j.arr.2025.102711}, pmid = {40021093}, issn = {1872-9649}, mesh = {*Alzheimer Disease/psychology/metabolism/therapy ; Humans ; Cognition/physiology ; Cognitive Reserve/physiology ; }, abstract = {Alzheimer's disease (AD) is a globally recognized neurodegenerative disorder that severely impairs cognitive function and imposes substantial psychological and financial burdens on patients and their families. The hallmark pathological features of AD include progressive neurodegeneration, extracellular beta-amyloid (Aβ) plaque accumulation, and intracellular hyperphosphorylated tau protein tangles. However, recent studies have identified a subset of patients exhibiting cognitive resilience, characterized by a slower cognitive decline or the preservation of high cognitive function despite the presence of AD pathology. Cognitive resilience is influenced by a complex interplay of genetic, environmental, and lifestyle factors. In addition, cognitive resilience contributes to the new perspectives on the diagnosis and personalized treatment of AD. This review aims to provide a comprehensive analysis of current studies on cognitive resilience in AD and to explore future research directions of AD diagnosis and treatment.}, }
@article {pmid40020826, year = {2025}, author = {Li, Z and Zheng, G and Fang, C and Mei, J and Liang, H and Yang, L}, title = {Comparation of brain-targeting chitosan/sodium tripolyphosphate and ovalbumin/sodium carboxymethylcellulose nanoparticles on dihydromyricetin delivery and cognitive impairment in obesity-related Alzheimer's disease.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {141517}, doi = {10.1016/j.ijbiomac.2025.141517}, pmid = {40020826}, issn = {1879-0003}, abstract = {The brain-gut axis plays an important role in regulating cognitive ability in obesity-related Alzheimer's disease (AD). In this study, we aimed to investigate the correlation between the barrier penetration ability of the DMY nanodelivery system in vivo and the regulation of the gut-brain axis to alleviate cognitive impairment. Brain-targeted peptide (TGN: TGNYKALHPHNG) and DMY loaded chitosan (CS)/sodium tripolyphosphate (TPP) nanoparticles (TGN-DMY-CS/TPP-NPs) and ovalbumin (OVA)/sodium carboxymethylcellulose (CMC) nanoparticles (TGN-DMY-OVA/CMC-NPs) were prepared. TGN-DMY-CS/TPP-NPs demonstrated superior mucus penetration and BBB targeting ability compared to TGN-DMY-OVA/CMC-NPs, while the latter showed notable intestinal accumulation. TGN-DMY-CS/TPP-NPs treatment significantly increased the relative abundance of Alistipes and Rikenellaceae_RC9_gut_group, and TGN-DMY-OVA/CMC-NPs treatment obviously enhanced the relative abundance of Lactobacillus. Furthermore, both nanoparticles alleviated lipid metabolism disorder, oxidative stress, and inflammation in the liver, reduced oxidative stress and neuroinflammation in the brain, inhibited neuronal apoptosis, and enhanced mitochondrial biogenesis and synaptic plasticity in obesity-related AD mice. Despite different mucus penetration and biodistribution, their similar efficacy in improving obesity-related AD is attributed to the gut-brain bidirectional connection.}, }
@article {pmid40020805, year = {2025}, author = {Wang, C and Hou, T and Shao, X and Wang, C and Wang, X and Guan, P and Wu, Y and Hu, X}, title = {Functionalized carbon dots with guanidine salt ionic liquid regulate oxidative damage and amyloid aggregation.}, journal = {International journal of biological macromolecules}, volume = {306}, number = {Pt 2}, pages = {141531}, doi = {10.1016/j.ijbiomac.2025.141531}, pmid = {40020805}, issn = {1879-0003}, abstract = {An imbalance in the brain microenvironment, involving oxidative stress and β-amyloid (Aβ) accumulation, is thought to be one of the primary characteristics of early Alzheimer's disease (AD). To address the intricate pathophysiology of AD, therapeutic approaches that can concurrently control several diseases in the AD microenvironment are desperately needed. This study created a guanidine salt ionic liquid functionalized carbon dots (CDs@TGM-IL) to mitigate Aβ aggregation-induced cytotoxicity and scavenge reactive oxygen species (ROS) simultaneously. In vitro studies have shown that CDs@TGM-IL can effectively inhibit Aβ42 protein aggregation, disaggregate mature Aβ42 fibrils, and effectively remove ROS. In vivo studies have found that CDs@TGM-IL can cross the blood-brain barrier (BBB) and improve cognitive performance in AD mice. Just as importantly, CDs@TGM-IL has been shown to have unparalleled biocompatibility. This means that CDs@TGM-IL is expected to be a possible treatment for AD.}, }
@article {pmid40020795, year = {2025}, author = {Li, JQ and Ma, XH and Dai, H and Wang, CC and Zhang, J and Meng, XL}, title = {Isoliensinine ameliorates cognitive dysfunction in AlCl3/D-gal-induced Alzheimer's disease-like mice by inhibiting the calcium signaling pathway.}, journal = {Journal of ethnopharmacology}, volume = {344}, number = {}, pages = {119567}, doi = {10.1016/j.jep.2025.119567}, pmid = {40020795}, issn = {1872-7573}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Aluminum Chloride/toxicity ; *Galactose ; Mice ; *Cognitive Dysfunction/drug therapy ; Male ; *Disease Models, Animal ; *Calcium Signaling/drug effects ; Isoquinolines/pharmacology ; Neuroprotective Agents/pharmacology ; Hippocampus/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {The embryos of lotus (Nelumbo nucifera Gaertn.) is a famous traditional Chinese medicine used to treat insomnia, memory decline, and dementia for a long time. However, the underlying material basis and mechanisms of this medicine are still unclear. Isoliensinine (IL) is a major alkaloid derived from lotus embryos. Our previous research has demonstrated that IL can exert strong anti-inflammatory and neuroprotective effects in vitro.
AIM OF THE STUDY: To reveal the underlying therapeutic effect and mechanism of IL on Alzheimer's disease (AD)-like mice induced by AlCl3 and D-galactose (D-gal) in vivo.
MATERIALS AND METHODS: The AD-like mice were modeled by intragastric injection (i.g.) of AlCl3 (20 mg/kg/day) and intraperitoneal injection (i.p.) of D-gal (120 mg/kg/day) for 8 weeks. Starting from the third week, AD-like mice were treated with IL (1, 3, or 10 mg/kg/day; i.p.) for 6 weeks. Cognitive impairment in AD-like mice was evaluated through some behavioral experiments including nest building, open field, novel object recognition, Y maze, and Morris water maze tests. The cortex and hippocampus (DG, CA1, and CA3) regions were analyzed as follows: Neuronal pathological changes and neurofibrillary tangles (NFTs) formation were observed by hematoxylin-eosin (HE) and silver staining, respectively; The production of Aβ plaques and the activation of microglia and astrocytes were detected by immunohistochemistry; The levels of Ca[2+] levels were determined by the ortho-cresolphtalein complexone method. The levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β) were analyzed using the ELISA kits. The expression of CaM, p-CaMKII, Calpain, CDK5, p35/p25, p-Tau, ADAM10, BACE1, PSEN1, APP, Aβ1-42, p-IκBα, and IκBα were evaluated by western blotting.
RESULTS: IL (1, 3, and 10 mg/kg) treatment effectively ameliorated cognitive impairment in AD-like model mice. IL inhibited the decrease of brain index and body weight in AD-like mice and alleviated neuronal damage in the cortex and hippocampus (DG, CA1, and CA3). IL decreased the levels of Ca[2+] and reduce high expression of CaM and Calpain in the cortex and hippocampus of AD-like mice. IL treatment did not affect the expression of CDK5 but inhibited the expression of p-CaMKII and p25/p35, and reduced Tau phosphorylation and NFTs formation. IL also down-regulated the high expression of Aβ1-42 and APP and regulated the expression of APP-cleavage secretase (reducing the expression of BACE1 and PSEN1, while increasing the expression of ADAM10), thereby inhibited the production of Aβ plaques in AD-like mouse brain. Moreover, IL inhibited the phosphorylation and degradation of IκBα, as well as the production of inflammatory cytokines (TNF-α, IL-6, and IL-1β), and prevented the activation of microglia and astrocytes in AD-like mice.
CONCLUSIONS: IL has a significant therapeutic effect on pathological alterations and cognitive impairment in AlCl3 and D-gal-induced AD-like mice, indicating that IL may have the potential to treat AD. The anti-AD activity of IL may be associated with its regulation of the Ca[2+] homeostasis and downstream signaling molecules such as CaM and Calpain.}, }
@article {pmid40019895, year = {2025}, author = {Park, JM and Tsai, LH}, title = {Innovations in noninvasive sensory stimulation treatments to combat Alzheimer's disease.}, journal = {PLoS biology}, volume = {23}, number = {2}, pages = {e3003046}, pmid = {40019895}, issn = {1545-7885}, support = {F99 AG073558/AG/NIA NIH HHS/United States ; K00 AG073558/AG/NIA NIH HHS/United States ; R01 AG069232/AG/NIA NIH HHS/United States ; R56 AG069232/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/therapy/physiopathology ; Humans ; Animals ; *Brain/physiopathology ; Acoustic Stimulation/methods ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide. There is no known cure for AD, highlighting an urgent need for new, innovative treatments. Recent studies have shed light on a promising, noninvasive approach using sensory stimulation as a potential therapy for AD. Exposing patients to light and sound pulses at a frequency of 40 hertz induces brain rhythms in the gamma frequency range that are important for healthy brain activity. Using this treatment in animal models, we are now beginning to understand the molecular, cellular, and circuit-level changes that underlie improvements in disease pathology, cognition, and behavior. A mechanistic understanding of the basic biology that underlies the 40-hertz treatment will inform ongoing clinical trials that offer a promising avenue of treatment without the side effects and high costs typically associated with pharmacological interventions. Concurrent advancements in neurotechnology that can also noninvasively stimulate healthy brain rhythms are illuminating new possibilities for alternative therapies. Altogether, these noninvasive approaches could herald a new era in treating AD, making them a beacon of hope for patients, families, and caregivers facing the challenges of this debilitating condition.}, }
@article {pmid40018518, year = {2025}, author = {Wang, S and Xu, H and Liu, G and Chen, L}, title = {Non-pharmacological treatment of Alzheimer's disease: an update.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1527242}, pmid = {40018518}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impairs memory, cognitive function, and the ability to perform daily tasks. The pathological features of AD include β-amyloid plaques, neurofibrillary tangles, and neuronal loss. Current AD treatments target pathological changes but often fail to noticeably slow disease progression and can cause severe complications, limiting their effectiveness. In addition to therapies targeting the core pathology of AD, a more comprehensive approach may be needed for its treatment. In recent years, non-pharmacological treatments such as physical therapy, exercise therapy, cell therapy, and nanoparticles have shown great potential in mitigating disease progression and alleviating clinical symptoms. This article reviews recent advances in non-pharmacological treatment approaches for AD, highlighting their contributions to AD management and facilitating the exploration of novel therapeutic strategies.}, }
@article {pmid40018516, year = {2025}, author = {Komaki, S and Amiri, P and Safari, S and Abbasi, E and Ramezani-Aliakbari, F and Golipoor, M and Kourosh-Arami, M and Rashno, M and Komaki, A}, title = {Investigation of protective effects of olanzapine on impaired learning and memory using behavioral tests in a rat model of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1376074}, pmid = {40018516}, issn = {1663-4365}, abstract = {INTRODUCTION: Evidence suggests that oxidative stress plays a critical role in the pathogenesis and progression of Alzheimer's disease (AD). Consequently, antioxidants may mitigate neurotoxicity induced by beta-amyloid (Aβ) and potentially reduce cell death. Previous research has demonstrated that olanzapine (OLZ) possesses antioxidant and neuroprotective properties. In this study, we investigated the protective and therapeutic effects of OLZ on an animal model of AD induced by Aβ using behavioral assessments.
METHODS: Rats were randomly assigned to one of five groups (n = 10 rats per group): a control group, a sham group that received an intracerebrovascular (ICV) injection of phosphate-buffered saline (the solvent for Aβ), an AD group that received an ICV injection of Aβ, an OLZ group that received OLZ via gavage for two months, and an AD + OLZ group that received OLZ for one month before and one month after AD induction.
RESULTS: We used the Elevated Plus Maze (EPM), Novel Object Recognition Test (NORT), Barnes Maze (BM), Passive Avoidance Test (PAT), and Morris Water Maze (MWM) to assess behavioral performance in the experimental rats. Aβ administration impaired cognition and increased anxiety-like behavior. Treatment with OLZ improved cognitive decline and reduced anxiety-like behavior in Aβ-infused rats.
CONCLUSION: Our findings suggest that OLZ can restore cognitive performance and alleviate anxiety-like behavior following Aβ injection. Thus, OLZ may have both preventive and therapeutic potential for AD and could be considered a viable pharmacological option.}, }
@article {pmid40018325, year = {2025}, author = {Abughofah, Y and Deardorff, R and Vosmeier, A and Hottle, S and Dage, JL and Dempsey, D and Apostolova, LG and Brosch, J and Clark, D and Farlow, M and Foroud, T and Gao, S and Wang, S and Zetterberg, H and Blennow, K and Saykin, AJ and Risacher, SL}, title = {Association between BrainAGE and Alzheimer's disease biomarkers.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {1}, pages = {e70094}, pmid = {40018325}, issn = {2352-8729}, support = {R01 AG019771/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; R01 AG061788/AG/NIA NIH HHS/United States ; K01 AG049050/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: The brain age gap estimation (BrainAGE) method uses a machine learning model to generate an age estimate from structural magnetic resonance imaging (MRI) scans. The goal was to study the association of brain age with Alzheimer's disease (AD) imaging and plasma biomarkers.
METHODS: One hundred twenty-three individuals from the Indiana Memory and Aging Study underwent structural MRI, amyloid and tau positron emission tomography (PET), and plasma sampling. The MRI scans were processed using the software program BrainAgeR to receive a "brain age" estimate. Plasma biomarker concentrations were measured, and partial Pearson correlation models were used to evaluate their relationship with brain age gap (BAG) estimation (BrainAGE = chronological age - MRI estimated brain age).
RESULTS: Significant associations between BAG and amyloid and tau levels on PET and in plasma were observed depending on diagnostic categories.
DISCUSSION: These findings suggest that BAG is potentially a biomarker of pathology in AD which can be applied to routine brain imaging.
HIGHLIGHTS: Novel research that uses an artificial intelligence learning tool to estimate brain age.Findings suggest that brain age gap is associated with plasma and positron emission tomography Alzheimer's disease (AD) biomarkers.Differential relationships are seen in different stages of disease (preclinical vs. clinical).Results could play a role in early AD diagnosis and treatment.}, }
@article {pmid40018263, year = {2024}, author = {Kaser, AN and Mikula, CM and Kiselica, AM}, title = {Technology Assistance in Dementia (Tech-AiD): A Framework for Care in the Digital Age.}, journal = {Journal of health service psychology}, volume = {50}, number = {1}, pages = {37-46}, pmid = {40018263}, issn = {2662-2653}, support = {R01 AG082783/AG/NIA NIH HHS/United States ; U54 AG063546/AG/NIA NIH HHS/United States ; }, abstract = {Recent advances in digital technologies hold promise for supporting aging adults and their care partners as they navigate changes in cognitive and daily functioning associated with Alzheimer's disease and related dementias (ADRD). Commonly owned digital technologies, like smartphones, include features that could help maintain independence and reduce caregiver burden. However, we lack models for successful integration of technologies into treatment of persons with ADRD. We propose the Technology Assistance in Dementia (Tech-AiD) framework for aiding persons with ADRD and their care partners with using digital technologies to reach individualized goals. We discuss how technology use is impacted by a multitude of factors, including severity of cognitive impairment, technology proficiency, and barriers to adequate and equitable care, all of which are further complicated by health disparities. Further, we explore the potential benefits of technology use among patients with ADRD and their care partners, highlighting pertinent clinical and ethical challenges and drawing from evidence-based strategies to promote practical recommendations.}, }
@article {pmid40017464, year = {2025}, author = {Nguyen, TN and Shalaby, RA and Lee, E and Kim, SS and Ro Kim, Y and Kim, S and Je, HS and Kwon, HS and Chung, E}, title = {Ultrafast optical imaging techniques for exploring rapid neuronal dynamics.}, journal = {Neurophotonics}, volume = {12}, number = {Suppl 1}, pages = {S14608}, pmid = {40017464}, issn = {2329-423X}, abstract = {Optical neuroimaging has significantly advanced our understanding of brain function, particularly through techniques such as two-photon microscopy, which captures three-dimensional brain structures with sub-cellular resolution. However, traditional methods struggle to record fast, complex neuronal interactions in real time, which are crucial for understanding brain networks and developing treatments for neurological diseases such as Alzheimer's, Parkinson's, and chronic pain. Recent advancements in ultrafast imaging technologies, including kilohertz two-photon microscopy, light field microscopy, and event-based imaging, are pushing the boundaries of temporal resolution in neuroimaging. These techniques enable the capture of rapid neural events with unprecedented speed and detail. This review examines the principles, applications, and limitations of these technologies, highlighting their potential to revolutionize neuroimaging and improve the diagnose and treatment of neurological disorders. Despite challenges such as photodamage risks and spatial resolution trade-offs, integrating these approaches promises to enhance our understanding of brain function and drive future breakthroughs in neuroscience and medicine. Continued interdisciplinary collaboration is essential to fully leverage these innovations for advancements in both basic and clinical neuroscience.}, }
@article {pmid40016632, year = {2025}, author = {Hitt, EM}, title = {Brexpiprazole: A Balance of Risks and Benefits.}, journal = {The Senior care pharmacist}, volume = {40}, number = {3}, pages = {115-122}, doi = {10.4140/TCP.n.2025.115}, pmid = {40016632}, issn = {2639-9636}, mesh = {Humans ; *Quinolones/therapeutic use/adverse effects ; *Thiophenes/therapeutic use/adverse effects/pharmacology ; *Antipsychotic Agents/therapeutic use/adverse effects ; *Alzheimer Disease/drug therapy ; Psychomotor Agitation/drug therapy/etiology ; Risk Assessment ; Aged ; }, abstract = {Alzheimer's disease is the most common cause of dementia. Behavioral and psychological symptoms in dementia (BPSD) are neuropsychiatric signs accompanying dementia that carry a significant impact on prognosis and management. Management of BPSD is challenging because of its complex and multifactorial nature. Historically, no medications were specifically approved for the treatment of BPSD, and any pharmacological use was considered off-label. In May 2023, brexpiprazole was the first and only atypical antipsychotic agent to receive US Food and Drug Administration approval for the treatment of agitation associated with dementia because of Alzheimer's disease. The purposes of this article are to discuss the clinical characteristics of brexpiprazole with a focus on safety and efficacy in older adults, to review the studies that led to the approval for agitation associated with dementia, and to examine its potential place in therapy and impact on patient care. Brexpiprazole is a second-generation antipsychotic with affinity for multiple monoaminergic receptors. Efficacy, safety, and tolerability of brexpiprazole for the treatment of agitation associated with dementia because of Alzheimer's disease was evaluated in two Phase III studies with results suggesting that brexpiprazole has potential to be a safe, effective, and well-tolerated treatment for this indication. Given the individualized and complicated nature of BPSD, brexpiprazole is another option in the treatment landscape that may improve symptoms of agitation but requires careful assessment to ensure benefits outweigh any risks.}, }
@article {pmid40015759, year = {2025}, author = {Perez-Arce, F and Burke, J and Rabinovich, L and Zhang, Q and Monfared, AAT and Mattke, S}, title = {American's overall and equity-based societal valuation of a disease-modifying Alzheimer's treatment: Results from a discrete choice experiment.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {3}, pages = {100036}, doi = {10.1016/j.tjpad.2024.100036}, pmid = {40015759}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/economics ; United States ; Male ; Female ; Aged ; Middle Aged ; Choice Behavior ; Ethnic and Racial Minorities ; Health Services Accessibility/economics ; Social Class ; }, abstract = {OBJECTIVES: To estimate Americans' willingness-to-pay (WTP) for universal access to a disease-modifying Alzheimer's disease (AD) treatment with a discrete choice experiment in a nationally representative sample. As part of this experiment, we examined whether providing information about the higher disease burden among minorities and persons of lower socioeconomic status (SES) changes WTP.
METHODS: We conducted an information experiment using the nationally representative Understanding America Study (UAS) panel. Participants were provided with general information about AD and a hypothetical treatment that reduces disease progression by 30 %. Two-thirds of the sample were randomized to receive additional information about the higher prevalence of Alzheimer's among either lower SES groups or racial/ethnic minorities. We measured participants' WTP for making the treatment nationally available as a fixed annual fee and income-proportionate fee. Differences in WTP between those exposed to the additional information and those who were not provide the societal valuation of the equity-enhancing effects of the AD treatment.
RESULTS: Average valuations were $252, $260 and $247 per year, and 0.59 %, 0.59 % and 0.61 % of earned income, for the control, race/ethnicity and SES frames, respectively-all statistically indistinguishable. These average results imply that Americans would be willing to pay $33.7 billion based on the fixed fee and $51.4 billion based on the income-related charge for universal access to an AD treatment annually, but their valuation does not further increase when informed about equity considerations.
CONCLUSIONS: While Americans value universal access to an AD treatment highly, health equity considerations did not significantly alter respondents' WTP.}, }
@article {pmid40015753, year = {2025}, author = {Ozawa, T and Selzler, KJ and Ball, DE and Deckert, A and MacLeod, T and Corrêa Dos Santos Filho, O and Govia, I and Robinson, JN and Kowa, H and Lopez-Ortega, M and McKean, A and Chambers, W and Smith, SR and Baksh, M and Willis, DR and Fowler, NR and Mattke, S and , }, title = {Effects of the Davos Alzheimer's Collaborative early detection of cognitive impairment program on clinician attitudes, engagement, and confidence.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {3}, pages = {100038}, doi = {10.1016/j.tjpad.2024.100038}, pmid = {40015753}, issn = {2426-0266}, mesh = {Humans ; *Early Diagnosis ; *Attitude of Health Personnel ; *Cognitive Dysfunction/diagnosis ; Male ; Female ; Alzheimer Disease/diagnosis ; Primary Health Care ; United States ; Japan ; Brazil ; Health Personnel/psychology ; Mexico ; Scotland ; }, abstract = {BACKGROUND: The number of people with dementia is expected to grow substantially across the world due to population aging, but cognitive impairment remains undetected and undiagnosed, especially in early stages. Newly available diagnostic tools such as digital cognitive assessments and blood biomarker tests may be well suited to increase the rates of early detection of dementia in primary care.
OBJECTIVES: The objective of the Davos Alzheimer's Collaborative Healthcare System Preparedness (DAC-SP) Early Detection Flagship Program was to improve the rate of early detection of cognitive impairment in primary care and non-specialty settings. We aimed to understand the program's impact on clinician attitudes, engagement, and confidence in diagnosing and managing cognitive impairment.
DESIGN: Survey of participating healthcare professionals before and after the intervention.
SETTING: The DAC Healthcare System Preparedness Early Detection Flagship Program was implemented in seven sites across six countries: Brazil, Jamaica, Japan, Mexico, Scotland, and the United States (2 sites).
PARTICIPANTS: 110 healthcare professionals, including, primary care physicians, specialists (neurologists and psychologists), nurses, nurse practitioners, physician assistants, social workers, and healthcare support workers completed the pre-intervention survey. 68 healthcare professionals completed the post-intervention survey.
INTERVENTION: Participating sites implemented a digital cognitive assessment tool and a blood biomarker test for the Alzheimer's pathology and were trained in the administration of the digital cognitive assessment tool. The intervention was adapted to each site for cultural relevance and operational feasibility.
MEASUREMENTS: Participants completed the General Practitioners Attitude and Confidence Scale for Dementia (GPACS-D), a 15-item scale with three subscales: Attitude to Care (six items), Confidence in Clinical Abilities (six items), and Engagement (three items). In addition to the subscale scores, the total GPACS-D score was reported.
RESULTS: Across all sites, there was a significant increase in the Confidence in Clinical Abilities score from 2.98 (SD = 0.77) pre-intervention to 3.27 (SD = 0.72) post-intervention (p = 0.01), and in the total GPACS-D score from 3.48 (SD = 0.48) to 3.65 (SD = 0.39) (p = 0.01). There were non-significant increases in the Attitude to Care and Engagement scores across all sites.
CONCLUSIONS: The implementation of digital cognitive assessment tools and a blood biomarker test was associated with an increase in healthcare professionals' confidence in diagnosing and managing patients with cognitive impairment in primary care and non-specialty settings. Digital cognitive assessments and blood biomarker tests are promising tools that could be utilized in primary care to increase clinicians' confidence in detecting dementia and lead to timely clinical evaluation, treatment, and referral to supportive resources.}, }
@article {pmid40015468, year = {2025}, author = {Gupta, A and Choudhary, P and Ranjan, S and Singh, S}, title = {Exploring the therapeutic potential of Diosgenin as a Semaphorin-4D antagonist against neurodegenerative disorders.}, journal = {Archives of biochemistry and biophysics}, volume = {768}, number = {}, pages = {110356}, doi = {10.1016/j.abb.2025.110356}, pmid = {40015468}, issn = {1096-0384}, abstract = {Neurodegenerative disorders represent a significant health challenge for the population, with their mechanisms of action being poorly understood. The development of inhibitory pharmaceuticals has encountered several obstacles, resulting in therapies that lacks the necessary efficacy. Neurodegenerative disorders are marked by a gradual deterioration of neurons, leading to a decline in various functions directed by central nervous system (CNS) including motor and non-motor symptoms. Recent focus has turned towards targeting Sema4D as a potential target for mitigating neuroinflammation and inhibiting demyelination, prevalent in various neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, etc. But despite the efforts the treatment options developed poses a major hindrance in terms of side effects. An effective answer to this is Ayurvedic phytochemicals. Phytochemicals of the Piperaceae family have been known to reverse the adversities caused by neurodegeneration. In pursuit of effective interventions, this study has conducted In-silico and In-vitro studies to evaluate the efficacy of Piper nigrum and Piper betle bioactive phytochemicals as antagonists against Sema4D. Among these, Diosgenin has emerged with notable promise, demonstrating a remarkable binding affinity of -8.84 kcal/mol with Sema4D. Molecular dynamics simulations (RMSF, RMSD, PCA, SASA, FEL, etc.) have further underscored its stability, exhibiting a consistent complex structure over 100 ns. In addition to its favourable binding properties, Diosgenin has exhibited compelling effects In-vitro. It's not only enhanced cellular viability and proliferation but also exerts protective effects against oxidative stress-induced injury in PC12 cells. These findings suggest Diosgenin's potential as a therapeutic agent against Sema4D, offering a promising avenue in the battle against neurodegenerative diseases. However, further studies are required to elucidate its precise molecular mechanisms, assess its bioavailability and toxicity in vivo, and validate its therapeutic efficacy in animal models and clinical settings.}, }
@article {pmid40015072, year = {2025}, author = {Daksh, R and Mathew, MS and Bosco, AM and Sojan, C and Tom, AA and Bojja, SL and Nampoothiri, M}, title = {The role of exosomes in diagnosis, pathophysiology, and management of Alzheimer's Disease.}, journal = {Biochemical and biophysical research communications}, volume = {754}, number = {}, pages = {151526}, doi = {10.1016/j.bbrc.2025.151526}, pmid = {40015072}, issn = {1090-2104}, mesh = {*Exosomes/metabolism ; *Alzheimer Disease/therapy/diagnosis/metabolism/physiopathology ; Humans ; Drug Delivery Systems/methods ; Animals ; Biomarkers/metabolism ; Brain/metabolism/physiopathology/pathology ; Drug Carriers ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder associated with impaired cognitive function and memory loss. Currently, available therapeutics can effectively alleviate the symptoms of AD, but there is a lack of treatment to halt the progression of the disease. In recent years, exosomes have gained much attention due to their involvement in various neurological disorders. Exosomes are small extracellular vesicles comprising lipids, proteins, DNA, non-coding RNA, and mRNAs, can carry various therapeutic molecules, and are potential drug delivery vehicles. Exosomes are known as a double-edged sword due to their involvement in both the pathogenesis and management of AD. This review explores the function of exosomes in the pathophysiology, treatment, and diagnosis of AD, also emphasizing their potential as a targeted drug delivery carrier to the brain. This review seeks to provide novel perspectives to understand better the onset, targeted treatment, and diagnosis of AD using exosomes.}, }
@article {pmid40014257, year = {2025}, author = {Uvarajan, D and Gnanarajan, R and Karuppusamy, PA and Ravichandran, N and Govindasamy, C and Vellingiri, B and Narayanaswamy, A and Wang, W}, title = {Neuroprotective Effects of Berberine Chloride Against the Aluminium Chloride-Induced Alzheimer's Disease in Zebra Fish Larvae.}, journal = {Molecular biotechnology}, volume = {}, number = {}, pages = {}, pmid = {40014257}, issn = {1559-0305}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease distinguished by cognitive and memory deficits. A lack of memory, cognition, and other forms of cognitive dissonance characterizes AD, which affects approximately 50 million people worldwide. This study aimed to identify the neuroprotective effects of berberine chloride (BC) against aluminium chloride (AlCl3)-induced AD in zebrafish larvae by inhibiting oxidative stress and neuroinflammation. BC toxicity was assessed by evaluating survival rates, malformations, and heart rates in zebrafish larvae following treatment with varying concentrations of BC. This study elucidates the mechanisms of BC through an extensive range of biochemical assays, behavioral testing, and molecular docking analysis. The developmental toxicity assessment of BC indicated that doses up to 40 μM did not cause any developmental abnormalities until 96 h post fertilization. The LC50 value of BC in zebrafish larvae was found to be 50.16 μM. The biochemical and behavioral changes induced by AlCl3 in zebrafish larvae were significantly mitigated by BC treatment. Our findings demonstrate that BC can reduce total cholesterol and triglyceride levels in AlCl3-induced AD zebrafish larvae. Our molecular docking results indicated that BC significantly interacted with the ABCA1 protein, suggesting that BC may act as an ABCA1 agonist. Based on our results, it can be concluded that BC may serve as an effective therapeutic agent for mitigating oxidative stress by altering cholesterol metabolism in AlCl3-induced AD.}, }
@article {pmid40014129, year = {2025}, author = {Rathi, KM and Undale, VR and Wavhale, RD and Mohammed, FS and Karwa, PN and Patil, H}, title = {From computational screening to zebrafish testing: repurposing of doxazosin, donepezil, and dolutegravir for neuroprotective potential in Alzheimer's disease.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40014129}, issn = {1432-1912}, abstract = {Amyloid-beta (Aß) plaques and neurofibrillary tangles are distinctive features of Alzheimer's disease (AD), a progressive disorder that results in considerable memory loss and decline in cognitive function. Presently available therapies, such as donepezil and other medications that inhibit acetylcholinesterase, mainly provide relief from symptoms but do not change the course of the disease. This research article intends to investigate the possible reuse of two FDA-approved medications, doxazosin and dolutegravir, discovered through computerized screening using shape similarity, docking energy, and molecular dynamics stability, for the purpose of targeting human acetylcholinesterase (AChE) in the development of disease-altering treatments. In order to mimic neurotoxicity similar to Alzheimer's disease, zebrafish (Danio rerio) were treated with aluminum chloride (AlCl3). Various behavioral assessments, such as the open field test, mirror biting test, novel tank test, social preference test, and dark-light preference test, were carried out to assess cognitive function, movement, and anxiety-related behaviors. The results indicated that doxazosin, a drug that blocks alpha-1 adrenergic receptors, successfully decreased neuroinflammation and improved cognitive abilities. Additionally, dolutegravir, which is mainly used as an antiviral medication, showed notable benefits in protecting the nervous system. This study highlights the possibility of using doxazosin and dolutegravir as effective alternative treatments for Alzheimer's disease. Upcoming preclinical and clinical research is necessary to confirm the safety and effectiveness of AD treatment, paving the way for new opportunities in therapeutic intervention.}, }
@article {pmid40013817, year = {2025}, author = {Fu, J and Zhu, M and Zhang, L and Li, C and Liang, T and Li, Z and Liu, Z}, title = {Visualization of Oxidative Stress in the Early Stage of Alzheimer's Disease with a NIR-IIb Probe.}, journal = {Analytical chemistry}, volume = {97}, number = {9}, pages = {5038-5048}, doi = {10.1021/acs.analchem.4c05780}, pmid = {40013817}, issn = {1520-6882}, mesh = {*Alzheimer Disease/metabolism/diagnosis/diagnostic imaging/pathology ; *Oxidative Stress ; Humans ; Animals ; Fluorescent Dyes/chemistry ; Infrared Rays ; Optical Imaging ; Lanthanoid Series Elements/chemistry ; Brain/diagnostic imaging/metabolism/pathology ; Mice ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, is associated with the complete loss of cognition, and its pathogenesis has been suggested to be closely linked to oxidative stress in the early stage. However, there is currently a lack of effective methods to provide direct evidence for dynamic development of the oxidative stress status during AD progression. Herein, through manipulating the multiple energy transfer between 4f electronic levels of lanthanide ions (Ln[3+]), we proposed an energy interception strategy to construct activatable NIR-IIb nanoprobe for visualizing oxidative stress level. By utilizing an organic molecule, A1094 that absorbs light at wavelength matching the emission of Nd[3+] and Yb[3+], NIR-IIb emission from Er[3+] can be modulated upon the response of A1094 to oxidative species. This nanoprobe can not only clearly outline and distinguish oxidative stress regions in AD brains with adjacent age but also provide fast feedback on the efficacy of early interventional treatment for AD.}, }
@article {pmid40013172, year = {2025}, author = {Namrouti, A and Desamour, P and Marquez, A and Lorenzen, C and Cervantes, O and Hodges, TB and Alvarez, G and Chandra, S}, title = {Atypical Early Onset Alzheimer's Disease in a Young Female: A Case Report.}, journal = {Cureus}, volume = {17}, number = {1}, pages = {e78082}, pmid = {40013172}, issn = {2168-8184}, abstract = {Early-onset Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the development of amyloid plaques and neurofibrillary tangles at an earlier age. It affects multiple cognitive domains, including memory, executive function, and motor abilities. Here, we present a case of atypical early-onset AD. A 33-year-old woman with no significant medical history experienced a two-year decline in cognitive function, resulting in job loss and incidents such as cooking-related fires. Neurological examination revealed impaired attention, myoclonus, hyperreflexia, and a dystaxic gait. Imaging and tests showed minor abnormalities, with normal cerebrospinal fluid (CSF), genetic, autoimmune, and metabolic workups. Brain magnetic resonance imaging (MRI) and positron emission tomography (PET) fluorodeoxyglucose (FDG) scans indicated cortical atrophy and parietal hypometabolism. The patient was referred to a memory center for further evaluation and potential treatment with lecanemab. This case highlights the challenges in diagnosing early-onset neurodegenerative disorders, which can present atypically and mimic other conditions. The extensive diagnostic workup emphasizes the difficulty of diagnosing these disorders, particularly in the absence of specific biomarkers. Early diagnosis of neurodegenerative disorders in young adults requires heightened clinical suspicion and a comprehensive diagnostic workup, including advanced brain imaging, such as MRI and PET scans, to ensure timely diagnosis and referral to specialized centers.}, }
@article {pmid40012567, year = {2025}, author = {Chen, S and Wang, H and Zhang, L and Xi, Y and Lu, Y and Yu, K and Zhu, Y and Regina, I and Bi, Y and Tong, F}, title = {Glymphatic system: a self-purification circulation in brain.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1528995}, pmid = {40012567}, issn = {1662-5102}, abstract = {The glymphatic system theory introduces a new perspective on fluid flow and homeostasis in the brain. Here, cerebrospinal fluid and interstitial fluid (CSF-ISF) moves from the perivascular spaces (PVS) of arteries to those of veins for drainage. Aquaporin-4 (AQP4) plays a crucial role in driving fluid within the PVS. The impairment to AQP4 is closely linked to the dysfunction of the glymphatic system. The function of the glymphatic system is less active during waking but enhanced during sleep. The efficiency of the glymphatic system decreases with aging. Damage to the glymphatic system will give rise to the development and progression of many brain diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE), and vascular dementia (VaD). Here, we reviewed previous research associated with the glymphatic system, including its concepts, principles, and influencing factors. We hypothesize that AQP4 could be a target for the prevention and treatment of certain brain diseases through the regulation on the glymphatic system.}, }
@article {pmid40012393, year = {2025}, author = {Gulin, W and Oziemblewska, M and Zając-Lamparska, L}, title = {Use of Virtual Reality to Improve Spatial Orientation in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050374807250224044204}, pmid = {40012393}, issn = {1875-5828}, abstract = {BACKGROUND: Alzheimer's disease is a chronic, neurodegenerative condition that leads to a significant cognitive decline. One of the symptoms that greatly reduces the quality of daily functioning is the deterioration of spatial orientation abilities. A non-pharmacological treatment option for Alzheimer's disease, which is also employed to improve the cognitive functioning of individuals with mild cognitive impairment, is virtual reality training.
OBJECTIVE: To the best of the authors' knowledge, there is no existing systematic review on the use of virtual reality training to enhance spatial orientation in individuals with Alzheimer's disease or mild cognitive impairment. The review was therefore conducted to fill this gap. The findings of this review may support the efficacy of virtual reality in enhancing spatial orientation.
METHODS: Five databases were searched. The primary inclusion criteria were study participants aged over 60 years with a diagnosis of Alzheimer's disease or mild cognitive impairment and the use of virtual reality for improving spatial orientation. Six studies meeting these criteria were ultimately included in the review.
RESULTS: All included studies demonstrated an improvement in the spatial orientation of individuals with Alzheimer's disease or mild cognitive impairment following virtual reality training. This indicates the effectiveness of virtual reality technology in cognitive rehabilitation.
CONCLUSION: As virtual reality cognitive training has proven effective, its use should be more widely adopted. Further research on the application of virtual reality for enhancing spatial orientation in individuals with dementia is recommended.}, }
@article {pmid40012390, year = {2025}, author = {Singh, NK and Bhushan, B}, title = {Biochanin-A: A Potential Candidate for the Treatment of Alzheimer's Disease.}, journal = {Current pharmaceutical biotechnology}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892010362795250223160707}, pmid = {40012390}, issn = {1873-4316}, abstract = {Alzheimer's disease (AD), the most common form of dementia, is a multifactorial neurological condition characterized by progressive loss of memory and learning, uncontrollable movement, difficulty processing visual images, and impairment of reasoning and/or judgment skills. Although the exact cause of AD is still unknown, recent evidence suggests that environmental, lifestyle, and genetic factors are common contributors to the disease's progression. Pathophysiological features of AD include amyloid beta (Aβ) accumulation, abnormal deposition of neuritic plaques and neurofibrile tangles, cholinergic dysfunction, neuroinflammation, and oxidative stress burden along with mitochondrial dysfunction. There are currently no pharmaceutical methods or medications that can stop the progression of a disease. More attention is now being paid to natural products, herbal medicines, and different bioactive phytoconstituents, particularly flavonoids, as alternative therapies and useful resources for finding new drug candidates for the treatment of AD-like symptoms. A dietary isoflavone, biochanin-A, which is isolated from the leaves and stems of Trifolium pretense L. (family: Leguminosae), possesses remarkable anti-inflammatory and antioxidant properties along with cognitive-enhancing effects. Biochanin-A exhibits notable neuroprotective effects by reducing Aβ deposition, decreasing apoptosis, and preventing the production of pro-inflammatory mediators, including TNF-α, IL- 1β, and NO. Various preclinical reports explore the pharmacological role of biochanin-A against experimentally-induced AD and highlight that it can alter numerous signaling pathways, including Nrf2, NF-κB, JNK, MAPK, and Bcl-2/Bax. The present review article summarizes the numerous research studies that have evaluated the role of biochanin-A for dementia associated with AD. As part of a comprehensive program, biochanin-A has very exceptional potential to prevent and treat AD-related cognitive impairment. It is envisaged that these potential chemical moieties can be employed in the drug discovery process to identify efficacious and safe therapy for the treatments for AD-like manifestation.}, }
@article {pmid40012182, year = {2025}, author = {Shan, G and Zhang, Y and Lu, X and Li, Y and Lu, M and Li, Z}, title = {Sample size determination for a study with variable follow-up time.}, journal = {Journal of biopharmaceutical statistics}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/10543406.2025.2469879}, pmid = {40012182}, issn = {1520-5711}, abstract = {For a study to detect the outcome change at the follow-up visit from baseline, the pre-test and post-test design is commonly used to assess the treatment-control difference. Several existing methods were developed for sample size calculation including the subtraction method, analysis of covariance (ANCOVA), and linear mixed model. The first two methods can be used when the follow-up time is the same as scheduled. Although the linear mixed model can analyze the repeated measures by including the actual visit time to account for the variability of the follow-up time, it often assumes a constant treatment-control difference at any follow-up time which may not be correct in practice. We propose to develop a new statistical model to compare the treatment-control difference at the planned follow-up time while controlling for the follow-up time variation. The spline functions are used to estimate the trajectories of the treatment arm and the control arm. We compared the performance of these methods with regards to type I error rate, statistical power, and sample size under various conditions. These four methods all control for the type I error rate. The new method and the ANCOVA method are often more powerful than the other two methods, and they have similar statistical power when a linear disease progression is satisfied. For a study with non-linear disease progression, the new method can be more powerful than the ANCOVA method. We used data from a completed Alzheimer's disease trial to illustrate the application of the proposed method.}, }
@article {pmid40011826, year = {2025}, author = {Liu, J and Yu, X and Fukuyama, H and Murai, T and Wu, J and Li, Q and Zhang, Z}, title = {CSEPC: a deep learning framework for classifying small-sample multimodal medical image data in Alzheimer's disease.}, journal = {BMC geriatrics}, volume = {25}, number = {1}, pages = {130}, pmid = {40011826}, issn = {1471-2318}, support = {62103404//National Natural Science Foundation of China/ ; 62103404//National Natural Science Foundation of China/ ; 62103404//National Natural Science Foundation of China/ ; 62103404//National Natural Science Foundation of China/ ; 62103404//National Natural Science Foundation of China/ ; KQTD20180413181834876//Shenzhen Overseas Innovation Team Project/ ; KQTD20180413181834876//Shenzhen Overseas Innovation Team Project/ ; KQTD20180413181834876//Shenzhen Overseas Innovation Team Project/ ; KQTD20180413181834876//Shenzhen Overseas Innovation Team Project/ ; KQTD20180413181834876//Shenzhen Overseas Innovation Team Project/ ; JCYJ20210324101402008//Shenzhen Basic Research Program/ ; JCYJ20210324101402008//Shenzhen Basic Research Program/ ; JCYJ20210324101402008//Shenzhen Basic Research Program/ ; JCYJ20210324101402008//Shenzhen Basic Research Program/ ; JCYJ20210324101402008//Shenzhen Basic Research Program/ ; GJHZ20210705141405016//Shenzhen Science and Technology Program/ ; GJHZ20210705141405016//Shenzhen Science and Technology Program/ ; GJHZ20210705141405016//Shenzhen Science and Technology Program/ ; GJHZ20210705141405016//Shenzhen Science and Technology Program/ ; GJHZ20210705141405016//Shenzhen Science and Technology Program/ ; 21K15614//Japan Society for the Promotion of Science/ ; 21K15614//Japan Society for the Promotion of Science/ ; 21K15614//Japan Society for the Promotion of Science/ ; 21K15614//Japan Society for the Promotion of Science/ ; 21K15614//Japan Society for the Promotion of Science/ ; 21K15614//Japan Society for the Promotion of Science/ ; 2023A1515012929//Guang Dong Basic and Applied Basic Research Foundation/ ; 2023A1515012929//Guang Dong Basic and Applied Basic Research Foundation/ ; 2023A1515012929//Guang Dong Basic and Applied Basic Research Foundation/ ; 2023A1515012929//Guang Dong Basic and Applied Basic Research Foundation/ ; 2023A0505050162//International Cooperation Projects of Science and Technology of Guangdong Province/ ; 2023A0505050162//International Cooperation Projects of Science and Technology of Guangdong Province/ ; 2023A0505050162//International Cooperation Projects of Science and Technology of Guangdong Province/ ; 2023A0505050162//International Cooperation Projects of Science and Technology of Guangdong Province/ ; }, mesh = {*Alzheimer Disease/classification/diagnostic imaging ; Humans ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; Aged ; *Multimodal Imaging/methods ; Female ; Male ; Neuroimaging/methods ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impacts health care worldwide, particularly among the elderly population. The accurate classification of AD stages is essential for slowing disease progression and guiding effective interventions. However, limited sample sizes continue to present a significant challenge in classifying the stages of AD progression. Addressing this obstacle is crucial for improving diagnostic accuracy and optimizing treatment strategies for those affected by AD.
METHODS: In this study, we proposed cross-scale equilibrium pyramid coupling (CSEPC), which is a novel diagnostic algorithm designed for small-sample multimodal medical imaging data. CSEPC leverages scale equilibrium theory and modal coupling properties to integrate semantic features from different imaging modalities and across multiple scales within each modality. The architecture first extracts balanced multiscale features from structural MRI (sMRI) data and functional MRI (fMRI) data using a cross-scale pyramid module. These features are then combined through a contrastive learning-based cosine similarity coupling mechanism to capture intermodality associations effectively. This approach enhances the representation of both inter- and intramodal features while significantly reducing the number of learning parameters, making it highly suitable for small sample environments. We validated the effectiveness of the CSEPC model through experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset and demonstrated its superior performance in diagnosing and staging AD.
RESULTS: Our experimental results demonstrate that the proposed model matches or exceeds the performance of models used in previous studies in AD classification. Specifically, the model achieved an accuracy of 85.67% and an area under the curve (AUC) of 0.98 in classifying the progression from mild cognitive impairment (MCI) to AD. To further validate its effectiveness, we used our method to diagnose different stages of AD. In both classification tasks, our approach delivered superior performance.
CONCLUSIONS: In conclusion, the performance of our model in various tasks has demonstrated its significant potential in the field of small-sample multimodal medical imaging classification, particularly AD classification. This advancement could significantly assist clinicians in effectively managing and intervening in the disease progression of patients with early-stage AD.}, }
@article {pmid40011745, year = {2025}, author = {Rödström, KEJ and Eymsh, B and Proks, P and Hayre, MS and Cordeiro, S and Mendez-Otalvaro, E and Madry, C and Rowland, A and Kopec, W and Newstead, S and Baukrowitz, T and Schewe, M and Tucker, SJ}, title = {Cryo-EM structure of the human THIK-1 K2P K[+] channel reveals a lower Y gate regulated by lipids and anesthetics.}, journal = {Nature structural & molecular biology}, volume = {}, number = {}, pages = {}, pmid = {40011745}, issn = {1545-9985}, abstract = {THIK-1 (KCNK13) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K[+] channel implicated in microglial activation and neuroinflammation, and a current target for the treatment of neurodegenerative disorders, for example Alzheimer's disease and amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little is known about the structural and functional properties of THIK-1. Here we present a 3.16-Å-resolution cryo-EM structure of human THIK-1 that reveals several distinct features, in particular, a tyrosine in M4 that contributes to a lower 'Y gate' that opens upon activation by physiologically relevant G-protein-coupled receptor and lipid signaling pathways. We demonstrate that linoleic acid bound within a modulatory pocket adjacent to the filter influences channel activity, and that halothane inhibition involves a binding site within the inner cavity, both resulting in conformational changes to the Y gate. Finally, the extracellular cap domain contains positively charged residues that line the ion exit pathway and contribute to the distinct biophysical properties of this channel. Overall, our results provide structural insights into THIK-1 function and identify distinct regulatory sites that expand its potential as a drug target for the modulation of microglial function.}, }
@article {pmid40011632, year = {2025}, author = {Zhong, M and Xu, QQ and Huang, MQ and Zhan, RT and Huang, XQ and Yang, W and Lin, ZX and Xian, YF}, title = {Rhynchophylline alleviates cognitive deficits in multiple transgenic mouse models of Alzheimer's disease via modulating neuropathology and gut microbiota.}, journal = {Acta pharmacologica Sinica}, volume = {}, number = {}, pages = {}, pmid = {40011632}, issn = {1745-7254}, abstract = {Amyloid-beta (Aβ) aggregation, phosphorylated tau accumulation and neuroinflammation are considered as three hallmarks of Alzheimer's disease (AD). Rhynchophylline (RN), the major alkaloid of a Chinese medicinal plant Uncaria rhynchophylla, has been shown to possess potent anti-AD effects. This study explored the effects of RN on Aβ pathology, tauopathy, and neuroinflammation using three AD mouse models, including TgCRND8, 3×Tg-AD, and 5×FAD, with RN treatment lasting for 4, 6, and 6 months, respectively, followed by behavioral tests and biological assays. In addition, BV2 cells were employed to further evaluate the biological effects of RN. RN treatment improved cognitive functions by reducing anxiety-like behaviors, enhancing recognition ability, and ameliorating learning impairments. It modulated Aβ processing through reducing the Aβ-producing enzyme activities and enhancing degradation enzyme activities, thereby diminishing Aβ accumulation. RN also decreased hyperphosphorylated tau proteins at Thr181, Thr205, Ser396, and Ser404 sites. Moreover, RN diminished neuroinflammation by reducing microglia and astrocyte activation and lowering the release of inflammatory cytokines. Furthermore, RN treatment could restore gut microbiota dysbiosis in 5×FAD mice. In BV2 cells, knockdown of p53, HDAC2, and Galectin-3 markedly enhanced the anti-inflammatory effects of RN. Overall, the anti-AD properties of RN were attributed to its regulation of multiple biological pathways, including regulation of the p53/PINK1 signaling pathway, inhibition of the HDAC2/AMPK signaling pathway, suppression of the Galectin-3/C/EBPβ/AEP signaling pathway, and modulation of gut microflora dysbiosis. This pioneering study unambiguously revealed the effects of RN on cognitive impairments, APP processing, tauopathy, and neuroinflammation in different transgenic mouse models with differing AD burdens, highlighting its potential as an anti-AD therapeutic agent and enhancing the scientific basis for its clinical use in treating AD.}, }
@article {pmid40011292, year = {2025}, author = {Li, Q and Han, X and Dong, M and Bai, L and Zhang, W and Liu, W and Wang, F and Zhu, X}, title = {FDA-Approved Secukinumab Alleviates Glial Activation and Immune Cell Infiltration in MPTP-Induced Mouse Model of Parkinson's Disease.}, journal = {Inflammation}, volume = {}, number = {}, pages = {}, pmid = {40011292}, issn = {1573-2576}, support = {82471276//National Natural Science Foundation of China/ ; TJYXZDXK-060B//Tianjin Key Medical Discipline (Specialty) Construction Projec/ ; }, abstract = {Interleukin-17A (IL-17A) has been implicated in the progression of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, the effect of the FDA-approved Secukinumab (SEC), an IL-17A inhibitor, on PD remains unclear. This study aimed to investigate the neuroprotective effect of SEC and its potential mechanisms in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Male C57BL/6 J mice were mainly assigned to three groups: Sham, MPTP, and MPTP + SEC. Motor coordination was assessed using the climbing rod and rotarod tests. Dopaminergic neurons (TH +) and glial cells (Iba-1 + , GFAP +) in the substantia nigra were evaluated using immunohistochemistry and immunofluorescence. Flow cytometry was used to analyze immune cell populations in the brain and spleen. Inflammatory cytokines and chemokines were quantified using RT-PCR. SEC treatment significantly alleviated the loss of dopaminergic neurons and improved motor coordination in MPTP mice. It also reduced the infiltration of peripheral immune cells, including CD4 + T cells, NK cells, and monocyte-macrophages into the brain. SEC attenuated glial activation (Iba-1 + , GFAP +) and decreased the expression of pro-inflammatory cytokines and chemokines (CCL2, CXCL9), which recruit immune cells into the brain. These results suggest that Secukinumab protects dopaminergic neurons and attenuates neuroinflammation in MPTP-induced model. SEC treatment in PD might be an effective therapeutic approach for clinical application in the future. HIGHLIGHTS: • Secukinumab reduces the loss of dopaminergic neurons and axons in MPTP mice. • Secukinumab inhibits the infiltration of peripheral immune cells into the brain in MPTP mice. • Secukinumab inhibits the activation of glial cells and reduces neuroinflammation in MPTP mice.}, }
@article {pmid40011174, year = {2025}, author = {Rosen, J and Jessen, F}, title = {Patient eligibility for amyloid-targeting immunotherapies in Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {4}, pages = {100102}, doi = {10.1016/j.tjpad.2025.100102}, pmid = {40011174}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology ; *Immunotherapy/methods ; Male ; Aged ; Female ; *Amyloid beta-Peptides/metabolism/immunology ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Retrospective Studies ; Aged, 80 and over ; Patient Selection ; Eligibility Determination ; }, abstract = {BACKGROUND: Amyloid beta (Aβ) targeting immunotherapies have evolved as promising treatment options for patients with early symptomatic Alzheimer's disease (AD). Understanding how eligibilty criteria impact on the number of patients potentially qualifying for treatment is of high relevance for designing diagnostic workflows in clinical practice and for estimating required ressources and costs.
OBJECTIVES: We aimed at estimating the number of potentially eligible patients for treatment with the Aβ targeting antibodies aducanumab, lecanemab and donanemab in a specialized center real-world sample by the applying the phase 3 clinical trial and the appropriate use recommendations (AUR) inclusion and exclusion criteria to the data set. The post-mortem report was used for defining amyloid positivity and the presence of AD pathology in this study.
DESIGN: Retrospective, descriptive study.
SETTING: The multicenter National Alzheimer's Coordinating Center-Uniform Data Set (NACC-UDS) and Neuropathology Data Set (NACCNP).
PARTICIPANTS: We included all 3,343 participants of the NACC dataset with available post-mortem pathology reports.
MEASUREMENTS/RESULTS: 887 participants were potential candidates for anti-Aβ immunotherapy as they presented with amnestic mild cognitive impairment or mild dementia and the clinical diagnosis of AD (amnestic AD syndrome). Applying the criterion of amyloid positivity (post mortem report) and the clinical trial inclusion and exclusion criteria to this sample resulted in 83 (9 %), 275 (31 %), and 172 (19 %) participants eligible for treatment with aducanumab, lecanemab, and donanemab, respectively. Applying the criteria of the AUR resulted in 242 (27 %) and 266 (30 %) participants eligible for treatment with aducanumab or lecanemab, respectively. The eligible participant groups for each antibody showed partial, but not full overlap. Co-pathologies were common.
CONCLUSIONS: The number of eligible participants varies between the different antibodies and the selected groups only partly overlap, indicating partly different groups of eligible participants for each antibody. Since not all inclusion and exclusion criteria can be extracted from the NACC-UDS dataset, the real number of eligible patients will be smaller.}, }
@article {pmid40011173, year = {2025}, author = {Villain, N and Planche, V and Lilamand, M and Cordonnier, C and Soto-Martin, M and Mollion, H and Bombois, S and Delrieu, J and , }, title = {Lecanemab for early Alzheimer's disease: Appropriate use recommendations from the French federation of memory clinics.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {4}, pages = {100094}, doi = {10.1016/j.tjpad.2025.100094}, pmid = {40011173}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis ; France ; *Antibodies, Monoclonal, Humanized/therapeutic use ; }, abstract = {Lecanemab, a monoclonal antibody targeting β-amyloid protofibrils, has shown promising results in a Phase III clinical trial for the treatment of early stages of Alzheimer's disease (AD) and has been approved by the European Medicines Agency. An Early Market Authorization could be submitted to the French regulatory agencies, potentially allowing for the drug's use in clinical practice in France in 2025. To guide French clinicians in administering lecanemab in a standardized way, the French Federation of Memory Clinics has developed appropriate use recommendations for lecanemab that highlight relevant questions established to ensure an optimal risk-benefit ratio. The recommendations emphasize that lecanemab treatment requires a comprehensive individualized evaluation of the risk-benefit ratio, which should occur in multidisciplinary meetings. When approved, the guidelines support the use of blood biomarkers, proposing specific cutoffs for patients eligible for lecanemab under restricted conditions. In addition to the European Medicines Agency restrictions in patients on anticoagulants, and APOE4 homozygotes, the guidelines recommend against lecanemab treatment for patients with high amyloid-related hemorrhagic risk such as probable cerebral amyloid angiopathy (Boston criteria v1.5) until further data become available. Additionally, we recommend that MRI monitoring be started before the third infusion to account for early Amyloid Related Imaging Abnormalities (ARIA) occurring on lecanemab. It is recommended to establish a specific clinical care pathway with protocols for patients with ARIA, with trained physicians and radiologists with expertise in neurological emergency and intensive care. Finally, a discontinuation protocol based on dementia severity assessment after 18 months of lecanemab treatment is suggested. Access to lecanemab requires a personalized biological and genetic diagnosis of AD, which is currently not necessary in most cases. Therefore, the healthcare system must rapidly adjust to new diagnostic procedures and treatment delivery to ensure equal access for all individuals.}, }
@article {pmid40010509, year = {2025}, author = {Kaur, V and Sunkaria, A}, title = {Unlocking the therapeutic promise of miRNAs in promoting amyloid-β clearance for Alzheimer's disease.}, journal = {Behavioural brain research}, volume = {484}, number = {}, pages = {115505}, doi = {10.1016/j.bbr.2025.115505}, pmid = {40010509}, issn = {1872-7549}, mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; *MicroRNAs/metabolism ; *Amyloid beta-Peptides/metabolism ; Animals ; Oligonucleotides, Antisense/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a neurological disorder that affects cognition and behavior, accounting for 60-70 % of dementia cases. Its mechanisms involve amyloid aggregates, hyperphosphorylated tau tangles, and loss of neural connections. Current treatments have limited efficacy due to a lack of specific targets. Recently, microRNAs (miRNAs) have emerged as key modulators in AD, regulating gene expression through interactions with mRNA. Dysregulation of specific miRNAs contributes to disease progression by disrupting clearance pathways. Antisense oligonucleotide (ASO)-based therapies show promise for AD treatment, particularly when combined with miRNA mimics or antagonists, targeting complex regulatory networks. However, miRNAs can interact with each other, complicating cellular processes and potentially leading to side effects. Our review emphasizes the role of miRNAs in regulating amyloid-beta (Aβ) clearance and highlights their potential as therapeutic targets and early biomarkers for AD, underscoring the need for further research to enhance their efficacy and safety.}, }
@article {pmid40010154, year = {2025}, author = {Millar, CL and Iloputaife, I and Baldyga, K and Norling, AM and Boulougoura, A and Vichos, T and Tchkonia, T and Deisinger, A and Pirtskhalava, T and Kirkland, JL and Travison, TG and Lipsitz, LA}, title = {A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease.}, journal = {EBioMedicine}, volume = {113}, number = {}, pages = {105612}, pmid = {40010154}, issn = {2352-3964}, mesh = {Humans ; *Alzheimer Disease/drug therapy/etiology ; Aged ; Male ; Female ; Pilot Projects ; *Cognition/drug effects ; *Quercetin/administration & dosage/therapeutic use/pharmacology ; *Biomarkers ; Senotherapeutics/pharmacology/therapeutic use/administration & dosage ; Aged, 80 and over ; Dasatinib/therapeutic use/administration & dosage/adverse effects ; Middle Aged ; }, abstract = {BACKGROUND: This single-arm study evaluates the feasibility, safety, and preliminary effects of two senolytic agents, Dasatinib and Quercetin (DQ), in older adults at risk of Alzheimer's disease.
METHODS: Participants took 100 mg of Dasatinib and 1250 mg of Quercetin for two days every two weeks over 12 weeks. Recruitment rate, adverse events, absolute changes in functional outcomes, and percent changes in biomarkers were calculated. Spearman correlations between functional and biomarker outcomes were performed.
FINDINGS: Approximately 10% of telephone-screened individuals completed the intervention (n = 12). There were no serious adverse events related to the intervention. Mean Montreal Cognitive Assessment (MoCA) scores non-significantly increased following DQ by 1.0 point (95% CI: -0.7, 2.7), but increased significantly by 2.0 points (95% CI: 0.1, 4.0) in those with lowest baseline MoCA scores. Mean percent change in tumour necrosis factor-alpha (TNF-α), a key product of the senescence-associated secretory phenotype (SASP), non-significantly decreased following DQ by -3.0% (95% CI: -13.0, 7.1). Changes in TNF-α were significantly and inversely correlated with changes in MoCA scores (r = -0.65, p = 0.02), such that reductions in TNF- α were correlated with increases in MoCA scores.
INTERPRETATION: This study suggests that intermittent DQ treatment is feasible and safe; data hint at potential functional benefits in older adults at risk of Alzheimer's disease. The observed reduction in TNF-α and its correlation with increases in MoCA scores suggests that DQ may improve cognition by modulating the SASP. However, there was not an appropriate control group. Data are preliminary and must be interpreted cautiously.
FUNDING: National Institute on Ageing grants R21AG073886 and R33AG061456 funded this research.}, }
@article {pmid40010133, year = {2025}, author = {Almatary, AM and Al-Sanea, MM and Nasr, EE and Haikal, A and Thompson, GS and Abood, A and Ibrahim, MAA and Elgazar, AA and Hamdi, A}, title = {"Triazole-linked thiazolidinedione-Benzothiazole hybrids: Design and biological evaluation as AChE inhibitors".}, journal = {Bioorganic chemistry}, volume = {157}, number = {}, pages = {108295}, doi = {10.1016/j.bioorg.2025.108295}, pmid = {40010133}, issn = {1090-2120}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Triazoles/chemistry/pharmacology/chemical synthesis ; *Acetylcholinesterase/metabolism ; Animals ; Mice ; *Drug Design ; Structure-Activity Relationship ; *Butyrylcholinesterase/metabolism ; *Thiazolidinediones/pharmacology/chemistry/chemical synthesis ; *Benzothiazoles/pharmacology/chemistry/chemical synthesis ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Dose-Response Relationship, Drug ; RAW 264.7 Cells ; Anti-Inflammatory Agents/pharmacology/chemistry/chemical synthesis ; }, abstract = {Novel 2,4-thiazolidinedione-benzothiazole-triazole hybrids (7a-7l) were designed and synthesized as therapeutic agents with pleotropic activity for Alzheimer's disease (AD). These compounds were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. Compound 7k, exhibited exceptional AChE inhibition (IC50 = 0.083 μM), while compound 7d, showed potent activity (IC50 = 0.119 μM). Kinetic studies revealed that 7k was able to exert its action through mixed types of inhibition. Also, the anti-inflammatory potential of these lead compounds was assessed in LPS-stimulated RAW 264.7 macrophages. Both compounds demonstrated significant dose-dependent inhibition of key inflammatory mediators, including NO, TNF-α, IL-6, and IL-1β at non-cytotoxic concentrations (≤10 μM). Notably, compound 7k exhibited superior anti-inflammatory activity, achieving 92 % NO inhibition, 65 % TNF-α reduction, and 61.1 % IL-1β suppression at 10 μM. Moreover, compound 7k exerted neuroprotective activity against H2O2 induced neurotoxicity in SH-Sy5y cell line leading to reduction in LDH, ROS levels and improving cell survival. Finally, compound 7k was able to prevent Aβ aggregation at IC50 = 5 μM. Molecular docking studies provided structural insights into the possible binding interactions of compounds 7d and 7k within the AChE active site. The stability and binding energies of compounds 7d and 7k complexed with AChE were assessed over 100 ns molecular dynamics simulations and compared with Donepezil. The MM/GBSA binding energy calculations indicated that compound 7k exhibited a higher affinity for AChE in comparison with compound 7d and Donepezil, with ΔGbinding values of -46.1, -42.6, and - 24.0 kcal/mol, respectively. These findings suggest that these novel hybrid molecules represent promising multi-target therapeutic candidates for AD treatment, effectively addressing both cholinergic dysfunction and neuroinflammation.}, }
@article {pmid40009384, year = {2025}, author = {Matt, E and Mitterwallner, M and Radjenovic, S and Grigoryeva, D and Weber, A and Stögmann, E and Domitner, A and Zettl, A and Osou, S and Beisteiner, R}, title = {Ultrasound Neuromodulation With Transcranial Pulse Stimulation in Alzheimer Disease: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2459170}, pmid = {40009384}, issn = {2574-3805}, mesh = {Humans ; *Alzheimer Disease/therapy ; Female ; Male ; Aged ; Double-Blind Method ; *Transcranial Direct Current Stimulation/methods ; Cross-Over Studies ; Treatment Outcome ; Aged, 80 and over ; Middle Aged ; Neuropsychological Tests/statistics & numerical data ; }, abstract = {IMPORTANCE: Given the increasing prevalence of dementia and the limited treatment options available, ultrasound neuromodulation could serve as a novel add-on therapy to standard treatments for Alzheimer disease (AD). As ultrasound neuromodulation is still in its early stages, further research is essential to fully explore its potential in treating brain disorders.
OBJECTIVE: To evaluate clinical and functional imaging effects of transcranial pulse stimulation (TPS) in patients with AD.
A randomized, double-blind, sham-controlled, crossover clinical trial was conducted at the Medical University of Vienna between January 1, 2017, and July 27, 2022. Sixty patients with clinically diagnosed AD receiving state-of-the-art treatment were randomly allocated to treatment sequence groups verum-sham (first cycle verum, second cycle sham, n = 30) and sham-verum (n = 30). Data analysis was performed from July 28, 2022, to September 5, 2024.
INTERVENTION: Each participant received 6 verum and 6 sham TPS sessions (6000 pulses, 0.20 mJ/mm2, 5 Hz) to frontoparietal brain areas.
MAIN OUTCOMES AND MEASURES: Neuropsychological tests, including the primary outcome Consortium to Establish a Registry for Alzheimer's Disease (CERAD) corrected total score (CTS), were performed at baseline and 1 week, 1 month, and 3 months following the stimulations in each cycle. Primary and secondary outcomes, including functional magnetic resonance imaging and Beck Depression Inventory-II, were analyzed by intention-to-treat analysis and, for sensitivity, by per protocol analysis.
RESULTS: For the intention-to-treat analysis, 60 patients between ages 51 and 82 years (mean [SD], 70.65 [8.16] years; 30 females; 30 males) were included. The CERAD CTS increased by a mean (SD) of 2.22 (6.87) points in the verum condition from 70.93 (14.27) points at baseline to 73.15 (14.90) 3 months after stimulation, while the mean (SD) score in the sham condition increased by 1.00 (6.82) point vs baseline from 71.68 (13.62] at baseline to 72.68 (14.48) 3 months after stimulation. Primary data analysis of the condition × session interaction was not significant (P = .68; partial η2 [ηp2] = 0.01), but its interaction with age was P = .003; ηp2 = 0.08, followed by post hoc analyses of age subsamples. Although several patients older than 70 years benefited from verum TPS, only the younger subgroup (≤70 years) showed significantly higher CTS increases for verum in all poststimulation sessions (condition × session: P = .005; ηp2 = 0.16). At 3 months after stimulation, for example, a mean (SD) 3.91 (7.86)-point increase was found for verum TPS in the younger patients, but a mean (SD) CTS decrease of 1.83 (5.80) was observed for sham. Memory-associated brain activation was significantly higher after verum TPS in the precuneus, visual, and frontal areas, while resting state functional connectivity was significantly upregulated in the dorsal attention network. In the per protocol sample, a significant reduction of the Beck Depression Inventory-II scores 3 months following verum TPS was found (verum baseline: 7.27 [5.87]; verum 3 months after stimulation: 5.27 [5.27]; sham baseline: 6.70 [5.65]; sham 3 months after stimulation: 6.22 [4.40]; P = .008; ηp2 = 0.23). During both verum and sham conditions, the most common observed adverse symptom was depression; no major neuropathologic change was detected in the patients by detailed neuroradiologic assessments.
CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of TPS in patients with AD, a 2-week verum treatment improved cognitive scores in the younger subgroup, ameliorated depressive symptoms, and induced upregulation of functional brain activation and connectivity. These findings suggest TPS may be a safe and promising add-on therapy for patients with AD receiving state-of-the-art treatment.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03770182.}, }
@article {pmid40009301, year = {2025}, author = {Ramakrishan, P and Rajangam, J and Mahinoor, SS and Bisht, S and Mekala, S and Upadhyay, DK and Solomon, VR and Sabarees, G and Pelluri, R}, title = {Unveiling the mTOR pathway modulation by SGLT2 inhibitors: a novel approach to Alzheimer's disease in type 2 diabetes.}, journal = {Metabolic brain disease}, volume = {40}, number = {3}, pages = {132}, pmid = {40009301}, issn = {1573-7365}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Diabetes Mellitus, Type 2/drug therapy/metabolism ; *TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Animals ; }, abstract = {Alzheimer's disease (AD) is a neurological condition causing cognitive deterioration, leading to severe consequences. As the global prevalence of AD increases, new treatment approaches are needed to supplement current conventional therapies, as traditional treatments are not meeting the increasing demand for alternative treatments. It is increasingly evident that treating metabolic disorders like diabetes mellitus, obesity, and AD by blocking mechanistic target of rapamycin (mTOR) signalling is advantageous. Chronic mTOR activation may cause AD's metabolic, lysosomal, and mitochondrial dysfunction, tau hyperphosphorylation, amyloid plaque development, and disruption of the blood-brain barrier through endothelial cell malfunction. Chronic glucose loss through sodium-glucose transporter 2 (SGLT2) inhibitions can restore mTOR cycling, potentially halting or slowing AD pathogenesis. Chronic activation of mTOR is implicated in pathophysiological aspects of AD, such as metabolic dysfunction, tau hyperphosphorylation, amyloid plaque formation, and disruption of the blood-brain barrier. SGLT-2 inhibitors, commonly used in treating Type 2 Diabetes, have been shown to reduce mTOR activation and restore circadian regularity, a new finding in cognitive decline and metabolic disorders. Conversely, SGLT2 inhibitors decrease oxidative damage, inflammation, insulin signaling pathways, and proliferation of endothelial cells to enhance vascular tone, flexibility, and contractility. Along with reducing the formation of plaque containing amyloid and improving brain function, neural plasticity, acetylcholinesterase (AChE) activity, damage to the brain, and cognitive decline, they also regulate the mTOR pathway in the brain. Thus, repurposing SGLT-2 inhibitors, primarily used in diabetes treatment, presents a promising avenue for changing the way that AD is managed. The purpose of this review was to focus on the mTOR signalling cascade of SGLT 2 inhibitors to AD management in Type 2 Diabetes mellitus.}, }
@article {pmid40009144, year = {2025}, author = {Milani, SA and Westra, J and Kuo, YF and Downer, B and Raji, MA}, title = {Dementia Medications and Their Association with Pain Medication Use in Medicare Beneficiaries with Alzheimer's Disease/Alzheimer's Disease-Related Dementias and Chronic Pain.}, journal = {Drugs & aging}, volume = {42}, number = {3}, pages = {267-274}, pmid = {40009144}, issn = {1179-1969}, support = {K01 AG075254/AG/NIA NIH HHS/United States ; R01-DA039192/DA/NIDA NIH HHS/United States ; P30-AG059301/AG/NIA NIH HHS/United States ; K01-AG075254)/AG/NIA NIH HHS/United States ; P30 AG059301/AG/NIA NIH HHS/United States ; P30-AG024832/AG/NIA NIH HHS/United States ; R01 DA039192/DA/NIDA NIH HHS/United States ; }, mesh = {Humans ; United States ; *Chronic Pain/drug therapy ; *Alzheimer Disease/drug therapy ; Male ; *Medicare/statistics & numerical data ; Aged ; Female ; Aged, 80 and over ; *Dementia/drug therapy ; *Memantine/therapeutic use ; Cholinesterase Inhibitors/therapeutic use ; Analgesics/therapeutic use ; Analgesics, Opioid/therapeutic use ; Pain Management/methods/statistics & numerical data ; }, abstract = {INTRODUCTION: Chronic pain is prevalent among older adults with Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD). Memantine and acetylcholinesterase inhibitors (ACHEI; donepezil, rivastigmine, and galantamine) are approved for the treatment of dementia symptoms and may also have analgesic properties. However, findings on the clinical utility of these dementia medications for chronic pain treatment are mixed, and little is known about differences in the use of pain medication according to whether an older adult with AD/ADRD is using dementia medications.
METHODS: We selected a 20% national sample of Medicare enrollees with a diagnosis of AD/ADRD and chronic pain in 2020. We calculated the odds of having any pain management prescription (opioids, serotonin and norepinephrine reuptake, gapapentinoids, or non-steroidal anti-inflammatory drugs), having an opioid prescription, and having a long-term (≥ 90 days) opioid prescription, by dementia medication (none, memantine, ACHEI, or memantine and ACHEI).
RESULTS: Among 103,564 patients, 5.5% received a memantine prescription, 14.4% received an ACHEI prescription, and 8.6% received a prescription for both. Over 70% of all patients had a pain management prescription. The percentage of patients who had an opioid prescription ranged from 54.5% for those without a dementia medication prescription to 44.0% for those with a prescription for both memantine and ACHEI. Similarly, the percentage of patients who had a long-term opioid prescription was highest for those without a dementia medication prescription (12.2%) and lowest for those with a prescription for both memantine and ACHEI (8.8%). Having a prescription for memantine only was associated with lower odds of any pain management prescription (odds ratio [OR]: 0.94; 95% confidence interval [CI]: 0.88-1.00; p < 0.05). Having a prescription for either memantine (OR: 0.79; 95% CI 0.75-0.84), ACHEI (OR: 0.85; 95% CI 0.82-0.89), or both (OR: 0.75; 95% CI 0.72-0.79) was associated with lower odds of having an opioid prescription (p < 0.05). Lastly, having a prescription for either memantine (OR: 0.85; 95% CI 0.77-0.94), ACHEI (OR: 0.92; 95% CI 0.86-0.98), or both (OR: 0.83; 95% CI 0.77-0.90) was associated with lower odds of having a long-term opioid prescription.
DISCUSSION: Older adults with co-occurring AD/ADRD and chronic pain who were on dementia medications had lower odds of being prescribed opioid analgesics. Memantine and ACHEIs should be explored as potential opioid-sparing medications for older adults with AD/ADRD, given their relatively safe profiles. Future studies are needed to examine repurposing dementia medications for pain treatment.}, }
@article {pmid40008891, year = {2025}, author = {Habibatni, S and Maiuolo, J and Davì, F and Samir, Z and Lyas, B and Cacciola, F and Laganà Vinci, R and Mondello, L and Taviano, MF and Miceli, N}, title = {Characterization of the phenolic profile, antioxidant and neuroprotective activity of leaf hydroalcoholic extracts of Euphorbia bupleuroides subsp. luteola (Kralik) maire growing wild in Algeria.}, journal = {International journal of environmental health research}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/09603123.2025.2461098}, pmid = {40008891}, issn = {1369-1619}, abstract = {The objective of this research was to investigate the phenolic profile and some biological properties of the leaves of Euphorbia bupleuroides subsp. luteola grown wild in Algeria, still unexplored. The leaves were subjected to extraction with 80% MeOH using simple maceration (SM) and ultrasound-assisted maceration (UM) to establish the most efficient conditions for the recovery of phenolic compounds. The study of antioxidant potential suggested that SM and UM extracts displayed a superimposable activity both in the DPPH test and in the reducing power assay. On the other hand, in the Fe2+ chelating activity assay, SM was more active than UM. SM extract prevented damage induced by β-amyloid protein (Aβ) being more effective against ROS generated after treatment with Aβ. In addition, SM exhibited later protection against malondialdehyde. In conclusion, it is possible to state that simple maceration represents an effective technique for the recovery of compounds with antioxidant and neuroprotective properties from E. bupleuroides subsp. luteola leaves.}, }
@article {pmid40008329, year = {2025}, author = {Scheijbeler, EP and de Haan, W and Coomans, EM and den Braber, A and Tomassen, J and Ten Kate, M and Konijnenberg, E and Collij, LE and van de Giessen, E and Barkhof, F and Visser, PJ and Stam, CJ and Gouw, AA}, title = {Amyloid-β deposition predicts oscillatory slowing of magnetoencephalography signals and a reduction of functional connectivity over time in cognitively unimpaired adults.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcaf018}, pmid = {40008329}, issn = {2632-1297}, abstract = {With the ongoing developments in the field of anti-amyloid therapy for Alzheimer's disease, it is crucial to better understand the longitudinal associations between amyloid-β deposition and altered network activity in the living human brain. We included 110 cognitively unimpaired individuals (67.9 ± 5.7 years), who underwent [[18]F]flutemetamol (amyloid-β)-PET imaging and resting-state magnetoencephalography (MEG) recording at baseline and 4-year follow-up. We tested associations between baseline amyloid-β deposition and MEG measures (oscillatory power and functional connectivity). Next, we examined the relationship between baseline amyloid-β deposition and longitudinal MEG measures, as well as between baseline MEG measures and longitudinal amyloid-β deposition. Finally, we assessed associations between longitudinal changes in both amyloid-β deposition and MEG measures. Analyses were performed using linear mixed models corrected for age, sex and family. At baseline, amyloid-β deposition in orbitofrontal-posterior cingulate regions (i.e. early Alzheimer's disease regions) was associated with higher theta (4-8 Hz) power (β = 0.17, P < 0.01) in- and lower functional connectivity [inverted Joint Permutation Entropy (JPEinv) theta, β = -0.24, P < 0.001] of these regions, lower whole-brain beta (13-30 Hz) power (β = -0.13, P < 0.05) and lower whole-brain functional connectivity (JPEinv theta, β = -0.18, P < 0.001). Whole-brain amyloid-β deposition was associated with higher whole-brain theta power (β = 0.17, P < 0.05), lower whole-brain beta power (β = -0.13, P < 0.05) and lower whole-brain functional connectivity (JPEinv theta, β = -0.21, P < 0.001). Baseline amyloid-β deposition in early Alzheimer's disease regions also predicted future oscillatory slowing, reflected by increased theta power over time in early Alzheimer's disease regions and across the whole brain (β = 0.11, β = 0.08, P < 0.001), as well as decreased whole-brain beta power over time (β = -0.04, P < 0.05). Baseline amyloid-β deposition in early Alzheimer's disease regions also predicted a reduction in functional connectivity between these regions and the rest of the brain over time (JPEinv theta, β = -0.07, P < 0.05). Baseline whole-brain amyloid-β deposition was associated with increased whole-brain theta power over time (β = 0.08, P < 0.01). Baseline MEG measures were not associated with longitudinal amyloid-β deposition. Longitudinal changes in amyloid-β deposition in early Alzheimer's disease regions were associated with longitudinal changes in functional connectivity of early Alzheimer's disease regions (JPEinv theta, β = -0.19, P < 0.05) and the whole brain [corrected amplitude envelope correlations alpha (8-13 Hz), β = -0.22, P < 0.05]. Finally, longitudinal changes in whole-brain amyloid-β deposition were associated with longitudinal changes in whole-brain relative theta power (β = 0.21, P < 0.05). Disruptions of oscillatory power and functional connectivity appear to represent early functional consequences of emerging amyloid-β deposition in cognitively unimpaired individuals. These findings suggest a role for neurophysiology in monitoring disease progression and potential treatment effects in pre-clinical Alzheimer's disease.}, }
@article {pmid40007468, year = {2025}, author = {Feigin, A and Evans, EE and Fisher, TL and Zauderer, M}, title = {Pepinemab: a SEMA4D antagonist for treatment of Huntington's and other neurodegenerative diseases.}, journal = {Expert opinion on investigational drugs}, volume = {34}, number = {3}, pages = {109-119}, doi = {10.1080/13543784.2025.2473055}, pmid = {40007468}, issn = {1744-7658}, mesh = {Humans ; *Huntington Disease/drug therapy/physiopathology ; Animals ; *Semaphorins/antagonists & inhibitors ; *Neurodegenerative Diseases/drug therapy/physiopathology ; Antigens, CD ; Multiple Sclerosis/drug therapy/physiopathology ; Drug Development ; Gliosis/drug therapy ; Antibodies, Monoclonal/pharmacology/adverse effects/administration & dosage ; }, abstract = {INTRODUCTION: Huntington's Disease (HD) is a progressive fatal neurodegenerative disease with an unmet need for disease-modifying therapies. Neuroinflammation, particularly astrogliosis, plays a crucial role in the pathogenesis of HD and modulation of this damaging activity and its downstream effects presents a promising therapeutic avenue. Pepinemab, a semaphorin 4D (SEMA4D) blocking antibody, has the potential to serve this purpose.
AREAS COVERED: We review the proposed mechanisms of action of pepinemab, published safety and efficacy results from the 'SIGNAL' Phase 2 trial in HD and supporting data from a Phase 1 trial in multiple sclerosis (MS).
EXPERT OPINION: Pepinemab's potential to reduce reactive gliosis and inflammation is a novel mechanism of action (MOA) that may be effective as a standalone therapy as well as one that may complement other strategies to reduce toxic disease associated processes. Pepinemab has demonstrated a favorable safety profile and treatment benefits in fluid biomarkers, imaging endpoints, and measures of cognitive function that encourage continued development in HD and other neurodegenerative diseases.}, }
@article {pmid40006083, year = {2025}, author = {Rao, IY and Hanson, LR and Frey Ii, WH}, title = {Brain Glucose Hypometabolism and Brain Iron Accumulation as Therapeutic Targets for Alzheimer's Disease and Other CNS Disorders.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {2}, pages = {}, pmid = {40006083}, issn = {1424-8247}, abstract = {Two common mechanisms contributing to multiple neurological disorders, including Alzheimer's disease, are brain glucose hypometabolism (BGHM) and brain iron accumulation (BIA). Currently, BGHM and BIA are both widely acknowledged as biomarkers that aid in diagnosing CNS disorders, distinguishing between disorders with similar symptoms, and tracking disease progression. Therapeutics targeting BGHM and BIA in Alzheimer's disease can be beneficial in treating neurocognitive symptoms. This review addresses the evidence for the therapeutic potential of targeting BGHM and BIA in multiple CNS disorders. Intranasal insulin, which is anti-inflammatory and increases brain cell energy, and intranasal deferoxamine, which reduces oxidative damage and inflammation, represent promising treatments targeting these mechanisms. Both BGHM and BIA are promising therapeutic targets for AD and other CNS disorders.}, }
@article {pmid40005231, year = {2025}, author = {Thawabteh, AM and Ghanem, AW and AbuMadi, S and Thaher, D and Jaghama, W and Karaman, D and Karaman, R}, title = {Promising Natural Remedies for Alzheimer's Disease Therapy.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {4}, pages = {}, pmid = {40005231}, issn = {1420-3049}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Plant Extracts/chemistry/therapeutic use/pharmacology ; Biological Products/therapeutic use/chemistry/pharmacology ; Animals ; Phytotherapy/methods ; Phytochemicals/therapeutic use/chemistry/pharmacology ; Plants, Medicinal/chemistry ; Blood-Brain Barrier/drug effects/metabolism ; }, abstract = {This study examines the intricacies of Alzheimer's disease (AD), its origins, and the potential advantages of various herbal extracts and natural compounds for enhancing memory and cognitive performance. Future studies into AD treatments are encouraged by the review's demonstration of the effectiveness of phytoconstituents that were extracted from a number of plants. In addition to having many beneficial effects, such as improved cholinergic and cognitive function, herbal medicines are also much less harmful, more readily available, and easier to use than other treatments. They also pass without difficulty through the blood-brain barrier (BBB). This study focused on natural substances and their effects on AD by using academic databases to identify peer-reviewed studies published between 2015 and 2024. According to the literature review, 66 phytoconstituents that were isolated from 21 distinct plants have shown efficacy, which could be encouraging for future research on AD therapies. Since most clinical trials produce contradictory results, the study suggests that larger-scale studies with longer treatment durations are necessary to validate or refute the therapeutic efficacy of herbal AD treatments.}, }
@article {pmid40005187, year = {2025}, author = {Capó, T and Rebassa, JB and Raïch, I and Lillo, J and Badia, P and Navarro, G and Reyes-Resina, I}, title = {Future Perspectives of NMDAR in CNS Disorders.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {4}, pages = {}, pmid = {40005187}, issn = {1420-3049}, support = {PID2020-113430RB-I00//Spanish Ministry of Economy and Innovation/ ; #2021 SGR 00304//Regional Catalonian Government/ ; }, mesh = {*Receptors, N-Methyl-D-Aspartate/metabolism ; Humans ; Animals ; *Central Nervous System Diseases/metabolism/drug therapy ; Neurodegenerative Diseases/metabolism/drug therapy ; }, abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's diseases are among the leading causes of physical and cognitive disability across the globe. Fifty million people worldwide suffer these diseases, and that number is expected to rise as the population ages. Ictus is another pathology that also courses with neurodegeneration and is a leading cause of mortality and long-term disability in developed countries. Schizophrenia is not as common as other mental disorders, affecting approximately 24 million people worldwide. All these disorders have in common that still there is not an effective pharmacological treatment to cure them. The N-methyl-D-aspartate (NMDA) receptor (NMDAR) has attracted attention as a potential therapeutic target due to its important role in learning and memory and also due to its implication in excitotoxicity processes. Some drugs targeting NMDARs are already being used to treat symptoms of disorders affecting the central nervous system (CNS). Here, we aim to review the implications of NMDAR in these CNS pathologies, its role as a potential therapeutic target, and the future perspectives for developing new treatments focused on these receptors.}, }
@article {pmid40005082, year = {2025}, author = {Wang, X and Yi, Z and Zhang, Y and Zhang, J and Li, X and Qi, D and Wang, Q and Chai, X and Liu, H and Wang, G and Pan, Y and Liu, Y and Yu, G}, title = {Identification and Therapeutic Potential of Polymethoxylated Flavones in Citri Reticulatae Pericarpium for Alzheimer's Disease: Targeting Neuroinflammation.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {4}, pages = {}, pmid = {40005082}, issn = {1420-3049}, support = {CI2021A00511//China Academy of Chinese Medical Sciences (CACMS) Innovation Fund/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Flavones/pharmacology/chemistry/therapeutic use ; Animals ; *Citrus/chemistry ; Mice ; Disease Models, Animal ; Neuroinflammatory Diseases/drug therapy/metabolism ; Flavonoids/chemistry/pharmacology/therapeutic use ; Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use ; Male ; Plant Extracts/chemistry/pharmacology ; }, abstract = {Neuroinflammation is a significant driving force in the pathogenesis and progression of central nervous system (CNS) disorders. Polymethoxylated flavones (PMFs), the key lipid-soluble constituents in Citri Reticulatae Pericarpium (CRP), exhibit excellent blood-brain barrier permeability and anti-inflammatory properties, holding therapeutic potential for CNS disorders. However, the specific bioactive components and therapeutic effects of PMFs in treating CNS disorders are not well understood. This study employed a comprehensive sequential metabolism approach to elucidate the dynamic biotransformation of PMFs in vivo and identified seven brain-targeting components. Subsequently, network pharmacology and experimental validation were utilized to explore the potential mechanisms of PMFs. The results suggested that PMFs have potential therapeutic value for Alzheimer's disease (AD)-like mice, with the inhibition of neuroinflammation likely being a key mechanism of their anti-AD effects. Notably, sinensetin, tangeretin, nobiletin, and 3,5,6,7,8,3',4'-heptamethoxyflavone were identified as potent neuroinflammatory inhibitors. This research elucidated the chemical and therapeutic foundations of PMFs, indicating their potential as treatments or nutritional supplements for AD prevention and treatment. Moreover, the integrated triad approach of sequential metabolism, network pharmacology, and experimental validation may serve as a promising strategy for screening bioactive compounds in herbs or functional foods, as well as for elucidating their therapeutic mechanisms.}, }
@article {pmid40004604, year = {2025}, author = {Sin, MK and Dage, JL and Nho, K and Dowling, NM and Seyfried, NT and Bennett, DA and Levey, AI and Ahmed, A}, title = {Plasma Biomarkers for Cerebral Amyloid Angiopathy and Implications for Amyloid-Related Imaging Abnormalities: A Comprehensive Review.}, journal = {Journal of clinical medicine}, volume = {14}, number = {4}, pages = {}, pmid = {40004604}, issn = {2077-0383}, support = {R01 AG073474/AG/NIA NIH HHS/United States ; R03 AG070579/AG/NIA NIH HHS/United States ; R03 AG072110/AG/NIA NIH HHS/United States ; RF1 AG069121/AG/NIA NIH HHS/United States ; }, abstract = {Anti-amyloid therapies (AATs) are increasingly being recognized as promising treatment options for Alzheimer's disease (AD). Amyloid-related imaging abnormalities (ARIAs), small areas of edema and microbleeds in the brain presenting as abnormal signals in MRIs of the brain for patients with AD, are the most common side effects of AATs. While most ARIAs are asymptomatic, they can be associated with symptoms like nausea, headache, confusion, and gait instability and, less commonly, with more serious complications such as seizures and death. Cerebral amyloid angiopathy (CAA) has been found to be a major risk for ARIA development. The identification of sensitive and reliable non-invasive biomarkers for CAA has been an area of AD research over the years, but with the approval of AATs, this area has taken on a new urgency. This comprehensive review highlights several potential biomarkers, such as Aβ40, Aβ40/42, phosphorylated-tau217, neurofilament light chain, glial fibrillary acidic protein, secreted phosphoprotein 1, placental growth factor, triggering receptor expressed on myeloid cells 2, cluster of differentiation 163, proteomics, and microRNA. Identifying and staging CAA even before its consequences can be detected via neuroimaging are critical to allow clinicians to judiciously select appropriate candidates for AATs, stratify monitoring, properly manage therapeutic regimens for those experiencing symptomatic ARIAs, and optimize the treatment to achieve the best outcomes. Future studies can test potential plasma biomarkers in human beings and evaluate predictive values of individual markers for CAA severity.}, }
@article {pmid40004175, year = {2025}, author = {Sadiq, AH and Alam, MJ and Begum, F and Hasan, M and Kristof, J and Mamun, MA and Maniruzzaman, M and Shimizu, K and Kanazawa, T and Kahyo, T and Setou, M and Shimizu, K}, title = {Enhancing Galantamine Distribution in Rat Brain Using Microplasma-Assisted Nose-to-Brain Drug Delivery.}, journal = {International journal of molecular sciences}, volume = {26}, number = {4}, pages = {}, pmid = {40004175}, issn = {1422-0067}, support = {JP23K17473, and JP24H00794//Japan Society for the Promotion of Science (JSPS) under the KAKENHI program/ ; }, mesh = {*Galantamine/pharmacokinetics/administration & dosage ; Animals ; Rats ; *Brain/metabolism ; *Drug Delivery Systems/methods ; *Administration, Intranasal ; Male ; Nasal Mucosa/metabolism ; Blood-Brain Barrier/metabolism ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Plasma Gases ; Rats, Sprague-Dawley ; Tissue Distribution ; }, abstract = {Nose-to-brain (N2B) drug delivery is a promising technique for the treatment of brain diseases. It allows a drug to enter the brain without passing through the blood-brain barrier. However, the nasal cavity and nasal mucosa can restrict the amount of drug absorbed. Recent studies of non-thermal plasma (NTP) have shown improvement in in vitro drug delivery to cells and tissues. However, whether NTP treatments can enhance the in vivo delivery of drugs for neurodegenerative disease like Alzheimer's disease (AD) into the brain via the N2B technique remains unclear. The drug used in this study was galantamine hydrobromide. Galantamine is used to treat patients with mild to moderate AD. Based on the principle of NTP, a type of dielectric barrier discharge (DBD) plasma, which we called spiral DBD microplasma, was designed. It was inserted into the nose of a rat to a depth of 2 mm. The spiral DBD microplasma was driven by a sinusoidal voltage for 4 min, followed by the immediate administration of galantamine. The effect of the microplasma treatment on the distribution of galantamine in the brain was evaluated using matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS). The results showed a high distribution of galantamine in the left and right brain hemispheres of the rat treated with plasma discharge compared to a control treated without plasma discharge. The spiral DBD microplasma is a novel contribution to DBD plasma designs. In addition, this technique for drug delivery has also created a novel approach with potential for becoming a non-invasive method of enhancing drug distribution in the brain for the treatment of neurological disorders.}, }
@article {pmid40003952, year = {2025}, author = {Wang, Y and Zhao, J and Zhao, L}, title = {L-Lactate Administration Improved Synaptic Plasticity and Cognition in Early 3xTg-AD Mice.}, journal = {International journal of molecular sciences}, volume = {26}, number = {4}, pages = {}, pmid = {40003952}, issn = {1422-0067}, support = {2022YFC3600201//National Key Research and Development Program of China/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; *Neuronal Plasticity/drug effects ; *Hippocampus/metabolism/drug effects ; *Lactic Acid/pharmacology/metabolism ; *Cognition/drug effects ; *Long-Term Potentiation/drug effects ; *Mice, Transgenic ; *Disease Models, Animal ; Male ; Synapses/drug effects/metabolism ; Synaptophysin/metabolism/genetics ; }, abstract = {Synaptic plasticity impairment and behavioral deficits constitute classical pathological hallmarks in early-stage Alzheimer's disease (AD). Emerging evidence suggests these synaptic dysfunctions may stem from metabolic dysregulation, particularly impaired aerobic glycolysis. As a key product of astrocyte-mediated aerobic glycolysis, lactate serves dual roles as both an energy substrate and a signaling molecule, playing a critical regulatory role in synaptic plasticity and long-term memory formation. This study investigated whether exogenous L-lactate supplementation could ameliorate synaptic dysfunction and cognitive deficits in early-stage AD models. Our findings reveal significant reductions in hippocampal lactate levels in experimental AD mice. Systemic administration of L-lactate (200 mg/kg) effectively restored physiological lactate concentrations in both hippocampal tissue and cerebrospinal fluid (CSF). Chronic L-lactate treatment significantly improved spatial learning and memory performance in behavioral assessments. Electrophysiological recordings demonstrated that either acute bath application of L-lactate (2 mM) to hippocampal slices or chronic intraperitoneal administration enhanced high-frequency stimulation (HFS)-induced long-term potentiation (LTP) magnitude in 3xTg-AD mice. Ultrastructural analysis revealed that L-lactate treatment enhanced synaptic density and improved morphological features of hippocampal synapses. At the molecular level, L-lactate administration upregulated synaptic marker synaptophysin (SYP) expression while downregulating activity-regulated cytoskeletal-associated protein (ARC) levels in AD mice. These multimodal findings demonstrate that exogenous L-lactate supplementation effectively restores synaptic plasticity and cognitive function in early-stage 3xTg-AD mice through concurrent improvements at behavioral, structural, and molecular levels.}, }
@article {pmid40002882, year = {2025}, author = {Shirvani, A and Shirvani, P and Jonah, U and Moore, BE and Holick, MF}, title = {Suspected Mitochondrial Dysfunction and Complex Pathophysiology in Fatal Hypermobile Ehlers-Danlos Syndrome: Insights from a Case Report and Post-Mortem Findings.}, journal = {Biomedicines}, volume = {13}, number = {2}, pages = {}, pmid = {40002882}, issn = {2227-9059}, abstract = {Background/Objectives: Hypermobile Ehlers-Danlos Syndrome (hEDS) is a complex connective tissue disorder with multi-systemic manifestations that significantly impact quality of life. This case report investigates the clinical course and molecular mechanisms of advanced hEDS through an in-depth case study and post-mortem findings. Methods: The clinical history of a 24-year-old patient with advanced hEDS was analyzed, focusing on progressive complications across multiple systems. Post-mortem examination and genetic analysis were performed to elucidate the underlying pathophysiology. Results: The patient's clinical course was marked by gastrointestinal, neurological, and immune complications requiring numerous surgical interventions. Post-mortem findings revealed severe gastrointestinal dysmotility and Alzheimer's Type II astrocytes. Genetic analysis identified variants in mtDNA genes ATP6, CYB, and ND, suggesting a potential role of impaired mitochondrial function in hEDS pathogenesis but requiring further validation through functional studies. Conclusions: This case report provides valuable insights into the potential role of mitochondrial dysfunction in advanced hEDS and highlights the need for further research in this area. Future studies should include comprehensive functional assays, longitudinal tissue sampling, family genetic analyses, and muscle biopsies to better understand the complex interplay between genetic factors, mitochondrial function, and clinical manifestations in hEDS. Establishing genetic bases and developing targeted therapies addressing both structural and metabolic aspects are crucial. The patient's legacy offers invaluable information that could significantly contribute to enhancing diagnostic accuracy and developing personalized treatment strategies for this challenging disorder, potentially leading to better care for individuals living with hEDS.}, }
@article {pmid40002846, year = {2025}, author = {Vuic, B and Milos, T and Kvak, E and Konjevod, M and Tudor, L and Farkas, S and Nedic Erjavec, G and Nikolac Perkovic, M and Zelena, D and Svob Strac, D}, title = {Neuroprotective Effects of Dehydroepiandrosterone Sulphate Against Aβ Toxicity and Accumulation in Cellular and Animal Model of Alzheimer's Disease.}, journal = {Biomedicines}, volume = {13}, number = {2}, pages = {}, pmid = {40002846}, issn = {2227-9059}, support = {IP-2019-04-6100//Croatian Science Foundation/ ; }, abstract = {Background/Objectives: Beneficial effects of neurosteroid dehydroepiandrosterone sulphate (DHEAS) on cognition, emotions and behavior have been previously reported, suggesting its potential in the prevention and treatment of various neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). This study aimed to investigate the potential neuroprotective actions of DHEAS against Aβ toxicity in both cellular and animal models of AD. Methods: After optimizing the AD model in vitro, we investigated the DHEAS effects on the viability and death of primary mouse neurons exposed to toxic Aβ42 oligomers for 24 h. In order to extend our research to an in vivo study, we further tested the acute effects of intraperitoneal DHEAS administration on the Aβ plaque density in different brain regions of 3xTg-AD mice, an animal model of AD. Results: In cell culture, DHEAS hampered the decrease in the neuronal viability caused by toxic Aβ oligomers, primarily by influencing mitochondrial function and apoptosis. DHEAS also counteracted the increase in the mRNA expression of selected genes (PI3K, Akt, Bcl2, Bax), induced in neuronal culture by treatment with Aβ42 oligomers. Obtained data suggested the involvement of mitochondria, caspases 3 and 7, as well as the PI3K/Akt and Bcl2 signaling network in the antiapoptotic properties of DHEAS in neurons. Forty-eight hours after DHEAS treatment, a significantly lower number of Aβ plaques was observed in the motor cortex but not in other brain areas of 3xTg-AD mice. Conclusions: Results indicated potential neuroprotective effects of DHEAS against Aβ toxicity and accumulation, suggesting that DHEAS supplementation should be further studied as a novel option for AD prevention and/or treatment.}, }
@article {pmid40002740, year = {2025}, author = {Meng, K and Jia, H and Hou, X and Zhu, Z and Lu, Y and Feng, Y and Feng, J and Xia, Y and Tan, R and Cui, F and Yuan, J}, title = {Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.}, journal = {Biomedicines}, volume = {13}, number = {2}, pages = {}, pmid = {40002740}, issn = {2227-9059}, support = {600791001//the Research Start-up Fund of Jining Medical University/ ; JYHL2021MS13//Research Fund for Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University/ ; 81700055//the National Natural Science Foundation of China/ ; Grant No. D2016021//Outstanding Talent Research Funding of Xuzhou Medical University/ ; BK20160229//Natural Science Foundation of Jiangsu Province/ ; tsqn201909147//Taishan Scholars Program of Shandong Province/ ; G2Y-kJS-SD-2023-097//Co-construction of Science and Technology Projects by the Science and Technology Department of the State Administration of Traditional Chinese Medicine/ ; }, abstract = {Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed.}, }
@article {pmid40002697, year = {2025}, author = {Kaštelan, S and Gverović Antunica, A and Puzović, V and Didović Pavičić, A and Čanović, S and Kovačević, P and Vučemilović, PAF and Konjevoda, S}, title = {Non-Invasive Retinal Biomarkers for Early Diagnosis of Alzheimer's Disease.}, journal = {Biomedicines}, volume = {13}, number = {2}, pages = {}, pmid = {40002697}, issn = {2227-9059}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain associated with ageing and is the most prevalent form of dementia, affecting an estimated 55 million people worldwide, with projections suggesting this number will exceed 150 million by 2050. With its increasing prevalence, AD represents a significant global health challenge with potentially serious social and economic consequences. Diagnosing AD is particularly challenging as it requires timely recognition. Currently, there is no effective therapy for AD; however, certain medications may help slow its progression. Existing diagnostic methods such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and biomarker analysis in cerebrospinal fluid tend to be expensive and invasive, making them impractical for widespread use. Consequently, research into non-invasive biomarkers that enable early detection and screening for AD is a crucial area of contemporary clinical investigation. One promising approach for the early diagnosis of AD may be retinal imaging. As an extension of the central nervous system, the retina offers a distinctive opportunity for non-invasive brain structure and function assessment. Considering their shared embryological origins and the vascular and immunological similarities between the eye and brain, alterations in the retina may indicate pathological changes in the brain, including those specifically related to AD. Studies suggest that structural and vascular changes in the retina, particularly within the neuronal network and blood vessels, may act as markers of cerebral changes caused by AD. These retinal alterations have the potential to act as biomarkers for early diagnosis. Since AD is typically diagnosed only after a significant neuronal loss has occurred, identifying early diagnostic markers could enable timely intervention and help prevent disease progression. Non-invasive retinal imaging techniques, such as optical coherence tomography (OCT) and OCT angiography, provide accessible methods for the early detection of changes linked to AD. This review article focuses on the potential of retinal imaging as a non-invasive biomarker for early diagnosis of AD. Investigating the ageing of the retina and its connections to neurodegenerative processes could significantly enhance the diagnosis, monitoring, and treatment of AD, paving the way for new diagnostic and therapeutic approaches.}, }
@article {pmid40002692, year = {2025}, author = {Dias, D and Socodato, R}, title = {Beyond Amyloid and Tau: The Critical Role of Microglia in Alzheimer's Disease Therapeutics.}, journal = {Biomedicines}, volume = {13}, number = {2}, pages = {}, pmid = {40002692}, issn = {2227-9059}, abstract = {Alzheimer's disease (AD) is traditionally viewed through the lens of the amyloid cascade hypothesis, implicating amyloid-beta and tau protein aggregates as the main pathological culprits. However, burgeoning research points to the brain's resident immune cells, microglia, as critical players in AD pathogenesis, progression, and potential therapeutic interventions. This review examines the dynamic roles of microglia within the intricate framework of AD. We detail the involvement of these immune cells in neuroinflammation, explaining how their activation and response fluctuations may influence the disease trajectory. We further elucidate the complex relationship between microglia and amyloid-beta pathology. This study highlights the dual nature of these cells, which contribute to both aggregation and clearance of the amyloid-beta protein. Moreover, an in-depth analysis of the interplay between microglia and tau unveils the significant, yet often overlooked, impact of this interaction on neurodegeneration in AD. Shifting from the conventional therapeutic approaches, we assess the current AD treatments primarily targeting amyloid and tau and introduce novel strategies that involve manipulating microglial functions. These innovative methods herald a potential paradigm shift in the management of AD. Finally, we explore the burgeoning field of precision diagnosis and the pursuit of robust AD biomarkers. We underline how a more profound comprehension of microglial biology could enrich these essential areas, potentially paving the way for more accurate diagnostic tools and tailored treatment strategies. In conclusion, this review expands on the conventional perspective of AD pathology and treatment, drawing attention to the multifaceted roles of microglia. As we continue to enhance our understanding of these cells, microglial-focused therapeutic interventions emerge as a promising frontier to bolster our arsenal to fight against AD.}, }
@article {pmid40002547, year = {2025}, author = {ALNasser, MN and Alboraiy, GM and Alsowig, EM and Alqattan, FM}, title = {Cholinesterase Inhibitors from Plants and Their Potential in Alzheimer's Treatment: Systematic Review.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002547}, issn = {2076-3425}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, primarily due to dysfunction of acetylcholine caused by acetylcholinesterase and butyrylcholinesterase. While synthetic cholinesterase inhibitors like donepezil, rivastigmine, and galantamine are commonly used, they have notable side effects, prompting interest in natural alternatives. Medicinal plants, rich in bioactive compounds like flavonoids and alkaloids, have shown potential as cholinesterase inhibitors with additional antioxidants and anti-inflammatory benefits. This study aimed to evaluate the cholinesterase-inhibiting effects of various plant species and their compounds to identify new therapeutic candidates and reduce side effects.
METHOD: A PRISMA-compliant review was conducted, screening studies from multiple databases, with a final inclusion of 64 in vivo studies.
RESULTS: These studies highlighted plant extracts such as Ferula ammoniacum, Elaeagnus umbellata, Bacopa monnieri, and Centella asiatica, which improved memory, reduced oxidative stress, and provided neuroprotection. Some extracts also reduced amyloid plaques, enhanced neuronal integrity, and restored cholinesterase activity, indicating their potential as therapeutic agents for AD and other neurodegenerative diseases.
CONCLUSIONS: The findings underscore the promise of plant-based compounds in treating cognitive decline and cholinergic dysfunction in AD, advocating for further research into their therapeutic potential.}, }
@article {pmid40002497, year = {2025}, author = {Lomelí Martínez, SM and Pacheco Moisés, FP and Bitzer-Quintero, OK and Ramírez-Jirano, J and Delgado-Lara, DLC and Cortés Trujillo, I and Torres Jasso, JH and Salazar-Flores, J and Torres-Sánchez, ED}, title = {Effect of N-Acetyl Cysteine as an Adjuvant Treatment in Alzheimer's Disease.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002497}, issn = {2076-3425}, abstract = {Oxidative stress levels are exacerbated in Alzheimer's disease (AD). This phenomenon feeds back into the overactivation of oxidase enzymes, mitochondrial dysfunction, and the formation of advanced glycation end-products (AGEs), with the stimulation of their receptors (RAGE). These factors stimulate Aβ peptide aggregation and tau hyperphosphorylation through multiple pathways, which are addressed in this paper. The aim of this study was to evaluate the regulatory effect of N-acetyl cysteine (NAC) on oxidant/antioxidant balance as an adjuvant treatment in patients with AD. The results obtained showed that NAC supplementation produced improved cognitive performance, decreased levels of oxidative stress markers, lowered activities of oxidase enzymes, increased antioxidant responses, and attenuated inflammatory and apoptotic markers. Moreover, NAC reversed mitochondrial dysfunction, lowered AGEs-RAGE formation, attenuated Aβ peptide oligomerization, and reduced phosphorylation of tau, thereby halting the formation of neurofibrillary tangles and the progression of AD.}, }
@article {pmid40002310, year = {2025}, author = {Zhou, Q and Wu, XN and Luo, WH and Huang, QH and Feng, LL and Wu, Y and Zhang, C}, title = {Discovery of Effective Inhibitors Against Phosphodiesterase 9, a Potential Therapeutic Target of Alzheimer's Disease with Antioxidant Capacities.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {2}, pages = {}, pmid = {40002310}, issn = {2076-3921}, support = {22370192, 21977127, and 82003652//National Natural Science Foundation of China/ ; }, abstract = {Alzheimer's disease (AD) is a widely recognized type of dementia that leads to progressive cognitive decline and memory loss, affecting a significant number of people and their families worldwide. Given the multifactorial nature of AD, multitarget-directed ligands (MTDLs) hold promise in developing effective drugs for AD. Phosphodiesterase-9 (PDE9) is emerging as a promising target for AD therapy. In this study, by combining a PDE9 inhibitor C33 with the antioxidant melatonin, we designed and discovered a series of pyrazolopyrimidinone derivatives that simultaneously inhibit PDE9 and possess antioxidant activities. Molecular docking, together with dynamics simulations, were applied to accelerate compound design and reduce synthetic work. Four out of the 14 compounds were validated as effective PDE9 inhibitors with comparable antioxidant activity. Notably, compounds 17b and 17d demonstrated IC50 values of 91 and 89 nM against PDE9, respectively, with good antioxidant activities (ORAC (Trolox) of 2.00 and 2.60). This work provides a new approach for designing MTDLs for the treatment of AD and offers insights for further structural modifications of PDE9 inhibitors with antioxidant capacities.}, }
@article {pmid40001529, year = {2025}, author = {Onu, CJ and Adu, M and Chakkour, M and Kumar, V and Greenberg, ML}, title = {Inositol Phosphates and Synthesizing Enzymes: Implications in Neurodegenerative Disorders.}, journal = {Biomolecules}, volume = {15}, number = {2}, pages = {}, pmid = {40001529}, issn = {2218-273X}, support = {R01 GM125082/GM/NIGMS NIH HHS/United States ; R35 GM149271/GM/NIGMS NIH HHS/United States ; GM149271/GF/NIH HHS/United States ; GM125082/GF/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Inositol Phosphates/metabolism ; Animals ; Parkinson Disease/metabolism ; Alzheimer Disease/metabolism ; Signal Transduction ; Inositol/metabolism ; }, abstract = {Inositol is a vital sugar molecule involved in numerous signaling pathways required for cellular homeostasis and cell survival. Myo-inositol and its phospho-derivatives, inositol phosphates (IPs), are the most prevalent forms of inositol found in living cells. They are involved in regulating ion channels, metabolic flux, stress response, and other key biological processes. While emerging research has highlighted the significant roles of inositol phosphates in immunity, cancer, and metabolic diseases, there is a lack of comprehensive reviews on their roles in psychiatric and neurological disorders. This review aims to fill that gap by analyzing the existing literature on the importance of inositol phosphates in severe psychiatric and neurological conditions such as Parkinson's disease, Alzheimer's disease, bipolar disorder, amyotrophic lateral sclerosis, schizophrenia, and Huntington's disease, underscoring the potential to pave the way for new treatment regimens for these debilitating disorders targeting inositol pathways.}, }
@article {pmid40001482, year = {2025}, author = {Kim, KS and Lee, R and Park, I and Hwang, SH and Kim, Y and Jang, JW and Kim, HS and Choi, SM and Kim, SJ and Cho, HJ and Cho, IH and Kim, JH and Kim, DG and Nah, SY}, title = {Gintonin Binds to Reduced LPA4 Receptor Subtype in Human Cortical Neurons in Alzheimer's Disease Brains.}, journal = {Biomolecules}, volume = {15}, number = {2}, pages = {}, pmid = {40001482}, issn = {2218-273X}, support = {2023R1A2C1003481//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Neurons/metabolism ; *Receptors, Lysophosphatidic Acid/metabolism ; *Cerebral Cortex/metabolism/pathology ; Male ; Female ; Aged ; Plant Extracts/pharmacology/chemistry ; Protein Binding ; }, abstract = {Ginseng, a traditional herbal medicine with a long history of use, is known to support human health, particularly by influencing brain function. Recent studies have identified gintonin, a lysophosphatidic acid (LPA) receptor ligand derived from ginseng, as a key bioactive. However, the specific LPA receptor subtypes targeted by gintonin in the human brain to exert its anti-Alzheimer's (AD) effects remain unclear. This study aimed to elucidate the LPA receptor subtype targeted by gintonin in the human cortex. Using a fluorescent gintonin conjugate, we investigated receptor binding in cortical samples from healthy individuals (n = 4) and AD patients (n = 4). Our results demonstrated that fluorescent gintonin selectively binds to human cortical neurons rather than glial cells and that gintonin-binding sites are co-localized with the LPA4 receptor subtype. Furthermore, the expression of LPA4 receptors was significantly reduced in the cortical neurons of AD patients. These results suggest that the LPA4 receptor may serve as a novel histopathological marker for AD and represent a promising therapeutic target for gintonin-based prevention and treatment strategies.}, }
@article {pmid40001197, year = {2025}, author = {Choi, H and Kim, HJ and Lee, SE and Song, HH and Kim, J and Han, J and Jeong, JH and Lee, DY and Chang, S and Mook-Jung, I}, title = {25-Hydroxycholesterol modulates microglial function and exacerbates Alzheimer's disease pathology: mechanistic insights and therapeutic potential of cholesterol esterification inhibition.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {50}, pmid = {40001197}, issn = {1742-2094}, support = {RS-2023-00274420//National Research Foundation of Korea/ ; RS-2020-KH106747//Korea Dementia Research Center/ ; }, mesh = {*Hydroxycholesterols/pharmacology/metabolism ; Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy ; Mice ; *Microglia/drug effects/metabolism/pathology ; *Mice, Transgenic ; Esterification ; Phagocytosis/drug effects ; Humans ; Cholesterol/metabolism ; Sulfonamides/pharmacology ; Mice, Inbred C57BL ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Cells, Cultured ; Acetamides ; }, abstract = {This study investigates the role of 25-hydroxycholesterol (25HC), a metabolite produced by cholesterol hydroxylase encoded by the Ch25h gene, in modulating microglial function and its potential implications in Alzheimer's disease (AD) pathology. We demonstrated that 25HC impairs microglial surveillance, reduces phagocytic capacity, and increases the production of pro-inflammatory cytokines. In vivo two-photon microscopy revealed that 25HC administration diminishes microglial response to brain lesions, while flow cytometry confirmed reduced phagocytosis in both in vivo and in vitro models. Additionally, amyloid-beta (Aβ) was shown to upregulate Ch25h expression and elevate 25HC levels in microglia, exacerbating these functional impairments. Mechanistically, 25HC was found to enhance cholesterol esterification, disrupt cell membrane dynamics, and further reduce microglial mobility and phagocytosis. Treatment with Avasimibe, a cholesterol esterification inhibitor, restored membrane dynamics and microglial function, leading to attenuated AD pathology in a 5XFAD mouse model. These findings suggest that 25HC-induced changes in microglial function contribute to AD progression, and targeting cholesterol metabolism could offer therapeutic potential.}, }
@article {pmid40000636, year = {2025}, author = {Grandke, F and Fehlmann, T and Kern, F and Gate, DM and Wolff, TW and Leventhal, O and Channappa, D and Hirsch, P and Wilson, EN and Meese, E and Liu, C and Shi, Q and Flotho, M and Li, Y and Chen, C and Yu, Y and Xu, J and Junkin, M and Wang, Z and Wu, T and Liu, L and Hou, Y and Andreasson, KI and Gansen, JS and Mass, E and Poston, K and Wyss-Coray, T and Keller, A}, title = {A single-cell atlas to map sex-specific gene-expression changes in blood upon neurodegeneration.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1965}, pmid = {40000636}, issn = {2041-1723}, support = {14446, 17047 (subc. 125491594)//Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)/ ; MJFF-021418//Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)/ ; 466168626//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; }, mesh = {Humans ; Female ; Male ; *Parkinson Disease/genetics/blood ; *Alzheimer Disease/genetics/blood ; *Single-Cell Analysis/methods ; Aged ; *Leukocytes, Mononuclear/metabolism ; *Cognitive Dysfunction/genetics/blood ; *Gene Expression Profiling/methods ; Middle Aged ; Transcriptome ; Neurodegenerative Diseases/genetics/blood ; Sex Factors ; Aged, 80 and over ; }, abstract = {The clinical course and treatment of neurodegenerative disease are complicated by immune-system interference and chronic inflammatory processes, which remain incompletely understood. Mapping immune signatures in larger human cohorts through single-cell gene expression profiling supports our understanding of observed peripheral changes in neurodegeneration. Here, we employ single-cell gene expression profiling of over 909k peripheral blood mononuclear cells (PBMCs) from 121 healthy individuals, 48 patients with mild cognitive impairment (MCI), 46 with Parkinson's disease (PD), 27 with Alzheimer's disease (AD), and 15 with both PD and MCI. The dataset is interactively accessible through a freely available website (https://www.ccb.uni-saarland.de/adrcsc). In this work, we identify disease-associated changes in blood cell type composition and the gene expression in a sex-specific manner, offering insights into peripheral and solid tissue signatures in AD and PD.}, }
@article {pmid40000573, year = {2025}, author = {Ackley, SF and Wang, J and Chen, R and Hill-Jarrett, TG and Rojas-Saunero, LP and Stokes, A and Shah, SJ and Glymour, MM and , }, title = {Methods to crosswalk between cognitive test scores using data from the Alzheimer's Disease Neuroimaging Cohort.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14597}, pmid = {40000573}, issn = {1552-5279}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; F99AG083306//NIH/NIA/ ; R00 AG073454/AG/NIA NIH HHS/United States ; F99 AG083306/AG/NIA NIH HHS/United States ; K76 AG074919/AG/NIA NIH HHS/United States ; P01 AG082653/AG/NIA NIH HHS/United States ; K99 AG073454/AG/NIA NIH HHS/United States ; K99AG073454//NIH/NIA/ ; T32 AG078115/AG/NIA NIH HHS/United States ; K23 AG084871/AG/NIA NIH HHS/United States ; R01AG057869//NIH/NIA/ ; R00AG073454//NIH/NIA/ ; P01AG082653//NIH/NIA/ ; R01 AG057869/AG/NIA NIH HHS/United States ; T32AG078115//NIH/NIA/ ; K00 AG068431/AG/NIA NIH HHS/United States ; K00AG068431//NIH/NIA/ ; /EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/diagnosis ; *Neuroimaging/methods ; *Mental Status and Dementia Tests/statistics & numerical data ; Aged ; Cohort Studies ; *Neuropsychological Tests/statistics & numerical data ; Male ; Female ; tau Proteins/blood ; Aged, 80 and over ; Cognition/physiology ; }, abstract = {INTRODUCTION: Studies use multiple different instruments to measure dementia-related outcomes, making head-to-head comparisons of interventions difficult.
METHODS: To address this gap, we developed two methods to crosswalk estimated treatment effects on cognitive outcomes that are flexible, broadly applicable, and do not rely on strong distributional assumptions.
RESULTS: We present two methods to crosswalk effect estimates using one measure to estimates using another measure, illustrated with global cognitive measures from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Specifically, we develop crosswalks for the following measures and associated change scores over time: the clinical dementia rating scale sum of box (CDR-SB), Montreal Cognitive Assessment (MoCA), and Mini-Mental State Examination (MMSE) scores. Finally, a setting in which crosswalking is not appropriate is illustrated with plasma phosphorylated tau (p-tau) concentration and global cognitive measures.
DISCUSSION: Given the inconsistent collection and reporting of dementia and cognitive outcomes across studies, these crosswalking methods offer a valuable approach to harmonizing and comparing results reported on different scales.
HIGHLIGHTS: Developed methods to crosswalk from one cognitive outcome to another in studies of dementia interventions. Methods illustrated using combinations of global cognitive tests: the CDR-SB, MoCA, and MMSE. Illustrates scenarios where crosswalking may not be appropriate for certain combinations of measures. Crosswalking methods support comparison of interventions with accurate error propagation. Facilitates inclusion of more studies in meta-analyses by increasing data comparability.}, }
@article {pmid40000385, year = {2025}, author = {Chen, Y and Zhang, D and Chen, T and Zhao, L and Wen, L and Hou, R}, title = {Traditional Chinese Medicine for Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {The American journal of Chinese medicine}, volume = {53}, number = {1}, pages = {1-15}, doi = {10.1142/S0192415X25500016}, pmid = {40000385}, issn = {1793-6853}, mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; *Medicine, Chinese Traditional/methods ; *Drugs, Chinese Herbal/therapeutic use ; *Cognition/drug effects ; Phytotherapy ; Activities of Daily Living ; Treatment Outcome ; }, abstract = {The treatment of Alzheimer's Disease (AD) remains a challenge for modern medicine due to its complex pathogenesis. Traditional Chinese Medicine (TCM) has demonstrated significant success in the prevention and treatment of variable medical conditions. For AD pharmacological management, TCM could provide promising approaches. This study aimed to systematically evaluate the current evidence of the effects of TCM therapies on AD. A systematic search of the literature was performed on electronic databases including PubMed, the Cochrane Library, the Chinese National Knowledge Infrastructure (CNKI), and Web of Science. Thirteen studies were included in this review, subject to inclusion and exclusion criteria. Screening, data extraction, and quality assessment were undertaken following the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Our results show that TCM offered a significant improvement in cognitive functioning compared to the control group, measured on both MMSE and ADAS-CoG scales, suggesting its potential utility in slowing cognitive decline and improving cognitive function as compared to conventional drug treatments and placebos. No significant difference was found for scores of neuropsychiatric symptoms (NPI) or ability to perform daily living activities (ADCS-ADL). These findings highlight TCM as a potential adjuvant therapy, in combination with conventional medicine, to improve the effectiveness and reduce the limitations of conventional AD drug regimes. Studies with larger sample sizes, rigorous study designs, accurate long-term reporting, and correlation to neuropathological markers are needed in the future to enhance the evidence base for the use of TCM in AD patients, and to further confirm its efficacy.}, }
@article {pmid40000032, year = {2025}, author = {Ng, S and Hornblass, A and Habibi, P and Ikramuddin, S and Chen, J and Feng, W and Cai, D}, title = {Updates on vascular dementia.}, journal = {Stroke and vascular neurology}, volume = {}, number = {}, pages = {}, doi = {10.1136/svn-2025-004048}, pmid = {40000032}, issn = {2059-8696}, abstract = {Vascular dementia (VaD) is the second leading cause of dementia after Alzheimer's disease (AD). In comparison to AD, there is a decline in the incidence of VaD due to recent improvements in cardiovascular risk factors. Brain hypoperfusion and hypoxia due to vascular pathologies have been postulated as the primary disease mechanism of VaD. However, other factors such as neuroinflammation may also contribute to the development of VaD. Non-modifiable and modifiable risk factors have been attributed to VaD. The clinical features overlapping between AD and VaD create significant challenges for physicians. Newly developed biomarkers may potentially help differentiate VaD from other forms of dementia. Unlike AD, there is no Food and Drug Administration-approved drug or device for treating VaD. Current treatment options mainly target symptoms rather than slowing the development or progression of VaD. There are ongoing research studies testing the efficacy of various therapeutic strategies for VaD. In this narrative review, we will summarise current findings on epidemiology, attributed risk factors and disease mechanisms, as well as emphasise the importance of optimising lifestyle modifications and comorbid condition management in preventing or slowing down the development of VaD. Finally, current therapies and ongoing research studies of novel therapeutic interventions such as stem-cell therapy and neuromodulation are highlighted.}, }
@article {pmid39999928, year = {2025}, author = {Vollhardt, A and Frölich, L and Stockbauer, AC and Danek, A and Schmitz, C and Wahl, AS}, title = {Towards a better diagnosis and treatment of dementia: Identifying common and distinct neuropathological mechanisms in Alzheimer's and vascular dementia.}, journal = {Neurobiology of disease}, volume = {208}, number = {}, pages = {106845}, doi = {10.1016/j.nbd.2025.106845}, pmid = {39999928}, issn = {1095-953X}, abstract = {Alzheimer's disease (AD) and vascular dementia (VaD) together contribute to almost 90 % of all dementia cases leading to major health challenges of our time with a substantial global socioeconomic burden. While in AD, the improved understanding of Amyloid beta (Aß) mismetabolism and tau hyperphosphorylation as pathophysiological hallmarks has led to significant clinical breakthroughs, similar advances in VaD are lacking. After comparing the clinical presentation, including risk factors, disease patterns, course of diseases and further diagnostic parameters for both forms of dementia, we highlight the importance of shared pathomechanisms found in AD and VaD: Endothelial damage, blood brain barrier (BBB) breakdown and hypoperfusion inducing oxidative stress and inflammation and thus trophic uncoupling in the neurovascular unit. A dysfunctional endothelium and BBB lead to the accumulation of neurotoxic molecules and Aß through impaired clearance, which in turn leads to neurodegeneration. In this context we discuss possible neuropathological parameters, which might serve as biomarkers and thus improve diagnostic accuracy or reveal targets for novel therapeutic strategies for both forms of dementia.}, }
@article {pmid39999809, year = {2025}, author = {Umoh, I and Xia, X and Winblad, B and Aye, S and Aho, E and Rhodius-Meester, HFM and Jönsson, L}, title = {Deciphering Perspectives: A European Survey on Clinical Decision Support Tools for Dementia and Alzheimer's Disease.}, journal = {Dementia and geriatric cognitive disorders}, volume = {}, number = {}, pages = {1-10}, doi = {10.1159/000544801}, pmid = {39999809}, issn = {1421-9824}, abstract = {INTRODUCTION: Technological advancements like digital monitoring tools, disease-modifying therapies, and artificial intelligence have been shown to improve the clinical management of neurocognitive diseases like Alzheimer's disease (AD). To enhance implementation in daily practice, users' input is essential in the technology development process. This study aimed to determine clinician's perspective of clinical decision support systems (CDSS) in the management of dementia and AD.
METHOD: A survey was conducted targeting clinicians practicing in the field of dementia across Europe. A sixty-five-item digital questionnaire was administered, and opinions were inquired across the domains of diagnosis, disease-modifying therapy, and prognosis, including factors that affect tool implementation and utilization.
RESULTS: Eighty-four clinicians (including specialist physicians, psychologists, and nurses) responded to this survey, and more than 50% had no knowledge or experience with CDSS. Most of the respondents reported the ability to predict the likelihood of AD as the most important diagnostic function. It was surprising to find the middling responses for the ability to predict amyloid positivity. The majority indicated assessment of treatment eligibility for disease-modifying therapy as vital, and the ability to predict cognitive and functional decline as the most important prognostic functions. Data accuracy and ease of use were noted as most necessary to facilitate CDSS adoption and implementation.
CONCLUSION: Findings from this study contribute to the future development of CDSS in this field, especially regarding the approval and imminent use of disease-modifying therapies, a comprehensive tool that is precise and user friendly would improve clinical decisions and efficiency.}, }
@article {pmid39999645, year = {2025}, author = {Djebari, S and Jiménez-Herrera, R and Iborra-Lázaro, G and Jiménez-Díaz, L and Navarro-López, JD}, title = {Social and contextual memory impairments induced by Amyloid-β oligomers are rescued by Sigma-1 receptor activation.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {184}, number = {}, pages = {117914}, doi = {10.1016/j.biopha.2025.117914}, pmid = {39999645}, issn = {1950-6007}, mesh = {*Receptors, sigma/metabolism/agonists ; Animals ; *Sigma-1 Receptor ; *Amyloid beta-Peptides/metabolism ; *Memory Disorders/metabolism/drug therapy ; Male ; *Peptide Fragments/pharmacology ; *Neuronal Plasticity/drug effects ; Alzheimer Disease/metabolism/drug therapy/physiopathology ; Memory/drug effects ; Mice ; Morpholines/pharmacology ; Hippocampus/drug effects/metabolism ; Disease Models, Animal ; Social Behavior ; }, abstract = {Sigma-1 receptors (S1Rs) are widely expressed throughout the central nervous system and modulate neuron intracellular calcium levels, leading to changes in neurotransmitter release and neuronal activity. They also interact with various proteins and signaling pathways, playing a key role in regulating synaptic plasticity in brain areas such as the hippocampus, thereby influencing learning and memory processes. This opens a research avenue to explore S1R modulation as a potential therapeutic target in diseases involving hippocampal synaptic alterations and compromised cognitive processes, such as Alzheimer's disease (AD). Here, we hypothesize that pharmacological activation of S1R could counteract synaptic plasticity deficits and hippocampal-dependent cognitive alterations in an early-stage amyloidosis model of Alzheimer's disease, induced by intracerebroventricular (icv) administration of Aβ1-42 oligomers (oAβ1-42). For that purpose, we investigate ex vivo CA3-CA1 synaptic plasticity, while in vivo, we performed open field habituation and social recognition tasks to assess contextual and social memory, respectively. Our data show that pharmacological activation of S1Rs with the selective agonist PRE-084 counteract oAβ1-42 deleterious effects on CA3-CA1 long-term synaptic plasticity (LTP), and hippocampal-dependent contextual and social memory, without alterations of spontaneous behaviors. Together, these results provide further evidence for the role of S1Rs in ameliorating hippocampal synaptic and contextual memory dysfunctions and introduce novel insight into their involvement in early amyloid-induced social memory deficits, highlighting their potential for developing comprehensive treatments for early AD. Also, the absence of adverse behavioral outcomes associated with PRE-084 treatment suggests a favorable safety profile in preclinical models, supporting its potential as a therapeutic option.}, }
@article {pmid39998958, year = {2025}, author = {Huang, C and Wei, Z and Zheng, N and Yan, J and Zhang, J and Ye, X and Zhao, W}, title = {The interaction between dysfunction of vasculature and tauopathy in Alzheimer's disease and related dementias.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14618}, pmid = {39998958}, issn = {1552-5279}, support = {81973919//the National Natural Science Foundation of China/ ; 2019A1515011299//Natural Science Foundation of Guangdong Province/ ; }, mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/physiopathology ; Tauopathies/pathology/metabolism/physiopathology ; Blood-Brain Barrier/pathology ; Animals ; tau Proteins/metabolism ; Dementia/pathology/physiopathology ; Risk Factors ; }, abstract = {Tauopathy is one of the pathological features of Alzheimer's disease and related dementias (ADRD). At present, there have been many studies on the formation, deposition, and intercellular transmission of tau in neurons and immune cells. The vasculature is an important component of the central nervous system. This review discusses the interaction between vasculature and tau in detail from three aspects. (1) The vascular risk factors (VRFs) discussed in this review include diabetes mellitus (DM), abnormal blood pressure (BP), and hypercholesterolemia. (2) In ADRD pathology, the hyperphosphorylation and deposition of tau interact with disrupted vasculature, such as different cells (endothelial cells, smooth muscular cells, and pericytes), the blood-brain barrier (BBB), and the cerebral lymphatic system. (3) The functions of vasculature are regulated by various signaling transductions. Endothelial nitric oxide synthase/nitric oxide, calcium signaling, Rho/Rho-associated coiled-coil containing Kinase, and receptors for advanced glycation end products are discussed in this review. Our findings indicate that the prevention and treatment of vascular health may be a potential target for ADRD combination therapy. HIGHLIGHTS: Persistent VRFs increase early disruption of vascular mechanisms and are strongly associated with tau pathology in ADRD. Cell dysfunction in the vasculature causes BBB leakage and drainage incapacity of the cerebral lymphatic system, which interacts with tau pathology. Signaling molecules in the vasculature regulate vasodilation and contraction, angiogenesis, and CBF. Abnormal signaling transduction is related to tau hyperphosphorylation and deposition.}, }
@article {pmid39998175, year = {2025}, author = {Yao, K and Wang, S and Xu, Z and Fan, Z and Chen, Z and Jia, P and Tu, S and Liu, Y and Lin, X and Xu, Y and Fang, Y and Dou, B and Guo, Y}, title = {Mechanisms of comorbidity between Alzheimer's disease and pain.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14605}, pmid = {39998175}, issn = {1552-5279}, support = {82030125//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Alzheimer Disease/epidemiology ; *Pain/epidemiology ; *Comorbidity ; Pain Management ; Neuroinflammatory Diseases/epidemiology ; Brain/pathology ; }, abstract = {Clinical studies have revealed a significant correlation between pain and neurodegenerative diseases, particularly Alzheimer's disease (AD). However, due to cognitive and speech impairments, AD patients, especially those in moderate to severe stages, are often overlooked in pain management. The challenges in obtaining pain-related information from this population exacerbate the issue. Although recent clinical research has increasingly recognized the comorbidity of AD and pain, the pathological alterations and interactive mechanisms underlying this relationship remain inadequately explored. This review provides a comprehensive analysis of the clinical features and pathological mechanisms of AD with and without pain comorbidity. It examines underlying processes, including neuroinflammation, peripheral-central immune interactions, and neurotransmitter dynamics. Furthermore, it highlights current pain assessment and management strategies in AD patients. By offering a theoretical framework, this review aims to support the development of effective pain management approaches and serve as a reference for clinical interventions targeting AD-associated pain. HIGHLIGHTS: The comorbidity between AD and CP encompasses multiple interrelated biological pathways, such as neurodegeneration and inflammatory responses. The damage to neurons and synapses in AD patients influences the brain regions responsible for processing pain, thereby reducing the pain response. Neuroinflammation plays a vital role in the development of both AD and CP. Enhanced inflammatory responses have an impact on the CNS and promote sensitization. Common neurotransmitter alterations exist in the comorbidity of AD and CP, influencing cognition, emotion, and pain perception.}, }
@article {pmid39998021, year = {2025}, author = {Khartabil, N and Awaness, A}, title = {Targeting Amyloid Pathology in Early Alzheimer's: The Promise of Donanemab-Azbt.}, journal = {Pharmacy (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {39998021}, issn = {2226-4787}, abstract = {OBJECTIVE: The purpose of this review is to examine the potential role of donanemab-azbt in the treatment and management of early-stage Alzheimer's disease (AD), with a focus on its efficacy, safety, and clinical relevance based on data from key clinical trials.
DATA SOURCES: A comprehensive literature search of PubMed was conducted using relevant keywords such as "donanemab", "Alzheimer's disease", "Kisunla", "TRAILBLAZER clinical trials", and "amyloid-related imaging abnormalities (ARIA)". Additional data were extracted from clinical trial records (clinicaltrials.gov), conference abstracts, and product monographs.
Only English-language studies conducted in human populations were included. Clinical trials and peer-reviewed studies detailing the efficacy, safety, and mechanistic insights of donanemab-azbt were prioritized.
DATA SYNTHESIS: Key findings from the TRAILBLAZER series of clinical trials highlighted the potential of donanemab-azbt in slowing cognitive and functional decline in early-stage AD: (1) TRAILBLAZER-ALZ (Phase 2): This trial focused on participants with intermediate levels of tau protein. Results demonstrated a statistically significant slowing of cognitive and functional decline. (2) TRAILBLAZER-ALZ 2 (Phase 3): A large-scale, randomized, double-blind, placebo-controlled study confirmed the efficacy of donanemab-azbt in reducing amyloid plaque accumulation and cognitive decline. Key results included a 35% slowing of decline on the Integrated Alzheimer's Disease Rating Scale (iADRS) and a 36% slowing on the Clinical Dementia Rating-Sum of Boxes (CDR-SB). Additional secondary outcomes showed improvements in activities of daily living and reduced risk of disease progression. (3) TRAILBLAZER-ALZ 3: This ongoing trial is evaluating donanemab's potential in delaying or preventing Alois Alzheimer in cognitively normal individuals with amyloid plaques, broadening the scope of early intervention strategies. (4) TRAILBLAZER-ALZ 4: A head-to-head comparison with aducanumab revealed superior amyloid plaque clearance with donanemab. (5) TRAILBLAZER-ALZ 5: Currently recruiting, this trial aims to evaluate safety and efficacy across diverse populations with varying tau levels and comorbidities. (6) TRAILBLAZER-ALZ 6 (Phase 3b): This trial investigates modified dosing regimens to reduce ARIA while maintaining efficacy, particularly in populations with genetic risk factors like ApoE ε4 homozygotes.
Donanemab-azbt represents a promising treatment option for patients with early-stage AD. It specifically targets and reduces amyloid beta plaques, a hallmark of the disease, potentially slowing progression and preserving cognitive function. However, its administration requires careful patient selection, including genetic testing for ApoE ε4 status, to mitigate risks of ARIA. Furthermore, the findings emphasize the importance of close monitoring during treatment.
CONCLUSIONS: Donanemab-azbt offers a new avenue for managing early-stage AD, showing promise in reducing amyloid burden and slowing cognitive decline. While its efficacy and safety have been demonstrated in clinical trials, further research is essential to validate long-term outcomes, assess effectiveness across diverse populations, and refine dosing strategies to minimize side effects. With continued investigation, donanemab-azbt could significantly impact the clinical landscape of AD treatment.}, }
@article {pmid39997718, year = {2025}, author = {Niu, H and Zhang, M and Zhang, K and Aishan, S and Li, H and Wu, W}, title = {In-Depth Investigation on Potential Mechanism of Forest-Grown Ginseng Alleviating Alzheimer's Disease via UHPLC-MS-Based Metabolomics.}, journal = {Metabolites}, volume = {15}, number = {2}, pages = {}, pmid = {39997718}, issn = {2218-1989}, support = {202410199035//National College Students' innovation and entrepreneurship training program/ ; 20240101334JC//Jilin Province Science and technology plan project/ ; }, abstract = {BACKGROUND: Alzheimer's disease is a central nervous system degenerative disease closely related to age with a complex pathogenesis. As a natural medicinal plant, forest-grown ginseng (GSF) contains abundant ginsenosides and offers significant neuroprotective effects.
METHODS: In this study, we comprehensively investigated the effect of GSF on the cell viability of PC12 cells in an AD model alongside metabolic changes in the serum and brains of mice, combined with an efficacy evaluation of PC12 cells in vitro and UHPLC-MS-based metabolomics in vivo. The goal of this study is to clarify the potential mechanism of GSF in treating AD.
RESULTS: The PC12 cell results showed that GSF can promote the proliferation of PC12 cells, reduce the content of IL-8, increase the activity of SOD, and alleviate the inflammation and oxidative stress induced by Aβ25~35. The immunohistochemical results for the mouse brain tissue also showed that GSF could reduce the inflammatory response of mouse brain tissue by reducing the overexpression of IBa1. AD was alleviated by reducing Aβ protein deposition in the mouse brain tissue. An untargeted metabolomics analysis was performed using UHPLC-Q-Exactive MS and principal component analysis (PCA) to identify the differentially expressed metabolites in the serum and brain tissue of AD mice after treatment. Twenty and seventeen different metabolites were identified in the serum and brain tissue, respectively. The pathway enrichment analysis of differential metabolites showed that GSF could treat AD by up-regulating succinic acid semialdehyde, carbamoyl phosphate, Sphingosine 1-phosphate, L-cystathionine, 2-ketobutyric acid, Vanillylmandelic acid, and D-Ribose to regulate sphingomyelin metabolism, the synthesis and metabolism of neurotransmitters and precursors, and energy metabolism.
CONCLUSIONS: GSF can reduce neuroinflammation and alleviate Alzheimer's disease by regulating the metabolic disorders of amino acids, sphingolipids, unsaturated fatty acids, and arachidonic acid in mice serum and brain tissue metabolites. These results suggest a link between metabolite imbalance and AD, and reveal the basis for the mechanism of ginsenosides in AD treatment.}, }
@article {pmid39997520, year = {2025}, author = {Benson, GS and Bartels, C and Stamatis, F and Belz, M and Esselmann, H and Frölich, L and Hausner, L}, title = {The Use and Understanding of Mild Cognitive Impairment in Routine Specialist Care: A Survey Among German Memory Clinics.}, journal = {Geriatrics (Basel, Switzerland)}, volume = {10}, number = {1}, pages = {}, pmid = {39997520}, issn = {2308-3417}, support = {LCM12365//Roche Pharma AG (Germany)/ ; }, abstract = {Objectives: Mild cognitive impairment (MCI) is a heterogeneous clinical syndrome and is important for the diagnosis and management of Alzheimer's disease (AD). With the expansion of biomarker-based diagnostics, the aim of this study is to clarify the current attitudes towards and the use of MCI, and MCI due to AD, in German memory clinics. Methods: An online survey (50 items) was performed in 2022 among specialized clinicians (N = 45) in German memory clinics to assess the use of MCI and biomarkers in current diagnosis and treatment. Attitudinal and frequency items were assessed with a five-point numeric scale (strongly disagree = 1 to completely agree = 5 and never = 1 to always = 5, respectively). Results: All respondents used MCI as a clinical diagnosis. The benefits of diagnosing MCI were labeling deficits as disease symptoms (M = 4.4, SD = 0.7), improving coping with symptoms (M = 4.1, SD = 0.9), and motivating risk reduction activities (M = 4.0, SD = 0.9). Overall, 37 respondents used specialized diagnostic criteria for MCI due to AD, and all had access to biomarker diagnostics. Patients with MCI due to AD received more frequent counseling on memory training (p < 0.001), other non-pharmacological treatments (p < 0.001), and antidementive drug treatment (p < 0.001) than patients with MCI of other etiologies. Acetylcholinesterase inhibitors were prescribed significantly more frequently to patients with MCI due to AD (p < 0.001) compared to other MCI patients. Conclusions: MCI is commonly used as a clinical diagnosis in German memory clinics. AD biomarker assessment is well established and influences patient counseling and treatment recommendations.}, }
@article {pmid39997199, year = {2025}, author = {Peng, P and Yu, H and Xian, M and Qu, C and Guo, Z and Li, S and Zhu, Z and Xiao, J}, title = {Preparation of Acetylcholinesterase Inhibitory Peptides from Yellowfin Tuna Pancreas Using Moderate Ultrasound-Assisted Enzymatic Hydrolysis.}, journal = {Marine drugs}, volume = {23}, number = {2}, pages = {}, pmid = {39997199}, issn = {1660-3397}, support = {32360578//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Tuna ; *Pancreas/enzymology ; *Cholinesterase Inhibitors/pharmacology/chemistry ; Hydrolysis ; *Molecular Docking Simulation ; *Acetylcholinesterase/metabolism ; *Peptides/pharmacology/chemistry/isolation & purification ; Fish Proteins/pharmacology/chemistry/isolation & purification ; Molecular Dynamics Simulation ; Ultrasonic Waves ; Tandem Mass Spectrometry ; Alzheimer Disease/drug therapy ; }, abstract = {Bioactive peptides represent a promising therapeutic approach for Alzheimer's disease (AD) by maintaining cholinergic system homeostasis through the inhibition of acetylcholinesterase (AChE) activity. This study focused on extracting AChE inhibitory peptides from yellowfin tuna pancreas using moderate ultrasound-assisted enzymatic hydrolysis (MUE). Firstly, papain and MUE stood out from five enzymes and four enzymatic hydrolysis methods, respectively, by comparing the degree of hydrolysis and AChE inhibitory activity of different pancreatic protein hydrolysates. Subsequently, the optimal MUE conditions were obtained by single-factor, Plackett-Burman, and response surface methodologies. The pancreatic protein hydrolysate prepared under optimal MUE conditions was then purified by ultrafiltration followed by RP-HPLC, from which a novel AChE inhibitory peptide (LLDF) was identified by LC-MS/MS and virtual screening. LLDF effectively inhibited AChE activity by a competitive inhibition mechanism, with an IC50 of 18.44 ± 0.24 μM. Molecular docking and molecular dynamic simulation revealed that LLDF bound robustly to the active site of AChE via hydrogen bonds. These findings provided a theoretical basis for the valuable use of yellowfin tuna pancreas and introduced a new viewpoint on the potential therapeutic advantages of AChE inhibitory peptides for future AD treatment.}, }
@article {pmid39997198, year = {2025}, author = {Liu, Y and Xu, X and Wu, X and Yang, G and Luo, J and Liang, X and Chen, J and Li, Y}, title = {TMF Attenuates Cognitive Impairment and Neuroinflammation by Inhibiting the MAPK/NF-κB Pathway in Alzheimer's Disease: A Multi-Omics Analysis.}, journal = {Marine drugs}, volume = {23}, number = {2}, pages = {}, pmid = {39997198}, issn = {1660-3397}, support = {82060697//National Natural Science Foundation of China/ ; 20212BBG71007//the Jiangxi Key Research and Development Program/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Cognitive Dysfunction/drug therapy ; Mice ; *NF-kappa B/metabolism ; *Neuroinflammatory Diseases/drug therapy ; *Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; Microglia/drug effects/metabolism ; Mice, Transgenic ; Male ; Flavones/pharmacology ; Humans ; Mice, Inbred C57BL ; Signal Transduction/drug effects ; Cell Line ; MAP Kinase Signaling System/drug effects ; Anti-Inflammatory Agents/pharmacology ; Multiomics ; }, abstract = {The rising prevalence of Alzheimer's disease (AD) underscores the urgent need for novel therapeutic agents derived from natural sources. Among flavonoids, 3',4',5,7-tetramethoxyflavone (TMF), a structural analog of luteolin, has gained attention for its favorable pharmacokinetics and potential neuroprotective properties. Despite the significant neuroprotective effects and favorable pharmacokinetics of TMF, its efficacy and mechanism of action in AD remain unclear. This study explored TMF's pharmacological effects in AD models, highlighting its ability to improve memory and cognitive deficits in APP/PS1 mice. TMF reduced Aβ plaques, NFTs formation, and glial activation while suppressing neuroinflammation through the MAPK/NF-κB pathway. Further analysis in LPS-induced BV2 cells revealed TMF's ability to reduce microglial activation. These findings highlight the anti-neuroinflammatory activity of TMF, suggesting its potential as a treatment for AD.}, }
@article {pmid39996839, year = {2025}, author = {Zheng, Y and Gao, X and Tang, J and Gao, L and Cui, X and Liu, K and Zhang, X and Jin, M}, title = {Exploring the Efficacy and Target Genes of Atractylodes Macrocephala Koidz Against Alzheimer's Disease Based on Multi-Omics, Computational Chemistry, and Experimental Verification.}, journal = {Current issues in molecular biology}, volume = {47}, number = {2}, pages = {}, pmid = {39996839}, issn = {1467-3045}, support = {2023YFC3505000//National Key Research and Development Program for Young Scientists/ ; tsqn202312233//Taishan Scholars Program for MJ/ ; 202228035//Jinan Talent Project for Universities/ ; WSR2024032//Two Hundred Foreign Experts Program/ ; }, abstract = {OBJECTIVE: To unveil the efficacy and ferroptosis-related mechanisms of Atractylodes Macrocephala Koidz (AMK) against Alzheimer's disease (AD), which is the most widespread neurodegenerative disease.
METHODS: Gene set variation analysis (GSVA) scores were used to investigate the relationship between ferroptosis and AD. Logistic regression with seven feature selections and a deep learning model were utilized to identify potential targets of AMK based on transcriptomic data from multiple tissues. A transcriptome-wide association study (TWAS), summary-data-based mendelian randomization (SMR), and mendelian randomization (MR) were utilized to validate the causal relationship between target genes and AD risk. A single-gene gene set enrichment analysis (GSEA) was employed to investigate the biological pathways associated with the target genes. Three molecular docking strategies and a molecular dynamics simulation were employed to verify the binding domains interacting with AMK. Furthermore, the anti-AD effects of AMK were validated in a zebrafish AD model by testing behavior responses, apoptosis, and the deposition of beta-amyloid (Aβ) in the brain. Ultimately, real-time qPCR was used to verify the ferroptosis-related targets, which was identified via multi-omics.
RESULTS: Ferroptosis is an important pathogenic mechanism of AD, as suggested by the GSVA scores. AMK may exert its anti-AD activity through targets genes identified in the brain (ATP5MC3, GOT1, SAT1, EGFR, and MAPK9) and blood (G6PD, PGD, ALOX5, HMOX1, and ULK1). EGFR and HMOX1 were further confirmed as target genes mediating the anti-AD activity of AMK through TWAS, SMR, and MR analyses. The GSEA results indicated that EGFR may be involved in oxidative phosphorylation-related pathways, while HMOX1 may be associated with lysosome and phagosome pathways. The results of three molecular docking strategies and molecular dynamics simulations implied that the kinase domain of EGFR and the catalytic domain of HMOX1 played pivotal roles in the interaction between AMK and the targets. In a zebrafish model, AD-like symptoms including motor slowness and delayed responses, neuronal apoptosis, and plaque deposition in the brain, were significantly improved after AMK treatment. Accordingly, AMK reversed the abnormal expression of egfra and hmox1a, two core targets genes involved in ferroptosis.
CONCLUSIONS: AMK significantly alleviated AD-like symptoms through the modulation of EGFR and HMOX1, which might reduce lipid peroxidation, thereby suppressing ferroptosis. This study provided evidence supporting the efficacy and therapeutic targets associated with ferroptosis in AMK-treated AD, which aid in the development of therapeutic interventions.}, }
@article {pmid39996836, year = {2025}, author = {Savulescu-Fiedler, I and Dorobantu-Lungu, LR and Dragosloveanu, S and Benea, SN and Dragosloveanu, CDM and Caruntu, A and Scheau, AE and Caruntu, C and Scheau, C}, title = {The Cross-Talk Between the Peripheral and Brain Cholesterol Metabolisms.}, journal = {Current issues in molecular biology}, volume = {47}, number = {2}, pages = {}, pmid = {39996836}, issn = {1467-3045}, abstract = {Cholesterol is an essential element for the development and normal function of the central nervous system. While peripheral cholesterol is influenced by liver metabolism and diet, brain cholesterol metabolism takes place in an isolated system due to the impermeability of the blood-brain barrier (BBB). However, cross-talk occurs between the brain and periphery, specifically through metabolites such as oxysterols that play key roles in regulating cholesterol balance. Several neurodegenerative conditions such as Alzheimer's disease or Parkinson's disease are considered to be affected by the loss of this balance. Also, the treatment of hypercholesterolemia needs to consider these discrete interferences between brain and peripheral cholesterol and the possible implications of each therapeutic approach. This is particularly important because of 27-hydroxycholesterol and 24-hydroxycholesterol, which can cross the BBB and are involved in cholesterol metabolism. This paper examines the metabolic pathways of cholesterol metabolism in the brain and periphery and focuses on the complex cross-talk between these metabolisms. Also, we emphasize the regulatory role of the BBB and the need for an integrated approach to cholesterol management.}, }
@article {pmid39996817, year = {2025}, author = {Dimitrova, D and Dimitrova, S and Kehayova, G and Dragomanova, S}, title = {Meroterpenoids from Terrestrial and Marine Fungi: Promising Agents for Neurodegenerative Disorders-An Updated Review.}, journal = {Current issues in molecular biology}, volume = {47}, number = {2}, pages = {}, pmid = {39996817}, issn = {1467-3045}, abstract = {BACKGROUND: Meroterpenoids represent a remarkably diverse class of natural secondary metabolites, some of which are synthesized via terpenoid biosynthetic pathways. Over the past ten years, these compounds have gained interest because of their wide range of biological activities, such as anti-cholinesterase, COX-2 inhibitory, antibacterial, antiviral, antidiabetic, antioxidant, anti-inflammatory, antineoplastic, and cardioprotective properties. This review aims to consolidate the recognized neuroprotective effects of meroterpenoids from marine and terrestrial fungi.
METHODS: Data compiled from several databases, including PubMed, Science Direct, Scopus, and Google Scholar, include articles published since 2000 using keywords such as "neuroprotective", "fungi", "mushroom", "marine sponge", "neurodegeneration", and "dementia" in connection with "meroterpenoids".
RESULTS: Meroterpenoids modulate different cell signaling pathways and exhibit different and often combined mechanisms of action to ameliorate neuronal damage and dysfunction. Reported activities include anti-cholinesterase, antioxidant, BACE1 inhibition, and anti-inflammatory activities, all of which have potential in the treatment of dementia associated with neurodegenerative diseases such as Alzheimer's and Parkinson's.
CONCLUSIONS: Meroterpenoids have the potential to be developed as effective tools for neuropathological diseases. Ongoing research to elucidate the various neuroprotective pathways remains essential and requires further investigation.}, }
@article {pmid39996737, year = {2025}, author = {Balkhi, S and Di Spirito, A and Poggi, A and Mortara, L}, title = {Immune Modulation in Alzheimer's Disease: From Pathogenesis to Immunotherapy.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, pmid = {39996737}, issn = {2073-4409}, support = {FAR2023//Fondi di Ateneo per la Ricerca, Università dell'Insubria/ ; FAR2024//Fondi di Ateneo per la Ricerca, Università dell'Insubria/ ; }, mesh = {*Alzheimer Disease/immunology/therapy/pathology ; Humans ; *Immunotherapy/methods ; Animals ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Microglia/immunology/pathology/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, affecting a significant proportion of the elderly population. AD is characterized by cognitive decline and functional impairments due to pathological hallmarks like amyloid β-peptide (Aβ) plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Microglial activation, chronic neuroinflammation, and disruptions in neuronal communication further exacerbate the disease. Emerging research suggests that immune modulation could play a key role in AD treatment given the significant involvement of neuroinflammatory processes. This review focuses on recent advancements in immunotherapy strategies aimed at modulating immune responses in AD, with a specific emphasis on microglial behavior, amyloid clearance, and tau pathology. By exploring these immunotherapeutic approaches, we aim to provide insights into their potential to alter disease progression and improve patient outcomes, contributing to the evolving landscape of AD treatment.}, }
@article {pmid39996369, year = {2025}, author = {Wolfe, MS}, title = {Presenilin, γ-Secretase, and the Search for Pathogenic Triggers of Alzheimer's Disease.}, journal = {Biochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.biochem.4c00830}, pmid = {39996369}, issn = {1520-4995}, abstract = {Cerebral plaques of the amyloid β-peptide (Aβ) are a defining pathology in Alzheimer's disease (AD). The amyloid hypothesis of AD pathogenesis has dominated the field for over 30 years, ostensibly validated by rare AD-causing mutations in the substrate and enzyme that produce Aβ. The γ-secretase complex carries out intramembrane proteolysis of the substrate derived from the amyloid precursor protein (APP). Mutations in APP and presenilin, the catalytic component of γ-secretase, typically increase the ratio of aggregation-prone 42-residue Aβ (Aβ42) over the more soluble 40-residue form (Aβ40). Nevertheless, the inability to clarify how Aβ aggregation leads to neurodegeneration, along with poor progress in developing effective AD therapeutics that target Aβ, raises concern about whether Aβ is the primary disease driver. γ-Secretase carries out processive proteolysis on the APP substrate, producing long Aβ peptides that are generally trimmed in tripeptide intervals to shorter secreted peptides. Recent studies on effects of AD-causing mutations on the complicated proteolytic processing of the APP substrate by γ-secretase has led to the discovery that these mutations reduce─but do not abolish─processive proteolysis. Reduced proteolysis is apparently due to stabilization of enzyme-substrate complexes, and these stalled substrate-bound γ-secretase complexes can trigger synaptic degeneration even in the absence of Aβ production. Thus, the stalled process rather than the proteolytic products may be a principal initiator of AD pathogenesis. This new amyloid-independent hypothesis suggests that pharmacological agents that rescue stalled γ-secretase enzyme-substrate complexes might be effective therapeutics for AD prevention and/or treatment.}, }
@article {pmid39996130, year = {2025}, author = {Dilliott, AA and Costanzo, MC and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, M and Flannick, J and Burtt, NP and Farhan, SMK}, title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.}, journal = {Neurology. Genetics}, volume = {11}, number = {2}, pages = {e200246}, pmid = {39996130}, issn = {2376-7839}, abstract = {Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively use the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for patients with neurodegenerative disease.}, }
@article {pmid39995763, year = {2025}, author = {Ahmed, RM and Piguet, O and Mummery, CJ and Naismith, SL and Irish, M}, title = {The Holy Grail: highlighting the need for equitable access to dementia treatments and clinical trials.}, journal = {The Lancet regional health. Western Pacific}, volume = {55}, number = {}, pages = {101492}, pmid = {39995763}, issn = {2666-6065}, abstract = {In the last 5 years significant progress has been made in potential dementia treatments, yet many of these treatments come with significant burdens on the healthcare system that may limit access to treatment and care for patients. Often patients in remote and rural regions and those in low income regions are disadvantaged. Many clinical trials for dementia patients are biased to recruiting a homogenous group of patients that does not represent cultural and linguistic diversity, meaning the generalisability of trials is limited. This viewpoint discusses the barriers to access to early treatments and clinical trials for patients with dementia and offers a potential framework to address these including provision of infrastructure, regulatory change and patient education.}, }
@article {pmid39995734, year = {2025}, author = {Yuan, Z and Qi, N and Zhou, Z and Ding, J and Chen, X and Wu, J and Wang, J and Zhao, J}, title = {Diagnosis of Alzheimer's disease using transfer learning with multi-modal 3D Inception-v4.}, journal = {Quantitative imaging in medicine and surgery}, volume = {15}, number = {2}, pages = {1455-1467}, pmid = {39995734}, issn = {2223-4292}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Deep learning (DL) technologies are playing increasingly important roles in computer-aided diagnosis in medicine. In this study, we sought to address issues related to the diagnosis of Alzheimer's disease (AD) based on multi-modal features, and introduced a multi-modal three-dimensional Inception-v4 model that employs transfer learning for AD diagnosis based on magnetic resonance imaging (MRI) and clinical score data.
METHODS: The multi-modal three-dimensional (3D) Inception-v4 model was first pre-trained using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Subsequently, independent validation data were used to fine-tune the model with pre-trained weight parameters. The model was quantitatively evaluated using the mean values obtained from five-fold cross-validation. Further, control experiments were conducted to verify the performance of the model patients with AD, and in the study of disease progression.
RESULTS: In the AD diagnosis task, when a single image marker was used, the average accuracy (ACC) and area under the curve (AUC) were 62.21% and 71.87%, respectively. When transfer learning was not employed, the average ACC and AUC were 75.74% and 83.13%, respectively. Conversely, the combined approach proposed in this study achieved an average ACC of 87.84%, and an average AUC of 90.80% [with an average precision (PRE) of 87.21%, an average recall (REC) of 82.52%, and an average F1 of 83.58%].
CONCLUSIONS: In comparison with existing methods, the performance of the proposed method was superior in terms of diagnostic accuracy. Specifically, the method showed an enhanced ability to accurately distinguish among various stages of AD. Our findings show that multi-modal feature fusion and transfer learning can be valuable resources in the treatment of patients with AD, and in the study of disease progression.}, }
@article {pmid39995599, year = {2025}, author = {Schindler, SE and Musiek, ES and Morris, JC}, title = {Anti-amyloid treatments: Why we think they are worth it.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70055}, pmid = {39995599}, issn = {2352-8737}, abstract = {UNLABELLED: Years of experience watching our patients progressively decline and die from complications of Alzheimer's disease (AD) has strongly motivated us to provide newly approved anti-amyloid treatments to appropriate patients. Following detailed and personalized discussions of the potential risks and benefits of these treatments with patients and their families, almost 300 patients at our clinic have chosen to receive lecanemab infusions. We have found the frequency and severity of complications, including amyloid-related imaging abnormalities (ARIA), to be manageable and as expected based on clinical trials. While the longer-term benefits of these treatments are not yet clear, our patients and their families are accepting of even a modest slowing of disease progression. We have experienced the complexities, burdens, costs, and major logistical challenges associated with the treatment of AD with anti-amyloid treatments. However, we also understand that for some of our current patients with early symptomatic AD, anti-amyloid treatments are their best option for fighting this devastating disease, and we find it worthwhile to provide these treatments to our patients.
HIGHLIGHTS: Many of our former patients have died from complications of AD.Our clinic now has nearly 300 patients receiving anti-amyloid treatments.We have found the complications of anti-amyloid treatments to be manageable.Despite the challenges, we find anti-amyloid treatments worthwhile.}, }
@article {pmid39995567, year = {2025}, author = {Paul, JK and Malik, A and Azmal, M and Gulzar, T and Afghan, MTR and Talukder, OF and Shahzadi, S and Ghosh, A}, title = {Advancing Alzheimer's Therapy: Computational strategies and treatment innovations.}, journal = {IBRO neuroscience reports}, volume = {18}, number = {}, pages = {270-282}, pmid = {39995567}, issn = {2667-2421}, abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative condition distinguished by the occurrence of memory impairment, cognitive deterioration, and neuronal impairment. Despite extensive research efforts, conventional treatment strategies primarily focus on symptom management, highlighting the need for innovative therapeutic approaches. This review explores the challenges of AD treatment and the integration of computational methodologies to advance therapeutic interventions. A comprehensive analysis of recent literature was conducted to elucidate the broad scope of Alzheimer's etiology and the limitations of conventional drug discovery approaches. Our findings underscore the critical role of computational models in elucidating disease mechanisms, identifying therapeutic targets, and expediting drug discovery. Through computational simulations, researchers can predict drug efficacy, optimize lead compounds, and facilitate personalized medicine approaches. Moreover, machine learning algorithms enhance early diagnosis and enable precision medicine strategies by analyzing multi-modal datasets. Case studies highlight the application of computational techniques in AD therapeutics, including the suppression of crucial proteins implicated in disease progression and the repurposing of existing drugs for AD management. Computational models elucidate the interplay between oxidative stress and neurodegeneration, offering insights into potential therapeutic interventions. Collaborative efforts between computational biologists, pharmacologists, and clinicians are essential to translate computational insights into clinically actionable interventions, ultimately improving patient outcomes and addressing the unmet medical needs of individuals affected by AD. Overall, integrating computational methodologies represents a promising paradigm shift in AD therapeutics, offering innovative solutions to overcome existing challenges and transform the landscape of AD treatment.}, }
@article {pmid39995296, year = {2025}, author = {Wang, C and Zhang, X and Zhuang, Y and Song, X and Sun, S and Chen, Y and Qi, G and Yang, Y and Li, P and Wei, W}, title = {Natural Bioactive Compounds Solanesol and Chlorogenic Acid Assembled Nanomicelles for Alzheimer's Disease Therapy.}, journal = {ACS applied materials & interfaces}, volume = {17}, number = {9}, pages = {14591-14603}, doi = {10.1021/acsami.4c22621}, pmid = {39995296}, issn = {1944-8252}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; Mice ; *Chlorogenic Acid/chemistry/pharmacology/therapeutic use ; *Amyloid beta-Peptides/metabolism ; *Micelles ; Reactive Oxygen Species/metabolism ; Humans ; Phenols/chemistry/pharmacology ; Nanoparticles/chemistry/therapeutic use ; Terpenes ; }, abstract = {Solanesol (Sol) and chlorogenic acid (CHA) are naturally active compounds. Sol exhibits a significant free radical absorption ability and strong antioxidant activity. CHA, a typical phenolic acid, exhibits excellent anticancer, anti-inflammation, and antibacterial properties. Herein, bifunctional nanomicelles (CI@SPK) were skillfully designed to take advantage of the unique properties of Sol and CHA to treat Alzheimer's disease (AD). Hydrophobic Sol was modified with poly(ethylene glycol) to self-assemble into stable nanomicelles (SP). CHA could be encapsulated into the hydrophobic core of these nanomicelles, which increased its bioavailability greatly. Short peptide K (CKLVFFAED) was incorporated (CI@SPK) to facilitate their crossing the blood-brain barrier. Then, CI@SPK targeted the AD lesion area, and CHA was released in greater quantities with the help of IR780 under irradiation with an 808 nm laser, resulting in synergistically scavenging reactive oxygen species (ROS) with Sol. Consequently, the nanomicelles CI@SPK demonstrated capabilities in scavenging ROS, inhibiting β-amyloid (Aβ) aggregation, and eventually modulating microglia phenotype from M1 to M2 to promote Aβ phagocytosis and clearance. In vivo studies indicated that nanomicelles CI@SPK improved the learning and cognitive impairments of APP/PS1 mice by reducing Aβ plaque and inflammation, signifying the potential value of CI@SPK in clinical application for AD treatment.}, }
@article {pmid39995125, year = {2025}, author = {Kalinin, AP and Zubkova, ES and Menshikov, MY and Parfyonova, YV}, title = {ISR Modulators in Neurological Diseases.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X361653250213114821}, pmid = {39995125}, issn = {1875-6190}, abstract = {The dysfunction of different cells lies in the pathogenesis of neurological diseases and is usually associated with cellular stress. Various stressors trigger the integrated stress response (ISR) signaling, whose highly conserved mechanism is primarily aimed at protecting a stress-exposed cell to cope as safely as possible with such stressful conditions. On the contrary, if a cell is unable to cope with excessive stress, the ISR can induce apoptosis. The ISR mechanism, whose main stage is the inhibition of translation machinery in favor of the synthesis of specific proteins, including the transcription factors ATF3, ATF4, CEBPA, and CEBPB, which function only as dimers and determine the uniqueness of the ISR response in each individual case, thus ensures different outcomes of the ISR. Inhibition of global protein synthesis is achieved through phosphorylation of eIF2α by PERK, HRI, PKR, or GCN2. To date, a number of compounds have been developed that modulate the ISR, including activators and inhibitors of the abovementioned ISR kinases as well as modulators of p-eIF2α dephosphorylation. They target different ISR stages, allowing a broad ISR modulation strategy. At the same time, there are no drugs that are both exceptionally safe and effective for the treatment of several neurological diseases, so there is an urgent need for new approaches to the treatment of these disorders. In this review, we represent ISR signaling as an important participant in the pathogenesis of neurological diseases. We also describe how various ISR modulators may become a part of future therapies for these diseases.}, }
@article {pmid39994624, year = {2025}, author = {Huang, Y and Zhai, Y and Zhao, D and Wu, M and Shen, Q and Zhao, W and Wang, Q and Yao, L and Li, W}, title = {UHPLC-Q Exactive-Orbitrap-MS and network pharmacology analyses to investigate the mechanism by which Danggui-Shaoyao-San affects 27-OHC-induced cell damage in SH-SY5Y/C6 coculture.}, journal = {BMC complementary medicine and therapies}, volume = {25}, number = {1}, pages = {75}, pmid = {39994624}, issn = {2662-7671}, support = {81973919//National Natural Science Foundation of China/ ; 82274616//National Natural Science Foundation of China/ ; 82074505//National Natural Science Foundation of China/ ; 2022A1515220121//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515011835//Basic and Applied Basic Research Foundation of Guangdong Province/ ; }, mesh = {*Drugs, Chinese Herbal/pharmacology ; Humans ; *Network Pharmacology ; Chromatography, High Pressure Liquid ; *Coculture Techniques ; Alzheimer Disease/drug therapy ; Cell Line, Tumor ; Animals ; Mass Spectrometry ; Rats ; }, abstract = {BACKGROUND: Danggui-Shaoyao-San (DSS) is a classic Chinese medicine formula that has been extensively studied for its efficacy in treating Alzheimer's disease (AD). However, its mechanism of action is still unclear.
METHODS: In this study, UHPLC-Q Exactive-Orbitrap-MS was used to analyze and identify the compounds in DSS. Network pharmacology was used to analyze the common targets of drug-containing serum chemistries and AD, as well as the AD pathways in which drug-containing serum chemistries may be involved. The 27-OHC-induced SH-SY5Y/C6 coculture cell injury model was used to explore the mechanism of action of DSS in the treatment of AD.
RESULTS: UHPLC-Q Exactive-Orbitrap-MS analysis identified 73 chemical constituents in DSS aqueous extract and 39 compounds in drug-containing serum. According to network pharmacology analysis, DSS and AD share 181 common targets, with interleukin-6 (IL-6) and tumor necrosis factor (TNF) being the main effective targets. Furthermore, DSS may treat AD through the modulation of lipid metabolism-related pathways and the interleukin-17 (IL-17) signaling pathway. 27-hydroxycholesterol acid (27-OHC) significantly reduced the viability of SH-SY5Y cells and C6 cells in vitro, while DSS administration upregulated the expression of cytochrome P450 46A1 (CYP46A1) and cytochrome P450 7B1 (CYP7B1) enzymes and reduced cholesterol levels in SH-SY5Y cells. Additionally, DSS decreased reactive oxygen species (ROS) levels and increased glutathione (GSH) levels in coculture systems. DSS downregulated the expression of IL-17 in 27-OHC-injured SH-SY5Y cells and downregulated the expression of TNF-α, IL-6 and transforming growth factor-β1 (TGF-β1) in 27-OHC-injured C6 cells.
CONCLUSION: This study revealed the effective components, targets and mechanisms of DSS in the treatment of AD, highlighting the significant potential of DSS in treating this disease.}, }
@article {pmid39994231, year = {2025}, author = {Arnold, M and Buyukozkan, M and Doraiswamy, PM and Nho, K and Wu, T and Gudnason, V and Launer, LJ and Wang-Sattler, R and Adamski, J and , and , and De Jager, PL and Ertekin-Taner, N and Bennett, DA and Saykin, AJ and Peters, A and Suhre, K and Kaddurah-Daouk, R and Kastenmüller, G and Krumsiek, J}, title = {Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1910}, pmid = {39994231}, issn = {2041-1723}, support = {N01AG12100/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; U19 AG063744/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; RC2 AG036547/AG/NIA NIH HHS/United States ; U01 AG061359/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; R01 AG046171/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; R01 AG030146/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; R01 AG069901/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; R01 AG036042/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; RF1 AG059093/AG/NIA NIH HHS/United States ; RF1 AG057473/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; U01 AG046161/AG/NIA NIH HHS/United States ; R01 AG048015/AG/NIA NIH HHS/United States ; P50 AG025711/AG/NIA NIH HHS/United States ; RF1 AG058942/AG/NIA NIH HHS/United States ; HHSN271201200022C/DA/NIDA NIH HHS/United States ; RF1 AG051550/AG/NIA NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 AG036836/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism ; Humans ; *Energy Metabolism ; *Carnitine/analogs & derivatives/metabolism/blood ; Male ; Aged ; Female ; *Biomarkers/blood/metabolism ; Aged, 80 and over ; Mitochondria/metabolism ; Brain/metabolism/diagnostic imaging ; Disease Progression ; Middle Aged ; Glucose/metabolism ; }, abstract = {Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD. Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.}, }
@article {pmid39993744, year = {2025}, author = {Tsuru, M and Ito, T and Komai, K and Kunitomo, F and Nakayama, Y and Murakami, T and Ohuchi, K and Shinkai, Y and Kimura, T and Miura, N and Kumagai, Y and Hozumi, I and Inden, M and Kurita, H}, title = {Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor, FG4592, Induces Endogenous Metallothionein3 Expression in Human Neuronal Cell Line, ReNcell CX Cells.}, journal = {Biological & pharmaceutical bulletin}, volume = {48}, number = {2}, pages = {137-143}, doi = {10.1248/bpb.b24-00792}, pmid = {39993744}, issn = {1347-5215}, mesh = {Humans ; *Metallothionein 3 ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics ; *Neurons/metabolism/drug effects ; Cell Line ; Isoquinolines/pharmacology ; Prolyl-Hydroxylase Inhibitors/pharmacology ; Nerve Tissue Proteins/metabolism/genetics ; Phenylurea Compounds/pharmacology ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism/antagonists & inhibitors ; Glycine/analogs & derivatives ; }, abstract = {Metallothionein (MT) is a small-molecule protein that functions in essential trace element homeostasis. Among MT isoforms, MT3 is involved in neuronal activity, and its expression is reported to be decreased in patients with neurodegenerative conditions such as Alzheimer's disease; however, only a few effective drugs have been reported to induce MT3 expression. In this study, we evaluated existing drugs for the induction of MT3 expression in the neuronal cell line of ReNcell CX cells. Using recombinant proteins of MT isoforms with the 3× Flag tag, we performed Western blotting (WB) with the primary antibodies against MT3 or Flag tag, and this method of WB for MT3 was confirmed specifically to detect the MT3 protein. We treated ReNcell CX cells with several HIF-PH inhibitors and evaluated MT3 expression via real-time RT-PCR. We found that FG4592 significantly enhanced MT3 expression at both RNA and protein levels. FG4592 treatment increased the amount of hypoxia-inducible factor 1 alpha (HIF1α) binding to the MT3 promoter. These findings indicate that FG4592 induces MT3 expression via increased HIF1α. In conclusion, we found FG4592 to be an endogenous MT3 inducer in the cells of the nervous system in this study. The findings of this study are expected to lead to the development of new MT3-inducing drugs for neurodegenerative diseases based on FG4592.}, }
@article {pmid39993451, year = {2025}, author = {Pattanaik, S and Ghose, A and Pakeeraiah, K and Paidesetty, SK and Prusty, SK and Sahu, PK}, title = {Repurposing drugs: promising therapeutic approach against Alzheimer's disease.}, journal = {Ageing research reviews}, volume = {106}, number = {}, pages = {102698}, doi = {10.1016/j.arr.2025.102698}, pmid = {39993451}, issn = {1872-9649}, mesh = {Humans ; *Drug Repositioning/methods ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Alzheimer's disease (AD) is an insidious, irreversible, complex neurodegenerative disorder characterized by progressive cognitive decline and memory loss; affecting millions worldwide. Despite decades of research, no effective disease-modifying treatment exists. However, drug repurposing is a progressive step in identifying new therapeutic uses of existing drugs. It has emerged as a promising strategy in the quest to combat AD. Various classes of repurposed drugs, such as antidiabetic, antihypertensive, antimicrobial, and anti-inflammatory, have shown potential neuroprotective effects in preclinical and clinical studies. These drugs act by combating free radicals generation, neuroinflammation, amyloid-beta aggregation, and tau hyper-phosphorylation. Furthermore, repurposing offers several advantages, including reduced time and cost compared to de novo drug development. It holds immense promise as a complementary approach to traditional drug discovery. Future research efforts should focus on elucidating the underlying mechanisms of repurposed drugs in AD, optimizing drug combinations, and conducting large-scale clinical trials to validate their efficacy and safety profiles. This review overviews recent advancements and findings in preclinical and clinical fields of different repurposed drugs for AD treatment.}, }
@article {pmid39992990, year = {2025}, author = {Liu, J and Chen, L and Zhang, ZL and Wen, W and Zhang, X and Wu, Z and Wang, S}, title = {Nano-Collision Electrochemistry for Real-Time Monitoring of Amyloid-β Oligomerization and Rapid Screening of Degrading Drugs.}, journal = {Analytical chemistry}, volume = {97}, number = {9}, pages = {4898-4905}, doi = {10.1021/acs.analchem.4c04598}, pmid = {39992990}, issn = {1520-6882}, mesh = {*Protein Multimerization ; *Amyloid beta-Peptides/chemistry/metabolism ; Metal Nanoparticles/chemistry ; Silver/chemistry ; *Drug Evaluation, Preclinical/methods ; *Electrochemical Techniques/methods ; Proteolysis/drug effects ; }, abstract = {Toxic oligomers of amyloid-β (Aβ) are important in the pathology of Alzheimer's disease (AD), and degradation of Aβ oligomers (AβO) in the brain is considered a promising strategy for drug development. However, conventional drug screening techniques face challenges in the rapid and real-time assessment of AβO. Here, we report a simple and reliable nanocollision electrochemical method based on silver nanoparticles (AgNPs) "tagging" that can in situ monitor Aβ oligomerization and screen potential AβO-degrading drugs. The differences in collision signals between AgNPs-Aβ complexes and AgNPs were compared to achieve rapid identification of Aβ complexes with different aggregation degrees. The degradation effect following the addition of AβO-degrading drugs can be quickly evaluated by the recovery of collision frequency (f, number of peaks per unit time), which is effective if f > 0.15. Degradation efficiency was further quantified using current lifetimes (τ, the time required for the current to decay to 1/e of the original), based on the percentage of τ ≤ 10 ms. The practicability of the method was tested using Aβ-degrading protease and several small molecules, confirming the rapid screening of AβO-degrading drugs and offering a novel strategy to accelerate the development of drugs for AD treatment.}, }
@article {pmid39992888, year = {2025}, author = {Hao, Z and Ji, R and Su, Y and Wang, H and Yang, W and Zhang, S and Liu, Y and Ma, S and Guan, F and Cui, Y}, title = {Indole-3-Propionic Acid Attenuates Neuroinflammation and Cognitive Deficits by Inhibiting the RAGE-JAK2-STAT3 Signaling Pathway.}, journal = {Journal of agricultural and food chemistry}, volume = {73}, number = {9}, pages = {5208-5222}, doi = {10.1021/acs.jafc.4c08548}, pmid = {39992888}, issn = {1520-5118}, mesh = {Animals ; *Janus Kinase 2/metabolism/genetics ; Mice ; *Indoles/pharmacology ; *STAT3 Transcription Factor/metabolism/genetics ; *Signal Transduction/drug effects ; *Cognitive Dysfunction/drug therapy/metabolism ; Male ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Mice, Inbred C57BL ; Humans ; Receptor for Advanced Glycation End Products/metabolism/genetics ; Cell Line ; Apoptosis/drug effects ; Propionates ; }, abstract = {Cognitive disorders such as Alzheimer's disease (AD) are highly prevalent and place heavy burdens on society. Neuroinflammation is a driver of cognitive impairment, with no effective drugs. Indole 3-propionic acid (IPA) is a tryptophan metabolite mainly produced byClostridium sporogenes, which exhibits multiple functions, including antioxidant, anti-inflammatory, antiaging, and neuroprotective properties. However, the restorative effects and molecular mechanisms of IPA in cognitive impairment remain to be investigated. In this study, we found that IPA reduced LPS-induced apoptosis and oxidative damage in HT22 cells and decreased LPS-induced inflammation in BV2 cells. Besides, IPA promoted neurogenesis, inhibited glial cell activation, maintained the integrity of the BBB and intestinal barrier, and remodeled the gut microbiota, thereby alleviating memory impairment in LPS-induced cognitively impaired mice. At the mechanistic level, IPA inhibited the RAGE-JAK2-STAT3 signaling pathway and thus ameliorated neuroinflammation. Interestingly, Colivelin TFA, an activator of JAK2-STAT3 signaling, partially reversed the neurorestorative effects of IPA. In conclusion, IPA ameliorates neuroinflammation and cognitive deficits via the inhibition of the RAGE-JAK2-STAT3 signaling pathway. Thus, IPA may be a potential drug for the treatment of cognitive disorders.}, }
@article {pmid39992792, year = {2025}, author = {Liu, M and Zhu, J and Zheng, J and Han, X and Jiang, L and Tong, X and Ke, Y and Guo, Z and Huang, W and Cong, J and Liu, M and Lin, SY and Zhu, S and Mei, L and Zhang, X and Zhang, W and Xin, WJ and Zhang, Z and Guo, Y and Chen, R}, title = {GPNMB and ATP6V1A interact to mediate microglia phagocytosis of multiple types of pathological particles.}, journal = {Cell reports}, volume = {44}, number = {3}, pages = {115343}, doi = {10.1016/j.celrep.2025.115343}, pmid = {39992792}, issn = {2211-1247}, mesh = {*Microglia/metabolism/pathology ; *Phagocytosis ; Animals ; *Membrane Glycoproteins/metabolism/genetics ; Mice ; *Vacuolar Proton-Translocating ATPases/metabolism ; Mice, Inbred C57BL ; Neurons/metabolism/pathology ; Humans ; Seizures/metabolism/pathology ; Hippocampus/metabolism/pathology ; Lysosomes/metabolism ; Apoptosis ; Amyloid beta-Peptides/metabolism ; Mice, Knockout ; Caspase 3/metabolism ; Eye Proteins ; }, abstract = {Pronounced elevation of glycoprotein non-metastatic melanoma B (GPNMB) is a common phenomenon in a variety of brain diseases, but the expression patterns, functions, and molecular signaling of GPNMB have not been well studied. Here, we showed that pathological factors, including neuronal degeneration caused by seizures, caspase-3-induced neuronal apoptosis, neuronal debris, and β-amyloid, induced "on-demand" GPNMB expression in hippocampal microglia. Genetic ablation of GPNMB did not affect acute seizures but worsened chronic epileptogenesis. We found that GPNMB functioned in phagocytosis, deficiency of which resulted in defects in both phagocytic engulfment and degradation. GPNMB could be internalized into cells, where it wrapped engulfed pathogenic particles and presented them to lysosomes through interaction with lysosomal vacuolar-type proton ATPase catalytic subunit A (ATP6V1A). Activating ATP6V1A was able to rescue GPNMB-deficiency-caused phagocytosis impairment. Thus, microglial GPNMB-ATP6V1A might be a common treatment target of a batch of chronic neurological disorders, and clearing the degenerative neurons might be more valuable than reserving them to protect the brain.}, }
@article {pmid39992588, year = {2025}, author = {Wang, YH and Wu, HY and Xin, C and Zhang, KX and Zhang, JW and Zhi, HW}, title = {Identification and Validation of Biomarkers for Alzheimer's Disease Based on Akt and Wnt Signaling Pathways in Mouse Models.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39992588}, issn = {1559-1182}, support = {82205064//Natural Science Foundation of China/ ; ZR2021QH110//Natural Science Foundation of Shandong Province/ ; Z-2022060//Shandong TCM science and technology development plan/ ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that remains challenging to treat. Akt and Wnt play a role in complex cellular signaling, which is crucial for examining the onset of AD. In this study, we aimed to identify and analyze Akt pathway-related genes (ARGs) and Wnt pathway-related genes (WRGs) as AD biomarkers, determine the effects of ARGs and WRGs on AD, and verify these effects in AD mouse models. We searched for differentially expressed genes in the Gene Expression Omnibus database, constructed candidate gene protein-protein interaction networks, and used least absolute shrinkage and selection operator regression analysis and the support vector machine-recursive feature elimination algorithm to screen key genes. Correlation and functional similarity analyses of key genes, immune infiltration analysis, competing endogenous RNA network construction, and drug prediction of key genes were performed. Expression of key genes in streptozotocin-treated (STZ)-treated AD mice was validated using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Bioinformatics analysis identified five key genes in AD: PRKACA, CDH3, ATP6V0C, DLL1, and CELSR2. Step-down tests, immunohistochemistry, and silver plate staining confirmed successful treatment of STZ-induced AD in mice. According to RT-qPCR analysis, the relative expression of DLL1 mRNA in AD mice was higher than that in control mice, whereas the relative expression of ATP6V0C and PRKACA mRNA in AD mice was lower than that in control mice; this was consistent with the results of bioinformatics analysis (p < 0.05). This study screened and validated AD biomarkers associated with the Akt and Wnt pathways in mouse models.}, }
@article {pmid39991517, year = {2025}, author = {Li, Y and Lu, R and Abuduhailili, X and Feng, Y}, title = {Apolipoprotein E: A Potential Prognostic and Diagnostic Biomarker for Hepatocellular Carcinoma.}, journal = {Journal of hepatocellular carcinoma}, volume = {12}, number = {}, pages = {301-324}, pmid = {39991517}, issn = {2253-5969}, abstract = {PURPOSE: The apolipoprotein E (APOE) gene is one of the strongest genetic determinants of the risk of developing late-onset Alzheimer's disease (AD) and may also increase the risk of cancer. However, its importance goes far beyond this. The aim of this study was to comprehensively analyze the potential role and prognostic value of APOE in hepatocellular carcinoma (HCC) using bioinformatics and multiplex fluorescence immunohistochemistry (mIHC).
METHODS: Clinicopathologic samples from 90 hCC patients enrolled between April 2007 and June 2012 were included in this study. Researchers used tissue microarrays (HLiv180Su09) and multiple fluorescent immunohistochemical analyses to validate APOE protein expression and patient prognosis. Several online databases were used to investigate APOE expression and prognosis in HCC, followed by a comprehensive analysis of correlations between APOE and clinicopathologic features, immune cell infiltration levels, immune checkpoint genes, mutations, and functional enrichment analysis. The distribution of APOE in immune cell populations was also determined using a single-cell database.
RESULTS: APOE mRNA was significantly overexpressed in HCC at both transcriptional and translational levels. Survival analysis suggested that APOE might be a favorable prognostic indicator for HCC patients. In addition to its involvement in immune cell infiltration, immune checkpoint gene expression, genetic variation, immunomodulatory genes, and methylation alterations in HCC, enrichment analysis showed that APOE was involved in multiple cancer-related signaling pathways.
CONCLUSION: This study comprehensively examines the critical role of APOE in HCC and highlights its significant potential as a biomarker and therapeutic target. This finding not only paves the way for new avenues of research in HCC, but also provides valuable insights into clinical diagnosis and treatment strategies.}, }
@article {pmid39991000, year = {2025}, author = {Lang, J and Xiong, Z}, title = {Protective effects of harpagoside on mitochondrial functions in rotenone‑induced cell models of Parkinson's disease.}, journal = {Biomedical reports}, volume = {22}, number = {4}, pages = {64}, pmid = {39991000}, issn = {2049-9442}, abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Currently, no radical treatment is available for this disease. Harpagoside is a proposed neuroprotective iridoid active ingredient that can be derived from Scrophulariae buergeriana, Scrophularia striata and Harpagophytum procumbens. The present study aimed to investigate the effects of harpagoside on mitochondrial functions in rotenone-induced cell models of Parkinson's disease (PD). Neuro-2A (N2A) cells were treated with rotenone to establish in vitro cell models of PD. Cell viability and survival were measured using a Cell Counting Kit-8 assay. Biochemical assays with spectrophotometry were used to measure complex I activity, mitochondrial swelling and caspase 3 activity. The cell survival rate was first found to be significantly decreased by rotenone (20 nmol/l) treatment. However, intervention with harpagoside (10 µmol/l) was found to increase the cell survival rate of rotenone-induced N2A cell models differentiated with 1 mmol/l of dibutyryl-cAMP. At ≥0.1 µmol/l concentration, harpagoside significantly alleviated rotenone-induced mitochondrial swelling, whereas at 1 µmol/l it significantly counteracted the inhibitory effects of rotenone on complex I activity. At 10 µmol/l harpagoside significantly inhibited rotenone-induced caspase 3 activation. These results suggest that harpagoside has the potential to protect mitochondrial functions against rotenone-induced injury in N2A cell models of PD.}, }
@article {pmid39990827, year = {2024}, author = {He, C and He, H and Yang, X and Xing, H and Lyu, S and Wu, M}, title = {[Research Progress in Applying Hyperpolarized [13]C Labeling Technology in Neurological Metabolic Diagnostics].}, journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition}, volume = {55}, number = {6}, pages = {1343-1349}, pmid = {39990827}, issn = {1672-173X}, mesh = {*Carbon Isotopes ; Humans ; *Magnetic Resonance Spectroscopy/methods ; Pyruvic Acid/metabolism ; Isotope Labeling/methods ; Glioma/metabolism/diagnostic imaging/diagnosis ; Alzheimer Disease/diagnosis/metabolism ; }, abstract = {By using hyperpolarized [13]C labeling technology, the magnetic resonance signals of [13]C-labeled metabolic substrates are enhanced, which enables the in vivo monitoring of their metabolic states through magnetic resonance spectroscopy. Compared with traditional non-invasive metabolic diagnostic technologies, hyperpolarized [13]C technology exhibits a number of strengths, including real-time monitoring, high precision, non-invasiveness, the absence of radiation, and the ability to assess a broader range of metabolic pathways, showing great potential for application in the treatment of glioma, stroke, Alzheimer disease, and cerebral injury. Following the approval of [1-[13]C]-pyruvate for clinical trials by U.S. Food and Drug Administration (FDA), there has been growing academic interest in this technology. Currently, the primary challenge lies in creating more probes and promoting their clinical applications. Herein, we outlined the principles of hyperpolarized [13]C labeling technology, examined its current role in neurological metabolic diagnostics, and explored the future directions, including conducting hyperpolarized [13]C magnetic resonance spectroscopy (MRS) technology at higher magnetic field strengths (such as 7T), designing additional magnetic resonance sequences specific to hyperpolarized [13]C MRS, and its integration with other neuro-metabolic diagnostic methods.}, }
@article {pmid39990823, year = {2024}, author = {Yang, X and Li, W and Yang, X and Chen, Q and Li, H and Lyu, S and Hu, N}, title = {[Radiological Identification and Evaluation of Amyloid-Related Imaging Abnormalities in Alzheimer's Disease].}, journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition}, volume = {55}, number = {6}, pages = {1364-1370}, pmid = {39990823}, issn = {1672-173X}, mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; *Magnetic Resonance Imaging/methods ; *Amyloid beta-Peptides/metabolism ; Brain/diagnostic imaging ; }, abstract = {Amyloid-related imaging abnormalities (ARIA), intracranial signal abnormalities observed in magnetic resonance imaging (MRI), represent one of the main adverse events associated with treating Alzheimer's disease (AD) with anti-amyloid-β (anti-Aβ) monoclonal antibodies. In severe cases, patients' lives may be threatened. As the first anti-Aβ antibody was approved for use in China, clinical departments are now confronted with an increased likelihood of encountering ARIA in real-world scenarios. Accurate pre-treatment risk assessment, timely identification during medication, and severity evaluation of ARIA are of great significance in guiding clinical decisions. The identification and assessment of ARIA can be conducted from two perspectives-imaging and clinical symptoms. This article focuses on imaging. We reviewed the pathophysiological mechanisms, epidemiological and clinical characteristics, and imaging protocols and assessment of ARIA. We also stated at the end of the review that most current research data on ARIA came from clinical drug trials involving Caucasian populations, and that there was a lack of treatment experience in the real-world application of anti-Aβ monoclonal antibodies in Chinese populations. Many issues concerning pre-treatment risk assessment still need to be explored. Additionally, whether there are other clinical factors and imaging indicators that can help predict drug risks, and whether using different imaging protocols can help make a difference in patient management in the real world all require further investigation.}, }
@article {pmid39990115, year = {2024}, author = {Yang, F and Chen, LS and Oveisgharan, S and Darbar, D and Bennett, DA}, title = {INTEGRATING MENDELIAN RANDOMIZATION WITH CAUSAL MEDIATION ANALYSES FOR CHARACTERIZING DIRECT AND INDIRECT EXPOSURE-TO-OUTCOME EFFECTS.}, journal = {The annals of applied statistics}, volume = {18}, number = {3}, pages = {2656-2677}, pmid = {39990115}, issn = {1932-6157}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; U01 MH139345/MH/NIMH NIH HHS/United States ; R01 GM154421/GM/NIGMS NIH HHS/United States ; T32 HL139439/HL/NHLBI NIH HHS/United States ; R01 GM108711/GM/NIGMS NIH HHS/United States ; R01 HL138737/HL/NHLBI NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; }, abstract = {Mendelian randomization (MR) assesses the total effect of exposure on outcome. With the rapidly increasing availability of summary statistics from genome-wide association studies (GWASs), MR leverages existing summary statistics and is widely used to study the causal effects among complex traits and diseases. The total effect in the population is a sum of indirect and direct effects. For complex disease outcomes with complicated etiologies, and/or for modifiable exposure traits, there may exist more than one pathway between exposure and outcome. The direct effect and the indirect effect via a mediator of interest could be of opposite directions, and the total effect estimates may not be informative for treatment and prevention decision-making or may be even misleading for different subgroups of patients. Causal mediation analysis delineates the indirect effect of exposure on outcome operating through the mediator and the direct effect transmitted through other mechanisms. However, causal mediation analysis often requires individual-level data measured on exposure, outcome, mediator and confounding variables, and the power of the mediation analysis is restricted by sample size. In this work, motivated by a study of the effects of atrial fibrillation (AF) on Alzheimer's dementia, we propose a framework for Integrative Mendelian randomization and Mediation Analysis (IMMA). The proposed method integrates the total effect estimates from MR analyses based on large-scale GWASs with the direct and indirect effect estimates from mediation analysis based on individual-level data of a limited sample size. We introduce a series of IMMA models, under the scenarios with or without exposure-mediator interaction and/or study heterogeneity. The proposed IMMA models improve the estimation and the power of inference on the direct and indirect effects in the population, as well as the characterization of the variation of effects. Our analyses showed a significant positive direct effect of AF on Alzheimer's dementia risk not through the use of the oral anticoagulant treatment and a significant indirect effect of AF-induced anticoagulant treatment in reducing Alzheimer's dementia risk. The results suggested potential Alzheimer's dementia risk prediction and prevention strategies for AF patients, and paved the way for future re-evaluation of anticoagulant treatment guidelines for AF patients. A sensitivity analysis was conducted to assess the sensitivity of the conclusions to a key assumption of the IMMA approach.}, }
@article {pmid39989768, year = {2025}, author = {Reddi Sree, R and Kalyan, M and Anand, N and Mani, S and Gorantla, VR and Sakharkar, MK and Song, BJ and Chidambaram, SB}, title = {Newer Therapeutic Approaches in Treating Alzheimer's Disease: A Comprehensive Review.}, journal = {ACS omega}, volume = {10}, number = {6}, pages = {5148-5171}, pmid = {39989768}, issn = {2470-1343}, abstract = {Alzheimer's disease (AD) is an aging-related irreversible neurodegenerative disease affecting mostly the elderly population. The main pathological features of AD are the extracellular Aβ plaques generated by APP cleavage through the amyloidogenic pathway, the intracellular neurofibrillary tangles (NFT) resulting from the hyperphosphorylated tau proteins, and cholinergic neurodegeneration. However, the actual causes of AD are unknown, but several studies suggest hereditary mutations in PSEN1 and -2, APOE4, APP, and the TAU genes are the major perpetrators. In order to understand the etiology and pathogenesis of AD, various hypotheses are proposed. These include the following hypotheses: amyloid accumulation, tauopathy, inflammation, oxidative stress, mitochondrial dysfunction, glutamate/excitotoxicity, cholinergic deficiency, and gut dysbiosis. Currently approved therapeutic interventions are donepezil, galantamine, and rivastigmine, which are cholinesterase inhibitors (ChEIs), and memantine, which is an N-methyl-d-aspartate (NMDA) antagonist. These treatment strategies focus on only symptomatic management of AD by attenuating symptoms but not regeneration of neurons or clearance of Aβ plaques and hyperphosphorylated Tau. This review focuses on the pathophysiology, novel therapeutic targets, and disease-altering treatments such as α-secretase modulators, active immunotherapy, passive immunotherapy, natural antioxidant products, nanomaterials, antiamyloid therapy, tau aggregation inhibitors, transplantation of fecal microbiota or stem cells, and microtubule stabilizers that are in clinical trials or still under investigation.}, }
@article {pmid39989718, year = {2025}, author = {Tang, Y and Zhang, Y and Chen, C and Cao, Y and Wang, Q and Tang, C}, title = {Gut microbiota: A new window for the prevention and treatment of neuropsychiatric disease.}, journal = {Journal of central nervous system disease}, volume = {17}, number = {}, pages = {11795735251322450}, pmid = {39989718}, issn = {1179-5735}, abstract = {Under normal physiological conditions, gut microbiota and host mutually coexist. They play key roles in maintaining intestinal barrier integrity, absorption, and metabolism, as well as promoting the development of the central nervous system (CNS) and emotional regulation. The dysregulation of gut microbiota homeostasis has attracted significant research interest, specifically in its impact on neurological and psychiatric disorders. Recent studies have highlighted the important role of the gut- brain axis in conditions including Alzheimer's Disease (AD), Parkinson's Disease (PD), and depression. This review aims to elucidate the regulatory mechanisms by which gut microbiota affect the progression of CNS disorders via the gut-brain axis. Additionally, we discuss the current research landscape, identify gaps, and propose future directions for microbial interventions against these diseases. Finally, we provide a theoretical reference for clinical treatment strategies and drug development for AD, PD, and depression.}, }
@article {pmid39989313, year = {2025}, author = {de Oliveira Só, YA and Costa, CVS and Camargo, LC and Veras, LG and Júnior, LAR and Mortari, MR and Gargano, R}, title = {Evaluation of the Ability of Wasp Venom Bioinspired Peptides (Fraternine-10 and Octovespin) in the Disaggregation and Anti-Aggregation of Amyloid-β Fibrils.}, journal = {Proteins}, volume = {}, number = {}, pages = {}, doi = {10.1002/prot.26806}, pmid = {39989313}, issn = {1097-0134}, support = {//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; //Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Fundação de Apoio à Pesquisa do Distrito Federal/ ; }, abstract = {Many neurodegenerative diseases are directly related to the formation of toxic protein aggregates, such as Alzheimer's disease, which is associated with the aggregation of amyloid-beta (Aβ). In this context, protein fibrils are the hallmark of these neurodegenerative diseases. In this sense, developing compounds capable of preventing or reducing the formation of protein aggregation in the brain can be of fundamental importance for the curative treatment of these diseases. Animals' venom compounds are known to be selected for nervous system targets, therefore, they are considered an interesting platform for developing pharmacological tools. This work presents a study of the ligands Octovespin (bioinspired by the wasp venom Polybia occidentalis) and Fraternine-10 (bioinspired by the wasp venom Parachartergus fraternus) concerning the disaggregation and anti-aggregation of fibrils of Aβ(17-42) sheets. First, we performed in silico calculations using molecular docking and molecular dynamics simulations with 200 ns. The results indicate that Octovespin and Fraternine-10 interact with the Aβ protein fibrils throughout all simulation time. The RMSD, RMSF, number of hydrogen and radius of gyration values and the interactions with amino acids responsible for fibril aggregation demonstrate that both Octovespin and Fraternine-10 have a significant disaggregation potential, which corroborates the in vitro and in vivo experimental observations. Furthermore, experimental data of Fraternine-10 demonstrated an anti-aggregation effect, indicating that it can promote fibril disaggregation and prevent them from aggregating again to form oligomers. However, in vivo data of Fraternine-10 did not show improvement. Even though in vivo results were not promising, the in vitro and in silico discoveries qualify these molecules as potential sources for developing new candidates to become medicines against Alzheimer's disease.}, }
@article {pmid39989154, year = {2025}, author = {Yu, D and Zhang, H and Du, X and Ren, J and Qu, X}, title = {Hydrogen-Bonded Organic Framework-Based NIR-II Activated Hydrogen Production for Treatment of Alzheimer's Disease Model Mice.}, journal = {Small (Weinheim an der Bergstrasse, Germany)}, volume = {21}, number = {13}, pages = {e2410063}, doi = {10.1002/smll.202410063}, pmid = {39989154}, issn = {1613-6829}, support = {2019YFA0709202//National Key R&D Program of China/ ; 2021YFF120070//National Key R&D Program of China/ ; 22437006//Natural Science Foundation of China/ ; 22237006//Natural Science Foundation of China/ ; 22407021//Natural Science Foundation of China/ ; 2023M740406//China Postdoctoral Science Foundation/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Hydrogen/chemistry ; *Disease Models, Animal ; Mice ; *Hydrogen Bonding ; Infrared Rays ; Porphyrins/chemistry ; Metal-Organic Frameworks/chemistry ; }, abstract = {Oxidative stress is the crucial pathologic factor for causing neuron death and cognitive impairment in the progression of Alzheimer's disease (AD). As a special antioxidant, molecular hydrogen (H2) is responsible for alleviating oxidative stress and associated inflammatory symptoms. However, in vivo continuous and efficient hydrogen accumulation is rather difficult to realize, thus frequent dosing is required to ensure the desired therapeutic effect. Herein, hydrogen-bonded organic frameworks (HOFs) composites are rationally designed to achieve sustainable near-infrared II (NIR-II) photocatalytic hydrogen evolution reaction for relieving neuroinflammation in AD model mice. The HOFs composites mainly consist of three parts: building block porphyrin as the photocatalyst, DSM (NIR-II-absorbing pyridinium hemicyanine dye) as fluorescent emitter, and platinum nanoparticles as co-catalyst. Under NIR-II laser illumination, DSM acts as an energy transducer to activate porphyrin to produce reductive hydrogen in situ. Specially, porphyrin selectively binds with the accumulated Cu ions in Aβ plaques and boosts H2 evolution. KLVFFAED (KD8) is covalently grafted on the HOFs to improve the blood-brain barrier permeability in vivo. This designed system exhibits an admirable therapeutic effect for relieving inflammation and recovering cognitive disorder in AD model mice, thus providing a new way for exploring HOFs used for sustainable hydrogen therapy.}, }
@article {pmid39988989, year = {2025}, author = {Grill, JD and Raman, R and Flournoy, C and Ernstrom, K and Pierce, A and Smith, A and Rosenberg, P and Burns, J and Karlawish, J and Aisen, P and Holdridge, KC and Mancini, M and Sperling, R and Sultzer, D and , }, title = {Disclosure of elevated amyloid status is not associated with long-term suicidality in a preclinical AD trial.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14623}, pmid = {39988989}, issn = {1552-5279}, support = {R01AG063689/AG/NIA NIH HHS/United States ; U24 AG057437/AG/NIA NIH HHS/United States ; U19 AG010483/AG/NIA NIH HHS/United States ; U19AG010483/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; //Eli Lilly/ ; U24AG057437/AG/NIA NIH HHS/United States ; R01 AG063689/AG/NIA NIH HHS/United States ; LEARN NIRG-12-243012//the Alzheimer's Association/ ; NIA P30-AG066519//GHR Foundation/ ; }, mesh = {Humans ; Female ; *Alzheimer Disease ; Male ; Aged ; *Biomarkers ; Disclosure ; Suicidal Ideation ; Positron-Emission Tomography ; Cohort Studies ; Amyloid/metabolism ; Suicide/psychology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Amyloid beta-Peptides/metabolism ; }, abstract = {INTRODUCTION: The long-term implications of disclosing Alzheimer's disease (AD) biomarker information to cognitively unimpaired individuals are unknown.
METHODS: We compared participants who disclosed their elevated amyloid imaging result in a preclinical AD trial to those who disclosed a not elevated result and enrolled in an observational cohort that underwent parallel assessments. Our primary outcome was a score > 0 on the Columbia Suicidality Severity Rating Scale (CSSRS) at any visit; we also considered suicidal behaviors (CSSRS > 5).
RESULTS: Among 1707 total participants (68% elevated amyloid, mean [standard deviation] age 71.5 [4.7], 60% female, 90% non-Hispanic White), followed for a mean 218 (74.1) weeks, there were no suicides and few indications of suicidal thoughts (n = 124 [7%]) or behaviors (n = 13 [<1%]). In a generalized estimating equation model controlling for covariates, we observed no effect of amyloid status on the primary outcome of CSSRS > 0 (odds ratio = 1.6, 95% confidence interval = 0.76, 3.37).
DISCUSSION: With a structured approach, brain amyloid results can be returned safely.
HIGHLIGHTS: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's study was among the first and largest studies to include biomarker disclosure in a population without cognitive impairment. Routine psychological assessment provided a novel assessment of the impact of disclosure in this sample. Learning an elevated brain amyloid result through a protocolized approach was not associated with suicidal thoughts or behaviors compared to a matched cohort who learned they did not have elevated brain amyloid. Future research will be needed to ensure similar safety in more real-world settings.}, }
@article {pmid39988952, year = {2025}, author = {Dittrich, A and Blennow, K and Tan, K and Benedet, AL and Skoog, I and Höglund, K and Ashton, NJ and Zetterberg, H and Kern, S}, title = {Evaluation of two plasma-based proteotyping assays against APOE ε4 genotyping in a memory clinic setting: The Gothenburg H70 Clinical Studies.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14610}, pmid = {39988952}, issn = {1552-5279}, support = {#FO2017-0243//Hjärnfonden/ ; #ALZ2022-0006//Hjärnfonden/ ; FO2024-0097//Hjärnfonden/ ; #ALFGBG-715986//Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement/ ; #ALFGBG-965240//Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement/ ; JPND2019-466-236//European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//Alzheimer's Association 2021 Zenith Award/ ; SG-23-1038904 QC/ALZ/Alzheimer's Association/United States ; //La Fondation Recherche Alzheimer/ ; //Paris, France/ ; //Kirsten and Freddy Johansen Foundation, Copenhagen, Denmark/ ; //Familjen Rönströms Stiftelse/ ; //Stockholm, Sweden/ ; #AF-930351//Swedish Alzheimer Foundation/ ; #AF-939721//Swedish Alzheimer Foundation/ ; #AF-968270//Swedish Alzheimer Foundation/ ; #AF-994551//Swedish Alzheimer Foundation/ ; #AF-940262//Swedish Alzheimer Foundation/ ; //Stiftelsen för Gamla Tjänarinnor/ ; #AARFD-22-974564//Alzheimer's Association Research Fellowship/ ; ALF965812//Swedish government and the county councils, the ALF-agreement/ ; ALF 716681//Swedish government and the county councils, the ALF-agreement/ ; #2023-00356//Swedish Research Council/ ; 2019-02075//Swedish Research Council/ ; 2015-02830//Swedish Research Council/ ; 2013-8717//Swedish Research Council/ ; 2017-00639//Swedish Research Council/ ; 2019-01096//Swedish Research Council/ ; 2022-00882//Swedish Research Council/ ; #2023-00356//Swedish Research Council/ ; 2019-02075//Swedish Research Council/ ; 2015-02830//Swedish Research Council/ ; 2013-8717//Swedish Research Council/ ; 2017-00639//Swedish Research Council/ ; 2019-01096//Swedish Research Council/ ; 2022-00882//Swedish Research Council/ ; #2023-00356//Swedish Research Council/ ; 2019-02075//Swedish Research Council/ ; #2022-01018//Swedish Research Council/ ; #2019-02397//Swedish Research Council/ ; #2023-00356//Swedish Research Council/ ; 2019-02075//Swedish Research Council/ ; 2019-02075_15//Swedish Research Council/ ; 2013-1202//Swedish Research Council for Health, Working Life and Wellfare/ ; 2018-00471//Swedish Research Council for Health, Working Life and Wellfare/ ; AGECAP 2013-2300//Swedish Research Council for Health, Working Life and Wellfare/ ; 2013-2496//Swedish Research Council for Health, Working Life and Wellfare/ ; 2018-00471//Swedish Research Council for Health, Working Life and Wellfare/ ; FO2014-0207//Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; FO2016-0214//Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; FO2018-0214//Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; FO2019-0163//Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; FO2020-0235//Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; FO2024-0341-HK-76//Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; AF-554461//Alzheimerfonden/ ; AF-647651//Alzheimerfonden/ ; AF-743701//Alzheimerfonden/ ; AF-844671//Alzheimerfonden/ ; AF-930868//Alzheimerfonden/ ; AF-940139//Alzheimerfonden/ ; AF-968441//Alzheimerfonden/ ; AF-980935//Alzheimerfonden/ ; //Swedish Research/ ; No 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #ADSF-21-831376-C//AD Strategic Fund and the/ ; #ADSF-21-831381-C//AD Strategic Fund and the/ ; #ADSF-21-831377-C//AD Strategic Fund and the/ ; #ADSF-24-1284328-C//AD Strategic Fund and the/ ; //European Partnership on Metrology/ ; //European Union's Horizon Europe Research/ ; NEuroBioStand #22HLT07//Innovation Programme and by the Participating States/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Olav Thon Foundation, the Erling-Persson Family Foundation/ ; #FO2022-0270//Hjärnfonden, Sweden/ ; //European Union's Horizon 2020/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute/ ; ALFGBG-1005471//UK Dementia Research Institute/ ; ALFGBG-965923//UK Dementia Research Institute/ ; ALFGBG-81392//UK Dementia Research Institute/ ; ALF GBG-771071//UK Dementia Research Institute/ ; AF-842471//UK Dementia Research Institute/ ; AF-737641//UK Dementia Research Institute/ ; AF-929959//UK Dementia Research Institute/ ; AF-939825//UK Dementia Research Institute/ ; //Stiftelsen Psykiatriska Forskningsfonden/ ; //UCLH Biomedical Research Centre/ ; 860197//H2020 Marie Skłodowska-Curie Actions/ ; //Familjen Erling-Perssons Stiftelse/ ; //Olav Thon Stiftelsen/ ; 201809-2016862//Alzheimer's Drug Discovery Foundation/ ; 2013-1202//Forskningsrådet om Hälsa, Arbetsliv och Välfärd/ ; 2018-00471//Forskningsrådet om Hälsa, Arbetsliv och Välfärd/ ; AGECAP 2013-2300//Forskningsrådet om Hälsa, Arbetsliv och Välfärd/ ; 2013-2496//Forskningsrådet om Hälsa, Arbetsliv och Välfärd/ ; 2018-00471//Forskningsrådet om Hälsa, Arbetsliv och Välfärd/ ; //Kirsten og Freddy Johansens Fond/ ; ALFGBG-984092//Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement/ ; }, mesh = {Humans ; *Apolipoprotein E4/genetics ; Female ; Male ; Aged ; *Genotype ; *Alzheimer Disease/genetics ; *Sensitivity and Specificity ; Middle Aged ; Aged, 80 and over ; Alleles ; Heterozygote ; Homozygote ; }, abstract = {INTRODUCTION: Apolipoprotein E (APOE) ε4 allele status is associated with an increased risk of Alzheimer's disease and should be determined prior to initiation of anti-amyloid beta antibody treatment, because of increased risk of treatment-related side effects. Plasma-based apoE4 proteotyping may be an alternative to genotyping, with limited clinical evidence.
METHODS: apoE4 proteotyping was performed on 164 memory-clinic patients, using one chemiluminescent enzyme immunoassay (CLEIA) and one nucleic acid-linked immunosandwich assay (NULISA). The assays were evaluated against APOE ε4 blood genotyping.
RESULTS: The CLEIA had a 100% sensitivity and 98.5% specificity to classify APOE ε4 homozygosity and carriership in relation to genotyping. The NULISA had a 92.9% sensitivity and 97.1% specificity to classify homozygosity and a 100% sensitivity and 98.5% specificity to classify carriership.
DISCUSSION: The high performance suggests that the assays may be used as an easily available tool for identifying individuals for definitive APOE ε4 genotyping in a two-step approach.
HIGHLIGHTS: Plasma-based proteotyping presented good to excellent sensitivity in identifying apolipoprotein E (APOE) ε4 homozygosity. The negative predictive value was also very good to excellent, allowing us to rule out APOE ε4 homozygosity with high precision. Assays with excellent precision show potential for identifying individuals for definitive APOE ε4 genotyping in a two-step approach.}, }
@article {pmid39988819, year = {2025}, author = {Cornford, N and Charnley, M}, title = {Hericium erinaceus: A possible future therapeutic treatment for the prevention and delayed progression of Alzheimer's disease? - A Narrative Review.}, journal = {Nutrition research reviews}, volume = {}, number = {}, pages = {1-45}, doi = {10.1017/S0954422425000058}, pmid = {39988819}, issn = {1475-2700}, abstract = {At present, the treatment of Alzheimer's disease involves only symptomatic medications which have continually demonstrated little efficacy, primarily due to the presence of biological barriers. Despite efforts, researchers have yet to discover a therapeutic treatment that delays neurodegenerative progression or restores associated Alzheimer neuropathological processes. For centuries, Hericium erinaceus (HE) has been used predominantly in Asian countries for its culinary and medicinal purposes, however, the use of this mushroom has not yet been utilised in western pharmacology. This review systematically investigates evidence pertaining to the use of HE as a potential future therapeutic treatment for the prevention and delayed progression of Alzheimer's disease, by highlighting any fundamental neurotrophic and neuroprotective properties. In total, 3 human clinical trials and 13 animal-model studies were included for review. The use of HE demonstrated positive significant differences in results obtained from behavioural, histological, and biochemical assessments from both human clinical trials and animal model studies accentuating its utility for the improvement of cognitive function. In addition, erinacine A enriched HE appears to demonstrate the highest bioactive potency of all HE extracted compounds providing the greatest effects, while also evidencing transportability ease across biological barriers. In conclusion, evidence suggests that an intake of HE may be an appropriate and relevant future therapeutic treatment for the prevention and delayed progression of Alzheimer's disease, however, continued research is necessary to provide increased significant evidence of this relationship, most likely through the increased quantity of human clinical trials.}, }
@article {pmid39988732, year = {2025}, author = {Tang, Q and Tang, K and Markby, GR and Parys, M and Phadwal, K and MacRae, VE and Corcoran, BM}, title = {Autophagy regulates cellular senescence by mediating the degradation of CDKN1A/p21 and CDKN2A/p16 through SQSTM1/p62-mediated selective autophagy in myxomatous mitral valve degeneration.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-23}, doi = {10.1080/15548627.2025.2469315}, pmid = {39988732}, issn = {1554-8635}, abstract = {Myxomatous mitral valve degeneration (MMVD) is one of the most important age-dependent degenerative heart valve disorders in both humans and dogs. It is characterized by the aberrant remodeling of extracellular matrix (ECM), regulated by senescent myofibroblasts (aVICs) transitioning from quiescent valve interstitial cells (qVICs), primarily under TGFB1/TGF-β1 control. In the present study, we found senescent aVICs exhibited impaired macroautophagy/autophagy as evidenced by compromised autophagy flux and immature autophagosomes. MTOR-dependent autophagy induced by rapamycin and torin-1 attenuated cell senescence and decreased the expression of cyclin-dependent kinase inhibitors (CDKIs) CDKN2A/p16[INK4A] and CDKN1A/p21[CIP1]. Furthermore, induction of autophagy in aVICs by ATG (autophagy related) gene overexpression restored autophagy flux, with a concomitant reduction in CDKN1A and CDKN2A expression and senescence-associated secretory phenotype (SASP). Conversely, autophagy deficiency induced CDKN1A and CDKN2A accumulation and SASP, whereas ATG re-expression alleviated senescent phenotypic transformation. Notably, CDKN1A and CDKN2A localized to autophagosomes and lysosomes following MTOR antagonism or MG132 treatment. SQSTM1/p62 was identified as the autophagy receptor to selectively sequester CDKN1A and CDKN2A cargoes for autophagic degradation. Our findings are the first demonstration that CDKN1A and CDKN2A are degraded through SQSTM1-mediated selective autophagy, independent of the ubiquitin-proteasome pathway. These data will inform development of therapeutic strategies for the treatment of canine and human MMVD, and for the treatment of Alzheimer disease, Parkinson disease and other age-related degenerative disorders.Abbreviations: ACTA2/α-SMA: actin alpha 2, smooth muscle; AKT: AKT serine/threonine kinase; aVICs: activated valve interstitial cells; ATG: autophagy related; baf-A1: bafilomycin A1; BrdU, bromodeoxyuridine; BSA: bovine serum albumin; CDKIs, cyclin-dependent kinase inhibitors; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; co-IP: co-immunoprecipitation; DMSO: dimethylsulfoxide; ECM, extracellular matrix; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; eGFP: green fluorescent protein; ELISA: enzyme-linked immunosorbent assay; HEK-293T, human embryonic kidney 293T; HRP: horseradish peroxidase; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LIR: MAP1LC3/LC3-interacting region; MFS: Marfan syndrome; MKI67/Ki-67: marker of proliferation Ki-67; MMVD: myxomatous mitral valve degeneration; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; OE: overexpression; PBST, phosphate-buffered saline with 0.1% Tween-20; PCNA: proliferating cell nuclear antigen; PIK3CA/PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PLA: proximity ligation assays; PSMA1: proteasome 20S subunit alpha 1; PSMB5: proteasome 20S subunit beta 5; qVICs: quiescent valve interstitial cells; qRT-PCR: quantitative real-time PCR; SA-GLB1/β-gal: SA-senescence-associated GLB1/β-galactosidase; ROS: reactive oxygen species; SASP: senescence-associated secretory phenotype; RPS6KB1/p70 S6K: ribosomal protein S6 kinase B1; SMAD: SMAD family member; SQSTM1/p62: sequestosome 1; STEM: scanning transmission electron microscopy; TGFB: transforming growth factor beta; TGFBR: transforming growth factor beta receptor; TP53/p53: tumor protein p53; UPS: ubiquitin-proteasome system; WT, wild-type.}, }
@article {pmid39988604, year = {2025}, author = {Keller, N and Christensen, TA and Wanberg, EJ and Salisbury, JL and Trushina, E}, title = {Neuroprotective mitochondria targeted small molecule restores synapses and the distribution of synaptic mitochondria in the hippocampus of APP/PS1 mice.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {6528}, pmid = {39988604}, issn = {2045-2322}, support = {RF1AG55549//National Institute for Health Care Management Foundation/ ; R01 NS107265/NS/NINDS NIH HHS/United States ; RO1AG062135//National Institute for Health Care Management Foundation/ ; RF1 AG062135/AG/NIA NIH HHS/United States ; RF1 AG055549/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Synapses/drug effects/metabolism ; *Mitochondria/metabolism/drug effects ; *Hippocampus/metabolism/drug effects ; Mice ; *Alzheimer Disease/metabolism/drug therapy ; *Mice, Transgenic ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Disease Models, Animal ; *Presenilin-1/genetics/metabolism ; Neuroprotective Agents/pharmacology ; Pyrones/pharmacology ; Male ; }, abstract = {Loss of synaptic activity correlates best with cognitive dysfunction in Alzheimer's disease (AD). We have previously shown that mild inhibition of mitochondrial complex I with the small molecule tricyclic pyrone compound CP2 restores long-term potentiation and cognitive function assessed by electrophysiology and behavior tests in multiple mouse models of AD. Using serial block-face scanning electron microscopy and three-dimensional electron microscopy reconstruction, we examined the effect of CP2 treatment on synapses, and the distribution and morphology of synaptic mitochondria in the hippocampus of APP/PS1 mice. Structural data confirmed the loss of synapses in APP/PS1 compared to non-transgenic (NTG) littermates. Mitochondrial distribution assessed in pre- and postsynaptic compartments was significantly altered in AD model demonstrating increased presence of mitochondria around dendritic spines compared to NTG mice, indicating the loss of mitochondrial ability to support synaptic function. CP2 treatment restored distribution of synaptic mitochondria and the number of synapses to the NTG control levels. Improved synaptic function in CP2-treated APP/PS1 mice was supported by RNA-seq analysis indicating upregulation of genes involved in axonal guidance, dendritic maturation and synaptic function, and Western blot analysis of brain tissue. Taken together, functional, imaging, biochemistry and structural findings further support the potential of targeting mitochondria as a therapeutic approach for AD.}, }
@article {pmid39987285, year = {2025}, author = {Fang, M and Zhou, Y and He, K and Lu, Y and Tao, F and Huang, H}, title = {Glucose Metabolic Reprogramming in Microglia: Implications for Neurodegenerative Diseases and Targeted Therapy.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39987285}, issn = {1559-1182}, support = {82204651//National Natural Science Foundation of China/ ; }, abstract = {As intrinsic immune cells in the central nervous system, microglia play a crucial role in maintaining brain homeostasis. Microglia can transition from homeostasis to various responsive states in reaction to different external stimuli, undergoing corresponding alterations in glucose metabolism. In neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), microglial glucose metabolic reprogramming is widespread. This reprogramming leads to changes in microglial function, exacerbating neuroinflammation and the accumulation of pathological products, thereby driving the progression of neurodegeneration. This review summarizes the specific alterations in glucose metabolism within microglia in AD, PD, ALS, and MS, as well as the corresponding treatments aimed at reprogramming glucose metabolism. Compounds that inhibit key glycolytic enzymes like hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2), or activate regulators of energy metabolism such as AMP-activated protein kinase (AMPK), have shown significant potential in the treatment of various neurodegenerative diseases. However, current research faces numerous challenges, including side effects and blood-brain barrier (BBB) penetration of compounds. Screening relevant drugs from natural products, especially flavonoids, is a reliable approach. On the one hand, longtime herbal medical practices provide a certain degree of assurance regarding clinical safety, and their chemical properties contribute to effective BBB permeability. On the other hand, the concurrent anti-tumor and anti-neuroinflammatory activities of flavonoids suggest that regulation of glucose metabolism reprogramming might be a potential common mechanism of action. Notably, considering the dynamic nature of microglial metabolism, there is an urgent need to develop technologies for real-time monitoring of glucose metabolism processes, which would significantly advance research in this field.}, }
@article {pmid39986222, year = {2025}, author = {Zeng, Y and Yang, S and Xie, Z and Li, Q and Wang, Y and Xiong, Q and Liang, X and Lu, H and Cheng, W}, title = {Tianqi Yizhi Granule alleviates cognitive dysfunction and neurodegeneration in SAMP8 mice via the PKC/ERK pathway.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {139}, number = {}, pages = {156542}, doi = {10.1016/j.phymed.2025.156542}, pmid = {39986222}, issn = {1618-095X}, mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology ; *Neuroprotective Agents/pharmacology ; Mice ; *Cognitive Dysfunction/drug therapy ; *Protein Kinase C/metabolism ; *Alzheimer Disease/drug therapy ; Male ; *Amyloid beta-Peptides/metabolism ; MAP Kinase Signaling System/drug effects ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Network Pharmacology ; Disease Models, Animal ; Cell Line ; Neurons/drug effects ; }, abstract = {BACKGROUND: Given the lack of satisfactory clinical treatments for Alzheimer's disease (AD), a neurodegenerative condition detrimental to health, developing alternative therapies is critical. Tianqi Yizhi Granule (TQYZ) is a preparation used to treat AD based on traditional Chinese medicine theory, the latent mechanisms of which await elucidation.
PURPOSE: This study sought to investigate the neuroprotective properties of TQYZ while exploring its potential therapeutic mechanisms using network pharmacology analyses and experimental validation.
METHODS: Network pharmacology analyses were performed. Cognitive and neurodegenerative alterations were evaluated through behavioral tests and histological staining. For in vivo and in vitro experiments, short hairpin RNA sequences were transfected via adeno-associated virus vectors to verify the predicted mechanism.
RESULTS: A total of 159 potential therapeutic targets of TQYZ overlapped with AD-related targets. In senescence-accelerated mouse prone 8 (SAMP8) mice, treatment with TQYZ significantly improved cognitive function, ameliorated neuronal damage and apoptosis, and upregulated the protein expression of PKC/ERK pathway members. TQYZ maintained the mitochondrial membrane potential, reduced the generation of reactive oxygen species, and inhibited neuronal apoptosis in Aβ25-35-induced HT22 cells. However, these neuroprotective effects were notably reduced in shRNA PRKCB-transfected HT22 cells and SAMP8 mice.
CONCLUSIONS: TQYZ mitigates the pathological degeneration process and cognitive impairment in SAMP8 mice and suppresses mitochondrial dysfunction and apoptosis in HT22 cells treated with Aβ25-35. Its neuroprotective mechanism is linked to PKC/ERK pathway activation. This study highlights a promising strategy for AD therapy.}, }
@article {pmid39986219, year = {2025}, author = {Lyu, L and Qin, X and Xiu, H and Qu, Y and Wang, Y and Yang, X and Dang, W and Kebreab, E}, title = {Neddylation inhibition affects cell proliferation and steroidogenesis in sheep follicular granulosa cells.}, journal = {Theriogenology}, volume = {237}, number = {}, pages = {99-109}, doi = {10.1016/j.theriogenology.2025.02.020}, pmid = {39986219}, issn = {1879-3231}, mesh = {Animals ; Female ; Sheep ; *Pyrimidines/pharmacology ; *NEDD8 Protein/metabolism/genetics ; *Cell Proliferation/drug effects ; *Granulosa Cells/drug effects/metabolism ; *Cyclopentanes/pharmacology ; RNA, Small Interfering/pharmacology ; Steroids/biosynthesis ; }, abstract = {Neddylation is a biological process that covalently links neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8) to its substrate. Its main function is to activate the cullin ubiquitin junction complex, thereby promoting substrate protein degradation. The research of neddylation mainly focus on cell senescence, Alzheimer's disease progression, and tumor treatment. However, the neddylation mechanism underlying follicular granulosa cells (GCs) proliferation and steroidogenesis remains unclear. Therefore, this study aimed to reveal the functions of neddylation in sheep follicular GCs. Here, immunohistochemistry results revealed that NEDD8 was expressed in sheep follicular GCs. The neddylation-specific inhibitor MLN4924 and NEDD8 small interfering (si) RNA (si-NEDD8) were used to inhibit neddylation, significantly attenuating sheep follicular GC proliferation. The RNA sequencing (RNA-Seq) showed that cytochrome P450 11A1 (CYP11A1) and steroidogenic acute regulator (StAR) were significantly downregulated via the inhibition of neddylation. Additionally, qRT-PCR results showed that CYP11A1, StAR and 3β-hydroxysteroid dehydrogenase (3β-HSD) mRNA abundance decreased significantly following the addition of various MLN4924 doses and si-NEDD8, however, CYP19A1 mRNA levels did not significantly differ. Western blotting results showed that inhibition of neddylation also significantly decreased the expression of CYP11A1, 3β-HSD, cytochrome P450 19A1 (CYP19A1), StAR, and androgen receptor (AR). The current study revealed that the inhibition of neddylation affects sheep follicular GC function by inhibiting proliferation and the enzymes involved in synthesis in sheep.}, }
@article {pmid39985481, year = {2025}, author = {Feng, Y and Cao, SQ and Shi, Y and Sun, A and Flanagan, ME and Leverenz, JB and Pieper, AA and Jung, JU and Cummings, J and Fang, EF and Zhang, P and Cheng, F}, title = {Human herpesvirus-associated transposable element activation in human aging brains with Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14595}, pmid = {39985481}, issn = {1552-5279}, support = {R25 AG083721/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; RF1 NS133812/NS/NINDS NIH HHS/United States ; R56AG074001/AG/NIA NIH HHS/United States ; 3R01AG066707-02S1/AG/NIA NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; R35AG071476/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; P50 AG025711/AG/NIA NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; 269901//Akershus University Hospital/ ; NINDS RO1NS139383/GM/NIGMS NIH HHS/United States ; 3R01AG066707-01S1/AG/NIA NIH HHS/United States ; R21 AG083003/AG/NIA NIH HHS/United States ; P30 AG062428/AG/NIA NIH HHS/United States ; R01AG076448/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; 262960//Akershus University Hospital/ ; NIA R25AG083721-01/GM/NIGMS NIH HHS/United States ; 262175 334361//Research Council of Norway/ ; 282952//Cure Alzheimer's Fund/ ; R01 AG082118/AG/NIA NIH HHS/United States ; R21AG083003/AG/NIA NIH HHS/United States ; U01AG073323/AG/NIA NIH HHS/United States ; R56 AG074001/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; 207819//Rosa sløyfe/Norwegian Cancer Society & Norwegian Breast Cancer Society/ ; RF1 AG082211/AG/NIA NIH HHS/United States ; RF1AG082211/AG/NIA NIH HHS/United States ; 282942//Molecule AG/VITADAO/ ; U01 AG061356/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; R01AG082118/AG/NIA NIH HHS/United States ; R01 AG030146/AG/NIA NIH HHS/United States ; U01 AG046170/AG/NIA NIH HHS/United States ; RF1NS133812/NS/NINDS NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; P30AG072959/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; R01 NS139383/NS/NINDS NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; R01 AG076448/AG/NIA NIH HHS/United States ; P20GM109025/GM/NIGMS NIH HHS/United States ; 119986//NordForsk Foundation/ ; TO01000215//Czech Republic-Norway KAPPA programme/ ; P20 GM109025/GM/NIGMS NIH HHS/United States ; R01AG066707/AG/NIA NIH HHS/United States ; 261973//Akershus University Hospital/ ; R01AG084250/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; NIA R35AG71476/GM/NIGMS NIH HHS/United States ; 281931//Civitan Norges Forskningsfond for Alzheimers sykdom/ ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 AG036836/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/virology/pathology ; *Brain/pathology/virology ; Aging/genetics ; DNA Transposable Elements/genetics ; Male ; Female ; Herpesviridae Infections/genetics/complications ; Herpesviridae/genetics ; Aged ; Long Interspersed Nucleotide Elements/genetics ; }, abstract = {INTRODUCTION: Human herpesvirus (HHV) has been linked to Alzheimer's disease (AD), but the underlying mechanisms remain unknown.
METHODS: We leveraged functional genomics data from Religious Orders Study or the Rush Memory and Aging Project (ROS/MAP) and Mount Sinai Brain Bank (MSBB) brain biobanks and single-cell RNA-sequencing data from HHV-infected forebrain organoids to investigate HHV-infection-associated transposable element (TE) dysregulation underlying AD etiologies.
RESULTS: We identified widespread TE dysregulation in HHV-positive human AD brains, including an astrocyte-specific upregulation of LINE1 subfamily TEs in HHV-positive human AD brains. We further pinpointed astrocyte-specific LINE1 upregulation that could potentially regulate target gene NEAT1 expression via long-range enhancer-promoter chromatin interactions. This LINE1 dysregulation can be partially reversed by the usage of anti-HHV drugs (valacyclovir and acyclovir) in a virus-infected human brain organoid model. Finally, we demonstrated that valacyclovir rescued tau-associated neuropathology and alleviated LINE1 activation in an experimental tau aggregation model.
DISCUSSION: Our analysis provides associations linking molecular, clinical, and neuropathological AD features with HHV infection, which warrants future clinical validation.
HIGHLIGHTS: Via analysis of bulk RNA-seq data in two large-scale human brain biobanks, ROS/MAP (n = 109 pathologically confirmed AD and n = 44 cognitively healthy controls) and MSBB (n = 284 AD and n = 150 cognitively healthy controls), we identified widespread TE activation in HHV-positive human AD brains and significantly positive associations of HHV RNA abundance with APOE4 genotype, Braak staging score, and CERAD score. We identified cell type-specific LINE1 upregulation in both microglia and astrocytes of human AD brains via long-range enhancer-promoter chromatin interactions on lncRNA nuclear enriched abundant transcript 1 (NEAT1). We determined that usage of valacyclovir and acyclovir was significantly associated with reduced incidence of AD in a large real-world patient database. Using the HEK293 tau P301S model and U2OS mt-Keima cell model, we determined that valacyclovir treatment rescued tau-associated neuropathology and alleviated activation of LINE1 with increased cellular autophagy-level mechanistically supported clinical benefits of valacyclovir in real-world patient data.}, }
@article {pmid39985292, year = {2025}, author = {Tripathi, R and Kumar, P}, title = {Identification of CXCR4 inhibitory activity in natural compounds using cheminformatics-guided machine learning algorithms.}, journal = {Integrative biology : quantitative biosciences from nano to macro}, volume = {17}, number = {}, pages = {}, doi = {10.1093/intbio/zyaf004}, pmid = {39985292}, issn = {1757-9708}, mesh = {*Receptors, CXCR4/metabolism/antagonists & inhibitors ; Humans ; *Machine Learning ; *Alzheimer Disease/drug therapy/metabolism ; *Cheminformatics/methods ; *Biological Products/pharmacology/chemistry ; *Algorithms ; *Parkinson Disease/drug therapy/metabolism/genetics ; *Drug Discovery ; Neuroprotective Agents/pharmacology ; }, abstract = {Neurodegenerative disorders are characterised by progressive damage to neurons that leads to cognitive impairment and motor dysfunction. Current treatment options focus only on symptom management and palliative care, without addressing their root cause. In our previous study, we reported the upregulation of the CXC motif chemokine receptor 4 (CXCR4), in Alzheimer's disease (ad) and Parkinson's disease (PD). We reached this conclusion by analysing gene expression patterns of ad and PD patients, compared to healthy individuals of similar age. We used RNA sequencing data from Gene Expression Omnibus to carry out this analysis. Herein, we aim to identify natural compounds that have potential inhibitory activity against CXCR4 through cheminformatics-guided machine learning, to aid drug discovery for neurodegenerative disorders, especially ad and PD. Natural compounds are gaining prominence in the treatment of neurodegenerative disorders due to their biocompatibility and potential neuroprotective properties, including their ability to modulate CXCR4 expression. Recent advances in artificial intelligence (AI) and machine learning (ML) algorithms have opened new avenues for drug discovery research across various therapeutic areas, including neurodegenerative disorders. We aim to produce an ML model using cheminformatics-guided machine learning algorithms using data of compounds with known CXCR4 activity, retrieved from the Binding Database, to analyse various physicochemical attributes of natural compounds obtained from the COCONUT Database and predict their inhibitory activity against CXCR4. Insight Box This work extends our previous study published in Integrative Biology (DOI: 10.1093/intbio/zyad012). We aim to demonstrate the effectiveness of AI and ML in identifying potential treatment options for Alzheimer's and Parkinson's diseases. By analysing vast amounts of data and identifying patterns that may not be apparent to human researchers, AI-powered systems can provide valuable insight into potential treatment options that may have been overlooked through traditional research methods. Our study underscores the significance of interdisciplinary collaboration between computational and experimental scientists in drug discovery and in developing a robust pipeline to identify potential leads for drug development.}, }
@article {pmid39983843, year = {2025}, author = {Arredouani, A}, title = {GLP-1 receptor agonists, are we witnessing the emergence of a paradigm shift for neuro-cardio-metabolic disorders?.}, journal = {Pharmacology & therapeutics}, volume = {269}, number = {}, pages = {108824}, doi = {10.1016/j.pharmthera.2025.108824}, pmid = {39983843}, issn = {1879-016X}, abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as groundbreaking therapeutic agents in managing a spectrum of metabolic disorders, demonstrating remarkable efficacy across multiple organ systems and disease states. These compounds are not only well-established in the treatment of type 2 diabetes (T2D) and obesity-conditions for which they have received widespread approval-but also exhibit promising potential in addressing cardiovascular disease (CVD) and Metabolic dysfunction-associated steatotic liver disease (MASLD). Recent investigations have begun to illuminate the utility of GLP-1RAs in the management of type 1 diabetes (T1D), as well as neurodegenerative disorders such as Alzheimer's and Parkinson's disease and various behavioral disorders. A plethora of clinical trials have consistently validated the capacity of GLP-1RAs to improve glycemic control, promote weight loss, and mitigate cardiovascular risk factors in individuals with T2D and obesity. While their application in T1D remains limited due to safety concerns-particularly regarding the risks of hypoglycemia and hyperglycemic ketoacidosis-emerging data suggest that GLP-1RAs may offer hepatoprotective benefits, potentially reducing liver fat content and decelerating the progression of MASLD. The neuroprotective attributes of GLP-1 RAs have garnered significant interest, with research indicating their potential to alleviate cognitive decline associated with neurodegenerative diseases. Furthermore, preliminary findings highlight the role of GLP-1 RAs in addressing behavioral disorders, emphasizing their extensive therapeutic promise. This comprehensive review synthesizes the current evidence supporting the diverse therapeutic applications of GLP-1RAs, positioning them as "magic drug" therapies for metabolic and neurological disorders. As ongoing research continues to explore innovative applications and combinations of GLP-1RAs, the landscape of disease management in metabolic and neurological contexts is poised for transformative advancements. This review will also critically assess safety considerations and underscore the need for personalized treatment strategies to optimize patient outcomes in these complex and often comorbid conditions.}, }
@article {pmid39983830, year = {2025}, author = {Qi, Z and Cao, J and Liu, J and Chen, J and Chen, S and Zhang, L and Xu, J and Wu, D and Wu, Y and Li, G}, title = {Toxicological mechanisms of carbon polymers in accelerating cognitive decline in Alzheimer's disease.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2025.02.017}, pmid = {39983830}, issn = {2090-1224}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is the primary cause of dementia and is emerging as a global threat to human health. Increased availability of processed food is identified as a crucial dietary risk factor underlying the prevalence of Alzheimer's disease. Carbon polymers (CPs), as neo-formed substances and ubiquitous in thermally processed foods, the relationship between them and AD onset remains unclear.
OBJECTIVES: The effect of CPs on AD onset was examined and the toxicological mechanisms of prolonged exposure to CPs derived from thermal processed foods on AD progression were comprehensively investigated using a scopolamine-induced neuroinflammatory cell models and the transgenic APPswe/PSEN1dE9 (APP/PS1) AD mouse.
METHODS: The CPs were extracted from thermally processed foods and the effects of CPs exposure on oxidative stress in neuroinflammatory cells were evaluated using scopolamine-induced PC12 cells as a neuroinflammation model. Furthermore, APP/PS1 AD mice were used to validate the potential adverse impacts of prolonged exposure to CPs on AD progression through the Morris water maze and open field test. In addition, histopathological examination, including immunofluorescence, immunohistochemistry, Nissl staining, and H&E, of the brain tissue in AD mice after chronic CPs treatment was performed to elucidate the underlying risk of dietary exposure to CPs on AD progression.
RESULTS: Exposure to CPs enhanced oxidative damage in neuroinflammatory cells, as demonstrated by impaired mitochondrial function and activated NF-κB/MAPK signaling pathways. Further results from electron spin resonance substantiated the catalytic properties of CPs, which accelerated oxidative damage through promoting free radical generation. Using transgenic AD mice model, our findings also demonstrated that prolonged CPs exposure aggravated AD-associated pathology, as evidenced by increased amyloid-beta deposition and glial cell activation, ultimately accelerating cognitive decline.
CONCLUSION: These findings provide compelling evidence of the potential health risks associated with long-term dietary exposure to CPs and provide insight into the relationship between foodborne risk factors and neurodegenerative diseases.}, }
@article {pmid39983826, year = {2025}, author = {Sun, M and Cai, X and Lan, Z and Liu, M and Zhou, M and Tang, Y and Liu, Y and Zhang, X and Zhao, X and Zhou, Y and Zhang, J and Meng, Z}, title = {The lysosomal-associated membrane protein 2-macroautophagy pathway is involved in the regulatory effects of hippocampal aromatase on Aβ accumulation and AD-like behavior.}, journal = {Life sciences}, volume = {366-367}, number = {}, pages = {123484}, doi = {10.1016/j.lfs.2025.123484}, pmid = {39983826}, issn = {1879-0631}, mesh = {Animals ; *Aromatase/metabolism/genetics ; Mice ; Female ; *Hippocampus/metabolism ; *Lysosomal-Associated Membrane Protein 2/metabolism/genetics ; *Autophagy/physiology ; *Alzheimer Disease/metabolism ; *Amyloid beta-Peptides/metabolism ; Ovariectomy ; Mice, Inbred C57BL ; }, abstract = {AIMS: Hippocampal aromatase (AROM) knockdown induces Aβ accumulation and Alzheimer's disease (AD)-like spatial learning and memory impairment, and early hippocampal AROM overexpression in APP/PS1 mice prevents Aβ deposition and memory loss later in life. The aim of this study was to elucidate the underlying mechanism and provide novel prevention and treatment targets for AD.
MATERIALS AND METHODS: AROM-inhibiting viral vectors were constructed and injected into the hippocampi of adult female mice, after which label-free LC-MS/MS proteomics and bioinformatics analysis were conducted. Additional viral vectors targeting LAMP2 or LC3 were constructed and used to treat HT22 cells. LAMP2 expression was verified, and macroautophagy levels, autophagosome formation and Aβ accumulation were examined. Additionally, ovariectomy combined with the hippocampal injection of LAMP2 inhibition/overexpression viral vectors was applied, and learning and memory abilities and Aβ accumulation were examined.
KEY FINDINGS: Proteomics revealed the enrichment of CMA and autophagy, and LAMP2 was the most significantly upregulated protein. Higher LAMP2 levels were correlated with lower macroautophagy and autophagosomes levels but were correlated with higher Aβ accumulation, and vice versa. Additionally, hippocampal LAMP2 mediated the effects of ovariectomy on spatial memory and Aβ accumulation.
SIGNIFICANCE: These results demonstrated the important role of the hippocampal LAMP2-macroautophagy pathway in mediating both hippocampal and ovarian estrogen regulation of Aβ accumulation and AD-like behavior, indicating that LAMP2 might be a novel target for both hippocampal and circulating estrogen deficiency-associated memory impairments, such as AD.}, }
@article {pmid39983802, year = {2025}, author = {Yang, X and Xiao, R and Liu, B and Xie, B and Yang, Z}, title = {The causal relationship of inflammation-related factors with osteoporosis: A Mendelian Randomization Analysis.}, journal = {Experimental gerontology}, volume = {202}, number = {}, pages = {112715}, doi = {10.1016/j.exger.2025.112715}, pmid = {39983802}, issn = {1873-6815}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Osteoporosis/genetics ; *Genome-Wide Association Study ; *Bone Density/genetics ; Risk Factors ; *Inflammation/genetics ; *Polymorphism, Single Nucleotide ; *Renal Insufficiency, Chronic/genetics ; Diabetes Mellitus, Type 2/genetics ; Female ; Genetic Predisposition to Disease ; Alzheimer Disease/genetics ; Male ; Europe ; White People/genetics ; White ; }, abstract = {BACKGROUND: We used Mendelian randomization (MR) approach to examine whether genetically determined inflammation-related risk factors play a role in the onset of osteoporosis (OP) in the European population.
METHODS: Genome-wide association studies (GWASs) summary statistics of estimated bone mineral density (eBMD) obtained from the public database GEnetic Factors for OSteoporosis Consortium (GEFOS) including 142,487 European people. For exposures, we utilized GWAS data of 9 risk factors including diseases chronic kidney disease (CKD) (41,395 cases and 439,303 controls), type 2 diabetes (T2D) (88,427 cases and 566,778 controls), Alzheimer's disease (AD) (71,880 cases, 383,378 controls) and major depression disorder (MDD) (9240 cases and 9519 controls) and lifestyle behaviors are from different consortiums. Inverse variance weighted (IVW) analysis was principal method in this study and random effect model was applied; MR-Egger method and weighted median method were also performed for reliable results. Cochran's Q test and MR-Egger regression were used to detect heterogeneity and pleiotropy and leave-one-out analysis was performed to find out whether there are influential SNPs.
RESULTS: We found that T2D (IVW: β = 0.05, P = 0.0014), FI (IVW: β = -0.22, P < 0.001), CKD (IVW: β = 0.02, P = 0.009), ALZ (IVW: β = 0.06, P = 0.005), Coffee consumption (IVW: β = 0.11, P = 0.003) were causally associated with OP (P<0.006after Bonferroni correction).
CONCLUSIONS: Our study revealed that T2D, FI, CKD, ALZ and coffee consumption are causally associated with OP. Future interventions targeting factors above could provide new clinical strategies for the personalized prevention and treatment of osteoporosis.}, }
@article {pmid39983325, year = {2025}, author = {Higgins, CM and Vishwanath, SH and McCarthy, FM and Gordon, ML and Peter, B and Miller, JE}, title = {Normative aging results in degradation of gene networks in a zebra finch basal ganglia nucleus dedicated to vocal behavior.}, journal = {Neurobiology of aging}, volume = {149}, number = {}, pages = {19-33}, doi = {10.1016/j.neurobiolaging.2025.02.002}, pmid = {39983325}, issn = {1558-1497}, mesh = {Animals ; *Finches/genetics ; *Vocalization, Animal/physiology ; *Gene Regulatory Networks/genetics ; *Aging/genetics/physiology ; Male ; *Basal Ganglia/metabolism ; Humans ; Neurodegenerative Diseases/genetics ; }, abstract = {Aging increases brain susceptibility to neurodegenerative diseases, but the mechanisms are not clear. Vocal behavior provides an accessible, reliable, and sensitive biomarker to address this because voice changes in middle age can be early indicators of neurodegenerative diseases. The adult male zebra finch is an excellent model organism for these studies due to well-characterized vocal brain circuitry and strong homology to human brain centers. We performed RNA sequencing of song-dedicated basal ganglia nucleus Area X followed by weighted gene co-expression network analyses to examine changes in gene patterns across younger adult, middle, and older ages. Song-correlated gene networks degrade with age, with modules losing their coherence and migrating to different sets of genes, and changes in connection strength particularly for hub genes including those associated with human speech, Parkinson's, and Alzheimer's diseases. Gene pathway enrichment analyses reveal a lack of ongoing metabolic and biogenic processes in older finches. Our findings provide a robust platform for targeting network hubs in the treatment of neurologically driven human vocal disorders.}, }
@article {pmid39982692, year = {2025}, author = {Soncu Büyükişcan, E}, title = {Neuropsychology of Alzheimer's disease: From preclinical phase to dementia.}, journal = {Applied neuropsychology. Adult}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/23279095.2025.2469236}, pmid = {39982692}, issn = {2327-9109}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by significant cognitive and functional decline, initially presenting with episodic memory impairment. A thorough neuropsychological assessment is essential for AD diagnosis, particularly in the early stages in which interventions may be more effective. This paper reviews the neuropsychology of Alzheimer's disease, highlighting the cognitive progression of the disease. In the typical forms of AD, episodic memory appears to be the first and foremost affected cognitive domain. As AD progresses, cognitive impairments extend beyond memory to affect various domains such as attention, executive functions, language, and visuospatial abilities. Neuropsychiatric issues, such as depression and anxiety, which often accompany cognitive decline, are also common, especially at the advanced stages of the disease. While episodic memory impairment is the earliest and most prominent feature in typical AD cases, comprehensive assessments, including social cognition and neuropsychiatric evaluations, are crucial for accurate diagnosis and treatment planning.}, }
@article {pmid39982688, year = {2025}, author = {Priyadarshini, S and Goyal, K and R, R and Gupta, S and Roy, A and Biswas, R and Patra, S and Chauhan, P and Wadhwa, K and Singh, G and Kamal, M and Iqbal, D and Alsaweed, M and Nuli, MV and Abomughaid, MM and Almutary, AG and Sinha, JK and Bansal, P and Rani, B and Walia, C and Sivaprasad, GV and Ojha, S and Nelson, VK and Jha, NK}, title = {Polypharmacology and Neuroprotective Effects of Gingerol in Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39982688}, issn = {1559-1182}, abstract = {Alzheimer's disease (AD) is a neurodegenerative condition that results in brain shrinkage and the death of brain cells. The search for new treatment agents with many targets is now crucial due to the insufficient effectiveness, and adverse effects, including pharmacokinetic issues of traditional AD medications. Although phytochemicals have anti-disease characteristics and thus are widely used and accepted by people, researchers have also determined some of their most beneficial functions. Sesquiterpenes, volatile oils, and aromatic ketones (gingerols) are abundant in ginger. The most pharmacologically active components of ginger are considered to be gingerols. These gingerols are the compounds that impart spicy characteristics to the plant. Besides, gingerols readily undergo dehydration and produce another class of compounds, shogaols. These gingerols, shogaols, and other compounds, like zingerone, are mainly responsible for their distinctive aroma and pharmacological effects. This review aims to delineate the therapeutic potentials of gingerol in different AD models by assessing available literature reporting its effect on various cellular and molecular pathways. Although ginger is well recognized as a non-toxic nutraceutical, existing clinical research lacks robust evidence to support its efficacy in treating NDs, including AD. Clinical studies did not provide sufficient data that supports its use in treating various NDs including AD. Therefore, further research is essential to establish the safety and effectiveness of ginger and its constituents, ultimately paving the way for its development as a potential therapeutic agent for AD.}, }
@article {pmid39982263, year = {2025}, author = {Trigo, FS and Pinto, NC and Pato, MV}, title = {Long-Term Insomnia Treatment with Benzodiazepines and Alzheimer's Disease: A Systematic Review.}, journal = {NeuroSci}, volume = {6}, number = {1}, pages = {}, pmid = {39982263}, issn = {2673-4087}, abstract = {Alzheimer's disease is the most common form of dementia. Benzodiazepines are the most widely used pharmacological class in the treatment of insomnia and other sleep disorders. Some literature suggests that the chronic use of benzodiazepines is associated with the development of cognitive decline. This review aims to evaluate the use of benzodiazepines and its association with the development of Alzheimer's disease. A systematic review of the literature was carried out using the MEDLINE and Embase databases. Protocols followed the PRISMA-P 2020 methodology, and, after the analysis of the included studies, a narrative synthesis of the results was carried out. Only two cohort studies were identified that met defined eligibility criteria. In the retrospective study, a significant risk of developing Alzheimer's disease after treatment with benzodiazepines was found. In the prospective study, the prevalence of Alzheimer's disease was not associated with treatment with benzodiazepines. Results suggest that only the largest study presented a significant risk of developing Alzheimer's disease. Given the scarce scientific evidence found, it is concluded that further research on this topic is necessary.}, }
@article {pmid39981456, year = {2025}, author = {Zarovniaeva, V and Anwar, S and Kazmi, S and Cortez Perez, K and Sandhu, S and Mohammed, L}, title = {The Role of PET Detection of Biomarkers in Early Diagnosis, Progression, and Prognosis of Alzheimer's Disease: A Systematic Review.}, journal = {Cureus}, volume = {17}, number = {1}, pages = {e77781}, pmid = {39981456}, issn = {2168-8184}, abstract = {Alzheimer's disease (AD) is a chronic neurologic disease characterized by the deposition of Aβ amyloid and tau protein in the neural tissue, which leads to gradual and irreversible deterioration of memory. Positron emission tomography (PET) showed high potential in diagnosing AD. It provided a unique opportunity to assess cerebral amyloid plaques and tau neurofibrillary tangle deposits in the brain tissue without invasive procedures in vivo. Many studies have been focused on PET diagnosis of AD in recent years, which has significantly improved diagnosis and treatment strategies. This review study aims to summarize the role and emphasize the benefits of PET detection of AD biomarkers in early stages, clinical and histological progression assessment, and predicting AD outcomes. Relevant articles published in the last five years, from September 1, 2019, to October 30, 2024, were searched through authentic databases such as PubMed, PubMed Central, Europe PubMed Central, Science Direct, Cochrane Library, and Google Scholar. In this systematic review, we included articles published in English, with available full text, based on human trials, with relevant information regarding participants who underwent PET of the brain to diagnose AD biomarkers. The study strictly followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and recommendations. The Joanna Briggs Institute (JBI) critical appraisal methods were used to evaluate all selected cross-sectional research, and the Newcastle-Ottawa Scale (NOS) was used to assess the cohort and longitudinal studies. Eleven relevant articles were included in this systematic review, and 2,203 males and females participated. The study revealed that the detection of beta-amyloid PET showed high-precious results in early diagnosis of AD. The detection of tau protein showed a high potential for estimation of the clinical and histological progression and prognosis of AD in longitudinal studies. Identifying amyloid and tau protein accumulation and glucose metabolism alterations is highly predictive of neurodegeneration in preclinical and mild cognitive impairment stages.}, }
@article {pmid39981405, year = {2025}, author = {Li, X and Su, W and Cai, L}, title = {A bibliometric analysis of research on dementia comorbid with depression from 2005 to 2024.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1508662}, pmid = {39981405}, issn = {1662-4548}, abstract = {INTRODUCTION: With the global rise in life expectancy, the incidence of dementia is increasing, often accompanied by depressive symptoms. Understanding the interplay between dementia and depression is crucial, as depression may not only co-occur with but also potentially exacerbate the progression of dementia. This study employs bibliometric analysis to map the global research landscape, identify prevailing themes, and discern future research directions.
METHODS: We analyzed reviews and original research articles on dementia and depression extracted from the Web of Science Core Collection spanning from 2005 to 2024. Utilizing tools such as CiteSpace, VOSviewer, and an R-based bibliometric analysis package, we assessed trends in publication volume, citation frequency, contributing countries, leading institutions, predominant journals, influential authors, and emergent keywords.
RESULTS: A total of 1972 publications were obtained, revealing a consistent increase in both the number of publications and their citation impact over the study period. The United States is the country with the most publications and the most extensive collaborations. The University of Toronto and the Journal of Alzheimer's Disease were identified as key contributors to this field. This research area is currently focused on cognitive impairments, the role of gut microbiota, and non-drug interventions. Future directions emphasize the importance of early detection and intervention, a deeper understanding of the gut-brain axis, and the integration of technology in treatment strategies. Additionally, there is a growing interest in the physiological and psychological interplays such as oxidative stress and its implications.
CONCLUSION: This study underscores pathogenesis, comorbid conditions, and non-drug interventions as primary research focal points, suggesting these areas as potential pathways for therapeutic innovation. These insights are intended to deepen our understanding, enhance diagnostics, and improve the management of dementia and depression, providing guidance for future research aimed at addressing these escalating global health challenges.}, }
@article {pmid39981365, year = {2025}, author = {Safi, A and Giunti, E and Melikechi, O and Xia, W and Melikechi, N}, title = {Identification of blood plasma protein ratios for distinguishing Alzheimer's disease from healthy controls using machine learning.}, journal = {Heliyon}, volume = {11}, number = {3}, pages = {e42349}, pmid = {39981365}, issn = {2405-8440}, abstract = {Early detection of Alzheimer's disease is essential for effective treatment and the development of therapies that modify disease progression. Developing sensitive and specific noninvasive diagnostic tools is crucial for improving clinical outcomes and advancing our understanding of this condition. Liquid biopsy techniques, especially those involving plasma biomarkers, provide a promising noninvasive method for early diagnosis and disease monitoring. In this study, we analyzed the plasma proteomic profiles of 38 healthy individuals, with an average age of 66.5 years, and 22 patients with Alzheimer's disease, with an average age of 79.7 years. Proteins in the plasma were quantified using specialized panels designed for proteomic extension assays. Through computational analysis using a linear support vector machine algorithm, we identified 82 differentially expressed proteins between the two groups. From these, we calculated 6642 possible protein ratios and identified specific combinations of these ratios as significant features for distinguishing between individuals with Alzheimer's disease and healthy individuals. Notably, the protein ratios kynureninase to macrophage scavenger receptor type 1, Neurocan to protogenin, and interleukin-5 receptor alpha to glial cell line-derived neurotrophic factor receptor alpha 1 achieving accuracy up to 98 % in differentiating between the two groups. This study underscores the potential of leveraging protein relationships, expressed as ratios, in advancing Alzheimer's disease diagnostics. Furthermore, our findings highlight the promise of liquid biopsy techniques as a noninvasive and accurate approach for early detection and monitoring of Alzheimer's disease using blood plasma.}, }
@article {pmid39981356, year = {2025}, author = {Talebi, M and Ayatollahi, SA and As'Habi, MA and Kobarfard, F and Khoramjouy, M and Boroujeni, FN and Faizi, M and Ghassempour, A}, title = {Investigating the neuroprotective effects of Dracocephalum moldavica extract and its effect on metabolomic profile of rat model of sporadic Alzheimer's disease.}, journal = {Heliyon}, volume = {11}, number = {3}, pages = {e42412}, pmid = {39981356}, issn = {2405-8440}, abstract = {Alzheimer's disease (AD) is a progressive condition marked by multiple underlying mechanisms. Therefore, the investigation of natural products that can target multiple pathways presents a potential gate for the understanding and management of AD. This study aimed to assess the neuroprotective effects of the hydroalcoholic extract of Dracocephalum moldavica (DM) on cognitive impairment, biomarker changes, and putative metabolic pathways in a rat model of AD induced by intracerebroventricular streptozotocin (ICV-STZ). The DM extract was standardized and quantified based on examining total phenolic, total flavonoid, rosmarinic acid, and quercetin contents using colorimetry and high-performance liquid chromatography (HPLC) methods. The antioxidant potential of the extract was evaluated by 2,2-Diphenyl-1-picrylhydrazyl and nitric oxide radical scavenging assays. Male Wistar rats were injected with STZ (3 mg/kg, single dose, bilateral ICV) to induce a sporadic AD (sAD) model. Following model induction, rats were orally administered with DM extract (100, 200, and 400 mg/kg/day) or donepezil (5 mg/kg/day) for 21 days. Cognitive function was assessed using the radial arm water maze behavioral test. The histopathological evaluations were conducted in the cortex and hippocampus regions. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) was used to assess metabolite changes in various brain regions. DM extract significantly attenuated cognitive dysfunction induced by ICV-STZ according to behavioral and histopathological investigations. Thirty-two discriminating metabolites related to the amino acid metabolism; the glutamate/gamma-aminobutyric acid/glutamine cycle; nucleotide metabolism; lipid metabolism (glycerophospholipids, sphingomyelins, ceramides, phosphatidylserines, and prostaglandins), and glucose metabolic pathways were identified in the brains of rats with sAD simultaneously for the first time in this model. Polyphenols in DM extract may contribute to the regulation of these pathways. After treatment with DM extract, 10 metabolites from the 32 identified ones were altered in the brain tissue of a rat model of sAD, most commonly at doses of 200 and 400 mg/kg. In conclusion, this study demonstrates the neuroprotective potential of DM by upregulation/downregulation of various pathophysiological biomarkers such as adenine, glycerophosphoglycerol, inosine, prostaglandins, and sphingomyelin induced by ICV-STZ in sAD. These findings are consistent with cognitive behavioral results and histopathological outcomes.}, }
@article {pmid39980294, year = {2025}, author = {Fatima, R and Khan, Y and Maqbool, M and Ramalingam, PS and Khan, MG and Bisht, AS and Hussain, MS}, title = {Amyloid-β Clearance with Monoclonal Antibodies: Transforming Alzheimer's Treatment.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037362037250205143911}, pmid = {39980294}, issn = {1875-5550}, abstract = {Alzheimer's disease (AD) is a progressive condition that causes the degeneration of nerve cells, leading to a decline in cognitive abilities and memory impairment, significantly affecting millions around the globe. The primary pathological feature of AD is the buildup of amyloid-β (Aβ) plaques in the brain, which has become a major target for therapeutic strategies. This thorough review examines the progress made in next-generation therapies that concentrate on monoclonal antibodies (mAbs) aimed at Aβ. We explore how these antibodies function, their effectiveness in clinical settings, and their safety profiles, specifically discussing notable mAbs, such as aducanumab, donanemab, lecanemab, etc. This review also addresses the difficulties related to Aβ-- targeted treatments. Furthermore, it examines the advancing field of biomarker development and tailored medicine strategies designed to improve the accuracy of AD treatment. By integrating the latest findings from clinical trials and new research, this review offers an in-depth evaluation of the possibilities and challenges associated with mAbs in modifying the progression of AD. Future considerations regarding combination therapies and novel drug delivery methods are also examined, emphasizing the necessity for ongoing research to achieve significant advancements in managing AD. Through this review, we seek to provide clinicians, researchers, and policymakers with insights into the current landscape and future directions of Aβ-targeted therapies, promoting a deeper understanding of their role in addressing AD.}, }
@article {pmid39979530, year = {2025}, author = {De Bondt, E and Locquet, P and López, MG and Soysal, P and Welsh, T and Shenkin, SD and Tournoy, J and , }, title = {Awareness of national dementia guidelines and management of oldest-old and frail people living with dementia: a European survey of geriatricians.}, journal = {European geriatric medicine}, volume = {}, number = {}, pages = {}, pmid = {39979530}, issn = {1878-7649}, abstract = {BACKGROUND: Management of dementia, particularly the use of pharmacological treatments, in the oldest old and those with frailty is complex because of the multiple types of dementia, comorbidities, polypharmacy, and side effects. Current national dementia guidelines lack recommendations for this group. This study assessed guideline awareness, usage, and pharmacological management practices for dementia in the oldest old and frail across Europe.
METHODS: An online anonymous survey was distributed in 2023 to the European Geriatric Medicine Society Dementia Special Interest Group and their contacts to investigate guideline awareness and pharmacological practices for the oldest old and frail. The CHERRIES checklist was followed for reporting. Responses were summarized using descriptive statistics and quotations of free text responses.
RESULTS: Forty-nine responses from fourteen countries were received. A total of 76.6% were aware of a national dementia guideline and 86.9% applied it frequently. Acetylcholinesterase inhibitors (AChEIs) were generally used as a first-line treatment in mild-to-moderate Alzheimer's disease (AD) (91.6% and 93.4%). Memantine was added or replaced AChEIs as dementia severity progresses. Gingko biloba was considered in mild and moderate AD (23.6% and 22.7%, respectively). Off-label drug use was common in other types of dementia. 88.5% of respondents reported no difference in treatment compared with a younger population.
CONCLUSION: There was awareness of various dementia guidelines, but none addressed the management of the oldest old and frail. Most respondents did not adapt their practices for this group, but many reported off-label treatments which resulted in non-evidence-based prescribing, overprescribing, and a lack of deprescribing. European consensus to guide the management of dementia in this complex population is needed.}, }
@article {pmid39978567, year = {2025}, author = {Rodriguez-Lopez, A and Esteban, D and Domínguez-Romero, AN and Gevorkian, G}, title = {Tg-SwDI transgenic mice: A suitable model for Alzheimer's disease and cerebral amyloid angiopathy basic research and preclinical studies.}, journal = {Experimental neurology}, volume = {387}, number = {}, pages = {115189}, doi = {10.1016/j.expneurol.2025.115189}, pmid = {39978567}, issn = {1090-2430}, mesh = {Animals ; *Mice, Transgenic ; *Cerebral Amyloid Angiopathy/genetics/pathology/metabolism ; *Alzheimer Disease/genetics/pathology/metabolism ; Humans ; Mice ; *Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics ; }, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease and the most frequent cause of dementia. Characteristic features observed in the brain of AD patients are the accumulation of amyloid beta peptide (Aβ) aggregates, neurofibrillary tangles (NFT) composed of hyperphosphorylated Tau protein, neuronal and synaptic loss, and elevated levels of oxidative stress and inflammatory markers. Cerebral amyloid angiopathy (CAA) is another common cause of cognitive decline characterized by the accumulation of Aβ in the cerebral vasculature. The precise overlapping pathogenic mechanisms underlying the co-occurrence of AD and CAA are not very well understood. However, vascular dysfunction observed at early stages is considered a key phenomenon. Tg-SwDI transgenic mice expressing human Aβ precursor protein (AβPP) harboring the Swedish K670N/M671L and vasculotropic Dutch/Iowa E693Q/D694N mutations in the brain have been extensively used to study many pathological features observed in AD/CAA patients and to design biomarkers and therapeutic strategies. The present review summarizes studies addressing different features mimicking human disease in Tg-SwDI mice: parenchymal and cerebral vascular amyloid accumulation, neuroinflammation, complement overactivation, cerebrovascular, mitochondrial and GABAergic system dysfunction, altered NO synthesis, circadian rhythm disruptions, lead exposure effect, among others. Also, reports that evaluated anti-Aβ and anti-inflammatory strategies and compounds capable of delaying or reversing vascular dysfunction and the impairment of GABAergic transmission in Tg-SwDI mice are analyzed. This review may help researchers determine this model's appropriateness for future studies of a particular mechanism or a novel treatment protocol.}, }
@article {pmid39978523, year = {2025}, author = {Asl, FSS and Malverdi, N and Mojahedian, F and Baziyar, P and Nabi-Afjadi, M}, title = {Discovery of effective GSK-3β inhibitors as therapeutic potential against Alzheimer's disease: A computational drug design insight.}, journal = {International journal of biological macromolecules}, volume = {306}, number = {Pt 1}, pages = {141273}, doi = {10.1016/j.ijbiomac.2025.141273}, pmid = {39978523}, issn = {1879-0003}, abstract = {Alzheimer's disease (AD) is mostly thought to be caused by overactivity of glycogen synthase kinase 3-beta (GSK3-β). Therefore, a GSK-3β inhibitor may be a suggested medicine for Alzheimer's therapy. Nowadays, computational techniques are thought to be among the quickest and most affordable options for therapeutic design and drug discovery. Following a preliminary screening of flavonoids for possible protection against cognitive illnesses such as Alzheimer's, Amentoflavone, Curcumin, and Notopterol were shown to be promising candidates. Using molecular docking, the ligand orientation and binding energy in the ATP-binding pocket of GSK-3β were ascertained. Amentoflavone formed a hydrogen bond with the GSK-3β protein's ATP binding site during the molecular docking phase, obtaining the highest negative binding energy. However, when the results moved closer to a molecular dynamics simulation, the findings changed, and Curcumin was shown to be the most potent inhibitor. All structures remained stable during the MD simulation of the GSK-3β protein and its ligands. Moreover, compared to other natural compounds, Curcumin showed higher binding free energy. Therefore, Curcumin may be useful as a polyphenolic flavonoid in the prevention and treatment of AD. Hence, additional research in vitro and in vivo can focus on these flavonoid compounds as an alternative treatment.}, }
@article {pmid39976589, year = {2025}, author = {Mun, JH and Jang, MJ and Kim, WS and Kim, SS and Lee, B and Moon, H and Oh, SJ and Ryu, CH and Park, KS and Cho, IH and Hong, GS and Choi, CW and Lee, C and Kim, MS}, title = {Enhanced Cognitive and Memory Functions via Gold Nanoparticle-Mediated Delivery of Afzelin through Synaptic Modulation Pathways in Alzheimer's Disease Mouse Models.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {5}, pages = {826-843}, doi = {10.1021/acschemneuro.4c00766}, pmid = {39976589}, issn = {1948-7193}, mesh = {Animals ; *Gold/chemistry/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; *Doublecortin Protein ; *Metal Nanoparticles ; Mice ; *Disease Models, Animal ; *Memory/drug effects ; *Neuroprotective Agents/pharmacology ; Cognition/drug effects ; Hippocampus/drug effects/metabolism ; Male ; Scopolamine/pharmacology ; }, abstract = {Gold nanoparticles (AuNPs) are valuable tools in pharmacological and biological research, offering unique properties for drug delivery in the treatment of neurodegenerative diseases. This study investigates the potential of gold nanoparticles loaded with afzelin, a natural chemical extracted from Ribes fasciculatum, to enhance its therapeutic effects and overcome the limitations of using natural compounds regarding low productivity. We hypothesized that the combined treatment of AuNPs with afzelin (AuNP-afzelin) would remarkably enforce neuroprotective effects compared with the single treatment of afzelin. Central administration of AuNP-afzelin (10 ng of afzelin) indicated improvements in cognition and memory-involved assessments of behavioral tests, comparing single treatments of afzelin (10 or 100 ng of afzelin) in scopolamine-induced AD mice. AuNP-afzelin also performed superior neuroprotective effects of rescuing mature neuronal cells and recovered cholinergic dysfunction compared to afzelin alone, according to further investigations of BDNF-pCREB-pAkt signaling, long-term potentiation, and doublecortin (DCX) expression in the hippocampus. This study highlights the potential of afzelin with gold nanoparticles as a promising therapeutic approach for mitigating cognitive impairments associated with neurodegenerative diseases and offers a new avenue for future research and drug development.}, }
@article {pmid39976261, year = {2025}, author = {Menendez-Gonzalez, M}, title = {Implementing a tridimensional diagnostic framework for personalized medicine in neurodegenerative diseases.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14591}, pmid = {39976261}, issn = {1552-5279}, support = {PI21/00467//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/diagnosis/genetics ; *Biomarkers ; Neuroimaging/methods ; }, abstract = {Neurodegenerative diseases (NDDs) pose a significant challenge in modern medicine due to their clinical heterogeneity, multifactorial etiologies, and frequent co-pathologies. Traditional diagnostic systems, based on clinical symptoms and post mortem findings, are limited in capturing the complex interactions among genetic, molecular, and neuroanatomical factors. This manuscript introduces a novel tridimensional diagnostic framework that integrates these factors across three key axes: etiology (genetic and environmental influences), molecular markers (primary and secondary biomarkers), and neuroanatomoclinical correlations. Through case studies, we demonstrate the framework's ability to synthesize incomplete datasets, stratify patients, and guide precision medicine. By incorporating omics technologies, neuroimaging, and AI-driven probabilistic modeling, the framework enhances diagnostic accuracy and clinical relevance. This approach may contribute to overcoming the limitations of traditional nosologies, offering a scalable and adaptable tool for both clinical practice and research and advancing the field of precision medicine in NDD management. HIGHLIGHTS: Tridimensional diagnostic system: We propose a new framework that incorporates three axes - etiology, molecular markers, and neuroanatomical-clinical correlations - to enhance diagnostic accuracy for NDDs. Personalized medicine: The tridimensional system enables the integration of genetic, molecular, and clinical data, allowing for highly personalized treatment strategies tailored to individual patients. Proteinopathies as key biomarkers: This diagnostic system emphasizes the use of primary proteinopathies (amyloid, tau, synuclein) and secondary biomarkers (eg, NfL, GFAP) to monitor disease progression and treatment efficacy. Addressing clinical heterogeneity: The framework accommodates the complexity and heterogeneity of NDDs, offering an adaptable diagnostic approach for classical conditions like Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and ALS. Case studies and real-world application: Practical case studies illustrate how this system can be implemented in clinical practice, enabling the combination of DMTs with symptomatic treatments.}, }
@article {pmid39975469, year = {2025}, author = {Galvin, JE and Germain, DM and Moore, CP and Jeanty, JA and Tofaeono, V and Wiese, LK}, title = {The Dementia Literacy Assessment (DeLA): A novel measure of Alzheimer's disease and related disorders health literacy in diverse populations.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70054}, pmid = {39975469}, issn = {2352-8737}, abstract = {INTRODUCTION: Low health literacy about Alzheimer's disease and related disorders (ADRD) may limit help-seeking, early detection, and enrollment in clinical trials, particularly in minoritized communities. We created the Dementia Literacy Assessment (DeLA) to improve ADRD health literacy.
METHODS: The DeLA, a storytelling method that included culturally adaptable vignettes embedded with important factoids about ADRD, was administered to 213 participants from urban and rural regions of Palm Beach and Broward County in Florida and 193 participants in American Samoa.
RESULTS: The DeLA increased dementia health literacy and performed well across different participant characteristics (age, sex, education, geographic locale, race, ethnicity, and cognitive performance). Gains in ADRD health literacy were associated with older age, more education, better socioeconomic status, greater resilience, and better cognitive performance.
DISCUSSION: Increasing ADRD health literacy could increase health-seeking behaviors in diverse populations for treatment, enrich recruitment into clinical trials, and may help reduce disparities in health outcomes.
HIGHLIGHTS: Low health literacy about Alzheimer's disease and related disorders (ADRD) may limit help-seeking, early detection, and enrollment in clinical trials, particularly in minoritized communities.The Dementia Literacy Assessment (DeLA), a storytelling method that included culturally adaptable vignettes embedded with important factoids about ADRD, was administered to 406 participants from urban and rural regions of Palm Beach and Broward County in Florida and American Samoa (11.8% White, 39.8% Black or African American, and 48.4% Pacific Islander [predominantly Samoan] individuals).The DeLA increased dementia health literacy and performed well across different participant characteristics (age, sex, education, geographic locale, race, and cognitive performance).Gains in ADRD health literacy were associated with older age, more education, better socioeconomic status, greater resilience, and better cognitive performance.Increasing ADRD health literacy could increase health-seeking behaviors in diverse populations for treatment, enrich recruitment into clinical trials, and help reduce disparities in health outcomes.}, }
@article {pmid39975163, year = {2025}, author = {Heller, LI and Lowe, AS and Del Rosario Hernández, T and Gore, SV and Chatterjee, M and Creton, R}, title = {Target the Heart: a new axis of Alzheimer's disease prevention.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975163}, issn = {2692-8205}, support = {R01 GM136906/GM/NIGMS NIH HHS/United States ; }, abstract = {Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer's disease. Utilizing a neural network model, Z-LaP Tracker, we previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved drugs using Z-LaP Tracker revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. 14 of these drugs were heart medications, including angiotensin receptor blockers, beta-blockers, alpha-adrenergic receptor antagonists, and a statin. This suggests some heart medications may be effective in preventing or ameliorating Alzheimer's disease pathology. Other studies have shown that many of these 14 drugs directly or indirectly inhibit the calcineurin-NFAT pathway, alike cyclosporine A. Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. This indicates that co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for Alzheimer's disease and cardiovascular dysfunction, while mitigating side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer's disease in many patients, physicians may be able to create a treatment regimen that simultaneously addresses both conditions. Our results suggest that cyclosporine A combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol are the most promising candidates for future exploration.}, }
@article {pmid39975097, year = {2025}, author = {Du, JH and Shen, M and Mathys, H and Roeder, K}, title = {Causal differential expression analysis under unmeasured confounders with causarray.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975097}, issn = {2692-8205}, support = {R01 MH123184/MH/NIMH NIH HHS/United States ; }, abstract = {Advances in single-cell sequencing and CRISPR technologies have enabled detailed case-control comparisons and experimental perturbations at single-cell resolution. However, uncovering causal relationships in observational genomic data remains challenging due to selection bias and inadequate adjustment for unmeasured confounders, particularly in heterogeneous datasets. To address these challenges, we introduce causarray, a doubly robust causal inference framework for analyzing array-based genomic data at both bulk-cell and single-cell levels. causarray integrates a generalized confounder adjustment method to account for unmeasured confounders and employs semiparametric inference with flexible machine learning techniques to ensure robust statistical estimation of treatment effects. Benchmarking results show that causarray robustly separates treatment effects from confounders while preserving biological signals across diverse settings. We also apply causarray to two single-cell genomic studies: (1) an in vivo Perturb-seq study of autism risk genes in developing mouse brains and (2) a case-control study of Alzheimer's disease using three human brain transcriptomic datasets. In these applications, causarray identifies clustered causal effects of multiple autism risk genes and consistent causally affected genes across Alzheimer's disease datasets, uncovering biologically relevant pathways directly linked to neuronal development and synaptic functions that are critical for understanding disease pathology.}, }
@article {pmid39974649, year = {2025}, author = {Jarne-Ferrer, J and Sánchez, J and Codony, S and Schneider, M and Müller, CE and Sanfeliu, C and Franco, R and Vazquez, S and Griñán-Ferré, C and Pallàs, M}, title = {Novel Soluble Epoxide Hydrolase Inhibitor: Toward Regulatory Preclinical Studies.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {2}, pages = {533-542}, pmid = {39974649}, issn = {2575-9108}, abstract = {Neuroinflammation is widely recognized as a key pathological hallmark of Alzheimer's disease (AD). Recently, inhibiting soluble epoxide hydrolase (sEH) has emerged as a promising therapeutic strategy for AD. sEH plays a pivotal role in neuroinflammation by hydrolyzing epoxyeicosatrienoic acids (EETs), which have anti-inflammatory and neuroprotective properties, into pro-inflammatory dihydroepoxyeicosatrienoic acids (DHETs). Furthermore, the overexpression of the enzyme in the brains of AD patients and animal models of the disease highlights its relevance as a therapeutic target. Our previous studies, using the inhibitor UB-SCG-51 demonstrated that sEH inhibition regulates neuroinflammation and other mechanisms, such as the unfolded protein response pathway, while reducing autophagy, apoptosis, and neuronal death, thereby promoting neuroprotection. Building on these findings, we evaluated the arginine salt of the compound, designated UB-SCG-74, which offers improved oral absorption compared to that of UB-SCG-51 while retaining high permeability, potency, and selectivity. In experiments using 5XFAD mice, UB-SCG-74 treatment significantly improved cognition and synaptic plasticity, outperforming donepezil, a standard AD drug, and ibuprofen, an anti-inflammatory drug. Remarkably, these benefits persisted for 4 weeks after administration cessation, suggesting lasting therapeutic effects. Safety pharmacology studies showed no toxicity, supporting the advancement of UB-SCG-74 into preclinical regulatory evaluation. Our findings further indicate that sEH inhibition engages multiple neuroprotective pathways, potentially modifying both AD symptoms and disease progression, thus reinforcing its therapeutic potential.}, }
@article {pmid39974075, year = {2025}, author = {Bateman, RJ and Li, Y and McDade, EM and Llibre-Guerra, JJ and Clifford, DB and Atri, A and Mills, SL and Santacruz, AM and Wang, G and Supnet, C and Benzinger, TLS and Gordon, BA and Ibanez, L and Klein, G and Baudler, M and Doody, RS and Delmar, P and Kerchner, GA and Bittner, T and Wojtowicz, J and Bonni, A and Fontoura, P and Hofmann, C and Kulic, L and Hassenstab, J and Aschenbrenner, AJ and Perrin, RJ and Cruchaga, C and Renton, AE and Xiong, C and Goate, AA and Morris, JC and Holtzman, DM and Snider, BJ and Mummery, C and Brooks, WS and Wallon, D and Berman, SB and Roberson, E and Masters, CL and Galasko, DR and Jayadev, S and Sanchez-Valle, R and Pariente, J and Kinsella, J and van Dyck, CH and Gauthier, S and Robin Hsiung, GY and Masellis, M and Dubois, B and Honig, LS and Jack, CR and Daniels, A and Aguillón, D and Allegri, R and Chhatwal, J and Day, G and Fox, N and Huey, E and Ikeuchi, T and Jucker, M and Lee, JH and Levey, AI and Levin, J and Lopera, F and Roh, J and Rosa-Neto, P and Schofield, PR and , }, title = {Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer's disease: an open label extension of the phase 2/3 multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU Trial.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39974075}, support = {R01 AG046179/AG/NIA NIH HHS/United States ; R01 AG053267/AG/NIA NIH HHS/United States ; R56 AG053267/AG/NIA NIH HHS/United States ; U01 AG042791/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Amyloid-plaque removal by monoclonal antibody therapies slows clinical progression in symptomatic Alzheimer's disease; however, the potential for delaying the onset of clinical symptoms in asymptomatic people is unknown. The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) is an ongoing platform trial assessing the safety and efficacy of multiple investigational products in participants with dominantly inherited Alzheimer's disease (DIAD) caused by mutations. On the basis of findings of amyloid removal and downstream biological effects from the gantenerumab arm of the platform trial, we continued a 3-year open-label extension (OLE) study to assess the safety and efficacy of long-term treatment with high doses of gantenerumab.
METHODS: The randomised, placebo-controlled, double-blind, phase 2/3 multi-arm trial (DIAN-TU-001) assessed solanezumab or gantenerumab versus placebo in participants who were between 15 years before to 10 years after their estimated years to symptom onset and had a Clinical Dementia Rating (CDR) global score of 0 (cognitively normal) to 1 (mild dementia). This study was followed by an OLE study of gantenerumab treatment, conducted at 18 study sites in Australia, Canada, France, Ireland, Puerto Rico, Spain, the UK, and USA. For inclusion in the OLE, participants at risk for DIAD had participated in the double-blind period of DIAN-TU-001 and were required to know their mutation status. We investigated increasing doses of gantenerumab up to 1500 mg subcutaneous every 2 weeks. Due to the lack of a regulatory path for gantenerumab, the study was stopped early after a pre-specified interim analysis (when most participants had completed 2 years of treatment) of the clinical measure CDR-SB. The primary outcome for the final analysis was the amyloid plaque measure PiB-PET SUVR at 3 years, assessed in the modified intention to treat population (defined as participants who received any gantenerumab treatment post-OLE baseline, had at least one PiB-PET SUVR assessment prior to gantenerumab treatment, and a post-baseline assessment). All participants who received at least one dose of study drug in the OLE were included in the safety analysis. DIAN-TU-001 (NCT01760005) and the OLE (NCT06424236) are registered with clinicaltrials.gov.
FINDINGS: Of 74 participants who were recruited into the OLE study between June 3, 2020 and April 22, 2021, 73 were enrolled and received gantenerumab treatment. 47 (64%) stopped dosing due to early termination of the study by the sponsor, and 13 (18%) prematurely discontinued the study for other reasons. The mITT population for the primary analysis comprised 55 participants. At the interim analysis, the hazard ratio for clinical decline of CDR-SB in asymptomatic mutation carriers was 0.79 (n=53, 95% CI 0.47 to 1.32) for participants who were treated with gantenerumab in either the double-blind or OLE period (Any Gant), and 0.53 (n=22, 0.27 to 1.03) for participants who were treated with gantenerumab the longest (Longest Gant). At the final analysis, the adjusted mean change from OLE baseline to year 3 in PiB-PET SUVR was -0.71 SUVR (95% CI -0.88 to -0.53, p<0.0001). Amyloid-related imaging abnormalities occurred in 53% (39/73) of participants: 47% (34/73) with microhaemorrhages, 30% (22/73) with oedema, and 6% (5/73) were associated with symptoms. No treatment-associated macrohaemorrhages or deaths occurred.
INTERPRETATION: Partial or short-term amyloid removal did not show significant clinical effects. However, long-term full amyloid removal potentially delayed symptom onset and dementia progression. Conclusions are limited due to the OLE design and use of external controls and need to be confirmed in long term trials.
FUNDING: National Institutes on Aging, Alzheimer's Association, GHR, F. Hoffmann-La Roche, Ltd/Genentech.}, }
@article {pmid39973828, year = {2024}, author = {Desai, Y and Karunakaran, D and Singh, J and Noronha, AR and Poojary, G and Chettri, B and Shenoy, R and Nampoothiri, M and Bojja, SL}, title = {Exploring the mechanism of sunflower seed oil against Alzheimer's disease through experimental and network pharmacology studies.}, journal = {Indian journal of pharmacology}, volume = {56}, number = {6}, pages = {396-404}, pmid = {39973828}, issn = {1998-3751}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; Male ; Mice ; *Scopolamine ; *Sunflower Oil ; *Disease Models, Animal ; *Network Pharmacology ; Molecular Docking Simulation ; Neuroprotective Agents/pharmacology/therapeutic use ; Seeds/chemistry ; Amnesia/drug therapy/chemically induced ; }, abstract = {OBJECTIVES: With the prevalence of Alzheimer's disease (AD) increasing exponentially, there has been a shift in the focus of drug discovery for AD from treating the symptoms to preventing the development of the disease. Several natural compounds are extensively studied as neuroprotectives in preventing disease progression. Helianthus annuus seed oil (HA) is widely used as cooking oil and is abundant in antioxidant activity. Therefore, we evaluated the effect of HA in mice model of scopolamine-induced amnesia and explored the potential underlying mechanisms.
METHODS: Twenty-four male mice were administered orally with either distilled water (control and scopolamine groups) or treatment groups (HA 100 and HA 200 mg/kg) for 8 consecutive days. All groups, except the control group, received an intraperitoneal injection of scopolamine at a dose of 1 mg/kg. Subsequently, novel object recognition task for cognition assessment and open field tests for locomotory activity were performed. In addition, network analysis was performed to identify the key bioactives and targets of HA against AD. Further, the binding affinity of HA bioactives to the key targets was verified by molecular docking analysis.
RESULTS: HA (100 mg/kg and 200 mg/kg) significantly ameliorated recognition memory compared to the scopolamine group, suggesting the protective effect of HA against cognitive impairment. Network analysis indicated that the key bioactives of HA, chlorogenic acid, and oleic acid act through multiple targets and pathways, particularly the mitogen-activated protein kinase (MAPK) pathway, to ameliorate AD symptoms. Importantly, chlorogenic acid showed good binding affinity with MAPKs, TP53, and EP300.
CONCLUSION: HA has therapeutic benefits in AD acting through the MAPK pathway. However, further studies need to be done to confirm the results derived and translate the potential use of HA as a dietary supplement for preventing AD.}, }
@article {pmid39973767, year = {2025}, author = {Wang, H and Yang, T and Fan, J and Zhang, H and Zhang, W and Ji, M and Miao, J}, title = {DML-MFCM: A multimodal fine-grained classification model based on deep metric learning for Alzheimer's disease diagnosis.}, journal = {Journal of X-ray science and technology}, volume = {33}, number = {1}, pages = {211-228}, doi = {10.1177/08953996241300023}, pmid = {39973767}, issn = {1095-9114}, mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; *Magnetic Resonance Imaging/methods ; *Deep Learning ; *Cognitive Dysfunction/diagnostic imaging ; *Brain/diagnostic imaging/pathology ; Aged ; Male ; Female ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder. There are no drugs and methods for the treatment of AD, but early intervention can delay the deterioration of the disease. Therefore, the early diagnosis of AD and mild cognitive impairment (MCI) is significant. Structural magnetic resonance imaging (sMRI) is widely used to present structural changes in the subject's brain tissue. The relatively mild structural changes in the brain with MCI have led to ongoing challenges in the task of conversion prediction in MCI. Moreover, many multimodal AD diagnostic models proposed in recent years ignore the potential relationship between multimodal information.
OBJECTIVE: To solve these problems, we propose a multimodal fine-grained classification model based on deep metric learning for AD diagnosis (DML-MFCM), which can fully exploit the fine-grained feature information of sMRI and learn the potential relationships between multimodal feature information.
METHODS: First, we propose a fine-grained feature extraction module that can effectively capture the fine-grained feature information of the lesion area. Then, we introduce a multimodal cross-attention module to learn the potential relationships between multimodal data. In addition, we design a hybrid loss function based on deep metric learning. It can guide the model to learn the feature representation method between samples, which improves the model's performance in disease diagnosis.
RESULTS: We have extensively evaluated the proposed models on the ADNI and AIBL datasets. The ACC of AD vs. NC, MCI vs. NC, and sMCI vs. pMCI tasks in the ADNI dataset are 98.75%, 95.88%, and 88.00%, respectively. The ACC on the AD vs. NC and MCI vs. NC tasks in the AIBL dataset are 94.33% and 91.67%.
CONCLUSIONS: The results demonstrate that our method has excellent performance in AD diagnosis.}, }
@article {pmid39973550, year = {2025}, author = {Cao, H and Zhang, W and Lin, J and Yu, E}, title = {Research Progress on Alzheimer's Disease Biomarkers Based on the ATX(N) Framework.}, journal = {Discovery medicine}, volume = {37}, number = {193}, pages = {258-275}, doi = {10.24976/Discov.Med.202537193.21}, pmid = {39973550}, issn = {1944-7930}, mesh = {*Alzheimer Disease/diagnosis/metabolism/blood ; Humans ; *Biomarkers/blood/metabolism ; tau Proteins/metabolism/blood ; Early Diagnosis ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Early diagnosis and treatment of AD are of paramount importance, with the concept of biomarkers being intrinsically linked to diagnosis and therapy. Biomarkers are indices that can be objectively measured to indicate normal biological processes, pathological conditions, or responses to therapeutic interventions. In 2023, the National Institute on Aging and Alzheimer's Association released updated clinical diagnostic guidelines, refining the 2018 research framework. These guidelines categorize AD biomarkers into three types: core AD biomarkers, non-specific biomarkers of tissue response related to AD pathophysiology, and biomarkers for non-AD comorbidities, thus enhancing the amyloid/tau/x/neurodegeneration (ATX(N)) framework. This article aimed to provide a comprehensive overview of the advancements within the ATX(N) framework and the progress in the study of various biomarkers under this framework. It analyzes how biomarkers can facilitate early disease diagnosis, discusses the challenges of translating biomarkers into effective treatments, and explores their therapeutic prospects.}, }
@article {pmid39973500, year = {2025}, author = {Factor, SA and Weinshenker, D and McKay, JL}, title = {A possible pathway to freezing of gait in Parkinson's disease.}, journal = {Journal of Parkinson's disease}, volume = {15}, number = {2}, pages = {282-290}, doi = {10.1177/1877718X241308487}, pmid = {39973500}, issn = {1877-718X}, mesh = {Humans ; *Parkinson Disease/complications/physiopathology/metabolism ; *Gait Disorders, Neurologic/etiology/physiopathology ; Norepinephrine/metabolism ; Amyloid beta-Peptides/metabolism ; Dopamine/metabolism ; Neuroinflammatory Diseases/metabolism/physiopathology/etiology ; }, abstract = {Freezing of gait (FOG), a common, perplexing gait disorder observed in Parkinson's disease (PD), is a leading cause of injurious falls and contributes significantly to social isolation. Unlike other PD cardinal features, FOG appears to develop independently, and its heterogeneity presents challenges for both definition and measurement. The pathophysiological mechanisms underlying FOG remain poorly understood, limiting the development of effective treatments. Although the roles of specific, targetable biomarkers in FOG development remain unidentified, evidence suggests that it is likely multimodal, potentially involving extranigral transmitter circuits. The diversity of FOG phenotypes may also reflect underlying differences in pathophysiology. In this paper, we first present evidence that FOG may occur independently of dopaminergic influence. We then review an expanding body of research supporting the hypothesis that FOG arises from a dysfunctional pathophysiological feedback loop, involving norepinephrine (NE) depletion, neuroinflammation, and amyloid-β (Aβ) accumulation. This biological disruption occurs concurrently with, but distinct from, the primary dopaminergic pathology of PD. When they occur on the background of dopamine loss, the interactions between NE, Aβ, and inflammation, as observed in Alzheimer's disease models, may similarly play a critical role in the development of FOG in PD and could serve as pathobiological markers. The proposed changes in the pathophysiological loop might even precede its onset, highlighting the need for further investigation. A deeper understanding of the involvement of Aβ, NE, and inflammatory markers in FOG could pave the way for rapid clinical trials to test existing amyloid-clearing therapies and noradrenergic drugs in appropriate patient populations.}, }
@article {pmid39971671, year = {2025}, author = {Perneczky, R and Darby, D and Frisoni, GB and Hyde, R and Iwatsubo, T and Mummery, CJ and Park, KH and van Beek, J and van der Flier, WM and Jessen, F}, title = {Real-world datasets for the International Registry for Alzheimer's Disease and Other Dementias (InRAD) and other registries: An international consensus.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {4}, pages = {100096}, doi = {10.1016/j.tjpad.2025.100096}, pmid = {39971671}, issn = {2426-0266}, mesh = {Humans ; *Registries ; *Alzheimer Disease/epidemiology ; *Consensus ; *Dementia/epidemiology ; Delphi Technique ; Cognitive Dysfunction/epidemiology ; Datasets as Topic ; }, abstract = {BACKGROUND: Many dementia and Alzheimer's disease (AD) registries operate at local or national levels without standardization or comprehensive real-world data (RWD) collection. This initiative sought to achieve consensus among experts on priority outcomes and measures for clinical practice in caring for patients with symptomatic AD, particularly in the mild cognitive impairment and mild to moderate dementia stages.
OBJECTIVE: The primary aim was to define a minimum dataset (MDS) and extended dataset (EDS) to collect RWD in the new International Registry for AD and Other Dementias (InRAD) and other AD registries. The MDS and EDS focus on informing routine clinical practice, covering relevant comorbidities and safety, and are designed to be easily integrated into existing data capture systems.
METHODS AND RESULTS: An international steering committee (ISC) of AD clinician experts lead the initiative. The first drafts of the MDS and EDS were developed based on a previous global inter-societal Delphi consensus on outcome measures for AD. Based on the ISC discussions, a survey was devised and sent to a wider stakeholder group. The ISC discussed the survey results, resulting in a consensus MDS and EDS covering: patient profile and demographics; lifestyle and anthropometrics; co-morbidities and diagnostics; imaging; treatment; clinical characterization; safety; discontinuation; laboratory tests; patient and care partner outcomes; and interface functionality.
CONCLUSION: By learning from successful examples in other clinical areas, addressing current limitations, and proactively enhancing data quality and analytical rigor, the InRAD registry will be a foundation to contribute to improving patient care and outcomes in neurodegenerative diseases.}, }
@article {pmid39971241, year = {2025}, author = {Yu, YJ and Rahman, MU and Balakrishnan, R and Kim, JM and Kim, JH and Choi, DK}, title = {The novel peptide DBCH reduces LPS-stimulated NF-κB/MAPK signaling in BV-2 microglia and ameliorates cognitive impairment in scopolamine-treated mice by modulating BDNF/CREB.}, journal = {Neurochemistry international}, volume = {185}, number = {}, pages = {105946}, doi = {10.1016/j.neuint.2025.105946}, pmid = {39971241}, issn = {1872-9754}, mesh = {Animals ; *Microglia/drug effects/metabolism ; *Scopolamine/toxicity ; Lipopolysaccharides/pharmacology/toxicity ; Mice ; *Cognitive Dysfunction/metabolism/drug therapy/chemically induced ; *Brain-Derived Neurotrophic Factor/metabolism ; *NF-kappa B/metabolism/antagonists & inhibitors ; Mice, Inbred C57BL ; Male ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *MAP Kinase Signaling System/drug effects/physiology ; Neuroprotective Agents/pharmacology ; Signal Transduction/drug effects/physiology ; *Peptides/pharmacology/therapeutic use ; }, abstract = {Microglial-mediated neuroinflammation significantly impacts cognitive impairment, and modulating neuroinflammatory responses has emerged as a promising target for treatment. However, the specific role of microglial-mediated neuroinflammation in cognitive impairment associated with Alzheimer's disease (AD) remains unclear. In our continuous endeavors to seek potent anti-Alzheimer's agents, we recently synthesized and developed a series of peptidomimetic compounds, including dipeptide-68 bis-cyclohexylpropyl histidinamide (DBCH), derived from a caryopsis-1 peptide that has demonstrated anti-inflammatory and anti-microbial properties in various infectious diseases. Among the bioactive peptides synthesized, DBCH exhibited good neuroprotective and anti-inflammatory activity and high potency. Therefore, in this study, the neuroprotective and anti-inflammatory effects of DBCH were assessed in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a scopolamine-induced C57BL/6 N amnesic mouse model. In the in vitro study, DBCH effectively suppressed the production and expression of nitric oxide (NO) and proinflammatory cytokines in BV-2 microglial cells stimulated with LPS. Furthermore, it effectively inhibited the LPS-triggered phosphorylation and activation of NF-κB/MAPK signaling and modulated inflammatory mediators, including iNOS and COX-2, in BV-2 microglial cells. In vivo results showed that DBCH administration of 5 or 10 mg/kg improved spatial memory learning and cognitive function in scopolamine-induced amnesic mice. Furthermore, DBCH treatment upregulated phosphorylated cAMP-response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) levels and downregulated the inflammatory response. Overall, DBCH effectively prevented both scopolamine-induced cognitive impairment and neuroinflammation. Our research findings suggest that DBCH may serve as a medication for cognitive decline associated with AD.}, }
@article {pmid39971019, year = {2025}, author = {Chen, Y and Zhu, Y and Tan, Z and Zhang, X and Hu, J and Zhu, R and Xie, M and Wang, J and Chen, L and Guo, Z}, title = {Jiajian Shuyu pills effectively ameliorate cognitive impairment via regulating the inflammation of microglia in an Alzheimer's disease mouse model.}, journal = {Journal of ethnopharmacology}, volume = {343}, number = {}, pages = {119508}, doi = {10.1016/j.jep.2025.119508}, pmid = {39971019}, issn = {1872-7573}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Microglia/drug effects/metabolism ; *Drugs, Chinese Herbal/pharmacology ; *Disease Models, Animal ; *Mice, Transgenic ; Mice ; *Cognitive Dysfunction/drug therapy ; Male ; Hippocampus/drug effects/metabolism ; Mice, Inbred C57BL ; Inflammation/drug therapy ; Cognition/drug effects ; Maze Learning/drug effects ; Neuroinflammatory Diseases/drug therapy ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments in the elderly. Microglia, the resident immune cells of the central nervous system, play a crucial role in modulating the pathological processes associated with AD. Jiajian Shuyu Pills (JJSYP) are frequently employed in the treatment of AD, purportedly by enhancing the physiological functions of human tissues and organs to modulate the immune response. Nevertheless, the underlying mechanisms by which JJSYP exert their therapeutic effects in the context of AD remain inadequately elucidated.
AIM OF THE STUDY: This study aimed to assess the effects of JJSYP on cognitive enhancement and the alleviation of neuroinflammation in the treatment of AD, as well as to explore the underlying mechanisms using mouse models.
MATERIALS AND METHODS: The components of JJSYP in serum were analyzed using HPLC-Q/TOF-MS. APP/PS1 transgenic mice served as AD models in this investigation. Cognitive function in the AD mice was assessed through the Mirror Water Maze Test and the Novel Object Recognition Test. The quantification of apoptotic hippocampal cells was conducted using Nissl staining and TUNEL staining. Immunofluorescence (IF) and Western blot (WB) analyses were employed to examine microglial activation and the expression of relevant proteins. Transcriptomic sequencing analysis and network pharmacology were administrated to explore the potential mechanisms of JJSYP in AD treatment. Inflammatory cytokine levels in the brain were measured using RT-PCR.
RESULTS: A total of 74 absorbed prototype components from JJSYP were identified. JJSYP effectively improved cognitive function and neuroapoptosis in AD model mice by modulating the activation of microglia. The JJSYP intervention alleviated neuroinflammation by suppressing microglial activation and reducing the accumulation of amyloid β-protein. Through transcriptome sequencing and WB verification, 34 differentially expressed genes (DEGs) were identified, including ACKR3, NR1H3 and Adra1a. Following treatment with a high dose of JJSYP, both ACKR3 and NR1H3 showed a significant decrease compared to the model group. Conversely, ADRA1A expression was reduced in model group compared to the control group, but increased following high dose JJSYP treatment. Research involving RNA sequencing and network pharmacology indicated that JJSYP altered the activation of CXCL12/ACKR3 signaling pathways in the hippocampus.
CONCLUSIONS: JJSYP exhibits potential anti-Alzheimer's Disease effects and warrants further investigation and development as a prosper treatment for AD.}, }
@article {pmid39970860, year = {2025}, author = {Weng, W and Lin, B and Zheng, J and Sun, Y and Li, Z and Chen, X and Wang, Y and Pan, X}, title = {Novel application of cycloastragenol target microglia for the treatment of Alzheimer's disease: Evidence from single-cell analysis, network pharmacology and experimental assessment.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {139}, number = {}, pages = {156502}, doi = {10.1016/j.phymed.2025.156502}, pmid = {39970860}, issn = {1618-095X}, mesh = {*Alzheimer Disease/drug therapy ; *Microglia/drug effects ; Animals ; Mice ; Humans ; *Sapogenins/pharmacology/chemistry ; *Network Pharmacology ; Phagocytosis/drug effects ; Molecular Docking Simulation ; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; Amyloid beta-Peptides/metabolism ; Hippocampus/drug effects ; Male ; Disease Models, Animal ; Mice, Transgenic ; Cognitive Dysfunction/drug therapy ; Cellular Senescence/drug effects ; }, abstract = {BACKGROUND: Cycloastragenol (CAG), a compound extracted from Astragalus, is known for its telomerase activation and anti-inflammatory, antioxidant properties. However, its potential pharmacological effects on Alzheimer's disease (AD) remain unclear.
PURPOSE: This study aimed to explore potential targets and molecular mechanisms for the role of CAG in alzheimer's disease (AD) treatment.
METHODS: CAG was administered to 5 × FAD mice. The senescent cell count was verified by senescence-associated β-galactosidase (SA-β-gal) staining. The impact of CAG on microglial phagocytosis was assessed by in vitro and in vivo assays. The potential targets of CAG were identified by network pharmacology and single-nucleus RNA sequencing (snRNA-seq). The underlying mechanism was validated by molecular docking, surface plasmon resonance (SPR) and western blotting.
RESULTS: CAG effectively ameliorated cognitive impairments and microglial senescence in 5 × FAD mice. In vivo and in vitro experiments revealed that CAG modulated microglial phagocytic activity and reduced hippocampal Aβ deposition The analysis of single-nucleus RNA sequencing data of AD patients reported 13 microglial targets for AD intervention. Phosphodiesterase 4B (PDE4B) was identified as the target through which CAG regulated microglial activity by utilizing network pharmacology, molecular docking and SPR. Western blotting revealed that the PDE4B/CREB/BDNF pathway may mediate the regulatory effect of CAG.
CONCLUSION: CAG can enhance microglial phagocytosis and alleviate memory dysfunction and amyloid plaque pathology. Our findings suggest that CAG may regulate microglial function through its interaction with PDE4B, providing a novel therapeutic strategy for AD.}, }
@article {pmid39970859, year = {2025}, author = {Tang, H and Li, L and Yu, Q and Chen, L and Xu, X and Meng, Z and Zeng, Y and Chen, F and Muzaffar, H and Wang, W and Zhao, X and Liang, G}, title = {Sclareol improves the pathology of Alzheimer's disease by inhibiting microglial inflammation via interacting with CDK9.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {139}, number = {}, pages = {156504}, doi = {10.1016/j.phymed.2025.156504}, pmid = {39970859}, issn = {1618-095X}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Microglia/drug effects ; Mice ; *Anti-Inflammatory Agents/pharmacology ; Male ; *Disease Models, Animal ; *Cyclin-Dependent Kinase 9/metabolism ; *Molecular Docking Simulation ; Inflammation/drug therapy ; Mice, Inbred C57BL ; Blood-Brain Barrier/drug effects ; Humans ; }, abstract = {BACKGROUND: Excessive activation of microglia triggers pro-inflammatory responses, exacerbating neuronal damage and accelerating the progression of Alzheimer's disease (AD). Thus, targeting abnormal microglial activation represents a promising therapeutic strategy for AD. In this study, we identified sclareol (SCL) through compound library screening as a potent anti-inflammatory agent capable of crossing the blood-brain barrier. However, there are currently no reports on whether SCL modulates microglial inflammation or ameliorates AD pathology.
OBJECTIVE: To evaluate the anti-inflammatory effects and underlying molecular mechanism of SCL on microglial-mediated inflammation and neuronal damage in AD.
METHODS: Drug Affinity Responsive Target Stability (DARTS), Liquid Chromatography-Tandem Mass Spectrometry (LC-MS), protein interaction assays, Biolayer Interferometry (BLI), and molecular docking were used to explore the interaction between SCL and cyclin-dependent kinase 9 (CDK9). Behavioral tests and immunofluorescent (IF) staining were performed to assess the effects of SCL on microglial activation and AD pathology. The molecular mechanism of the anti-inflammatory effect of SCL was analyzed by interfering with CDK9.
RESULTS: SCL significantly inhibited the release of proinflammatory mediators, reduced neuronal damage, and alleviated cognitive deficits in AD model mice. Notably, SCL demonstrated the ability to cross the blood-brain barrier (BBB), highlighting its therapeutic potential. Mechanistically, SCL binds directly to CDK9, which contributes to the inflammatory response through its interaction with NF-κB. Knockdown of CDK9 reduced the NF-κB-mediated inflammatory response, but did not have an additive effect on SCL, indicating that SCL's efficacy is mediated by CDK9 inhibition and subsequent suppression of the NF-κB signaling pathway.
CONCLUSION: This study demonstrates that SCL exerts neuroprotective effects in AD mice by targeting CDK9 and downstream NF-κB signaling pathway to reduce the inflammatory activation of microglia. These findings suggest that SCL is a promising candidate for the treatment of AD, offering a novel therapeutic approach to mitigate disease progression through modulation of microglial activation.}, }
@article {pmid39970376, year = {2025}, author = {Harvey, P and Curiel-Cid, R and Kallestrup, P and Mueller, A and Rivera-Molina, A and Czaja, S and Crocco, E and Loewenstein, D}, title = {Digital Migration of the Loewenstein Acevedo Scales for Semantic Interference and Learning (LASSI-L): Development and Validation Study in Older Participants.}, journal = {JMIR mental health}, volume = {12}, number = {}, pages = {e64716}, pmid = {39970376}, issn = {2368-7959}, mesh = {Humans ; Aged ; Male ; Female ; *Cognitive Dysfunction/diagnosis ; *Semantics ; Aged, 80 and over ; *Neuropsychological Tests/statistics & numerical data ; Reproducibility of Results ; Psychometrics/methods/instrumentation ; Learning/physiology ; }, abstract = {BACKGROUND: The early detection of mild cognitive impairment is crucial for providing treatment before further decline. Cognitive challenge tests such as the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) can identify individuals at highest risk for cognitive deterioration. Performance on elements of the LASSI-L, particularly proactive interference, correlate with the presence of critical Alzheimer disease biomarkers. However, in-person paper tests require skilled testers and are not practical in many community settings or for large-scale screening in prevention.
OBJECTIVE: This study reports on the development and initial validation of a self-administered computerized version of the Loewenstein-Acevedo Scales for Semantic Interference (LASSI), the digital LASSI (LASSI-D). A self-administered digital version, with an artificial intelligence-generated avatar assistant, was the migrated assessment.
METHODS: Cloud-based software was developed, using voice recognition technology, for English and Spanish versions of the LASSI-D. Participants were assessed with either the LASSI-L or LASSI-D first, in a sequential assessment study. Participants with amnestic mild cognitive impairment (aMCI; n=54) or normal cognition (NC; n=58) were also tested with traditional measures such as the Alzheimer Disease Assessment Scale-Cognition. We examined group differences in performance across the legacy and digital versions of the LASSI, as well as correlations between LASSI performance and other measures across the versions.
RESULTS: Differences on recall and intrusion variables between aMCI and NC samples on both versions were all statistically significant (all P<.001), with at least medium effect sizes (d>0.68). There were no statistically significant performance differences in these variables between legacy and digital administration in either sample (all P<.13). There were no language differences in any variables (P>.10), and correlations between LASSI variables and other cognitive variables were statistically significant (all P<.01). The most predictive legacy variables, proactive interference and failure to recover from proactive interference, were identical across legacy and migrated versions within groups and were identical to results of previous studies with the legacy LASSI-L. Classification accuracy was 88% for NC and 78% for aMCI participants.
CONCLUSIONS: The results for the digital migration of the LASSI-D were highly convergent with the legacy LASSI-L. Across all indices of similarity, including sensitivity, criterion validity, classification accuracy, and performance, the versions converged across languages. Future studies will present additional validation data, including correlations with blood-based Alzheimer disease biomarkers and alternative forms. The current data provide convincing evidence of the use of a fully self-administered digitally migrated cognitive challenge test.}, }
@article {pmid39969678, year = {2025}, author = {Sengupta, P and Mukhopadhyay, D}, title = {IGF1R/ARRB1 Mediated Regulation of ERK and cAMP Pathways in Response to Aβ Unfolds Novel Therapeutic Avenue in Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39969678}, issn = {1559-1182}, support = {RSI4002//Department of Atomic Energy, Government of India/ ; }, abstract = {IGF1R/INSR signaling is crucial for understanding Alzheimer's disease (AD) and may aid in the development of potent therapeutic strategies. This study investigated the expression and activity of these receptors and their potential to form functional hybrids in response to amyloid beta (Aβ). IGF1R, INSR, and ARRB1 were found to be upregulated in AD. The propensity for functional hybrid formation was also greater in the presence of Aβ. The association of IGF1R with ARRB1 reached a maximum at 60 min of Aβ treatment, which coincided with increased pERK activity at approximately the same time, indicating the importance of this association in pERK regulation. Knocking down IGF1R, INSR, and ARRB1 independently reduced cAMP, whereas overexpressing IGF1R significantly increased cAMP. Knocking down ARRB1 in IGF1R-overexpressing cells led to a reduction in cAMP, indicating that the interaction of ARRB1 and IGF1R possibly contributes to cAMP dysregulation. Since cAMP plays a crucial role in cognition and memory, alterations in cAMP after receptor hybridization could be significant in AD. Additionally, we noted hyperactivation of MAPK, which is associated with aberrant cellular activity, transcriptional control, and stress pathways. This finding highlights the importance of IGF1R and INSR dysregulation, which plays a major role in addition to conventional RTK signaling through multiple pathways. Here, we focused on the ARRB1 and IGF1R interaction and showed that picropodophyllin (PPP), an IGF1R-specific inhibitor, blocks this interaction and alters the ERK and cAMP status under disease conditions. Cell viability studies further revealed that the PPP substantially improved cell viability in the presence of Aβ. This highlights the role of the PPP in regulating these cascades and opens the arena for further therapeutic development for AD.}, }
@article {pmid39968692, year = {2025}, author = {Katsumi, Y and Touroutoglou, A and Brickhouse, M and Eloyan, A and Eckbo, R and Zaitsev, A and La Joie, R and Lagarde, J and Schonhaut, D and Thangarajah, M and Taurone, A and Vemuri, P and Jack, CR and Dage, JL and Nudelman, KNH and Foroud, T and Hammers, DB and Ghetti, B and Murray, ME and Newell, KL and Polsinelli, AJ and Aisen, P and Reman, R and Beckett, L and Kramer, JH and Atri, A and Day, GS and Duara, R and Graff-Radford, NR and Grant, IM and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, S and Turner, RS and Wingo, TS and Wolk, DA and Womack, K and Carrillo, MC and Rabinovici, GD and Apostolova, LG and Dickerson, BC and , }, title = {Dissociable spatial topography of cortical atrophy in early-onset and late-onset Alzheimer's disease: A head-to-head comparison of the LEADS and ADNI cohorts.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14489}, pmid = {39968692}, issn = {1552-5279}, support = {P30 AG066507/NH/NIH HHS/United States ; P30 AG062421/NH/NIH HHS/United States ; R21 AG073744/NH/NIH HHS/United States ; K23 DC016912/NH/NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; LDRFP-21-818464/ALZ/Alzheimer's Association/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG066515/NH/NIH HHS/United States ; P30 AG066506/NH/NIH HHS/United States ; R01 DC014296/DC/NIDCD NIH HHS/United States ; P30 AG062422/NH/NIH HHS/United States ; R56 AG057195/AG/NIA NIH HHS/United States ; P30 AG066511/NH/NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; R21 AG073744/AG/NIA NIH HHS/United States ; P50 AG005134/NH/NIH HHS/United States ; LDRFP-21-828356/ALZ/Alzheimer's Association/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; S10 RR021110/RR/NCRR NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; K01 AG084820/NH/NIH HHS/United States ; GENETICS-19-639372/ALZ/Alzheimer's Association/United States ; P30 AG072980/NH/NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; R01 DC014296/NH/NIH HHS/United States ; P30 AG010133/NH/NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R21 DC019567/NH/NIH HHS/United States ; U24 AG072122/NH/NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG072979/NH/NIH HHS/United States ; K23 DC016912/DC/NIDCD NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG066462/NH/NIH HHS/United States ; LDRFP-21-824473/ALZ/Alzheimer's Association/United States ; P30 AG072977/NH/NIH HHS/United States ; P30 AG062677/NH/NIH HHS/United States ; S10 RR023043/RR/NCRR NIH HHS/United States ; P41 EB015896/EB/NIBIB NIH HHS/United States ; S10 RR023401/RR/NCRR NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P30 AG066444/NH/NIH HHS/United States ; R21 DC019567/DC/NIDCD NIH HHS/United States ; K01 AG084820/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; *Atrophy/pathology ; Male ; Female ; *Magnetic Resonance Imaging ; Aged ; *Cognitive Dysfunction/pathology ; Middle Aged ; Cohort Studies ; Cerebral Cortex/pathology/diagnostic imaging ; Age of Onset ; }, abstract = {INTRODUCTION: Early-onset and late-onset Alzheimer's disease (EOAD and LOAD, respectively) have distinct clinical manifestations, with prior work based on small samples suggesting unique patterns of neurodegeneration. The current study performed a head-to-head comparison of cortical atrophy in EOAD and LOAD, using two large and well-characterized cohorts (LEADS and ADNI).
METHODS: We analyzed brain structural magnetic resonance imaging (MRI) data acquired from 377 sporadic EOAD patients and 317 sporadicLOAD patients who were amyloid positive and had mild cognitive impairment (MCI) or mild dementia (i.e., early-stage AD), along with cognitively unimpaired participants.
RESULTS: After controlling for the level of cognitive impairment, we found a double dissociation between AD clinical phenotype and localization/magnitude of atrophy, characterized by predominant neocortical involvement in EOAD and more focal anterior medial temporal involvement in LOAD.
DISCUSSION: Our findings point to the clinical utility of MRI-based biomarkers of atrophy in differentiating between EOAD and LOAD, which may be useful for diagnosis, prognostication, and treatment.
HIGHLIGHTS: Early-onset Alzheimer's disease (EOAD) and late-onset AD (LOAD) patients showed distinct and overlapping cortical atrophy patterns. EOAD patients showed prominent atrophy in widespread neocortical regions. LOAD patients showed prominent atrophy in the anterior medial temporal lobe. Regional atrophy was correlated with the severity of global cognitive impairment. Results were comparable when the sample was stratified for mild cognitive impairment (MCI) and dementia.}, }
@article {pmid39968517, year = {2025}, author = {Kocanci, FG}, title = {Effect of Pimecrolimus on apoptotic pathways in H2O2-treated neuron like differentiated-SH-SY5Y cells: a molecular docking and mechanistic study.}, journal = {Toxicology research}, volume = {14}, number = {1}, pages = {tfaf020}, pmid = {39968517}, issn = {2045-452X}, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's and Parkinson's, are marked by progressive neuronal loss, driven largely by oxidative stress and apoptosis. Developing neuroprotective strategies to counteract these processes is critical for managing such disorders. This study explores the neuroprotective effects of pimecrolimus, a calcineurin inhibitor, in mitigating hydrogen peroxide (H2O2)-induced cytotoxicity in neuron-like differentiated SH-SY5Y (d-SH-SY5Y) cells. The investigation focuses on apoptosis modulation, cell viability, and molecular docking interactions with apoptotic proteins. SH-SY5Y cells were differentiated with retinoic acid and treated with H2O2 (250 μM) alone or in combination with pimecrolimus (0.01, 0.1, and 1 μM) for 24 h. Cell viability was assessed using lactate dehydrogenase (LDH) assays. Additionally, malondialdehyde (MDA) levels were measured to assess oxidative stress in SH-SY5Y cells following the treatment conditions. Molecular docking analyses evaluated pimecrolimus' interactions with bax, bcl-2, caspase-3 and caspase-8 proteins, using Venetoclax as a positive control. Apoptosis-related protein levels were analyzed via ELISA, qRT-PCR, and immunofluorescence staining (cleaved caspase-3 and DAPI). Molecular docking showed strong binding of pimecrolimus to bax, bcl-2, caspase-3 and caspase-8, with comparable binding energies to Venetoclax. LDH and MDA assays demonstrated significant reductions in H2O2-induced cytotoxicity with pimecrolimus. ELISA and qRT-PCR revealed that H2O2 increased pro-apoptotic bax, caspase-3 and caspase-8 levels while decreasing anti-apoptotic bcl-2 levels. Pimecrolimus co-treatment reversed these effects in a dose-dependent manner. Immunofluorescence confirmed reduced apoptosis and cell death with pimecrolimus. Pimecrolimus effectively mitigates oxidative stress and apoptosis in H2O2-treated d-SH-SY5Y cells. These findings suggest its potential as a neuroprotective agent for managing (NDs).}, }
@article {pmid39968373, year = {2025}, author = {Dong, S and Zhang, R and Xue, J and Suo, Y and Wei, X}, title = {Quantitative simulation of near-infrared light treatment for Alzheimer's disease using patient-individualized optical-parametric phantoms.}, journal = {Neurophotonics}, volume = {12}, number = {1}, pages = {015010}, pmid = {39968373}, issn = {2329-423X}, abstract = {SIGNIFICANCE: Alzheimer's disease (AD) is a brain disorder characterized by its multifactorial nature and complex pathogenesis, highlighting the necessity for multimodal and individualized interventions. Among emerging therapies, near-infrared (NIR) light treatment shows promise as a therapeutic modality for AD. However, existing clinical studies lack sufficient data on light dosimetry, parameter optimization, and dose-response.
AIM: A versatile framework was developed to enable patient-individualized Monte Carlo simulation. A standardized dataset was established, including digital phantoms derived from 20 AD patients who received NIR light treatment.
APPROACH: The phantoms were synthesized and mapped with multispectral optical parameters, integrating cortical parcellation, subcortical segmentation, and sparse annotation. Structure-related light fluence pathways and dose-response relationships were elucidated using simulation results and cognitive/functional assessments.
RESULTS: The capability for enhancing simulation fidelity and exploring dose-response relationships was verified using standard templates and clinical data. Linear independence was identified between changes in activities of daily living scale scores and energy deposition in gray matter.
CONCLUSIONS: The framework offers a solution toward dose-response analysis, parameter optimization, and safety control in the clinical translation for multiple treatment paradigms, demonstrating promise for individualized, standardized, and precise intervention planning.}, }
@article {pmid39968005, year = {2025}, author = {Conic, JZ and Chetty, A and Chen, L and Marsh, A and Barry, S and Pattabhi, R and Reske, T and Aguilar, E and Ali, L}, title = {Effect of Steroids on the Progression of Alzheimer's Dementia: A Retrospective Chart Review.}, journal = {Aging medicine (Milton (N.S.W))}, volume = {8}, number = {1}, pages = {e70004}, pmid = {39968005}, issn = {2475-0360}, abstract = {OBJECTIVES: Alzheimer's disease (AD) is a prevalent age-related neurodegenerative disease that affects millions of individuals in the United States. Neuroinflammation is a driver of the neurodegenerative changes that characterize AD, prompting interest in how inflammation can be modulated for treatment and prevention.
METHODS: ICD-10 codes were quarried from electronic medical records to identify patients diagnosed with AD from 2012 to 2020. The patients were then divided into those who used systemic steroids and those who did not before the progression of their disease. Data on medication prescribed was used to measure the disease's progression. Clinical findings and laboratory results were collected to build a propensity score. Patients were followed until disease progression, death, or the last available visit. Kaplan-Meier curves and hazard ratios adjusted for the propensity score were used to compare the two groups.
RESULTS: Of the 459 patients identified, 77 were included in the study, and 13 used steroids. Of the 77 patients included in the study, 59 had progression of their disease, and of those, five used steroids. The median time to progression was 408.00 (191.00, 979.00) days for the overall sample. The hazard ratio (HR) comparing the group using steroids to those not using steroids was 0.26 with a 95% CI of (0.1013, 0.673) and a p value of 0.00064.
CONCLUSIONS: In our study, steroid use delayed the progression of dementia. Further study is needed to outline how steroids and anti-inflammatory medications can be used in the treatment and prevention of AD.}, }
@article {pmid39967803, year = {2025}, author = {Smadja, DM and Abreu, MM}, title = {Hyperthermia and targeting heat shock proteins: innovative approaches for neurodegenerative disorders and Long COVID.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1475376}, pmid = {39967803}, issn = {1662-4548}, abstract = {Neurodegenerative diseases (NDs) and Long COVID represent critical and growing global health challenges, characterized by complex pathophysiological mechanisms including neuronal deterioration, protein misfolding, and persistent neuroinflammation. The emergence of innovative therapeutic approaches, such as whole-body hyperthermia (WBH), offers promising potential to modulate underlying pathophysiological mechanisms in NDs and related conditions like Long COVID. WBH, particularly in fever-range, enhances mitochondrial function, induces heat shock proteins (HSPs), and modulates neuroinflammation-benefits that pharmacological treatments often struggle to replicate. HSPs such as HSP70 and HSP90 play pivotal roles in protein folding, aggregation prevention, and cellular protection, directly targeting pathological processes seen in NDs like Alzheimer's, Parkinson's, and Huntington's disease. Preliminary findings also suggest WBH's potential to alleviate neurological symptoms in Long COVID, where persistent neuroinflammation and serotonin dysregulation are prominent. Despite the absence of robust clinical trials, the therapeutic implications of WBH extend to immune modulation and the restoration of disrupted physiological pathways. However, the dual nature of hyperthermia's effects-balancing pro-inflammatory and anti-inflammatory responses-emphasizes the need for dose-controlled applications and stringent patient monitoring to minimize risks in vulnerable populations. While WBH shows potential interest, significant challenges remain. These include individual variability in response, limited accessibility to advanced hyperthermia technologies, and the need for standardized clinical protocols. Future research must focus on targeted clinical trials, biomarker identification, and personalized treatment strategies to optimize WBH's efficacy in NDs and Long COVID. The integration of WBH into therapeutic paradigms could mark a transformative step in addressing these complex conditions.}, }
@article {pmid39967802, year = {2025}, author = {Alves, SM and Lisboa-Filho, PN and Zilli Vieira, CL and Piacenti-Silva, M}, title = {Alzheimer's disease and gut-brain axis: Drosophila melanogaster as a model.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1543826}, pmid = {39967802}, issn = {1662-4548}, abstract = {Research indicates that by 2050, more than 150 million people will be living with Alzheimer's disease (AD), a condition associated with neurodegeneration due to the accumulation of amyloid-beta and tau proteins. In addition to genetic background, endocrine disruption, and cellular senescence, management of the gut microbiota has emerged as a key element in the diagnosis, progression, and treatment of AD, as certain bacterial metabolites can travel through the bloodstream and cross the blood-brain barrier. This mini-review explores the relationship between tau protein accumulation and gut dysbiosis in Drosophila melanogaster. This model facilitates the investigation of how gut-derived metabolites contribute to neurocognitive impairment and dementia. Understanding the role of direct and indirect bacterial by-products, such as lactate and acetate, in glial cell activation and tau protein dynamics may provide insights into the mechanisms of AD progression and contribute to more effective treatments. Here we discuss how the simplicity and extensive genetic tools of Drosophila make it a valuable model for studying these interactions and testing potential therapeutics, including probiotics. Integrating Drosophila studies with other established models may reveal conserved pathways and accelerate the translation of findings into clinical applications.}, }
@article {pmid39967643, year = {2025}, author = {Abdel-Magid, AF}, title = {Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors as Potential Treatment for Several Inflammatory and Neurodegenerative Diseases.}, journal = {ACS medicinal chemistry letters}, volume = {16}, number = {2}, pages = {204-206}, pmid = {39967643}, issn = {1948-5875}, abstract = {The invention in this patent application relates to 2-amino-[1,2,4]triazolo[1,5-a]pyridin derivatives represented generally herein as formula 1. These compounds have activities as receptor-interacting protein kinase 1 (RIPK1) inhibitors and may potentially provide treatment and/or prophylaxis of inflammatory and neurodegenerative diseases associated with aberrant RIPK1 activity such as ulcerative colitis, Crohn's disease, psoriasis, NASH, heart failure, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease.}, }
@article {pmid39967628, year = {2025}, author = {Abdel-Magid, AF}, title = {Potential of Histone Deacetylase 6 Inhibitors as a Treatment of Neurodegenerative Diseases.}, journal = {ACS medicinal chemistry letters}, volume = {16}, number = {2}, pages = {210-212}, pmid = {39967628}, issn = {1948-5875}, abstract = {The invention in this patent application relates to 2-substituted-6-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)isoindolin-1-one derivatives represented herein by formula 1. These compounds possess HDAC6 inhibitory activity and may be useful for the treatment of central nervous system diseases including neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy.}, }
@article {pmid39966464, year = {2025}, author = {Ramasamy, VS and Nathan, ABP and Choi, MC and Kim, SH and Ohn, T}, title = {Aβ42 induces stress granule formation via PACT/PKR pathway.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {5829}, pmid = {39966464}, issn = {2045-2322}, mesh = {*Amyloid beta-Peptides/metabolism ; Humans ; Animals ; *eIF-2 Kinase/metabolism/genetics ; *Peptide Fragments/metabolism ; *Signal Transduction ; Mice ; *Stress Granules/metabolism ; Cell Line, Tumor ; Alzheimer Disease/metabolism/pathology ; Adaptor Proteins, Vesicular Transport/metabolism/genetics ; Eukaryotic Initiation Factor-2/metabolism ; }, abstract = {Stress granule (SG) formation has been linked to several neurodegenerative disorders, such as Alzheimer's disease (AD). Amyloid-β42 (Aβ42) is a key player in the pathogenesis of AD and is known to trigger various stress-related signaling pathways. However, the impact of Aβ on SG formation has not been fully understood. The primary aim of this study is to analyze the SG-inducing properties of Aβ42 and to uncover the molecular mechanisms underlying this process. Our results revealed that exposure to 20 μM Aβ42 led to a significant SG formation in neuroblastoma-derived (SH-SY5Y) and glioma-derived (U87) cell lines. Interestingly, we observed elevated levels of p-eIF2α, while overall protein translation levels remained unchanged. Monomeric and oligomeric forms of Aβ42 exhibited a 4-5 times stronger ability to induce SG formation compared to fibrillar forms. Additionally, treatment with familial mutants of Aβ42 (Dutch and Flemish) showed distinct effects on SG induction. Moreover, our findings using eIF2α kinases knockout (KO) cell lines demonstrated that Aβ-induced SG formation is primarily dependent on Protein Kinase R (PKR). Subsequent proximity ligation assay (PLA) analysis revealed a close proximity of PACT and PKR in Aβ-treated cells and in AD mouse hippocampus. Taken together, our study suggests that Aβ42 promotes SG formation through PKR kinase activation, which in turn requires PACT involvement.}, }
@article {pmid39966100, year = {2025}, author = {Lobyntseva, A and Ganaiem, M and Ivashko-Pachima, Y and Barnstable, CJ and Weisinger, B and Parabucki, A and Segal, Y and Shohami, E and Gozes, I}, title = {Extremely Low-Frequency and Low-Intensity Electromagnetic Field Technology (ELF-EMF) Sculpts Microtubules.}, journal = {The European journal of neuroscience}, volume = {61}, number = {4}, pages = {e70023}, pmid = {39966100}, issn = {1460-9568}, support = {//BrainQ Technologies Ltd./ ; }, mesh = {*Microtubules/metabolism ; *tau Proteins/metabolism ; *Electromagnetic Fields ; Cell Line, Tumor ; Humans ; Zinc/metabolism ; Phosphorylation ; Animals ; Tubulin/metabolism ; Neurons/metabolism/radiation effects ; Magnetic Field Therapy/methods ; Mice ; }, abstract = {Aberrant microtubule dynamics coupled with a reduction in Tau-microtubule interaction are at the core of neuronal injuries resulting in microtubule disruption and aggregates of abnormally phosphorylated Tau. These pathological Tau aggregates define tauopathies such as Alzheimer's disease (AD), as well as the pathological sequelae following traumatic brain injury (TBI), stroke and spinal cord injury (SCI). We hypothesized that differential applications of extremely low-frequency and low-intensity electromagnetic field (ELF-EMF) will change microtubule function. To examine our hypothesis, we pre-applied ELF-EMF to a neuroblastoma neuronal cell line later exposed to 4 h of zinc intoxication, modelling Tau-microtubule dissociation. ELF-EMF (40 Hz and 1 G; multiple exposure schedules) enhanced microtubule dynamics and increased Tau-microtubule interaction in the face of zinc toxicity. Complementing these preconditioning neuroprotective effects, concomitant 1 h treatment protocols comparing 3.9 or 40 Hz and 1 G exposure, indicated effects on Tau phosphorylation accentuated with 40 Hz and reduction in beta tubulin isotypes, depending on electromagnetic frequencies, most pronounced at 3.9 Hz. Our results discovered ELF-EMF modulation on the microtubule cytoskeleton essential for brain health.}, }
@article {pmid39965691, year = {2025}, author = {Prabakaran, A and Rakshit, D and Patel, I and Susanna, KJ and Mishra, A and Radhakrishnanand, P and Sarma, P and Alexander, A}, title = {Chitosan-coated nanostructured lipid carriers for intranasal delivery of sinapic acid in Aβ1-42 induced C57BL/6 mice for Alzheimer's disease treatment.}, journal = {International journal of biological macromolecules}, volume = {305}, number = {Pt 2}, pages = {141136}, doi = {10.1016/j.ijbiomac.2025.141136}, pmid = {39965691}, issn = {1879-0003}, abstract = {Sinapic acid (SA) is a plant-derived antioxidant that exhibits neuroprotective activity. However, its poor bioavailability in the brain limits its therapeutic application in treating Alzheimer's disease (AD). Therefore, the present study hypothesizes that coating nanostructured lipid carriers (NLCs) with a biological macromolecule like chitosan (CH-SA-NLCs) could enhance the delivery of SA for AD treatment. The CH-SA-NLCs were spherical with sizes below 200 nm, confirmed by AFM, SEM, and TEM and achieved a sustained drug release of 76.5 % in pH 6.5 simulated nasal fluid over 24 h. Moreover, the histopathology study confirmed the safety of CH-SA-NLCs, validating its suitability for intranasal administration. Not only the in vitro sustained drug release closely correlated with in vivo pharmacokinetics of CH-SA-NLCs (i.n.), demonstrating a 1.7-fold increase in SA's half-life compared to plain SA (i.v.) in plasma but also CH-SA-NLCs (i.n.) achieved a superior AUC0-∞ of 7676.32 ± 2738.55 ng/g*h with a 2.6-fold improved drug targeting efficiency of SA in the brain of BALB/c mice. These improvements resulted in significant neuroprotective effects and decreased oxidative stress and inflammatory levels in Aβ1-42-induced mice. Overall, the study highlights safe and effective intranasal delivery of SA via chitosan-coated nanocarrier as a promising AD treatment strategy.}, }
@article {pmid39965199, year = {2025}, author = {Frederiksen, KS and Hahn-Pedersen, J and Crawford, R and Morrison, R and Jeppesen, R and Doward, L and Weidner, W}, title = {Traversing Shifting Sands-the Challenges of Caring for Someone With Alzheimer's Disease and the Impact on Care Partners: Social Media Content Analysis.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e55468}, pmid = {39965199}, issn = {1438-8871}, mesh = {*Alzheimer Disease/psychology ; Humans ; *Social Media ; *Caregivers/psychology ; *Quality of Life/psychology ; }, abstract = {BACKGROUND: Social media data provide a valuable opportunity to explore the effects that Alzheimer disease (AD) has on care partners, including the aspects of providing care that have the greatest impacts on their lives and well-being and their priorities for their loved ones' treatment.
OBJECTIVE: The objective of this social media review was to gain insight into the impact of caring for someone with AD, focusing particularly on impacts on psychological and emotional well-being, social functioning, daily life and ability to work, health-related quality of life, social functioning, and relationships.
METHODS: We reviewed social media posts from 4 sources-YouTube (Google), Alzheimer's Association, Alzheimer Society of Canada, and Dementia UK-to gain insights into the impact of AD on care partners. English-language posts uploaded between May 2011 and May 2021 that discussed the impact of AD on care partners were included and analyzed thematically.
RESULTS: Of the 279 posts identified, 55 posts, shared by 70 contributors (4 people living with AD and 66 care partners or family members), met the review criteria. The top 3 reported or observed impacts of AD discussed by contributors were psychological and emotional well-being (53/70, 76%), social life and relationships (37/70, 53%), and care partner overall health-related quality of life (27/70, 39%). An important theme that emerged was the emotional distress and sadness (24/70, 34%) associated with the care partners' experience of "living bereavement" or "anticipatory grief." Contributors also reported impacts on care partners' daily life (9/70, 13%) and work and employment (8/70, 11%). Care partners' emotional distress was also exacerbated by loved ones' AD-related symptoms (eg, altered behavior and memory loss). Caregiving had long-term consequences for care partners, including diminished personal well-being, family and personal sacrifices, loss of employment, and unanticipated financial burdens.
CONCLUSIONS: Insights from social media emphasized the psychological, emotional, professional, and financial impacts on individuals providing informal care for a person with AD and the need for improved care partner support. A comprehensive understanding of care partners' experiences is needed to capture the true impact of AD.}, }
@article {pmid39964126, year = {2025}, author = {McIntyre, RS and Rasgon, N and Goldberg, J and Wong, S and Le, GH and Mansur, RB and Rosenblat, JD and Teopiz, KM and Stahl, SM}, title = {The effect of glucagon-like peptide-1 and glucose dependent insulinotropic polypeptide receptor agonists on neurogenesis, differentiation, and plasticity (Neuro-GDP): potential mechanistically informed therapeutics in the treatment and prevention of mental disorders.}, journal = {CNS spectrums}, volume = {30}, number = {1}, pages = {e23}, doi = {10.1017/S1092852925000124}, pmid = {39964126}, issn = {1092-8529}, mesh = {Humans ; *Mental Disorders/drug therapy ; *Neuronal Plasticity/drug effects ; *Receptors, Gastrointestinal Hormone/agonists ; *Neurogenesis/drug effects ; Animals ; *Glucagon-Like Peptide 1/agonists/metabolism ; Glucagon-Like Peptide-1 Receptor ; }, abstract = {Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (RAs) mimic naturally occurring GLP-1 and GIP and are highly effective anti-diabetic and anti-obesity agents. In addition to their robust acute and long-term effects on weight, metabolism, and blood pressure, these agents also reduce cardiovascular mortality as well as stroke risk and associated consequences. A replicated and convergent body of preclinical evidence also indicates that incretin receptor agonists activate molecular effectors critical to neuroplasticity, neuroprotection, and anti-apoptosis. Herein, we propose that GLP-1 RAs and GIP RAs are promising transdiagnostic mechanistically informed therapeutics in the treatment and prevention of multiple domains of psychopathology, including general cognitive, reward, and motivation systems and mental disorders. Major neurocognitive disorders (eg, Alzheimer's Disease, Parkinson's Disease), alcohol and substance use disorders, traumatic brain injury, and depressive disorders are near-term therapeutic targets. In addition, GLP-1 RAs and GIP RAs have robust effects on comorbidities that differentially affect persons with mental disorders (eg, cardiovascular, cerebrovascular, and metabolic disorders) and psychotropic drug-related weight gain.}, }
@article {pmid39963928, year = {2025}, author = {Lomas, C and Dubey, RC and Perez-Alvarez, G and Lopez Hernandez, Y and Atmar, A and Arias, AY and Vashist, A and Aggarwal, S and Manickam, P and Lakshmana, MK and Vashist, A}, title = {Recent advances in nanotherapeutics for HIV-associated neurocognitive disorders and substance use disorders.}, journal = {Nanomedicine (London, England)}, volume = {20}, number = {6}, pages = {603-619}, pmid = {39963928}, issn = {1748-6963}, support = {R01 DA049657/DA/NIDA NIH HHS/United States ; R03 AG087475/AG/NIA NIH HHS/United States ; U01 ES033265/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/complications/drug therapy ; *Substance-Related Disorders ; *Blood-Brain Barrier/metabolism/drug effects ; Nanoparticles/chemistry ; Animals ; Neurocognitive Disorders/drug therapy/etiology ; Nanomedicine/methods ; AIDS Dementia Complex/drug therapy ; }, abstract = {Substance use disorders (SUD) and HIV-associated neurocognitive disorders (HAND) work synergistically as a significant cause of cognitive decline in adults and adolescents globally. Current therapies continue to be limited due to difficulties crossing the blood-brain barrier (BBB) leading to limited precision and effectiveness, neurotoxicity, and lack of co-treatment options for both HAND and SUD. Nanoparticle-based therapeutics have several advantages over conventional therapies including more precise targeting, the ability to cross the BBB, and high biocompatibility which decreases toxicity and optimizes sustainability. These advantages extend to other neurological disorders such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). This review summarizes recent advances in nanotechnology for application to HAND, SUD, and co-treatment, as well as other neurological disorders. This review also highlights the potential challenges these therapies face in clinical translation and long-term safety.}, }
@article {pmid39963471, year = {2025}, author = {Wright, AL and Weible, AP and Estes, OB and Wehr, M}, title = {Ketamine does not rescue plaque load or gap detection in the 5XFAD mouse model of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1505908}, pmid = {39963471}, issn = {1663-4365}, support = {R01 AG077681/AG/NIA NIH HHS/United States ; RF1 NS127305/NS/NINDS NIH HHS/United States ; }, abstract = {Ketamine has received growing attention for its effects on neuroplasticity and neuroinflammation, and as a treatment for depression and other mental health disorders. Recent evidence suggests that early sensory and behavioral deficits in Alzheimer's disease could be caused by synaptic disruption that occurs before irreversible neuropathology. This raises the possibility that ketamine could slow down or prevent network disruption and the ensuing sensory and behavioral deficits in Alzheimer's. Here we tested this idea in the 5XFAD mouse model of Alzheimer's, using either an acute single injection of ketamine, or chronic daily injections over 15 weeks. We tested the effects of ketamine on both amyloid plaque load and on a behavioral auditory gap detection task that is an early Alzheimer's biomarker in both mice and humans. We found that ketamine had no effect on plaque load, nor any effect on gap detection, for either acute or chronic dosing. Chronic ketamine facilitated startle responses specifically in 5XFAD mice, but this could simply be related to experience-dependent effects on stress or habituation rather than any rescue effect of ketamine on Alzheimer's-related deficits. We did find robust correlations between gap detection deficits and plaque load in auditory cortex and in the caudal pontine reticular nucleus, demonstrating that the behavioral deficits seen in 5XFAD mice are directly related to amyloid accumulation in these brain regions, and confirming the validity of gap detection as an early biomarker of Alzheimer's. Ketamine, however, had no effect on the strength of these correlations. We conclude that ketamine has no beneficial effect on the development of behavioral gap detection deficits or plaque load in the 5XFAD Alzheimer's mouse model, following either an acute single dose or a chronic daily dose regimen.}, }
@article {pmid39963432, year = {2025}, author = {Dhariwal, R and Jain, M and Mir, YR and Singh, A and Jain, B and Kumar, P and Tariq, M and Verma, D and Deshmukh, K and Yadav, VK and Malik, T}, title = {Targeted drug delivery in neurodegenerative diseases: the role of nanotechnology.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1522223}, pmid = {39963432}, issn = {2296-858X}, abstract = {Neurodegenerative diseases, characterized by progressive neuronal loss and cognitive impairments, pose a significant global health challenge. This study explores the potential of nanotherapeutics as a promising approach to enhance drug delivery across physiological barriers, particularly the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (B-CSFB). By employing nanoparticles, this research aims to address critical challenges in the diagnosis and treatment of conditions such as Alzheimer's, Parkinson's, and Huntington's diseases. The multifactorial nature of these disorders necessitates innovative solutions that leverage nanomedicine to improve drug solubility, circulation time, and targeted delivery while minimizing off-target effects. The findings underscore the importance of advancing nanomedicine applications to develop effective therapeutic strategies that can alleviate the burden of neurodegenerative diseases on individuals and healthcare systems.}, }
@article {pmid39963073, year = {2025}, author = {Li, B and Wang, L and Xiao, Y and Wang, Y and Wang, Y and Peng, Y and Zhang, A and Tang, Z and Qi, X}, title = {Gastrodin Ameliorates Tau Pathology and BBB Dysfunction in 3xTg-AD Transgenic Mice by Regulating the ADRA1/NF-κB/NLRP3 Pathway to Reduce Neuroinflammation.}, journal = {Phytotherapy research : PTR}, volume = {}, number = {}, pages = {}, doi = {10.1002/ptr.8461}, pmid = {39963073}, issn = {1099-1573}, support = {82260263//Chinese National Natural Science Foundation/ ; Qiankehe Platform Talents-GCC[2023]035//Guizhou Provincial Science and Technology Program Project/ ; Qiankehe Platform Talents-CXTD[2023]003//Guizhou Provincial Science and Technology Program Project/ ; Qiankehe Support [2023] General 232//Guizhou Provincial Science and Technology Program Project/ ; Qiankehe Basic-[2024] Youth 228//Guizhou Provincial Science and Technology Program Project/ ; QianJiaoji [2024]92//Guizhou Provincial Department of Education Youth Science and Technology Talent Project/ ; gzwkj2022-187//Science and Technology Fund Project of the Guizhou Provincial Health Commission/ ; }, abstract = {BACKGROUND AND AIM: Gastrodin, an active compound derived from the traditional Chinese herbal medicine Gastrodia, demonstrates a variety of pharmacological effects, particularly in the enhancement of neural functions. Thus, the aim of this study is to explore the therapeutic effects of gastrodin on Alzheimer's disease (AD) and its underlying molecular mechanisms.
EXPERIMENTAL PROCEDURE: Cognitive function was assessed via Morris water maze and Y-maze tests. Tau pathology, neuroinflammation, and BBB dysfunction were analyzed using various techniques, including Western blot, immunohistochemistry, and ELISA. ADRA1 overexpression was induced by lentiviral infection, and gastrodin's impact on NF-κB p65, NLRP3, IL-1β, and IL-18 levels was evaluated.
KEY RESULTS: In the in vivo experiment, gastrodin enhanced learning and spatial memory in 3xTg-AD mice, as well as reducing p-Tau protein expression in the hippocampus and cortex. Gastrodin inhibited the ADRA1/NF-κB/NLRP3 pathway, which decreased glial cell activation and inflammatory cytokines IL-1β and IL-18, improving neuron and BBB function. In the in vitro experiment, gastrodin inhibited the activation of the NF-κB/NLRP3 pathway due to ADRA1 overexpression and prevented the Aβ42-induced increase in ADRA1/NF-κB/NLRP3 protein expression in SH-SY5Y cells. It also reduced IL-1β and IL-18 cytokine release, restoring tight junction protein expression in bEnd.3 cells.
CONCLUSIONS AND IMPLICATIONS: gastrodin ameliorates learning and memory abilities by alleviating neuroinflammation and tau pathology, restoring the structure and function of neurons and BBB, suggesting that gastrodin may serve as an effective drug for the treatment of AD.}, }
@article {pmid39962970, year = {2025}, author = {Fiala, M and Hammock, BD and Hwang, SH and Whitelegge, J and Paul, K and Kaczor-Urbanowicz, KE and Urbanowicz, A and Kesari, S}, title = {Inhibitors of soluble epoxide hydrolase and cGAS/STING repair defects in amyloid-β clearance underlying vascular complications of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {104}, number = {1}, pages = {150-157}, pmid = {39962970}, issn = {1875-8908}, support = {U54 NS127758/NS/NINDS NIH HHS/United States ; P42 ES004699/ES/NIEHS NIH HHS/United States ; S10 OD025017/OD/NIH HHS/United States ; R35 ES030443/ES/NIEHS NIH HHS/United States ; R01 NS078410/NS/NINDS NIH HHS/United States ; }, mesh = {*Epoxide Hydrolases/metabolism/antagonists & inhibitors ; Humans ; *Alzheimer Disease/metabolism ; *Amyloid beta-Peptides/metabolism ; Male ; Macrophages/metabolism/drug effects ; Female ; Enzyme Inhibitors/pharmacology ; Aged ; Aged, 80 and over ; Peptide Fragments/metabolism ; }, abstract = {BackgroundAlzheimer's disease (AD) and its monoclonal antibody therapies are associated with brain vasculitis and amyloid-related imaging abnormalities. The naturally-formed epoxides (EpFAs) of polyunsaturated fatty acids (PUFAs), such as 11,12-epoxyeicosatetraenoic acid (EEQ), are anti-inflammatory and pro-resolution mediators, which are increased by dietary supplementation with ω-3 PUFAs. EpFAs are, however, enzymatically hydrolyzed by soluble epoxide hydrolase (sEH) in AD patients' macrophages in vivo and in vitro.ObjectiveTo repair amyloid-β 1-42 (Aβ) degradation by AD macrophages using the inhibitors of a) soluble epoxide hydrolase (sEHIs), termed TPPU and EC5026, together with EpFAs, or b) STING pathway termed H-151.MethodsImmunobiology, immunochemistry, RNA sequencing, and confocal microscopy were used.ResultsIn AD brain (examined postmortem), monocyte/macrophages upload Aβ in plaques and transfer it without degradation into brain microvessels, suffer apoptotis, and release Aβ, inducing vasculitis. The EpFAs of epoxyeicosatetraenoic acid (EEQ), along with the inhibitors TPPU and H-151, decrease inflammatory cytokines and regulate macrophage unfolded protein response to endoplasmic reticulum stress. Treatment of AD macrophages by TPPU with EEQ or by STING inhibitor H-151 increased uploading of Aβ after 2 hours and increased degradation of Aβ after 24 hours.ConclusionsThe sEHI inhibitor EC5026 and the STING inhibitor H-151 increased macrophage uptake and degradation of Aβ. EC5026 administration was safe in normal volunteers. EC5026 together with ω-3 PUFA supplementation are indicated for in a clinical trial in patients with mild cognitive impairment.}, }
@article {pmid39962563, year = {2025}, author = {Sarti, P and Varrasi, S and Guerrera, CS and Platania, GA and Furneri, G and Torre, V and Boccaccio, FM and Rivi, V and Tascedda, S and Pirrone, C and Santagati, M and Blom, JMC and Castellano, S and Caraci, F}, title = {Exploring apathy components and their relationship in cognitive decline: insights from a network cross-sectional study.}, journal = {BMC psychology}, volume = {13}, number = {1}, pages = {129}, pmid = {39962563}, issn = {2050-7283}, mesh = {Humans ; *Apathy ; Male ; Female ; *Cognitive Dysfunction/psychology ; Cross-Sectional Studies ; Aged ; *Alzheimer Disease/psychology ; Aged, 80 and over ; Neuropsychological Tests ; Middle Aged ; Disease Progression ; }, abstract = {BACKGROUND: Apathy worsens with age and cognitive decline, particularly in Alzheimer's, leading to functional and cognitive deterioration. Comprehending its broad impact is vital for customized, preventive treatments.
METHODS: The study examined 214 adults divided in three groups-Mild Cognitive Impairment, mild Alzheimer's, and controls-using neuropsychological tests and questionnaires, with statistical and network analysis to explore apathy's links with other group variables related to demographics and treatment.
RESULTS: Notable differences were observed among the groups' performance of administered tests. While inferential statistics failed to return a predictive model of apathy in mild Alzheimer's, networks and cluster analyses indicate that the demographic variables analysed have different importance at different times of disease progression and that cognitive apathy is particularly prominent in AD-related decline.
CONCLUSIONS: Network analysis revealed insights into dementia risk differentiation, notably the impact of sex and demographic factors, beyond the scope of traditional statistics. It highlighted cognitive apathy as a key area for personalized intervention strategies more than behavioural and emotional, emphasizing the importance of short-term goals and not taking away the person's autonomy when not strictly necessary.}, }
@article {pmid39961913, year = {2025}, author = {Cava, C and Castiglioni, I}, title = {Drug repositioning based on mutual information for the treatment of Alzheimer's disease patients.}, journal = {Medical & biological engineering & computing}, volume = {}, number = {}, pages = {}, pmid = {39961913}, issn = {1741-0444}, abstract = {Computational drug repositioning approaches should be investigated for the identification of new treatments for Alzheimer's patients as a huge amount of omics data has been produced during pre-clinical and clinical studies. Here, we investigated a gene network in Alzheimer's patients to detect a proper therapeutic target. We screened the targets of different drugs (34,006 compounds) using data available in the Connectivity Map database. Then, we analyzed transcriptome profiles of Alzheimer's patients to discover a network of gene-drugs based on mutual information, representing an index of dependence among genes. This study identified a network consisting of 25 genes and compounds and interconnected biological processes using computational approaches. The results also highlight the diagnostic role of the 25 genes since we obtained good classification performances using a neural network model. We also suggest 12 repurposable drugs (like KU-60019, AM-630, CP55940, enflurane, ginkgolide B, linopirdine, apremilast, ibudilast, pentoxifylline, roflumilast, acitretin, and tamibarotene) interacting with 6 genes (ATM, CNR1, GLRB, KCNQ2, PDE4B, and RARA), that we linked to retrograde endocannabinoid signaling, synaptic vesicle cycle, morphine addiction, and homologous recombination.}, }
@article {pmid39961726, year = {2025}, author = {Simpson, I}, title = {Therapeutic delivery - industry update covering October 2024.}, journal = {Therapeutic delivery}, volume = {16}, number = {2}, pages = {117-122}, pmid = {39961726}, issn = {2041-6008}, mesh = {Humans ; *Drug Delivery Systems/methods ; *Drug Industry ; }, abstract = {This Industry Update covers the period from 1[st] October through to 31 October 2024 and is based on information sourced from company press releases, scientific literature, patents, and various news websites. This month saw two biotech company acquisitions being made by larger biopharma companies with Modifi Biosciences, a company focussing on the development of novel small molecule anticancer therapeutics, being acquired Merck, and AbbVie acquiring Aliada Therapeutics, which focuses on the treatment of central nervous system disorders. Elektrofi and Archon Biosciences both announced new investments, respectively, to support the development of novel high concentration subcutaneous drug delivery technology and for the development Antibody cages for therapeutic applications. GSK and Cambridge University announced a new five-year collaboration focusing on kidney and respiratory disease, and Aeropump and Resyca announced the launch of a new soft mist nasal delivery system that they have been jointly developing. UCB gained FDA approval for a higher dose of its injectable drug, BIMZELX for the treatment of autoimmune disorders, and AbbVie FDA approval for a continuous infusion treatment for Parkinson's Disease. Eisai announced it has completed its submission to the FDA for a subcutaneous version of its already approved therapy for Alzheimer's Disease. Clinical research updates included Johnson and Johnson announcing termination of a Phase III trial evaluating an implanted combination device for the treatment of bladder cancer, and Lilly announced positive results for modified dosing regimen for its approved Alzheimer's drug, Kisunla (donanemab).In October, the PDA held its annual Universe of Prefilled Syringes conference at which several updates on developments in injectable drug delivery were made. Scientific updates relating to therapeutic delivery included: a controlled drug delivery technology that enables a complete course of antibiotics to be delivered; a new lipid-based delivery system that improves the safety and efficacy of gene therapies; and the use of tiny controllable robots to enable targeted drug delivery of multiple therapeutics.}, }
@article {pmid39960625, year = {2025}, author = {Ni, R and Jiang, J and Wang, F and Min, J}, title = {Treating incurable non-communicable diseases by targeting iron metabolism and ferroptosis.}, journal = {Science China. Life sciences}, volume = {}, number = {}, pages = {}, pmid = {39960625}, issn = {1869-1889}, abstract = {Both iron metabolism and ferroptosis (an iron-dependent form of programmed cell death) have been connected to the development and progression of many currently incurable non-communicable diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, metabolic dysfunction-associated steatohepatitis, heart failure, and both treatment-relapsed and refractory cancers, such as pancreatic ductal adenocarcinoma and triple-negative breast cancer. Thus, understanding the relationship between iron and these diseases can pave the way for the development of novel therapeutic strategies. Here, we summarize the latest evidence supporting the pathological roles of dysregulated iron metabolism and ferroptosis in a wide range of preclinical animal models of these currently incurable non-communicable diseases. We also summarize the feasibility of targeting iron metabolism and ferroptosis for the prevention and treatment of iron- and ferroptosis-related diseases that currently have limited treatment options. In addition, we provide our perspectives on the challenges and promises regarding the translational potential of targeting dysregulated iron metabolism and ferroptosis to treat diseases, highlighting the future roadmap for developing iron- and ferroptosis-targeted therapeutics.}, }
@article {pmid39960601, year = {2025}, author = {Padmakumar, L and Menon, RN and Gopala, S and Vilanilam, GC}, title = {MTH1 in the disorders of the central nervous system: scope beyond brain tumors and challenges.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {39960601}, issn = {2240-2993}, abstract = {Human MutT homolog 1 (MTH1) plays a crucial role in sanitizing oxidized DNA precursors by enzymatically hydrolyzing oxidized nucleotides. The absence of MTH1 activity in the cells results in the accumulation of oxidized nucleotides within the nucleus and mitochondria, leading to mutations, abnormal proteins, and neurodegeneration (in the central nervous system). It has garnered interest as a potential target for anticancer treatment through targeted inhibitor molecules but remains largely understudied in other neurological disorders. This review explores the understanding of MTH1 expression in glioma and its potential role in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease concerning disease mechanism and prognosis. Neurodegeneration, activation of glial cells, and mitochondrial dysfunction are common mechanisms involved in the progression of these diseases. This review also tries to identify the unexplored associations and research gaps that can reveal novel applications of the enzyme in epilepsy, in which MTH1 is studied less. The influence of the ROS environment and cell type on MTH1 expression and function is crucial to be studied for elucidating its role in a multitude of CNS pathologies. The involvement of microglial cell-mediated inflammatory responses through ROS production in epileptogenesis in mouse models highlights the interplay between oxidative stress and neuroinflammation in epilepsy. The possible existence of a similar association between MTH1 expression and pathogenesis of the discussed neurological disorders in vivo demands further exploration preclinically and in patient samples.}, }
@article {pmid39960561, year = {2025}, author = {Rajabian, A and Kioumarsi Darbandi, Z and Aliyari, M and Saberi, R and Amirahmadi, S and Amini, H and Salmani, H and Youseflee, P and Hosseini, M}, title = {Pioglitazone improves learning and memory in a rat model of cholinergic dysfunction induced by scopolamine, the roles of oxidative stress and neuroinflammation.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {39960561}, issn = {1432-1912}, abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by progressive cognitive decline. Among various experimental models, scopolamine-induced amnesia is widely used to mimic memory dysfunction. Pioglitazone (PG), a thiazolidinedione derivative, has recently demonstrated neuroprotective potential in neurodegenerative conditions. This study aimed to evaluate the potential benefits of PG in mitigating scopolamine-induced cholinergic dysfunction and the associated memory and learning deficits in male Wistar rats. Fifty male Wistar rats were randomly assigned to five groups: (1) Control, (2) Scopolamine, and (3-5) three treatment groups receiving daily injections of PG at doses of 20, 40, or 60 mg/kg for three weeks in addition to scopolamine administration. Cognitive impairment was induced using scopolamine in all groups except the control. Cognitive function was assessed using the Morris water maze (MWM) and passive avoidance (PA) tests. Biochemical analyses were conducted to measure malondialdehyde (MDA), superoxide dismutase (SOD), total thiol levels, and acetylcholinesterase (AChE) activity in the cortex and hippocampus. Additionally, mRNA expression levels of inflammatory markers (TNF-α, IL-1β, IL-6) were evaluated in the hippocampus. Scopolamine induced cognitive impairment, increased MDA levels and AChE activity, decreased SOD activity and thiol levels, and elevated mRNA expression of inflammatory cytokines. PG significantly reversed these effects by enhancing performance in the MWM and PA tests, reducing MDA levels and AChE activity, and increasing SOD activity and total thiol concentration. Additionally, PG downregulated TNF-α, IL-1β, and IL-6 expression in brain tissue. The present behavioral and neurochemical findings suggest that PG ameliorates scopolamine-induced memory impairment by reducing oxidative stress and neuroinflammation while enhancing cholinergic function.}, }
@article {pmid39959708, year = {2025}, author = {Shukla, R and Mishra, K and Singh, S}, title = {Exploring therapeutic potential of Bacopa monnieri bioactive compounds against Alzheimer's and Parkinson's diseases.}, journal = {3 Biotech}, volume = {15}, number = {3}, pages = {61}, pmid = {39959708}, issn = {2190-572X}, abstract = {UNLABELLED: Parkinson's disease (PD) and Alzheimer's disease (AD) consist of progressive illnesses of central nervous system that primarily affect the elderly and are characterized by movement symptoms, memory decline, and cognitive impairment. A number of variables, including the lack of a novel treatment, a steady rise in the patient population, and the high expense of care and treatment, have contributed to the growing significance of these diseases. In recent decades, we have gained a better understanding of the causes of diseases, but complex mechanisms of neuronal loss, combined with physiological factors that are incompatible, pose challenges in describing the pathogenic processes and devising effective treatments. Currently, there are no known treatments for most of these diseases, rendering them incurable. Therefore, there is a pressing need for therapeutic interventions that have the potential to effectively treat neurodegeneration. This study aimed to evaluate the efficacy of the ayurvedic herb Bacopa monnieri bioactive components against the therapeutic targets HTR1A, HTR1B, HTR2A, HTR2C, HTR7, alpha-synuclein, amyloid beta, and tau protein of Alzheimer's and Parkinson's illnesses. The docking analysis revealed the promising binding affinity with Quercetin, Apigenin, and Luteolin and Molecular mechanics/generalized Born surface area (MM/GBSA) further confirmed the stability of the complexes. In vitro investigation indicated that Quercetin is the most effective for treating AD and PD due to its considerable inhibition of alpha-synuclein production, whereas Luteolin is the favorable one for preventing both diseases by mitigating effects during Rotenone treatment. The future implications and constraints of the current study suggest that further validation in Invivo models of Alzheimer's and Parkinson's diseases is necessary to investigate the effects of Quercetin and Apigenin in the treatment of these conditions, as well as Luteolin and Quercetin for their prevention.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04224-6.}, }
@article {pmid39959287, year = {2025}, author = {Leibold, NS and Kotiya, D and Verma, N and Despa, F}, title = {Detection of Amylin-β-amyloid Hetero-Oligomers by Enzyme-Linked Immunosorbent Assay.}, journal = {Bio-protocol}, volume = {15}, number = {3}, pages = {e5179}, pmid = {39959287}, issn = {2331-8325}, support = {R01 AG053999/AG/NIA NIH HHS/United States ; R01 AG057290/AG/NIA NIH HHS/United States ; R01 NS116058/NS/NINDS NIH HHS/United States ; }, abstract = {Amylin is an amyloidogenic neuroendocrine hormone co-synthesized and co-secreted with insulin from the pancreas. It readily crosses the blood-brain barrier and synergistically forms mixed amyloid plaques with β-amyloid (Aβ) in brain parenchyma. Parenchymal amylin-Aβ plaques are found in both sporadic and early-onset familial Alzheimer's disease (AD), yet their (patho)physiological role remains elusive, particularly due to a lack of detection modalities for these mixed plaques. Previously, we developed an enzyme-linked immunosorbent assay (ELISA) capable of detecting amylin-Aβ hetero-oligomers in brain lysate and blood using a polyclonal anti-amylin antibody to capture hetero-oligomers and a monoclonal anti-Aβ mid-domain detection antibody combination. This combination allows for the recognition of distinct amylin epitopes, which remain accessible after amylin-Aβ oligomerization has begun, and precise detection of Aβ epitopes available after oligomer formation. The utility of this assay is evidenced in our previous report, wherein differences in hetero-oligomer content in brain tissue from patients with and without AD and patients with and without diabetes were distinguished. Additionally, using AD model rats, we provided evidence that our assay can be employed for the detection of amylin-Aβ in blood. This assay and protocol are important innovations in the field of AD research because they meet an unmet need to detect mixed amyloid plaques that, if targeted therapeutically, could reduce AD progression and severity. Key features • Detects amylin-Aβ hetero-oligomers in blood from patients with Alzheimer's disease. • Enables simultaneous, high-throughput analysis of hetero-oligomer content of brain and blood tissue. • Allows exploration into the amylin-Aβ interaction during AD pathogenesis, potentially leading to novel treatment mechanisms by controlling the amylin-Aβ interaction.}, }
@article {pmid39958500, year = {2025}, author = {Moon, WJ}, title = {[Preface for Special Issue on Alzheimer's Disease: New Diagnostic Criteria, Treatment, and the Role of Neuroimaging].}, journal = {Journal of the Korean Society of Radiology}, volume = {86}, number = {1}, pages = {4-5}, pmid = {39958500}, issn = {2951-0805}, }
@article {pmid39958499, year = {2025}, author = {Jeong, SY and Suh, CH and Lim, JS and Choi, Y and Kim, HS and Kim, SJ and Lee, JH}, title = {Anti-Amyloid Imaging Abnormality in the Era of Anti-Amyloid Beta Monoclonal Antibodies: Recent Updates for the Radiologist.}, journal = {Journal of the Korean Society of Radiology}, volume = {86}, number = {1}, pages = {17-33}, pmid = {39958499}, issn = {2951-0805}, abstract = {Lecanemab and donanemab have received full U.S. Food and Drug Administration (FDA) approval, and subsequently, lecanemab has been approved by the Korean FDA and it has recently entered commercial use in Korea. This has increased interest in anti-amyloid immunotherapy for Alzheimer's disease. Anti-amyloid immunotherapy has shown potential to modify the progression of the disease by specifically binding to amyloid β, a key pathological product in Alzheimer's disease, and eliminating accumulated amyloid plaques in the brain. However, this treatment can be accompanied by a side-effect, amyloid-related imaging abnormalities (ARIA), which requires periodic monitoring by MRI. It is crucial to detect ARIA and accurately assess the severity by radiology. The role of the radiologist is important in this context, requiring proficiency in basic knowledge of ARIA, and in diagnosing/evaluating ARIA. This review aims to comprehensively cover aspects of ARIA, including its definition, pathophysiology, incidence, risk factors, assessment of severity by radiology, differential diagnosis, and management.}, }
@article {pmid39958494, year = {2025}, author = {Yim, Y and Moon, WJ}, title = {[Diagnosis and Treatment of Alzheimer's Disease: Current Update].}, journal = {Journal of the Korean Society of Radiology}, volume = {86}, number = {1}, pages = {6-16}, pmid = {39958494}, issn = {2951-0805}, abstract = {Alzheimer's disease, one of the most common causes of dementia, places a significant socioeconomic burden on aging societies. Encouragingly, extensive research on this neurocognitive disorder has finally uncovered the underpinnings of its pathophysiology, igniting a new era of treatment possibilities. Furthermore, the advent of amyloid PET imaging has allowed diagnosis of the amyloid pathology, the underlying cause of Alzheimer's disease. Notwithstanding the initial setback with aducanumab, the subsequent full FDA approval of two anti-amyloid antibody drugs (Lecanemab and Donanemab) has revolutionized the treatment landscape. These disease-modifying drugs are designed to target and remove beta-amyloid. This review covers the updated diagnostic criteria for Alzheimer's disease and discusses recent developments in treatment strategies, including these new disease-modifying drugs.}, }
@article {pmid39958493, year = {2025}, author = {Kim, J and Kim, E and Park, M and Bae, YJ and Suh, CH and You, SH and Yim, Y and Lee, HJ and Choi, JW and Oh, SW and Moon, WJ and , }, title = {[Amyloid-Related Imaging Abnormalities in Anti-Amyloid Monoclonal Antibody Therapy for Alzheimer's Disease: Expert Recommendation for Standard MRI Protocol].}, journal = {Journal of the Korean Society of Radiology}, volume = {86}, number = {1}, pages = {34-44}, pmid = {39958493}, issn = {2951-0805}, abstract = {The introduction of anti-amyloid therapies for Alzheimer's disease (AD), such as lecanemab (Lequembi[®]), which was recently approved in Korea, necessitates careful monitoring for amyloid-related imaging abnormalities (ARIA) using brain MRI. To optimize ARIA monitoring in Korean clinical settings, the Korean Society of Neuroradiology (KSNR) and the Age and Neurodegeneration Imaging (ANDI) Study Group proposed MRI protocol recommendations on essential MR sequences, MRI acquisition parameters, timing and condition of MRI examinations, and essential details to provide a scientific basis for maximizing the safety and efficacy of AD treatment. A customized, standardized MRI protocol focusing on Korea's healthcare environment can improve ARIA management and ensure patient safety through early detection of potential anti-amyloid therapy side effects, thereby enhancing treatment quality.}, }
@article {pmid39958092, year = {2025}, author = {Szczerba, M and Hejnosz, A and Majewski, G and Grodzka, O and Domitrz, I}, title = {Asthma as a Modifiable Risk Factor for Dementia and Neurodegeneration: A Systematic Review.}, journal = {Cureus}, volume = {17}, number = {1}, pages = {e77540}, pmid = {39958092}, issn = {2168-8184}, abstract = {Asthma remains a significant health concern, with increasing incidence rates and a notable annual mortality rate. Although the pathophysiology of asthma and its impact on the respiratory system are well understood, leading to effective symptom control, the broader effects of chronic localized airway inflammation on the rest of the body remain less clear. One potential consequence of this persistent state is an elevated risk of developing dementia across various etiologies, including Alzheimer's disease (AD). This systematic review aims to elucidate the underlying mechanisms driving this association, with a particular focus on identifying neurodegeneration markers detectable through laboratory and imaging studies. Additionally, it examines the impact of asthma treatments on this potential risk, exploring their possible contributory role in the pathogenesis of dementia. Such insights should inform the development of personalized treatment strategies for asthma patients, aimed at preventing or delaying the onset of dementia. However, further research is necessary to understand the underlying mechanisms of the connection fully and crucial to integrate it with routine clinical practice.}, }
@article {pmid39957765, year = {2025}, author = {Meng, W and Chao, W and Kaiwei, Z and Sijia, M and Jiajia, S and Shijie, X}, title = {Bioactive compounds from Chinese herbal plants for neurological health: mechanisms, pathways, and functional food applications.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1537363}, pmid = {39957765}, issn = {2296-861X}, abstract = {Neurological disorders pose significant global public health challenges, with a rising prevalence and complex pathophysiological mechanisms that impose substantial social and economic burdens. Traditional Chinese Medicine (TCM), with its holistic approach and multi-target effects, has gained increasing attention in the treatment of neurological diseases. This review explores bioactive compounds derived from Chinese herbal plants, focusing on their mechanisms of action, underlying pathways, and potential applications in functional food development. The review highlights the neuroprotective properties of flavonoids, alkaloids, polysaccharides, and polyphenols found in key TCM herbs such as Scutellaria baicalensis, Salvia miltiorrhiza, Ligusticum chuanxiong, and Gastrodia elata. These compounds have demonstrated significant anti-inflammatory, antioxidant, and neurogenic effects, making them promising candidates for the prevention and treatment of neurological conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), and depression. Furthermore, the synergistic effects of TCM formulations targeting multiple signaling pathways offer advantages over single-target therapies, especially in combating neurodegenerative diseases. The review also discusses the challenges and future directions for integrating these bioactive compounds into functional foods and dietary supplements, aiming to improve neurological health and enhance clinical outcomes. Ultimately, this work aims to provide valuable insights into the potential of TCM-based interventions for promoting neurological well-being and addressing the global burden of neurological disorders.}, }
@article {pmid39957504, year = {2025}, author = {Jiang, X and Zheng, Y and Sun, H and Dang, Y and Yin, M and Xiao, M and Wu, T}, title = {Fecal Microbiota Transplantation Improves Cognitive Function of a Mouse Model of Alzheimer's Disease.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {2}, pages = {e70259}, pmid = {39957504}, issn = {1755-5949}, support = {81971237//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Alzheimer Disease/therapy ; *Fecal Microbiota Transplantation ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *Gastrointestinal Microbiome/physiology ; Cognition/physiology ; Amyloid beta-Peptides/metabolism ; Presenilin-1/genetics ; Male ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: A growing body of evidence suggests a link between the gut microbiota and Alzheimer's disease (AD), although the underlying mechanisms remain elusive. This study aimed to investigate the impact of fecal microbiota transplantation (FMT) on cognitive function in a mouse model of AD.
METHODS: Four-month-old 5 × FAD (familial Alzheimer's disease) mice underwent antibiotic treatment to deplete their native gut microbiota. Subsequently, they received FMT either weekly or every other day. After 8 weeks, cognitive function and β-amyloid (Aβ) load were assessed through behavioral testing and pathological analysis, respectively. The composition of the gut microbiota was analyzed using 16S rRNA sequencing.
RESULTS: Initial weekly FMT failed to alleviate memory deficits or reduce brain Aβ pathology in 5 × FAD mice. In contrast, FMT administered every other day effectively restored gut dysbiosis in 5 × FAD mice and decreased Aβ pathology and lipopolysaccharide levels in the colon and hippocampus. Mechanistically, FMT reduced the expression of amyloid β precursor protein, β-site APP cleaving enzyme 1, and presenilin-1, potentially by inhibiting the Toll-like receptor 4/inhibitor of kappa B kinase β/nuclear factor kappa-B signaling pathway. However, the cognitive benefits of FMT on 5 × FAD mice diminished over time.
CONCLUSION: These findings demonstrate the dose- and time-dependent efficacy of FMT in mitigating AD-like pathology, underscoring the potential of targeting the gut microbiota for AD treatment.}, }
@article {pmid39957048, year = {2025}, author = {Kandeda, AK and Mezui, C and Kengni, S and Baldagai, N and Mabou, ST}, title = {Kalanchoe crenata Haw. (Crassulacea) Decreases Hippocampal Neuron Loss and Improves Memory and Executive Function in Aged Rats: Implications for Anti-Inflammatory and Antioxidant Mechanisms.}, journal = {Brain and behavior}, volume = {15}, number = {2}, pages = {e70261}, pmid = {39957048}, issn = {2162-3279}, mesh = {Animals ; Rats ; *Plant Extracts/pharmacology/administration & dosage ; *Hippocampus/drug effects ; Male ; *Antioxidants/pharmacology/administration & dosage ; *Executive Function/drug effects/physiology ; *Rats, Wistar ; *Memory Disorders/drug therapy ; *Kalanchoe/chemistry ; *Galactose/pharmacology ; Neurons/drug effects ; Anti-Inflammatory Agents/pharmacology/administration & dosage ; Memory/drug effects ; Maze Learning/drug effects ; Oxidative Stress/drug effects ; Aging/drug effects/physiology ; Disease Models, Animal ; }, abstract = {INTRODUCTION: Alzheimer's disease is a neurodegenerative disease that alters learning and memory processes. Kalanchoe crenata (Crassulaceae) has long been used in Cameroonian traditional medicine to treat hypertension, malaria, and dementia. The present study aims to evaluate the anti-amnesic effect of an aqueous extract of K. crenata in D-galactose-treated rats and possible mechanisms of action.
METHODS: Memory impairment was induced in rats by subcutaneous injection of D-galactose (350 mg/kg) once daily for 30 days. At the end of the procedure, the animals were assessed for memory impairment using Morris water maze and object recognition tasks. Animals with memory impairment were divided into six groups of eight rats each and treated once daily for 24 days as follows: the negative control group received per os distilled water (10 mL/kg); the positive control group received donepezil (2 mg/kg, p.o.); and three test groups received the extract of K. crenata (62, 124, and 248 mg/kg, p.o.). A group of eight rats was added and served as a control group. After completion of the procedure, the memory deficit in rats was reassessed by the object recognition test on Day 15 of the treatment, the Morris water maze test on Day 18, and the open-field test on Day 24. At the end of behavioral experiments, the animals were sacrificed and some biochemical parameters in the hippocampus were estimated. In addition, histological analysis of the hippocampus was performed.
RESULTS: K. crenata significantly decreased the time to reach the platform and increased the time spent in the target quadrant of the Morris water maze. It also increased the discrimination index during the object recognition test. The extract significantly reversed D-galactose-induced oxidative stress and inflammation. This was confirmed by the attenuation of neuronal loss.
CONCLUSION: These findings suggest that K. crenata extract possesses an anti-amnesic-like effect probably mediated by antioxidant and anti-inflammatory mechanisms.}, }
@article {pmid39956886, year = {2025}, author = {Almutary, AG and Begum, MY and Siddiqua, A and Gupta, S and Chauhan, P and Wadhwa, K and Singh, G and Iqbal, D and Padmapriya, G and Kumar, S and Kedia, N and Verma, R and Kumar, R and Sinha, A and Dheepak, B and Abomughaid, MM and Jha, NK}, title = {Unlocking the Neuroprotective Potential of Silymarin: A Promising Ally in Safeguarding the Brain from Alzheimer's Disease and Other Neurological Disorders.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39956886}, issn = {1559-1182}, abstract = {Medicinal plants and their phytochemicals have been extensively employed worldwide for centuries to address a diverse range of ailments, boasting a history that spans several decades. These plants are considered the source of numerous medicinal compounds. For instance, silymarin is a polyphenolic flavonoid extract obtained from the milk thistle plant or Silybum marianum which has been shown to have significant neuroprotective effects and great therapeutic benefits. Neurodegenerative diseases (NDs) are a class of neurological diseases that have become more prevalent in recent years, and although treatment is available, there is no complete cure developed yet. Silymarin utilizes a range of molecular mechanisms, including modulation of MAPK, AMPK, NF-κB, mTOR, and PI3K/Akt pathways, along with various receptors, enzymes, and growth factors. These mechanisms collectively contribute to its protective effects against NDs such as Alzheimer's disease, Parkinson's disease, and depression. Despite its safety and efficacy, silymarin faces challenges related to bioavailability and aqueous solubility, hindering its development as a clinical drug. This review highlights the molecular mechanisms underlying silymarin's neuroprotective effects, suggesting its potential as a promising therapeutic strategy for NDs.}, }
@article {pmid39956674, year = {2025}, author = {Hammers, DB and Musema, J and Eloyan, A and Thangarajah, M and Taurone, A and La Joie, R and Touroutoglou, A and Vemuri, P and Kramer, J and Aisen, P and Dage, JL and Nudelman, KN and Kirby, K and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, I and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Womack, K and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, SJ and Turner, RS and Wingo, TS and Wolk, DA and Carrillo, MC and Rabinovici, GD and Dickerson, BC and Apostolova, LG and , }, title = {Characterizing and validating 12-month reliable cognitive change in Early-Onset Alzheimer's Disease for use in clinical trials.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {4}, pages = {100075}, pmid = {39956674}, issn = {2426-0266}, support = {P30 AG013854/AG/NIA NIH HHS/United States ; R56 AG057195/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; P50 AG047366/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; P50 AG005146/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; K23 AG080071/AG/NIA NIH HHS/United States ; U01 AG016976/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; Male ; Female ; *Neuropsychological Tests ; Middle Aged ; Longitudinal Studies ; Cognitive Dysfunction/diagnosis ; Reproducibility of Results ; Clinical Trials as Topic ; Age of Onset ; Cognition/physiology ; }, abstract = {BACKGROUND: As literature suggests that Early-Onset Alzheimer's Disease (EOAD) and late-onset AD may differ in important ways, need exists for randomized clinical trials for treatments tailored to EOAD. Accurately measuring reliable cognitive change in individual patients with EOAD will have great value for these trials.
OBJECTIVES: The current study sought to characterize and validate 12-month reliable change from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) neuropsychological battery.
DESIGN: Standardized regression-based (SRB) prediction equations were developed from age-matched cognitively intact participants within LEADS, and applied to clinically impaired participants from LEADS.
SETTING: Participants were recruited from outpatient academic medical centers.
PARTICIPANTS: Participants were enrolled in LEADS and diagnosed with amyloid-positive EOAD (n = 189) and amyloid-negative early-onset cognitive impairment not related to AD (EOnonAD; n = 43).
MEASUREMENT: 12-month reliable change (Z-scores) was compared between groups across cognitive domain composites, and distributions of individual participant trajectories were examined. Prediction of Z-scores by common AD biomarkers was also considered.
RESULTS: Both EOAD and EOnonAD displayed significantly lower 12-month follow-up scores than were predicted based on SRB equations, with declines more pronounced for EOAD across several domains. AD biomarkers of cerebral β-amyloid, tau, and EOAD-specific atrophy were predictive of 12-month change scores.
CONCLUSIONS: The current results support including EOAD patients in longitudinal clinical trials, and generate evidence of validation for using 12-month reliable cognitive change as a clinical outcome metric in clinical trials in EOAD cohorts like LEADS. Doing so will enhance the success of EOAD trials and permit a better understanding of individual responses to treatment.}, }
@article {pmid39956324, year = {2025}, author = {Hussain, N and Khan, MM and Sharma, A and Singh, RK and Khan, RH}, title = {Beyond plaques and tangles: The role of immune cell dysfunction in Alzheimer's disease.}, journal = {Neurochemistry international}, volume = {184}, number = {}, pages = {105947}, doi = {10.1016/j.neuint.2025.105947}, pmid = {39956324}, issn = {1872-9754}, mesh = {*Alzheimer Disease/immunology ; Humans ; Animals ; *Plaque, Amyloid/immunology/pathology ; Microglia/immunology/metabolism ; Neurofibrillary Tangles/immunology/pathology/metabolism ; Neuroinflammatory Diseases/immunology ; }, abstract = {The interplay between immune cell dysfunction and associated neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease. Neuroinflammation, orchestrated by microglia and peripheral immune cells, exacerbates synaptic dysfunction and neurodegeneration in AD. Emerging evidence suggests a systemic immune response in AD, challenging traditional views of neurocentric pathology. Therapeutic strategies targeting neuroinflammation hold promise, yet translating preclinical findings into clinical success remains elusive. This article presents recent advances in AD scientific studies, highlighting the pivotal role of immune cell dysfunction and signaling pathways in disease progression. We also discussed therapeutic studies targeting immune cell dysregulation, as treatment methods. This advocates for a paradigm shift towards holistic approaches that integrate peripheral and central immune responses, fostering a comprehensive understanding of AD pathophysiology and paving the way for transformative interventions.}, }
@article {pmid39955261, year = {2025}, author = {Cline, EN and Antwi-Berko, D and Sundell, K and Johnson, E and Hyland, M and Zhang, H and Vanderstichele, H and Kaplow, J and Dean, RA and Stoops, E and Vanmechelen, E and Koel-Simmelink, MJA and Teunissen, CE and Sethuraman, G and Feaster, T and Siemers, E and Jerecic, J}, title = {Biofluid biomarker changes following treatment with sabirnetug (ACU193) in INTERCEPT-AD, a phase 1 trial in early Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {4}, pages = {100082}, doi = {10.1016/j.tjpad.2025.100082}, pmid = {39955261}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid/blood ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Male ; Aged ; Female ; *tau Proteins/cerebrospinal fluid/blood ; Cognitive Dysfunction/drug therapy ; Double-Blind Method ; Dose-Response Relationship, Drug ; Peptide Fragments/blood/cerebrospinal fluid ; Middle Aged ; }, abstract = {OBJECTIVE: Sabirnetug (ACU193) is a humanized monoclonal antibody selective for soluble amyloid beta oligomers (AβOs), synaptotoxins that are early and persistent triggers of Alzheimer's disease (AD). Sabirnetug pharmacodynamics were examined in the INTERCEPT-AD phase 1 study in mild cognitive impairment and mild dementia due to AD (NCT04931459) using biofluid biomarkers associated with Aβ and tau pathology, synaptic dysfunction, neuroinflammation, and neurodegeneration.
METHODS: INTERCEPT-AD was a randomized, first-in-human study of sabirnetug versus placebo administered as a single (SAD; 2, 10, 25, 60 mg/kg) or multiple (MAD; three doses of 10 or 60 mg/kg every 4 weeks [Q4W] or 25 mg/kg Q2W) ascending doses. Biomarkers were measured pre-/post-dose in CSF and EDTA-plasma. Correlations of biomarker changes versus dose, exposure duration, and target engagement were determined.
RESULTS: In MAD cohorts, CSF pTau181 decreased significantly (60 mg/kg Q4W, p = 0.049). VAMP2 decreased significantly at all doses (p ≤ 0.041); neurogranin decreased significantly at 60 mg/kg Q4W (p = 0.037). Aβ1-42/Aβ1-40 trended upward with sabirnetug dose. Aβ1-42/Aβ1-40 and neurogranin changes correlated with sabirnetug-AβO target engagement (p ≤ 0.01). Decreases in tTau, VAMP2, and neurogranin correlated with exposure duration (p ≤ 0.007). Plasma pTau181, pTau217, GFAP, and NfL trended lower.
DISCUSSION: Following three sabirnetug doses, changes in CSF and plasma biomarkers were observed. The CSF biomarker response increased with increasing dose and exposure duration, consistent with previous reports that sabirnetug reaches the central compartment and engages its AβO target. The ongoing phase 2 ALTITUDE-AD study (NCT06335173) will test whether sabirnetug's pharmacodynamic effects can be substantiated with a larger sample size and longer treatment duration.}, }
@article {pmid39954841, year = {2025}, author = {Sripetchwandee, J and Kongkaew, A and Kumfu, S and Chattipakorn, N and Chattipakorn, SC}, title = {Modulating mitochondrial dynamics preserves cognitive performance via ameliorating iron-mediated brain toxicity in iron-overload rats.}, journal = {European journal of pharmacology}, volume = {993}, number = {}, pages = {177379}, doi = {10.1016/j.ejphar.2025.177379}, pmid = {39954841}, issn = {1879-0712}, mesh = {Animals ; *Mitochondrial Dynamics/drug effects ; Male ; *Rats, Wistar ; Rats ; *Cognition/drug effects ; *Iron Overload/metabolism/drug therapy ; *Brain/drug effects/metabolism/pathology ; Iron/metabolism ; Mitochondria/drug effects/metabolism ; Deferoxamine/pharmacology ; Behavior, Animal/drug effects ; Quinazolinones ; }, abstract = {This study aimed to demonstrate the pharmacological efficacy of mitochondrial dynamics modulators, including the fission inhibitor Mdivi-1 and the fusion promoter M1, on parameters in brain and cognitive performance in rats with iron overload condition. Forty male Wistar rats were randomly categorized into two groups to receive either 10% dextrose in normal saline (control, n = 8) or iron dextran (100 mg/kg, Fe group, n = 32) via intraperitoneal injection for six weeks. During the fifth week of injection, rats in the Fe group were further categorized into four groups (n = 8 each) to subcutaneously injected with 1) vehicle (10% DMSO in normal saline), 2) deferoxamine (DFO) (25 mg/kg), 3) Mdivi-1 (1.2 mg/kg), or 4) M1 (2 mg/kg) for further two weeks. Behavioral tests, such as novel object recognition and Morris water maze, were performed post-treatment. Non-heme iron levels in plasma and parameters in the brain, including tight junction-related blood-brain barrier proteins, lipocalin-2, iron levels, ferroptosis, inflammation, mitochondrial function, dynamics, mitophagy, and Alzheimer-like proteins, were assessed. DFO mitigated iron overload condition and brain abnormalities, partially ameliorating cognitive decline. Mdivi-1 and M1 showed superior effects by preventing brain inflammation, LCN2 elevation, and mitochondrial dysfunction, restoring memory function (hippocampal-dependent manner) and spatial cognition (recognition manner). These findings indicate that modulating mitochondrial dynamics via fission inhibitor and fusion promoter could be promising novel pharmacological interventions for the brain in iron overload condition.}, }
@article {pmid39954799, year = {2025}, author = {Chiang, MC and Nicol, CJB and Yang, YP and Chiang, T and Yen, C}, title = {The α-MG exhibits neuroprotective potential by reducing amyloid beta peptide-induced inflammation, oxidative stress, and tau aggregation in human neural stem cells.}, journal = {Brain research}, volume = {1852}, number = {}, pages = {149506}, doi = {10.1016/j.brainres.2025.149506}, pmid = {39954799}, issn = {1872-6240}, mesh = {*Oxidative Stress/drug effects ; Humans ; *Neuroprotective Agents/pharmacology ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; *Neural Stem Cells/drug effects/metabolism ; *Inflammation/metabolism/drug therapy ; *Xanthones/pharmacology ; Alzheimer Disease/metabolism/drug therapy ; Cell Survival/drug effects ; Antioxidants/pharmacology ; }, abstract = {Alzheimer's disease (AD) is the primary cause of dementia in older adults. Amyloid-beta (Aβ) and tau protein neurofibrillary tangles accumulate in the brain, leading to a progressive decline in memory, thinking, and behavior. Neuroinflammation and oxidative stress play a significant role in the development and progression of AD. Research has suggested that α-mangostin (α-MG), a compound found in mangosteen peels, may have anti-inflammatory, antioxidant, and neuroprotective properties, which could be beneficial in the context of AD. Further research is required to fully comprehend the therapeutic mechanisms of α-MG on AD and determine its potential as a treatment option. α-MG treatment significantly improves the viability of hNSCs exposed to Aβ and reduces caspase activity. Furthermore, this treatment is associated with a notable decrease in the expression of TNF-α and IL-1β. The treatment effectively restores alterations in the expression of IKK and NF-κB (p65) induced by Aβ, which are critical factors in the inflammatory response. Moreover, α-MG effectively reduces iNOS and COX-2 levels in Aβ-treated hNSCs, showcasing its potential therapeutic benefits. Treatment with α-MG protects hNSCs against Aβ-induced oxidative stress and effectively prevents the decrease in Nrf2 levels caused by Aβ. The treatment significantly enhances the activity and mRNA expression of Nrf2 downstream antioxidant target genes, including SOD-1, SOD-2, Gpx1, GSH, catalase, and HO-1, compared to Aβ-treated controls. α-MG significantly reduces tau and ubiquitin (Ub) aggregates, enhances proteasome activity, and increases the mRNA expression of HSF1, HSP27, HSP70, and HSP90 in Tau-GFP-expressed hNSCs. This study significantly improves our comprehension of the anti-inflammatory, antioxidative stress, and anti-aggregated effects of α-MG. These findings have potential therapeutic implications for developing treatments that could delay AD progression and promote healthy aging.}, }
@article {pmid39954619, year = {2025}, author = {Qi, Y and Zhang, J and Zhang, Y and Zhu, H and Wang, J and Xu, X and Jin, S and Wang, C and Zhang, F and Zhao, M and Wu, Z and Zhu, H and Yan, P}, title = {Curcuma wenyujin extract alleviates cognitive deficits and restrains pyroptosis through PINK1/Parkin mediated autophagy in Alzheimer's disease.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {139}, number = {}, pages = {156482}, doi = {10.1016/j.phymed.2025.156482}, pmid = {39954619}, issn = {1618-095X}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Pyroptosis/drug effects ; *Protein Kinases/metabolism ; Mice ; *Cognitive Dysfunction/drug therapy ; *Disease Models, Animal ; Male ; *Ubiquitin-Protein Ligases/metabolism ; *Curcuma/chemistry ; Autophagy/drug effects ; Amyloid beta-Peptides/metabolism ; Humans ; Plant Extracts/pharmacology ; Drugs, Chinese Herbal/pharmacology/chemistry ; Mitophagy/drug effects ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Pyroptosis and mitophagy have gained significant attention in Alzheimer's disease (AD) treatment. Curcumae Radix (CR), the dried radix of Curcuma wenyujin Y. H. Chen et C. Ling, is a traditional Chinese medicine (TCM) extensively utilized for neurological disorders. Yet, its impact and mechanistic role in AD remain unclear.
PURPOSE: This study aims to explore the active fraction of CR in AD treatment and its potential mechanisms.
METHODS: CR extracts were qualitatively analyzed using UHPLC-Triple-TOF/MS. Aβ1-42-induced mice received daily intragastric drug treatments for three weeks. Cognitive abilities of AD model mice were assessed through Y maze, novel object recognition, and eight-arm maze tests. Therapeutic targets of CR extracts were identified using quantitative proteomics. In both in vivo and in vitro settings, effects on pyroptosis and mitophagy were examined by Western blot (WB), immunofluorescence (IF) staining, and ELISA assays.
RESULTS: The ethyl acetate (EAC) fraction of CR extract exhibited optimal anti-AD effects. CR extracts enhanced memory and cognition in Aβ1-42-induced mice, improved neuronal morphology, and reduced Aβ accumulation in the brain. Proteomics analysis suggested the anti-AD properties of CR might involve inflammation reduction, cell survival enhancement, and mitophagy modulation. CR treatments in both AD mice and Aβ-induced SH-SY5Y cells resulted in reduced pyroptosis, increased LC3 and Beclin1 levels, and activation of the PINK1/Parkin pathway.
CONCLUSION: The EAC fraction of CR is effective in AD treatment by mitigating pyroptosis, reducing neuroinflammation, and promoting mitophagy, actions facilitated through the PINK1/Parkin pathway.}, }
@article {pmid39954613, year = {2025}, author = {Kaur, N and Gupta, S and Pal, J and Bansal, Y and Bansal, G}, title = {Design of BBB permeable BACE-1 inhibitor as potential drug candidate for Alzheimer disease: 2D-QSAR, molecular docking, ADMET, molecular dynamics, MMGBSA.}, journal = {Computational biology and chemistry}, volume = {116}, number = {}, pages = {108371}, doi = {10.1016/j.compbiolchem.2025.108371}, pmid = {39954613}, issn = {1476-928X}, mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Quantitative Structure-Activity Relationship ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; Humans ; *Molecular Docking Simulation ; *Molecular Dynamics Simulation ; *Drug Design ; *Blood-Brain Barrier/metabolism ; Molecular Structure ; Enzyme Inhibitors/chemistry/pharmacology ; Protease Inhibitors/chemistry/pharmacology/metabolism ; }, abstract = {BACE-1 is a prime therapeutic target for treatment of Alzheimer disease as it cleaves the β-site of APP leading to formation of amyloid plaques. A dataset of 229 benzo-fused heterocyclic compounds reported as BACE-1 inhibitors was utilized to develop various QSAR models (regression and classification) utilizing Monte Carlo algorithm. The dataset was randomly split into different sets for generation of models. The IIC and CCC were calculated to increase the predictive ability of generated models. Among various models, split-1 of Model-1 demonstrated the highest robustness and predictive accuracy for pIC50 values. Internal and external validation was performed which further confirmed the reliability of this model. Structural features responsible for enhancing or reducing pIC50 values were identified and were utilized to design library of 255 compounds. Compounds having pIC50> 5.0 were further screened on the basis of BBB permeability predicted via ADMET lab 3.0. Total nineteen compounds were found to be BBB permeable which were then docked into PDB: 2WJO. Finally, four compounds with high docking scores were identified and compared with existing BACE-1 inhibitor. MD simulations and MMGBSA analysis were performed and results demonstrated minimal fluctuations throughout the simulation of 100 ns with good binding affinity. This study highlights development of robust QSAR model which assists to design new compounds and predicts them for anti β-secretase activity. Design of novel four molecules were proposed which exhibits good potency, BBB permeability, excellent binding affinity and stable conformations with BACE-1 making them promising candidates for further development.}, }
@article {pmid39954353, year = {2025}, author = {Li, Y and Zhang, Q and Wang, X and Liu, Z and Chen, H and Su, Z and Xu, Y and Zhang, W and Du, Y and Tan, Z and Huang, S and Liu, W and Sang, Z}, title = {Development of novel rivastigmine derivatives as selective BuChE inhibitors for the treatment of AD.}, journal = {Bioorganic chemistry}, volume = {157}, number = {}, pages = {108245}, doi = {10.1016/j.bioorg.2025.108245}, pmid = {39954353}, issn = {1090-2120}, mesh = {*Rivastigmine/pharmacology/chemistry/chemical synthesis ; *Butyrylcholinesterase/metabolism ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Alzheimer Disease/drug therapy ; Animals ; Structure-Activity Relationship ; *Zebrafish ; Humans ; Molecular Structure ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Dose-Response Relationship, Drug ; Blood-Brain Barrier/metabolism/drug effects ; Molecular Docking Simulation ; Drug Development ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder among the elderly, and there are currently no effective treatment options available. Selective inhibition of butyrylcholinesterase (BuChE) has emerged as a promising strategy for AD therapeutics. In this study, we identified compound 6a as a lead candidate derived from the structural modification of rivastigmine. Our findings indicated that 6a acts as a potent selective BuChE inhibitor, demonstrating an IC50 value of 0.33 μM (SI > 151.5). Furthermore, compound 6a displayed favorable neuroprotective properties, along with excellent blood-brain barrier (BBB) permeability and drug-like characteristics. In vivo investigations utilizing an AlCl3-induced zebrafish model of AD revealed that compound 6a significantly improved cognitive function, which was further supported by its ability to mitigate memory impairment induced by scopolamine. Overall, these results highlight compound 6a as a promising selective BuChE inhibitor with potential therapeutic implications for the treatment of Alzheimer's disease.}, }
@article {pmid39953968, year = {2025}, author = {Schaller, E and Hofmann, J and Maher, P and Stigloher, C and Decker, M}, title = {Visualizing Intracellular Localization of Natural-Product-Based Chemical Probes Using Click-Correlative Light and Electron Microscopy.}, journal = {ACS chemical biology}, volume = {20}, number = {3}, pages = {721-730}, doi = {10.1021/acschembio.4c00849}, pmid = {39953968}, issn = {1554-8937}, support = {RF1 AG061296/AG/NIA NIH HHS/United States ; R01 AG069206/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Click Chemistry ; *Flavonols/chemistry ; *Flavonoids/chemistry ; Cell Line ; Biological Products/chemistry ; Microscopy, Fluorescence/methods ; Microscopy, Electron/methods ; Endoplasmic Reticulum/metabolism ; Hippocampus/cytology ; Molecular Probes/chemistry ; }, abstract = {Flavonoids such as sterubin and fisetin─and derivatives thereof─show strong neuroprotective effects in vitro as well as in vivo, combined with negligible toxicity and can therefore be considered novel treatment options for neurodegenerative diseases such as Alzheimer's disease. However, their subcellular locations responsible for neuroprotection and exact modes of action still remain unclear. Here, we present chemical probes based on both flavonoids sterubin and fisetin that were utilized in fluorescence microscopy and click-correlative light and electron microscopy to detect and visualize the localization of specific intracellular targets. We successfully adapted the workflow of correlative light and electron microscopy to a click-chemistry-based approach in a murine hippocampal cell line (HT22) on ultrathin resin sections making visualization of a small molecule for the first time possible in this setup. Utilizing this newly adapted technique, we could demonstrate that sterubin and fisetin show specific enrichment in the endoplasmic reticulum.}, }
@article {pmid39953602, year = {2025}, author = {Wu, DP and Wei, YS and Hou, LX and Du, YX and Yan, QQ and Liu, LL and Zhao, YD and Yan, RY and Yu, C and Zhong, ZG and Huang, JL}, title = {Circular RNA APP contributes to Alzheimer's disease pathogenesis by modulating microglial polarization via miR-1906/CLIC1 axis.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {44}, pmid = {39953602}, issn = {1758-9193}, support = {BK20231179//Natural Science Foundation of Jiangsu Province/ ; 82003718//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *RNA, Circular/metabolism/genetics ; *Microglia/metabolism ; *Chloride Channels/metabolism/genetics ; *MicroRNAs/metabolism/genetics ; Mice ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Mice, Transgenic ; Hippocampus/metabolism/pathology ; Male ; Humans ; Disease Models, Animal ; }, abstract = {BACKGROUND: Abnormal microglial polarization phenotypes contribute to the pathogenesis of Alzheimer's disease (AD). Circular RNAs (circRNAs) have garnered increasing attention due to their significant roles in human diseases. Although research has demonstrated differential expression of circRNAs in AD, their specific functions in AD pathogenesis remain largely unexplored.
METHODS: CircRNA microarray was performed to identify differentially expressed circRNAs in the hippocampus of APP/PS1 and WT mice. The stability of circAPP was assessed via RNase R treatment assay. CircAPP downstream targets miR-1906 and chloride intracellular channel 1 (CLIC1) were identified using bioinformatics and proteomics, respectively. RT-PCR assay was conducted to detect the expression of circAPP, miR-1906 and CLIC1. Morris water maze (MWM) test, passive avoidance test and novel object recognition task were used to detect cognitive function of APP/PS1 mice. Microglial M1/M2 polarization and AD pathology were assessed using Western blot, flow cytometry and Golgi staining assays. CLIC1 expression and channel activity were evaluated using Western blot and functional chloride channel assays, respectively. The subcellular location of circAPP was assessed via FISH and RT-PCR assays. RNA pull-down assay was performed to detect the interaction of miR-1906 with circAPP and 3' untranslated region (3'UTR) of CLIC1 mRNA.
RESULTS: In this study, we identified a novel circRNA, named circAPP, that is encoded by amyloid precursor protein (APP) and is implicated in AD. CircAPP is a stable circRNA that was upregulated in Aβ-treated microglial cells and the hippocampus of APP/PS1 mice. Downregulation of circAPP or CLIC1, or overexpression of miR-1906 in microglia modulated microglial M1/M2 polarization in Aβ-treated microglial cells and the hippocampus of APP/PS1 mice, and improved AD pathology and the cognitive function of APP/PS1 mice. Further results revealed that circAPP was mainly distributed in the cytoplasm, and circAPP could regulate CLIC1 expression and channel activity by interacting with miR-1906 and affecting miR-1906 expression, thereby regulating microglial polarization in AD.
CONCLUSIONS: Taken together, our study elucidates the regulatory role of circAPP in AD microglial polarization via miR-1906/CLIC1 axis, and suggests that circAPP may act as a critical player in AD pathogenesis and represent a promising therapeutic target for AD.}, }
@article {pmid39953559, year = {2025}, author = {Liang, Y and Xie, S and Jia, J}, title = {Pathway-based network medicine identifies novel natural products for Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {43}, pmid = {39953559}, issn = {1758-9193}, support = {No.2021ZD0201802//the STI2030-Major Projects/ ; U20A20354//the Key Project of the National Natural Science Foundation of China/ ; Z201100005520016, Z201100005520017//Beijing Brain Initiative from Beijing Municipal Science & Technology Commission/ ; CX23YZ15//the grant from the Chinese Institutes for Medical Research/ ; 31627803//the National Key Scientific Instrument and Equipment Development Project/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Mice, Transgenic ; Mice ; *Biological Products/pharmacology/therapeutic use ; *Mice, Inbred C57BL ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics ; Gene Regulatory Networks/drug effects ; Male ; Maze Learning/drug effects ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia, characterized by a complex pathogenesis that complicates the development of effective treatments. Natural products are promising multitarget agents because of their ability to interact with multiple molecular targets. Network-based medicine presents a robust strategy for discovering such agents, which can address the intricate mechanisms underlying AD.
METHODS: In this study, we constructed an AD-related pathway-gene network via text mining and pathway database construction. This network facilitated the identification of natural products that target multiple pathways and genes associated with AD. We evaluated the safety profiles of two selected natural products in C57BL/6J mice through assessments of general behavior, body weight changes, vital organ weight and morphology, and hematological and biochemical parameters. APP/PS1 transgenic mice were subsequently treated with these natural products-either individually or in combination-to assess their therapeutic effects. Cognitive function was evaluated via behavioral tests, such as novel object recognition, Y-maze, and Morris water maze tests. Additionally, immunohistochemical staining and enzyme-linked immunosorbent assays were performed to examine Aβ-associated pathological changes. Transcriptomic analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to elucidate the mechanisms underlying the effects of the natural products.
RESULTS: The constructed AD-related pathway-gene network encompassed three perspectives: (i) Most Studied Pathways (21 pathways with 5325 genes), (ii) Gene-Associated Pathways (26 pathways with 2557 genes), and (iii) Popular Pathways (24 pathways with 3435 genes). Two natural products, (-)-Vestitol and Salviolone, were selected for further validation. Their safety was confirmed in C57BL/6J mice. Notably, the combination of (-)-Vestitol and Salviolone synergistically affected cognitive function in APP/PS1 transgenic mice by reducing Aβ deposition and lowering toxic soluble Aβ levels in the brain. Transcriptomic analysis and qRT-PCR experiments revealed that their combination regulated AD-related pathways and genes more comprehensively, particularly affecting the Neuroactive ligand-receptor interaction and Calcium signaling pathway.
CONCLUSIONS: Our findings demonstrate that screening potential natural products through an AD-related pathway-gene network is a promising strategy for discovering novel therapeutics for AD. The therapeutic potential of (-)-Vestitol and Salviolone as novel candidates for AD treatment is underscored by their synergistic effects, attributed to their comprehensive regulation of AD-associated pathways and genes.}, }
@article {pmid39953505, year = {2025}, author = {Xie, Z and Li, L and Hou, W and Fan, Z and Zeng, L and He, L and Ji, Y and Zhang, J and Wang, F and Xing, Z and Wang, Y and Ye, Y}, title = {Critical role of Oas1g and STAT1 pathways in neuroinflammation: insights for Alzheimer's disease therapeutics.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {182}, pmid = {39953505}, issn = {1479-5876}, support = {196//Guangzhou Municipal Research Collaborative Innovation Projects/ ; 82101327//National Natural Science Foundation of China/ ; 2022A1515012362//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 202201020111//Guangzhou Municipal Science and Technology Project/ ; }, mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; Animals ; *Microglia/metabolism/pathology ; *STAT1 Transcription Factor/metabolism/genetics ; *2',5'-Oligoadenylate Synthetase/metabolism/genetics ; *Neuroinflammatory Diseases/metabolism ; *Signal Transduction ; Mice ; Humans ; Gene Regulatory Networks ; Mice, Inbred C57BL ; Gene Expression Regulation ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) has a significant impact on an individual's health and places a heavy burden on society. Studies have emphasized the importance of microglia in the progression and development of AD. Interferon responses and Interferon-stimulated genes (ISGs) significantly function in neuroinflammatory and neurodegenerative diseases involving AD. Therefore, further exploration of the relationship among microglia, ISGs, and neuroinflammation in AD is warranted.
METHODS: Microglia datasets from the GEO database were retrieved, along with additional microglia RNA-seq data from laboratory mice. Weighted Correlation Network Analysis was used on the training dataset to identify gene co-expression networks. Genes from the black module were intersected with interferon-stimulated genes, and differentially expressed genes (DEGs) were identified. Machine learning algorithms were applied to DEGs, and genes selected by both methods were identified as hub genes, with ROC curves used to evaluate their diagnostic accuracy. Gene Set Enrichment Analysis was performed to reveal functional pathways closely relating to hub genes. Microglia cells were transfected with siRNAs targeting Oas1g and STAT1. Total RNA from microglia cells and mouse brain tissues was extracted, reverse-transcribed, and analyzed via qRT-PCR. Proteins were extracted from cells, quantified, separated by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies. Microglia cells were fixed, permeabilized, blocked, and stained with antibodies for STAT1, then visualized and photographed.
RESULTS: Bioinformatics and machine learning algorithms revealed that Oas1g was identified as a hub gene, with an AUC of 0.812. Enrichment Analysis revealed that Oas1g is closely associated with interferon-related pathways. Expression of Oas1g was validated in AD mouse models, where it was significantly upregulated after microglial activation. Knockdown experiments suggested siOas1g attenuated the effect of siSTAT1, and the expressions of STAT1 and p-STAT1 were elevated. siOas1g could reverse the effect of siSTAT1, indicating that Oas1g potentially regulates the ISGs through the STAT1 pathway.
CONCLUSION: We demonstrated that Oas1g was identified as a hub ISG in AD and can downregulate the activation of IFN-β and STAT1, reducing the expression of ISGs in neuroinflammation. Oas1g might potentially be a beneficial candidate for both prevention and treatment of AD.}, }
@article {pmid39952696, year = {2025}, author = {Supuran, CT}, title = {Multi- and polypharmacology of carbonic anhydrase inhibitors.}, journal = {Pharmacological reviews}, volume = {77}, number = {1}, pages = {100004}, doi = {10.1124/pharmrev.124.001125}, pmid = {39952696}, issn = {1521-0081}, mesh = {*Carbonic Anhydrase Inhibitors/pharmacology/therapeutic use/chemistry ; Humans ; Animals ; *Carbonic Anhydrases/metabolism/drug effects ; *Polypharmacology ; }, abstract = {Eight genetically distinct families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) have been described in organisms overall in the phylogenetic tree. They catalyze the hydration of CO2 to bicarbonate and protons and are involved in pH regulation, chemosensing, and metabolism. The 15 α-CA isoforms present in humans are pharmacological drug targets known for decades, their inhibitors being used as diuretics, antiglaucoma, antiepileptic, or antiobesity drugs, as well as for the management of acute mountain sickness, idiopathic intracranial hypertension, and recently, as antitumor theragnostic agents. Other potential applications include the use of CA inhibitors (CAIs) in inflammatory conditions, cerebral ischemia, neuropathic pain, or Alzheimer/Parkinson disease management. CAs from pathogenic bacteria, fungi, protozoans, and nematodes have started to be considered as drug targets in recent years, with notable advances being registered. CAIs have a complex multipharmacology probably unique to this enzyme, which has been exploited intensely but may lead to other relevant applications in the future due to the emergence of drug design approaches that afforded highly isoform-selective compounds for most α-CAs known to date. They belong to a multitude of chemical classes (sulfonamides and isosteres, [iso]coumarins and related compounds, mono- and dithiocarbamates, selenols, ninhydrines, boronic acids, benzoxaboroles, etc). The polypharmacology of CAIs will also be discussed because drugs originally discovered for the treatment of non-CA related conditions (topiramate, zonisamide, celecoxib, pazopanib, thiazide, and high-ceiling diuretics) show effective inhibition against many CAs, which led to their repurposing for diverse pharmacological applications. SIGNIFICANCE STATEMENT: CAIs have multiple pharmacologic applications, such as diuretics, antiglaucoma, antiepileptic, antiobesity, antiacute mountain sickness, anti-idiopathic intracranial hypertension, and antitumor drugs. Their use in inflammatory conditions, cerebral ischemia, neuropathic pain, or neurodegenerations has started to be investigated recently. Parasite carbonic anhydrases are also drug targets for anti-infectives with novel mechanisms of action that can bypass drug resistance to commonly used agents. Drugs discovered for the management of other conditions that effectively inhibit these enzymes exert interesting polypharmacologic effects.}, }
@article {pmid39952328, year = {2025}, author = {Bashir, B and Gulati, M and Vishwas, S and Gupta, G and Dhanasekaran, M and Paudel, KR and Chellappan, DK and Anand, K and Negi, P and Singh, PK and Rajput, A and Dua, K and Singh, SK}, title = {Bridging gap in the treatment of Alzheimer's disease via postbiotics: Current practices and future prospects.}, journal = {Ageing research reviews}, volume = {105}, number = {}, pages = {102689}, doi = {10.1016/j.arr.2025.102689}, pmid = {39952328}, issn = {1872-9649}, mesh = {Humans ; *Alzheimer Disease/metabolism/therapy/microbiology/prevention & control ; *Gastrointestinal Microbiome/physiology ; Animals ; Probiotics/therapeutic use ; Dysbiosis ; Aging ; }, abstract = {Aging is an extremely significant risk associated with neurodegeneration. The most prevalent neurodegenerative disorders (NDs), such as Alzheimer's disease (AD) are distinguished by the prevalence of proteinopathy, aberrant glial cell activation, oxidative stress, neuroinflammation, defective autophagy, cellular senescence, mitochondrial dysfunction, epigenetic changes, neurogenesis suppression, increased blood-brain barrier permeability, and intestinal dysbiosis that is excessive for the patient's age. Substantial body studies have documented a close relationship between gut microbiota and AD, and restoring a healthy gut microbiota may reduce or even ameliorate AD symptoms and progression. Thus, control of the microbiota in the gut has become an innovative model for clinical management of AD, and rising emphasis is focused on finding new techniques for preventing and/or managing the disease. The etiopathogenesis of gut microbiota in driving AD progression and supplementing postbiotics as a preventive and therapeutic treatment for AD is discussed. The review additionally discusses the use of postbiotics in AD prophylaxis and therapy, portraying them as substances that address senescence-triggered dysfunctions and are worthy of translating from bench to biopharmaceutical market in response to "silver consumers" needs. The current review examines and evaluates the impact of postbiotics as whole and specific metabolites, such as short-chain fatty acids (SCFAs), lactate, polyamines, polyphenols, tryptophan metabolites, exopolysaccharides, and bacterial extracellular vesicles, on the aging-associated processes that reinforce AD. Moreover, it provides an overview of the most recent data from both clinical and preclinical research involving the use of postbiotics in AD.}, }
@article {pmid39952201, year = {2025}, author = {Cheng, M and Li, M and Zhang, Y and Gu, X and Gao, W and Zhang, S and Liu, J}, title = {Exploring the mechanism of PPCPs on human metabolic diseases based on network toxicology and molecular docking.}, journal = {Environment international}, volume = {196}, number = {}, pages = {109324}, doi = {10.1016/j.envint.2025.109324}, pmid = {39952201}, issn = {1873-6750}, mesh = {*Molecular Docking Simulation ; Humans ; *Metabolic Diseases ; Alzheimer Disease ; Pharmaceutical Preparations/metabolism/chemistry ; Diabetes Mellitus, Type 2/metabolism ; Environmental Pollutants/toxicity ; Atherosclerosis ; }, abstract = {This research endeavor seeks to delve into the potential mechanisms by which pharmaceutical and personal care products (PPCPs), recognized as emerging pollutants, could contribute to the human metabolic disorders and then trigger metabolic diseases. Therefore, we have selected lipid and atherosclerosis, Alzheimer's disease, and type Ⅱ diabetes mellitus as representative metabolic diseases, aiming to systematically explore the critical molecular pathways that may be disrupted by PPCPs for the metabolic disease development. By employing advanced network toxicology and molecular docking techniques, we have successfully elucidated the molecular mechanisms that trigger the three diseases. We pinpointed the potential targets associated with the disease by leveraging databases including PubChem, ADEMTlab2.0, SwissADME, and GeneCards. We further employed STRING analysis and Cytoscape software to pinpoint the core targets that were most significantly associated with these metabolic diseases. In addition, enrichment analysis of these core targets was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways within the David database. To obtain the structural aspects of the target proteins, we also employed AlphaFold 3 for protein structure prediction. Finally, we validated the binding affinity of PPCPs to these target proteins using molecular docking with AutoDock Vina. Our findings suggested that PPCPs could potentially trigger metabolic diseases by modulating the expression of microRNAs, influencing cellular apoptosis and proliferation, and affecting signal transduction pathways. Interestingly, we also found the correlations among lipid and atherosclerosis, Alzheimer's disease, and type Ⅱ diabetes mellitus. Taken together, our study provides innovative insights into both the mechanisms of how environmental pollutants trigger human diseases and revealing the correlations among different diseases, thereby laying a theoretical foundation for disease prevention and treatment.}, }
@article {pmid39951718, year = {2025}, author = {Shimada, H and Doi, T and Tsutsumimoto, K and Makino, K and Harada, K and Tomida, K and Morikawa, M and Makizako, H}, title = {A New Computer-Based Cognitive Measure for Early Detection of Dementia Risk (Japan Cognitive Function Test): Validation Study.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e59015}, pmid = {39951718}, issn = {1438-8871}, mesh = {Humans ; *Dementia/diagnosis ; Aged ; Female ; Male ; Japan ; Early Diagnosis ; Aged, 80 and over ; Cognitive Dysfunction/diagnosis ; Cognition ; Neuropsychological Tests/standards/statistics & numerical data ; Diagnosis, Computer-Assisted/methods ; }, abstract = {BACKGROUND: The emergence of disease-modifying treatment options for Alzheimer disease is creating a paradigm shift in strategies to identify patients with mild symptoms in primary care settings. Systematic reviews on digital cognitive tests reported that most showed diagnostic performance comparable with that of paper-and-pencil tests for mild cognitive impairment and dementia. However, most studies have small sample sizes, with fewer than 100 individuals, and are based on case-control or cross-sectional designs.
OBJECTIVE: This study aimed to examine the predictive validity of the Japanese Cognitive Function Test (J-Cog), a new computerized cognitive battery test, for dementia development.
METHODS: We randomly assigned 2520 older adults (average age 72.7, SD 6.7 years) to derivation and validation groups to determine and validate cutoff points for the onset of dementia. The Mini-Mental State Examination (MMSE) was used for comparison purposes. The J-Cog consists of 12 tasks that assess orientation, designation, attention and calculation, mental rotation, verbal fluency, sentence completion, working memory, logical reasoning, attention, common knowledge, word memory recall, and episodic memory recall. The onset of dementia was monitored for 60 months. In the derivation group, receiver operating characteristic curves were plotted to determine the MMSE and J-Cog cutoff points that best discriminated between the groups with and without dementia. In the validation group, Cox proportional regression models were developed to predict the associations of the group classified using the cutoff points of the J-Cog or MMSE with dementia incidence. Harrell C-statistic was estimated to summarize how well a predicted risk score described an observed sequence of events. The Akaike information criterion was calculated for relative goodness of fit, where lower absolute values indicate a better model fit.
RESULTS: Significant hazard ratios (HRs) for dementia incidence were found using the MMSE cutoff between 23 and 24 point (HR 1.93, 95% CI 1.13-3.27) and the J-Cog cutoff between 43 and 44 points (HR 2.42, 95% CI 1.50-3.93). In the total validation group, the C-statistic was above 0.8 for all cutoff points. Akaike information criterion with MMSE cutoff between 23 and 24 points as a reference showed a poor fit for MMSE cutoff between 28 and 29 points, and a good fit for the J-Cog cutoff between 43 and 44 points.
CONCLUSIONS: The J-Cog has higher accuracy in predicting the development of dementia than the MMSE and has advantages for use in the community as a test of cognitive function, which can be administered by nonprofessionals.}, }
@article {pmid39951414, year = {2025}, author = {Yan, H and Mubonanyikuzo, V and Komolafe, TE and Zhou, L and Wu, T and Wang, N}, title = {Hybrid-RViT: Hybridizing ResNet-50 and Vision Transformer for Enhanced Alzheimer's disease detection.}, journal = {PloS one}, volume = {20}, number = {2}, pages = {e0318998}, pmid = {39951414}, issn = {1932-6203}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Magnetic Resonance Imaging/methods ; *Deep Learning ; Brain/diagnostic imaging/pathology ; Neural Networks, Computer ; Male ; Female ; Aged ; }, abstract = {Alzheimer's disease (AD) is a leading cause of disability worldwide. Early detection is critical for preventing progression and formulating effective treatment plans. This study aims to develop a novel deep learning (DL) model, Hybrid-RViT, to enhance the detection of AD. The proposed Hybrid-RViT model integrates the pre-trained convolutional neural network (ResNet-50) with the Vision Transformer (ViT) to classify brain MRI images across different stages of AD. The ResNet-50 adopted for transfer learning, facilitates inductive bias and feature extraction. Concurrently, ViT processes sequences of image patches to capture long-distance relationships via a self-attention mechanism, thereby functioning as a joint local-global feature extractor. The Hybrid-RViT model achieved a training accuracy of 97% and a testing accuracy of 95%, outperforming previous models. This demonstrates its potential efficacy in accurately identifying and classifying AD stages from brain MRI data. The Hybrid-RViT model, combining ResNet-50 and ViT, shows superior performance in AD detection, highlighting its potential as a valuable tool for medical professionals in interpreting and analyzing brain MRI images. This model could significantly improve early diagnosis and intervention strategies for AD.}, }
@article {pmid39951299, year = {2025}, author = {Wu, Z and Xu, L and Xie, Y and Sambangi, A and Swaminathan, S and Pei, Z and Ji, W and Li, Z and Guo, Y and Li, Z and Chen, G}, title = {Brain-Wide Neuroregenerative Gene Therapy Improves Cognition in a Mouse Model of Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e2410080}, doi = {10.1002/advs.202410080}, pmid = {39951299}, issn = {2198-3844}, support = {202206060002//Key Technologies Research and Development Program of Guangzhou Municipality/ ; 2021ZT09Y552//Guangdong Provincial Introduction of Innovative Research and Development Team/ ; 2022A1515012294//Natural Science Foundation of Guangdong Province/ ; }, abstract = {Alzheimer's disease (AD) is a progressive and irreversible brain disorder with extensive neuronal loss in the neocortex and hippocampus. Current therapeutic interventions focus on the early stage of AD but lack effective treatment for the late stage of AD, largely due to the inability to replenish the lost neurons and repair the broken neural circuits. In this study, by using engineered adeno-associated virus vectors that efficiently cross the blood-brain-barrier in the mouse brain, a brain-wide neuroregenerative gene therapy is developed to directly convert endogenous astrocytes into functional neurons in a mouse model of AD. It is found that ≈500 000 new neurons are regenerated and widely distributed in the cerebral cortex and hippocampus. Importantly, it is demonstrated that the converted neurons can integrate into pre-existing neural networks and improve various cognitive performances in AD mice. Chemogenetic inhibition of the converted neurons abolishes memory enhancement in AD mice, suggesting a pivotal role for the newly converted neurons in cognitive restoration. Together, brain-wide neuroregenerative gene therapy may provide a viable strategy for the treatment of AD and other brain disorders associated with massive neuronal loss.}, }
@article {pmid39951190, year = {2025}, author = {Brennan, SO and Tinworth, AC}, title = {Genetically Proxied Phosphodiesterase Type 5 (PDE5) Inhibition and Risk of Dementia: A Drug Target Mendelian Randomization Study.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39951190}, issn = {1559-1182}, abstract = {Phosphodiesterase-5 (PDE5) inhibitors have gained interest as a potential treatment for dementia. However, current evidence is limited to observational and pre-clinical studies. We conducted a drug-target Mendelian randomization (MR) analysis to investigate the on-target effects of pharmacological PDE5 inhibition on dementia subtypes and related phenotypes. We selected variants from around the PDE5A locus associated with diastolic and systolic blood pressure, as well as circulating PDE5A levels, to create three instruments for genetically proxied PDE5A inhibition. Using two-sample MR, we validated the instruments against erectile dysfunction and pulmonary arterial hypertension before assessing their associations with dementia subtypes, dementia-related proteins, and neuroimaging traits. After correcting for multiple comparisons, genetically proxied PDE5 inhibition, per one SD lower in diastolic blood pressure, was associated with higher odds of Alzheimer's disease (OR 1.09, 95% CI 1.07-1.11) and Lewy body dementia (OR 1.32, 95% CI 1.23-1.41), but a trend towards lower odds of vascular dementia across all instruments. Genetically proxied PDE5 inhibition was associated with both beneficial and adverse effects on brain MRI traits. This included lower volumes of white matter hyperintensities (SD change - 0.035, 95% CI - 0.025, - 0.045), indicating potential benefits, but also reduced volumes of other structures, including the thalamus, suggesting potential adverse effects. PDE5 inhibition was associated with the concentrations of several proteins implicated in dementia pathophysiology. Our findings suggest that while PDE5 inhibition may be associated with a lower risk of vascular dementia, possibly by preventing white matter hyperintensities, it may increase risk of Alzheimer's disease and Lewy body dementia, warranting further investigation before clinical trials.}, }
@article {pmid39951189, year = {2025}, author = {Ayyubova, G and Madhu, LN}, title = {Microglial NLRP3 Inflammasomes in Alzheimer's Disease Pathogenesis: From Interaction with Autophagy/Mitophagy to Therapeutics.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39951189}, issn = {1559-1182}, abstract = {The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, discovered 20 years ago, is crucial in controlling innate immune reactions in Alzheimer's disease (AD). By initiating the release of inflammatory molecules (including caspases, IL-1β, and IL-18), the excessively activated inflammasome complex in microglia leads to chronic inflammation and neuronal death, resulting in the progression of cognitive deficiencies. Even though the involvement of NLRP3 has been implicated in neuroinflammation and widely explored in several studies, there are plenty of controversies regarding its precise roles and activation mechanisms in AD. Another prominent feature of AD is impairment in microglial autophagy, which can be either the cause or the consequence of NLRP3 activation and contributes to the aggregation of misfolded proteins and aberrant chronic inflammatory state seen in the disease course. Studies also demonstrate that intracellular buildup of dysfunctional and damaged mitochondria due to defective mitophagy enhances inflammasome activation, further suggesting that restoration of impaired autophagy and mitophagy can effectively suppress it, thereby reducing inflammation and protecting microglia and neurons. This review is primarily focused on the role of NLRP3 inflammasome in the etiopathology of AD, its interactions with microglial autophagy/mitophagy, and the latest developments in NLRP3 inflammasome-targeted therapeutic interventions being implicated for AD treatment.}, }
@article {pmid39950370, year = {2025}, author = {Xiong, K and Wang, X and Feng, C and Zhang, K and Chen, D and Yang, S}, title = {Vectors in CRISPR Gene Editing for Neurological Disorders: Challenges and Opportunities.}, journal = {Advanced biology}, volume = {9}, number = {3}, pages = {e2400374}, doi = {10.1002/adbi.202400374}, pmid = {39950370}, issn = {2701-0198}, support = {81874304//National Natural Science Foundation of China/ ; 22122409//National Natural Science Foundation of China/ ; 22A350017//Key Scientific Research Projects/ ; 21HASTIT043//Programs for Science &Technology Innovation Talents in Universities of Henan Province/ ; ZYQR201912191//Outstanding Young Talents in Henan Province/ ; }, mesh = {Humans ; *Gene Editing/methods ; *Genetic Vectors/genetics ; *Nervous System Diseases/therapy/genetics ; *CRISPR-Cas Systems/genetics ; *Genetic Therapy/methods ; Dependovirus/genetics ; Animals ; Gene Transfer Techniques ; }, abstract = {Diseases of the nervous system are recognized as the second leading cause of death worldwide. The global prevalence of neurological diseases, such as Huntington's disease, Alzheimer's disease, and Parkinson's disease has seen a significant rise due to the increasing proportion of the aging population. The discovery of the clustered regularly interspaced short palindromic repeats (CRISPR) genome editing technique has paved way for universal neurological diseases treatment. However, finding a safe and effective method to deliver CRISPR gene-editing tools remains a main challenge for genome editing therapies in vivo. Adeno-associated virus (AAV) is currently one of the most commonly used vector systems, but some issues remain unresolved, including capsid immunogenicity, off-target mutations, and potential genotoxicity. To address these concerns, researchers are actively encouraging the development of new delivery systems, like virus-like particles and nanoparticles. These novel systems have the potential to enhance targeting efficiency, thereby offering possible solutions to the current challenges. This article reviews CRISPR delivery vectors for neurological disorders treatment and explores potential solutions to overcome limitations in vector systems. Additionally, the delivery strategies of CRISPR systems are highlighted as valuable tools for studying neurological diseases, and the challenges and opportunities that these vectors present.}, }
@article {pmid39950283, year = {2025}, author = {Kumar, B and Sahoo, A and Singhal, M and Varshney, G and Haldar, T and Bali, V}, title = {An Emerging Prospective of Antipsychotics for Treating Neurodegenerative Disorders.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128344910241211112452}, pmid = {39950283}, issn = {1873-4286}, abstract = {CNS illnesses specified by slow deprivation of especially preganglionic neurons, as opposed to the selective static neuronal loss caused by a toxic or metabolic condition, are known as Neurodegenerative disorders. Neurodegenerative disorders are differentiated clinically by behavioral or cognitive problems. The management and treatment of neurodegenerative disorders pose significant challenges, necessitating a multidimensional approach. While primarily designed for psychiatric conditions, antipsychotics have shown potential in ameliorating behavioral and psychological symptoms in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. This review explores the existing literature, highlighting the potential benefits, risks, and considerations associated with incorporating antipsychotics into the treatment paradigm for neurodegenerative disorders. Additionally, it discusses the evolving landscape of personalized treatment strategies, emphasizing the need for a multidisciplinary approach to optimize patient outcomes in the complex realm of neurodegenerative disorder management.}, }
@article {pmid39950075, year = {2025}, author = {Zhang, Y and Wang, Y and Liu, Q and Xiao, J and Huang, L and Zhou, L and Liu, X}, title = {Exploring the effects of combined nostalgic activities and music therapy on Alzheimer's disease outcomes.}, journal = {Frontiers in psychology}, volume = {16}, number = {}, pages = {1526761}, pmid = {39950075}, issn = {1664-1078}, abstract = {OBJECTIVE: Exploring the effects of combination of nostalgic activity-based therapies, including music therapy on cognitive function, negative emotions, and sleep quality in patients with mild to moderate Alzheimer's disease.
METHODS: A total of 63 patients with mild to moderate Alzheimer's disease who were treated at the Sichuan Provincial Psychiatric Center of the People's Hospital of Sichuan Province from January to June 2023 were selected as the research subjects. They were randomly divided into a study group (n = 31) and a control group (n = 32) using a random number table method. The control group received routine treatment and nursing care, while the study group received nostalgic music therapy intervention on the basis of the control group. The Mini Mental State Examination (MMSE), Montreal Cognitive Assessment Scale (MOCA), Self Rating Anxiety and Depression Scale (SAS, SDS), and Pittsburgh Sleep Quality Index (PSQI) of the two groups were compared.
RESULTS: A total of 30 cases from each group completed the study. After 12 weeks of intervention, the MMSE and MOCA scores of both groups of patients increased, and the treatment group was higher than the control group (P < 0.05); SAS, SDS and PSQI scores decreased compared with those before intervention, and the treatment group was lower than the control group (P < 0.05).
CONCLUSION: Nostalgic music therapy can improve cognitive function, alleviate negative emotions, and improve sleep quality in patients with mild to moderate Alzheimer's disease.}, }
@article {pmid39949872, year = {2025}, author = {Hartz, SM and Schindler, SE and Streitz, ML and Moulder, KL and Mozersky, J and Wang, G and Xiong, C and Morris, JC}, title = {Assessing the clinical meaningfulness of slowing CDR-SB progression with disease-modifying therapies for Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70033}, pmid = {39949872}, issn = {2352-8737}, support = {R01 AA029308/AA/NIAAA NIH HHS/United States ; R01 AG070941/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; U10 AA008401/AA/NIAAA NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; R01 AG067505/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R01 AG065234/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: For many patients and caregivers, a major goal of disease-modifying treatments (DMTs) for Alzheimer's disease (AD) dementia is to extend independence in instrumental and basic activities of daily living (IADLs and BADLs). The goal of this study was to estimate the effect of treatments on the time remaining independent in IADLs and BADLs.
METHODS: Participants at the Knight Alzheimer Disease Research Center (Knight ADRC) who met eligibility criteria for recent DMT trials were studied: age ≥60 years at baseline, clinical diagnosis of very mild or mild AD dementia (global Clinical Dementia Rating [CDR] score 0.5 or 1), biomarker confirmation of amyloid pathology, and at least one follow-up CDR assessment within 5 years. For IADLs, a subset of the Functional Assessment Questionnaire (FAQ) was examined that rated the degree of independence in the following: paying bills, driving, remembering medications and appointments, and preparing meals. For BADLs, the Personal Care domain of the CDR was used. Mixed-effects logistic and ordinal regression models were used to examine the relationship between CDR Sum of Boxes (CDR-SB) and the individual functional outcomes and their components. The change in CDR-SB over time was estimated with linear mixed-effects models.
RESULTS: A total of 282 participants were followed for an average of 2.9 years (standard deviation [SD] 1.3 years). For 50% of individuals, loss of independence in IADLs occurred at CDR-SB >4.5 and in BADLs at CDR-SB >11.5. For individuals with a baseline CDR-SB = 2, treatment with lecanemab would extend independence in IADLs for 10 months (95% confidence interval [CI] 4-18 months) and treatment with donanemab in the low/medium tau group would extend independence in IADLs by 13 months (95% CI 6-24 months).
DISCUSSION: Independence in ADLs can be related to CDR-SB and used to demonstrate the effect of AD treatments in extending the time of independent function, a meaningful outcome for patients and their families.
HIGHLIGHTS: We estimated time to loss of independence for people with AD dementiaEstimating time to loss of independence can help with clinical decision-makingDisease-modifying treatments for AD dementia can extend independence.}, }
@article {pmid39949834, year = {2025}, author = {Tie, J and Wu, H and Liu, W and Li, Y and Li, L and Zhao, S and Yuan, Z and Mahmood, K and Chen, S and Wu, H}, title = {Overexpression of SFPQ Improves Cognition and Memory in AD Mice.}, journal = {Neural plasticity}, volume = {2025}, number = {}, pages = {3934591}, pmid = {39949834}, issn = {1687-5443}, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics ; Mice ; *Cognition/physiology ; PTB-Associated Splicing Factor/metabolism ; Memory/physiology ; Hippocampus/metabolism ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Male ; Mice, Transgenic ; tau Proteins/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Peptide Fragments/metabolism ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder with multifaceted pathogenesis, which has been extensively investigated, yet effective treatments remain lacking. Splicing factor proline and glutamine rich (SFPQ) is known to play a crucial role in neurodegenerative diseases, including antioxidant-related functions and regulating gene expression within brain neurons. However, the specific role of SFPQ in AD pathology is not well understood. In this study, an AD mouse model was established through lateral ventricular injection of amyloid-beta1-42 (Aβ 1-42). Subsequently, adeno-associated virus was administered to overexpress SFPQ in the hippocampus of AD mice. The results demonstrate that SFPQ overexpression improves recognition and memory in AD mice, while reducing AD-related marker proteins such as amyloid precursor protein (APP) and Tau. Additionally, synaptic and memory-associated proteins, as well as antioxidant proteins like glutathione S-transferase (GST) and heme oxygenase-1 (HO-1), were upregulated. The ratio of antiapoptotic protein Bcl-2 to proapoptotic protein Bax also increased. Furthermore, phosphorylated phosphoinositide 3-kinase (p-PI3K)/PI3K and phosphorylated protein kinase B (p-AKT)/AKT ratios were elevated, indicating activation of the PI3K/AKT signaling pathway. These findings suggest that SFPQ may serve as a promising molecular target for the prevention and treatment of AD.}, }
@article {pmid39949498, year = {2025}, author = {Tiong, SQ and Mohgan, RN and Quek, JY and Liew, JYS and Wong, GYS and Thang, ZQ and Chan, ZL and Gan, SY and Chan, EWL}, title = {Inhibition of the Transforming Growth Factor-β Signaling Pathway Confers Neuroprotective Effects on Beta-Amyloid-Induced Direct Neurotoxicity and Microglia-Mediated Neuroinflammation.}, journal = {Neurology research international}, volume = {2025}, number = {}, pages = {8948290}, pmid = {39949498}, issn = {2090-1852}, abstract = {Background: Abnormal elevation of transforming growth factor-beta (TGF-β) has been observed among Alzheimer's disease (AD) patients. This may be due to microglia-mediated release of proinflammatory cytokines, which promote neuroinflammation and neuronal apoptosis. Silencing of TGFBR1, a gene encoding TGF-β receptor type I (TGF-βR1), has resulted in neuronal survival from amyloid-beta (Aβ)-induced neurotoxicity. Therefore, the present study investigated the neuroprotective effect of TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Methods: The neuroprotective effect of TGF-βR1 inhibitors against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation were investigated using the RealTime-Glo™ MT Cell Viability Assay. The inhibitory effect of TGF-βR1 inhibitors on Aβ-induced microglia-mediated production of proinflammatory cytokines (TNF-α and IL-1β) was determined using enzyme-linked immunosorbent assay (ELISA). Results: TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) at the tested concentrations (6.25-150 nM) showed no significant cytotoxicity effects on SH-SY5Y and BV-2 cells. Moreover, treatments with these inhibitors exhibited neuroprotection on SH-SY5Y cells against Aβ-induced direct neurotoxicity. The trend of cell viability after 24 h treatment also supports the microscopic images of the cells' morphology. Furthermore, pretreatment with these inhibitors conferred indirect neuroprotective effect against Aβ-induced microglia-mediated neuroinflammation by attenuating the production of proinflammatory cytokines (TNF-α and IL-1β). Conclusion: The inhibition of the TGF-β signaling pathway in neuronal and microglia cells by TGF-βR1 inhibitors resulted in neuroprotection against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Hence, targeting the TGF-β signaling pathway in both neuronal and microglia cells could provide a promising therapeutic strategy in AD.}, }
@article {pmid39949308, year = {2025}, author = {Karimpourvazifehkhorani, A and Hekmati, I and Rezvanizadeh, A and Amiri, N and Kadkhoda, M and Arasteh, F}, title = {Brief Behavioral Activation Therapy is effective on apathy symptoms of the older adults with mild Alzheimer's disease but not with moderate Alzheimer's disease.}, journal = {Aging & mental health}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/13607863.2025.2464712}, pmid = {39949308}, issn = {1364-6915}, abstract = {OBJECTIVES: This study aimed to investigate the effectiveness of Brief Behavioral Activation Therapy (BBAT) on apathy symptoms in older adults with Alzheimer's disease (AD) in a medical center facility.
METHOD: In an experimental design, 90 older adults with AD were replaced into three groups including two experimental groups (mild AD group (n = 30), moderate AD group (n = 30)) and a control group (15 participants with mild AD and 15 participants with moderate AD). All participants completed the Dimensional Apathy Scale (DAS) before and after an eight-session BBAT intervention, with follow-up conducted two months post-treatment. A 3 x 3 mixed ANOVA was performed to analyze differences in apathy levels across groups over time, using SPSS version 26.
RESULTS: The mixed ANOVA revealed significant differences in all apathy dimensions (executive, emotional and initial symptoms) among the groups. Specifically, significant between-subject and within-subject differences, respectively for group main effect and time main effect, along with a significant interaction between group and time. These findings indicated that apathy symptoms in patients with mild AD significantly decreased from pretest to post- intervention, but there wasn't significant change in moderate AD and control group.
CONCLUSION: The findings suggested that BBAT is effective in reducing apathy symptoms in patients with mild AD. Early evaluation, diagnosis and treatment of apathy in the mild stages of AD are crucial for improving patient outcomes.}, }
@article {pmid39948905, year = {2024}, author = {Koike, T and Karino, M and Tatsumi, H and Fujioka-Kobayashi, M and Kanno, T}, title = {[The End-of-Life Care Experienced by a Patient with Oral Cancer and Dementia Who Requested Home Palliative Care].}, journal = {Gan to kagaku ryoho. Cancer & chemotherapy}, volume = {51}, number = {13}, pages = {1504-1507}, pmid = {39948905}, issn = {0385-0684}, mesh = {Humans ; Male ; *Palliative Care ; *Home Care Services ; Aged, 80 and over ; *Terminal Care ; *Dementia/therapy ; Mouth Neoplasms/therapy/complications ; Carcinoma, Squamous Cell/therapy/complications ; Fatal Outcome ; }, abstract = {The number of patients and families who wish to spend their final moments at home is increasing, and in the future, there may be more opportunities to provide end-of-life care for oral cancer at home. We report our experience with palliative treatment for a terminal oral cancer patient with dementia who wished for home palliative care. The patient was an 87-year-old male with a history of Alzheimer's dementia and chronic heart failure. In late September 2022, he visited a nearby internal medicine clinic with complaints of loss of appetite and pain in the right maxillary gingiva and was referred to a tertiary medical institution in the prefecture for further examination and treatment. At the initial visit, a 40×30 mm easily bleeding ulcerative lesion was observed in the right maxillary molar gingiva. Based on various examinations, he was diagnosed with squamous cell carcinoma of the right maxillary gingiva(cT4bN0M0, Stage ⅣB). However, due to dementia and severe cardiac dysfunction, he was not eligible for chemoradiotherapy and a plan for palliative treatment was made. The patient strongly wished for treatment at home and at a local hospital, and palliative treatment with a view to home palliative care was initiated. He was admitted to our internal medicine department in mid-November. Our department continued local treatment for the tumor and specialized oral care by a dental hygienist, but he passed away due to cardiac arrest in early January 2023. Although the patient passed away before transitioning to home care, smooth implementation of home palliative care requires cooperation not only from hospitals but also from the entire community, and the establishment of a comprehensive home medical support system is crucial.}, }
@article {pmid39948600, year = {2025}, author = {Yang, S and Zhang, X and Du, X and Yan, P and Zhang, J and Wang, W and Wang, J and Zhang, L and Sun, H and Liu, Y and Xu, X and Di, Y and Zhong, J and Wu, C and Reinhardt, JD and Zheng, Y and Wu, T}, title = {Prediction of cognitive conversion within the Alzheimer's disease continuum using deep learning.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {41}, pmid = {39948600}, issn = {1758-9193}, support = {81772454//National Natural Science Foundation of China/ ; BE2023023-2//The Key Project of Jiangsu Province's Key Research and Development Program/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/psychology/diagnosis ; *Deep Learning ; Female ; Male ; Aged ; *Cognitive Dysfunction/diagnosis/diagnostic imaging ; *Disease Progression ; *Neuropsychological Tests ; Longitudinal Studies ; Aged, 80 and over ; Neuroimaging/methods ; Prognosis ; Cohort Studies ; }, abstract = {BACKGROUND: Early diagnosis and accurate prognosis of cognitive decline in Alzheimer's disease (AD) is important to timely assignment to optimal treatment modes. We aimed to develop a deep learning model to predict cognitive conversion to guide re-assignment decisions to more intensive therapies where needed.
METHODS: Longitudinal data including five variable sets, i.e. demographics, medical history, neuropsychological outcomes, laboratory and neuroimaging results, from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort were analyzed. We first developed a deep learning model to predicted cognitive conversion using all five variable sets. We then gradually removed variable sets to obtained parsimonious models for four different years of forecasting after baseline within acceptable frames of reduction in overall model fit (AUC remaining > 0.8).
RESULTS: A total of 607 individuals were included at baseline, of whom 538 participants were followed up at 12 months, 482 at 24 months, 268 at 36 months and 280 at 48 months. Predictive performance was excellent with AUCs ranging from 0.87 to 0.92 when all variable sets were considered. Parsimonious prediction models that still had a good performance with AUC 0.80-0.84 were established, each only including two variable sets. Neuropsychological outcomes were included in all parsimonious models. In addition, biomarker was included at year 1 and year 2, imaging data at year 3 and demographics at year 4. Under our pre-set threshold, the rate of upgrade to more intensive therapies according to predicted cognitive conversion was always higher than according to actual cognitive conversion so as to decrease the false positive rate, indicating the proportion of patients who would have missed upgraded treatment based on prognostic models although they actually needed it.
CONCLUSIONS: Neurophysiological tests combined with other indicator sets that vary along the AD continuum can improve can provide aid for clinical treatment decisions leading to improved management of the disease.
ClinicalTrials.gov Identifier: NCT00106899 (Registration Date: 31 March 2005).}, }
@article {pmid39948447, year = {2025}, author = {Gao, Q and Wang, J and Fang, R and Sun, H and Wang, T}, title = {A doubly robust estimator for continuous treatments in high dimensions.}, journal = {BMC medical research methodology}, volume = {25}, number = {1}, pages = {35}, pmid = {39948447}, issn = {1471-2288}, support = {82204163//National Natural Science Foundation of China/ ; 82073674//National Natural Science Foundation of China/ ; 202203021212382//Fundamental Research Program of Shanxi Province/ ; }, mesh = {Humans ; *Propensity Score ; Computer Simulation ; Models, Statistical ; Algorithms ; Observational Studies as Topic/methods/statistics & numerical data ; Alzheimer Disease/drug therapy ; }, abstract = {BACKGROUND: Generalized propensity score (GPS) methods have become popular for estimating causal relationships between a continuous treatment and an outcome in observational studies with rich covariate information. The presence of rich covariates enhances the plausibility of the unconfoundedness assumption. Nonetheless, it is also crucial to ensure the correct specification of both marginal and conditional treatment distributions, beyond the assumption of unconfoundedness.
METHOD: We address limitations in existing GPS methods by extending balance-based approaches to high dimensions and introducing the Generalized Outcome-Adaptive LASSO and Doubly Robust Estimate (GOALDeR). This novel approach integrates a balance-based method that is robust to the misspecification of distributions required for GPS methods, a doubly robust estimator that is robust to the misspecification of models, and a variable selection technique for causal inference that ensures an unbiased and statistically efficient estimation.
RESULTS: Simulation studies showed that GOALDeR was able to generate nearly unbiased estimates when either the GPS model or the outcome model was correctly specified. Notably, GOALDeR demonstrated greater precision and accuracy compared to existing methods and was slightly affected by the covariate correlation structure and ratio of sample size to covariate dimension. Real data analysis revealed no statistically significant dose-response relationship between epigenetic age acceleration and Alzheimer's disease.
CONCLUSION: In this study, we proposed GOALDeR as an advanced GPS method for causal inference in high dimensions, and empirically demonstrated that GOALDeR is doubly robust, with improved accuracy and precision compared to existing methods. The R package is available at https://github.com/QianGao-SXMU/GOALDeR .}, }
@article {pmid39946000, year = {2025}, author = {Elyasi, L and Rosenholm, JM and Jahanshahi, M and Jesmi, F}, title = {The Effect of Picein on Inhibitory Avoidance Memory and Activity of Antioxidant Enzymes in Hippocampus of Male Rats with Scopolamine-Induced Injury.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39946000}, issn = {1559-1182}, support = {IR.GOUMS.REC.1400.161//Golestan University of Medical Sciences Neuroscience Research Center/ ; }, abstract = {Alzheimer disease (AD) is a common neurologic disorder, impairing memory and spatial perception. Consistent with the extensive search for its treatment, we investigated the effect of Picein on inhibitory avoidance memory, lipid peroxidation, and the activity of hippocampal antioxidant enzymes in rats. Forty adult male Wistar rats were randomized into control group (no intervention), model group (intraperitoneal injection of 3-mg/kg scopolamine), and three interventional groups (1.5-, 2.5-, and 5-mg/kg intraventricular Picein, once a day for 7 days, 24 h after scopolamine injection). After behavioral test, the rats' hippocampus was isolated for measuring oxidative stress markers, including enzymes superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GPX), catalase (CAT), and total antioxidant capacity (TAC). One-way ANOVA was used for comparing numeric variables among the groups using SPSS v.21. The results showed scopolamine decreased SOD, GPX, and CAT enzymes, and TAC level, and increased MDA level, compared with the control group (P < 0.001) that confirmed the scopolamine-induced AD model. The two doses of 2.5- and 5-mg/kg Picein increased latency for entering the dark room, compared to the scopolamine group (P < 0.05), making them similar to the control group. The number of entries into the dark room in the 2.5-mg/kg Picein reduced and approached the control group (P < 0.05). The 2.5-mg/kg Picein decreased MDA and increased SOD, GPX, and TAC, more than 5 mg/kg Picein, both different than scopolamine; only 2.5-mg/kg Picein had different CAT, compared to scopolamine group (P < 0.05). In conclusion, by lowering oxidative stress in the hippocampus, Picein was able to prevent the scopolamine-induced impaired learning and avoidance memory in rats.}, }
@article {pmid39945003, year = {2024}, author = {Cai, W and Zhang, H and Wu, Y and Yao, Y and Zhang, J}, title = {Comparative the efficacy and safety of Gosuranemab, Semorinemab, Tilavonemab, and Zagotenemab in patients with Alzheimer's disease: a systematic review and network meta-analysis of randomized controlled trials.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1465871}, pmid = {39945003}, issn = {1663-4365}, abstract = {OBJECTIVE: The aim of this study was to compare the efficacy and safety of anti-tau protein monoclonal antibodies for Alzheimer's disease (AD). Tau protein aggregation, a key pathological feature of AD, is closely associated with neurodegeneration and cognitive decline. Targeting tau protein has emerged as a promising therapeutic strategy. By investigating the effects of monoclonal antibodies on cognitive function, disease progression, and overall quality of life in patients with AD, which can provide valuable insights into their potential as a therapeutic option for this devastating neurodegenerative disorder.
METHODS: The randomized controlled trials (RCTs) investigating the efficacy of Gosuranemab, Semorinemab, Tilavonemab, and Zagotenemab in Alzheimer's disease (AD) were systematically searched across PubMed, Embase, Web of Science and Cochrane Library, up to May 2024. The control group included placebo. The efficacy indicators were change in the Mini Mental State Examination (MMSE), Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL) from baseline until the time of efficacy observation. Statistical analysis was conducted using Stata 14 and RevMan 5.4. The purpose of data processing, including generating network evidence plots, surface under the cumulative ranking curve (SUCRA) ranking, league plots, and funnel plots, is to visually summarize and evaluate the relative effectiveness and safety and potential publication bias of multiple interventions. Mean differences (MD) and 95% confidence interval (95%CI) as effect sizes to analyze continuous variables.
RESULTS: This study encompassed six RCTs involving 2,193 patients. Semorinemab were more effective than placebo in MMSE and ADAS-Cog scores (MDs ranging between 0.52 and 3.21; MDs ranging between 0.17 and 3.30). Placebo showed relatively good efficacy according to SUCRA ranking on change in CDR-SB and ADCS-ADL scores (75.7 and 79.5%). Tilavonemab and Semorinemab exhibited efficacy similar to that of a placebo in the analysis of the two indicators. Tilavonemab showed a lower incidence of AE, SAE, fall, and urinary tract infections than placebo, and the differences were statistically significant. Most safety analysis results showed no statistical difference.
CONCLUSION: The results indicated that anti-tau protein monoclonal antibodies, such as Semorinemab and Tilavonemab, showed promise in terms of efficacy and safety for managing AD. Further studies are needed to confirm these findings, assess long-term effects, and refine treatment protocols.
https://www.crd.york.ac.uk/prospero/#myprospero, CRD42024583388.}, }
@article {pmid39944951, year = {2025}, author = {Zhou, Z and Fan, B and Chen, Q and Li, X and Ke, X}, title = {Individual and combined effects of dietary vitamin intake on cognitive function in elderly adults: the potential mediating role of serum neurofilament light chain levels.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1485648}, pmid = {39944951}, issn = {2296-861X}, abstract = {BACKGROUND: Vitamins are essential micronutrients for the prevention and treatment of neurodegenerative diseases. The objectives of the present study were to evaluate the association between dietary vitamin intake and cognitive function in elderly adults and to explore the potential impact of serum neurofilament light chain (NfL) concentration.
METHODS: Data from 468 elderly individuals, including information on the dietary consumption of 10 vitamins, were used. Cognitive performance was assessed according to a composite Z-score of the Animal Fluency Test (AFT), Consortium to Establish a Registry for Alzheimer's Disease (CERAD), and Digit Symbol Substitution Test (DSST). Serum NfL levels were measured using a highly sensitive immunoassay. Bayesian kernel machine regression (BKMR) models were used to estimate the combined effects of vitamin mixtures on cognitive function.
RESULTS: In both single- and multiple-vitamin models, individuals with a higher intake of dietary vitamin K exhibited greater global cognitive function, compared to those with a lower vitamin intake. BKMR revealed positive associations between vitamin mixtures and global cognitive function, AFT Z-scores, and DSST Z-scores. Individuals in the third vitamin K intake tertile exhibited lower serum NfL levels than those in the first tertile (regression coefficient, β = -0.16 [95% confidence interval -0.29 to -0.02]; p = 0.023). Serum NfL levels mediated the association between higher vitamin K intake and global cognitive function (8.73%).
CONCLUSION: Vitamin mixtures were positively associated with global cognitive function in elderly participants. The association between vitamin K intake and cognitive function may be mediated by serum NfL concentration.}, }
@article {pmid39944895, year = {2025}, author = {Du, H and Ma, F and Cao, Y and Bai, M and Gao, X and Yang, Z and Xu, Y and Yan, Y}, title = {Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agents.}, journal = {Frontiers in chemistry}, volume = {13}, number = {}, pages = {1545908}, pmid = {39944895}, issn = {2296-2646}, abstract = {INTRODUCTION: The multi-targeted ligands (MTDL) strategy has been recognized as a promising Approach for the development of effective treatments against Alzheimer's disease (AD), due to the presence of multiple pathological mechanisms in AD. In this study, a series of bis(7)-harmine derivatives were designed and synthesized as multifunctional drugs for the treatment of AD.
METHODS: The derivatives were synthesized by chemical methods and their structure was confirmed by nuclear magnetic resonance (NMR). The Ellman's assay was utilized to assess the inhibitory potential of derivatives against hAChE and hBuChE. The inhibitory activity of these derivatives on both hMAO-A and hMAO-B was assessed using a fluorescence-based method. The thioflavin T (Th-T) fluorescence assay was used to assess the inhibition of Aβ 1-42 self-aggregation. The cytotoxicity was evaluated using the MTT assay. The Surflex-Dock program in Sybyl-X2.0 Software was employed for molecular docking.
RESULTS: In vitro studies revealed that numerous synthesized compounds exhibited potent inhibitory activity against hAChE, and hMAO-B (IC50 < 1 μM), as well as Aβ 1-42 aggregation (IC50 < 20 μM). Importantly, the multitarget compounds 6d, 8c, and 8d exhibited remarkable efficacy in simultaneously mitigating Aβ-induced toxicity in SH-SY5Y cells while demonstrating minimal cytotoxicity. Furthermore, predicted ADMET results suggested that 6d, 8c, and 8d possessed favorable pharmacokinetic properties and demonstrated low toxicity levels. Additionally, molecular docking studies of 6d within the activesites of hAChE, hMAO-B, and Aβ 1-42 elucidated the inhibition mechanism.
DISCUSSION AND CONCLUSION: Based on these findings, it is evident that 6d, 8c, and 8d hold potential as promising multi-functional drugs for AD treatment.}, }
@article {pmid39944627, year = {2025}, author = {Zhu, Y and Xu, H and Yu, C and Jiang, W and Hou, X and Ma, M and Wu, J}, title = {Polymers for the treatment of Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1512941}, pmid = {39944627}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is one of the most common diseases of the central nervous system in the middle-aged and elderly population. It is a neurodegenerative disorder, and its main clinical symptoms include the loss of established memories, a decline in learning capacity, and the buildup of β-amyloid peptides. The disease is often accompanied by neurodegenerative changes and the formation of neurofibrillary tangles. However, the number of drugs available for the clinical treatment of AD remains limited. Currently, existing medications are not effective in completely curing the disease or stopping its progression. Due to their excellent biocompatibility and biodegradability, polymers have been widely used as drug delivery carriers in various fields including cancer therapy and wound healing. The use of polymers enables targeted drug delivery and prolonged release profiles. In recent years, researchers have made significant progress in utilizing polymers such as polyethylene glycol, poly (lactic-co-glycolic acid) (PLGA), and chitosan (CS) to deliver drugs and blood-brain barrier receptor ligands for the treatment of AD. Moreover, many polymers with inherent therapeutic properties have been developed, including the already marketed GV-971 as well as experimental polymers such as PLGA and CS oligosaccharide. This review summarizes the applications of polymers in AD treatment over the past few years and highlights their current limitations to help researchers better understand current advancements in polymer development and identify future research directions.}, }
@article {pmid39944545, year = {2025}, author = {Peng, D and Huang, W and Liu, R and Zhong, W}, title = {From pixels to prognosis: radiomics and AI in Alzheimer's disease management.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1536463}, pmid = {39944545}, issn = {1664-2295}, abstract = {Alzheimer's disease (AD), the leading cause of dementia, poses a growing global health challenge due to an aging population. Early and accurate diagnosis is essential for optimizing treatment and management, yet traditional diagnostic methods often fall short in addressing the complexity of AD pathology. Recent advancements in radiomics and artificial intelligence (AI) offer novel solutions by integrating quantitative imaging features and machine learning algorithms to enhance diagnostic and prognostic precision. This review explores the application of radiomics and AI in AD, focusing on key imaging modalities such as PET and MRI, as well as multimodal approaches combining structural and functional data. We discuss the potential of these technologies to identify disease-specific biomarkers, predict disease progression, and guide personalized interventions. Additionally, the review addresses critical challenges, including data standardization, model interpretability, and the integration of AI into clinical workflows. By highlighting current achievements and identifying future directions, this article underscores the transformative potential of AI-driven radiomics in reshaping AD diagnostics and care.}, }
@article {pmid39944528, year = {2025}, author = {Byeon, G and Kang, DW and Kim, Y and Kim, GH and Kim, KW and Kim, HJ and Na, S and Park, KH and Park, YH and Suh, J and Shin, JH and Shim, Y and Yang, Y and Um, YH and Oh, SI and Wang, SM and Yoon, B and Lee, SM and Lee, J and San Lee, J and Rhee, HY and Lim, JS and Jung, YH and Chin, J and Jang, H and Hong, YJ and Choi, M and Jang, JW and , }, title = {Clinical Practice Guidelines for Dementia: Recommendations for the Pharmacological Treatment of Behavioral and Psychological Symptoms.}, journal = {Dementia and neurocognitive disorders}, volume = {24}, number = {1}, pages = {24-43}, pmid = {39944528}, issn = {2384-0757}, abstract = {BACKGROUND AND PURPOSE: Dementia often accompanies behavioral and psychological symptoms of dementia (BPSD), including agitation, aggression, depression, and psychosis, which impact patients' quality of life and caregiver burden. Effective management of BPSD is essential to support patient and caregiver well-being. This study presents evidence-based clinical practice guidelines for pharmacological treatments of BPSD in dementia, focusing on antipsychotics, antidepressants, cognitive enhancers, and other medications.
METHODS: This guideline was developed by the Korean Dementia Association's Quality Management Committee. Key questions were framed using the Population, Intervention, Comparison, Outcome methodology, followed by systematic literature searches. Randomized controlled trials were assessed for quality, and recommendations were graded based on evidence levels, employing the Grading of Recommendations, Assessment, Development and Evaluation system to establish strength and applicability.
RESULTS: Recommendations vary by medication type and symptom severity. Antipsychotics, such as risperidone, are conditionally recommended for managing aggression and psychosis in dementia, while antidepressants, specifically citalopram, are advised for agitation in Alzheimer's disease. Cognitive enhancers, including cholinesterase inhibitors and memantine, showed moderate efficacy for general BPSD improvement and rapid eye movement sleep behavior disorder in Lewy body dementia. Specific drugs, like pimavanserin, demonstrated efficacy in addressing psychosis in Alzheimer's patients.
CONCLUSIONS: These guidelines provide a structured approach to pharmacological management of BPSD in dementia, addressing efficacy and safety profiles across drug categories. The recommendations emphasize personalized treatment plans to optimize therapeutic outcomes while minimizing risks, with a conditional approach suggested in cases with limited evidence.}, }
@article {pmid39944527, year = {2025}, author = {Kim, Y and Kang, DW and Kim, GH and Kim, KW and Kim, HJ and Na, S and Park, KH and Park, YH and Byeon, G and Suh, J and Shin, JH and Shim, Y and Yang, Y and Um, YH and Oh, SI and Wang, SM and Yoon, B and Lee, SM and Lee, J and San Lee, J and Lim, JS and Jung, YH and Chin, J and Jang, H and Choi, M and Hong, YJ and Rhee, HY and Jang, JW and , }, title = {Clinical Practice Guidelines for Dementia: Recommendations for Cholinesterase Inhibitors and Memantine.}, journal = {Dementia and neurocognitive disorders}, volume = {24}, number = {1}, pages = {1-23}, pmid = {39944527}, issn = {2384-0757}, abstract = {BACKGROUND AND PURPOSE: This clinical practice guideline provides evidence-based recommendations for treatment of dementia, focusing on cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists for Alzheimer's disease (AD) and other types of dementia.
METHODS: Using the Population, Intervention, Comparison, Outcomes (PICO) framework, we developed key clinical questions and conducted systematic literature reviews. A multidisciplinary panel of experts, organized by the Korean Dementia Association, evaluated randomized controlled trials and observational studies. Recommendations were graded for evidence quality and strength using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.
RESULTS: Three main recommendations are presented: (1) For AD, cholinesterase inhibitors (donepezil, rivastigmine, galantamine) are strongly recommended for improving cognition and daily function based on moderate evidence; (2) Cholinesterase inhibitors are conditionally recommended for vascular dementia and Parkinson's disease dementia, with a strong recommendation for Lewy body dementia; (3) For moderate to severe AD, NMDA receptor antagonist (memantine) is strongly recommended, demonstrating significant cognitive and functional improvements. Both drug classes showed favorable safety profiles with manageable side effects.
CONCLUSIONS: This guideline offers standardized, evidence-based pharmacologic recommendations for dementia management, with specific guidance on cholinesterase inhibitors and NMDA receptor antagonists. It aims to support clinical decision-making and improve patient outcomes in dementia care. Further updates will address emerging treatments, including amyloid-targeting therapies, to reflect advances in dementia management.}, }
@article {pmid39942725, year = {2025}, author = {Zhang, X and Subbanna, S and Williams, CRO and Canals-Baker, S and Hashim, A and Wilson, DA and Weiss, LM and Shukla, S and Chokkalingam, P and Das, S and Das, BC and Saito, M}, title = {Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {3}, pages = {}, pmid = {39942725}, issn = {1420-3049}, support = {R01 AI132614/AI/NIAID NIH HHS/United States ; R01AI132614-04S1/GF/NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Microglia/drug effects/metabolism ; Mice ; *Disease Models, Animal ; *Aminopeptidases/antagonists & inhibitors/metabolism ; *Inflammation/drug therapy/chemically induced ; Male ; Lipopolysaccharides ; Anti-Inflammatory Agents/pharmacology ; Cell Line ; Methionyl Aminopeptidases/antagonists & inhibitors ; Metalloendopeptidases ; }, abstract = {Methionine aminopeptidase 2 (MetAP2) plays an important role in the regulation of protein synthesis and post-translational processing. Preclinical/clinical applications of MetAP2 inhibitors for the treatment of various diseases have been explored because of their antiangiogenic, anticancer, antiobesity, antidiabetic, and immunosuppressive properties. However, the effects of MetAP2 inhibitors on CNS diseases are rarely examined despite the abundant presence of MetAP2 in the brain. Previously, we synthesized a novel boron-containing MetAP2 inhibitor, BL6, and found that it suppressed angiogenesis and adipogenesis yet improved glucose uptake. Here, we studied the anti-inflammatory effects of BL6 in SIM-A9 microglia and in a mouse model of Alzheimer's disease generated by the intracerebroventricular (icv) injection of streptozotocin (STZ). We found that BL6 reduced proinflammatory molecules, such as nitric oxide, iNOS, IL-1β, and IL-6, together with phospho-Akt and phospho-NF-κB p65, which were elevated in lipopolysaccharide (LPS)-activated microglial SIM-A9 cells. However, the LPS-induced reduction in Arg-1 and CD206 was attenuated by BL6, suggesting that BL6 promotes microglial M1 to M2 polarization. BL6 also decreased glial activation along with a reduction in phospho-tau and an elevation in synaptophysin in the icv-STZ mouse model. Thus, our experiments demonstrate an anti-neuroinflammatory action of BL6, suggesting possible clinical applications of MetAP2 inhibitors for brain disorders in which neuroinflammation is involved.}, }
@article {pmid39942548, year = {2025}, author = {Cui, S and Jin, Z and Yu, T and Guo, C and He, Y and Kan, Y and Yan, L and Wu, L}, title = {Effect of Glycosylation on the Enzymatic Degradation of D-Amino Acid-Containing Peptides.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {3}, pages = {}, pmid = {39942548}, issn = {1420-3049}, support = {51972302//National Natural Science Foundation of China/ ; 21778054//National Natural Science Foundation of China/ ; 51772289//National Natural Science Foundation of China/ ; 2192058//Beijing Municipal Natural Science Foundation/ ; K20180202//State Key Laboratory of Natural and Biomimetic Drugs/ ; ZR2024QB225//Fundamental Research Funds for the Central Universities, Shandong Provincial Natural Science Foundation/ ; 2024BS22//Weifang University Doctor Startup Foundation/ ; }, mesh = {Glycosylation ; *Amino Acids/chemistry/metabolism ; *Molecular Docking Simulation ; *Chymotrypsin/chemistry/metabolism ; Peptides/chemistry/metabolism ; Proteolysis ; Hydrogen Bonding ; Glycopeptides/chemistry/metabolism ; }, abstract = {The accumulation of D-amino acid-containing peptides is associated with age-related diseases such as Alzheimer's disease and cataracts, while glycosylation is an important modification of proteins and plays a key role in improving the physicochemical properties of peptides and facilitating their regulation in biological systems. This study investigates the effects of glycosylation position, glycan number, and monosaccharide structure on the conformation and enzymatic degradation of D-amino acid-containing peptides, using KYNEtWRSED (5-t) as a model peptide and six monosaccharides as model glycans. The results demonstrated that glycosylation inhibited the enzymatic degradation of 5-t in the presence of most serine-like proteases. However, in the presence of chymotrypsin, glycosylation with modified monosaccharides (except for β-D-GalNAc) promoted the degradation of 5-t. Furthermore, glycosylation had no effect on the cleavage site of 5-t. Molecular docking analysis revealed that the hydrogen bonding and electrostatic interactions between the glycopeptide and chymotrypsin were markedly strengthened, likely serving as a key determinant of the enzymatic effects. Collectively, these findings highlight the potential of glycosylation to enhance the therapeutic and biomedical applications of D-amino acid-containing peptides in disease treatment and drug design.}, }
@article {pmid39942106, year = {2025}, author = {Freis, AM and Vemulapalli, SPB}, title = {Analysis of the Generation of Harmful Aldehydes in Edible Oils During Sunlight Exposure and Deep-Frying Using High-Field Proton Nuclear Magnetic Resonance Spectroscopy.}, journal = {Foods (Basel, Switzerland)}, volume = {14}, number = {3}, pages = {}, pmid = {39942106}, issn = {2304-8158}, abstract = {Edible oils are essential dietary components that provide crucial micronutrients. However, their quality can deteriorate during frying-a common cooking method-and with prolonged light exposure due to chemical reactions such as hydrolysis, oxidation, and polymerization. These processes lead to the formation of harmful compounds, particularly aldehydes. This study investigates how thermal and light exposure impact the chemical composition of five widely used edible oils: olive, rapeseed, sunflower, sesame, and peanut oils. For the thermal treatment, the oils were heated to 190 ± 5 °C in a commercial fryer, with samples taken at the start and after 10 min and 60 min of heating, while intermittently frying chicken nuggets to simulate typical frying conditions. For the light exposure treatment, the oil samples were exposed to direct sunlight for 3 and 8 h, with control samples being collected beforehand. The oil composition was analyzed using an advanced 800 MHz nuclear magnetic resonance (NMR) instrument with a triple-resonance inverse cryoprobe, providing high sensitivity and resolution. The results revealed a significant increase in various aldehyde compounds in all oils under both thermal and light exposure conditions. Notably, this study identified the generation of genotoxic and cytotoxic α,β-unsaturated aldehydes, including 4-hydroperoxy-(E)-2-alkenals, 4-hydroxy-(E)-2-alkenals, and 4,5-epoxy-(E)-2-alkenals. Given the established association of aldehydes with health risks, including cancer, Alzheimer's, and Parkinson's diseases, these findings highlight the importance of monitoring oil degradation during cooking and the appropriate storage of oils to minimize light exposure to reduce potential health risks.}, }
@article {pmid39941597, year = {2025}, author = {Arendash, GW}, title = {The Brain Toxin Cleansing of Sleep Achieved During Wakefulness.}, journal = {Journal of clinical medicine}, volume = {14}, number = {3}, pages = {}, pmid = {39941597}, issn = {2077-0383}, support = {R44 AG073096/AG/NIA NIH HHS/United States ; 9R44AG073096-02A1//NIH/NIA/ ; }, abstract = {A primary purpose of sleep for humans is to remove toxins and metabolic wastes from the brain (e.g., Aβ, tau, lactate) that would otherwise build up and compromise brain functionality. There are currently no drugs or devices that have been clinically shown in humans to enhance brain toxin removal, either during sleep or wakefulness. This perspective article focuses on a recently (re)discovered major route of toxin drainage from the human brain through meningeal lymphatic vessels (mLVs) and the primary enhancer of their flow-the cytokine Vascular Endothelial Growth Factor (VEGF). The purpose of this perspective article is to present pre-clinical and clinical evidence relevant to a new bioengineered technology (Transcranial Radiofrequency Treatment; TRFT) that appears to enhance mLV flow to increase brain toxin cleansing in humans during wakefulness. In being both safe and non-invasive, TRFT is administered in-home, presently through a device called "MemorEM". Two months of daily TRFT during wakefulness increased the typically low plasma/brain levels of VEGF in Alzheimer's Disease (AD) subjects, which was associated with increased Aβ and tau toxin removal from their brains during wakefulness-ostensibly through VEGF-increased mLV flow. Even irrespective of baseline VEGF levels, brain toxin cleansing was increased by TRFT in AD subjects, who also experienced a notable reversal of their cognitive impairment after TRFT. Additional clinical studies are nonetheless required to firmly establish TRFT's brain cleansing abilities during wakefulness. In performing a major duty of sleep, TRFT during wakefulness is proposed as a viable intervention to counter the decline in nighttime brain toxin cleansing that occurs with aging and in multiple brain diseases, most notably Alzheimer's Disease. The implications of TRFT for insomnia and for sleep deprivation are also discussed, as is the potential for TRFT to extend healthy human longevity.}, }
@article {pmid39941562, year = {2025}, author = {Agavriloaei, LM and Iliescu, BF and Pintilie, RM and Turliuc, DM}, title = {Therapeutic Potential of Experimental Stereotactic Hippocampal Cell Transplant in the Management of Alzheimer's Disease.}, journal = {Journal of clinical medicine}, volume = {14}, number = {3}, pages = {}, pmid = {39941562}, issn = {2077-0383}, abstract = {Due to a continuous increase in life expectancy and the progress made in specialized healthcare, the incidence of Alzheimer's disease (AD) has dramatically increased to the point that it has become one of the main challenges of contemporary medicine. Despite a huge scientific and clinical effort, current treatments manage just a temporary alleviation of symptomatology but offer no cure. Modern trials involving cell transplantation in experimental animals require the involvement of neurosurgeons in the treatment protocol. CSF shunting, intraventricular infusions, or DBS for symptoms relief have been an integral part of the therapeutic arsenal from the very beginning. The development of stereotactic surgery has facilitated the experimental potential of cell transplantation in the hippocampus for Alzheimer's disease. We conducted a narrative review of the literature in the top three medical databases (PubMed, Science Direct, and Google Scholar) using the keywords "Alzheimer's disease", "hippocampus", and "transplant". After eliminating duplicates, 241 papers were selected and screened by title and abstract. Two reviewers independently analyzed the 88 papers and chose 32 experiments that involved stereotactic hippocampal transplantation of cells in experimental animals with AD. The stereotactic transplantation of cells such as mesenchymal stem cells (MSCs), neuronal stem cells (NSCs), induced pluripotent cells (iPSCs), astrocytes, and derivates from stem cells was analyzed. The experiments used either a chemically induced or transgenic AD model and observed the impact of the stereotactic transplantation with behavioral testing, MRS spectroscopy, and biochemical analysis. The stereotaxic method delivers minimal invasive treatment option by cell transplantation at the hippocampus. The results showed that amyloid deposits were lower after transplantation, showing a positive impact. Other impactful results involve proliferation of neurogenesis, downregulation of anti-inflammatory response, and increased neuronal plasticity. The increased precision with which the stereotaxic method manages to target deep structures of the brain and the results of the reviewed papers could represent an argument for future human trials. More studies are needed to confirm the viability of the transplanted cells and the long-term effects.}, }
@article {pmid39941290, year = {2025}, author = {Momeni, F and Shahbazi-Gahrouei, D and Mahmoudi, T and Mehdizadeh, A}, title = {Transfer Learning and Neural Network-Based Approach on Structural MRI Data for Prediction and Classification of Alzheimer's Disease.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {3}, pages = {}, pmid = {39941290}, issn = {2075-4418}, abstract = {Background: Alzheimer's disease (AD) is a neurodegenerative condition that has no definitive treatment, and its early diagnosis can help to prevent or slow down its progress. Structural magnetic resonance imaging (sMRI) and the progress of artificial intelligence (AI) have significant attention in AD detection. This study aims to differentiate AD from NC and distinguish between LMCI and EMCI from the other two classes. Another goal is the diagnostic performance (accuracy and AUC) of sMRI for predicting AD in its early stages. Methods: In this study, 398 participants were used from the ADNI and OASIS global database of sMRI including 98 individuals with AD, 102 with early mild cognitive impairment (EMCI), 98 with late mild cognitive impairment (LMCI), and 100 normal controls (NC). Results: The proposed model achieved high area under the curve (AUC) values and an accuracy of 99.7%, which is very remarkable for all four classes: NC vs. AD: AUC = [0.985], EMCI vs. NC: AUC = [0.961], LMCI vs. NC: AUC = [0.951], LMCI vs. AD: AUC = [0.989], and EMCI vs. LMCI: AUC = [1.000]. Conclusions: The results reveal that this model incorporates DenseNet169, transfer learning, and class decomposition to classify AD stages, particularly in differentiating EMCI from LMCI. The proposed model performs well with high accuracy and area under the curve for AD diagnostics at early stages. In addition, the accurate diagnosis of EMCI and LMCI can lead to early prediction of AD or prevention and slowing down of AD before its progress.}, }
@article {pmid39941289, year = {2025}, author = {Huang, SY and Wu, MT and Sun, CF and Yang, FY}, title = {Volume Changes in Brain Subfields of Patients with Alzheimer's Disease After Transcranial Ultrasound Stimulation.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {3}, pages = {}, pmid = {39941289}, issn = {2075-4418}, support = {NSTC 112-2218-E-A49-009- and NSTC 109-2321-B-010-004-//National Science and Technology Council of Taiwan/ ; CY11322 and CY11113//Cheng Hsin General Hospital/ ; }, abstract = {Background/Objectives: Alzheimer's disease (AD) is characterized by progressive brain atrophy marked by cognitive decline and memory loss, which significantly affect patients' quality of life. Transcranial ultrasound stimulation (TUS) is a potential physical treatment for AD patients. However, the specific brain regions stimulated by TUS and its therapeutic effects remain unclear. Methods: In this study, magnetic resonance imaging (MRI) and FreeSurfer segmentation were employed to assess alterations in the brain volume of AD patients after TUS. Results: Our findings revealed significant volume increases in the corpus callosum (CC) and lateral orbitofrontal cortex (lOFC) in the TUS group. Moreover, the volumetric changes in the CC were strongly correlated with improvements in the Mini-Mental State Examination score, which is a widely used measure of cognitive function of AD patients. Conclusions: TUS has the potential to alleviate disease progression and offers a non-invasive therapeutic approach to the improvement of cognitive function in AD patients.}, }
@article {pmid39941125, year = {2025}, author = {Di Vincenzo, M and Pellegrino, P and Schiappa, G and Campanati, A and Del Vescovo, V and Piccirillo, S and Ambrogini, P and Arnaldi, G and Orciani, M}, title = {Role of 11β-Hydroxysteroid Dehydrogenase and Mineralocorticoid Receptor on Alzheimer's Disease Onset: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39941125}, issn = {1422-0067}, support = {2022XF7XZF//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology/genetics ; *11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism/antagonists & inhibitors/genetics ; Animals ; *Receptors, Mineralocorticoid/metabolism/genetics ; 11-beta-Hydroxysteroid Dehydrogenases/metabolism/genetics/antagonists & inhibitors ; }, abstract = {The role of 11β-HSD1 in Alzheimer's disease (AD) has garnered significant attention due to its involvement in glucocorticoid metabolism, neuroinflammation, and cognitive decline. This review explores the current understanding of 11β-HSD1 in AD, examining genetic, preclinical, and clinical research. Genetic studies have identified 11β-HSD1 polymorphisms that may influence AD risk, although findings remain inconsistent. Mechanistically, 11β-HSD1 promotes neurodegeneration through the dysregulation of glucocorticoid activity, contributing to hippocampal atrophy, amyloid plaque formation, and tau pathology. Preclinical studies have shown that 11β-HSD1 inhibitors offer neuroprotective effects, including enhanced cognitive function, reduced inflammation, and improved mitochondrial activity. However, clinical trials, including those involving ABT-384 and Xanamem, have produced mixed results, with no substantial cognitive improvements despite effective enzyme inhibition. These inconsistencies highlight the complexity of AD and the challenges in translating preclinical findings into clinical outcomes. Moreover, while 11β-HSD1 inhibition holds therapeutic potential, other strategies targeting neuroinflammation, autophagy, and glucocorticoid signaling are also being explored. Ongoing research is focusing on optimizing 11β-HSD1 inhibitors, identifying biomarkers for patient selection, and investigating combination therapies to enhance treatment efficacy. Ultimately, 11β-HSD1's role in AD presents a promising therapeutic target, but further studies are required to fully understand its potential in managing the disease.}, }
@article {pmid39941101, year = {2025}, author = {Orywal, K and Socha, K and Iwaniuk, P and Kaczyński, P and Farhan, JA and Zoń, W and Łozowicka, B and Perkowski, M and Mroczko, B}, title = {Vitamins in the Prevention and Support Therapy of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39941101}, issn = {1422-0067}, support = {NdS/551580/2022/2022//Polish Ministry of Education and Science/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/prevention & control/metabolism ; *Vitamins/therapeutic use ; Dietary Supplements ; Animals ; Alzheimer Disease/prevention & control/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), which are a consequence of the progressive loss of neuronal function and structure, cause significant cognitive impairment. The incidence of these diseases in the world's population is constantly increasing as a result of an aging population. Although genetic and environmental factors are most often mentioned as the pathogenetic factors of these diseases, increasing evidence points to the important role of proper nutrition in the prevention and support of the treatment of these disorders. A healthy, balanced diet can mitigate the risks associated with the risk factors mentioned above and slow the progression of the disease by reducing oxidative stress and inflammation. Vitamins B, D, E, C, K, and A have been shown to support cognitive functions and protect the nervous system. This review demonstrates the importance of vitamins in preventing and supporting the therapy of neurodegenerative diseases. Information regarding the health-promoting properties of these vitamins must be effectively communicated to consumers seeking to protect their health, particularly in the context of neurodegenerative diseases. Consequently, this review also examines the authorized health claims under EU food law related to these vitamins, assessing their role in promoting awareness of the vitamins' potential benefits for neuroprotection and the management of neurodegenerative diseases.}, }
@article {pmid39941068, year = {2025}, author = {Martínez-Orozco, H and Bencomo-Martínez, A and Maya-Arteaga, JP and Rubio-De Anda, PF and Sanabria-Romero, F and Casas, ZGM and Rodríguez-Vargas, I and Hernández-Puga, AG and Sablón-Carrazana, M and Menéndez-Soto Del Valle, R and Rodríguez-Tanty, C and Díaz-Cintra, S}, title = {CNEURO-201, an Anti-amyloidogenic Agent and σ1-Receptor Agonist, Improves Cognition in the 3xTg Mouse Model of Alzheimer's Disease by Multiple Actions in the Pathology.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39941068}, issn = {1422-0067}, support = {Pronace-Salud No. 322514//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; IN-206322//PAPIIT-DGAPA UNAM/ ; Fondo para el Desarrollo del Cono-759 cimiento UAQ-2022//Universidad Autónoma de Querétaro/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *Receptors, sigma/agonists/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; *Cognition/drug effects ; Sigma-1 Receptor ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/drug effects/pathology ; Cognitive Dysfunction/drug therapy/metabolism ; Male ; Acetylcholine/metabolism ; Morpholines ; }, abstract = {The complexity of Alzheimer's disease (AD) pathophysiology represents a significant challenge in the development of effective therapeutic agents for its treatment. CNEURO-201 (CN, also Amylovis-201) is a novel pharmaceutical agent with dual activity as an anti-amyloid-β (Aβ) agent and σ1 receptor agonist. CN exhibits great efficacy at very low doses, delaying cognitive impairment and alleviating Aβ load in animal models of AD. However, CN functions on other remains related to this pathology remain to be investigated. The present study sought to evaluate the effects of CN treatment at a dosage of 0.1 mg kg[-1] (p.o) over an eight-week period in the 3xTg-AD mouse model. In silico studies, as well as biochemical and immunofluorescence assays, were conducted on brain tissue to investigate the CN effects on acetylcholine metabolism, redox system, and glial cell activation-related biomarkers in brain regions that are relevant for memory. The results demonstrated that CN effectively rescues cognitive impairment of 3xTg-AD mice by influencing glial activity to reduce existing Aβ plaques but also modulating acetylcholine metabolism and the enzymatic response of proteins involved in the redox system. Our outcomes reinforced the potential of CN in treating AD by acting on multiple pathways altered in this disease.}, }
@article {pmid39940989, year = {2025}, author = {Mertaş, B and Boşgelmez, Iİ}, title = {The Role of Genetic, Environmental, and Dietary Factors in Alzheimer's Disease: A Narrative Review.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940989}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/genetics/etiology ; Diet ; Gene-Environment Interaction ; Epigenesis, Genetic ; Risk Factors ; Genetic Predisposition to Disease ; Diet, Mediterranean ; Gastrointestinal Microbiome ; Animals ; }, abstract = {Alzheimer's disease (AD) is one of the most common and severe forms of dementia and neurodegenerative disease. As life expectancy increases in line with developments in medicine, the elderly population is projected to increase in the next few decades; therefore, an increase in the prevalence of some diseases, such as AD, is also expected. As a result, until a radical treatment becomes available, AD is expected to be more frequently recorded as one of the top causes of death worldwide. Given the current lack of a cure for AD, and the only treatments available being ones that alleviate major symptoms, the identification of contributing factors that influence disease incidence is crucial. In this context, genetic and/or epigenetic factors, mainly environmental, disease-related, dietary, or combinations/interactions of these factors, are assessed. In this review, we conducted a literature search focusing on environmental factors such as air pollution, toxic elements, pesticides, and infectious agents, as well as dietary factors including various diets, vitamin D deficiency, social factors (e.g., tobacco and alcohol use), and variables that are affected by both environmental and genetic factors, such as dietary behavior and gut microbiota. We also evaluated studies on the beneficial effects of antibiotics and diets, such as the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) and Mediterranean diets.}, }
@article {pmid39940973, year = {2025}, author = {Shan, X and Li, D and Yin, H and Tao, W and Zhou, L and Gao, Y and Xing, C and Zhang, C}, title = {Recent Insights on the Role of Nuclear Receptors in Alzheimer's Disease: Mechanisms and Therapeutic Application.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940973}, issn = {1422-0067}, support = {513006//Project of National Natural Science Foundation of China/ ; 202203a07020031//Anhui Province Key Research and Development Program Project/ ; KJ2021ZD0065, KJ2019A0314, KJ2018ZD031 and 1408085MH196//the Provincial Natural Science Foundation of Anhui Province/ ; 2023CXMMTCM014//Grand Health Research Institute of Hefei Comprehensive National Science Center, Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM 'Jie Bang Gua Shuai' Project/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology/drug therapy ; Humans ; *Receptors, Cytoplasmic and Nuclear/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; }, abstract = {Nuclear receptors (NRs) are ligand-activated transcription factors that regulate a broad array of biological processes, including inflammation, lipid metabolism, cell proliferation, and apoptosis. Among the diverse family of NRs, peroxisome proliferator-activated receptors (PPARs), estrogen receptor (ER), liver X receptor (LXR), farnesoid X receptor (FXR), retinoid X receptor (RXR), and aryl hydrocarbon receptor (AhR) have garnered significant attention for their roles in neurodegenerative diseases, particularly Alzheimer's disease (AD). NRs influence the pathophysiology of AD through mechanisms such as modulation of amyloid-beta (Aβ) deposition, regulation of inflammatory pathways, and improvement of neuronal function. However, the dual role of NRs in AD progression, where some receptors may exacerbate the disease while others offer therapeutic potential, presents a critical challenge for their application in AD treatment. This review explores the functional diversity of NRs, highlighting their involvement in AD-related processes and discussing the therapeutic prospects of NR-targeting strategies. Furthermore, the key challenges, including the necessity for the precise identification of beneficial NRs, detailed structural analysis through molecular dynamics simulations, and further investigation of NR mechanisms in AD, such as tau pathology and autophagy, are also discussed. Collectively, continued research is essential to clarify the role of NRs in AD, ultimately facilitating their potential use in the diagnosis, prevention, and treatment of AD.}, }
@article {pmid39940966, year = {2025}, author = {Jamerlan, AM and Shim, KH and Sharma, N and An, SSA}, title = {Multimer Detection System: A Universal Assay System for Differentiating Protein Oligomers from Monomers.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940966}, issn = {1422-0067}, support = {RS-2023-00251396//National Research Foundation of Korea/ ; 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Protein Multimerization ; alpha-Synuclein/metabolism/chemistry ; Amyloid beta-Peptides/metabolism/chemistry ; Neurodegenerative Diseases/metabolism/diagnosis ; Protein Aggregates ; DNA-Binding Proteins/metabolism/chemistry ; tau Proteins/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer's disease (AD); α-synuclein in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington's disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics.}, }
@article {pmid39940900, year = {2025}, author = {la Torre, A and Lo Vecchio, F and Angelillis, VS and Gravina, C and D'Onofrio, G and Greco, A}, title = {Reinforcing Nrf2 Signaling: Help in the Alzheimer's Disease Context.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940900}, issn = {1422-0067}, mesh = {*NF-E2-Related Factor 2/metabolism ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Humans ; *Signal Transduction ; *Oxidative Stress ; Animals ; Antioxidants/metabolism/therapeutic use ; Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Oxidative stress plays a role in various pathophysiological diseases, including neurogenerative diseases, such as Alzheimer's disease (AD), which is the most prevalent neuro-pathology in the aging population. Oxidative stress has been reported to be one of the earliest pathological alterations in AD. Additionally, it was demonstrated that in older adults, there is a loss of free radical scavenging ability. The Nrf2 transcription factor is a key regulator in antioxidant defense systems, but, with aging, both the amount and the transcriptional activity of Nrf2 decrease. With the available treatments for AD being poorly effective, reinforcing the antioxidant defense systems via the Nrf2 pathway may be a way to prevent and treat AD. To highlight the predominant role of Nrf2 signaling in defending against oxidative stress and, therefore, against neurotoxicity, we present an overview of the natural compounds that exert their own neuroprotective roles through the activation of the Nrf2 pathway. This review is an opportunity to promote a holistic approach in the treatment of AD and to highlight the need to further refine the development of new potential Nrf2-targeting drugs.}, }
@article {pmid39940653, year = {2025}, author = {Silva, CFM and Guerrinha, APDMS and Carvalho, S and Pinto, DCGA and Silva, AMS}, title = {1,3,5-Triazine: A Promising Molecular Scaffold for Novel Agents for the Treatment of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940653}, issn = {1422-0067}, support = {UIDP/50006/2020//Fundação para a Ciência e Tecnologia/ ; UIDB/50006/2020//Fundação para a Ciência e Tecnologia/ ; LA/P/0008/2020//Fundação para a Ciência e Tecnologia/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Triazines/chemistry/therapeutic use/pharmacology ; Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Animals ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors/chemistry ; Acetylcholinesterase/metabolism/chemistry ; }, abstract = {Currently, Alzheimer's disease (AD) is one of the most frequent forms of dementia. From a molecular perspective, the molecular characteristics that better define this disease consist of abnormal protein deposits between neuronal cells, namely senile plaques (SPs) and neurofibrillary tangles (NFTs), consisting of protein aggregates of amyloid-β and hyperphosphorylated tau protein, respectively. In addition to these protein aggregates, a third molecular hallmark of AD consists of depleted neurotransmitter acetylcholine levels. To date, the treatments developed for this disease are mostly focused on the use of AChE inhibitors, presenting only a symptomatic approach against the disease instead of a cure. Triazines are nitrogen-containing heterocyclic compounds that, throughout the years, have attracted a lot of curiosity from medicinal chemists for presenting numerous biological properties and being widely present in nature. In particular, this class of compounds has been associated with inhibiting several biological targets, emerging as a promising class for developing new pharmacological agents. However, there is still a scarcity of knowledge regarding the potential of this type of compound against any of the hallmarks of AD. For this reason, this paper intends to fulfill this absence by highlighting the potential of a subclass of triazines, 1,3,5-triazines (sym-triazines), as promising molecules for developing novel AD treatments. Thus, an in-depth analysis of 1,3,5-triazine derivatives is performed regarding its inhibitory activity against AChE (cholinergic hypothesis) and its capability to inhibit amyloid-β formation and aggregation (amyloid hypothesis). Through this analysis, it is possible to indicate some structural features optimal for each described activity, a compilation that we believe to be essential for the scientific community in this never-ending pursuit.}, }
@article {pmid39940249, year = {2025}, author = {Reiriz, M and Beltrán-Velasco, AI and Echeverry-Alzate, V and Martínez-Miguel, E and Gómez-Senent, S and Uceda, S and Clemente-Suárez, VJ}, title = {Bifidobacterium infantis and Bifidobacterium breve Improve Symptomatology and Neuronal Damage in Neurodegenerative Disease: A Systematic Review.}, journal = {Nutrients}, volume = {17}, number = {3}, pages = {}, pmid = {39940249}, issn = {2072-6643}, mesh = {Humans ; *Bifidobacterium breve ; *Probiotics/therapeutic use ; *Neurodegenerative Diseases/therapy ; *Parkinson Disease/therapy/microbiology ; Animals ; *Alzheimer Disease/therapy/microbiology ; Bifidobacterium longum subspecies infantis ; Neurons ; }, abstract = {Background/Objectives: This systematic review focused on collecting the most significant findings on the impact of the administration of Bifidobacterium infantis (or Bifidobacterium longum subps. infantis) and Bifidobacterium breve, alone, in conjunction, or in combination with other strains, in the treatment of neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). These diseases are characterized by the progressive degeneration of neurons, resulting in a broad spectrum of clinical manifestations. AD is typified by a progressive decline in cognitive abilities, while PD is marked by motor symptoms associated with the loss of dopamine (DA). Methods: Five different databases, ScienceDirect, Scopus, Wiley, PubMed, and Web of Science (WoS), were reviewed and the studies were screened for inclusion by the following criteria: (i) studies that specifically evaluated the use of Bifidobacterium infantis, Bifidobacterium longum subsp. infantis, or Bifidobacterium breve as a therapeutic intervention, either in human or animal models, in the context of neurodegenerative diseases; (ii) the studies were required to address one or more of the pathologies examined in this article, and the pathologies included, but were not limited to, neurodegeneration, Alzheimer's disease, Parkinson's disease, and oxidative stress; (iii) the full text was accessible online; and (iv) the article was written in English. Results: The data suggest that these probiotics have neuroprotective effects that may delay disease progression. Conclusions: This study provides updated insights into the use of these Bifidobacterium strains in neurodegenerative diseases like AD and PD, with the main limitation being the limited number of clinical trials available.}, }
@article {pmid39939891, year = {2025}, author = {Zúñiga, CH and Acosta, BI and Menchaca, R and Amescua, CA and Hong, S and Hui, L and Gil, M and Rhee, YH and Yoon, S and Kim, M and Chang, PY and Kim, YM and Song, PY and Betito, K}, title = {Treatment of Alzheimer's Disease subjects with expanded non-genetically modified autologous natural killer cells (SNK01): a phase I study.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {40}, pmid = {39939891}, issn = {1758-9193}, mesh = {Humans ; Male ; *Alzheimer Disease/therapy/cerebrospinal fluid/immunology ; Female ; Aged ; *Killer Cells, Natural/drug effects/immunology ; Middle Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; Treatment Outcome ; tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid ; Cytokines/cerebrospinal fluid/metabolism ; }, abstract = {BACKGROUND: The importance of natural killer (NK) cells of the innate immune system in neurodegenerative disease has largely been overlooked despite studies demonstrating their ability to reduce neuroinflammation (thought to be mediated by the elimination of activated T cells, degradation of protein aggregates and secretion of anti-inflammatory cytokines). SNK01 is an autologous non-genetically modified NK cell product showing increased activity in vitro. We hypothesized that SNK01 can be safely infused to reduce neuroinflammation in Alzheimer's Disease (AD) patients.
METHODS: SNK01 was produced and characterized for its ability to eliminate activated T cells, degrade protein aggregates and secrete anti-inflammatory cytokines. In this phase 1 study, SNK01 was administered intravenously every three weeks for a total of 4 treatments using a 3 + 3 dose escalation design (1, 2 and 4 × 10[9] cells) in subjects with either mild, moderate, or severe AD (median CDR-SB 10.0). Cognitive assessments and cerebrospinal fluid biomarkers associated with protein aggregation, neurodegeneration and neuroinflammation including amyloid-β42 and 42/40, α-synuclein, total Tau, pTau217 and pTau181, neurofilament light, GFAP and YKL-40 analyses were performed at baseline, at 1 and 12 weeks after the last dose. The primary endpoint was safety; secondary endpoints included changes in cognitive assessments and biomarker levels.
RESULTS: In preclinical in vitro studies, SNK01 were able to uptake and degrade the protein aggregates of amyloid-β and α-synuclein, produce anti-inflammatory cytokines and eliminate activated T cells. In the phase 1 clinical study, eleven subjects were enrolled (10 evaluable). No drug-related adverse events were observed. Despite 70% of subjects being treated at relatively low doses of SNK01 (1 and 2 × 10[9] cells), 50-70% of all enrolled subjects had stable/improved CDR-SB, ADAS-Cog and/or MMSE scores and 90% had stable/improved ADCOMS at one-week after the last dose. SNK01 also appeared to have beneficial effects on protein aggregate levels and neuroinflammatory biomarkers in the cerebrospinal fluid, with decreases in pTau181 and GFAP appearing to be dose-dependent.
CONCLUSIONS: SNK01 was well tolerated and appeared to have clinical activity in AD while also having beneficial effects on cerebrospinal fluid protein and neuroinflammatory biomarker levels. A larger trial with a higher dosing/duration has been initiated in the USA in 2023.
TRIAL REGISTRATION: www.
CLINICALTRIALS: gov NCT04678453, date of registration: 2020-12-22.}, }
@article {pmid39939242, year = {2025}, author = {Kuriyama, M and Wang, CF and Nagase, T and Sohma, Y and Kanai, M and Hori, Y and Tomita, T}, title = {Proteolytic therapeutic modalities for amyloidoses: Insights into immunotherapy, PROTAC, and photo-oxygenation.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {}, number = {}, pages = {e00548}, doi = {10.1016/j.neurot.2025.e00548}, pmid = {39939242}, issn = {1878-7479}, abstract = {Amyloidoses, which are characterized by abnormal accumulation of amyloid proteins leading to organ dysfunction, represent a major therapeutic challenge. They include neurodegenerative diseases, such as Alzheimer disease (AD), tauopathies and synucleinopathies. Since amyloids are causative factors in these diseases, the importance of proteolytic methods to remove amyloid, such as immunotherapy and Proteolysis Targeting Chimera (PROTAC) technology, has been recognized. Immunotherapy removes target proteins by antibody-mediated reactions and is the most studied method in practical use for the treatment of AD. PROTAC is a small molecule that uses the ubiquitin-proteasome system to degrade intracellular target proteins and has demonstrated efficacy in clinical trials for other diseases. In addition, a new modality called photo-oxygenation has been developed. Photo-oxygenation is a method of selectively adding oxygen to amyloid using a photocatalyst, which is a small molecule compound that is activated by light. Studies both in vitro and in vivo have shown promising results in inhibiting amyloid aggregation and enhancing the clearance of amyloid proteins. In this review, we introduce and discuss these proteolytic modalities, and provide insights into potential future directions for the clinical application in amyloidoses.}, }
@article {pmid39938752, year = {2025}, author = {Zhu, Y and Tian, M and Lu, S and Qin, Y and Zhao, T and Shi, H and Li, Z and Qin, D}, title = {The antioxidant role of aromatic plant extracts in managing neurodegenerative diseases: A comprehensive review.}, journal = {Brain research bulletin}, volume = {222}, number = {}, pages = {111253}, doi = {10.1016/j.brainresbull.2025.111253}, pmid = {39938752}, issn = {1873-2747}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Antioxidants/therapeutic use/pharmacology ; *Plant Extracts/therapeutic use/pharmacology ; *Oxidative Stress/drug effects ; Animals ; Flavonoids/therapeutic use/pharmacology ; Polyphenols/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative diseases (NDDs) are a class of cognitive and motor disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), and others. They are caused by lesions in cells and tissues of the central nervous system, resulting in corresponding dysfunctions and consequent decline in cognitive and motor functions. Neural tissues are extremely vulnerable to oxidative stress, which plays critical biological roles in NDDs. Aromatic compounds are found extensively in natural plants and have substantial effects of anti-oxidative stress damage, which not only have a wide range of research applications in cosmetics, foods, etc., but are also frequently utilized in the treatment of various central nervous system diseases. This review summarizes the relevant oxidative stress mechanisms in NDDs (AD, PD, HD, and ALS) and reviews aromatic compounds such as polyphenols, terpenoids, and flavonoids that can be used in the management of neurodegenerative diseases, as well as their specific mechanisms of antioxidant action. This review will serve as a reference for future experimental studies on neurodegenerative illnesses while also offering fresh insights into clinical therapy.}, }
@article {pmid39938597, year = {2025}, author = {Ratne, N and Jari, S and Tadas, M and Katariya, R and Kale, M and Kotagale, N and Madia, D and Umekar, M and Taksande, B}, title = {Neurobiological role and therapeutic potential of exercise-induced irisin in Alzheimer's disease management.}, journal = {Ageing research reviews}, volume = {105}, number = {}, pages = {102687}, doi = {10.1016/j.arr.2025.102687}, pmid = {39938597}, issn = {1872-9649}, mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; *Fibronectins/metabolism ; *Exercise/physiology ; Animals ; Exercise Therapy/methods ; }, abstract = {Alzheimer's disease (AD) poses a significant obstacle in today's healthcare landscape, with limited effective treatments. Recent studies have revealed encouraging findings about how exercise-triggered irisin might help slow down the advancement of AD. Irisin, a myokine, released during physical activity, has garnered significant attention for its pleiotropic effects, extending beyond its traditional role in metabolic regulation. This review explores irisin's multifaceted potential in combating AD. Research indicates that irisin enhances synaptic plasticity, crucial for learning and memory, and exhibits neuroprotective properties that may slow AD progression by safeguarding neurons from degeneration. Additionally, irisin's ability to modulate inflammatory responses is significant, as neuroinflammation is a key feature of AD pathology. Irisin may also influence the metabolism and clearance of amyloid-beta plaques and tau tangles, hallmark pathological markers of AD. Furthermore, irisin boosts brain-derived neurotrophic factor expression, vital for neuronal health, and improves insulin glucose regulation, addressing impaired brain insulin signaling observed in AD. Exercise-induced irisin presents a non-pharmacological strategy, leveraging physical activity's brain health benefits. Future research should focus on elucidating irisin's mechanisms and conducting clinical trials to assess its therapeutic efficacy and safety in AD patients. Overall, irisin therapy offers a promising avenue for AD treatment, potentially slowing disease progression and enhancing cognitive function, paving the way for innovative therapeutic strategies in the fight against AD.}, }
@article {pmid39938415, year = {2025}, author = {Roney, M and Uddin, MN and Khan, AA and Fatima, S and Mohd Aluwi, MFF and Hamim, SMI and Ahmad, A}, title = {Repurposing of dipeptidyl peptidase FDA-approved drugs in Alzheimer's disease using network pharmacology and in-silico approaches.}, journal = {Computational biology and chemistry}, volume = {116}, number = {}, pages = {108378}, doi = {10.1016/j.compbiolchem.2025.108378}, pmid = {39938415}, issn = {1476-928X}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Dipeptidyl-Peptidase IV Inhibitors/chemistry/pharmacology/therapeutic use ; *Drug Repositioning ; Molecular Docking Simulation ; Network Pharmacology ; Molecular Dynamics Simulation ; Dipeptidyl Peptidase 4/metabolism/chemistry ; United States ; Drug Approval ; United States Food and Drug Administration ; Principal Component Analysis ; }, abstract = {Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) have similar clinical characteristics in the brain and islet, as well as an increased incidence with ageing and familial susceptibility. Therefore, in recent years there has been a great desire for research that elucidates how anti-diabetic drugs affect AD. This work attempts to first elucidate the possible mechanism of action of DPP-IV inhibitors in the treatment of AD by employing techniques from network pharmacology, molecular docking, molecular dynamic simulation, principal component analysis, and MM/PBSA. A total of 463 targets were identified from the SwissTargetPrediction and 784 targets were identified from the SuperPred databases. 79 common targets were screened using the PPI network. The GO and KEGG analyses indicated that the activity of DPP-IV against AD potentially involves the hsa04080 neuroactive ligand-receptor interaction signalling pathway, which contains 17 proteins, including CHRM2, CHRM3, CHRNB1, CHRNB4, CHRM1, PTGER2, CHRM4, CHRM5, TACR2, HTR2C, TACR1, F2, GABRG2, MC4R, HTR7, CHRNG, and DRD3. Molecular docking demonstrated that sitagliptin had the greatest binding affinity of -10.7 kcal/mol and established hydrogen bonds with the Asp103, Ser107, and Asn404 residues in the active site of the CHRM2 protein. Molecular dynamic simulation, PCA, and MM/PBSA were performed for the complex of sitagliptin with the above-mentioned proteins, which revealed a stable complex throughout the simulation. The work identifies the active component and possible molecular mechanism of sitagliptin in the treatment of AD and provides a theoretical foundation for future fundamental research and practical implementation.}, }
@article {pmid39937020, year = {2025}, author = {Spina, E and Ferrari, RR and Pellegrini, E and Colombo, M and Poloni, TE and Guaita, A and Davin, A}, title = {Mitochondrial Alterations, Oxidative Stress, and Therapeutic Implications in Alzheimer's Disease: A Narrative Review.}, journal = {Cells}, volume = {14}, number = {3}, pages = {}, pmid = {39937020}, issn = {2073-4409}, support = {PNRR-MAD-2022-12375822//European Union/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Mitochondria/metabolism ; *Oxidative Stress ; Animals ; Reactive Oxygen Species/metabolism ; }, abstract = {The relationship between aging, mitochondrial dysfunction, neurodegeneration, and the onset of Alzheimer's disease (AD) is a complex area of study. Aging is the primary risk factor for AD, and it is associated with a decline in mitochondrial function. This mitochondrial dysfunction is believed to contribute to the neurodegenerative processes observed in AD. Neurodegeneration in AD is characterized by the progressive loss of synapses and neurons, particularly in regions of the brain involved in memory and cognition. It is hypothesized that mitochondrial dysfunction plays a pivotal role by disrupting cellular energy metabolism and increasing the production of reactive oxygen species (ROS), which can damage cellular components and exacerbate neuronal loss. Despite extensive research, the precise molecular pathways linking mitochondrial dysfunction to AD pathology are not fully understood. Various hypotheses have been proposed, including the mitochondrial cascade hypothesis, which suggests that mitochondrial dysfunction is an early event in AD pathogenesis that triggers a cascade of cellular events leading to neurodegeneration. With this narrative review, we aim to summarize some specific issues in the literature on mitochondria and their involvement in AD onset, with a focus on the development of therapeutical strategies targeting the mitochondria environment and their potential application for the treatment of AD itself.}, }
@article {pmid39936411, year = {2025}, author = {Si, Y and Meng, B and Qi, F}, title = {Age- and Genotype-Dependent Effects of Chronic Nicotine on Presenilin1/2 Double Knockout Mice: From Behavior to Molecular Pathways.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050363992250127072919}, pmid = {39936411}, issn = {1875-5828}, abstract = {INTRODUCTION: The potential therapeutic role of nicotine in Alzheimer's disease (AD) remains controversial, particularly regarding its age-dependent effects and underlying mechanisms.
METHOD: This study investigated the impact of chronic nicotine administration on cognitive function and molecular pathways in Presenilin 1/2 double knockout (DKO) mice, an amyloid-β-independent model of AD. Three-month-old and eight-month-old DKO and wild-type (WT) mice received oral nicotine treatment (100 μg/ml) for three months. Behavioral assessments revealed that while the 6-month-old cohort showed no significant differences between nicotine-treated and control groups regardless of genotype, nicotine improved contextual fear memory in 11-month-old DKO mice but impaired nest-building ability and cued fear memory in age-matched WT controls. Transcriptome analysis of the prefrontal cortex identified distinct molecular responses to nicotine between genotypes.
RESULT: In DKO mice, nicotine modulated neuropeptide signaling and reduced astrocyte activation, while in WT mice, it disrupted cytokine-cytokine receptor interaction and neuroactive ligand- receptor interaction pathways. Western blot analysis revealed that nicotine treatment significantly reduced tau hyperphosphorylation and GFAP expression in 11-month-old DKO mice, which was further confirmed by immunohistochemistry showing decreased astrocyte activation in multiple brain regions.
CONCLUSION: These findings demonstrate that nicotine's effects on cognition and molecular pathways are both age- and genotype-dependent, suggesting its therapeutic potential may be limited to specific stages of neurodegeneration while potentially having adverse effects in healthy aging brains.}, }
@article {pmid39936324, year = {2025}, author = {Divya, and Faruq, M and Nazir, SS and Kaushik, P and Parvez, S and Vohora, D}, title = {Ganaxolone Reverses the Effect of Amyloid β-Induced Neurotoxicity by Regulating the Liver X Receptor Expression in APP Transfected SH-SY5Y Cells and Murine Model of Alzheimer's Disease.}, journal = {Journal of neurochemistry}, volume = {169}, number = {2}, pages = {e70007}, doi = {10.1111/jnc.70007}, pmid = {39936324}, issn = {1471-4159}, support = {45/05/2020-PHA/BMS//Indian Council of Medical Research/ ; IIRP/2023/1050//Indian Council of Medical Research/ ; }, mesh = {*Liver X Receptors/metabolism ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; *Amyloid beta-Peptides/toxicity ; Humans ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Mice, Transgenic ; Peptide Fragments/toxicity ; Male ; Neuroprotective Agents/pharmacology ; Transfection ; Mice, Inbred C57BL ; Pregnanolone/analogs & derivatives ; }, abstract = {Inhibiting β-amyloid aggregation and enhancing its clearance are the key strategies in Alzheimer's disease (AD) treatment. Liver X receptors (LXRs) plays a crucial role in cholesterol homeostasis and inflammation, and their activation can clear Aβ aggregates in AD. Allopregnanolone, a neurosteroid, positively influences AD through LXR regulation, while ganaxolone, its synthetic analog, is known for its neuroprotective properties. This study explores the effect of ganaxolone on LXR activation and regulation of genes involved in mitigating Aβ toxicity and tauopathy in SH-SY5Y cells transfected with APP695 Swe/Ind plasmid and an Aβ1-42 induced AD mouse model. Molecular docking stimulations indicated ganaxolone's binding and interaction with LXRβ. Subsequently, transfected neuronal cells exhibited increased mRNA levels of APP, TNF-α and IL-1β, decreased cell viability, reduced MMP and altered protein expression of Aβ, LXR, BCL-2, APOE, ABCA1, along with increased levels of mROS, Bax, and caspase 3 activity. Ganaxolone treatment significantly abrogated Aβ-induced effect in transfected neuronal cells by enhancing LXRβ expression, inducing LXR:RXR colocalization, thereby increasing APOE and ABCA1 expression. It also decreased tau mRNA levels in transfected cells. Importantly, in AD mice, ganaxolone ameliorated cognitive impairment, reduced Aβ toxicity, tau levels, and neuroinflammatory markers, restored mitochondrial function, and decreased neuronal apoptosis. Taken together, these novel results highlight the central role of LXR in mediating Aβ-induced toxicity and provide preclinical evidence for ganaxolone as a potential agent to reduce toxicity in an LXR-dependent manner. This may serve as a promising treatment strategy to slow or prevent neurodegeneration in AD patients.}, }
@article {pmid39936091, year = {2025}, author = {Wu, J and Sun, H and Zhao, Y and Lian, L and Bian, H and Guo, Y and Li, D and Huang, L}, title = {The spectrum-efficacy correlation of Kai-Xin-San for cognition of Aβ42 transgenic Drosophila and verification of its active ingredients.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1538837}, pmid = {39936091}, issn = {1663-9812}, abstract = {INTRODUCTION: This study aims to establish the fingerprint spectra of Kai-Xin-San (KXS) and investigate its spectrum-effect relationship in treating Alzheimer's disease (AD).
METHODS: Initially, the fingerprints of 15 batches of KXS were established and analyzed using HPLC, with the method's precision, stability, and repeatability thoroughly evaluated. Subsequently, the effects of the 15 batches of KXS were assessed in an olfactory escape memory experiment, utilizing Aβ42 transgenic drosophila as a model. Finally, the spectrum-effect relationship between the KXS fingerprint and memory improvement was analyzed, with the active ingredients subjected to validation testing.
RESULTS: The results identified seventeen common peaks in the fingerprint, and eight active components were determined: polygalaxanthone III, 3-6-disinapoylsucrose, ginsenoside Rg1, ginsenoside Rb1, β-asarone, α-asarone, dehydrotumulosic acid, and dehydropachymic acid. Treatment with KXS (1%, for 4 days) significantly enhanced the performance index of Aβ42 flies in the olfactory experiment. Both spectrum-effect analysis and validation tests indicated that polygalaxanthone III, ginsenoside Rg1, ginsenoside Rb1, β-asarone, and α-asarone were positively correlated with the performance index and improved the performance index in the olfactory experiment. The HPLC fingerprint method for KXS demonstrated excellent precision, accuracy, and reproducibility, making it suitable for quality evaluation and control of KXS. Polygalaxanthone III, ginsenoside Rg1, ginsenoside Rb1, β-asarone, and α-asarone are identified as potential active ingredients of KXS for anti-AD effects.
DISCUSSION: These findings provide an experimental basis for developing new drugs based on KXS and its active ingredient combinations.}, }
@article {pmid39935618, year = {2025}, author = {Petersen, RC and Graf, A and Brady, C and De Santi, S and Florian, H and Landen, J and Pontecorvo, M and Randolph, C and Sink, K and Carrillo, M and Weber, CJ}, title = {Operationalizing selection criteria for clinical trials in Alzheimer's disease: Biomarker and clinical considerations: Proceedings from the Alzheimer's Association Research Roundtable (AARR) Fall 2021 meeting.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70038}, pmid = {39935618}, issn = {2352-8737}, abstract = {UNLABELLED: The design of clinical trials in Alzheimer's disease (AD) must consider the development of new plasma, cerebrospinal fluid (CSF), and imaging biomarkers. They must also define clinically meaningful outcomes for patients and set endpoints that measure these outcomes accurately. With the accelerated United States Food and Drug Administration (FDA) approval of the first anti-amyloid, disease-modifying treatment for AD, a monoclonal antibody called aducanumab, the landscape of clinical trial design is evolving. Enrolment in clinical trials may be impacted by the availability of this and other treatments, and trial design must take into consideration that patients may desire a disease-modifying treatment rather than potentially being randomized to the placebo arm. The Alzheimer's Association Research Roundtable (AARR) Fall 2021 meeting discussed the consideration of well-defined AD staging criteria in protocol design and how they influence more standardized inclusion/exclusion criteria for trials, as well as what constitutes meaningful differentiation between the stages. Discussion explored the current state of knowledge regarding biomarkers and how they can inform AD staging criteria, as many trials are now designed based on specific biomarker features, further underscoring the importance of coordinating AD staging criteria and biomarkers. The relationship between cognition and biomarkers has been studied and this must continue as trials move forward. Researchers, patients, clinicians, regulatory scientists, and payers discussed the state of the field as well as the future of symptomatic Alzheimer's disease clinical trials.
HIGHLIGHTS: The Alzheimer's Association Research Roundtable (AARR) convened leaders from academia and industry as well as patients, care partners, clinicians, regulators, and payers to discuss the topic of operationalizing selection criteria for clinical trials and the role of biomarkers.Well-defined Alzheimer's disease (AD) staging criteria are an important consideration in study protocol design.Staging criteria and biomarkers must be coordinated to yield high-quality clinical trial results that have meaning for patients with AD by selecting a population most likely to benefit from a specific treatment.}, }
@article {pmid39935616, year = {2025}, author = {Hajós, M and Pandey, K and Singer, AC and Duong, D and Bitarafan, S and Shpokayte, M and Malchano, Z and Kern, R and Lah, JJ and Levey, AI and Seyfried, NT}, title = {CSF proteomics reveals changes in myelin and synaptic biology after Spectris treatment.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70051}, pmid = {39935616}, issn = {2352-8737}, abstract = {INTRODUCTION: Brain steady-state gamma oscillations evoked using a non-invasive medical device (Spectris) have shown potential clinical benefits in patients with mild-moderate Alzheimer's disease (AD), including reduced functional and cognitive decline, reduced brain volume and myelin loss, and increased brain functional connectivity. We analyzed changes in cerebrospinal fluid (CSF) proteins after Spectris treatment in mild cognitive impairment (MCI) and their relationship to established biological pathways implicated in AD.
METHODS: Unbiased proteomic analysis of CSF samples from participants with amyloid-positive MCI (n = 10) was conducted from the FLICKER (NCT03543878) clinical trial. Participants used the Cognito Therapeutics medical device (Spectris), confirmed to evoke steady-state gamma oscillations. Participants were instructed to use the device daily for 1 hour each day during the trial. CSF was collected prior to the start of stimulation and after 4 and 8 weeks of treatment. The proteome was analyzed using tandem mass tag mass spectrometry.
RESULTS: Differential expression analysis of proteins at baseline and after 8 weeks of treatment (N = 5) revealed that 110 out of 2951 proteins met the significance threshold (analysis of variance, P < 0.05, no false discovery rate). Sixty proteins were upregulated, and 50 proteins were downregulated after treatment. Changes in protein expression were mapped to the consensus human AD protein network, representing co-expressed and functionally linked modules linked to cell type and biochemical pathways. Treatment altered CSF proteins linked to AD-related brain proteome modules, including those involved in myelination (proteolipid protein 1, ecotropic viral integration site 2A), synaptic and neuroimmune functions, and regulation of cellular lipid transportation. Biological pathway analysis revealed that most impacted pathways were associated with lipoproteins, cholesterol, phospholipids processing, and phosphatidylcholine biosynthesis.
DISCUSSION: The CSF proteomic changes observed in this study suggest pleiotropic effects on multiple pathways involved in AD, including myelination, synaptic and neuroimmune function, and lipid transport. These findings are also consistent with observations of white matter and myelin preservation after Spectris treatment of AD.
HIGHLIGHTS: We analyzed changes in cerebrospinal fluid (CSF) proteins in response to sensory-evoked gamma oscillations in individuals with mild cognitive impairment.Sensory evoked steady-state gamma oscillations were evoked by Spectris medical device.Changes in CSF proteins were observed after 8 weeks of daily 1 hour treatment.Affected proteins were related to myelination, synaptic and neuroimmune functions, and regulation of cellular lipid transportation.Proteomic changes support clinical outcomes and myelin preservation of Spectris treatment.}, }
@article {pmid39935341, year = {2025}, author = {Menon, J and Kantipudi, SJ and Vinoth, S and Kuchipudi, JD}, title = {Prevalence of subjective cognitive decline and its association with physical health problems among urban community dwelling elderly population in South India.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14505}, pmid = {39935341}, issn = {1552-5279}, mesh = {Humans ; India/epidemiology ; Male ; Female ; *Cognitive Dysfunction/epidemiology ; Aged ; Prevalence ; *Urban Population/statistics & numerical data ; *Independent Living ; Middle Aged ; Neuropsychological Tests/statistics & numerical data ; Mental Status and Dementia Tests ; Surveys and Questionnaires ; Health Status ; }, abstract = {INTRODUCTION: No studies in India have explored subjective cognitive decline (SCD), a hallmark of stage II of preclinical Alzheimer's disease. This study aims to assess the prevalence and correlates of SCD in a South Indian, urban, elderly population.
METHODS: We screened 403 individuals 60 years of age and older using the Subjective Memory Complaints Questionnaire (SMCQ) and measured objective cognition with the Montreal Cognitive Assessment (MoCA). Physical health parameters were evaluated for all participants.
RESULTS: Among the participants, 377 (93.5%) reported subjective memory complaints. Of the 26 individuals without SCD, 15(57.7%) had objective cognitive impairment (MoCA <25). A total of 182 participants (45.2%) were identified with SCD. Higher educational attainment was significantly associated with fewer SCD reports and better cognitive performance (p < 0.001).
DISCUSSION: Subjective cognitive decline (SCD) is highly prevalent among older adults. Screening for SCD can help identify individuals at risk for Alzheimer's disease. SCD assessement combined with cost-effective biomarkers that confirms AD will help individuals to be identified for disease-modifying therapies.
HIGHLIGHTS: Nearly half of older adults population screened has reported subjective cognitive decline (SCD), highlighting the widespread occurrence of SCD in urban South India. Participants with higher educational attainment had significantly fewer memory complaints and performed better on cognitive assessments. SCD was prevalent even among individuals without major comorbid conditions such as diabetes and hypertension and those who were on regular treatment for metabolic and cardiovascular disorders. Identifying subjective cognitive decline (SCD) can facilitate early and accurate diagnosis of cognitive disorders and help delay progression to dementia. This highlights the importance of developing and implementing improved public health strategies to address these challenges. Further longitudinal studies are necessary to explore the progression of SCD to dementia, focusing on the interplay between cognitive health, biomarkers, and educational factors in the Indian population.}, }
@article {pmid39934538, year = {2025}, author = {Balde, A and Benjakul, S and Nazeer, RA}, title = {A review on NLRP3 inflammasome modulation by animal venom proteins/peptides: mechanisms and therapeutic insights.}, journal = {Inflammopharmacology}, volume = {33}, number = {3}, pages = {1013-1031}, pmid = {39934538}, issn = {1568-5608}, support = {IF220025//Department of Science and Technology, Ministry of Science and Technology, India/ ; }, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Animals ; *Inflammasomes/metabolism ; Humans ; *Peptides/pharmacology ; Venoms/pharmacology ; Inflammation/drug therapy/metabolism ; Signal Transduction/drug effects ; }, abstract = {The venom peptides from terrestrial as well as aquatic species have demonstrated potential in regulating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a sophisticated assemblage present in immune cells responsible for detecting and responding to external mediators. The NLRP3 inflammasome plays a role in several pathological conditions such as type 2 diabetes, hyperglycemia, Alzheimer's disease, obesity, autoimmune disorders, and cardiovascular disorders. Venom peptides derived from animal venoms have been discovered to selectively induce certain signalling pathways, such as the NLRP3 inflammasome, mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Experimental evidence has demonstrated that venom peptides can regulate the expression and activation of the NLRP3 inflammasome, resulting in the secretion of pro-inflammatory cytokines including interleukin (IL)-1β and IL-18. Furthermore, these peptides have been discovered to impede the activation of the NLRP3 inflammasome, therefore diminishing inflammation and tissue injury. The functional properties of venom proteins and peptides obtained from snakes, bees, wasps, and scorpions have been thoroughly investigated, specifically targeting the NLRP3 inflammasome pathway, venom proteins and peptides have shown promise as therapeutic agents for the treatment of certain inflammatory disorders. This review discusses the pathophysiology of NLRP3 inflammasome in the onset of various diseases, role of venom as therapeutics. Further, various venom components and their role in the modulation of NLRP3 inflammasome are discoursed. A substantial number of venomous animals and their toxins are yet unexplored, and to comprehensively grasp the mechanisms of action of them and their potential as therapeutic agents, additional research is required which can lead to the development of novel therapeutics.}, }
@article {pmid39933302, year = {2025}, author = {Li, H and Qiao, Z and Xiao, X and Cao, X and Li, Z and Liu, M and Jiao, Q and Chen, X and Du, X and Jiang, H}, title = {G protein-coupled receptors: A golden key to the treasure-trove of neurodegenerative diseases.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {46}, number = {}, pages = {155-168}, doi = {10.1016/j.clnu.2025.01.032}, pmid = {39933302}, issn = {1532-1983}, mesh = {Humans ; *Receptors, G-Protein-Coupled/metabolism ; *Neurodegenerative Diseases/drug therapy ; *Signal Transduction/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Parkinson Disease/drug therapy/metabolism ; }, abstract = {G protein-coupled receptors (GPCRs) are a class of transmembrane proteins that distribute in various organs extensively. They can regulate physiological functions such as perception, neurotransmission and endocrinology through the synergies of signaling pathways. At present, Food and Drug Administration (FDA) have approved more than 500 drugs targeting GPCRs to treat a variety of conditions, including neurological diseases, gastrointestinal diseases and tumors. Conformational diversity and dynamic changes make GPCRs a star target for the treatment of neurodegenerative diseases. Moreover, GPCRs can also open biased signaling pathways for G protein and β-arrestin, which has unique functional selectivity and the possibility of overcoming side effects. Some studies believe that biased drugs will be the mainstream direction of drug innovation in the future. To disclose the essential role and research process of GPCRs in neurodegenerative diseases, we firstly reviewed several pivotal GPCRs and their mediated signaling pathways in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Then we focused on the biased signaling pathway of GPCRs in these diseases. Finally, we updated the GPCR drugs under research for the treatment of neurodegenerative diseases in the clinical trials or approval. This review could provide valuable targets for precision therapy to cope with the dysfunction of neurodegenerative diseases in the future.}, }
@article {pmid39932809, year = {2025}, author = {Pallares Di Nunzio, M and Martín Tenti, J and Arlego, M and Rosso, OA and Montani, F}, title = {Exploring the role of synaptic plasticity in the frequency-dependent complexity domain.}, journal = {Chaos (Woodbury, N.Y.)}, volume = {35}, number = {2}, pages = {}, doi = {10.1063/5.0239820}, pmid = {39932809}, issn = {1089-7682}, mesh = {*Neuronal Plasticity/physiology ; *Models, Neurological ; Humans ; Neurons/physiology ; Entropy ; Nonlinear Dynamics ; Action Potentials/physiology ; Nerve Net/physiology ; }, abstract = {The involvement of the neocortex in memory processes depends on neuronal plasticity, the ability to restructure inter-neuronal connections, which is essential for learning and long-term memory. Understanding these mechanisms is crucial for advancing early diagnosis and treatment of cognitive disorders such as Parkinson's, epilepsy, and Alzheimer's disease. This study explores a neuronal model with expanded populations, using information-theoretic cues to uncover dynamics underlying plasticity. By employing Bandt-Pompe's entropy-complexity (H×C) and Fisher entropy-information (H×F) planes, hidden patterns in neuronal activity are revealed. These methodologies are particularly suitable for analyzing nonlinear dynamics and causal relationships in time series. In addition, the Hénon map is applied to capture nonlinear behaviors, such as neural firing, highlighting the trade-off between stability and unpredictability in neural networks. Our approach integrates local field potential and intracranial electroencephalograms' data in multiple frequency bands, connecting computational models with experimental evidence. By addressing higher-order interactions, such as action potential triplets, this work advances the understanding of synaptic adjustments and their implications for neuronal complexity and cognitive disorders.}, }
@article {pmid39932549, year = {2025}, author = {Grünblatt, E and Yde Ohki, CM and Schmitt-Böhrer, GA and Riederer, P and Walitza, S}, title = {Exploring the interplay of glucose metabolism, insulin resistance, and neurodegenerative pathologies: insights from streptozotocin and hypoglycaemic in vitro models.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {39932549}, issn = {1435-1463}, abstract = {Neurodegenerative diseases raise public health concerns. Recent evidence indicates that Alzheimer's disease (AD) sufferers will triple by 2050. The rising incidence of dementia diagnoses raises concerns about the socio-economical and emotional impact of this uncurable illness, which reduces quality of life through cognitive decline. Although genetic and environmental factors may contribute to its aetiology, neuropathological mechanisms underlying these disorders are still under investigation. One is brain insulin resistance (BIR), which has been associated with clinical cognitive dysfunction and linked to mitochondrial dysfunction, neurogenesis deficits, and cell death. Not limited to neurodegeneration, these phenotypes have been associated with other neuropsychiatric disorders. Streptozotocin (STZ), a diabetes-causing drug that targets pancreatic β-cells, may imitate BIR in suitable models. From patients' neuroimaging to in vitro approaches, scientists have been striving to understand the pathophysiology of such disorders at the behavioural, molecular, and cellular levels. Although animal models are useful for studying insulin resistance's systemic effects, in vitro phenotypic research represents an alternative to study molecular and cellular aspects. STZ and hypoglycaemia-like scenarios have been successful for studying neurodegenerative disorders in primary cell culture (e.g., neuroblastoma cells) and patient-specific neural cell lines derived from pluripotent stem cells (iPSCs). Intriguingly, STZ treatment or hypoglycaemia-like conditions in a dish were able to induce AD pathological characteristics such Aβ plaque deposition and Tau protein hyperphosphorylation. Such approaches have shown potential in understanding molecular and cellular implications of metabolic changes in neuropsychiatric disorders, according to this review. Furthermore, these models may help identify novel treatment targets.}, }
@article {pmid39932239, year = {2025}, author = {Yang, L and Wang, Y and Shang, P and Ma, G}, title = {Dual-Functional Synthetic Linear and Cyclic Peptides with Anti-Amyloid and Antimicrobial Activities for Alzheimer's Disease.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {31}, number = {15}, pages = {e202404349}, doi = {10.1002/chem.202404349}, pmid = {39932239}, issn = {1521-3765}, support = {21973024//National Natural Science Foundation of China/ ; B2016201034//Natural Science Foundation of Hebei Province/ ; B2023201108//Natural Science Foundation of Hebei Province/ ; 22567620H//Hebei Province Innovation Capability Enhancement Plan Project/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Peptides, Cyclic/chemistry/pharmacology ; *Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors ; Humans ; Microbial Sensitivity Tests ; Anti-Bacterial Agents/pharmacology/chemistry ; Peptide Fragments/chemistry/pharmacology ; Anti-Infective Agents/pharmacology/chemistry ; }, abstract = {Dual-functional peptides exhibiting both anti-amyloid and antimicrobial activities have attracted attention as promising candidates for Alzheimer's disease treatment. The advantage of these peptides lies in their ability to simultaneously target both the amyloid cascade hypothesis and the microbial infection hypothesis, in contrast to single-function inhibitors. However, most of the reported dual-functional peptides to date are natural peptides, and the development of synthetic peptides in this area remains limited. In this study, we propose two strategies to aid in the discovery of synthetic dual-functional peptides. We then report four distinct synthetic dual-functional peptides identified using these strategies, with the Aβ1-40/Aβ1-42 fibrillation system and common bacterial strains serving as a proof-of-concept platform. One strategy involves repurposing existing knowledge, while the other breaks from established conventions. Using the first strategy, we discovered a very short dual-functional linear peptide. With the second strategy, we identified a simple dual-functional cyclic peptide. Furthermore, by combining these two strategies, we developed a hybrid dual-functional peptide incorporating both linear and cyclic structures. We hope that our findings will contribute to the future discovery of more synthetic dual-functional peptides for treating Alzheimer's disease.}, }
@article {pmid39931990, year = {2025}, author = {Khan, B and Khalid Iqbal, M and Khan, H and Kiyani, M and Bashir, S and Shao, L}, title = {Abnormality of Voltage-Gated Sodium Channels in Disease Development of the Nervous System. A Review Article.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273347470250126185122}, pmid = {39931990}, issn = {1996-3181}, abstract = {Sodium channels are necessary for electrical activity in modules of the nervous system. When such channels fail to work properly, it may cause different neurological diseases. This review will discuss how particular mutation in these channels leads to different diseases. Positive alterations can lead to such diseases as epilepsy, or any muscle disorder due to over activation of neurons. Conversely, loss-of-function mutations may cause heart diseases and problems regarding motor and mental activity since neurons are not functioning well because of lost machinery. The review would discuss over familiar channelopathies such as genetic epilepsies, the familial hemiplegic migraine, and Para myotonia congenital and relatively new interrelations with the complex ailments including Alzheimer's, Parkinson's and multiple sclerosis. Thus, knowledge of these mechanisms is important in designing specific therapeutic approaches. There is a rationale for altering the sodium channel activity in the treatment of these neurological disorders by drugs or indeed genetic methods. Thus, the review is undertaken to provide clear distinctions and discuss the issues related to sodium channel mutations for the potential development of individualized medicine. The review also gives information on the function and general distribution of voltage-gated sodium channels (VGSCs), how their activity is controlled, and what their structure is like. The purpose therefore is to draw understanding over the apparently multifaceted functions exerted by VGSCs in the nervous system relative to several diseases. This knowledge is imperative in the attempt to produce treatments for these disabling disorders.}, }
@article {pmid39931983, year = {2025}, author = {Zheng, CB and Wu, LZ and Song, WY and Luo, L and Cai, JT and Huang, ZH and Tian, KQ}, title = {The Role and Molecular Mechanism of Icaritin in the Treatment of Alzheimer's Disease.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673354454250124074057}, pmid = {39931983}, issn = {1875-533X}, abstract = {Alzheimer's disease (AD), a degenerative disease of the central nervous system, affects approximately 70 million individuals worldwide. As the number of elderly in the population increases, the prevalence and incidence of AD are increasing annually. Although the drugs are currently used to alleviate certain cognitive symptoms, their overall therapeutic efficacy remains unclear. Consequently, there is significant societal demand for safe and effective therapeutic options. Icaritin (ICT), a bioactive compound derived from Epimedium brevicornu Maxim, has anti-apoptotic, antioxidant, anti-neuroinflammatory, anti-aging, and neuroprotective properties. In recent years, it has garnered significant interest because of its potential preventative and therapeutic effects in the context of AD. In this review, we analyze the therapeutic effects of ICT on AD, namely the inhibition of neuroinflammation, effects against oxidative stress and apoptosis, and promotion of cellular autophagy. The aim of this review was to provide a general reference for the research and development of new drugs, in particular ICT, for the prevention and treatment of AD.}, }
@article {pmid39931956, year = {2025}, author = {Nuovo, GJ and Rice, M and Zanesi, N and Sawant, D and Crilly, C and Tili, E}, title = {The Prevention of Fatal Tauopathy in a Mouse Model of Alzheimer Disease by Blocking BCL2.}, journal = {Applied immunohistochemistry & molecular morphology : AIMM}, volume = {}, number = {}, pages = {}, doi = {10.1097/PAI.0000000000001251}, pmid = {39931956}, issn = {1533-4058}, abstract = {A major goal in Alzheimer disease (AD) research is the reduction of the abnormal tau burden. Using multispectral analyses on brain tissues from humans who died of AD it was documented that neurons with hyperphosphorylated tau protein accumulate many proteins of the BCL2 family, including those that block cell turnover (eg, BCL2, MCL1, BCLXL) and those that promote cell turnover (eg, NOXA, PUMA, BAK, BAX). A mouse model of AD with the humanized hyperphosphorylated tau protein was used to test the hypothesis that shifting this balance to a pro-cell turnover milieu would reduce the tau burden with concomitant clinical improvement. Here, we show that a mouse model of AD with death at 11 to 15 months due to CNS tauopathy had a marked reduction in the tau burden after treatment with the FDA-approved drug venetoclax, which blocks BCL2. The reduction of the number of target neurons positive for hyperphosphorylated tau protein after venetoclax treatment in the brain and spinal cord neurons was 94.5% as determined by immunohistochemistry and 98.1% as documented with the modified Bielchowsky stain. The venetoclax treatment began after documented neurofibrillary tangles (NFTs) were evident and there was a concomitant reduction in neuroinflammation. The treated mice were robust until sacrificed at 13 months as compared with the untreated mice that showed unequivocal evidence of brain and spinal cord damage both clinically and at autopsy. We conclude that otherwise inexorable abnormal tau protein deposition, even after initiation, can be prevented by a drug that blocks one anti-cell turnover protein abundant in the NFTs of human AD.}, }
@article {pmid39931916, year = {2025}, author = {Jin, L and Nie, L and Deng, Y and Khana, GJ and He, N}, title = {The Application of Polymeric Nanoparticles as Drug Delivery Carriers to Cells in Neurodegenerative Diseases.}, journal = {Cell proliferation}, volume = {}, number = {}, pages = {e13804}, doi = {10.1111/cpr.13804}, pmid = {39931916}, issn = {1365-2184}, support = {62071119//National Natural Science Foundation of China/ ; 62075098//National Natural Science Foundation of China/ ; 2017YFA0205301//National Key Research and Development Program of China/ ; 2018YFC1602905//National Key Research and Development Program of China/ ; }, abstract = {In spite of great advances in modern medicine, there are a few effective strategies for the treatment of neurodegenerative diseases characterised by neuron loss or degeneration. This results from complex pathogenesis of the diseases and the limited drug uptake of the brain due to the presence of blood-brain barrier. Nanoparticle-based drug delivery systems are expected to improve the drug utilisation. Polymeric nanoparticles represent promising drug delivery carriers to the brain due to their unique advantages such as good biodegradability and biocompatibility, flexibility in surface modification and nontoxicity. In addition, the delivery of genetic drugs may stop the progression of neurodegenerative diseases at the genetic level and even avoid the irreversible damage in the central nervous system. In this review, an overview of studies on polymer-based nanoparticles for drug delivery to the central nervous system in typical neurodegenerative diseases, especially Alzheimer's diseases and Parkinson's diseases, is described. Meanwhile, their applications in gene delivery in these disorders are discussed. And the challenges and future perspectives for the development of polymeric nanoparticles as drug delivery carriers in neurodegenerative diseases are concluded.}, }
@article {pmid39931856, year = {2025}, author = {Mumtaz, and Ahmed, F and Rabbani, SA and El-Tanani, M and Najmi, AK and Ali, J and Khan, MA}, title = {Tauopathy in AD: Therapeutic Potential of MARK-4.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050358397250126151707}, pmid = {39931856}, issn = {1875-5828}, abstract = {Alzheimer's disease (AD) is one of the leading causes of cognitive decline, which leads to dementia and poses significant challenges for its therapy. The reason is primarily the ineffective available treatments targeting the underlying pathology of AD. It is a neurodegenerative disease that is mainly characterised by the various molecular pathways contributing to its complex pathology, including extracellular amyloid beta (Aβ) plaques, intracellular neurofibrillary tangles (NFTs), oxidative stress, and neuroinflammation. One of the crucial features is the hyperphosphorylation of tau proteins, which is facilitated by microtubule affinity-regulating kinase-4 (MARK-4). The kinase plays a crucial role in the disease development by modifying microtubule integrity, leading to neuronal dysfunction and death. MARK-4 is thus a druggable target and has a pivotal role in AD. Amongst MARK-4 inhibitors, 16 compounds demonstrate significant capacity in molecular docking studies, showing high binding affinity to MARK-4 and promising potential for tau inhibition. Further, in-vitro investigations provide evidence of their neuroprotective properties. The present review mainly focuses on the role of MARK-4 and its potential inhibitors used in treating AD, which have been thoroughly investigated in silico and in vitro.}, }
@article {pmid39931801, year = {2025}, author = {Kong, D and Meng, L and Lin, P and Wu, G}, title = {Advancements in PROTAC-based therapies for neurodegenerative diseases.}, journal = {Future medicinal chemistry}, volume = {17}, number = {5}, pages = {591-605}, pmid = {39931801}, issn = {1756-8927}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Proteolysis/drug effects ; Small Molecule Libraries/chemistry/pharmacology/therapeutic use ; Animals ; }, abstract = {Neurodegenerative diseases are characterized by impairments in movement and cognitive functions. These disorders are frequently associated with the accumulation of misfolded protein aggregates, which present significant challenges for treatment with conventional small-molecule inhibitors. While FDA-approved amyloid-beta-directed antibodies, such as Lecanemab, have recently shown clinical success in modifying disease progression, there are currently no treatments capable of curing neurodegenerative diseases. Emerging technologies like proteolysis-targeting chimeras (PROTACs) offer additional promise by targeting disease-causing proteins for degradation, potentially opening new therapeutic avenues. Recent experiments have demonstrated that PROTACs can specifically target and degrade pathogenic proteins associated with neurodegenerative diseases, thereby offering potential therapeutic avenues. This review discusses the latest advances in employing PROTACs for treating neurodegenerative diseases and delves into the associated challenges and opportunities. Our goal is to provide researchers in drug development with new insights on creating novel PROTACs for therapeutic applications.}, }
@article {pmid39931645, year = {2025}, author = {Cho, Y and Lee, J and Kim, JS and Jeon, Y and Han, S and Cho, H and Lee, Y and Kim, TK and Hong, JM and Lee, Y and Byun, Y and Chae, M and Park, S and Palomera, LF and Park, SY and Kim, H and Kim, S and Kang, S and Jee, JG and An, H and Yim, JH and Kim, SH and Jo, DG}, title = {RA-PR058, a novel ramalin derivative, reduces BACE1 expression and phosphorylation of tau in Alzheimer's disease mouse models.}, journal = {Animal cells and systems}, volume = {29}, number = {1}, pages = {122-134}, pmid = {39931645}, issn = {1976-8354}, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated in vitro and in vivo. In vitro studies used SH-SY5Y cells under oxidative stress conditions to assess BACE1 expression, while in vivo effects were studied in 3xTg-AD mice following one month of oral RA-PR058 treatment. Behavioral assessments, biochemical analyses, transcriptomic profiling, and pharmacokinetic evaluations were performed to determine the efficacy of RA-PR058. RA-PR058 significantly reduced oxidative stress-induced BACE1 expression in vitro and decreased cortical BACE1 expression in 3xTg-AD mice. In vivo treatment alleviated anxiety-like behavior and reduced tau phosphorylation at disease-relevant sites (Ser202/Thr205, Thr231, and Ser396). Transcriptomic analysis revealed RA-PR058-mediated gene expression changes related to central nervous system development, response to hypoxia, and neuroactive ligand-receptor interactions, suggesting broader regulatory effects on AD-related pathways. Pharmacokinetic analysis demonstrated that RA-PR058 exhibits high metabolic stability, minimal cytochrome P450 interactions, and moderate blood-brain barrier penetration. RA-PR058 demonstrates potential as a multi-target AD therapeutic by reducing BACE1 expression, tau hyperphosphorylation, and anxiety-like behavior, coupled with favorable pharmacokinetics. Additional studies are needed to assess cognitive effects and clarify molecular mechanisms, but RA-PR058 may represent a promising advancement in addressing AD's complex pathology.}, }
@article {pmid39931556, year = {2025}, author = {Ding, J and Long, Z and Liu, Y and Wang, M}, title = {Study on influencing factors of age-adjusted Charlson comorbidity index in patients with Alzheimer's disease based on machine learning model.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1497662}, pmid = {39931556}, issn = {2296-858X}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a widespread neurodegenerative disease, often accompanied by multiple comorbidities, significantly increasing the risk of death for patients. The age adjusted Charlson Comorbidity Index (aCCI) is an important clinical tool for measuring the burden of comorbidities in patients, closely related to mortality and prognosis. This study aims to use the MIMIC-V database and various regression and machine learning models to screen and validate features closely related to aCCI, providing a theoretical basis for personalized management of AD patients.
METHODS: The research data is sourced from the MIMIC-V database, which contains detailed clinical information of AD patients. Multiple logistic regression, LASSO regression, random forest, Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost) models were used to screen for feature factors significantly correlated with aCCI. By comparing model performance, evaluating the classification ability and prediction accuracy of each method, and ultimately selecting the best model to construct a regression model and a nomogram. The model performance is evaluated through classification accuracy, net benefit, and robustness. The feature selection results were validated by regression analysis.
RESULTS: Multiple models have performed well in classifying aCCI patients, among which the model constructed using LASSO regression screening feature factors has the best performance, with the highest classification accuracy and net benefit. LASSO regression identified the following 11 features closely related to aCCI: age, respiratory rate, base excess, glucose, red blood cell distribution width (RDW), alkaline phosphatase (ALP), whole blood potassium, hematocrit (HCT), phosphate, creatinine, and mean corpuscular hemoglobin (MCH). The column chart constructed based on these feature factors enables intuitive prediction of patients with high aCCI probability, providing a convenient clinical tool.
CONCLUSION: The results of this study indicate that the features screened by LASSO regression have the best predictive performance and can significantly improve the predictive ability of aCCI related comorbidities in AD patients. The column chart constructed based on this feature factor provides theoretical guidance for personalized management and precise treatment of AD patients.}, }
@article {pmid39931431, year = {2024}, author = {Silva-Llanes, I and Madruga, E and Martínez, A and Lastres-Becker, I}, title = {RIPK1 expression and inhibition in tauopathies: implications for neuroinflammation and neuroprotection.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1530809}, pmid = {39931431}, issn = {1662-4548}, abstract = {Tauopathies are a group of neurodegenerative diseases characterized by the alteration/aggregation of TAU protein. One of the main challenges of these diseases is that they have neither biomarkers nor pharmacological targets to stop the neurodegenerative process. Apart from the neurodegenerative process, tauopathies are also characterized by a chronic low-grade neuroinflammation process, where the receptor-interacting protein kinase 1 (RIPK1) protein plays an essential role. Our research aimed to explore the role of RIPK1 in various tauopathies. We examined mouse models of frontotemporal dementia (FTD), as well as brain tissue samples from patients with progressive supranuclear palsy (PSP), a primary form of 4R tauopathy, and Alzheimer's disease (AD), which is considered a secondary tauopathy. Our findings show elevated levels of RIPK1 mRNA levels across various forms of tauopathies, in both mouse models and human tissue samples associated with primary and secondary TAU-related disorders. Furthermore, we investigated the potential of using a RIPK1 inhibitor, known as GSK2982772, in a mouse model as a novel treatment strategy for FTD. The data showed that GSK2982772 treatment effectively reduced the reactive astrocyte response triggered by TAU[P301L] overexpression. However, this RIPK1 inhibitor failed to protect against the neurodegeneration caused by elevated TAU[P301L] levels in the hippocampal region. These results suggest that although inhibiting RIPK1 activity may help reduce TAU-related astrogliosis in the brain, the complexity of the inflammatory pathways involved could explain the absence of neuroprotective effects against TAU-induced neurodegeneration.}, }
@article {pmid39931375, year = {2024}, author = {Permana, A and Akili, AWR and Hardianto, A and Latip, JB and Sulaeman, AP and Herlina, T}, title = {Virtual Screening, Toxicity Evaluation and Pharmacokinetics of Erythrina Alkaloids as Acetylcholinesterase Inhibitor Candidates from Natural Products.}, journal = {Advances and applications in bioinformatics and chemistry : AABC}, volume = {17}, number = {}, pages = {179-201}, pmid = {39931375}, issn = {1178-6949}, abstract = {PURPOSE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options, necessitating the development of safer and more effective therapies. The potential of alkaloids derived from the genus Erythrina as acetylcholinesterase (AChE) inhibitors is being investigated to enhance acetylcholine levels in the brain, which is crucial for the treatment of AD. The objective of this study is to identify Erythrina alkaloids with strong inhibitory capacity against AChE and favorable pharmacokinetic profiles.
MATERIALS AND METHODS: A multi-step computational approach was employed, beginning with the virtual screening of 143 Erythrina alkaloid structures using molecular docking against the human AChE crystal structure. The binding affinities were compared with the known AChE inhibitor, galantamine. The top alkaloid, 8-oxoerymelanthine (128), was subjected to further analysis through molecular dynamics simulations, with the objective of evaluating its stability and interactions. In silico ADMET predictions were conducted to assess the pharmacokinetic properties. The applicability of Lipinski's Rule of Five was applied to evaluate oral drug-likeness.
RESULTS: 8-Oxoerymelanthine (128) exhibited the highest binding affinity and remarkable stability in molecular dynamics simulations. The toxicity predictions indicated a low risk of mutagenicity, hepatotoxicity, and cardiotoxicity. Pharmacokinetic assessments indicated good absorption, moderate blood-brain barrier penetration, and favorable metabolic and excretion profiles, supporting its potential as an orally active drug candidate.
CONCLUSION: 8-Oxoerythmelanthine (128) exhibits strong potential as an AChE inhibitor with a favorable balance of efficacy, safety, and pharmacokinetic properties. These results warrant further investigation in preclinical and clinical studies to validate its therapeutic potential and safety for Alzheimer's disease treatment.}, }
@article {pmid39930497, year = {2025}, author = {Jang, YJ and Kang, SJ and Park, HS and Lee, DH and Kim, JH and Kim, JE and Kim, DI and Chung, CH and Yoon, JK and Bhang, SH}, title = {Drug delivery strategies with lipid-based nanoparticles for Alzheimer's disease treatment.}, journal = {Journal of nanobiotechnology}, volume = {23}, number = {1}, pages = {99}, pmid = {39930497}, issn = {1477-3155}, support = {KEIT 20018560//Ministry of Trade, Industry and Energy/ ; NTIS 2410005252//Ministry of Trade, Industry and Energy/ ; RS-2024-00448758//Ministry of Trade, Industry and Energy/ ; RS-2024-00405818//National Research Foundation of Korea/ ; RS-2023-00213691//National Research Foundation of Korea/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Nanoparticles/chemistry ; *Blood-Brain Barrier/metabolism ; Animals ; *Drug Delivery Systems/methods ; *Lipids/chemistry ; *Amyloid beta-Peptides/metabolism ; Drug Carriers/chemistry ; Liposomes/chemistry ; }, abstract = {Alzheimer's disease (AD) is a distinctive form of dementia characterized by age-related cognitive decline and memory impairment. A key hallmark of AD is the irreversible overaccumulation of beta-amyloid (Aβ) in the brain, associated with neuroinflammation and neuronal death. Although Aβ clearance and immunoregulation have been the major therapeutic strategies for AD, highly selective transport across the blood-brain barrier (BBB) negatively affects the delivery efficacy of the drugs without the ability to cross the BBB. In this review, we discuss the potential of lipid-based nanoparticles (LBNs) as promising vehicles for drug delivery in AD treatment. LBNs, composed of phospholipid mono- or bilayer, have attracted attention due to their exceptional cellular penetration capabilities and drug loading capabilities, which also facilitate cargo transcytosis across the BBB. Recent advances in the development and engineering of LBNs overcome the existing limitations of the current clinical approaches for AD treatment by addressing off-target effects and low therapeutic efficacy. Here, we review the transport pathways across the BBB, as well as various types of LBNs for AD therapy, including exosomes, liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), to elucidate their distinctive properties, preparation methodologies, and therapeutic efficacy, thereby offering innovative avenues for novel drug development for clinical translation in AD therapy.}, }
@article {pmid39930283, year = {2025}, author = {Song, H and Xia, M and Zhao, P and Yang, J and Yu, W}, title = {Overexpression of TGFBR3 Aggravates Cognitive Impairment and Neuroinflammation by Promoting Microglia M1 Polarization in the APP/PS1 Mouse Model of Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39930283}, issn = {1559-1182}, support = {[2023]015//Department of Education of Guizhou Province (Guizhou Teaching and Technology)/ ; (2020)1Z060//Science and Technology Plan Project of Guizhou Province (Basic Science and Technology Cooperation)/ ; }, abstract = {Transforming growth factor beta receptor 3 (TGFBR3), also known as betaglycan, is a member of the TGF-β receptor family. In our previous study, bioinformatics analysis revealed that TGFBR3 levels are elevated in patients with Alzheimer's disease (AD) and identified TGFBR3 as a potential risk factor for the disease. However, the precise role of TGFBR3 in the pathogenesis of AD remains largely unclear. In this study, we first validated the elevated levels of TGFBR3 in postmortem brain tissues from AD patients using immunohistochemical staining. Subsequently, gain-of-function experiments and behavioral tests were conducted to explore the functional role of TGFBR3 in the APP/PS1 mouse model. Our findings confirmed that TGFBR3 levels were significantly increased in AD patients compared to normal controls. Overexpression of TGFBR3 in APP/PS1 mice impaired spatial learning and memory abilities and promoted amyloid-β (Aβ) accumulation. Additionally, TGFBR3 overexpression exacerbated neuronal apoptosis and synaptic loss. We also observed that overexpression of TGFBR3 triggered an inflammatory response by promoting microglial polarization to the M1 phenotype, although it had no effect on astrocyte activation. In conclusion, our study demonstrates that increased TGFBR3 levels worsen cognitive impairment and accelerate pathological progression in APP/PS1 mice, suggesting that TGFBR3 could serve as a potential therapeutic target for AD treatment.}, }
@article {pmid39929615, year = {2025}, author = {Zhou, ZH and Xing, HY and Liang, Y and Gao, J and Liu, Y and Zhang, T and Zhu, L and Qian, JL and Zhou, C and Li, G}, title = {[Molecular mechanism of verbascoside in promoting acetylcholine release of neurotransmitter].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {2}, pages = {335-348}, doi = {10.19540/j.cnki.cjcmm.20240802.702}, pmid = {39929615}, issn = {1001-5302}, mesh = {Animals ; Rats ; *Acetylcholine/metabolism ; PC12 Cells ; *Glucosides/pharmacology ; *Phenols/pharmacology/chemistry ; Alzheimer Disease/metabolism/drug therapy ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Neurotransmitter Agents/metabolism ; Molecular Docking Simulation ; Humans ; Calcium/metabolism ; Phosphorylation/drug effects ; Polyphenols ; }, abstract = {The molecular mechanism of verbascoside(OC1) in promoting acetylcholine(ACh) release in the pathogenesis of Alzheimer's disease(AD) was studied. Adrenal pheochromocytoma cells(PC12) of rats induced by β-amyloid protein(1-42)(Aβ_(1-42)) were used as AD models in vitro and were divided into control group, model group(Aβ_(1-42) 10 μmol·L~(-1)), OC1 treatment group(2 and 10 μg·mL~(-1)). The effect of OC1 on phosphorylated proteins in AD models was analyzed by whole protein phosphorylation quantitative omics, and the selectivity of OC1 for calcium channel subtypes was virtually screened in combination with computer-aided drug design. The fluorescence probe Fluo-3/AM was used to detect Ca~(2+) concentration in cells. Western blot analysis was performed to detect the effects of OC1 on the expression of phosphorylated calmodulin-dependent protein kinase Ⅱ(p-CaMKⅡ, Thr286) and synaptic vesicle-related proteins, and UPLC/Q Exactive MS was used to detect the effects of OC1 on ACh release in AD models. The effects of OC1 on acetylcholine esterase(AChE) activity in AD models were detected. The results showed that the differentially modified proteins in the model group and the OC1 treatment group were related to calcium channel activation at three levels: GO classification, KEGG pathway, and protein domain. The results of molecular docking revealed the dominant role of L-type calcium channels. Fluo-3/AM fluorescence intensity decreased under the presence of Ca~(2+) chelating agent ethylene glycol tetraacetic acid(EGTA), L-type calcium channel blocker verapamil, and N-type calcium channel blocker conotoxin, and the effect of verapamil was stronger than that of conotoxin. This confirmed that OC1 promoted extracellular Ca~(2+) influx mainly through its interaction with L-type calcium channel protein. In addition, proteomic analysis and Western blot results showed that the expression of p-CaMKⅡ and downstream vesicle-related proteins was up-regulated after OC1 treatment, indicating that OC1 acted on vesicle-related proteins by activating CaMKⅡ and participated in synaptic remodeling and transmitter release, thus affecting learning and memory. OC1 also decreased the activity of AChE and prolonged the action time of ACh in synaptic gaps.}, }
@article {pmid39929614, year = {2025}, author = {Xiang, JB and Wen, W and Xu, SJ}, title = {[Mechanism of Jiawei Xionggui Decoction in ameliorating cognitive impairment in APP/PS1 mice based on network pharmacology and metabolomics].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {2}, pages = {322-342}, doi = {10.19540/j.cnki.cjcmm.20240902.704}, pmid = {39929614}, issn = {1001-5302}, mesh = {Animals ; Mice ; *Drugs, Chinese Herbal/pharmacology ; *Cognitive Dysfunction/drug therapy/metabolism/genetics ; *Metabolomics ; *Network Pharmacology ; *Mice, Inbred C57BL ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Male ; Amyloid beta-Protein Precursor/genetics/metabolism ; Brain/metabolism/drug effects ; Presenilin-1/genetics/metabolism ; Humans ; Mice, Transgenic ; Disease Models, Animal ; }, abstract = {This study explored the action mechanism of Jiawei Xionggui Decoction in the treatment of Alzheimer's disease(AD) by integrating mouse brain tissue metabolomics and network pharmacology. Six-month-old amyloid precursor protein/presenilin 1(APP/PS1) mice were selected and divided into the APP/PS1 group and Jiawei Xionggui Decoction intervention group, with age-matched C57BL/6 mice serving as controls. Cognitive abilities and pathological damage in the mice were observed. Gas chromatography-mass spectrometry/mass spectrometry(GC-MS/MS) technology was utilized to analyze the metabolic profiles of mice brain tissue. Differential metabolites were screened, and relevant metabolic pathways were enriched. Network pharmacology was adopted to screen the active components of Jiawei Xionggui Decoction, so as to construct a protein-protein interaction network of its core targets for AD treatment and conduct Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis of potential targets for Jiawei Xionggui Decoction in treating AD. Finally, a "metabolite-reaction-enzyme-gene" network was constructed for combined analysis of metabolomics and network pharmacology. The results showed that Jiawei Xionggui Decoction significantly reversed the trends of 18 differential metabolites involved in 15 metabolic pathways such as glyoxylate and dicarboxylate metabolism, glycine, serine, and threonine metabolism, pyruvate metabolism, alanine, aspartate, and glutamate metabolism, and tricarboxylic acid cycle(TCA) in mouse brain tissue. Furthermore, 383 core targets of Jiawei Xionggui Decoction were implicated in pathways like the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway and calcium signaling pathway. Overall analysis indicated that energy metabolism, amino acid metabolism, and fatty acid metabolism were crucial metabolic pathways for Jiawei Xionggui Decoction in treating AD. The findings suggest that Jiawei Xionggui Decoction can protect neuronal cells in mouse brain tissue, thus improving cognitive impairment.}, }
@article {pmid39929613, year = {2025}, author = {Xing, HW and Yang, Y and Yin, YP and Xie, L and Fang, F}, title = {[Kaixin San-medicated serum attenuates Aβ_(25-35)-induced injury in SH-SY5Y cells by regulating autophagy].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {2}, pages = {313-321}, doi = {10.19540/j.cnki.cjcmm.20241012.401}, pmid = {39929613}, issn = {1001-5302}, mesh = {*Autophagy/drug effects ; Humans ; *Amyloid beta-Peptides/toxicity ; *TOR Serine-Threonine Kinases/metabolism/genetics ; *Proto-Oncogene Proteins c-akt/metabolism/genetics ; Cell Survival/drug effects ; Cell Line, Tumor ; Drugs, Chinese Herbal/pharmacology ; Peptide Fragments ; Microtubule-Associated Proteins/genetics/metabolism ; Serum/chemistry ; }, abstract = {The aim of this study is to investigate the regulation of Kaixin San-medicated serum(KXS-MS) on autophagy induced by Aβ_(25-35) in SH-SY5Y cells. The SH-SY5Y cell model of Aβ_(25-35)(25 μmol·L~(-1))-induced injury was established, and different concentrations of KXS-MS were added into the culture media of cells, which were then incubated for 24 h. Cell viability was measured by the methyl thiazolyl tetrazolium(MTT) assay. The protein levels of microtubule-associated protein 1 light chain 3(LC3)Ⅰ, LC3Ⅱ, protein kinase B(Akt), p-Akt, mammalian target of rapamycin(mTOR), and p-mTOR were assessed by Western blot. Furthermore, the combination of rapamycin(Rapa)/3-methyladenine(3-MA) and low concentration of KXS-MS was added to the culture medium of SH-SY5Y cells injured by Aβ_(25-35), and the cell viability and the expression levels of the above proteins were determined. The results showed that Aβ_(25-35) decreased the cell viability, up-regulated the expression levels of LC3Ⅱ and LC3Ⅱ/LC3Ⅰ, and down-regulated the expression levels of p-Akt, p-mTOR, p-Akt/Akt, and p-mTOR/mTOR. Compared with the Aβ_(25-35) model group, KXS-MS treatment attenuated Aβ_(25-35)-induced injury and enhanced the survival of SH-SY5Y cells. Meanwhile, KXS-MS down-regulated the LC3Ⅱ/LC3Ⅰ level and up-regulated the p-Akt/Akt and p-mTOR/mTOR levels. Compared with the low-concentration KXS-MS group, Rapa did not affect the cell survival and the levels of p-Akt and p-Akt/Akt, while it up-regulated the levels of LC3Ⅱ and LC3Ⅱ/LC3Ⅰ and down-regulated the levels of p-mTOR and p-mTOR/mTOR. 3-MA significantly reduced the cell survival rate and p-Akt, p-Akt/Akt level in the KXS-MS group, while it had no significant effect on the levels of LC3Ⅱ, LC3Ⅱ/LC3Ⅰ, p-mTOR, and p-mTOR/mTOR. The above results indicate that KXS-MS exhibits protective effects against Aβ_(25-35)-induced damage in SH-SY5Y cells by up-regulating Akt/mTOR activity to inhibit autophagy.}, }
@article {pmid39929589, year = {2025}, author = {Hirabayashi, S and Uyeda, A and Manabe, I and Yonezu, Y and Saito, T and Saido, TC and Misawa, H and Ogasawara, Y and Kinoshita, K and Muramatsu, R}, title = {CCN1 derived from vascular endothelial cells impairs cognitive function in Alzheimer's disease model mice.}, journal = {Journal of pharmacological sciences}, volume = {157}, number = {3}, pages = {146-155}, doi = {10.1016/j.jphs.2025.01.004}, pmid = {39929589}, issn = {1347-8648}, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics ; *Cysteine-Rich Protein 61/genetics/metabolism ; *Disease Models, Animal ; *Endothelial Cells/metabolism ; *Cognition ; *Hippocampus/metabolism ; Cells, Cultured ; Male ; Mice ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Mice, Inbred C57BL ; Gene Expression ; Spatial Learning ; }, abstract = {Vascular endothelial cell-expressing molecules regulate neuronal function. Although cerebrovascular dysregulation is a hallmark of Alzheimer's disease (AD), the effect of changes in molecular expression on neuronal function in vascular endothelial cells during disease progression is not clear. In this study, we demonstrated that the cellular communication network factor 1 (CCN1), which is highly expressed in vascular endothelial cells during the chronic stage of AD in mice, is involved in the impairment of cognitive function. Vascular endothelial cells isolated from the brains of App[NL-G-F] mice show differential expression of genes, including CCN1. CCN1 treatment decreased the synaptic number in cultured hippocampal cells, with changes in the expression of genes associated with morphological changes. In vivo, App[NL-G-F] mice with CCN1 silencing in vascular endothelial cells demonstrated high spine density and improved spatial learning. No significant change was observed in the number of microglia/macrophages, astrocytes, and amyloid-beta (Aβ) accumulation in the hippocampus of the mice. These results suggest that CCN1 is a key factor modulating neurological dysfunction through neurovascular interactions.}, }
@article {pmid39928236, year = {2025}, author = {Kaspute, G and Ramanavicius, A and Prentice, U}, title = {Natural drug delivery systems for the treatment of neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {217}, pmid = {39928236}, issn = {1573-4978}, support = {S-MIP-24-111//Research Council of Lithuania (LMTLT)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Drug Delivery Systems/methods ; *Biological Products/administration & dosage ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; Liposomes ; Anti-Inflammatory Agents/administration & dosage ; Nanoparticles/chemistry ; }, abstract = {Today, herbal drugs are prominent in the pharmaceutical industry due to their well-known therapeutic and side effects. Plant-based compounds often face limitations such as poor solubility, low bioavailability, and instability in physiological environments, restricting their therapeutic efficacy and delivery. Nanotechnology-based solutions, including nanoparticle formulations and advanced delivery systems like liposomes and transfersomes, address these issues by enhancing solubility, stability, bioavailability, and targeted delivery, thereby optimizing the therapeutic potential of phytoactive compounds. Neuroinflammation can be a cause of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, or amyotrophic lateral sclerosis. Consequently, there is a need for the optimal delivery of a pharmacological anti-inflammatory agents to the CNS. Thus, the non-invasive administration of a stable compound at a therapeutic concentration is needed to assure molecule crossing through the blood-brain barrier. Natural resources have more structural diversity and novelty than synthetic compounds, e.g. plant-derived drug products have higher molecular weights, incorporate more oxygen atoms, and are more complex. As a result, plant-derived products have unique features which can be used to effectively modulate neuroinflammation. Therefore, this review aims to identify herbal molecules capable of targeting neuroinflammation and present novel strategies for their efficient delivery.}, }
@article {pmid39926413, year = {2025}, author = {Almehdi, AM and Aboubaker, DH and Hamdy, R and El-Keblawy, A}, title = {Nanotherapeutic smart approaches for combating Alzheimer's disease and overcoming existing obstacles: A novel eco-friendly green approach.}, journal = {Toxicology reports}, volume = {14}, number = {}, pages = {101906}, pmid = {39926413}, issn = {2214-7500}, abstract = {The scientific community has united to raise awareness of Alzheimer's disease (AD) as a critical condition for future generations because recent predictions indicate that it will become common among the elderly within a few years. Nevertheless, the intricacies of the disease's progression demand exhaustive investigations to unravel its potential mechanisms. Only then can clinicians develop more efficacious therapeutic strategies. Cognitive impairment caused by amyloid aggregation, the development of hyperphosphorylated neurofibrillary tangles, and a malfunctioning cholinergic system are the hallmarks of AD. Even after the disease has started, brain tissue integrity may degenerate. The physiological characteristics of the highly selective blood-brain barrier and the electrostatic charge of the nanoporous extracellular matrix have long placed restrictions on the treatment of brain disorders. A prospective revolution in drug delivery for the treatment of AD is the use of nanomedicine. It depends on enhancing the way that medications are distributed pharmacokinetically throughout the central nervous system. Several types of nanoparticles (Nps) are available thanks to nanotechnology, and these Nps could target the brain and have a long half-life with few systemic side effects and motor problems. With the latest technological developments, scientists are working to develop unique approaches for the treatment of AD. To evaluate the prospective uses of medicinal plants, their components, and different nanomedicine techniques, it was determined that this literature study was necessary. To provide an overview of the various challenges and approaches related to using nanoparticles (NPs) to combat Alzheimer's disease (AD), this introductory review article was developed.}, }
@article {pmid39926335, year = {2025}, author = {Li, G and Chen, B and Sun, W and Liu, Z}, title = {A stacking classifier for distinguishing stages of Alzheimer's disease from a subnetwork perspective.}, journal = {Cognitive neurodynamics}, volume = {19}, number = {1}, pages = {38}, pmid = {39926335}, issn = {1871-4080}, abstract = {Accurately distinguishing stages of Alzheimer's disease (AD) is crucial for diagnosis and treatment. In this paper, we introduce a stacking classifier method that combines six single classifiers into a stacking classifier. Using brain network models and network metrics, we employ t-tests to identify abnormal brain regions, from which we construct a subnetwork and extract its features to form the training dataset. Our method is then applied to the ADNI (Alzheimer's Disease Neuroimaging Initiative) datasets, categorizing the stages into four categories: Alzheimer's disease, mild cognitive impairment (MCI), mixed Alzheimer's mild cognitive impairment (ADMCI), and healthy controls (HCs). We investigate four classification groups: AD-HCs, AD-MCI, HCs-ADMCI, and HCs-MCI. Finally, we compare the classification accuracy between a single classifier and our stacking classifier, demonstrating superior accuracy with our stacking classifier from a subnetwork-based viewpoint.}, }
@article {pmid39926227, year = {2025}, author = {Liu, L and He, H and Du, B and He, Y}, title = {Nanoscale drug formulations for the treatment of Alzheimer's disease progression.}, journal = {RSC advances}, volume = {15}, number = {6}, pages = {4031-4078}, pmid = {39926227}, issn = {2046-2069}, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective disease-modifying treatments. The blood-brain barrier hinders drug delivery to the brain, limiting therapeutic efficacy. Nanoparticle-based systems have emerged as promising tools to overcome these challenges. This review highlights recent advances in nanoparticle technologies for AD treatment, including liposomes, polymeric, inorganic, and biomimetic nanoparticles. These nanoparticles improve drug delivery across the blood-brain barrier, improve stability and bioavailability, and enable targeted delivery to affected brain regions. Functionalization strategies further enhance their therapeutic potential. Multifunctional nanoparticles combining therapeutic and diagnostic properties offer theranostic approaches. While progress has been made, challenges related to safety, targeting precision, and clinical translation remain. Future perspectives emphasize the need for collaborative efforts to optimize nanoparticle design, conduct rigorous studies, and accelerate the development of effective nanotherapeutics. With continued innovation, nanoparticle-based delivery systems hold great promise for revolutionizing AD treatment.}, }
@article {pmid39925735, year = {2025}, author = {Bindra, S and Mostafa, EM and Abdelgawad, MA and Selim, S and Kumar, S and Mathew, B}, title = {Synthetic strategies and medicinal chemistry perspectives of dual acting carbonic anhydrase modulators with monoamine oxidase and cholinesterase inhibitors.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {39925735}, issn = {2632-8682}, abstract = {Multi-target drug design (MTDD) represents the paradigm shift in pharmaceutical research, moving beyond the conventional one-drug-one-target approach to address the complexity of multifactorial diseases. This strategy aims to develop single therapeutic candidates that can simultaneously modulate multiple biological targets, offering more comprehensive disease management and reducing the likelihood of drug resistance. In this article, we highlighted the design, synthesis, and structure-activity relationships (SARs) of various dual acting inhibitors involved in treatment of neurodegenerative diseases. Dual acting inhibitors targeting carbonic anhydrases (CAs), monoamine oxidases (MAOs), and cholinesterases (ChEs) have emerged as promising therapeutic agents due to their potential in treating complex neurodegenerative and psychiatric disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). By integrating CA inhibitors with MAO and ChE inhibition, researchers aim to address both the neuroprotective and symptomatic aspects of these disorders. The review also discusses key SAR studies that have guided the optimization of dual inhibitors, focusing on achieving selectivity and potency while minimizing off-target effects. From a medicinal chemistry perspective, the dual inhibition approach offers advantages such as improved efficacy, reduced polypharmacy, and better management of disease progression. However, challenges remain, including maintaining selectivity for target isoforms and overcoming pharmacokinetic limitations. Overall, the development of dual-acting CA-MAO-ChE inhibitors represents a compelling avenue in drug discovery, with the potential to significantly impact the treatment of neurodegenerative diseases.}, }
@article {pmid39925461, year = {2024}, author = {Ouyang, Z and Wang, L and , }, title = {Imputation-Based Variable Selection Method for Block-Wise Missing Data When Integrating Multiple Longitudinal Studies.}, journal = {Mathematics (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {39925461}, issn = {2227-7390}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; P50 DA054039/DA/NIDA NIH HHS/United States ; R01 CE003497/CE/NCIPC CDC HHS/United States ; R01 ES033515/ES/NIEHS NIH HHS/United States ; }, abstract = {When integrating data from multiple sources, a common challenge is block-wise missing. Most existing methods address this issue only in cross-sectional studies. In this paper, we propose a method for variable selection when combining datasets from multiple sources in longitudinal studies. To account for block-wise missing in covariates, we impute the missing values multiple times based on combinations of samples from different missing pattern and predictors from different data sources. We then use these imputed data to construct estimating equations, and aggregate the information across subjects and sources with the generalized method of moments. We employ the smoothly clipped absolute deviation penalty in variable selection and use the extended Bayesian Information Criterion criteria for tuning parameter selection. We establish the asymptotic properties of the proposed estimator, and demonstrate the superior performance of the proposed method through numerical experiments. Furthermore, we apply the proposed method in the Alzheimer's Disease Neuroimaging Initiative study to identify sensitive early-stage biomarkers of Alzheimer's Disease, which is crucial for early disease detection and personalized treatment.}, }
@article {pmid39924888, year = {2025}, author = {Silva, RPDS and Barbosa, BJAP}, title = {Exploring the potential of acupuncture as a complementary treatment for Alzheimer's disease: Pushing the boundaries forward.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {104}, number = {2}, pages = {331-333}, doi = {10.1177/13872877251316572}, pmid = {39924888}, issn = {1875-8908}, mesh = {*Alzheimer Disease/therapy ; Humans ; *Acupuncture Therapy/methods ; Cognition/physiology ; Randomized Controlled Trials as Topic ; }, abstract = {Acupuncture has emerged as a promising adjunctive symptomatic therapy for Alzheimer's disease, demonstrating potential benefits in cognitive function and neuroprotection. Recent meta-analyses and randomized clinical trials have investigated the potential of acupuncture to improve cognitive assessments, signaling pathways, and gut regulation in Alzheimer's disease, underscoring its potential clinical application. However, the limited number of studies, small sample sizes, and lack of detailed mapping of acupuncture's core targets must be considered when interpreting these positive results.}, }
@article {pmid39924842, year = {2025}, author = {Ndukwe, K and Serrano, PA and Rockwell, P and Xie, L and Figueiredo-Pereira, ME}, title = {Brain-penetrant histone deacetylase inhibitor RG2833 improves spatial memory in females of an Alzheimer's disease rat model.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {104}, number = {1}, pages = {173-190}, doi = {10.1177/13872877251314777}, pmid = {39924842}, issn = {1875-8908}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; Female ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Male ; *Spatial Memory/drug effects ; Rats ; *Disease Models, Animal ; Rats, Inbred F344 ; Rats, Transgenic ; Hippocampus/drug effects/metabolism ; Early Growth Response Protein 1/metabolism/genetics ; Brain/drug effects/metabolism ; Maze Learning/drug effects ; Sex Characteristics ; Benzamides ; Cytoskeletal Proteins ; Nerve Tissue Proteins ; Phenylenediamines ; }, abstract = {BackgroundNearly two-thirds of Alzheimer's disease (AD) patients are women. Therapeutics for women are critical to lowering their elevated risk of developing this major cause of adult dementia. Moreover, targeting epigenetic processes such as histone acetylation that regulate multiple cellular pathways is advantageous given the multifactorial nature of AD. Histone acetylation takes part in memory consolidation, and its disruption is linked to AD.ObjectiveDetermine whether the investigational drug RG2833 has repurposing potential for AD. RG2833 is a histone deacetylase HDAC1/3 inhibitor that is orally bioavailable and permeates the blood-brain-barrier.MethodsRG2833 effects were determined on cognition, transcriptome, and AD-like pathology in 11-month TgF344-AD female and male rats. Treatment started early in the course of pathology when therapeutic intervention is predicted to be most effective.ResultsRG2833-treatment of 11-month TgF344-AD rats: (1) Significantly improved hippocampal-dependent spatial memory in females but not males. (2) Upregulated expression of immediate early genes, such as Arc, Egr1 and c-Fos, and other genes involved in synaptic plasticity and memory consolidation in females. Remarkably, out of 17,168 genes analyzed for each sex, no significant changes in gene expression were detected in males at p < 0.05, false discovery rate <0.05, and fold-change equal or > 1.5. (3) Failed to improve amyloid beta accumulation and microgliosis in female and male TgF344-AD rats.ConclusionsOur study highlights the potential of histone-modifying therapeutics such as RG2833 to improve cognitive behavior and drive the expression of immediate early, synaptic plasticity and memory consolidation genes, especially in female AD patients.}, }
@article {pmid39924695, year = {2025}, author = {Liu, S and Geng, D}, title = {White-Matter Structural Connectivity and Alzheimer's Disease: A Mendelian Randomization Study.}, journal = {Brain and behavior}, volume = {15}, number = {2}, pages = {e70286}, pmid = {39924695}, issn = {2162-3279}, support = {82372048//National Natural Science Foundation of China/ ; 22TS1400900//Science and Technology Commission of Shanghai Municipality/ ; 22ZR1409500//Science and Technology Commission of Shanghai Municipality/ ; 23S31904100//Science and Technology Commission of Shanghai Municipality/ ; 24SF1904200//Science and Technology Commission of Shanghai Municipality/ ; 24SF1904201//Science and Technology Commission of Shanghai Municipality/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/pathology/diagnostic imaging ; *Mendelian Randomization Analysis ; *White Matter/diagnostic imaging/pathology ; *Genome-Wide Association Study ; Genetic Predisposition to Disease ; White ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) and white-matter structural connectivity have been linked in some observational studies, although it is unknown if this is a causal relationship. The purpose of this study was to examine the impact of various white-matter structural connectivity on AD via a two-sample multivariate Mendelian randomization (MR) approach.
METHODS: The genome-wide association study (GWAS) of Wainberg et al. provided the summary data on white-matter structural connectivity, and Bellenguez et al.'s study provided the GWAS aggregated data for AD. MR methods included inverse variance weighted, Mendelian randomization Egger, simple mode, weighted median, and weighted mode. Heterogeneity, horizontal pleiotropy, and "leave-one-out" analysis guaranteed the robustness of causation. Finally, reverse MR analysis was conducted on the white-matter structural connectivity that showed positive results in the forward MR analysis.
RESULTS: Among 206 white-matter structural connections, we identified 10 connections were strongly correlated with genetic susceptibility to AD. Right-hemisphere limbic network to thalamus white-matter structural connectivity and Right-hemisphere salience_ventral attention network to accumbens white-matter structural connectivity were positively correlated with the likelihood of AD, while the remaining 8 white-matter structural connections were negatively related with AD. None of the above 10 white-matter structural connections have a reverse causal relationship with AD.
CONCLUSION: Our MR study reveals a certain degree of association between white-matter structural connectivity and AD, which may provide support for future diagnosis and treatment of AD.}, }
@article {pmid39923958, year = {2025}, author = {Zhang, H and Bi, F and Zhao, P and Cui, H and Tao, X and Zhang, J and Li, C and Cao, Y and Wang, N and Li, H}, title = {Longan Aril polysaccharides ameliorate cognitive impairment in AD mice via restoration of the immune phagocytosis of microglia.}, journal = {Journal of ethnopharmacology}, volume = {343}, number = {}, pages = {119464}, doi = {10.1016/j.jep.2025.119464}, pmid = {39923958}, issn = {1872-7573}, mesh = {Animals ; *Microglia/drug effects ; *Polysaccharides/pharmacology ; *Alzheimer Disease/drug therapy/immunology ; Mice ; Male ; *Phagocytosis/drug effects ; *Amyloid beta-Peptides ; Cognitive Dysfunction/drug therapy ; Peptide Fragments ; Lipopolysaccharides ; Disease Models, Animal ; Cell Line ; Maze Learning/drug effects ; }, abstract = {Alzheimer's disease (AD) belongs to the category of "forgetfulness" or "dementia" in traditional Chinese medicine, and is often caused by deficiency of five zang-viscera. Longan Aril (the aril of Dimocarpus longan Lour., LA) possesses properties beneficial for heart and spleen health, blood nourishment, and mind tranquility, suggesting its potential as a treatment for AD. This study aimed to investigate the therapeutic effects of Longan Aril polysaccharides (LAPs), a primary active constituent of LA, on lipopolysaccharides (LPS) and amyloid β-peptide (Aβ) induced immune tolerance in AD mice. Further, BV2 cells were employed to explore the mechanism of LAPs in improving immune tolerance.
MATERIAL AND METHODS: LAPs were prepared by water extraction and alcohol precipitation. The monosaccharide composition was determined by high-performance liquid chromatography (HPLC). An AD mouse model of immune tolerance was established by intraperitoneal (i.p) injection of LPS combined with intracerebroventricular (ICV) injection of Aβ25-35. The LAPs group mice received LAPs (1.4 g/kg) daily for 40 days. The anti-AD efficacy and mechanism of LAPs in vivo was evaluated by the Y maze, Morris water maze, Degenerating Neurons Stain (FJC staining), hematoxylin-eosin (H&E) staining, Nissl staining, measurements of lactate, tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) secretion levels, immunofluorescence and western blot. Furthermore, the mechanism of LAPs in improving the function of immune-tolerant BV2 cells was explored in vitro using lactic acid kits, ELISA kits, and western blot. The phagocytic function of BV2 cells was evaluated by the fluorescent dye Alexa Fluor 488 labeled Aβ (AF448-Aβ).
RESULTS: LAPs contained five monosaccharides. LAPs improved cognitive function and increased the number of Nissl bodies, lactate secretion, the IL-10 content, the relative fluorescence intensity of the IBA1 and AXL proteins, and the protein expression levels of AXL, Mertk, Glut1, HK2, PI3K, p-Akt/Akt, p-mTOR/mTOR and HIF-1α of immune-tolerant AD mice. LAPs also reduced the TNF-α content, and the protein expression level of CD68 in immune-tolerant AD mice. In vitro, LAPs elevated the IL-10 content and protein expression levels of PI3K, Akt, p-Akt, and HIF-1α, while reducing lactate secretion and the TNF-α content in immune-tolerant BV2 cells. LAPs promoted the phagocytic activity of BV2 cells, and their effects are completely inhibited by 2-DG and partially inhibited by BAY and Rapa.
CONCLUSIONS: LAPs can enhance the cognitive abilities of immune-tolerant AD mice and diminish their pathological damage. The mechanism involves the regulation of glycolysis and the PI3K/Akt/mTOR/HIF-1α signaling pathway to promote microglial immune phagocytosis.}, }
@article {pmid39923891, year = {2025}, author = {Shan, G and Zhang, Y and Tang, Z and Wang, G and Wu, SS}, title = {Disease progression trajectory curves to estimate saved time in Alzheimer's disease trials.}, journal = {Contemporary clinical trials}, volume = {151}, number = {}, pages = {107814}, doi = {10.1016/j.cct.2025.107814}, pmid = {39923891}, issn = {1559-2030}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Disease Progression ; *Donepezil/therapeutic use ; Randomized Controlled Trials as Topic/methods ; Area Under Curve ; Time Factors ; Computer Simulation ; }, abstract = {With the recent successful disease-modifying therapies against Alzheimer's disease (AD), there have been discussions on easily interpretable measures for treatment effects. Among them, saved time for patients treated with a new drug as compared to patients randomized to the placebo group offers easier interpretation than the reduced percentage in outcome decline at last visit which were commonly used in AD trials. The existing method to calculate saved time utilized the disease progression trajectory of the placebo group and the treatment effect at the last visit. We propose to develop two new methods that use disease progression trajectories of both groups: (1) slope adjusted method; and (2) area under the curve method. We used data from the two donanemab trials and the donepezil trial to illustrate the application of the proposed methods and conducted simulation studies to compare these methods. When a drug has a constant treatment effect over time or early and middle difference in the disease progression, the area under the curve method often has the saved time being longer than the existing method. When the treatment effect is an increasing function of time before the last visit as observed in disease-modifying therapy trials, the slope adjusted method could have a larger saved time as compared to the existing method. In many cases, the area under the curve method often has the smallest standard deviation of saved time.}, }
@article {pmid39923885, year = {2025}, author = {Li, T and Wang, W and Liu, W and Sun, M and Wang, Q and Li, Z and Hao, J and Yu, Y}, title = {Macrophage membrane coated functionalized nanoparticles for targeted drug delivery and neural function repair in cerebral ischemia-reperfusion injury.}, journal = {International journal of pharmaceutics}, volume = {672}, number = {}, pages = {125329}, doi = {10.1016/j.ijpharm.2025.125329}, pmid = {39923885}, issn = {1873-3476}, mesh = {Animals ; *Reperfusion Injury/drug therapy ; Mice ; *Neuroprotective Agents/administration & dosage/pharmacology ; *Reactive Oxygen Species/metabolism ; *Macrophages/drug effects ; *Indoles/administration & dosage/chemistry/pharmacology ; *Nanoparticles ; *Polymers/chemistry ; Male ; Brain Ischemia/drug therapy ; Drug Delivery Systems ; Oxidative Stress/drug effects ; Disease Models, Animal ; Cell Membrane/drug effects/metabolism ; Apoptosis/drug effects ; Dementia, Vascular/drug therapy ; Neurons/drug effects ; Mice, Inbred C57BL ; Nanoparticle Drug Delivery System/chemistry ; Isoflavones ; }, abstract = {Vascular dementia (VD) is the second leading cause of cognitive impairment after Alzheimer's disease, posing a heavy burden to families and society. The majority of causes of VD are vascular diseases such as stroke, with ischemic stroke accounting for a large proportion. After ischemia-reperfusion, factors such as mitochondrial damage and increased xanthine oxidase lead to excessive production of reactive oxygen species (ROS) at the ischemic site, further exacerbating brain injury. Therefore, developing effective ROS scavengers is crucial. Polydopamine has become one of the widely used surface functionalized materials in recent years, due to its excellent biocompatibility and antioxidant properties. This paper proposed a macrophage membrane disguised polydopamine (PDA) nanoplatform for loading the neuroprotective drug puerarin (PUE). The as made PUE@PDA@CMs (PPCs) nanoplatforms can significantly and effectively clear ROS, alleviate oxidative microenvironment, and protect neurons from oxidative stress damage. The macrophage membranes modification enables PPCs to respond to lymphocyte recruitment at the site of cerebral ischemia-reperfusion injury, thereby targeting and aggregating to the injury site. In a mouse model of vascular dementia, PPCs treatment significantly reduced neuronal apoptosis and provided significant cognitive and memory function recovery, providing new strategies and prospects for the treatment of central nervous system diseases.}, }
@article {pmid39923646, year = {2025}, author = {Haghi, M and Masoudi, R and Ataellahi, F and Yousefi, R and Najibi, SM}, title = {Role of Tau and Amyloid-beta in autophagy gene dysregulation through oxidative stress.}, journal = {Tissue & cell}, volume = {93}, number = {}, pages = {102765}, doi = {10.1016/j.tice.2025.102765}, pmid = {39923646}, issn = {1532-3072}, mesh = {*Oxidative Stress/drug effects ; *tau Proteins/metabolism/genetics ; Animals ; *Autophagy/drug effects/genetics ; *Amyloid beta-Peptides/metabolism ; *Drosophila melanogaster/genetics/metabolism ; *Animals, Genetically Modified ; *Alzheimer Disease/metabolism/genetics/drug therapy/pathology ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Humans ; Drosophila Proteins/metabolism/genetics ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by memory impairment and cognitive decline. Our previous research has demonstrated that pathological Tau and Amyloid-beta (Aβ) disrupt autophagy gene expression, independently. Other studies have shown that these pathological aggregates create a vicious cycle with oxidative stress.
METHODS: In the current research, the effect of Tau and Amyloid-beta was compared on behavioral function, autophagy gene dysfunction, and oxidative stress in the Drosophila model for AD. Thymoquinone (TQ), an antioxidant agent, was then tested to examine if it could ameliorate the adverse effects of Tau and Amyloid-beta. In addition, the impact of TQ on Tau aggregation was investigated in vitro.
RESULTS: Our data showed that Tau and Amyloid-beta induced behavioral disability, autophagy gene dysregulation, and oxidative stress. TQ treatment significantly improved conditions in both types of transgenic flies, with a more profound alleviation in Tau transgenic flies, despite tau having a greater impact on autophagy gene dysregulation. Furthermore, TQ prevented the aggregation of Tau in vitro.
CONCLUSION: To sum up, Tau may exert its toxic effect on autophagy and behavioral dysfunctions significantly through oxidative stress while Amyloid-beta may confer its toxicity through multiple pathways, including oxidative stress. Moreover, since TQ ameliorates the adverse effect of tau and amyloid beta, it could be considered a promising approach for treating AD, probably in combination with other medications against Aβ or Tau.}, }
@article {pmid39922688, year = {2025}, author = {Webeck, JA and Laing, K and Andrews, DM}, title = {Improvement in gait and functional abilities in an adult with posterior cortical atrophy after translingual neuromodulation with neurorehabilitation physical therapy: a case report.}, journal = {Physiotherapy theory and practice}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/09593985.2025.2464849}, pmid = {39922688}, issn = {1532-5040}, abstract = {BACKGROUND: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive damage to the brain's visual and association areas, resulting in impaired spatial awareness, visual processing, and functional independence.
PURPOSE: This report examines the effects of a 14-week treatment protocol consisting of translingual neuromodulation via a portable neuromodulation stimulator (PoNS®[1]) in conjunction with physical therapy on balance, gait, and functional mobility in an adult male with PCA.
CASE DESCRIPTION: Assessments included objective and subjective measures of balance and gait - the 10-Metre Walk Test, Functional Gait Assessment (FGA), Dynamic Gait Index (DGI), Community Balance and Mobility Scale (CB&M), Neuro-Quality of Life (Neuro-QoL), and Activities-specific Balance Confidence (ABC) Scale. These were performed at baseline and weeks 4, 8, and 14 to evaluate the protocol's efficacy in improving balance, stability, and gait.
OUTCOMES: Postural stability, balance, gait patterning, and gait speed improved, enhancing daily functioning abilities and self-confidence. Gait speed improved by 0.48 m/s (comfortable) and 0.46 m/s (fast), exceeding MDC thresholds. The participant's FGA score increased 21 points and DGI increased 17 points, both exceeding their respective MDC thresholds (6 points for FGA, 3.2 points for DGI), reflecting marked gait improvements. The CB&M score rose 24 points, exceeding the MDC of 9.6 points. Despite these gains, gait speed remained below age-related norms.
CONCLUSION: Given the largely positive response to the protocol, further investigation should be undertaken to continue to explore the efficacy of PoNS® and physical therapy to determine its viability as a treatment for symptoms of PCA.}, }
@article {pmid39922422, year = {2025}, author = {Zheng, N and Zhang, Z and Liu, H and Zong, S and Zhang, L and Cui, X and Liu, Y and Wang, C and Chen, R and Lu, Z}, title = {MK886 ameliorates Alzheimer's disease by activating the PRKCI/AKT signaling pathway.}, journal = {European journal of pharmacology}, volume = {993}, number = {}, pages = {177359}, doi = {10.1016/j.ejphar.2025.177359}, pmid = {39922422}, issn = {1879-0712}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; *Proto-Oncogene Proteins c-akt/metabolism ; *Signal Transduction/drug effects ; Mice ; *Hippocampus/drug effects/metabolism/pathology ; Male ; Amyloid beta-Peptides/metabolism ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Neurons/drug effects/metabolism/pathology ; Mice, Transgenic ; Molecular Docking Simulation ; Disease Models, Animal ; Cell Line ; Cognition/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, associated with oxidative stress, neuronal apoptosis, and the accumulation of amyloid-β (Aβ) plaques. Despite advances in understanding AD pathology, effective treatments remain limited. This study aimed to investigate the therapeutic efficacy and underlying molecular mechanisms of MK886, a selective inhibitor of the 5-lipoxygenase pathway, in the context of AD. Network pharmacology analyses were employed to evaluate MK886's potential as a treatment for AD, revealing promising interactions with key molecular targets implicated in the disease. In vitro experiments demonstrated that MK886 effectively mitigated Aβ1-42 oligomer-induced oxidative stress, apoptosis, and ferroptosis in mouse hippocampal neuronal cells (HT22). These effects were validated using techniques such as immunofluorescence, JC-1 staining, TUNEL staining, and flow cytometry. In vivo studies involved administering MK886 to APPswe/PS1dE9 (APP/PS1) mice, which resulted in significant improvements in cognitive and emotional functions as assessed by the Y-maze and Morris water maze tests. Histological evaluations, including Nissl staining, immunofluorescence, and immunohistochemistry, revealed that MK886 preserved hippocampal neuron integrity and reduced Aβ deposition. Proteomics and molecular docking analyses identified the PRKCI/AKT signaling pathway as a key mediator of MK886's neuroprotective effects. This finding was further validated through Western blotting experiments incorporating an AKT inhibitor. Overall, these findings suggest that MK886 holds promise as a potential therapeutic agent for Alzheimer's disease by enhancing neuronal protection and cognitive function through the activation of the PRKCI/AKT pathway.}, }
@article {pmid39922347, year = {2025}, author = {Zhang, Y and Zhang, X and Zhou, J and Li, Y and Kai, T and Zhang, L}, title = {Lycium ruthenicum Murray exosome-like nanovesicles alleviated Alzheimer's disease-like symptoms induced by Aβ protein in transgenic Caenorhabditis elegans through the DAF-16 pathway.}, journal = {International journal of biological macromolecules}, volume = {304}, number = {Pt 1}, pages = {140758}, doi = {10.1016/j.ijbiomac.2025.140758}, pmid = {39922347}, issn = {1879-0003}, mesh = {Animals ; *Caenorhabditis elegans/drug effects ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Animals, Genetically Modified ; *Exosomes/metabolism ; *Forkhead Transcription Factors/metabolism ; Disease Models, Animal ; Nanoparticles/chemistry ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Lycium/chemistry ; }, abstract = {Alzheimer's disease (AD) is predominantly characterized by cholinergic dysfunction, mitochondrial impairment, oxidative stress, and inflammation, primarily driven by amyloid-beta (Aβ) peptides. This study investigates the protective effects of Lycium ruthenicum Murray-derived exosome-like nanoparticles (LELN) in AD models using transgenic Caenorhabditis elegans (C. elegans). Findings showed that C. elegans effectively internalized LELN, which remained stable in vivo. Compared with untreated controls, treatment with 600 μg/mL LELN significantly extended the lifespan of CL4176 [myo-3p::Aβ1-42] and CL2006 [unc-54/Aβ1-42] worms by 34.78 % and 34.85 %, respectively, and delayed Aβ-induced paralysis by 52.42 % and 42.72 %, respectively. Furthermore, LELN increased the chemotaxis index of CL2355 [snb-1::Aβ1-42] worms from 11.11 % to 55.56 %. Mechanistically, LELN reduced the levels of Aβ oligomers and monomers via the DAF-16 pathway, consequently alleviating AD-like symptoms in transgenic C. elegans. The effects of LELN include inhibiting acetylcholinesterase activity to mitigate cholinergic dysfunction, restoring mitochondrial membrane potential and adenosine triphosphate production to ameliorate mitochondrial dysfunction, and reducing oxidative stress and inflammation. Collectively, these results highlight the protective role of LELN against Aβ-induced AD pathology and underscore their potential as a therapeutic candidate for AD treatment.}, }
@article {pmid39922232, year = {2025}, author = {Prabha, S and Choudhury, A and Islam, A and Thakur, SC and Hassan, MI}, title = {Understanding of Alzheimer's disease pathophysiology for therapeutic implications of natural products as neuroprotective agents.}, journal = {Ageing research reviews}, volume = {105}, number = {}, pages = {102680}, doi = {10.1016/j.arr.2025.102680}, pmid = {39922232}, issn = {1872-9649}, mesh = {*Alzheimer Disease/drug therapy/metabolism/therapy ; Humans ; *Biological Products/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a leading cause of dementia, affecting more than 24.3 million people worldwide in 2024. Sporadic AD (SAD) is more common and occurs in the geriatric population, while familial AD (FAD) is rare and appears before the age of 65 years. Due to progressive cholinergic neuronal loss and modulation in the PKC/MAPK pathway, β-secretase gets upregulated, leading to Aβ aggregation, which further activates tau kinases that form neurofibrillary tangles (NFT). Simultaneously, antioxidant enzymes are also upregulated, increasing oxidative stress (OS) and reactive species by impairing mitochondrial function, leading to DNA damage and cell death. This review discusses the classifications and components of several natural products (NPs) that target these signaling pathways for AD treatment. NPs, including alkaloids, polyphenols, flavonoids, polysaccharides, steroids, fatty acids, tannins, and polypeptides derived from plants, microbes, marine animals, venoms, insects, and mushrooms, are explored in detail. A synergistic combination of plant metabolites, together with prebiotics and probiotics has been shown to decrease Aβ aggregates by increasing the production of bioactive compounds. Toxins derived from venomous organisms have demonstrated effectiveness in modulating signaling pathways and reducing OS. Marine metabolites have also shown neuroprotective and anti-inflammatory properties. The cholera toxin B subunit and an Aβ15 fragment have been combined to create a possible oral AD vaccine, that showed enhancement of cognitive function in mice. Insect tea is also a reliable source of antioxidants. A functional edible mushroom snack bar showed an increment in cognitive markers. Future directions and therapeutic approaches for the treatment of AD can be improved by focusing more on NPs derived from these sources.}, }
@article {pmid39921833, year = {2025}, author = {Stewart, D and Johnson, EL}, title = {The Bidirectional Relationship Between Epilepsy and Alzheimer's Disease.}, journal = {Current neurology and neuroscience reports}, volume = {25}, number = {1}, pages = {18}, pmid = {39921833}, issn = {1534-6293}, support = {K23AG063899/GF/NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/complications/physiopathology ; *Epilepsy/complications/physiopathology/diagnosis ; Anticonvulsants/therapeutic use ; Animals ; Cognitive Dysfunction/etiology/physiopathology ; }, abstract = {PURPOSE OF REVIEW: Epilepsy has long been considered a late-stage consequence of Alzheimer's Disease (AD), but recent studies highlight its role early in the disease process, even preceding cognitive symptoms. Population studies reveal a two- to fourfold increased epilepsy risk in AD, particularly in early-onset cases, with seizures clustering around diagnosis. Furthermore, individuals with late-onset unexplained epilepsy have an elevated risk of developing mild cognitive impairment and dementia, underscoring a bidirectional relationship between AD and epilepsy.
RECENT FINDINGS: Experimental models support this connection, demonstrating amyloid and tau pathology-induced hyperexcitability at pre-symptomatic stages, implicating soluble Aβ oligomers and inhibitory interneuron dysfunction in excitatory/inhibitory imbalance. Subclinical or clinical epileptiform activity, detectable in 20-50% of AD patients, is associated with cognitive decline, possibly due to sleep-related memory consolidation disruption. Emerging biomarkers, such as TIRDA and high-frequency oscillations, show promise for early detection and intervention. Anti-seizure medications (ASMs), particularly low-dose levetiracetam, show potential not only for seizure control but also for mitigating amyloid deposition, tau hyperphosphorylation, and cognitive decline. However, treatment complexities remain due to variable ASM efficacy, age-related side effects, and limited clinical trials. The bidirectional nature of AD and epilepsy emphasizes the need for integrated diagnostics, including EEG and biomarker assessments, to guide early intervention and targeted therapies. Future research should focus on the mechanistic interplay between amyloid, tau, and hyperexcitability, alongside trials of ASM regimens, to refine therapeutic strategies and improve outcomes in this population.}, }
@article {pmid39921369, year = {2025}, author = {Abdulghani, MF and Barzegari, R and Almagharbeh, WT and Yazdani, Z and Amandadi Ghotbabadi, A and Seyed Bagheri, SH and Alnaiem, M and Dehghan, M}, title = {Treatments of psychosomatic symptoms in Alzheimer's disease: a scoping review of the potential therapeutic effects of essential oils.}, journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society}, volume = {25}, number = {2}, pages = {e70007}, doi = {10.1111/psyg.70007}, pmid = {39921369}, issn = {1479-8301}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Oils, Volatile/therapeutic use ; Aromatherapy/methods ; Psychophysiologic Disorders/drug therapy ; Plant Oils/therapeutic use ; Phytotherapy/methods ; }, abstract = {Alzheimer's disease, a type of dementia, poses serious challenges to patients, especially older people, and no definitive treatment is available for this disease, with drug treatments having many side effects. As essential oils of plants deserve particular attention in the treatment of diseases, this study aimed to review the potential therapeutic effects of essential oils on treatment of psychosomatic aspects of Alzheimer's disease. To collect information, we searched different databases, including MagIran, SID, IranDoc and IranMedex, Embase, Science Direct, PubMed, Google Scholar, Scopus and Web of Science using the keywords of essential oil, Alzheimer, acetylcholinesterase, memory, forgetfulness, aromatherapy, medicinal plant, herbal drugs, and their Persian equivalents from January 2010 to June 2022; the search included both single and multiple keywords. We retrieved 233 articles, reviewed the titles, abstracts, and full texts of the articles, and then included 25 related articles in this review (11 in vitro studies and 14 in vivo studies). The study results of in vitro and in vivo studies showed the effectiveness of different essential oils such as salvia family, tangerine and lemon oils, Juniperus communis, Anthriscus nemorosa, olibanum, inhaled coriander, Schisandra chinensis, lavender, rose essential oil, Nepeta cataria, Cinnamomum zeylanicum and Lippia origanoides, on memory and learning, enzymes, oxidative stress and inflammation, behavioural and cognitive symptoms in Alzheimer's disease. These findings suggest that essential oils can serve as complementary therapies for neurodegenerative diseases like Alzheimer's and for addressing memory impairments, although further research, especially human clinical trials, is needed to validate these findings, determine optimal dosages, and explore the long-term safety of essential oils in clinical settings.}, }
@article {pmid39921150, year = {2025}, author = {Carrol, D and Busse, WW and Frye, CJ and Klaus, DR and Bach, JC and Floerke, H and Bendlin, BB and Zetterberg, H and Blennow, K and Heslegrave, A and Hoel, R and Rosenkranz, MA}, title = {Regional brain structural alterations in reward and salience networks in asthma.}, journal = {Brain, behavior, and immunity}, volume = {126}, number = {}, pages = {80-97}, doi = {10.1016/j.bbi.2025.01.028}, pmid = {39921150}, issn = {1090-2139}, support = {RF1 AG082215/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Chronic systemic inflammation is highly prevalent and has deleterious effects on the brain, impacting both function and structure, and manifesting in elevations in psychological symptoms transdiagnostically. Asthma is a chronic inflammatory disease of the airway that affects more than 300 million people worldwide and is known to be highly comorbid with psychological and cognitive dysfunction. Though a growing corpus of work has identified functional brain abnormalities associated with asthma, limited research has investigated structural differences which may partially underlie functional changes. Identifying and characterizing asthma-related structural brain changes will shed light on the neurobiology through which asthma impacts mental function and has the potential to inform prophylaxis and treatment.
METHODS: We examined differences in regional brain volume, cortical thickness, and surface area, in 128 individuals with asthma compared to 134 non-asthma healthy controls. Five regions of interest were examined a priori, based on their previous implication in inflammation-related functional consequences (dorsal and ventral striatum, pallidum, and insula), or previous evidence of asthma-related structural impact (hippocampus and thalamus). We supplemented our region of interest approach with a voxel-wise whole-brain analysis. Additionally, we examined the association of brain structure with depression symptoms, asthma severity, degree of inflammation, and plasma biomarkers of neuroinflammation, neurodegeneration, and Alzheimer's disease specific pathology.
RESULTS: Compared to non-asthma control participants, those with asthma had smaller nucleus accumbens volumes, thicker orbitofrontal cortices, larger middle frontal cortex surface areas, and greater diencephalon volumes. Those with more severe asthma had smaller nucleus accumbens and dorsal striatal volumes, reduced anterior cingulate cortex surface area, and greater amygdala volume compared to those with mild asthma. In untreated asthma patients, greater depressive symptoms were associated with smaller striatal volume, suggesting a potential CNS-protective effect of medications that reduce airway inflammation in asthma. In addition, a plasma marker of astrogliosis was associated with larger diencephalon, cerebellum, brainstem, and thalamus volumes, but reduced insula thickness and surface area.
CONCLUSIONS: Patterns of structural brain changes in participants with asthma encompass key regions of reward and salience networks, which may in part give rise to the functional alterations in these networks characteristic of chronic systemic inflammation.}, }
@article {pmid39920976, year = {2025}, author = {Panda, SP and Sinha, S and Kesharwani, A and Kumar, S and Singh, M and Kondepudi, GM and Samuel, A and Sanghi, AK and Thapliyal, S and Chaubey, KK and Guru, A}, title = {Role of OX/OXR cascade in insomnia and sleep deprivation link Alzheimer's disease and Parkinson's disease: Therapeutic avenue of Dual OXR Antagonist (DORA).}, journal = {Biochemical pharmacology}, volume = {233}, number = {}, pages = {116794}, doi = {10.1016/j.bcp.2025.116794}, pmid = {39920976}, issn = {1873-2968}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Sleep Initiation and Maintenance Disorders/drug therapy/metabolism ; *Orexin Receptor Antagonists/therapeutic use/pharmacology ; Animals ; *Parkinson Disease/drug therapy/metabolism ; *Sleep Deprivation/drug therapy/metabolism/complications ; Orexins/metabolism ; Orexin Receptors/metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {Sleep plays a role in the elimination of neurotoxic metabolites that are accumulated in the waking brain as a result of neuronal activity. Long-term insomnia and sleep deprivation are associated with oxidative stress, neuroinflammation, amyloid beta (Aβ) deposition, and Lewy body formation, which are known to increase the risk of mild cognitive impairment (MCI) and dementia. Orexin A (OXA) and orexin B (OXB), two neuropeptides produced in the lateral hypothalamus, are known to influence the sleep-wake cycle and the stress responses through their interactions with OX receptor 1 (OX1R) and OX receptor 2 (OX2R), respectively. OX/OXR cascade demonstrates intricate neuroprotective and anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-kB) and PLC/Ca[2+] pathway activation. OX1R binds OXA more strongly than OXB by one-order ratio, whereas OX2R binds both OXA and OXB with equal strengths. Overexpression of OXs in individuals experiences sleep deprivation, circadian rhythm disturbances, insomnia-associated MCI, Parkinson's disease (PD), and Alzheimer's disease (AD). Many dual OXR antagonists (DORAs) have been effective in their clinical studies, with suvorexant and daridorexant receiving FDA clearance for insomnia therapy in 2014 and 2022 respectively. The results of clinical studies suggested that there is a new pharmaceutical option for treating insomnia and the sleep deprivation-AD/PD relationship by targeting the OXR system. DORAs treatment reduces Aβ deposition in the brain and improves synaptic plasticity and circadian expression. This review indicates the link between sleep disorders and MCI, DORAs are an appropriate medication category for treating insomnia, and sleep deprivation links AD and PD.}, }
@article {pmid39919860, year = {2025}, author = {Yin, G and Sun, Y and Luo, Y and Cheng, Y and Xue, S and Wang, H and Lu, Q and Du, F and Yin, P}, title = {Fluorescence imaging of homocysteine dynamics: Complementary diagnostic applications in Alzheimer's disease.}, journal = {Analytica chimica acta}, volume = {1342}, number = {}, pages = {343688}, doi = {10.1016/j.aca.2025.343688}, pmid = {39919860}, issn = {1873-4324}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis/metabolism ; *Homocysteine/analysis/blood/metabolism ; Animals ; *Optical Imaging ; Mice ; Humans ; *Fluorescent Dyes/chemistry ; Biomarkers/analysis/blood/metabolism ; Amyloid beta-Peptides/analysis/metabolism ; Blood-Brain Barrier/metabolism ; }, abstract = {With the continue emergence of Alzheimer's disease (AD)-modifying therapies, pinpointing the treatments that offer the greatest benefits to patients is increasingly critical. Complementary diagnostics are powerful tests that can provide crucial biomarker dynamics about the drug usage that can improve treatment outcomes by individualized pharmacotherapy. Herein, we exploited a robust near-infrared fluorescent probe, by attenuating the pre-twisting tendency and the twist intramolecular charge transfer effect, for sensing of Hcy in vitro and in vivo with high quantum yield, excellent selectivity, and remarkable sensitivity. The probe is capable of monitoring endogenous Hcy dynamics in cells, tissues and in vivo with exceptional blood-brain barrier permeability. Specifically, we revealed that Hcy can contribute to the onset and development of AD by facilitating the formation of amyloid-β aggregates, elucidating the intricate relationship between brain Hcy levels and AD progression. Furthermore, we investigated the effect of four licensed drugs on endogenous marker Hcy dynamics in cells and in mice with AD model. Our study provides a valuable molecular probe platform utilizing Hcy as a biomarker for supplementary diagnosis applications.}, }
@article {pmid39919551, year = {2025}, author = {Gangarde, P and Bhatt, S and Pujari, R}, title = {Assessment of neuroprotective potential of Cuscuta reflexa in aluminium chloride-induced experimental model of Alzheimer's disease: In vitro and in vivo studies.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {88}, number = {}, pages = {127612}, doi = {10.1016/j.jtemb.2025.127612}, pmid = {39919551}, issn = {1878-3252}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; *Aluminum Chloride ; *Neuroprotective Agents/pharmacology ; Rats ; *Cuscuta/chemistry ; *Plant Extracts/pharmacology/chemistry ; *Disease Models, Animal ; PC12 Cells ; Male ; Oxidative Stress/drug effects ; Rats, Wistar ; Maze Learning/drug effects ; }, abstract = {BACKGROUND & AIMS: Cuscuta reflexa (family Convolvulaceae), commonly known as giant dodder or Amarbel, is a parasitic plant that has garnered attention in pharmacological research due to its diverse bioactive compounds and potential therapeutic applications. Scientific studies have validated its traditional uses in folk medicine, highlighting its pharmacological activities. Alzheimer's Disease (AD) is a neurodegenerative disorder marked by the buildup of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) in the brain, leading to synaptic impairment and the gradual loss of neurons. Currently, no effective medication is available to treat the development and progression of the disease. Hence, there is a rising concern about using alternative therapy such as herbal medicine to limit the progression of AD and improve the quality of a patient's life with minimum side effects. The plant Cuscuta reflexa has traditionally been claimed to possess neuroprotective effects but has not yet been validated scientifically. The present study aimed to investigate the potential of the hydroalcoholic extract of Cuscuta reflexa (CRE) to ameliorate the neurodegenerative effect of aluminium chloride (AlCl3) using in vitro and in vivo studies.
METHODS: The neuroprotective activity of CRE was evaluated using in vitro and in vivo experimental models of AlCl3-induced AD.
RESULTS: The in vitro study showed that CRE markedly reduced AlCl3-induced cytotoxicity in PC12 cells. The in vivo study using the AlCl3-induced AD rat model showed that CRE treatment improved learning and memory, as evaluated using the open field test (OFT) and Morris water maze (MWM) test. CRE also showed the reduction in oxidative stress induced by AlCl3 in the brains of the rats by virtue of the significant decrease in oxidative stress biomarker malondialdehyde (MDA) and increase in the antioxidant parameters such as reduced glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD). Further, CRE exhibited its cholinergic activity by lowering the AlCl3-induced enhanced levels of acetylcholinesterase (AChE) in the brains of rats. Histopathological analysis of the brains of rats showed that CRE treatment prevented the reactive changes and the damage in the neuronal tissue caused due to the AlCl3.
CONCLUSION: Conclusively, CRE ameliorated AlCl3-induced neurobehavioural toxicity in the rat model of AD by virtue of its anti-inflammatory, antioxidant, cholinergic and neuroprotective effects which suggests its use in the treatment of progressive neural damage and cognitive deficits in AD patients.}, }
@article {pmid39919463, year = {2025}, author = {Ban, SY and Nam, Y and Do, TT and Kim, BH and Shin, SJ and Thi Nguyen, MT and Kim, J and Moon, M and Park, JT}, title = {Liver-X receptor β-selective agonist CE9A215 regulates Alzheimer's disease-associated pathology in a 3xTg-AD mouse model.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {184}, number = {}, pages = {117895}, doi = {10.1016/j.biopha.2025.117895}, pmid = {39919463}, issn = {1950-6007}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology/genetics ; *Liver X Receptors/agonists/metabolism ; *Disease Models, Animal ; Mice ; *Mice, Transgenic ; *Mice, Knockout ; *Mice, Inbred C57BL ; tau Proteins/metabolism ; Brain/metabolism/drug effects/pathology ; Male ; Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier/metabolism/drug effects ; Humans ; Signal Transduction/drug effects ; }, abstract = {In Alzheimer's disease (AD), tau pathology is closely associated with disease progression. Therefore, therapeutics that alleviate tau pathology are essential. Liver-X receptor (LXR) has garnered interest as a potential target for the treatment of AD. We previously investigated the potent anti-allergic and anti-inflammatory effects of inotodiol, hereafter referred to as CE9A215, in various disease models. In this study, we explored the potential of CE9A215 as a treatment for AD. CE9A215 preferentially activated LXRβ (EC50 <10 nM), with no significant activation observed for LXRα at concentrations up to 1000 nM. Pharmacokinetic analysis confirmed that CE9A215 crosses the blood-brain barrier and accumulates in the brain. Moreover, CE9A215 modulated the expression of ABCA1, APOE, SREBP-1c and AQP4 in the brains of wild-type and LXR α/β knockout mice in LXRβ-dependent manner. The efficacy of CE9A215 on AD-related pathologies was evaluated using 3xTg-AD mice. CE9A215 exerted both prophylactic and therapeutic effects on AD-associated behaviors and pathologies, including reductions in amyloid-β, phosphorylated tau, and neuroinflammation in the hippocampus. Transcriptomic analysis revealed that CE9A215 induced significant changes in genes associated with tau pathology, particularly in pathways related to protein phosphorylation and PI3K/AKT signaling. Our findings suggest that CE9A215 could be a promising therapeutic candidate for AD, particularly in mitigating tau hyperphosphorylation and related AD pathologies.}, }
@article {pmid39919076, year = {2025}, author = {Liu, N and Deng, Q and Peng, Z and Mao, D and Huang, Y and Meng, F and Zhang, X and Shen, J and Li, Z and Yan, W and Peng, J}, title = {Characterization of gene expression profiles in Alzheimer's disease and osteoarthritis: A bioinformatics study.}, journal = {PloS one}, volume = {20}, number = {2}, pages = {e0316708}, pmid = {39919076}, issn = {1932-6203}, mesh = {Humans ; *Osteoarthritis/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism ; *Computational Biology/methods ; *Protein Interaction Maps/genetics ; *Gene Expression Profiling ; Transcriptome ; Receptors, GABA/genetics/metabolism ; Gene Regulatory Networks ; Extracellular Matrix Proteins/genetics/metabolism ; Databases, Genetic ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) and Osteoarthritis (OA) have been shown to have a close association in previous studies, but the pathogenesis of both diseases are unclear. This study explores the potential common molecular mechanisms between AD and OA through bioinformatics analysis, providing new insights for clinical treatment strategies.
METHODS: The AD and OA-related datasets were downloaded from the gene expression database GEO. The datasets were analyzed to obtain differentially expressed gene (DEG) datasets for OA and AD, respectively. The intersection of these DEGs was analyzed to identify common DEGs (Co-DEGs). Subsequently, the Co-DEGs were enriched, and a protein-protein interaction network was constructed to identify core genes. The expression of these genes was validated in a separate dataset, and their diagnostic value for the diseases was analyzed. In addition, the core genes were analyzed using gene set enrichment analysis and single-gene genome variation analysis.
RESULTS: Analysis of DEGs on gene chips from OA and AD patients revealed significant changes in gene expression patterns. Notably, EFEMP2 and TSPO, genes associated with inflammatory responses, showed lower expression levels in both AD and OA patients, suggesting a downregulation in the pathological backgrounds of these diseases. Additionally, GABARAPL1, which is crucial for the maturation of autophagosomes, was found to be upregulated in both conditions. These findings suggest the potential of these genes as diagnostic biomarkers and potential therapeutic targets. However, to confirm the effectiveness of these genes as therapeutic targets, more in-depth mechanistic studies are needed in the future, particularly to explore the feasibility and specific mechanisms of combating disease progression by regulating the expression of these genes.
CONCLUSIONS: This study suggests that AD and OA shares common molecular mechanisms. The identification of EFEMP2, GABARAPL1, and TSPO as key target genes highlights potential common factors in both diseases. Further investigation into these findings could lead to new candidate targets and treatment directions for AD and OA, offering promising avenues for developing more effective and targeted therapeutic interventions.}, }
@article {pmid39918606, year = {2025}, author = {Cantone, AF and Burgaletto, C and Di Benedetto, G and Gaudio, G and Giallongo, C and Caltabiano, R and Broggi, G and Bellanca, CM and Cantarella, G and Bernardini, R}, title = {Rebalancing Immune Interactions within the Brain-Spleen Axis Mitigates Neuroinflammation in an Aging Mouse Model of Alzheimer's Disease.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {20}, number = {1}, pages = {15}, pmid = {39918606}, issn = {1557-1904}, support = {PNRR MAD-2022-12375802//Regione Sardegna, legge regionale 7 agosto 2007 n.7- promozione della ricerca scientifica e dell'innovazione tecnologica in Sardegna/ ; }, mesh = {Animals ; *Alzheimer Disease/immunology/metabolism/pathology ; Mice ; *Brain/immunology/metabolism/pathology ; *Mice, Transgenic ; *Spleen/immunology/metabolism ; *Disease Models, Animal ; *Neuroinflammatory Diseases/immunology ; *Aging/immunology ; Mice, Inbred C57BL ; Male ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia worldwide, characterized by accumulation of amyloid-β protein and hyperphosphorylated tau protein in the brain. Neuroinflammation, resulting from chronic activation of brain-resident innate immune cells as well as enhanced peripheral leukocyte access across the blood-brain barrier, crucially affects AD progression. In this context, TNFSF10, a cytokine substantially expressed in the AD brain, has been shown to modulate both the innate and the adaptive branches of the immune response in AD-related neuroinflammation. In this study, we explored whether a TNFSF10-neutralizing treatment could represent a tool to re-balance the overall overshooting inflammatory response in a mouse model of AD. Specifically, 3xTg-AD mice were treated sub-chronically with an anti-TNFSF10 monoclonal antibody for three months, and were then sacrificed at 15 months. TNFSF10 neutralization reduced the expression of the inflammatory marker CD86, inversely related to levels of the anti-inflammatory marker CD206 in the brain of 3xTg-AD mice, suggesting a switch of microglia towards a neuroprotective phenotype. Similar results were observed in the splenic macrophage population. Moreover, flow cytometry revealed a significant decrease of CD4[+]CD25[+]FOXP3[+] T regulatory cells as well as reduced number of CD11b[+]LY6C[high] proinflammatory monocytes in both the brain and the spleen of 3xTg-AD mice treated with anti-TNFSF10 monoclonal antibody. Finally, the treatment resulted in lower count of splenic CD4[+] and CD8[+] T cells expressing PD1. The data suggest that TNFSF10 system-targeted treatment effectively restrain overshooting central and peripheral inflammation by rebalancing the overall immune response, mitigating the progression of AD pathology.}, }
@article {pmid39918090, year = {2025}, author = {Lee, H and Chater, JM and Heinitz, CC and Wang, Y}, title = {Evaluation of metabolite profiles and neuroprotective potential in four pomegranate cultivars for Alzheimer's disease prevention.}, journal = {Journal of the science of food and agriculture}, volume = {}, number = {}, pages = {}, doi = {10.1002/jsfa.14176}, pmid = {39918090}, issn = {1097-0010}, support = {//Agricultural Marketing Service/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss, with oxidative stress and neuroinflammation playing crucial roles in its progression. Current treatments, such as acetylcholinesterase (AChE) inhibitors, offer limited symptomatic relief and can have side effects. With growing interest in functional foods that have fewer side effects, pomegranate (Punica granatum L.) has gained attention because of its rich antioxidant content. The present study aims to evaluate the antioxidant and neuroprotective effects of four pomegranate cultivars: 'Wonderful', 'Phoenicia', 'Azadi' and 'Eversweet'. Additionally, it investigates their metabolite profiles and predicts potential bioactive compounds that could help prevent AD.
RESULTS: The 'Wonderful' cultivar demonstrated the highest levels of total phenolic content, total flavonoid content, total anthocyanin content and radical scavenging activities. The AChE and butyrylcholinesterase (BuChE) inhibition rates were highest in 'Phoenicia' and 'Wonderful' cultivars, suggesting potential neuroprotective effects. PC12 cell assays indicated that these cultivars significantly improved cell viability, reduced reactive oxygen species and malondialdehyde levels, and also enhanced catalase activity. Metabolomics analysis identified 141 metabolites, with the 'Wonderful' cultivar showing the highest metabolite abundance. Molecular docking studies indicated that some metabolites, such as taxifolin, demonstrated strong binding affinities for AChE and BuChE, suggesting potential for AD treatment.
CONCLUSION: The 'Wonderful' and 'Phoenicia' cultivars demonstrated the most promising antioxidant and neuroprotective effects among the evaluated pomegranates, likely because of their high taxifolin content. These findings suggest that these cultivars could be valuable for developing functional foods aimed at AD prevention and treatment. © 2025 Society of Chemical Industry.}, }
@article {pmid39917595, year = {2025}, author = {Zhang, Y and Deng, Z and Seaman, J and Koleck, TA}, title = {Thinking About It All Together: A Descriptive Analysis to Understand Comorbidities in People Living With Dementia.}, journal = {Health science reports}, volume = {8}, number = {2}, pages = {e70449}, pmid = {39917595}, issn = {2398-8835}, support = {OT2 OD026556/OD/NIH HHS/United States ; U2C OD023196/OD/NIH HHS/United States ; OT2 OD025315/OD/NIH HHS/United States ; OT2 OD026551/OD/NIH HHS/United States ; U24 OD023121/OD/NIH HHS/United States ; OT2 OD026552/OD/NIH HHS/United States ; OT2 OD026549/OD/NIH HHS/United States ; OT2 OD025337/OD/NIH HHS/United States ; OT2 OD025277/OD/NIH HHS/United States ; OT2 OD026555/OD/NIH HHS/United States ; OT2 OD026550/OD/NIH HHS/United States ; OT2 OD026553/OD/NIH HHS/United States ; OT2 OD023205/OD/NIH HHS/United States ; OT2 OD025276/OD/NIH HHS/United States ; OT2 OD026557/OD/NIH HHS/United States ; OT2 OD026554/OD/NIH HHS/United States ; U24 OD023163/OD/NIH HHS/United States ; OT2 OD023206/OD/NIH HHS/United States ; U24 OD023176/OD/NIH HHS/United States ; OT2 OD026548/OD/NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: The prevalence of Alzheimer's disease and related dementia (ADRD) is on the rise. There is a corresponding escalation in the number of persons living with dementia who require complex, longitudinal support in care due to the progressive declines in cognitive and clinical profiles of persons living with dementia when delivering individualized person-centered care that promotes overall health and well-being. Hence, we aim to describe the presence and patterns of co-occurring comorbidities in persons living with dementia.
METHODS: This study is a retrospective, cross-sectional descriptive analysis based on curated electronic health record data from the All of Us Research Program from October 1, 2015, to June 30, 2022. We included individuals who were 65 years of age or older with at least one dementia-related diagnosis. We categorized 14 comorbidities by the Charlson Comorbidity Index, and defined all diseases based on the International Classification of Diseases Tenth Revision Diagnosis codes. We employed descriptive statistics and visualized data with UpSet Plots. Demographic characteristics (i.e., age, sex, race, and ethnicity) between people with and without co-occurring comorbidities were compared with either chi-square or Wilcoxon signed-rank tests.
RESULTS: Persons living with dementia (N = 4003) were a mean of 73 years old, 72.5% non-Hispanic White, and 47.5% female. Approximately 87% of persons living with dementia were diagnosed with at least one additional comorbidity. The most common comorbidities included diabetes (67.82%), renal disease (40.24%), chronic pulmonary disease (39.85%), congestive heart failure (37.37%), and peripheral vascular disease (34.57%). Heterogeneous patterns of co-occurring comorbidity were noted among persons living with dementia.
CONCLUSION: Our study demonstrates the high prevalence of co-occurring comorbid illness among persons living with dementia. It is critical that the impact of these co-occurring conditions on patients' disease trajectories be better understood to promote treatment choices that are person-centered and goal-concordant.}, }
@article {pmid39915859, year = {2025}, author = {Putcha, D and Katsumi, Y and Touroutoglou, A and Eloyan, A and Taurone, A and Thangarajah, M and Aisen, P and Dage, JL and Foroud, T and Jack, CR and Kramer, JH and Nudelman, KNH and Raman, R and Vemuri, P and Atri, A and Day, GS and Duara, R and Graff-Radford, NR and Grant, IM and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, S and Turner, RS and Wingo, TS and Wolk, DA and Womack, K and Carrillo, MC and Rabinovici, GD and Dickerson, BC and Apostolova, LG and Hammers, DB and , }, title = {Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer's disease: a neuropsychological data-driven approach.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {38}, pmid = {39915859}, issn = {1758-9193}, support = {R56 AG057195/AG/NIA NIH HHS/United States ; K23 AG065450/NH/NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; R01 AG075802/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; U01AG6057195/NH/NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/psychology ; Female ; Male ; *Neuropsychological Tests ; *Phenotype ; Middle Aged ; *Magnetic Resonance Imaging ; Atrophy ; Aged ; Age of Onset ; Longitudinal Studies ; Cerebral Cortex/pathology/diagnostic imaging ; Cohort Studies ; }, abstract = {BACKGROUND: The clinical presentations of early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort.
METHODS: Neuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of impairment between each cognitive domain, we applied a cut-off of 1 SD below all other domain scores to indicate a phenotype of "predominant" impairment in a given cognitive domain. Individuals were otherwise considered to have multidomain impairment. Whole-cortex general linear modeling of cortical atrophy was applied as an MRI-based validation of these distinct clinical phenotypes.
RESULTS: We identified 6 phenotypic subtypes of EOAD: Dysexecutive Predominant (22% of sample), Amnestic Predominant (11%), Language Predominant (11%), Visuospatial Predominant (15%), Mixed Amnestic/Dysexecutive Predominant (11%), and Multidomain (30%). These phenotypes did not differ by age, sex, or years of education. The APOE ɛ4 genotype was enriched in the Amnestic Predominant group, who were also rated as least impaired. Cortical thickness analysis validated these clinical phenotypes with dissociations in atrophy patterns observed between the Dysexecutive and Amnestic Predominant groups. In contrast to the heterogeneity observed from our neuropsychological data-driven approach, diagnostic classifications for this same sample based solely on clinical judgment indicated that 82% of individuals were amnestic-predominant, 9% were non-amnestic, 4% met criteria for Posterior Cortical Atrophy, and 5% met criteria for Primary Progressive Aphasia.
CONCLUSION: A neuropsychological data-driven method to phenotype EOAD individuals uncovered a more detailed understanding of the presenting heterogeneity in this atypical AD sample compared to clinical judgment alone. Clinicians and patients may over-report memory dysfunction at the expense of non-memory symptoms. These findings have important implications for diagnostic accuracy and treatment considerations.}, }
@article {pmid39915222, year = {2025}, author = {Guan, T and Shang, L and Yang, P and Tan, Z and Liu, Y and Dong, C and Li, X and Hu, Z and Su, H and Zhang, Y}, title = {Joint ensemble learning-based risk prediction of Alzheimer's disease among mild cognitive impairment patients.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {4}, pages = {100083}, doi = {10.1016/j.tjpad.2025.100083}, pmid = {39915222}, issn = {2426-0266}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; *Alzheimer Disease/diagnosis ; Female ; Male ; Aged ; Risk Assessment/methods ; Proportional Hazards Models ; Machine Learning ; Algorithms ; Aged, 80 and over ; }, abstract = {OBJECTIVE: Due to the recognition for the importance of early intervention in Alzheimer's disease (AD), it is important to focus on prevention and treatment strategies for mild cognitive impairment (MCI). This study aimed to establish a risk prediction model for AD among MCI patients to provide clinical guidance for primary medical institutions.
METHODS: Data from MCI subjects were obtained from the NACC. Importance ranking and the SHapley Additive exPlanations (SHAP) method for the Random Survival Forest (RSF) and Extreme Gradient Boosting (XGBoost) algorithms in ensemble learning were adopted to select the predictors, and hierarchical clustering analysis was used to mitigate multicollinearity. The RSF, XGBoost and Cox proportional hazard regression (Cox) models were established to predict the risk of AD among MCI patients. Additionally, the effects of the three models were evaluated.
RESULTS: A total of 3674 subjects with MCI were included. Thirteen predictors were ultimately identified. In the validation set, the concordance indices were 0.781 (RSF), 0.781 (XGBoost), and 0.798 (Cox), and the Integrated Brier Score was 0.087 (Cox). The prediction effects of the XGBoost and RSF models were not better than those of the Cox model.
CONCLUSION: The ensemble learning method can effectively select predictors of AD risk among MCI subjects. The Cox proportional hazards regression model could be used in primary medical institutions to rapidly screen for the risk of AD among MCI patients once the model is fully clinically validated. The predictors were easy to explain and obtain, and the prediction of AD was accurate.}, }
@article {pmid39914702, year = {2025}, author = {Geng, F and Zhao, N and Ren, Q}, title = {Circadian rhythm, microglia-mediated neuroinflammation, and Alzheimer's disease.}, journal = {Neuroscience and biobehavioral reviews}, volume = {170}, number = {}, pages = {106044}, doi = {10.1016/j.neubiorev.2025.106044}, pmid = {39914702}, issn = {1873-7528}, mesh = {*Alzheimer Disease/immunology/physiopathology/pathology/metabolism ; Humans ; *Circadian Rhythm/physiology ; *Microglia/immunology/metabolism ; Animals ; *Neuroinflammatory Diseases/immunology/physiopathology ; Brain/immunology/physiopathology/pathology/metabolism ; }, abstract = {Microglia, the brain's resident macrophages, are key mediators of neuroinflammation, responding to immune pathogens and toxins. They play a crucial role in clearing cellular debris, regulating synaptic plasticity, and phagocytosing amyloid-β (Aβ) plaques in Alzheimer's disease (AD). Recent studies indicate that microglia not only exhibit intrinsic circadian rhythms but are also regulated by circadian clock genes, influencing specific functions such as phagocytosis and the modulation of neuroinflammation. Disruption of the circadian rhythm is closely associated with AD pathology. In this review, we will provide an overview of how circadian rhythms regulate microglia-mediated neuroinflammation in the progression of AD, focusing on the pathway from the central nervous system (CNS) and the peripheral immune system. We also discuss potential therapeutic targets, including hormone modulation, lifestyle interventions, and anti-inflammatory therapies, aimed at maintaining brain health in AD. This will shed light on the involvement of circadian rhythm in AD and explore new avenues for AD treatment.}, }
@article {pmid39914573, year = {2025}, author = {Hatakawa, Y and Tanaka, A and Furubayashi, T and Katsumi, H and Nakamura, R and Konishi, M and Akizawa, T and Sakane, T}, title = {Efficient nose-to-brain delivery of nine residues peptide (JAL-TA9) exhibiting hydrolytic activity against amyloid-β.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {208}, number = {}, pages = {114661}, doi = {10.1016/j.ejpb.2025.114661}, pmid = {39914573}, issn = {1873-3441}, mesh = {Animals ; *Administration, Intranasal ; *Amyloid beta-Peptides/metabolism/administration & dosage ; Rats ; Mice ; *Brain/metabolism/drug effects ; Male ; Blood-Brain Barrier/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Rats, Sprague-Dawley ; Hydrolysis ; Peptide Fragments/administration & dosage/pharmacokinetics ; Drug Delivery Systems/methods ; Tissue Distribution ; Injections, Intravenous ; Half-Life ; }, abstract = {JAL-TA9 (YKGSGFRMI), is a 9-residue catalytic peptide that cleaves amyloid β (Aβ) 42. Nasal administration was chosen to bypass the blood-brain barrier for efficient brain delivery of JAL-TA9 to treat Alzheimer's disease (AD). Plasma clearance of JAL-TA9 after intravenous bolus injection in rats was very rapid, with a half-life of <1 min. The stability of JAL-TA9 in cerebrospinal fluid (CSF) was much better than that in plasma and whole blood in vitro, suggesting the advantage of direct nasal delivery to avoid rapid elimination from the blood. JAL-TA9 in CSF was 0.115 μg/mL 10 min after nasal administration to rats, but below the detection limit after intravenous injection, indicating a significant direct delivery of JAL-TA9 to the brain. In mice brain, JAL-TA9 concentration was higher after nasal administration than that after intraperitoneal administration. Additionally, peak concentration in the olfactory bulb (OB) after nasal application was at 5 min, whereas in the frontal and occipital brains peaked at 30 and 60 min, respectively, suggesting sequential backward translocation of JAL-TA9 within the brain after direct transport from the nasal cavity to the OB. Therefore, nasal administration allows the efficient delivery of JAL-TA9 to the brain and may be a potential in AD treatment.}, }
@article {pmid39914538, year = {2025}, author = {Cai, M and Zhang, X and Gao, X and Huo, Q and Sun, Y and Dai, X}, title = {Chitooligosaccharide ameliorates cognitive deficits and neuroinflammation in APP/PS1 mice associated with the regulation of Nrf2/NF-κB axis.}, journal = {International journal of biological macromolecules}, volume = {303}, number = {}, pages = {140683}, doi = {10.1016/j.ijbiomac.2025.140683}, pmid = {39914538}, issn = {1879-0003}, mesh = {Animals ; *NF-E2-Related Factor 2/metabolism/genetics ; Mice ; *NF-kappa B/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Chitosan/pharmacology ; *Oligosaccharides/pharmacology ; *Signal Transduction/drug effects ; *Microglia/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Protein Precursor/metabolism/genetics ; Mice, Transgenic ; Disease Models, Animal ; Chitin/analogs & derivatives/pharmacology ; Humans ; Lipopolysaccharides/adverse effects ; Presenilin-1/genetics/metabolism ; Male ; Inflammation/drug therapy/metabolism ; }, abstract = {Mounting evidence suggests that neuroinflammation is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Amyloid β peptide (Aβ) could recruit and activate microglia, leading to the generation of pro-inflammatory factors, and ultimately neuroinflammation. Chitooligosaccharide (COS) is widely recognized as anti-inflammation bioactive substance, though whether it exerts beneficial effect on AD is unclear. In this study, we explored the effect of COS on AD prevention and treatment. We found that COS ameliorated cognitive deficiency, increased the expression of Nrf2 but decreased Aβ levels and the activation of NF-κB in APP/PS1 mice. In vitro, COS decreased the secretions of IL-6, IL-1β and TNF-α in Aβ25-35 + lipopolysaccharides (LPS) -exposed BV2 microglia. Meanwhile, COS down-regulated the expressions of iNOS, COX-2, NLRP3, caspase 1 and the nuclear translocation of NF-κB p65, while upregulated the expressions of Nrf2 and HO-1. Further, COS improved the viability of SK-N-SH cells that exposed to Aβ25-35 + LPS-stimulated microglial conditioned media, and the repressive effect of COS on NLRP3, iNOS, and phospho-NF-κB p65 expressions were markedly compromised upon Nrf2-siRNA transfection. Collectively, COS improved cognitive decline and suppressed neuroinflammation via the Nrf2/NF-κB signaling axis, suggesting COS might be a promising candidate in down-regulating inflammatory responses during AD progression.}, }
@article {pmid39914536, year = {2025}, author = {Song, D and Gui, F and Li, G and Zhuang, S and Sun, J and Tan, X and Hong, C and Huang, J}, title = {Neuritin improves cognitive impairments in APP/PS1 Alzheimer's disease mice model by mitigating neuronal ferroptosis via PI3K/Akt activation.}, journal = {International journal of biological macromolecules}, volume = {303}, number = {}, pages = {140662}, doi = {10.1016/j.ijbiomac.2025.140662}, pmid = {39914536}, issn = {1879-0003}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Ferroptosis/drug effects ; *Proto-Oncogene Proteins c-akt/metabolism ; *Disease Models, Animal ; *Phosphatidylinositol 3-Kinases/metabolism ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism ; *GPI-Linked Proteins/metabolism ; *Neurons/drug effects/metabolism ; *Hippocampus/drug effects/metabolism ; Neuropeptides/pharmacology/metabolism ; Oxidative Stress/drug effects ; Male ; Signal Transduction/drug effects ; Mice, Transgenic ; Amyloid beta-Protein Precursor/metabolism ; Presenilin-1/genetics ; Nerve Tissue Proteins ; }, abstract = {The neurotrophic factor Neuritin is known to enhance cognitive capacity and to mitigate synaptic impairments in the APP/PS1 Alzheimer's disease (AD) mouse model, suggesting therapeutic potential for clinical treatment. However, the core molecular mechanisms remain elusive. Ferroptosis, a form of programmed cell death linked to iron dysregulation and oxidative stress, contributes to neurodegeneration in AD in part by accelerating amyloid-β deposition and neurofibrillary tangle formation. Here we examined if Neuritin can mitigate cognitive decline and neural degeneration in AD model mice by suppressing ferroptosis. Age-dependent cognitive decline was associated with Neuritin downregulation and increased ferroptosis in the hippocampus. Intracerebroventricular injection of exogenous Neuritin mitigated spatial and fear learning deficits as well as neural oxidative stress, apoptosis, and ferroptosis in the hippocampus without causing deleterious side effects. Neuritin injection also upregulated the activity of NAD+ kinase (NADK), the enzyme responsible for converting NAD to anti-ferroptotic NADPH, in the hippocampus of AD mice as well as in cultured hippocampal neurons. Reduced Neuritin expression in the hippocampus AD mice was associated with reduced phosphorylation (activation) of Akt (p-Akt), and Neuritin administration enhanced p-Akt expression in both HT22 cells and AD model mice. Conversely, blocking the PI3K/Akt pathway in HT22 cells reversed the Neuritin-induced increase in NADK activity and reduction in ferroptosis, indicating that Neuritin protects neurons from AD-induced damage by enhancing NADK activity through the PI3K/Akt pathway. Collectively, our results support Neuritin upregulation as a potential therapeutic strategy for early-phase AD.}, }
@article {pmid39914200, year = {2025}, author = {Madhagi, HA and Nassar, H}, title = {Harnessing network pharmacology and in silico drug discovery to uncover new targets and therapeutics for Alzheimer's disease.}, journal = {Computers in biology and medicine}, volume = {187}, number = {}, pages = {109781}, doi = {10.1016/j.compbiomed.2025.109781}, pmid = {39914200}, issn = {1879-0534}, mesh = {*Alzheimer Disease/drug therapy/metabolism/genetics ; Humans ; *Drug Discovery ; *RNA, Circular/genetics/metabolism ; Network Pharmacology ; Computer Simulation ; RNA, Messenger/genetics/metabolism ; MicroRNAs/genetics/metabolism ; }, abstract = {Alzheimer's disease (AD) is the leading cause of progressive neurodegenerative dementia, affecting approximately 50 million individuals globally. Recent studies have highlighted the differential expression of circular RNAs (circRNAs) in AD, which may disrupt the circRNA-miRNA-mRNA regulatory networks in neuronal cells. This work aims to integrate network pharmacology with in silico drug design to identify novel druggable targets for AD and propose promising drug candidates. We analyzed two circRNA datasets from the Gene Expression Omnibus, employing enrichment analysis and constructing a circRNA-miRNA-mRNA network. The RNAenrich platform facilitated the identification of hub genes and potential druggable targets. The identified target was subjected to virtual screening against a chemical drug library comprising over 6000 compounds in clinical trials while ensuring compliance with Lipinski's Rule of Five. Our findings reveal that differentially expressed circRNAs are significantly involved in gland development, apoptosis regulation, hypoxic response, and neuronal death. Notably, CDK-6 emerged as the most promising druggable target, exhibiting strong binding affinity with five selected ligands: DB06963, DB06888, DB07020, DB08683, and DB06976. These ligands demonstrated distinct binding modes and stable interactions over 500 ns of molecular dynamics simulations conducted via Desmond. In conclusion, our study identifies CDK-6 as a viable target for therapeutic intervention in Alzheimer's disease. The top five ligands present a compelling case for further investigation as innovative CDK-6 inhibitors and potential drug candidates for AD treatment.}, }
@article {pmid39912605, year = {2025}, author = {Zhang, C and Ye, Y and Wang, W and Wang, C and Gao, P and Wan, P}, title = {Effects of Lingzhi or Reishi Medicinal Mushroom Ganoderma lucidum (Agaricomycetes) Triterpene on Motor and Spatial Learning Disorders in 5xFAD Mice.}, journal = {International journal of medicinal mushrooms}, volume = {27}, number = {4}, pages = {21-37}, doi = {10.1615/IntJMedMushrooms.2024057835}, pmid = {39912605}, issn = {1940-4344}, mesh = {Animals ; *Triterpenes/pharmacology ; Mice ; *Reishi/chemistry ; *Alzheimer Disease/drug therapy ; Spatial Learning/drug effects ; Disease Models, Animal ; Male ; Memory/drug effects ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that gradually destroys cognitive, memory, and thinking skills. Although increasing evidence has demonstrated that Ganoderma lucidum triterpenoids (GLT) can ameliorate the motor and spatial learning disorders of AD, the underlying mechanism remains unclear. Hence, in this study, GLT were obtained by using a traditional Chinese medicine processing method, and then the effects of GLT on motor and spatial learning disorders in 5xFAD mice were investigated by using various techniques such as behavioral analysis, micro-dialysis, and neurophysiological recording. Compared with the 5xFAD group, 0.5 g/kg GLT could decrease escape latency, the total number of limb errors, and the duration of errors. This dose could also increase the number of crossing the original platform, the total movement time, and the distance in the central region of the open-field box, as well as the maximum movement speed and continuous movement time on the rotating rod. After GLT treatment, the glutamate (Glu) content and variation coefficient of a simple spike of Purkinje cells decreased compared with the 5xFAD group, thereby improving the spatial learning and memory ability. Overall, this study shows that GLT may be a potential therapeutic method for patients with AD.}, }
@article {pmid39912369, year = {2025}, author = {Wolner, SH and Gleerup, HS and Musaeus, CS and Høgh, P and Ashton, NJ and Brinkmalm, A and Nilsson, J and Grötschel, L and Zetterberg, H and Blennow, K and Hasselbalch, SG and Walls, AB and Simonsen, AH}, title = {Synaptosomal-Associated Protein 25 kDA (SNAP-25) Levels in Cerebrospinal Fluid: Implications for Alzheimer's Disease Diagnosis and Monitoring.}, journal = {Synapse (New York, N.Y.)}, volume = {79}, number = {2}, pages = {e70010}, pmid = {39912369}, issn = {1098-2396}, support = {//Kirsten and Freddy Johansen Foundation/ ; //Fondation pour la Recherche sur Alzheimer/ ; //Swedish Alzheimer Foundation/ ; //UK Dementia Research Institute/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; //European Union Joint Programme - Neurodegenerative Disease Research/ ; //European Union's Horizon 2020 research and innovation programme/ ; //Hjärnfonden/ ; //Stiftelsen för Gamla Tjänarinnor/ ; //Familjen Rönströms Stiftelse/ ; //Familjen Erling-Perssons Stiftelse/ ; //Olav Thon Stiftelsen/ ; //Cure Alzheimer's Fund/ ; //Bluefield Project/ ; //AD Strategic Fund/ ; //Alzheimer's Drug Discovery Foundation/ ; //European Union's Horizon Europe/ ; //Swedish Research Council/ ; //Absalon Foundation/ ; }, mesh = {*Synaptosomal-Associated Protein 25/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Humans ; Aged ; Female ; Male ; Middle Aged ; *Biomarkers/cerebrospinal fluid ; Retrospective Studies ; Cognitive Dysfunction/cerebrospinal fluid/diagnosis ; tau Proteins/cerebrospinal fluid ; Prospective Studies ; Aged, 80 and over ; }, abstract = {Synaptic degeneration has been linked to cognitive decline. The presynaptic protein, synaptosomal-associated protein 25 kDA (SNAP-25), is crucial for synaptic transmission and has been suggested as a biomarker in Alzheimer's disease (AD). In the current study, we investigated the ability of SNAP-25 to differentiate between heterogenous dementia etiologies and whether SNAP-25 could be a staging marker in AD. SNAP-25 in the cerebrospinal fluid (CSF) from a retrospective (n = 187) and a prospective (n = 134) cohort was investigated with immunoprecipitation mass spectrometry (IP-MS) and single-molecule array (Simoa), respectively. Both cohorts consisted of healthy controls (HC) and patients with cognitive decline of different etiologies. CSF SNAP-25 concentration was higher in AD and non-neurodegenerative diseases (i.e., vascular dementia) compared with controls but did not differ between AD and non-AD neurodegenerative diseases. We found a trend toward an association between SNAP-25 and disease burden when comparing HC, mild cognitive impairment due to AD, and AD. CSF SNAP-25 concentrations were strongly associated with CSF phosphorylated tau (p-tau) concentrations, thus strengthening the link between synaptic dysfunction and tau pathophysiology in AD. Our initial findings suggest that SNAP-25 may be a potential biomarker for differentiating AD from dementia due to other etiologies. However, due to the significant association between SNAP-25 and p-tau proteins, the clinical utility of SNAP-25 as a diagnostic biomarker for AD may be limited, while SNAP-25 may be useful for monitoring disease progression or treatment response.}, }
@article {pmid39911544, year = {2025}, author = {Pakhariya, RP and Bhatnagar, A and Pemawat, G}, title = {Quinoline analogs: multifaceted heterocyclic compounds with varied synthetic strategies and potent antitubercular properties.}, journal = {RSC advances}, volume = {15}, number = {5}, pages = {3646-3663}, pmid = {39911544}, issn = {2046-2069}, abstract = {Tuberculosis cases have continuously increased by 64% over the last nine years, from 2014 to 2023. Approximately 33% of the global population is affected by TB. It is a bacterial disease, and Mycobacterium tuberculosis is the most common bacteria that affects the lungs of human beings during the infection. Other hazardous bacterial species causing tuberculosis are M. pinnipedii, M. canettii, M. caprae, M. bovis, M. africanum, and M. microti. TB symptoms in TB-infected patients include fever, chest pain, weight loss, and fatigue. Depending on the stage of infection, the treatment for TB can take approximately six months to two years. Quinoline comprises a pyridine ring fused with a benzene ring, and both these rings share two adjacent carbon atoms and can take part in electrophilic substitution reactions. Quinoline-based heterocyclic compounds are attracting substantial interest owing to their vital role as a class of synthetic and natural molecules. Quinoline and its derivatives display various biological activities, including anti-TB, anticonvulsant, antibiotic, antifungal, antimalarial, antipsychotic, antihypertensive, antileishmanial, antioxidant, tyrosine kinase inhibitory, anti-inflammatory, anticancer, anti-asthmatic, cardiotonic, anthelmintic, antiprotozoal, anti-HIV, and anti-Alzheimer effects. Some fused analogs of quinoline, such as graveolinine, ciprofloxacin, kokusaginine, bedaquiline, levofloxacin, moxifloxacin, and mefloquine, are commercially available as antitubercular drugs. There are various methods available to synthesize quinoline-containing antitubercular drugs. In this review paper, we present three types of synthetic methods in which substituted quinolines, substituted anilines, and miscellaneous starting materials are used and outline MIC values for all the synthesized compounds to signify their anti-TB activity.}, }
@article {pmid39911331, year = {2025}, author = {Yi, Y and Kim, B and Kim, M and Ko, YH and Kim, JH and Lim, MH}, title = {Zn(ii)-driven impact of monomeric transthyretin on amyloid-β amyloidogenesis.}, journal = {Chemical science}, volume = {16}, number = {10}, pages = {4366-4373}, pmid = {39911331}, issn = {2041-6520}, abstract = {Extracellular accumulation of amyloid-β (Aβ) peptides in the brain plays a significant role in the development of Alzheimer's disease (AD). While the co-localization and interaction of proteins and metal ions with Aβ in extracellular milieu are established, their precise pathological associations remain unclear. Here we report the impact of Zn(ii) on the anti-amyloidogenic properties of monomeric transthyretin (M-TTR), which coexists spatially with Aβ and Zn(ii) in extracellular fluids. Our findings demonstrate the Zn(ii)-promoted ternary complex formation involving M-TTR, Aβ, and Zn(ii) as well as M-TTR's proteolytic activity towards Aβ. These interactions decrease the inhibitory effect of M-TTR on the primary nucleation process of Aβ as well as its ability to improve cell viability upon treatment of Aβ. This study unveils the variable activities of M-TTR towards Aβ, driven by Zn(ii), providing insights into how metal ions influence the entanglement of M-TTR in the Aβ-related pathology linked to AD.}, }
@article {pmid39910867, year = {2025}, author = {Guo, R and Li, D and Li, F and Ji, L and Liu, H and Qiao, H and Lv, Z and Tang, Y and Wang, D}, title = {Effects of whole-head 810 nm near-infrared therapy on cognitive and neuropsychiatric symptoms in Alzheimer's disease: A pilot study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {104}, number = {1}, pages = {52-60}, doi = {10.1177/13872877251313819}, pmid = {39910867}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Pilot Projects ; Male ; Female ; Aged ; Treatment Outcome ; Aged, 80 and over ; Neuropsychological Tests ; Cognition/physiology ; Infrared Rays/therapeutic use ; Mental Status and Dementia Tests ; Middle Aged ; }, abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by significant cognitive and behavioral impairments. Near-infrared (NIR) light treatment has shown potential in cognitive improvement in previous studies. However, clinical trials of NIR for AD remain limited.ObjectiveThis study investigated the safety and effects of whole-head 810 nm NIR therapy in AD patients, including long-term efficacy.MethodsAn open-label pilot study on whole-head NIR treatment for AD patients was conducted. Nine AD patients completed 4-month treatment (810 nm, 100 mW/cm[2], 30 min/session, 6 sessions weekly). Safety and efficacy were evaluated at baseline, months 2 and 4, and 2-month post-treatment.ResultsAfter four months of whole-head NIR treatment, mean changes from baseline on the Mini-Mental State Examination were 3.2 (p = 0.02). Mean changes from baseline on the Alzheimer's Disease Assessment Scale-Cognitive were -5.0 (p = 0.05), mean changes from baseline on the Montreal Cognitive Assessment were 1.9 (p = 0.12). Mean changes from baseline on the Neuropsychiatric Inventory were -4.2 (p = 0.47). These benefits were sustained two months at least. With no device-related adverse effects were reported.ConclusionsWhole-head 810 nm NIR light is safe and offers promising benefits for AD patients. To fully confirm its efficacy, durability, and underlying mechanisms, further large-scale randomized controlled trials are necessary.}, }
@article {pmid39910679, year = {2025}, author = {Han, G and Xuewu, G and Meng, Z and Yuejing, W and Yuchun, W and Keshuang, Z and Hongbo, Y}, title = {Therapeutic effect of dihydroartemisinin on Alzheimer's disease model mice with senile macular degeneration.}, journal = {European journal of medical research}, volume = {30}, number = {1}, pages = {81}, pmid = {39910679}, issn = {2047-783X}, support = {LH2021H122//Natural Science Foundation of Heilongjiang Province of China/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Artemisinins/pharmacology/therapeutic use ; Mice ; *Disease Models, Animal ; *Molecular Docking Simulation ; Macular Degeneration/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Autophagy/drug effects ; Male ; Maze Learning/drug effects ; Donepezil/pharmacology/therapeutic use ; }, abstract = {OBJECTIVES: This study focuses on the preventive and therapeutic effects of Dihydroartemisinin (DHA) on Alzheimer's disease (AD) model mice and the effects of DHA and donepezil on amyloid β-protein deposition and autophagy in nerve cells.
METHODS: Six autophagy related targets were selected for molecular docking with DHA to predict the affinity between DHA and the target. The AD mouse model was established and treated with donepezil and DHA, respectively. Morris water maze was used to detect the spatial learning and memory ability of AD mice. Hematoxylin eosin (he) staining was used to observe the structural changes of cerebral cortical neurons and retina, and transmission electron microscope was used to observe the structural changes of mitochondria and synapses. Immunohistochemistry (IHC) and immunofluorescence staining were used to detect the deposition of amyloid beta protein. Western blot was used to detect the expression of apoptosis and autophagy related proteins in the brain tissue of mice in each group.
RESULTS: The results of molecular docking showed that the selected active compounds had good binding activity with the target. The binding energy between DHA and Aβ, Bcl-2, ATG5, LC3, Caspase3, LAMP1 is -5.7, -7.0, -5.8, -7.2, -6.9 kcal/mol. The water maze test showed that compared with the wild type (WT) group, the spatial memory ability of AD model group mice (5× FAD) was significantly decreased, and the search time (27.62 ± 6.51 s vs. 282.80 ± 17.15 s) and average path (106.30 ± 29.65 cm vs. 993.20 ± 135.80 cm) were significantly prolonged. The application of donepezil and DHA significantly shortened the exploration time and average path (donepezil: 116.10 ± 10.58 s, 529.40 ± 106.00 cm; DHA: 99.71 ± 14.22 s, 373.30 ± 60.97 cm). The path to find the platform in DHA treatment group was shorter than donepezil treatment group (P < 0.05). HE staining showed that the arrangement of nerve cells in 5× FAD mice was disordered, and IHC showed that amyloid β-protein deposition was obvious. DHA and donepezil could improve the damage of cerebral cortex structure and reduce the deposition of extracellular amyloid β-protein in AD mice. Transmission electron microscopy showed that DHA and donepezil could reduce mitochondrial vacuolation and synaptic edema. The above results showed that DHA treatment effect was better than donepezil. Compared with the conventional feeding group, autophagy and apoptosis related proteins B-cell lymphoma-2 (BCL2) and anti-thymocyte globulin (ATG) were significantly down regulated in the 5× FAD group, and the expressions of BCL2 and ATG were increased after treatment with DHA and donepezil.
CONCLUSIONS: DHA combined with BCL2 and ATG protein, through promoting autophagy protein, can reduce the damage of cerebral cortex structure in AD mice, reduce the deposition of extracellular β-amyloid protein, and then improve the memory ability of AD model mice. DHA treatment is superior to donepezil monotherapy.}, }
@article {pmid39910616, year = {2025}, author = {Lee, BH and Cevizci, M and Lieblich, SE and Galea, LAM}, title = {Sex-specific influences of APOEε4 genotype on hippocampal neurogenesis and progenitor cells in middle-aged rats.}, journal = {Biology of sex differences}, volume = {16}, number = {1}, pages = {10}, pmid = {39910616}, issn = {2042-6410}, support = {2018-04301//Natural Sciences and Engineering Research Council of Canada/ ; 2018-04301//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {Animals ; *Neurogenesis ; Male ; Female ; *Sex Characteristics ; *Hippocampus/cytology ; *Apolipoprotein E4/genetics ; *Microglia/cytology ; *Neural Stem Cells/cytology ; Genotype ; Rats ; Rats, Transgenic ; Aging ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) disproportionately and uniquely affects females, and these sex differences are further exacerbated by the presence of Apolipoprotein (APOE) ε4 alleles, the top genetic risk factor for late-onset AD. To expand our understanding about how late-onset AD risk might differentially influence males and females, this study explores how APOEε4 affects hippocampal neurogenesis and microglia, key neuroplastic markers involved in AD pathogenesis, differently by sex in middle-aged rats.
METHODS: A rat model expressing the humanized (h) APOEε4 allele was characterized to examine markers of adult neurogenesis (neural progenitor cells and new-born neurons) and immune cells (microglia) in the dentate gyrus of the hippocampus in 13 month-old male and female rats.
RESULTS: We observed basal sex differences in neurogenesis at middle age, as wildtype male rats had greater densities of neural progenitor cells and new-born neurons in the dentate gyrus than wildtype female rats. Male hAPOEε4 rats exhibited fewer neural progenitor cells, fewer new-born neurons, and more microglia than male wildtype rats. On the other hand, female hAPOEε4 rats exhibited more new-born neurons than female wildtype rats. Interestingly, females had more microglia than males regardless of genotype. Correlations were conducted to further elucidate any sex differences in the relationships between these biomarkers. Notably, there was a significant positive correlation between neural progenitor cells and new-born neurons, and a significant negative correlation between new-born neurons and microglia, but only in male rats.
CONCLUSION: In contrast to the clear pattern of effects of the hAPOEε4 risk factor on hippocampal neurogenesis in males, females had unaltered levels of neural progenitor cells and increased density of new-born neurons. Furthermore, relationships between neurogenesis and microglia were significantly correlated within males, and not females. This suggests that females may be presenting a compensatory response to the hAPOEε4 genotype at middle age. Collectively, these results exemplify the importance of thoroughly examining influences of sex on AD endophenotypes, as it may reveal sex-specific pathways and protective mechanisms relevant to AD.}, }
@article {pmid39910474, year = {2025}, author = {Linzhu, and Zhang, J and Fan, W and Su, C and Jin, Z}, title = {Influence of immune cells and inflammatory factors on Alzheimer's disease axis: evidence from mediation Mendelian randomization study.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {49}, pmid = {39910474}, issn = {1471-2377}, mesh = {Humans ; *Alzheimer Disease/genetics/immunology/epidemiology ; *Mendelian Randomization Analysis/methods ; Inflammation/genetics/immunology ; Sialic Acid Binding Ig-like Lectin 3/genetics ; Cytokines/metabolism ; HLA-DR Antigens/genetics ; Leukocyte Common Antigens/metabolism/genetics ; Interleukin-2/genetics ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most common forms of dementia in the elderly, characterized by progressive neurodegeneration. While the exact etiology of AD remains unclear, immune inflammation is known to play a significant role in the disease.
METHODS: This study utilized a two-sample Mendelian randomization (MR) approach to assess the causal relationship between different types of immune cells and AD, while considering inflammatory factors as intermediate variables. Data were collected from three sources: immune cell data (731 phenotypes), inflammatory factors (48 cytokines from 8,293 individuals), and AD data (35,274 cases, 59,163 controls). Multiple MR methods were employed to minimize bias, and detailed descriptions of instrumental variable selection and statistical methods were provided.
RESULTS: The study findings suggest potential causal relationships between six different types of immune cells and AD, as well as causal relationships between 13 immune cells and inflammatory factors. Additionally, two statistically significant inflammatory factors were found to have potential causal relationships with AD. Specifically, immune cells CD33-HLA DR + and CD45 on CD33-HLA DR + may further influence AD by regulating Interleukin-2 levels.
CONCLUSION: This study provides valuable insights into the immunoinflammatory pathogenesis of AD and offers partial guidance for the development of relevant interventions, thereby contributing beneficial information for the prevention and treatment of related diseases.}, }
@article {pmid39910202, year = {2025}, author = {Gao, W and Yang, G and Liu, X and Hu, K and Pan, J and Wang, X and Zhao, Y and Xu, Y}, title = {Network pharmacology and experimental verification to investigate the mechanism of isoliquiritigenin for the treatment of Alzheimer's disease.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {4379}, pmid = {39910202}, issn = {2045-2322}, support = {82174003//General Program of National Natural Science Foundation of China/ ; }, mesh = {*Chalcones/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; *Molecular Docking Simulation ; Humans ; *Network Pharmacology ; *Protein Interaction Maps/drug effects ; *Microglia/drug effects/metabolism ; Mice ; Animals ; Lipopolysaccharides ; Cell Line ; Anti-Inflammatory Agents/pharmacology/chemistry ; Gene Ontology ; }, abstract = {Isoliquiritigenin (ISL), a flavone isolated from licorice, has been demonstrated to exhibit anti-inflammatory and antioxidant properties in the treatment of Alzheimer's disease (AD). However, the molecular details of the contribution of ISL to AD remain largely elusive. The present study aimed to investigate the molecular mechanisms of ISL against AD. In this study, AD targets and ISL targets were collected via different databases. The overlapped targets between AD and ISL were generated with Venny. Then we performed Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses on these common targets. The protein-protein interaction (PPI) network was constructed and clusters were obtained using the Molecular Complex Detection (MCODE) and the Cytohubba plugins. Further, molecular docking study was performed for these core targets. Subsequently, the receiver operating characteristic (ROC) curve analysis and the assessment of hub gene expression levels between AD and healthy individuals were used to estimate a possible link between target genes in AD. Finally, experiments were conducted to verify the therapeutic mechanism of ISL in lipopolysaccharide (LPS)-induced BV2 microglial cells. GO and KEGG pathway analysis found that ISL was significantly enriched in regulation of mitogen-activated protein kinase (MAPK) signaling pathway. The PPI network manifested 7 key targets including albumin (ALB), epidermal growth factor receptor (EGFR), solute carrier family 2 member 1 (SLC2A1), insulin-like growth factor 1 (IGF1), mitogen-activated protein kinase 1 (MAPK1), peroxisome proliferator activated receptor alpha (PPARA) and peroxisome proliferator activated receptor gamma (PPAR-γ, PPARG). Molecular docking showed that ISL had high binding affinity with these key targets. The experimental results revealed that ISL decreased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and increased the expression of PPAR-γ, and suppressed the production of proinflammatory mediators. Our work revealed that ISL might be an effective treatment strategy in the treatment of AD by its anti-inflammatory effect towards microglia through the ERK/PPAR-γ pathway.}, }
@article {pmid39909068, year = {2025}, author = {Richards, KC and Fry, LM and Lozano, AJ and Ji, W and Morrison, JD and Britt, KC and Bliwise, DL and Gooneratne, NS and Hanlon, AL}, title = {Treatment of Restless Legs Syndrome Improves Agitation and Sleep in Persons with Dementia: A Randomized Trial.}, journal = {Journal of the American Medical Directors Association}, volume = {26}, number = {5}, pages = {105485}, doi = {10.1016/j.jamda.2025.105485}, pmid = {39909068}, issn = {1538-9375}, abstract = {OBJECTIVES: Restless legs syndrome (RLS), a common, treatable, sensorimotor disorder of nighttime uncomfortable leg sensations that interfere with sleep, may prompt nighttime agitation in persons with dementia.
DESIGN: This randomized trial was double-blind and placebo-controlled. Participants received a Food and Drug Administration-approved drug for RLS, gabapentin enacarbil (GEn) (Horizant) or placebo.
SETTING AND PARTICIPANTS: Older adults (N = 147) with dementia due to Alzheimer's disease, nighttime agitation, and RLS, residing in long-term care or at home, participated.
METHODS: The primary outcome was change from baseline to 8 weeks in nighttime agitation between 5 pm and 7 am on the Cohen-Mansfield Agitation Inventory Index, Direct Observation. Multivariable linear mixed effects regression models based on multiply imputed data were estimated on nighttime agitation and sleep, with treatment group, week, the 2-way interaction of group and week as predictors, and mean arterial pressure as a covariate based on baseline group imbalances.
RESULTS: Mean age ± SD was 83.4 ± 9.1 years. Most were female (72.0%), white (92.3%), non-Hispanic (84.6%), and lived in nursing homes (76.9%). Nighttime agitation, by group over time, was significant at 8 weeks (estimate, -1.67; P = .003) and 2 weeks. Total sleep time (actigraphy) by group over time was significant at 8 weeks (estimate, 48.45; P = .026). Observed nighttime wake by group over time was significant at 2 (estimate, -12.54; P = .006) and 8 weeks (estimate, -11.12; P = .015). The number having ≥1 adverse events was 60 in the GEn group (81.1%) and 50 in the placebo group (68.5%); with 12 serious adverse events in placebo and 10 in the GEn group. The GEn group had a trend toward more falls (P = .066).
CONCLUSIONS AND IMPLICATIONS: Our findings suggest a novel approach for nighttime agitation in persons with dementia: assessing for RLS and initiating interventions. Larger and longer trials are needed.}, }
@article {pmid39908690, year = {2025}, author = {Olluri, A}, title = {Clinical trials targeting tau should be halted.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {134}, number = {}, pages = {111101}, doi = {10.1016/j.jocn.2025.111101}, pmid = {39908690}, issn = {1532-2653}, mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/drug therapy ; *Clinical Trials as Topic/methods ; }, abstract = {Experimental drugs lowering brain tau are heralded as improvements in the treatment of Alzheimer's disease. However, the outcomes in clinical trials testing these agents have consistently failed to improve patient outcomes, i.e. slow down disease or improving cognition. Furthermore, the scientific rationale behind such drugs is rather poor in the first place and has been questioned. Therefore, I argue that trials of anti-tau drugs should be halted.}, }
@article {pmid39908485, year = {2025}, author = {Yang, P and Shuai, W and Wang, X and Hu, X and Zhao, M and Wang, A and Wu, Y and Ouyang, L and Wang, G}, title = {Mitophagy in Neurodegenerative Diseases: Mechanisms of Action and the Advances of Drug Discovery.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {4}, pages = {3970-3994}, doi = {10.1021/acs.jmedchem.4c01779}, pmid = {39908485}, issn = {1520-4804}, mesh = {Humans ; *Mitophagy/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Drug Discovery ; *Mitochondria/drug effects/metabolism ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Signal Transduction/drug effects ; Alzheimer Disease/drug therapy/metabolism/pathology ; }, abstract = {Neurodegenerative diseases (NDDs), such as Parkinson's disease (PD) and Alzheimer's disease (AD), are devastating brain diseases and are incurable at the moment. Increasing evidence indicates that NDDs are associated with mitochondrial dysfunction. Mitophagy removes defective or redundant mitochondria to maintain cell homeostasis, whereas deficient mitophagy accelerates the accumulation of damaged mitochondria to mediate the pathologies of NDDs. Therefore, targeting mitophagy has become a valuable therapeutic pathway for the treatment of NDDs. Several mitophagy modulators have been shown to ameliorate neurodegeneration in PD and AD. However, it remains to be further investigated for other NDDs. Here, we describe the mechanism and key signaling pathway of mitophagy and summarize the roles of defective mitophagy on the pathogenesis of NDDs. Further, we underline the development advances of mitophagy modulators for PD and AD therapy, discuss the therapeutic challenges and limitations of the existing modulators, and provide guidelines for mitophagy mechanism exploration and drug design.}, }
@article {pmid39908361, year = {2025}, author = {Wu, X and Miller, JA and Lee, BTK and Wang, Y and Ruedl, C}, title = {Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer's disease mouse model.}, journal = {Science advances}, volume = {11}, number = {6}, pages = {eadq6038}, pmid = {39908361}, issn = {2375-2548}, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Microglia/metabolism ; *Phagocytosis ; *Disease Models, Animal ; *Amyloid beta-Peptides/metabolism ; *Mice, Transgenic ; Mice ; Lipid Metabolism ; Macrophages/metabolism ; Brain/metabolism/pathology ; Lipid Droplets/metabolism ; Humans ; Plaque, Amyloid/metabolism/pathology ; CX3C Chemokine Receptor 1/metabolism/genetics ; }, abstract = {Macrophages accumulate lipid droplets (LDs) under stress and inflammatory conditions. Despite the presence of LD-loaded macrophages in many tissues, including the brain, their contribution to neurodegenerative disorders remains elusive. This study investigated the role of lipid metabolism in Alzheimer's disease (AD) by assessing the contribution of LD-loaded brain macrophages, including microglia and border-associated macrophages (BAMs), in an AD mouse model. Particularly, BAMs and activated CD11c[+] microglia localized near β amyloid (Aβ) plaques exhibited a pronounced lipid-associated gene signature and a high LD load. Having observed that elevated intracellular LD content correlated inversely with microglial phagocytic activities, we subsequently inhibited LD formation specifically in CX3CR1[+] brain macrophages using an inducible APP-KI/Fit2[i][Δ][M][φ] transgenic mouse model. We demonstrated that reducing LD content in microglia and CX3CR1[+] BAMs remarkably improved their phagocytic ability. Furthermore, lowering microglial LDs consistently enhanced their efferocytosis capacities and notably reduced Aβ deposition in the brain parenchyma. Therefore, mitigating LD accumulation in brain macrophages provides perspectives for AD treatment.}, }
@article {pmid39908354, year = {2025}, author = {He, S and Li, X and Mittra, N and Bhattacharjee, A and Wang, H and Song, S and Zhao, S and Liu, F and Han, X}, title = {Microglial cGAS Deletion Preserves Intercellular Communication and Alleviates Amyloid-β-Induced Pathogenesis of Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {12}, pages = {e2410910}, pmid = {39908354}, issn = {2198-3844}, support = {T32 AG021890/AG/NIA NIH HHS/United States ; //Methodist Hospital Foundation/ ; R01 AG085545/AG/NIA NIH HHS/United States ; P30 AG013319/AG/NIA NIH HHS/United States ; //William and Ella Owens Medical Research Foundation/ ; //Cure Alzheimer's Fund/ ; R01 AG061729/AG/NIA NIH HHS/United States ; T32AG021890/AG/NIA NIH HHS/United States ; RF1 AG061729/AG/NIA NIH HHS/United States ; //University of Texas Health Science Center at San Antonio intramural institutional research funds/ ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG044271/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *Microglia/metabolism ; Mice ; *Nucleotidyltransferases/metabolism/genetics ; *Disease Models, Animal ; *Mice, Knockout ; *Amyloid beta-Peptides/metabolism/genetics ; Signal Transduction/genetics ; Cell Communication/genetics ; Immunity, Innate ; }, abstract = {Innate immune activation plays a crucial role in the pathogenesis of Alzheimer's disease (AD) and related dementias (ADRD). The cytosolic DNA sensing pathway, involving cGAMP synthase (cGAS) and Stimulator of Interferon Genes (STING), has emerged as a key mediator of neurodegenerative diseases. However, the precise mechanisms through which cGAS activation influences AD progression remain poorly understood. In this study, we observed significant up-regulation of cGAS-STING signaling pathway in AD. Notably, this increase is primarily attributed to microglia, rather than non-microglial cell types. Using an inducible, microglia-specific cGAS knockout mouse model in the 5xFAD background, we demonstrated that deleting microglial cGAS at the onset of amyloid-β (Aβ) pathology profoundly restricts plaque accumulation and protects mice from Aβ-induced cognitive impairment. Mechanistically, our study revealed cGAS promotes plaque-associated microglia accumulation and is essential for inflammasome activation. Moreover, we showed that restricting cGAS-mediated innate immunity is crucial for preserving inter-cellular communication in the brain and induces pleiotrophin, a neuroprotective factor. These findings offer novel insights into the specific roles of the innate immune system in AD employing a cell-type-specific approach. The conclusions provide a foundation for targeted interventions to modulate the microglial cGAS-STING signaling pathway, offering promising therapeutic strategy for AD treatment.}, }
@article {pmid39907966, year = {2025}, author = {Hey, JA and Yu, JY and Abushakra, S and Schaefer, JF and Power, A and Kesslak, P and Paul, J and Tolar, M}, title = {Clinical Pharmacokinetics of Oral ALZ-801/Valiltramiprosate in a 2-Year Phase 2 Trial of APOE4 Carriers with Early Alzheimer's Disease.}, journal = {Clinical pharmacokinetics}, volume = {64}, number = {3}, pages = {407-424}, pmid = {39907966}, issn = {1179-1926}, mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; *Apolipoprotein E4/genetics ; Male ; Female ; Aged ; Middle Aged ; Administration, Oral ; Prodrugs/pharmacokinetics/administration & dosage ; Heterozygote ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Magnetic Resonance Imaging ; Biomarkers/blood ; Taurine/analogs & derivatives ; }, abstract = {INTRODUCTION: ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of β-amyloid (Aβ) oligomer formation in late-stage development as a potential disease-modifying therapy for Alzheimer's disease (AD). ALZ-801, a valine-conjugated prodrug, is rapidly converted to tramiprosate after oral dosing. Upon conversion to tramiprosate, it generates a single metabolite, 3-sulfopropanoic acid (3-SPA). Both tramiprosate and 3-SPA are active anti-Aβ oligomer agents that mediate ALZ-801's central mechanism of action (MOA). We summarize herein the pharmacokinetics (PK) of ALZ-801 in apolipoprotein ε4 (APOE4) carrier subjects with early AD from a phase 2 trial.
METHODS: The ALZ-801 phase 2 study was designed to evaluate longitudinal effects of ALZ-801 (265 mg BID) on plasma, cerebrospinal fluid (CSF) and volumetric magnetic resonance imaging (MRI) AD biomarkers, and clinical outcomes over 104 weeks in APOE4 carriers with early AD. Eighty-four subjects (31 APOE4/4 homozygotes and 53 APOE3/4 heterozygotes) with positive CSF biomarkers of amyloid and tau pathology were enrolled. The phase 2 study included a substudy of 24 subjects to provide 8-h steady-state PK at 65 weeks. Sparse PK samples were also analyzed. The relationships between plasma PK exposure and clinical characteristics [i.e., sex, APOE genotype, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), concomitant acetylcholinesterase inhibitor (AChEI) use, and tablet lot] were evaluated.
RESULTS: The steady-state plasma PK results were closely aligned with the previous 2-week PK in the ALZ-801 phase 1b study in APOE4 carrier subjects with AD, as well as a phase 1 7-day PK study in heathy elderly volunteers. Following oral dosing, ALZ-801 was rapidly converted to the active moieties, tramiprosate and 3-SPA. The intersubject variability in plasma drug levels was low, confirming the superior performance of ALZ-801 versus oral tramiprosate tablet (150 mg BID) from the earlier tramiprosate phase 3 trials. Correlation analysis versus clinical characteristics showed that plasma exposures (Cmax and AUC8h) for ALZ-801, tramiprosate, and 3-SPA were not affected by sex, APOE genotype, age, BMI, concomitant AChEI use, or tablet lot. Plasma exposures of both tramiprosate and 3-SPA, but not ALZ-801, were inversely correlated with eGFR, in line with renal excretion as the primary route of elimination. ALZ-801 was well tolerated without new safety signals or events of amyloid-related imaging abnormalities (ARIA).
CONCLUSIONS: The steady-state PK profile of oral ALZ-801 in subjects with early AD was not affected by sex, APOE genotype, age, BMI, concomitant use of AChEI, or tablet lot. The inverse relationship of plasma exposures of tramiprosate and 3-SPA, but not ALZ-801, versus eGFR is consistent with renal clearance as the primary route of elimination for tramiprosate and 3-SPA (active moieties), and with the efficient conversion of ALZ-801 prodrug to the active moieties after dosing. These results demonstrate that ALZ-801 displays favorable PK properties without evidence of interactions with demographic characteristics and support its development as an oral disease-modifying treatment for AD.
TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04693520 .}, }
@article {pmid39907903, year = {2025}, author = {Ma, K and Tian, T and Li, X and Pang, H and Ning, X and Li, M and Li, J and Luo, Z and Liu, T and Liu, M and Wang, M and Zhao, C and Song, X and Du, H and Jin, M}, title = {Silica Nanoparticles Induce SH-SY5Y Cells Death Via PARP and Caspase Signaling Pathways.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39907903}, issn = {1559-1182}, abstract = {A growing stream of research indicates that exposure to Silica nanoparticles (SiNPs) can cause nervous system damage, leading to the occurrence of neurodegenerative diseases such as Alzheimer's disease. However, the specific mechanism by which SiNPs cause neuroblast injury remains unclear and requires further research. This study established an in vitro experimental model of SH-SY5Y cells exposed to SiNPs and observed cell growth through an inverted fluorescence microscope. Cell viability was measured using an MTT assay. The intracellular ROS and Ca[2+] levels were detected by flow cytometry. Cell apoptosis was observed using both Hoechst33342 staining and TUNEL staining. The activities of SOD and ATPase and the content of ATP in the cells were tested by biochemical methods. The genes including parp-1, aif, par, ucp2, vdac and prdx3 were explored using quantitative real-time PCR. The expressions of PARP, AIF, PAR, Caspase-3, Caspase-9 and Cyt C proteins were evaluated by Western Blot. The immunofluorescence technique was used to observe the distribution of Parthanatos-related proteins induced by SiNPs. The results showed that SiNPs reduced cell survival rate, induced excessive ROS and Ca[2+] overload, decreased SOD activity, ATPase activity, intracellular and mitochondrial ATP content, increased the expression of mitochondrial function and PARP pathway related genes, as well as PARP and Caspase pathway protein expression, ultimately inducing cell apoptosis. As a further test of the roles of PARP and Caspase pathways in SiNPs induced SH-SY5Y cells death, we selected the PARP inhibitor Olaparib and Caspase inhibitor Z-VAD, and the above effects were significantly improved after treatment with the inhibitors. Conclusively, this study confirmed that SiNPs can generate excessive ROS production in SH-SY5Y cells, alter mitochondrial function, and induce cell death through Parthanatos and caspase dependent apoptotic pathways, which can coexist and interact with each other.}, }
@article {pmid39907698, year = {2025}, author = {Xavier-de-Britto, I and Gomes-da-Silva, NC and Gomes Soares, MA and Follmer, C and Dabkiewicz, D and Alencar, LMR and Sant'Anna, C and Ferreira, TPT and Martins, PMRES and Ricci-Junior, E and Fechine, PBA and Santos-Oliveira, R}, title = {Therapeutic Potential of Arimoclomol Nanomicelles: In Vitro Impact on Alzheimer's and Parkinson's Pathology and Correlation with In Vivo Inflammatory Response.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {4}, pages = {699-710}, pmid = {39907698}, issn = {1948-7193}, mesh = {*Parkinson Disease/drug therapy ; *Alzheimer Disease/drug therapy ; Animals ; *alpha-Synuclein/metabolism/drug effects ; *Amyloid beta-Peptides/metabolism ; Humans ; Inflammation/drug therapy ; Micelles ; Anti-Inflammatory Agents/pharmacology ; Nanoparticles ; Peptide Fragments/pharmacology ; }, abstract = {This study investigates the potential of arimoclomol-loaded nanomicelles for the treatment of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as their anti-inflammatory properties. Arimoclomol, a coinducer of heat shock proteins (HSPs), has shown clinical promise in mitigating protein misfolding, a hallmark of these diseases. In this work, arimoclomol nanomicelles significantly reduced the aggregation of β-amyloid (Aβ1-42) and α-synuclein (α-syn), key pathological proteins in Alzheimer's and Parkinson's. Additionally, the nanomicelles demonstrated potent anti-inflammatory effects, reducing leukocyte and neutrophil counts in an acute inflammation model. These results suggest that arimoclomol nanomicelles could enhance clinical outcomes by targeting both neurodegenerative and inflammatory processes, offering a promising therapeutic strategy for long-term disease management.}, }
@article {pmid39907502, year = {2025}, author = {Harrison, KL and Morgan, BE and Friend, J and Garrett, SB and Looi, D and Halim, M and James, JE and Boyd, ND and Gilissen, J and Geschwind, MD and Ritchie, CS and Smith, AK}, title = {"By the Time We Knew …": Poetic Analysis of End-of-Life Caregiving Experiences for Rapidly Progressive and Slower-Duration Dementia Syndromes.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.19382}, pmid = {39907502}, issn = {1532-5415}, support = {P30AG044281/AG/NIA NIH HHS/United States ; 5T32AG049663/AG/NIA NIH HHS/United States ; //Global Brain Health Institute (GBHI), Alzheimer's Association, and Alzheimer's Society Pilot Awards for Global Brain Health Leaders/ ; K01AG059831/AG/NIA NIH HHS/United States ; R01AG031189/AG/NIA NIH HHS/United States ; R24AG065175/AG/NIA NIH HHS/United States ; T35AG026736/AG/NIA NIH HHS/United States ; R56AG055619/AG/NIA NIH HHS/United States ; K24AG068312/AG/NIA NIH HHS/United States ; 2P30AG062421/AG/NIA NIH HHS/United States ; P30 AG044281/AG/NIA NIH HHS/United States ; //Global Brain Health Institute/ ; T32HS022241//Agency for Healthcare Research and Quality (AHRQ)/ ; R01AG062562/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: One in three older adults in the United States dies with or from dementia. Little is known about whether end-of-life caregiving experiences differ by dementia diagnosis.
METHODS: We conducted a secondary analysis of two qualitative studies. Participants included caregivers of decedents with "rapid-type" sporadic Creutzfeldt-Jakob Disease (sCJD, survival prognosis of < 1 year) or "slow-type" Alzheimer's disease and related dementias (survival prognosis of 5-20 years). We used reflexive thematic analysis and a novel method, poetic analysis, to compare end-of-life caregiving experiences.
RESULTS: "Rapid-type" caregivers (n = 12) had a median age of 59 (range 45-73) years; 6 were female, and 9 were spouses. "Slow-type" caregivers (n = 15) had a median age of 69 (45-82) years; 9 were female, and 11 were spouses. We identified three main areas of differential experience that were influenced by syndrome rarity and participation in research yet hinged on time. Time enables preparation: Due to the rarity of sCJD, "rapid-type" caregivers struggled to obtain accurate diagnoses, which prevented preparation for end-of-life care. Weeks or months before death, specialists simultaneously disclosed sCJD diagnoses and recommended hospice. In contrast, for "slow-type" dementia, preparation began years before death. Time complicates conflict: Most "rapid-type" caregivers described conflicts, rarely resolved before death, about code status, treatment, or care location decisions. Fewer "slow-type" caregivers experienced such conflicts, and these were typically resolved before death; instead, they experienced conflict between needs and what the care system provides. Postmortem experience contrasts with perimortem: For "rapid-type" dementia, short perimortem periods contrasted with elongated and often intense postmortem logistics and grief. For "slow-type" caregivers, preparation and perimortem grieving typically led to shorter duration and minimally intrusive postmortem logistics and grief.
CONCLUSIONS: End-of-life care for dementia should attend to and support axes of differential experience based on diagnosis and rarity, time since symptom onset (affecting preparation and conflict resolution), and participation in research studies.}, }
@article {pmid39907297, year = {2024}, author = {Čižek Sajko, M and Suklan, J and Osmanović, D and Peterlin, B}, title = {Translational Research on Polygenic Risk Scores in Common Neurodegenerative Diseases - A Scoping Review Protocol.}, journal = {Acta medica academica}, volume = {53}, number = {3}, pages = {303-308}, pmid = {39907297}, issn = {1840-2879}, mesh = {Humans ; Alzheimer Disease/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics ; Genetic Predisposition to Disease ; Genetic Risk Score ; *Multifactorial Inheritance ; Multiple Sclerosis/genetics ; *Neurodegenerative Diseases/genetics ; Parkinson Disease/genetics/diagnosis ; Research Design ; Risk Assessment ; Risk Factors ; *Translational Research, Biomedical ; Scoping Review as Topic ; }, abstract = {OBJECTIVE: The purpose of this protocol is to clearly describe the process for the scoping review we plan to conduct on the topic of polygenic risk scores (PRS) in common neurodegenerative diseases. We will present the review's objective, the strategy for evidence search, the data extraction and analysis procedure, and how the results will be presented.
METHODS: The inclusion criteria for the planned scoping review will focus on evidence sources that involve PRS applied to neurogenerative diseases such as Multiple sclerosis, Parkinson's disease, Alzheimer's disease, and Amyotrophic lateral sclerosis in any phase of translational research, from early development to clinical implementation. This includes its use in risk prediction, early diagnosis, prognosis, and treatment decision-making. The research questions were created based on the population, context, and concept framework. We will consider both peer-reviewed papers and grey literature published in English or German for inclusion. Two independent reviewers will search for information.
CONCLUISON: The findings from the scoping review will be presented descriptively and summarized according to the research questions to illustrate the current status of translational research on PRS in common neurodegenerative diseases.}, }
@article {pmid39906286, year = {2025}, author = {Darabi, S and Gorgich, EAC and Moradi, F and Rustamzadeh, A}, title = {Lipidopathy disrupts peripheral and central amyloid clearance in Alzheimer's disease: Where are our knowledge.}, journal = {IBRO neuroscience reports}, volume = {18}, number = {}, pages = {191-199}, pmid = {39906286}, issn = {2667-2421}, abstract = {Amyloid-beta (Aβ) production is a normal physiological process, essential for neuronal function. However, an imbalance in Aβ production and clearance is the central pathological feature of Alzheimer's disease (AD), leading to the accumulation of Aβ plaques in the brain. Low-density lipoprotein receptor-related protein 1 (LRP1) plays a critical role in both the central clearance of Aβ from the brain and its peripheral transport to visceral organs. Disruptions in these processes contribute to the accumulation of Aβ in the central nervous system (CNS) and the progression of AD. Recent research emphasizes the need for a broader focus on the systemic effects of organs outside the brain, particularly in the context of AD prevention and treatment. The contribution of peripheral systems, such as the liver, in Aβ clearance, is vital, given that Aβ levels in the plasma correlate closely with those in the brain. Consequently, targeting systemic processes, rather than focusing solely on the CNS, may offer promising therapeutic approaches. Furthermore, high-density lipoprotein (HDL) facilitates the formation of lipoprotein-amyloid complexes, which are important for Aβ transport and clearance, using proteins such as apolipoproteins E and J (ApoE and ApoJ) to form complexes that help manage Aβ accumulation. On the other hand, low-density lipoprotein (LDL) facilitates Aβ efflux from the brain by binding to LRP1, promoting its clearance. Given the relationship between lipid profiles and Aβ levels, along with lipid-modifying drugs, may be effective in managing Aβ accumulation and mitigating AD progression.}, }
@article {pmid39905477, year = {2025}, author = {Zheng, H and Mizokami, A and Romera-Giner, S and Llera-Oyola, J and Yamawaki, Y and Sano, T and Jimi, E and García-García, F and Kanematsu, T}, title = {Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia.}, journal = {Biology of sex differences}, volume = {16}, number = {1}, pages = {9}, pmid = {39905477}, issn = {2042-6410}, support = {SPRING JPMJSP2136//Japan Science and Technology Agency/ ; 22K09904//Japan Society for the Promotion of Science/ ; PID2021-124430OA-I00//Ministerio de Ciencia e Innovación/ ; }, mesh = {*Microglia/metabolism ; Animals ; Male ; *MicroRNAs/metabolism/genetics ; Female ; *Sex Characteristics ; *Signal Transduction ; *Fatty Acids/metabolism ; *Mice, Inbred C57BL ; Cell Line ; *Testosterone ; Lipopolysaccharides/pharmacology ; Hippocampus/metabolism ; Mice ; Neuroinflammatory Diseases/metabolism ; }, abstract = {BACKGROUND: Significant sex differences exist in the prevalence and incidence of Alzheimer's disease (AD). Notably, testosterone has been reported to regulate cognitive functions in the brain, with low serum testosterone levels correlating with increased AD risk. However, the specific mechanisms underlying this relationship remain unclear. Recent studies have demonstrated that microglia, the primary innate immune cells in the brain, play a crucial role in AD development. Therefore, this study aimed to explore sex differences in microglial function, specifically focusing on the role of testosterone in miRNA-mediated regulation of microglial gene expression.
METHODS: Microglia were isolated from pooled hippocampal tissue of five 8-month-old male and female mice. Total RNA was extracted and subjected to miRNA microarray analysis. The mouse microglial cell line MG6 was used for in vitro experiments. Following testosterone treatment, miRNA, gene, and protein expression levels were investigated. An inflammatory response was induced using lipopolysaccharide (LPS) stimulation, and subsequent p65 phosphorylation was assessed.
RESULTS: Sex-dependent differences were observed in miRNA-mediated biological processes, with males exhibiting greater changes. Male-enriched miRNAs were associated with fatty acid synthesis and metabolism pathways. In MG6 cells, testosterone treatment upregulated the expression of several miRNAs enriched in male microglia, particularly those targeting genes related to fatty acid synthesis. Additionally, testosterone significantly reduced the gene expression of fatty acid synthase (FASN). This testosterone-induced inhibition of FASN expression attenuated NF-κB/p65 phosphorylation. Consequently, the suppression of FASN expression led to reduced expression and secretion of tumor necrosis factor-alpha following LPS stimulation in MG6 cells.
CONCLUSIONS: These findings suggest that testosterone modulates inflammation in male microglia by regulating fatty acid synthesis, potentially contributing to the observed sex differences in AD pathogenesis.}, }
@article {pmid39905390, year = {2025}, author = {Ogunro, OB and Karigidi, ME and Gyebi, GA and Turkistani, A and Almehmadi, AH}, title = {Tangeretin offers neuroprotection against colchicine-induced memory impairment in Wistar rats by modulating the antioxidant milieu, inflammatory mediators and oxidative stress in the brain tissue.}, journal = {BMC complementary medicine and therapies}, volume = {25}, number = {1}, pages = {40}, pmid = {39905390}, issn = {2662-7671}, mesh = {Animals ; *Rats, Wistar ; *Oxidative Stress/drug effects ; Male ; Rats ; *Colchicine/pharmacology ; *Neuroprotective Agents/pharmacology ; *Antioxidants/pharmacology ; *Memory Disorders/drug therapy/chemically induced ; Brain/drug effects/metabolism ; Donepezil/pharmacology ; Disease Models, Animal ; Flavones/pharmacology ; Inflammation Mediators/metabolism ; }, abstract = {BACKGROUND: Tangeretin, a flavone compound (O-polymethoxylated) naturally present in tangerine and other citrus peels has demonstrated effectiveness as an anti-inflammatory and neuroprotective agent in several disease model. This study evaluated the impact of tangeretin in mitigating cognitive dysfunction and oxidative stress induced by colchicine in rats, comparing its efficacy with donepezil hydrochloride.
METHODS: Cognitive dysfunction was induced by administering colchicine (15 µg/rat) intracerebroventricularly (ICV) via a stereotaxic apparatus in male Wistar rats. Colchicine resulted in poor memory retention in acquiring and retaining a spatial navigation task, passive avoidance apparatus, and Morris water maze paradigms. Chronic treatment with tangeretin (at doses of 50, 100, and 200 mg/kg, p.o. once daily) and donepezil hydrochloride (at a dose of 10 mg/kg, p.o. daily) for 28 days, starting seven days before colchicine injection, significantly ameliorated colchicine-induced cognitive impairment.
RESULTS: The biochemical analysis showed that chronic administration of tangeretin effectively reversed the colchicine-induced increase in the level/activity of lipid peroxidation, hydrogen peroxide (H2O2), myeloperoxidase (MPO), nitrite, reactive oxygen species (ROS), tumour necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), serotonin, dopamine, glutamate, amyloid beta (Aβ) peptide, and caspase-3. Tangeretin also reversed the colchicine-induced reduction in the level/activity of brain-derived neurotrophic factor (BDNF), amma-aminobutyric acid (GABA), acetylcholinesterase (AChE), glutathione S-Transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), and total thiol (T-SH) in rat brains. However, donepezil hydrochloride did not prevent oxidative stress.
CONCLUSIONS: These findings suggest that chronic administration of tangeretin at 50, 100, and 200 mg/kg, p.o. once daily, was protective in mitigating colchicine-induced cognitive impairment and associated oxidative stress. At the same time, donepezil hydrochloride did not demonstrate similar effects.}, }
@article {pmid39905278, year = {2025}, author = {Zhu, H and Huang, C and Luo, Z and Wu, L and Cheng, X and Wu, H}, title = {Porphyromonas gingivalis Induces Disturbance of Kynurenine Metabolism Through the Gut-Brain Axis: Implications for Alzheimer's Disease.}, journal = {Journal of dental research}, volume = {104}, number = {4}, pages = {439-448}, doi = {10.1177/00220345241303141}, pmid = {39905278}, issn = {1544-0591}, mesh = {*Porphyromonas gingivalis/metabolism ; *Kynurenine/metabolism/analogs & derivatives ; *Alzheimer Disease/microbiology/metabolism ; Animals ; *Gastrointestinal Microbiome/physiology ; *Brain-Gut Axis/physiology ; Dysbiosis ; Bacteroidaceae Infections/microbiology ; Male ; Mice ; Apoptosis ; Tryptophan/metabolism ; Disease Models, Animal ; Alveolar Bone Loss/microbiology/metabolism ; }, abstract = {Porphyromonas gingivalis is one of the major pathogens of chronic periodontitis. P. gingivalis can cause systemic inflammation, amyloid β protein deposition, and hyperphosphorylation of tau protein, leading to Alzheimer's disease (AD)-like lesions. P. gingivalis oral infection causes gut microbiota alteration, gut barrier dysfunction, and intestinal immune response and inflammation. The microbiota-gut-brain axis has a potential role in the pathogenesis of AD. Whether P. gingivalis affects AD-like lesions via the gut-brain axis needs more study. In this study, orally administered P. gingivalis induced alveolar resorption, intestinal barrier impairment, and AD-like lesions. Oral infection with P. gingivalis induced oral and gut microflora dysbiosis, imbalance of the tryptophan metabolism pathway of gut microbiota, and elevated levels of 3-hydroxykynurenine in the sera and hippocampi. The key metabolite, 3-hydroxykynurenine, suppressed Bcl2 gene expression, leading to neuronal apoptosis and promoting AD-like lesions in vivo and in vitro. These findings suggest that P. gingivalis can induce AD pathogenesis through the gut-brain axis, providing new ideas for the prevention and treatment of AD.}, }
@article {pmid39905093, year = {2025}, author = {Zhang, HX and Hamit, D and Li, Q and Hu, X and Li, SF and Xu, F and Wang, MY and Bao, GQ and Li, HY}, title = {Integrative bioinformatic approach reveals novel melatonin-related biomarkers for Alzheimer's disease.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {4193}, pmid = {39905093}, issn = {2045-2322}, support = {null//Tianchi Talent Program/ ; }, mesh = {*Alzheimer Disease/genetics/metabolism ; Humans ; *Computational Biology/methods ; *Biomarkers/metabolism ; *Melatonin/metabolism ; Gene Regulatory Networks ; Molecular Docking Simulation ; Gene Expression Profiling ; }, abstract = {BACKGROUND: Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in AD through bioinformatic analysis.
METHODS: First, the key cells in the single-cell dataset GSE138852 were screened out based on the proportion of annotated cells and Fisher's test between the AD and control groups. The differentially expressed genes (DEGs) in the key cell and GSE5281 datasets were identified, and the MRGs in GSE5281 were selected via weighted gene coexpression network analysis. After intersecting two sets of DEGs and MRGs, we performed Mendelian randomization analysis to identify the MRGs causally related to AD. Biomarkers were further ascertained through receiver operating characteristic curve (ROC) and expression analysis in GSE5281 and GSE48350. Furthermore, gene set enrichment analysis, immune infiltration analysis and correlation analysis with metabolic pathways were conducted, as well as construction of a regulator network and molecular docking.
RESULTS: According to the Fisher test, oligodendrocytes were regarded as key cells due to their excellent abundance in the GSE138852 dataset, in which there were 281 DEGs between the AD and control groups. After overlapping with 3,490 DEGs and 550 MRGs in GSE5281, four genes were found to be causally related to AD, namely, G protein-coupled receptor, family C, group 5, member B (GPRC5B), Methyltransferase-like protein 7 A (METTL7A), NF-κB inhibitor alpha (NFKBIA) and RAS association domain family 4(RASSF4). Moreover, GPRC5B, NFKBIA and RASSF4 were deemed biomarkers, except for METTL7A, because of their indistinctive expression between the AD and control groups. Biomarkers might be involved in oxidative phosphorylation, adipogenesis and heme metabolism. Moreover, T helper type 17 cells, natural killer cells and CD56dim natural killer cells were significantly correlated with biomarkers. Transcription factors (GATA2, POU2F2, NFKB1, etc.) can regulate the expression of biomarkers. Finally, we discovered that all biomarkers could bind to MLT with a strong binding energy.
CONCLUSION: Our study identified three novel biomarkers related to MLT for AD, namely, GPRC5B, NFKBIA and RASSF4, providing a novel approach for the investigation and treatment of AD patients.}, }
@article {pmid39904782, year = {2025}, author = {Mofatteh, M and Mohamed, A and Mashayekhi, MS and Skandalakis, GP and Neudorfer, C and Arfaie, S and MohanaSundaram, A and Sabahi, M and Anand, A and Aboulhosn, R and Liao, X and Horn, A and Ashkan, K}, title = {Deep brain stimulation of the hypothalamic region: a systematic review.}, journal = {Acta neurochirurgica}, volume = {167}, number = {1}, pages = {33}, pmid = {39904782}, issn = {0942-0940}, mesh = {*Deep Brain Stimulation/methods ; Humans ; *Hypothalamus/physiopathology ; Female ; Male ; Alzheimer Disease/therapy ; Prader-Willi Syndrome/therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Deep brain stimulation (DBS) has been successfully used for the treatment of circuitopathies including movement, anxiety, and behavioral disorders. The hypothalamus is a crucial integration center for many peripheral and central pathways relating to cardiovascular, metabolic, and behavioral functions and constitutes a potential target for neuromodulation in treatment-refractory conditions. To conduct a systematic review, investigating hypothalamic targets in DBS, their indications, and the primary clinical findings.
METHODS: PubMed, Scopus, and Web of Science databases were searched in accordance with the PRISMA guideline to identify papers published in English studying DBS of the hypothalamus in humans.
RESULTS: After screening 3,148 papers, 34 studies consisting of 412 patients published over two decades were included in the final review. Hypothalamic DBS was indicated in refractory headaches (n = 238, 57.8%), aggressive behavior (n = 100, 24.3%), mild Alzheimer's disease (n = 58, 14.1%), trigeminal neuralgia in multiple sclerosis (n = 5, 1.2%), Prader-Willi syndrome (n = 4, 0.97%), and atypical facial pain (n = 3, 0.73%). The posterior hypothalamus was the most common DBS target site across 30 studies (88.2%). 262 (63.6%) participants were males, and 110 (26.7%) were females. 303 (73.5%) patients were adults whereas 33 (8.0%) were pediatrics. The lowest mean age of participants was 15.25 ± 4.6 years for chronic refractory aggressiveness, and the highest was 68.5 ± 7.9 years in Alzheimer's disease patients. The mean duration of the disease ranged from 2.2 ± 1.7 (mild Alzheimer's disease) to 19.8 ± 10.1 years (refractory headaches). 213 (51.7%) patients across 29 studies (85.3%) reported symptom improvements which ranged from 23.1% to 100%. 25 (73.5%) studies reported complications, most of which were associated with higher voltage stimulations.
CONCLUSIONS: DBS of the hypothalamus is feasible in selected patients with various refractory conditions ranging from headaches to aggression in both pediatric and adult populations. Future large-scale studies with long-term follow-up are required to validate the safety and efficacy data and extend these findings.}, }
@article {pmid39903975, year = {2025}, author = {Giannakis, A and Konitsiotis, S}, title = {A new paradigm for neurodegenerative diseases classification: A clinical perspective.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {134}, number = {}, pages = {111099}, doi = {10.1016/j.jocn.2025.111099}, pmid = {39903975}, issn = {1532-2653}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/classification ; Lewy Body Disease/diagnosis/classification ; Alzheimer Disease/diagnosis/classification ; }, abstract = {A vast progress has been made in the understanding of neurodegenerative diseases during the past few years. However, clinical diagnostic accuracy continues to be very low, despite the introduction of various diagnostic tools and repeated revisions of diagnostic criteria. For instance, patients with Alzheimer's disease (AD) may present with symptoms that overlap with other neurodegenerative conditions like dementia with Lewy bodies (DLB), making accurate diagnosis challenging. This diagnostic uncertainty can lead to delayed or incorrect treatment, significantly impacting patients' quality of life and prognosis. Thus, the definite diagnosis still relies on post-mortem pathological findings, placing a significant burden on both clinicians and researchers. As a growing body of evidence indicates, co-pathology seems to be the rule among neurodegenerative diseases. Additionally, a single pathological diagnosis, such as AD, can manifest in various clinical presentations, ranging from predominantly cognitive impairment to significant motor symptoms. Each of these presentations currently requires its own set of complicated diagnostic criteria. Perhaps, the time has come for a much-needed radical revision of existing clinical diagnostic criteria. Inclusion of patients do not neatly fit into existing diagnostic categories for neurodegenerative diseases, in future large-scale, longitudinal studies and/or clinical trials, and systematic assessment of their clinical features and disease progression using machine learning could generate valuable data on patients with mixed pathologies and improve our understanding of how to effectively treat these complex cases.}, }
@article {pmid39903369, year = {2025}, author = {Tang, C and Border, JJ and Zhang, H and Gregory, A and Bai, S and Fang, X and Liu, Y and Wang, S and Hwang, SH and Gao, W and Morgan, GC and Smith, J and Bunn, D and Cantwell, C and Wagner, KM and Morisseau, C and Yang, J and Shin, SM and O'Herron, P and Bagi, Z and Filosa, JA and Dong, Y and Yu, H and Hammock, BD and Roman, RJ and Fan, F}, title = {Inhibition of soluble epoxide hydrolase ameliorates cerebral blood flow autoregulation and cognition in alzheimer's disease and diabetes-related dementia rat models.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {39903369}, issn = {2509-2723}, support = {U54NS127758//Foundation for the National Institutes of Health/ ; R35ES030443//Foundation for the National Institutes of Health/ ; R35 ES030443/ES/NIEHS NIH HHS/United States ; P42 ES004699/ES/NIEHS NIH HHS/United States ; AG057842//Foundation for the National Institutes of Health/ ; 5P42ES004699//Foundation for the National Institutes of Health/ ; A25-1690//Harrington Discovery Institute, University Hospitals/ ; 25PRE1365157//American Heart Association/ ; RF1 AG079336/AG/NIA NIH HHS/United States ; AG079336//Foundation for the National Institutes of Health/ ; P20GM104357//Foundation for the National Institutes of Health/ ; TRIBA Faculty Startup Fund//Augusta University/ ; }, abstract = {Alzheimer's Disease and Alzheimer's Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1c levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.}, }
@article {pmid39903342, year = {2025}, author = {Wang, J and Meng, X and Yang, J and Tang, Y and Zeng, F and Wang, Y and Chen, Z and Chen, D and Zou, R and Liu, W}, title = {Improvements in Exercise for Alzheimer's Disease: Highlighting FGF21-Induced Cerebrovascular Protection.}, journal = {Neurochemical research}, volume = {50}, number = {2}, pages = {95}, pmid = {39903342}, issn = {1573-6903}, support = {No. 2023JJ30429//the Hunan Provincial Natural Science Foundation/ ; No. kq2202251//Changsha City Natural Science Foundation/ ; }, mesh = {Humans ; *Fibroblast Growth Factors/metabolism ; *Alzheimer Disease/prevention & control/metabolism ; Animals ; Exercise/physiology ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Exercise Therapy ; }, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease. Currently, it has shown a trend of earlier onset, with most patients experiencing a progressive decline in cognitive function following the disease's onset, which places a heavy burden on society and family. Since no drug cure for AD exists, exploring new ways for its treatment and prevention has become critical. Early vascular damage is an initial trigger for neuronal injury in AD, underscoring the importance of vascular health in the early stages of the disease. Patients with early AD experience abnormal blood-brain barrier transport of amyloid-β (Aβ) peptides, with excess Aβ being deposited in the cerebral vasculature. The toxic effects of Aβ lead to abnormalities in cerebrovascular structure and function. Fibroblast growth factor21 (FGF21) is an endocrine factor that positively regulates energy homeostasis and glucose-lipid metabolism. Notably, it is one of the effective targets for metabolic disease prevention and treatment. Recent studies have found that FGF21 has anti-aging and vasoprotective effects, with receptors for FGF21 present in the brain. Exercise stimulates the liver to produce large amounts of FGF21, which enters the blood-brain barrier with the blood to exert neurovascular protection. Therefore, we review the biological properties of FGF21, its role in the cerebrovascular structure and function in AD, and the mechanism of exercise-regulated FGF21 action on AD-related cerebrovascular changes, aiming to provide a new theoretical basis for using exercise to ameliorate degenerative neurological diseases.}, }
@article {pmid39903213, year = {2025}, author = {Nester, CO and De Vito, AN and Prieto, S and Kunicki, ZJ and Strenger, J and Harrington, KD and Roque, N and Sliwinski, MJ and Rabin, LA and Thompson, LI}, title = {Association of Subjective Cognitive Concerns With Performance on Mobile App-Based Cognitive Assessment in Cognitively Normal Older Adults: Observational Study.}, journal = {JMIR aging}, volume = {8}, number = {}, pages = {e64033}, pmid = {39903213}, issn = {2561-7605}, support = {T32 AG049676/AG/NIA NIH HHS/United States ; U2C AG060408/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Female ; *Mobile Applications ; Male ; Aged ; *Cognition/physiology ; Middle Aged ; Neuropsychological Tests ; Cognitive Dysfunction/diagnosis/psychology ; }, abstract = {BACKGROUND: Subjective cognitive concerns (SCCs) may be among the earliest clinical symptoms of dementia. There is growing interest in applying a mobile app-based cognitive assessment to remotely screen for cognitive status in preclinical dementia, but the relationship between SCC and relevant mobile assessment metrics is uncertain.
OBJECTIVE: This study aimed to characterize the relationship between SCC and adherence, satisfaction, and performance on mobile app assessments in cognitively unimpaired older adults.
METHODS: Participants (N=122; Meanage=68.85 [SD 4.93] years; Meaneducation=16.85 [SD 2.39] years; female: n=82, 66.7%; White:n=106, 86.2%) completed 8 assessment days using Mobile Monitoring of Cognitive Change (M2C2), an app-based testing platform, with brief daily sessions within morning, afternoon, and evening time windows (24 total testing sessions). M2C2 includes digital working memory, processing speed, and episodic memory tasks. Participants provided feedback about their satisfaction and motivation related to M2C2 upon study completion. SCC was assessed using the Cognitive Function Instrument. Regression analyses evaluated the association between SCC and adherence, satisfaction, and performance on M2C2, controlling for age, sex, depression, and loneliness. Linear-mixed effects models evaluated whether SCC predicted M2C2 subtest performance over the 8-day testing period, controlling for covariates.
RESULTS: SCC was not associated with app satisfaction or protocol motivation, but it was significantly associated with lower rates of protocol adherence (ß=-.20, P=.37, 95% CI -.65 to -.02). Higher SCC endorsement significantly predicted worse overall episodic memory performance (ß=-.20, P=.02, 95% CI -.02 to -.01), but not working memory or processing speed. There was a main effect of SCC on working memory performance at day 1 (estimate=-1.05, SE=0.47, P=.03) and a significant interaction between SCC and working memory over the 8-day period (estimate=0.05, SE=0.02, P=.03), such that SCC was associated with initially worse, then progressively better working memory performance.
CONCLUSIONS: SCCs are associated with worse overall memory performance on mobile app assessments, patterns of cognitive inefficiency (variable working memory), and mildly diminished adherence across an 8-day assessment period. Findings suggest that mobile app assessments may be sensitive to subtle cognitive changes, with important implications for early detection and treatment for individuals at risk for dementia.}, }
@article {pmid39902055, year = {2025}, author = {Pillarisetti, L and Agrawal, DK}, title = {Semaglutide: Double-edged Sword with Risks and Benefits.}, journal = {Archives of internal medicine research}, volume = {8}, number = {1}, pages = {1-13}, pmid = {39902055}, issn = {2688-5654}, support = {R01 HL144125/HL/NHLBI NIH HHS/United States ; R01 HL147662/HL/NHLBI NIH HHS/United States ; R25 AI179582/AI/NIAID NIH HHS/United States ; }, abstract = {Type 2 Diabetes Mellitus therapy has evolved over the years to now include a new class of therapeutics, semaglutide. This article reviews the mechanism of action and formulation of semaglutide therapy, potential benefits, contraindications, adverse effects, and drug interactions. Oral and subcutaneous semaglutide therapies have shown effectiveness in improving glycemic control, weight loss, and reducing cardiovascular risks associated with diabetes mellitus. Semaglutide has also shown potential in being used as a therapeutic strategy in Alzheimer's disease due to its anti-neuroinflammatory effects and being used to treat polycystic ovary syndrome. However, semaglutide therapy is also associated with concerning adverse effects like acute pancreatitis, anesthetic risks like pulmonary aspiration or residual gastric content, acute kidney injury, acute gallbladder injury, nonarteritic anterior ischemic optic neuropathy and diabetic retinopathy. Contraindications of semaglutide include history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, and pregnancy. Drug interactions to consider with semaglutide therapy include those also used in diabetes treatment, like metformin, as well as anti-psychotics, due to anti-psychotics associated weight gain. The findings of this article emphasize the need for a cross-disciplinary approach to understand the molecular mechanisms and clinical implications of semaglutide on patients with complex medical histories and treatment regimens. The potential anesthetic risks of semaglutide therapy warrant careful consideratiion with ethical concerns. Further studies can assess if there is a need to modify pre-operative guidelines to account for patient using semaglutide and how delayed gastric emptying and constitpation will affect surgical outcomes and complications. While semaglutide therapy for diabetes mellitus has been established, there is a need for extensive research on repurposing semaglutide in neurodegenerative disease treatment.}, }
@article {pmid39901180, year = {2025}, author = {Wang, S and Li, B and Li, J and Cai, Z and Hugo, C and Sun, Y and Qian, L and Tcw, J and Chui, HC and Dikeman, D and Asante, I and Louie, SG and Bennett, DA and Arvanitakis, Z and Remaley, AT and Kerman, BE and Yassine, HN}, title = {Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {15}, pmid = {39901180}, issn = {1750-1326}, support = {R01 AG067063/AG/NIA NIH HHS/United States ; R01 AG055770/AG/NIA NIH HHS/United States ; RF1 AG076124/AG/NIA NIH HHS/United States ; RF1AG076124, R01AG055770, R01AG067063, R01AG054434, R21AG056518, and P30AG066530/AG/NIA NIH HHS/United States ; R21 AG056518/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; R01 AG054434/AG/NIA NIH HHS/United States ; }, mesh = {*ATP Binding Cassette Transporter 1/metabolism ; Animals ; Humans ; *Cellular Senescence/physiology ; Mice ; *Alzheimer Disease/metabolism ; *Cholesterol/metabolism ; *Lysosomes/metabolism ; *Apolipoprotein E4/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Brain/metabolism ; Male ; Mice, Knockout ; }, abstract = {BACKGROUND: Cellular senescence, a hallmark of aging, has been implicated in Alzheimer's disease (AD) pathogenesis. Cholesterol accumulation is known to drive cellular senescence; however, its underlying mechanisms are not fully understood. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis, and its expression and trafficking are altered in APOE4 and AD models. However, the role of ABCA1 trafficking in cellular senescence associated with APOE4 and AD remains unclear.
METHODS: We examined the association between cellular senescence and ABCA1 expression in human postmortem brain samples using transcriptomic, histological, and biochemical analyses. Unbiased proteomic screening was performed to identify the proteins that mediate cellular ABCA1 trafficking. We created ABCA1 knock out cell lines and mouse models to validate the role of ABCA1 in cholesterol-induced mTORC1 activation and senescence. Additionally, we used APOE4-TR mice and induced pluripotent stem cell (iPSC) models to explore cholesterol-ABCA1-senescence pathways.
RESULTS: Transcriptomic profiling of the human dorsolateral prefrontal cortex from the Religious Order Study/Memory Aging Project (ROSMAP) cohort revealed the upregulation of cellular senescence transcriptome signatures in AD, which correlated with ABCA1 expression and oxysterol levels. Immunofluorescence and immunoblotting analyses confirmed increased lipofuscin-stained lipids and ABCA1 expression in AD brains and an association with mTOR phosphorylation. Discovery proteomics identified caveolin-1, a sensor of cellular cholesterol accumulation, as a key promoter of ABCA1 endolysosomal trafficking. Greater caveolin-1 expression was observed in APOE4-TR mouse models and AD human brains. Oxysterol induced mTORC1 activation and senescence were regulated by ABCA1 lysosomal trapping. Treatment of APOE4-TR mice with cyclodextrin reduced brain oxysterol levels, ABCA1 lysosome trapping, mTORC1 activation, and attenuated senescence and neuroinflammation markers. In human iPSC-derived astrocytes, the reduction of cholesterol by cyclodextrin attenuated inflammatory responses.
CONCLUSIONS: Oxysterol accumulation in APOE4 and AD induced ABCA1 and caveolin-1 expression, contributing to lysosomal dysfunction and increased cellular senescence markers. This study provides novel insights into how cholesterol metabolism accelerates features of brain cellular senescence pathway and identifies therapeutic targets to mitigate these processes.}, }
@article {pmid39900729, year = {2025}, author = {Sohn, E and Kim, BY and Kim, YJ and Kim, JH and Jeong, SJ}, title = {Bauhinia coccinea extract prevents memory loss induced by scopolamine through activation of antiapoptotic and antioxidant pathways in mice.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {4037}, pmid = {39900729}, issn = {2045-2322}, support = {KSN1515293//Korea Institute of Oriental Medicine,South Korea/ ; NRF-2020R1A2C2012917//National Research Foundation of Korea/ ; }, mesh = {Animals ; *Scopolamine ; *Memory Disorders/drug therapy/chemically induced/metabolism ; *Plant Extracts/pharmacology/chemistry ; *Apoptosis/drug effects ; Mice ; *Antioxidants/pharmacology ; Male ; *Mice, Inbred ICR ; *Bauhinia/chemistry ; Oxidative Stress/drug effects ; Acetylcholinesterase/metabolism ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; Brain/metabolism/drug effects/pathology ; Acetylcholine/metabolism ; }, abstract = {Alzheimer's disease (AD) is characterized by oxidative stress-mediated memory dysfunction and neuronal cell death. This study investigated the effects of an ethanol extract from Bauhinia coccinea (EEBC) on memory impairment and neuronal damage in a memory deficit mouse model. EEBC was administered to ICR mice at doses of 50, 100, or 200 mg/kg daily for 3 weeks. Cognitive impairment was induced via scopolamine (SCO) injection. Brain tissues were analyzed for acetylcholine (ACh) levels, acetylcholinesterase (AChE) activity, neuronal apoptosis, and antioxidant markers. Behavioral tests showed that SCO injection induced memory loss, whereas EEBC significantly ameliorated SCO-mediated memory impairment. EEBC regulated the cholinergic system by decreasing ACh levels and enhancing AChE activity. Nissl staining and immunohistochemistry for NeuN showed that EEBC exerted neuroprotective effects in SCO-injected mice brains. Moreover, EEBC significantly reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic cells increased by SCO treatment. EEBC also reversed the SCO-induced changes in apoptosis-related protein expression in brain tissues. Furthermore, EEBC significantly reduced malondialdehyde levels and activated catalase in SCO-administered brains. Quantitative RNA sequencing showed involvement of lipid metabolism in EEBC memory function regulation. Thus, EEBC is a promising candidate for attenuating AD progression as it targets the cholinergic system and neuronal apoptosis.}, }
@article {pmid39898049, year = {2025}, author = {Fuller, OK and McLennan, ED and Egan, CL and Perera, N and Terry, LV and Pyun, J and de Mendonca, M and Telles, GD and Smeuninx, B and Burrows, EL and Siddiqui, G and Creek, DJ and Scott, JW and Pearen, MA and Fonseka, P and Nicolazzo, JA and Mathivanan, S and Hannan, AJ and Ramm, GA and Whitham, M and Febbraio, MA}, title = {Extracellular vesicles contribute to the beneficial effects of exercise training in APP/PS1 mice.}, journal = {iScience}, volume = {28}, number = {2}, pages = {111752}, pmid = {39898049}, issn = {2589-0042}, abstract = {Exercise improves cognitive function in Alzheimer's disease (AD) via mechanism that are not fully clear. Here, we first examined the effect of voluntary exercise training (VET) on energy metabolism and cognitive function in the APP/PS1 transgenic mouse (Tg) model of familial AD. Next, we profiled extracellular vesicles (EVs) and examined whether they may play a role in the protective effects of VET via intranasal administration of EVs, purified from the blood of sedentary (sEV) and/or acutely exercised (eEV) donor wild-type mice into APP/PS1Tg mice. We show that VET reduced resting energy expenditure (REE) and improved cognition in APP/PS1 Tg mice. Administration of eEV, but not sEV, also reduced REE, but had no effect on cognition. Taken together, these data show that exercise is effective intervention to improve symptoms of AD in APP/PS1Tg mice. In addition, eEVs mediate some of these effects, implicating EVs in the treatment of age-related neurodegenerative diseases.}, }
@article {pmid39897852, year = {2025}, author = {Artime-Naveda, F and Hevia, D and Alonso-Arias, R and Martínez, C and Quirós-González, I and Cernuda-Cernuda, R and Alvarez-Artime, A and Menéndez-Valle, I and Sainz, RM and Mayo, JC}, title = {Interplay between oxidative stress, neuroinflammatory cytokines and melatonin in Alzheimer's disease: Insights from cerebrospinal fluid analysis.}, journal = {Heliyon}, volume = {11}, number = {2}, pages = {e41841}, pmid = {39897852}, issn = {2405-8440}, abstract = {BACKGROUND: Among neurodegenerative disorders Alzheimer's disease (AD) displays the highest prevalence and the projected increase in its incidence will require new advances in early diagnosis and treatment, particularly for distinguishing AD from other dementias. While beta-amyloid (Aβ) and tau biomarkers are currently used to discriminate AD from other tauopathies and dementias, additional indicators could enhance patient stratification for specific dementia types. The present study was designed to find potential associations among the classic neurologic markers, Aβ, total and phospho-tau (T-tau and P-tau), with other biomarkers including melatonin and its oxidative-derived metabolite, Formyl-N-acetyl-5-methoxykynurenamine (AFMK) levels, assayed in patients' cerebrospinal fluid (CSF) taken previously for diagnostic purposes. Other factors previously associated with the aetiology of AD, including redox indicators or proinflammatory biomarkers, were also included.
METHODS: The cross-sectional study included a cohort of 148 patients showing signs of dementia. A group of age-matched patients without neurological disorders were used as controls. CSF levels of Aβ, T-tau and P-tau were assayed, and patients were further classified according to threshold CSF levels of the three markers protein following the criteria of NIA-AA.
RESULTS: Correlational and group analysis showed a positive association between oxidative stress and neuronal damage. TNF-α negatively correlated with CSF Aβ levels (amyloid plaques) while only RANTES/CCL5 correlated positively with T-tau and P-tau. Qualitative analysis of the proinflammatory cytokines assayed showed a higher detection level in Aβ-positive patients. Regarding melatonin in the CSF, indolamine levels did not correlate with its major oxidative-derived metabolite, i.e., AFMK. However, melatonin CSF levels were significantly reduced in AD patients but not in OT. On the contrary, AFMK showed the opposite pattern, with higher levels in samples from patients displaying high T-tau and P-tau levels. Neuroinflammation was associated with Aβ deposits (low concentration in CSF), while oxidative stress significantly correlated with high T-tau and P-tau levels. Finally, among all the parameters assayed in CSF samples from the cohort studied, P-tau, in combination with antioxidant capacity, offered the best ROC curve for the diagnostic capacity to discriminate between AD and OT, showing an 85 % specificity.
CONCLUSION: While oxidative stress is instead associated with high T- and P-tau levels, higher neuroinflammatory cytokines correlate with low CSF Aβ levels. An intriguing lack of correlation between neuroinflammation and melatonin found in this study could be as a result of sample size and requires further studies with a larger sample size. Even though indolamine levels in CSF drop significantly in AD, they do not correlate with AFMK, suggesting a different kynurenine synthesis source. None of them appear to discriminate between AD and OT. Finally, among all the parameters assayed in this study, P-tau in combination with antioxidant capacity, offered the best ROC curve for the diagnostic ability capacity to discriminate between AD and OT, showing an 85 % specificity. This study holds the potential to significantly improve patient stratification and contribute to the early diagnosis and treatment of Alzheimer's disease.}, }
@article {pmid39897171, year = {2024}, author = {Sharo, C and Zhang, J and Zhai, T and Bao, J and Garcia-Epelboim, A and Mamourian, E and Shen, L and Huang, Z}, title = {Repurposing FDA-Approved Drugs Against Potential Drug Targets Involved in Brain Inflammation Contributing to Alzheimer's Disease.}, journal = {Targets (Basel)}, volume = {2}, number = {4}, pages = {446-469}, pmid = {39897171}, issn = {2813-3137}, support = {R01 AG071470/AG/NIA NIH HHS/United States ; U01 AG066833/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease is a neurodegenerative disease that continues to have a rising number of cases. While extensive research has been conducted in the last few decades, only a few drugs have been approved by the FDA for treatment, and even fewer aim to be curative rather than manage symptoms. There remains an urgent need for understanding disease pathogenesis, as well as identifying new targets for further drug discovery. Alzheimer's disease (AD) is known to stem from a build-up of amyloid beta (Aβ) plaques as well as tangles of tau proteins. Furthermore, inflammation in the brain is known to arise from the degeneration of tissue and the build-up of insoluble material. Therefore, there is a potential link between the pathology of AD and inflammation in the brain, especially as the disease progresses to later stages where neuronal death and degeneration levels are higher. Proteins that are relevant to both brain inflammation and AD thus make ideal potential targets for therapeutics; however, the proteins need to be evaluated to determine which targets would be ideal for potential drug therapeutic treatments, or 'druggable'. Druggability analysis was conducted using two structure-based methods (i.e., Drug-Like Density analysis and SiteMap), as well as a sequence-based approach, SPIDER. The most druggable targets were then evaluated using single-nuclei sequencing data for their clinical relevance to inflammation in AD. For each of the top five targets, small molecule docking was used to evaluate which FDA approved drugs were able to bind with the chosen proteins. The top targets included DRD2 (inhibits adenylyl cyclase activity), C9 (binds with C5B8 to form the membrane attack complex), C4b (binds with C2a to form C3 convertase), C5AR1 (GPCR that binds C5a), and GABA-A-R (GPCR involved in inhibiting neurotransmission). Each target had multiple potential inhibitors from the FDA-approved drug list with decent binding infinities. Among these inhibitors, two drugs were found as top inhibitors for more than one protein target. They are C15H14N2O2 and v316 (Paracetamol), used to treat pain/inflammation originally for cataracts and relieve headaches/fever, respectively. These results provide the groundwork for further experimental investigation or clinical trials.}, }
@article {pmid39897094, year = {2025}, author = {Li, Y and Jönsson, L}, title = {The health and economic burden of brain disorders: Consequences for investment in diagnosis, treatment, prevention and R&D.}, journal = {Cerebral circulation - cognition and behavior}, volume = {8}, number = {}, pages = {100377}, pmid = {39897094}, issn = {2666-2450}, abstract = {Brain disorders are prevalent across all age groups but particularly in the elderly, highlighting the importance of preserving brain health in ageing populations. There have been few previous studies to address the complete scope of burden of brain disorders, including direct and indirect costs as well as intangible costs from morbidity and mortality. We seek to illustrate the full health and economic impact of brain disorders by leveraging data from previous large-scale epidemiological and health economic studies to estimate the total direct, indirect and intangible cost of brain disorders in 2019. Two alternative methods were used to estimate indirect costs: the human capital (HC) method (data from the CBDE2010 study), and the willingness-to-pay (WTP) per DALY method (data from GBD2019). Less than 10% of the costs of Alzheimer's disease (AD) and other dementias are incurred by the health care system, while Alzheimer's disease and other dementias is the costliest condition using the HC approach and stroke is the costliest condition due to the large number of life-years lost, followed by AD using the WTP approach. Using per-capita GDP as a proxy for WTP, the indirect costs were nearly four times higher compared to the conventional HC approach. We found that Indirect costs of brain disorders outweigh the direct costs for diagnosis, treatment and care even in high-income countries with advanced, universally accessible systems in Europe. There is likely underinvestment in R&D for brain disorders, and health care systems may lack sufficient incentives to invest in their treatment and prevention.}, }
@article {pmid39897039, year = {2025}, author = {Kim, Y and Ha, TY and Lee, MS and Chang, KA}, title = {Regulatory Mechanisms and Therapeutic Implications of Lysosomal Dysfunction in Alzheimer's Disease.}, journal = {International journal of biological sciences}, volume = {21}, number = {3}, pages = {1014-1031}, pmid = {39897039}, issn = {1449-2288}, mesh = {*Lysosomes/metabolism ; Humans ; *Alzheimer Disease/metabolism ; *Autophagy/physiology ; Animals ; Microglia/metabolism ; }, abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs) formed from hyperphosphorylated Tau, and widespread neuronal loss. The autophagy-lysosomal pathway plays a crucial role in maintaining cellular homeostasis by degrading and recycling of damaged organelles and aggregate amyloid proteins implicated in AD. Lysosomes are key effectors of autophagic process, responsible for the breakdown of a variety of damaged organelles and aggregate or dysfunctional proteins. This review examines the role of lysosomal dysfunction in AD pathophysiology, focusing on genetic factors, acidification abnormalities, and other contributing factors. We also explore the involvement of lysosomal dysfunction of microglia in AD pathology, and cover the role of lysosomal stress response (LSR) in cellular response to neuronal injury associated with AD. Furthermore, we discuss potential therapeutic strategies targeting lysosomal proteolysis pathway and addressing lysosomal dysfunction for AD treatment, including the pharmacologically activating lysosomal activity, regulating TFEB, and considering other emerging approaches.}, }
@article {pmid39896474, year = {2025}, author = {Pinto, A and Haytural, H and Loss, CM and Alvarez, C and Ertas, A and Curtis, O and Williams, AR and Murphy, G and Salleng, K and Gografe, S and Altıntaş, A and Kafri, T and Barres, R and Deshmukh, AS and van Praag, H}, title = {Muscle Cathepsin B treatment improves behavioral and neurogenic deficits in a mouse model of Alzheimer's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39896474}, issn = {2692-8205}, support = {R01 HL155986/HL/NHLBI NIH HHS/United States ; }, abstract = {Muscle secretes factors during exercise that enhance cognition. Myokine Cathepsin B (Ctsb) is linked to memory function, but its role in neurodegenerative disease is unclear. Here we show that AAV-vector-mediated Ctsb overexpression in skeletal muscle in an Alzheimer's Disease (AD) mouse model (APP/PS1), improves motor coordination, memory function and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment modifies hippocampal, muscle and plasma proteomic profiles to resemble that of wildtype controls. Conversely, in wildtype mice, Ctsb expression causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. In AD mice, Ctsb treatment increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult hippocampal neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes, and reduces inflammatory responses. In muscle, Ctsb expression elevates protein translation in AD mice, whereas in wildtype mice mitochondrial proteins decrease. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.}, }
@article {pmid39896355, year = {2024}, author = {Henríquez, PA and Araya, N}, title = {Multimodal Alzheimer's disease classification through ensemble deep random vector functional link neural network.}, journal = {PeerJ. Computer science}, volume = {10}, number = {}, pages = {e2590}, pmid = {39896355}, issn = {2376-5992}, abstract = {Alzheimer's disease (AD) is a condition with a complex pathogenesis, sometimes hereditary, characterized by the loss of neurons and synapses, along with the presence of senile plaques and neurofibrillary tangles. Early detection, particularly among individuals at high risk, is critical for effective treatment or prevention, yet remains challenging due to data variability and incompleteness. Most current research relies on single data modalities, potentially limiting comprehensive staging of AD. This study addresses this gap by integrating multimodal data-including clinical and genetic information-using deep learning (DL) models, with a specific focus on random vector functional link (RVFL) networks, to enhance early detection of AD and mild cognitive impairment (MCI). Our findings demonstrate that ensemble deep RVFL (edRVFL) models, when combined with effective data imputation techniques such as Winsorized-mean (Wmean), achieve superior performance in detecting early stages of AD. Notably, the edRVFL model achieved an accuracy of 98.8%, precision of 98.3%, recall of 98.4%, and F1-score of 98.2%, outperforming traditional machine learning models like support vector machines, random forests, and decision trees. This underscores the importance of integrating advanced imputation strategies and deep learning techniques in AD diagnosis.}, }
@article {pmid39895108, year = {2025}, author = {Tezen, D and Koçhan Kızılkılıç, E and Akkan Suzan, A and Öz, A and Gulmammadli, N and Arslan, S and Kızılkılıç, O and Konukoğlu, D and Demirbilek, V and Bozluolçay, M}, title = {Correlation between serum YKL-40 and VILIP 1 levels and brain volume in dementia patients.}, journal = {Geriatrics & gerontology international}, volume = {25}, number = {3}, pages = {374-379}, doi = {10.1111/ggi.15075}, pmid = {39895108}, issn = {1447-0594}, mesh = {Humans ; *Chitinase-3-Like Protein 1/blood ; Male ; Female ; Aged ; *Alzheimer Disease/blood/diagnostic imaging/pathology ; *Biomarkers/blood ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/pathology ; *Neurocalcin/blood ; Case-Control Studies ; Aged, 80 and over ; Organ Size ; Middle Aged ; Dementia/blood ; }, abstract = {AIM: Alzheimer's disease (AD) is a chronic, progressive cognitive disorder characterized by prominent episodic memory impairment. The contribution of neuronal damage and neuroinflammation to this process has been investigated by measuring various substances. Two of the most promising substances in serum and plasma studies are visinin-like protein 1 (VILIP-1) and tyrosine (Y), lysine (K), leucine (L)-40 (YKL-40). These markers may lead to early diagnosis and new treatment options.
METHODS: Serum VILIP-1 and YKL-40 levels were analyzed in 33 probable AD patients and 23 healthy controls. Cranial magnetic resonance imaging (MRI) was used for volumetric measurements. The results were compared with the control group and then the correlation analyze between markers and volumetric measurements of the patient group was achieved.
RESULTS: The right and left hippocampus and amygdala, left medial temporal, right rostral anterior cingulate, total brain, cortex, white matter, gray matter, subcortical gray matter, right and left total cortex volumes of the probable AD group were significantly lower than those of the control group. In the correlation analysis, the YKL-40 level and left posterior cingulate volume and the VILIP-1 level and left amygdala volume were negatively correlated.
CONCLUSIONS: In AD, there is atrophy of the limbic structures, cortex, and white matter. While the relationship between these regions and neurodegenerative markers remains unclear, our findings highlight a notable correlation between YKL-40 and VILIP-1 levels and the left amygdala and left posterior cingulate cortex, respectively. Geriatr Gerontol Int 2025; 25: 374-379.}, }
@article {pmid39894909, year = {2025}, author = {Thorwald, MA and Sta Maria, NS and Chakhoyan, A and O'Day, PA and Jacobs, RE and Zlokovic, B and Finch, CE}, title = {Iron chelation by oral deferoxamine treatment decreased brain iron and iron signaling proteins.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {4}, pages = {1180-1190}, doi = {10.1177/13872877241313031}, pmid = {39894909}, issn = {1875-8908}, mesh = {Animals ; *Deferoxamine/pharmacology ; *Iron/metabolism ; *Mice, Inbred C57BL ; *Iron Chelating Agents/pharmacology/therapeutic use ; Mice ; *Brain/metabolism/drug effects/diagnostic imaging ; Magnetic Resonance Imaging ; Administration, Oral ; Signal Transduction/drug effects ; Male ; Amyloid beta-Protein Precursor/genetics/metabolism ; }, abstract = {BACKGROUND: Deferoxamine (DFO) and other iron chelators are clinically used for cancer and stroke. They may also be useful for Alzheimer's disease (AD) to diminish iron from microbleeds. DFO may also stimulate antioxidant membrane repair which is impaired during AD. DFO and other chelators do enter the brain despite some contrary reports.
OBJECTIVE: Low dose, oral DFO was given in lab chow to wildtype (WT) C57BL/6 mice to evaluate potential impact on iron levels, iron-signaling and storage proteins, and amyloid-β protein precursor (AβPP) and processing enzymes. Young WT mice do not have microbleeds or disrupted blood-brain barrier of AD mice.
METHODS: Iron was measured by MRI and chemically after two weeks of dietary DFO. Cerebral cortex was examined for changes in iron metabolism, antioxidant signaling, and AβPP processing by western blot.
RESULTS: DFO decreased brain iron 18% (p < 0.01) estimated by R2 MRI and decreased seven major proteins that mediate iron metabolism by at least 25%. The iron storage proteins ferritin light and heavy chain decreased by at least 30%. AβPP and secretase enzymes also decreased by 30%.
CONCLUSIONS: WT mice respond to DFO with decreased AβPP, amyloid processing enzymes, and antioxidant repair. Potential DFO treatment for early-stage AD by DFO should consider the benefits of lowered AβPP and secretase enzymes.}, }
@article {pmid39894843, year = {2025}, author = {Chen, L and Shen, Q and Liu, Y and Zhang, Y and Sun, L and Ma, X and Song, N and Xie, J}, title = {Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {31}, pmid = {39894843}, issn = {2059-3635}, support = {32471049//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32170984//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32200802//National Natural Science Foundation of China (National Science Foundation of China)/ ; ZR2020YQ23//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; ZR2024MC153//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; }, mesh = {Humans ; *Iron/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; *Homeostasis ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Copper/metabolism ; Metals/metabolism ; Ferroptosis/genetics ; Oxidative Stress ; Zinc/metabolism ; Alzheimer Disease/metabolism/genetics/pathology/drug therapy ; Animals ; }, abstract = {As essential micronutrients, metal ions such as iron, manganese, copper, and zinc, are required for a wide range of physiological processes in the brain. However, an imbalance in metal ions, whether excessive or insufficient, is detrimental and can contribute to neuronal death through oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation. These processes have been found to be involved in the pathological mechanisms of neurodegenerative diseases. In this review, the research history and milestone events of studying metal ions, including iron, manganese, copper, and zinc in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), will be introduced. Then, the upstream regulators, downstream effector, and crosstalk of mental ions under both physiologic and pathologic conditions will be summarized. Finally, the therapeutic effects of metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives for the treatment of neurodegenerative diseases will be discussed. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed. This review will not only provide a comprehensive understanding of the role of metal ions in disease development but also offer perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.}, }
@article {pmid39894695, year = {2025}, author = {Leikin, JB}, title = {Foreword for Atypical Alzheimer's dementia: Addressing the subtypes, epidemiology, atypical presentations, diagnostic biomarkers, and treatment updates.}, journal = {Disease-a-month : DM}, volume = {}, number = {}, pages = {101862}, doi = {10.1016/j.disamonth.2025.101862}, pmid = {39894695}, issn = {1557-8194}, }
@article {pmid39894694, year = {2025}, author = {Vora, N and Patel, P and Marsool, MDM and Marsool, ADM and Sunasra, R and Ladani, P and Pati, S and Khoont, D and Prajjwal, P and Ranjan, R}, title = {Atypical Alzheimer's dementia: Addressing the subtypes, epidemiology, atypical presentations, diagnostic biomarkers, and treatment updates.}, journal = {Disease-a-month : DM}, volume = {}, number = {}, pages = {101863}, doi = {10.1016/j.disamonth.2025.101863}, pmid = {39894694}, issn = {1557-8194}, abstract = {Alzheimer's disease is a progressive neurodegenerative disorder that primarily affects the elderly population; and is characterized by the gradual loss of memory, cognition, and ability to carry out daily activities. However, a growing body of research indicates that there exists a subtype of Alzheimer's disease known as Atypical Alzheimer's disease. Atypical Alzheimer's disease is a rare form of dementia that differs from the typical presentation of Alzheimer's disease, such as variations in the age of onset, distribution of brain pathology, and clinical symptoms. The patients affected have a younger age of onset and have predominantly visual, language, executive function, motor, and behavioral dysfunction. The diagnosis requires a comprehensive neurological evaluation with specific attention to cognitive and behavioral changes while ruling out other potential causes of dementia. Emerging biomarkers including CSF profiles, amyloid and tau PET imaging, and advanced neuroimaging techniques offer promising avenues for improving diagnostic accuracy and understanding disease mechanisms. In this article, we focus on atypical presentations seen in the posterior cortical variant, frontal variant, progressive aphasic variant, corticobasal syndrome and look at the specific biomarkers used in the diagnosis of each variant along with focusing on the treatment of the disease. We also aim to provide an understanding of Atypical Alzheimer's disease, its clinical features, the biomarkers helping in diagnosing the disease, the current treatment guidelines, and the current scientific advancements in the field.}, }
@article {pmid39894421, year = {2025}, author = {Valderrama-Mantilla, AI and Martín-Cuevas, C and Gómez-Garrido, A and Morente-Montilla, C and Crespo-Facorro, B and García-Cerro, S}, title = {Shared molecular signature in Alzheimer's disease and schizophrenia: A systematic review of the reelin signaling pathway.}, journal = {Neuroscience and biobehavioral reviews}, volume = {169}, number = {}, pages = {106032}, doi = {10.1016/j.neubiorev.2025.106032}, pmid = {39894421}, issn = {1873-7528}, mesh = {Humans ; *Reelin Protein ; *Alzheimer Disease/metabolism/genetics ; *Schizophrenia/metabolism/genetics/physiopathology ; *Signal Transduction/physiology ; *Nerve Tissue Proteins/metabolism/genetics ; *Extracellular Matrix Proteins/metabolism/genetics ; *Cell Adhesion Molecules, Neuronal/metabolism/genetics ; *Serine Endopeptidases/genetics/metabolism ; Animals ; }, abstract = {The Reelin signaling pathway, particularly the RELN-APOER2-DAB1 complex, has emerged as a key contributor to the neuropathology of Alzheimer's disease (AD) and Schizophrenia (SZ). Despite being distinct clinical conditions, these disorders exhibit similar patterns of cognitive decline, including early disruptions in synaptic function and memory impairments. Notably, individuals with SZ have a 2-4 fold increased risk of developing AD or other dementias, highlighting potential shared molecular mechanisms, and positioning Reelin as a pivotal link between them. This systematic review explores the role of Reelin and its signaling components across these disorders. In AD, Reelin disruption correlates with hallmark features such as Tau hyperphosphorylation, amyloid-beta accumulation, and cognitive deficits. In SZ, alterations in Reelin signaling, including epigenetic modifications affecting RELN expression, are linked to disruptions in neuronal development and synaptic plasticity, particularly in the parietal and prefrontal cortices. Additionally, genomic studies reveal specific RELN variants and allelic imbalances that may influence disease severity and treatment response in SZ, suggesting RELN's role as a potential biomarker for therapeutic outcomes. Region-specific Reelin alterations in both AD and SZ suggest differing impacts yet underscore a potential common molecular origin. Our findings highlight the Reelin pathway as a molecular convergence point, warranting further investigation as a therapeutic and diagnostic target for AD, SZ, and potentially other neuropsychiatric disorders. The interplay between genetic and epigenetic regulation of RELN may provide novel insights into neurodegeneration, with implications for personalized intervention strategies in AD and SZ.}, }
@article {pmid39893357, year = {2025}, author = {Bhatia, V and Chandel, A and Minhas, Y and Kushawaha, SK}, title = {"Advances in biomarker discovery and diagnostics for alzheimer's disease".}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39893357}, issn = {1590-3478}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by intracellular neurofibrillary tangles with tau protein and extracellular β-amyloid plaques. Early and accurate diagnosis is crucial for effective treatment and management.
OBJECTIVE: The purpose of this review is to investigate new technologies that improve diagnostic accuracy while looking at the current diagnostic criteria for AD, such as clinical evaluations, cognitive testing, and biomarker-based techniques.
METHODS: A thorough review of the literature was done in order to assess both conventional and contemporary diagnostic methods. Multimodal strategies integrating clinical, imaging, and biochemical evaluations were emphasised. The promise of current developments in biomarker discovery was also examined, including mass spectrometry and artificial intelligence.
RESULTS: Current diagnostic approaches include cerebrospinal fluid (CSF) biomarkers, imaging tools (MRI, PET), cognitive tests, and new blood-based markers. Integrating these technologies into multimodal diagnostic procedures enhances diagnostic accuracy and distinguishes dementia from other conditions. New technologies that hold promise for improving biomarker identification and diagnostic reliability include mass spectrometry and artificial intelligence.
CONCLUSION: Advancements in AD diagnostics underscore the need for accessible, minimally invasive, and cost-effective techniques to facilitate early detection and intervention. The integration of novel technologies with traditional methods may significantly enhance the accuracy and feasibility of AD diagnosis.}, }
@article {pmid39893320, year = {2025}, author = {Groo, AC and Curel, T and Malzert-Fréon, A and Séguy, L and Bento, O and Corvaisier, S and Culerier, T and Legrand, R and Callizot, N and Henriques, A and Culley, G and Claeysen, S and Rochais, C and Dallemagne, P}, title = {Evidence from a mouse model supports repurposing an anti-asthmatic drug, bambuterol, against Alzheimer's disease by administration through an intranasal route.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {155}, pmid = {39893320}, issn = {2399-3642}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Administration, Intranasal ; Mice ; *Disease Models, Animal ; *Terbutaline/analogs & derivatives/administration & dosage/pharmacology/pharmacokinetics ; *Drug Repositioning ; Anti-Asthmatic Agents/administration & dosage/pharmacology/pharmacokinetics ; Male ; Rats ; Hippocampus/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Neuroprotective Agents/administration & dosage/pharmacology/pharmacokinetics ; Neurons/drug effects/metabolism ; }, abstract = {Bambuterol is a long-acting anti-asthmatic prodrug which releases terbutaline. Terbutaline is an agonist of the β2-adrenergic receptors which is formed by decarbamoylation of bambuterol by butyrylcholinesterase. Inhibition of the latter, as well as activation of β2-AR, are of interest for the treatment of Alzheimer's disease (AD). Combining these two activities, bambuterol could express a good clinical efficacy against AD. The present work firstly confirmed the capacity of bambuterol to display in cellulo neuroprotective activities, reduction of Tau hyperphosphorylation and preservation of synapses in rat hippocampal neuronal cultures intoxicated with Aβ peptides. Further, bambuterol, in the form of a liposomal gel, showed a good bioavailability in CNS after intranasal administration, which should reduce any side effects linked to peripheral terbutaline release. Indeed, even if the latter is more selective than other β2-mimetics towards bronchial β2-AR, cardiovascular effects (tachycardia, arrhythmias…) could occur upon cardiac β1-AR activation. Finally, intranasal administration of low doses of bambuterol gel in mice intoxicated with Aβ peptides, prevented long-term spatial memory impairment and showed beneficial effects on the survival of neurons and on synapse preservation.}, }
@article {pmid39893139, year = {2025}, author = {Smith, EE and Phillips, NA and Feldman, HH and Borrie, M and Ganesh, A and Henri-Bhargava, A and Desmarais, P and Frank, A and Badhwar, A and Barlow, L and Bartha, R and Best, S and Bethell, J and Bhangu, J and Black, SE and Bocti, C and Bronskill, SE and Burhan, AM and Calon, F and Camicioli, R and Campbell, B and Collins, DL and Dadar, M and DeMarco, ML and Ducharme, S and Duchesne, S and Einstein, G and Fisk, JD and Gawryluk, JR and Grossman, L and Ismail, Z and Itzhak, I and Joshi, M and Harrison, A and Kröger, E and Kumar, S and Laforce, R and Lanctot, KL and Lau, M and Lee, L and Masellis, M and Massoud, F and Mitchell, SB and Montero-Odasso, M and Myers Barnett, K and Nygaard, HB and Pasternak, SH and Peters, J and Rajah, MN and Robillard, JM and Rockwood, K and Rosa-Neto, P and Seitz, DP and Soucy, JP and Trenaman, SC and Wellington, CL and Zadem, A and Chertkow, H and , }, title = {Use of lecanemab and donanemab in the Canadian healthcare system: Evidence, challenges, and areas for future research.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {3}, pages = {100068}, doi = {10.1016/j.tjpad.2025.100068}, pmid = {39893139}, issn = {2426-0266}, mesh = {Humans ; Canada ; *Alzheimer Disease/drug therapy ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antibodies, Monoclonal/therapeutic use ; Delivery of Health Care ; Amyloid beta-Peptides/metabolism ; }, abstract = {Lecanemab and donanemab are monoclonal antibody therapies that remove amyloid-beta from the brain. They are the first therapies that alter a fundamental mechanism, amyloid-beta deposition, in Alzheimer disease (AD). To inform Canadian decisions on approval and use of these drugs, the Canadian Consortium on Neurodegeneration in Aging commissioned Work Groups to review evidence on the efficacy and safety of these new therapies, as well as their projected impacts on Canadian dementia systems of care. We included persons with lived experience with Alzheimer disease in the discussion about the benefits and harms. Our review of the trial publications found high quality evidence of statistically significant group differences, but also recognized that there are mixed views on the clinical relevance of the observed differences and the value of therapy for individual patients. The drugs are intended for persons with early AD, at a stage of mild cognitive impairment or mild dementia. If patients are treated, then confirmation of AD by positron emission tomography or cerebrospinal fluid analysis and monitoring for risk of amyloid-related imaging abnormalities was recommended, as done in the clinical trials, although it would strain Canadian resource capacity. More data are needed to determine the size of the potentially eligible treatment population in Canada.}, }
@article {pmid39892653, year = {2025}, author = {Muratori, BG and da Veiga, IET and Medeiros, GN and Silva, SMSE and Soliani, AG and Prado, CM and Cerutti, SM}, title = {Standardized extract of Ginkgo biloba induced memory consolidation in female mice with hypofunction of vesicular acetylcholine transporter.}, journal = {Behavioural brain research}, volume = {482}, number = {}, pages = {115455}, doi = {10.1016/j.bbr.2025.115455}, pmid = {39892653}, issn = {1872-7549}, mesh = {Animals ; *Ginkgo biloba ; Female ; *Vesicular Acetylcholine Transport Proteins/metabolism ; *Plant Extracts/pharmacology/administration & dosage ; Mice ; *Hippocampus/drug effects/metabolism ; *Memory Consolidation/drug effects/physiology ; Recognition, Psychology/drug effects/physiology ; Donepezil/pharmacology ; Avoidance Learning/drug effects/physiology ; Anxiety/drug therapy/metabolism ; Ginkgo Extract ; }, abstract = {Basal forebrain cholinergic neurons are pivotal for cholinergic signaling in the neocortex and hippocampal formation, crucially implicated in neurodegenerative diseases like late-onset Alzheimer's disease (LOAD), recognition memory impairments, and decision-making. The acetylcholine transporter (VAChT) is essential for loading acetylcholine into synaptic vesicles. Building on our previous findings showing that Ginkgo biloba extract (EGb) preserves recognition memory, we hypothesized EGb would enhance memory in female mice with varying VAChT reductions. We also explored whether reduced cholinergic signaling induces anxiety-like behavior and whether EGb could alleviate such symptoms. Three-month-old female mice with severe VAChT reduction (knockdown homozygotes; VAChT KD[HOM]), moderate reduction (heterozygotes; VAChT KD[HET]), and wild-type (WT) mice received the vehicle, 5 mg/kg Donepezil, or EGb at doses of 250, 500, and 1000 mg/kg for 30 days. Memory assessments included aversive tasks like discriminative avoidance memory and non-aversive tasks like object recognition and location memory. We assessed VAChT protein expression in the hippocampal formation (HF) using Western blotting and quantified VAChT-immunopositive cells (IR[+]) in specific HF subfields (dCA1, dCA3, dDG) using immunohistochemistry. Chronic EGb treatment significantly improved long-term memory in female VAChT KD[HOM] mice in object recognition and locations memories in a dose-dependent manner, unlike Donepezil. Enhanced memory was correlated with an increase in VAChT-IR[+] cells in the dCA1 of VAChT KD[HOM] mice. Additionally, EGb reduced VAChT-IR[+] cells in the dDG of VAChT KD[HET] mice, which was associated with decreased anxiety-like behavior. These findings suggest that EGb effectively mitigates deficits caused by cholinergic deficiency in hippocampal-dependent memory consolidation, thereby improving our understanding of its role in modulating long-term memory and hippocampal plasticity.}, }
@article {pmid39892523, year = {2025}, author = {Kuo, YF and Westra, J and Harvey, EP and Raji, MA}, title = {Use of Medications for Opioid Use Disorder in Older Adults.}, journal = {American journal of preventive medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.amepre.2025.01.019}, pmid = {39892523}, issn = {1873-2607}, abstract = {INTRODUCTION: The American population diagnosed with opioid use disorder is growing, particularly those aged ≥65 years. Less than 30% of opioid use disorder patients receive medication for opioid use disorder, and even fewer older adults.
METHODS: Using 20% national Medicare data, beneficiaries aged over 65 years diagnosed with opioid use disorder in 2017-2022 were selected to assess the trend and types of medication for opioid use disorder use, including methadone, buprenorphine, or naltrexone. In the 2022 cohort (n=69,380), a multivariable logistic regression model was constructed to examine the factors associated with use of medication for opioid use disorder. Analyses were performed in 2024.
RESULTS: Use of medications for opioid use disorder among older adults increased from 4.8% in 2017 to 7.5% in 2019 and 15.0% in 2022. The larger increase coincided with implementation of a new Medicare payment policy covering methadone for opioid use disorder. About 79% of opioid use disorder patients had chronic pain and arthritis; 50% had anemia, depression, or anxiety. Males, Black patients, Hispanic patients, older patients, and rural residents had lower odds of receiving medication for opioid use disorder. Enrollees with dual coverage from Medicaid had higher odds of receiving medication for opioid use disorder. Patients with alcohol or tobacco use disorders, anxiety, depression, hypothyroidism, or liver disease were more likely to receive medication for opioid use disorder; conversely, those with non-Alzheimer's dementia, cancer, chronic kidney disease, stroke, chronic pain, or arthritis were less likely to receive medication for opioid use disorder.
CONCLUSIONS: The rate of medication for opioid use disorder use was low in older adults. The disparity in medication for opioid use disorder use underscores the need for improved access to comprehensive opioid treatment programs and increased medication for opioid use disorder coverage. Additional studies of treatment patterns are also warranted.}, }
@article {pmid39892386, year = {2025}, author = {Vandal, M and Institoris, A and Reveret, L and Korin, B and Gunn, C and Hirai, S and Jiang, Y and Lee, S and Lee, J and Bourassa, P and Mishra, RC and Peringod, G and Arellano, F and Belzil, C and Tremblay, C and Hashem, M and Gorzo, K and Elias, E and Yao, J and Meilandt, B and Foreman, O and Roose-Girma, M and Shin, S and Muruve, D and Nicola, W and Körbelin, J and Dunn, JF and Chen, W and Park, SK and Braun, AP and Bennett, DA and Gordon, GRJ and Calon, F and Shaw, AS and Nguyen, MD}, title = {Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction.}, journal = {Neuron}, volume = {113}, number = {6}, pages = {876-895.e11}, doi = {10.1016/j.neuron.2025.01.006}, pmid = {39892386}, issn = {1097-4199}, mesh = {Animals ; Male ; Mice ; Female ; Humans ; *Reelin Protein ; *Adaptor Proteins, Signal Transducing/genetics/metabolism ; Cerebrovascular Circulation/physiology ; Alzheimer Disease/metabolism/genetics ; Endothelial Cells/metabolism ; Nerve Tissue Proteins/genetics/metabolism ; Amyloid beta-Peptides/metabolism ; Cell Adhesion Molecules, Neuronal/metabolism/genetics ; Sex Characteristics ; Extracellular Matrix Proteins/metabolism/genetics ; Brain/metabolism ; Mice, Transgenic ; Serine Endopeptidases/metabolism/genetics ; Cerebrovascular Disorders/metabolism/genetics/physiopathology ; Mice, Inbred C57BL ; Neurovascular Coupling/physiology ; Mice, Knockout ; Sex Factors ; Cytoskeletal Proteins ; LDL-Receptor Related Proteins ; }, abstract = {Polymorphisms in CD2-associated protein (CD2AP) predispose to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. Here, we show that loss of CD2AP in cerebral blood vessels is associated with cognitive decline in AD subjects and that genetic downregulation of CD2AP in brain vascular endothelial cells impairs memory function in male mice. Animals with reduced brain endothelial CD2AP display altered blood flow regulation at rest and during neurovascular coupling, defects in mural cell activity, and an abnormal vascular sex-dependent response to Aβ. Antagonizing endothelin-1 receptor A signaling partly rescues the vascular impairments, but only in male mice. Treatment of CD2AP mutant mice with reelin glycoprotein that mitigates the effects of CD2AP loss function via ApoER2 increases resting cerebral blood flow and even protects male mice against the noxious effect of Aβ. Thus, endothelial CD2AP plays critical roles in cerebrovascular functions and represents a novel target for sex-specific treatment in AD.}, }
@article {pmid39891801, year = {2025}, author = {Eo, H and Kim, SH and Ju, IG and Lee, JH and Oh, MS and Kim, YJ}, title = {NXP032 Improves Memory Impairment Through Suppression of Tauopathy in PS19 Mice and Attenuates Okadaic Acid-Induced Tauopathy in SH-SY5Y Cells.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {20}, number = {1}, pages = {10}, pmid = {39891801}, issn = {1557-1904}, support = {2022R1A6A3A01087061//National Research Foundation of Korea/ ; NRF-1711194418//National Research Foundation of Korea/ ; GS-5-JO-NON-20222608//the BK21 FOUR program of National Research Foundation of Korea/ ; KHU-20222128//Nexmos/ ; }, mesh = {Animals ; *Tauopathies/drug therapy/pathology/metabolism ; *Okadaic Acid/pharmacology ; Mice ; Humans ; *Mice, Transgenic ; *Memory Disorders/drug therapy/chemically induced ; tau Proteins/metabolism ; Cell Line, Tumor ; Ascorbic Acid/pharmacology/therapeutic use ; Male ; }, abstract = {Tauopathy is widely observed in multiple neurodegenerative diseases such as Alzheimer's disease (AD) and characterized by abnormal tau protein phosphorylation, aggregation and its accumulation as a form of neurofibrillary tangle (NFT) in the brain. However, there are no effective treatments targeting tau pathology in the AD. Vitamin C is known to reduce tauopathy and modulate one of its regulators called glycogen synthase kinase 3 (GSK3) in the body. Nevertheless, vitamin C has a limitation of its stability during metabolism due to its chemical properties. Thus, in the current study, NXP032 (a vitamin C/aptamer complex) was tested as a candidate for tau-targeting treatment because it can preserve antioxidative efficacy of vitamin C before it can reach the target tissue. In this context, the current study aimed to investigate the therapeutic effect of NXP032 on tauopathy in vivo and in vitro. As a result, NXP032 attenuated cognitive and memory decline and reduced NFT and tau hyperphosphorylation in the P301S mutant human tau transgenic mice (or called PS19 mice). In addition, NXP032 suppressed neuroinflammation found in the PS19 mice. Furthermore, NXP032 protected SH-SY5Y human neuroblastoma cells from okadaic acid (OKA)-induced cytotoxicity. Especially, 10 ng/ml of NXP032 reduced tau hyperphosphorylation and GSK3 activation though its phosphorylation at Tyr216 site which were promoted by OKA treatment in the SH-SY5Y cells. Taken together, our results suggest that NXP032 might be a potential therapy for AD and tauopathy-related neurodegenerative disorders as well.}, }
@article {pmid39891777, year = {2025}, author = {Abdelhamed, HG and Hassan, AA and Sakraan, AA and Al-Deeb, RT and Mousa, DM and Aboul Ezz, HS and Noor, NA and Khadrawy, YA and Radwan, NM}, title = {Brain interleukins and Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {40}, number = {2}, pages = {116}, pmid = {39891777}, issn = {1573-7365}, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Interleukins/metabolism ; *Brain/metabolism/pathology ; Animals ; }, abstract = {The central nervous system (CNS) is immune-privileged by several immuno-modulators as interleukins (ILs). ILs are cytokines secreted by immune cells for cell-cell signaling communications and affect the functions of the CNS. ILs were reported to orchestrate different molecular and cellular mechanisms of both physiological and pathological events, through overproduction or over-expression of their receptors. They interact with numerous receptors mediating pro-inflammatory and/or anti-inflammatory actions. Interleukins have been implicated to participate in neurodegenerative diseases. They play a critical role in Alzheimer's disease (AD) pathology which is characterized by the over-production of pro-inflammatory ILs. These may aggravate neurodegeneration, in addition to their contribution to detrimental mechanisms as oxidative stress, and excitotoxicity. However, recent research on the relation between ILs and AD revealed major discrepancies. Most of the major ILs were shown to play both pro- and anti-inflammatory roles in different experimental settings and models. The interactions between different ILs through shared pathways also add to the difficulty of drawing solid conclusions. In addition, targeting the different ILs has not yielded consistent results. The repeated failures of therapeutic drugs in treating AD necessitate the search for novel agents targeting multiple mechanisms of the disease pathology. In this context, the understanding of interleukins and their roles throughout the disease progression and interaction with other systems in the brain may provide promising therapeutic targets for the prevention or treatment of AD.}, }
@article {pmid39891738, year = {2025}, author = {Brennan, GS and Goriely, A}, title = {A network aggregation model for amyloid- β dynamics and treatment of Alzheimer's diseases at the brain scale.}, journal = {Journal of mathematical biology}, volume = {90}, number = {2}, pages = {22}, pmid = {39891738}, issn = {1432-1416}, support = {EP/R020205/1//Engineering and Physical Sciences Research Council/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Amyloid beta-Peptides/metabolism ; *Brain/metabolism ; *Mathematical Concepts ; Protein Aggregation, Pathological/metabolism/drug therapy ; Disease Progression ; Models, Neurological ; }, abstract = {Neurodegenerative diseases are associated with the assembly of specific proteins into oligomers and fibrillar aggregates. At the brain scale, these protein assemblies can diffuse through the brain and seed other regions, creating an autocatalytic protein progression. The growth and transport of these assemblies depend on various mechanisms that can be targeted therapeutically. Here, we use spatially-extended nucleation-aggregation-fragmentation models for the dynamics of prion-like neurodegenerative protein-spreading in the brain to study the effect of different drugs on whole-brain Alzheimer's disease progression.}, }
@article {pmid39891708, year = {2025}, author = {Knezovic, A and Salkovic-Petrisic, M}, title = {Cholinergic neurotransmission in the brain of streptozotocin-induced rat model of sporadic Alzheimer's disease: long-term follow up.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {39891708}, issn = {1435-1463}, support = {10/64//Unity through Knowledge Fund/ ; 108-1080003-0020//Ministarstvo znanosti i obrazovanja/ ; }, abstract = {Rats treated intracerebroventricularly with streptozotocin (STZ-icv) develop pathologic features, which resemble those in Alzheimer's disease and have been proposed as a non-transgenic model for sporadic type of the disease (sAD). We aimed to characterize cholinergic transmission in the rat brain as a function of STZ-icv dose and time after the treatment. Acetylcholinesterase (AChE) activity and expression of muscarinic (M1, M4) and nicotinic (α7) receptors, cholin acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP) were measured in hippocampus (HPC) and parietotemporal cortex (CTX) of STZ-icv and age-matched control rats one week, and one, three, six and nine months after the icv administration of STZ (0.3, 1 and 3 mg/kg), respectively. Cholinergic and astroglial changes were found most pronounced with a highest STZ dose in time-dependent manner. The cortex and hippocampus exhibited specific alterations in cholinergic transmission following STZ-icv administration, with either similar or distinct patterns depending on the parameter observed: increased AChE activity in HPC and invariable in CTX; increased M4 and ChAT levels in both regions; substantial cortical M1 level increment and moderate hippocampal M1 decrement; and decreased α7 levels in both regions, with subsequent increase observed only in HPC. Alterations in cerebral cholinergic neurotransmission in STZ-icv rat model were mostly following a threephasic time pattern: acute response (Phase I), complete/partial compensation (Phase II), and reappearance/progression of changes (Phase III). Staging structure of cholinergic changes in STZ-icv rat model might be speculated to partly correlate with cholinergic pathology in clinical AD stages.}, }
@article {pmid39891319, year = {2025}, author = {Canet, G and Zussy, C and Vitalis, M and Morin, F and Chevallier, N and Hunt, H and Claeysen, S and Blaquière, M and Marchi, N and Planel, E and Meijer, OC and Desrumaux, C and Givalois, L}, title = {Advancing Alzheimer's disease pharmacotherapy: efficacy of glucocorticoid modulation with dazucorilant (CORT113176) in preclinical mouse models.}, journal = {British journal of pharmacology}, volume = {182}, number = {9}, pages = {1930-1956}, doi = {10.1111/bph.17457}, pmid = {39891319}, issn = {1476-5381}, support = {SM2016#1512//Association France Alzheimer & Fédération pour la Recherche sur le Cerveau/ ; MND202003011477-OPA//Fondation pour la Recherche Médicale/ ; ANR-11-LABEX-0021-LipSTIC//Agence Nationale de la Recherche/ ; ANR-AAP2022-R22102FF-EpiNeurAge//Agence Nationale de la Recherche/ ; Postdoctoral fellowship//Alzheimer Society of Canada/ ; CBS2 PhD program//Université de Montpellier/ ; MUSE-AAP20REC-FRS09-GAiA//Université de Montpellier/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice, Transgenic ; Disease Models, Animal ; Receptors, Glucocorticoid/metabolism ; Mice ; *Glucocorticoids/metabolism/blood ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Humans ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND AND PURPOSE: Exposure to chronic stress and high levels of glucocorticoid hormones in adulthood has been associated with cognitive deficits and increased risk of Alzheimer's disease (AD). Dazucorilant has recently emerged as a selective glucocorticoid receptor (NR3C1) modulator, exhibiting efficacy in counteracting amyloid-β toxicity in an acute model of AD. We aim to assess the therapeutic potential of dazucorilant in reversing amyloid and tau pathologies through the inhibition of glucocorticoid receptor pathological activity, and providing additional evidence for its consideration in AD treatment.
EXPERIMENTAL APPROACH: The efficacy of dazucorilant was evaluated in two transgenic mouse models of amyloid pathology. The slowly progressing J20 and the aggressively pathological 5xFAD mice. Behavioural analysis was conducted to evaluate welfare, cognitive performances and anxiety levels. The activity of the glucocorticoid receptor system, neuroinflammation, amyloid burden and tau phosphorylation were examined in hippocampi.
KEY RESULTS: In both AD models, chronic treatment with dazucorilant improved working and long-term spatial memories along with the inhibition of glucocorticoid receptor-dependent pathogenic processes and the normalization of plasma glucocorticoid levels. Dazucorilant treatment also resulted in a reduction in tau hyperphosphorylation and amyloid production and aggregation. Additionally, dazucorilant seemed to mediate a specific re-localization of activated glial cells onto amyloid plaques in J20 mice, suggesting a restoration of physiological neuroinflammatory processes.
CONCLUSION AND IMPLICATIONS: Dazucorilant exhibited sustained disease-modifying effects in two AD models. Given that this compound has demonstrated safety and tolerability in human subjects, our results provide pre-clinical support for conducting clinical trials to evaluate its potential in AD.}, }
@article {pmid39890844, year = {2025}, author = {Xie, Z and Situ, Y and Deng, L and Liang, M and Ding, H and Guo, Z and Xu, Q and Liang, Z and Shao, Z}, title = {Identification of therapeutic targets for Alzheimer's Disease Treatment using bioinformatics and machine learning.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {3888}, pmid = {39890844}, issn = {2045-2322}, mesh = {*Alzheimer Disease/drug therapy/genetics/metabolism/pathology ; Humans ; *Machine Learning ; *Computational Biology/methods ; Gene Expression Profiling/methods ; Gene Regulatory Networks ; Molecular Targeted Therapy/methods ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder that currently lacks effective treatment options. This study aimed to identify potential therapeutic targets for the treatment of AD using comprehensive bioinformatics methods and machine learning algorithms. By integrating differential gene expression analysis, weighted gene co-expression network analysis, Mfuzz clustering, single-cell RNA sequencing, and machine learning algorithms including LASSO regression, SVM-RFE, and random forest, five hub genes related to AD, including PLCB1, NDUFAB1, KRAS, ATP2A2, and CALM3 were identified. PLCB1, in particular, exhibited the highest diagnostic value in AD and showed significant correlation with Braak stages and neuronal expression. Furthermore, Noscapine, PX-316, and TAK-901 were selected as potential therapeutic drugs for AD based on PLCB1. This research provides a comprehensive and reliable method for the discovery of AD therapeutic targets and the construction of diagnostic models, offering important insights and directions for future AD treatment strategies and drug development.}, }
@article {pmid39887820, year = {2025}, author = {Lu, X and Bai, S and Feng, L and Yan, X and Lin, Y and Huang, J and Liao, X and Wang, H and Li, L and Yang, Z and Yan, LYC and Yang, B and Wang, M and Jin, J and Zong, Z and Jiang, Z and Huang, C and Liu, C and Zhang, X and Su, H and Wang, Y and Lee, WY and Jiang, X and Tortorella, MD and Lin, S and Ko, H and Li, G}, title = {Cranial bone maneuver ameliorates Alzheimer's disease pathology via enhancing meningeal lymphatic drainage function.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14518}, pmid = {39887820}, issn = {1552-5279}, support = {82172430//National Natural Science Foundation of China/ ; 82272505//National Natural Science Foundation of China/ ; 82472454//National Natural Science Foundation of China/ ; 81874000//National Natural Science Foundation of China/ ; 82122001//National Natural Science Foundation of China/ ; 14108720//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; 14121721//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; 14202920//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; 14100122//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; 14119124//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; 14113723//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; N_CUHK472/22//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; C7030-18G//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; C6027-19GF//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; C7074-21GF//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; T13-402/17-N//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; AoE/M-402/20//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; AoE/M-604/16//University Grants Committee, Research Grants Council of the Hong Kong Special Administrative Region, China/ ; 17180831//Heath Medical Research Fund (HMRF) of Food and Health Bureau Hong Kong/ ; 08190416//Heath Medical Research Fund (HMRF) of Food and Health Bureau Hong Kong/ ; 09203436//Heath Medical Research Fund (HMRF) of Food and Health Bureau Hong Kong/ ; PRP/050/19FX//Hong Kong Innovation Technology Commission Funds/ ; 2023A1515011040//Natural Science Foundation of Guangdong Province/ ; }, mesh = {Animals ; *Alzheimer Disease/therapy ; Mice ; *Meninges ; *Skull ; *Disease Models, Animal ; Mice, Transgenic ; Lymphangiogenesis/physiology ; Lymphatic Vessels ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia. Recent research highlights meningeal lymphatics as key regulators in neurological diseases, suggesting that enhancing their drainage function could be a potential therapeutic strategy for AD. Our proof-of-concept study demonstrated that cranial bone transport can improve meningeal lymphatic drainage function and promote ischemic stroke recovery.
METHODS: This study defined cranial bone maneuver (CBM) technique. After osteotomy, a small circular bone flap was made and attached to an external fixator for subsequent maneuver in a controlled fashion for a defined period using 5xFAD mice.
RESULTS: CBM treatment improved memory functions, reduced amyloid deposits, and promoted meningeal lymphatic drainage function. CBM induced cascades of inflammatory and lymphangiogenic processes in skull and meninges. Meningeal lymphatics are indispensable elements for the therapeutic effects of CBM.
DISCUSSION: CBM might be a promising innovative therapy for AD management, warranting further clinical investigation.
HIGHLIGHTS: Cranial bone maneuver (CBM) alleviated memory deficits and amyloid depositions. CBM promoted meningeal lymphangiogenesis and lymphatic drainage function. The beneficial effects of CBM lasted for a long time following the CBM procedures. CBM induced cascades of inflammatory and lymphangiogenic processes in the meninges. Meningeal lymphatic vessels are indispensable elements for CBM therapeutic effects.}, }
@article {pmid39887549, year = {2025}, author = {Andrews, D and Ducharme, S and Chertkow, H and Sormani, MP and Collins, DL and , }, title = {The higher benefit of lecanemab in males compared to females in CLARITY AD is probably due to a real sex effect.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14467}, pmid = {39887549}, issn = {1552-5279}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; //Brain Canada Foundation/ ; //McGill University/ ; FRN-165921/CAPMC/CIHR/Canada ; //Famille Louise & André Charron/ ; }, mesh = {Humans ; Male ; Female ; *Alzheimer Disease ; Aged ; Cognitive Dysfunction ; Sex Characteristics ; Sex Factors ; Disease Progression ; }, abstract = {INTRODUCTION: The phase 3 trial CLARITY AD found lecanemab slowed cognitive decline by 27%. However, subgroup analyses indicated a significant 31% sex difference in the effect and suggested no or limited effectiveness in females. We used simulations constrained by the trial design to determine whether that difference reflects a pre-existing sex difference in Alzheimer's disease progression or was a random event.
METHODS: Simulations were generated using linear mixed models of cognitive decline fit to data from Alzheimer's Disease Neuroimaging Initiative participants satisfying CLARITY AD inclusion criteria.
RESULTS: The statistically non-significant 7.9% smaller cognitive decline rate in our cohort's males versus females does not explain CLARITY AD's 31% sex difference in lecanemab's effect. A ≥ 31% difference occurred randomly in only 12 of our 10,000 simulations (0.0012 probability).
DISCUSSION: CLARITY AD's sex difference was probably not random. Lecanemab is likely less effective in females than males, but we cannot conclude the drug is ineffective in females.
HIGHLIGHTS: Lecanemab is more clinically effective in males than in females. Forest plots should only report subgroup-specific effects in well-powered subgroups. Trial simulations based on real data enable investigation of subgroup drug effects. We cannot conclude that lecanemab is clinically ineffective in females. A sex difference in lecanemab's efficacy could be linked to its action mechanism.}, }
@article {pmid39887500, year = {2025}, author = {Bittner, T and Tonietto, M and Klein, G and Belusov, A and Illiano, V and Voyle, N and Delmar, P and Scelsi, MA and Gobbi, S and Silvestri, E and Barakovic, M and Napolitano, A and Galli, C and Abaei, M and Blennow, K and Barkhof, F}, title = {Biomarker treatment effects in two phase 3 trials of gantenerumab.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14414}, pmid = {39887500}, issn = {1552-5279}, support = {//F. Hoffmann-La Roche AG/ ; }, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Biomarkers/cerebrospinal fluid/blood ; *Amyloid beta-Peptides/cerebrospinal fluid/blood ; *Positron-Emission Tomography ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Male ; *Magnetic Resonance Imaging ; Female ; *tau Proteins/cerebrospinal fluid/blood ; Aged ; Brain/diagnostic imaging/pathology ; Middle Aged ; Treatment Outcome ; }, abstract = {INTRODUCTION: We report biomarker treatment effects in the GRADUATE I and II phase 3 studies of gantenerumab in early Alzheimer's disease (AD).
METHODS: Amyloid and tau positron emission tomography (PET), volumetric magnetic resonance imaging (vMRI), cerebrospinal fluid (CSF), and plasma biomarkers used to assess gantenerumab treatment related changes on neuropathology, neurodegeneration, and neuroinflammation over 116 weeks.
RESULTS: Gantenerumab reduced amyloid PET load, CSF biomarkers of amyloid beta (Aβ)40, total tau (t-tau), phosphorylated tau 181 (p-tau181), neurogranin, S100 calcium-binding protein B (S100B), neurofilament light (NfL), alpha-synuclein (α-syn), neuronal pentraxin-2 (NPTX2), and plasma biomarkers of t-tau, p-tau181, p-tau217, and glial fibrillary acidic protein (GFAP) while increasing plasma Aβ40, Aβ42. vMRI showed increased reduction in whole brain volume and increased ventricular expansion, while hippocampal volume was unaffected. Tau PET showed no treatment effect.
DISCUSSION: Robust treatment effects were observed for multiple biomarkers in GRADUATE I and II. Comparison across anti-amyloid antibodies indicates utility of p-tau and GFAP as biomarkers of amyloid plaque removal while NfL and tau PET seem unsuitable as consistent indicators of clinical efficacy. vMRI might be confounded by non-neurodegenerative brain volume changes. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV IDENTIFIER): NCT03444870 and NCT03443973.
HIGHLIGHTS: Gantenerumab significantly reduced brain amyloid load. Tau positron emission tomography showed no treatment effect in a small subset of participants. Volumetric magnetic resonance imaging showed increased whole brain volume reduction under treatment while hippocampal volume was unaffected. Robust treatment effects on cerebrospinal fluid and plasma biomarkers were found, despite lack of clinical efficacy.}, }
@article {pmid39887156, year = {2025}, author = {Ellakwa, DE and Rashed, LA and Ali, OS and El-Sabbagh, NA}, title = {A study to determine the effect of nano-selenium and thymoquinone on the Nrf2 gene expression in Alzheimer's disease.}, journal = {Future science OA}, volume = {11}, number = {1}, pages = {2458434}, pmid = {39887156}, issn = {2056-5623}, abstract = {INTRODUCTION: Alzheimer's disease is a developing public health concern in aging communities that affects a sizable section of the global population. The risk of Alzheimer's disease increases with age; it affects one-third of males and two-thirds of women[.] This research attempts to assess the effect of nano-selenium and thymoquinone on Nrf2 gene expression levels in Alzheimer's disease (AD).
METHODS: There were five identical groups of 50 albino male rats: a control group that was healthy; an AD positive control group; an AD group that received nano-selenium (5 mg/kg); an AD group that received thymoquinone (2 mg/kg); and an AD group that received both. The duration of treatment was 4 weeks. The levels of Nrf2 in brain tissues were evaluated using real-time PCR.
RESULTS: Nrf2 mean expression levels in the nano-selenium-treated rats, the thymoquinone-treated rats, and the rats that were given both treatments all increased significantly compared to AD rats with no treatment.
CONCLUSIONS: This study showed that nano-selenium and thymoquinone elevated Nrf2 gene expression levels in AD.}, }
@article {pmid39886794, year = {2025}, author = {Gupta, B and Malviya, R and Sundram, S and Sridhar, SB and Singh, DP}, title = {Melatonin Overexpression in the Management of Alzheimer's Disease: Therapeutic Exploration.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266327614241121050448}, pmid = {39886794}, issn = {1873-4294}, abstract = {Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is characterized by the accumulation of neurofibrillary tangles and β-amyloid plaques, leading to a decline in cognitive function. AD is characterized by tau protein hyperphosphorylation and extracellular β-amyloid accumulation. Even after much research, there are still no proven cures for AD. The neuroprotective, anti-inflammatory, and antioxidant qualities of melatonin, a hormone mostly produced by the pineal gland, have drawn interest as a possible treatment option for AD. This study looks at new evidence that suggests melatonin overexpression to be a promising therapy option for AD. Melatonin levels naturally decline with age and decrease more significantly in individuals with AD, worsening neurodegenerative processes. Melatonin has therapeutic potential as it inhibits Aβ formation, prevents amyloid fibril extension through structure-dependent interactions, and protects neurons from Aβ-induced toxicity. Melatonin promotes neurogenesis, which is decreased in AD, suggesting it may treat the disease's many pathologies. The review emphasizes the importance of melatonin's mechanisms of action, including its capacity to reduce neuroinflammation, regulate mitochondrial function, scavenge free radicals, and influence apoptotic pathways. As research into AD continues, this article provides a forward-looking perspective on how future studies could leverage melatonin's multifaceted neuroprotective properties to develop more effective treatments for AD.}, }
@article {pmid39886562, year = {2024}, author = {Nouh, CD and Younes, K}, title = {Diagnosis and Management of Progressive Corticobasal Syndrome.}, journal = {Current treatment options in neurology}, volume = {26}, number = {7}, pages = {319-338}, pmid = {39886562}, issn = {1092-8480}, support = {P30 AG066515/AG/NIA NIH HHS/United States ; }, abstract = {PURPOSE OF REVIEW: The purpose of this review is to discuss the clinical, radiological, and neuropathological heterogeneity of corticobasal syndrome (CBS), which can complicate the determination of underlying etiology and lead to inaccurate treatment decisions. Though the most common diagnosis is corticobasal degeneration (CBD), the spectrum of underlying pathologies expands beyond CBD and can overlap with other neurodegenerative diseases and even the neuroimmunology field. We will review possible clinical presentations and cues that can point towards the etiology. We will also discuss the most recent available biomarkers to facilitate a more accurate diagnosis. Additionally, we will examine current and future potential therapeutic options.
RECENT FINDINGS: The range of available fluid and neuroimaging biomarkers is increasing and some are already being used in clinical practice. While the treatment of neurodegenerative diseases is largely aimed at managing symptoms, early detection and accurate diagnosis are crucial for initiating early management and enrollment in clinical trials. The recent approval of a disease-modifying therapy for Alzheimer's disease (AD) has raised hopes for the development of more therapeutic options for other proteinopathies. Several candidates are currently being studied in clinical trial pipelines, particularly those targeting tau pathology.
SUMMARY: Recent advancements in understanding the genetic and neuropathological diversity of CBS, along with the promising development of fluid and imaging biomarkers, are driving clinical trial research forward, instilling optimism for creating more effective disease-modifying treatments for brain proteinopathies.}, }
@article {pmid39886067, year = {2025}, author = {Vecchio, D and Piras, F and Natalizi, F and Banaj, N and Pellicano, C and Piras, F}, title = {Evaluating conversion from mild cognitive impairment to Alzheimer's disease with structural MRI: a machine learning study.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcaf027}, pmid = {39886067}, issn = {2632-1297}, abstract = {Alzheimer's disease is a disabling neurodegenerative disorder for which no effective treatment currently exists. To predict the diagnosis of Alzheimer's disease could be crucial for patients' outcome, but current Alzheimer's disease biomarkers are invasive, time consuming or expensive. Thus, developing MRI-based computational methods for Alzheimer's disease early diagnosis would be essential to narrow down the phenotypic measures predictive of cognitive decline. Amnestic mild cognitive impairment (aMCI) is associated with higher risk for Alzheimer's disease, and here, we aimed to identify MRI-based quantitative rules to predict aMCI to possible Alzheimer's disease conversion, applying different machine learning algorithms sequentially. At baseline, T1-weighted brain images were collected for 104 aMCI patients and processed to obtain 146 volumetric measures of cerebral grey matter regions [regions of interest (ROIs)]. One year later, patients were classified as converters (aMCI-c = 32) or non-converters, i.e. clinically and neuropsychologically stable (aMCI-s = 72) based on cognitive performance. Feature selection was performed by random forest (RF), and the identified seven ROIs volumetric data were used to implement support vector machine (SVM) and decision tree (DT) classification algorithms. Both SVM and DT reached an average accuracy of 86% in identifying aMCI-c and aMCI-s. DT found a critical threshold volume of the right entorhinal cortex (EC-r) as the first feature for differentiating aMCI-c/aMCI-s. Almost all aMCI-c had an EC-r volume <1286 mm[3], while more than half of the aMCI-s patients had a volume above the identified threshold for this structure. Other key regions for the classification between aMCI-c/aMCI-s were the left lateral occipital (LOC-l), the middle temporal gyrus and the temporal pole cortices. Our study reinforces previous evidence suggesting that the morphometry of the EC-r and LOC-l best predicts aMCI to Alzheimer's disease conversion. Further investigations are needed prior to deeming our findings as a broadly applicable predictive framework. However, here, a first indication was derived for volumetric thresholds that, being easy to obtain, may assist in early identification of Alzheimer's disease in clinical practice, thus contributing to establishing MRI as a useful non-invasive prognostic instrument for dementia onset.}, }
@article {pmid39886010, year = {2024}, author = {Petersen, KK and Nallapu, BT and Lipton, RB and Grober, E and Ezzati, A}, title = {MRI-guided clustering of patients with mild dementia due to Alzheimer's disease using self-organizing maps.}, journal = {Neuroimage. Reports}, volume = {4}, number = {4}, pages = {}, pmid = {39886010}, issn = {2666-9560}, support = {R21 AG056920/AG/NIA NIH HHS/United States ; R01 AG062622/AG/NIA NIH HHS/United States ; R01 AG048642/AG/NIA NIH HHS/United States ; K23 AG063993/AG/NIA NIH HHS/United States ; U10 NS077308/NS/NINDS NIH HHS/United States ; RF1 AG054548/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; R01 AG060933/AG/NIA NIH HHS/United States ; U24 NS113847/NS/NINDS NIH HHS/United States ; UG3 FD006795/FD/FDA HHS/United States ; R56 AG057548/AG/NIA NIH HHS/United States ; RF1 AG057531/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a phenotypically and pathologically heterogenous neurodegenerative disorder. This heterogeneity can be studied and disentangled using data-driven clustering techniques.
METHODS: We implemented a self-organizing map clustering algorithm on baseline volumetric MRI measures from nine brain regions of interest (ROIs) to cluster 1041 individuals enrolled in the placebo arm of the EXPEDITION3 trial. Volumetric MRI differences were compared among clusters. Demographics as well as baseline and longitudinal cognitive performance metrics were used to evaluate cluster characteristics.
RESULTS: Three distinct clusters, with an overall silhouette coefficient of 0.491, were identified based on MRI volumetrics. Cluster 1 (N = 400) had the largest baseline volumetric measures across all ROIs and the best cognitive performance at baseline. Cluster 2 (N = 269) had larger hippocampal and medial temporal lobe volumes, but smaller parietal lobe volumes in comparison with the third cluster (N = 372). Significant between-group mean differences were observed between Clusters 1 and 2 (difference, 2.38; 95% CI, 1.85 to 2.91; P < 0.001), Clusters 1 and 3 (difference, 1.93; 95% CI, 1.41 to 2.44; P < 0.001), but not between Clusters 2 and 3 (difference, 0.45; 95% CI, -0.11 to 1.02; P = 0.146) in ADAS-14.
CONCLUSIONS: Volumetric MRI can be used to identify homogenous clusters of amyloid positive individuals with mild dementia. The groups identified differ in baseline and longitudinal characteristics. Cluster 1 shows little ADAS-14 change over the first 40 weeks of study on placebo treatment and may be unsuitable for identifying early benefits of treatment.}, }
@article {pmid39885146, year = {2025}, author = {Fang, LP and Lin, CH and Medlej, Y and Zhao, R and Chang, HF and Guo, Q and Wu, Z and Su, Y and Zhao, N and Gobbo, D and Wyatt, A and Wahl, V and Fiore, F and Tu, SM and Boehm, U and Huang, W and Bian, S and Agarwal, A and Lauterbach, MA and Yi, C and Niu, J and Scheller, A and Kirchhoff, F and Bai, X}, title = {Oligodendrocyte precursor cells facilitate neuronal lysosome release.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1175}, pmid = {39885146}, issn = {2041-1723}, support = {BA 8014/1-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; SFB1158//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; SPP 1757//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; HOMFORexzellent2018//Universität des Saarlandes (Saarland University)/ ; NanoBioMed Young Investigator grant 2021//Universität des Saarlandes (Saarland University)/ ; GradUS global2019 and 2020//Universität des Saarlandes (Saarland University)/ ; Mini-proposal of SFB1027//Universität des Saarlandes (Saarland University)/ ; HOMFORexzellent2020//Universität des Saarlandes (Saarland University)/ ; NanoBioMed Young Investigator grant 2020//Universität des Saarlandes (Saarland University)/ ; H2020-MSCA-ITN EU-GliaPhD//European Commission (EC)/ ; }, mesh = {Animals ; *Lysosomes/metabolism ; *Oligodendrocyte Precursor Cells/metabolism/cytology ; *Neurons/metabolism ; Mice ; *Alzheimer Disease/metabolism/pathology ; Exocytosis/physiology ; Oligodendroglia/metabolism/cytology ; Mice, Inbred C57BL ; Humans ; Disease Models, Animal ; Male ; Cells, Cultured ; }, abstract = {Oligodendrocyte precursor cells (OPCs) shape brain function through many non-canonical regulatory mechanisms beyond myelination. Here we show that OPCs form contacts with their processes on neuronal somata in a neuronal activity-dependent manner. These contacts facilitate exocytosis of neuronal lysosomes. A reduction in the number or branching of OPCs reduces these contacts, which is associated with lysosome accumulation and altered metabolism in neurons and more senescent neurons with age. A similar reduction in OPC branching and neuronal lysosome accumulation is seen in an early-stage mouse model of Alzheimer's disease. Our findings have implications for the prevention of age-related pathologies and the treatment of neurodegenerative diseases.}, }
@article {pmid39884636, year = {2025}, author = {Bajad, NG and Jangra, J and T A, G and Kumar, A and Krishnamurthy, S and Singh, SK}, title = {Discovery of pyrazoline analogs as multi-targeting cholinesterase, β-secretase and Aβ aggregation inhibitors through lead optimization strategy.}, journal = {International journal of biological macromolecules}, volume = {301}, number = {}, pages = {140436}, doi = {10.1016/j.ijbiomac.2025.140436}, pmid = {39884636}, issn = {1879-0003}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry ; Animals ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; *Pyrazoles/pharmacology/chemistry ; Humans ; Mice ; Alzheimer Disease/drug therapy/metabolism ; Blood-Brain Barrier/drug effects/metabolism ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism ; Drug Discovery ; Protein Aggregates/drug effects ; Butyrylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; Male ; }, abstract = {The multi-target directed ligands (MTDLs) strategy has been evolved as the propitious approach for the development of therapeutics for Alzheimer's disease (AD). In an earlier report, we described the novel series of chalcone derivatives bearing N-aryl piperazine scaffold as MTDLs for the treatment of AD. Herein, we report the lead optimization of the series culminating in potent, multi-targeting compounds (32-57), evaluated through in-vitro and in-vivo biological studies. The optimal compound 48 exhibited potent inhibitory activities against AChE (IC50 = 2.89 ± 0.706 μM), BuChE (IC50 = 0.151 ± 0.089 μM), along with BACE-1 (% inhibition = 36.64 ± 1.343 %) and amyloid-β aggregation inhibition. Compound 48 showed excellent blood-brain barrier permeability (Pe = 7.28 ± 0.474 × 10[-6] cm s[-1]) in PAMPA assay and was found safe in the in vivo acute oral toxicity study. The molecular binding interaction pattern and protein-ligand stability was displayed by lead compound 48 with selected targets. Furthermore, in-vivo behavioural studies demonstrated the amelioration of cognitive dysfunctions and significant memory improvement in Y-maze test (scopolamine-induced amnesia model) in mice on the administration of compound 48 at a dose of 20 mg/kg. The reduction in the level of AChE and increased in ACh activity was observed in ex vivo biochemical analysis. Moreover, compound 48 displayed antioxidant potential on measurement of catalase (CAT) and malondialdehyde (MDA) activity in ex vivo analysis. We anticipate that compound 48, from the pyrazoline series, may be a lead molecule for the discovery of safe and effective therapeutic agents for AD.}, }
@article {pmid39884492, year = {2025}, author = {Pinky, and Anwar, S and Neha, and Parvez, S}, title = {Paeoniflorin inhibits pyruvate dehydrogenase kinase 3 and promotes BDNF activity by modulating neuronal activity and TNF-α.}, journal = {Brain research}, volume = {1851}, number = {}, pages = {149476}, doi = {10.1016/j.brainres.2025.149476}, pmid = {39884492}, issn = {1872-6240}, mesh = {*Neurons/drug effects/metabolism ; *Brain-Derived Neurotrophic Factor/metabolism ; Animals ; *Tumor Necrosis Factor-alpha/metabolism ; *Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism ; Molecular Docking Simulation/methods ; Glucosides/pharmacology ; Humans ; Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Metabolic dysregulation causes diseases like diabetes and cancer, making PDKs attractive targets. However, a thorough investigation into the unique roles played by the different members of the PDK family, especially PDK3, about memory loss and related diseases like Alzheimer's disease (AD) is still lacking. The current study investigates PF's potential to reduce PDK3-associated toxicity in neurodegenerative illnesses, including AD. The association between PF and PDK3 presents a significant opportunity for medication development and AD therapy approaches. PF efficiently suppresses PDK3 activity, as demonstrated by molecular docking and biophysical characterization, providing an in-depth understanding of their molecular interactions. PF significantly inhibited PDK3 in a concentration-dependent manner with an IC50 value of 4.88 µM. Considering this, the current investigation also explores the biological component of PF, which exhibits potential in treating AD and is primarily associated with neuroprotection. In the present study, a 3-hour pre-treatment of PF was administered at varying concentrations (4, 6, and 8 µM) in response to the 24-hour SCP (2 mM)-mediated toxicity. Based on the results of in silico and biophysical characterization, it is concluded that PF inhibits the PDK3 activity. Additionally, it can enhance cell viability, suppress ROS expression, impede apoptosis, and downregulate TNF-α expression. When combined, these actions help to prevent neuronal death in an in vitro model of SCP. PF strengthens the memory marker, which is confirmed through BDNF expression. This study found that all results were more effective at lower and moderate doses of PF. Our research indicates that PF boosts memory, decelerates the progression of oxidative stress, and could potentially serve as a dose-dependent treatment for AD.}, }
@article {pmid39884484, year = {2025}, author = {Lai, B and Wu, D and Xiao, Q and Wang, Z and Niu, Q and Chen, Q and Long, Q and He, L}, title = {Qiangji decoction mitigates neuronal damage, synaptic and mitochondrial dysfunction in SAMP8 mice through the regulation of ROCK2/Drp1-mediated mitochondrial dynamics.}, journal = {Journal of ethnopharmacology}, volume = {342}, number = {}, pages = {119424}, doi = {10.1016/j.jep.2025.119424}, pmid = {39884484}, issn = {1872-7573}, mesh = {Animals ; *Dynamins/metabolism ; *Drugs, Chinese Herbal/pharmacology ; *Mitochondrial Dynamics/drug effects ; *rho-Associated Kinases/metabolism ; Mice ; *Neurons/drug effects/metabolism ; *Synapses/drug effects/metabolism/ultrastructure ; Male ; *Mitochondria/drug effects/metabolism/ultrastructure ; *Hippocampus/drug effects/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; }, abstract = {Qiangji Decoction (QJD), a Chinese medicine, is widely used in Traditional Chinese Medicine to treat amnesia and Alzheimer's disease (AD), showing significant anti-AD effects. However, the precise mechanisms behind these effects are not well understood and require more research.
AIM OF THE STUDY: This study aims to elucidate the mechanisms by which QJD ameliorates neuronal damage, synaptic dysfunction, and mitochondrial impairment in AD through the regulation of ROCK2/Drp1-mediated mitochondrial dynamics.
MATERIALS AND METHODS: UPLC-Q-TOF-MS/MS was used to identify active components in QJD extract. The study used SAMP8 mice for AD modeling and SAMR1 mice as controls. Cognitive function in SAMP8 mice was assessed with the Morris Water Maze after following treatment with QJD and the mitochondrial fission inhibitor Mdivi-1. Nissl and FJB staining evaluated QJD's effect on hippocampal injury. Synaptic integrity was examined with Golgi-Cox staining, transmission electron microscopy, and immunofluorescence. Mitochondrial function in hippocampal neurons was assessed using electron microscopy, JC-1 staining, and reagent kits. Western blot analyzed expression of proteins related to mitochondrial fission (ROCK2, Drp1, Fis1, Mff) and fusion (Mfn1, Mfn2, OPA1).
RESULTS: The analysis of QJD extract via UPLC-Q-TOF-MS/MS led to the identification of 46 active compounds. In SAMP8 mice, administration of QJD resulted in decreased escape latency, increased platform crossings, and extended duration in the target quadrant. Additionally, QJD exhibited neuroprotective effects on the hippocampus of SAMP8 mice, effectively preventing neuronal loss and damage. QJD also facilitated the extension and thickening of dendritic spines, enhanced the ultrastructure of hippocampal synapses, and upregulated synaptic function-related proteins, including PSD95 and SYN1. Furthermore, QJD ameliorated mitochondrial damage, improved mitochondrial membrane potential and ATP content, and reduced ROS expression in hippocampal neurons of SAMP8 mice. These effects were mediated through the downregulation of ROCK2, phosphorylated Drp1 (Ser616), Fis1, and Mff, as well as the upregulation of Mfn1, Mfn2, and OPA1.
CONCLUSIONS: QJD may reduce neuronal damage, synaptic dysfunction, and mitochondrial impairment in SAMP8 mice by regulating mitochondrial dynamics through the ROCK2/Drp1 pathway.}, }
@article {pmid39884096, year = {2025}, author = {He, F and Guo, Y and Shen, X and Li, L and Li, D and Liu, X and Gao, P}, title = {Design and synthesis three novel series of derivatives using natural acetylcholinesterase inhibitor-RLMS as template and in vitro, in vivo and in silico activities verification.}, journal = {European journal of medicinal chemistry}, volume = {286}, number = {}, pages = {117309}, doi = {10.1016/j.ejmech.2025.117309}, pmid = {39884096}, issn = {1768-3254}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Drug Design ; Humans ; *Acetylcholinesterase/metabolism ; Animals ; *Zebrafish ; Structure-Activity Relationship ; *Molecular Docking Simulation ; Molecular Structure ; Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Dose-Response Relationship, Drug ; Cell Line, Tumor ; Alzheimer Disease/drug therapy ; Biological Products/pharmacology/chemistry/chemical synthesis ; Apoptosis/drug effects ; }, abstract = {Acetylcholinesterase (AChE) is a pivotal enzyme in nerve conduction, controlling its activity with its inhibitor (AChEI) is crucial for the treatment of Alzheimer's disease (AD). However, current AChEIs are associated with considerable adverse effects. Previous work has identified 2α,3β,19α,23-tetrahydroxy-12-ene-28-oic acid (RLMS) as a promising natural AChEI. This study synthesized three novel series of AChEIs to elucidate the interaction mechanisms between the title enzyme and RLMS. Among the compounds, 1 and 22 emerged as the most potent and selective inhibitors exhibiting both irreversible and mixed competitive inhibition types against AChE. Molecular docking studies at the AChE active sites revealed binding modes that justify its potent enzyme inhibitory effects. Additionally, molecular dynamic simulations demonstrated robust and stable interactions of 1 and 22 with the binding sites of their target. In vitro assays showed derivates, especially 22, exhibited potential neuroprotective activities on H2O2-induced SH-SY5Y cell injury model. In vivo experiments showed that zebrafish models of AD treated with varying concentrations of 22 displayed obviously increased movement distance and speed, notably, at 25 μM level, 22 effectively reduced apoptosis in zebrafish brain cells. Collectively, this research delineates the intricate relationship between AChE and 22, suggesting its potential as a therapeutic agent for combating AD.}, }
@article {pmid39883631, year = {2025}, author = {Guerguer, FZ and Rossafi, B and Abchir, O and Raouf, YS and Albalushi, DB and Samadi, A and Chtita, S}, title = {Potential Azo-8-hydroxyquinoline derivatives as multi-target lead candidates for Alzheimer's disease: An in-depth in silico study of monoamine oxidase and cholinesterase inhibitors.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0317261}, pmid = {39883631}, issn = {1932-6203}, mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology/therapeutic use ; *Monoamine Oxidase/metabolism/chemistry ; Humans ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; *Acetylcholinesterase/chemistry/metabolism ; Butyrylcholinesterase/metabolism/chemistry ; Oxyquinoline/chemistry/analogs & derivatives ; Computer Simulation ; Azo Compounds/chemistry/pharmacology ; }, abstract = {Cognitive dysfunction in Alzheimer's disease results from a complex interplay of various pathological processes, including the dysregulation of key enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidase B (MAO-B). This study proposes and designs a series of novel molecules derived from 8-hydroxyquinoline (Azo-8HQ) as potential multi-target lead candidates for treating AD. An exhaustive in silico analysis was conducted, encompassing docking studies, ADMET analysis, density functional theory (DFT) studies, molecular dynamics simulations, and subsequent MM-GBSA calculations to examine the pharmacological potential of these molecules with the specific targets of interest. Out of the 63 Azo-8HQ derivatives analysed, two molecules, 14c and 17c, demonstrated strong affinities for AChE, BuChE, and MAO-B, along with favourable pharmacokinetic profiles and electronic properties. Molecular dynamics simulations confirmed the stability of these molecules within the active sites of the targets, and MM-GBSA calculations revealed low binding energies, indicating robust interactions. These findings identify molecules 14c and 17c as promising multi-target candidates for the treatment of AD, based on an in-depth computational study aimed at minimizing drug development costs and time. Future work will include the synthesis of these molecules followed by in-depth in vitro and in vivo testing to validate their potential therapeutic efficacy.}, }
@article {pmid39882364, year = {2024}, author = {Sun, X and Zhu, J and Li, R and Peng, Y and Gong, L}, title = {The global research of magnetic resonance imaging in Alzheimer's disease: a bibliometric analysis from 2004 to 2023.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1510522}, pmid = {39882364}, issn = {1664-2295}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder worldwide and the using of magnetic resonance imaging (MRI) in the management of AD is increasing. The present study aims to summarize MRI in AD researches via bibliometric analysis and predict future research hotspots.
METHODS: We searched for records related to MRI studies in AD patients from 2004 to 2023 in the Web of Science Core Collection (WoSCC) database. CiteSpace was applied to analyze institutions, references and keywords. VOSviewer was used for the analysis of countries, authors and journals.
RESULTS: A total of 13,659 articles were obtained in this study. The number of published articles showed overall exponential growth from 2004 to 2023. The top country and institution were the United States and the University of California System, accounting for 40.30% and 9.88% of the total studies, respectively. Jack CR from the United States was the most productive author. The most productive journal was the Journal of Alzheimers Disease. Keyword burst analysis revealed that "machine learning" and "deep learning" were the keywords that frequently appeared in the past 6 years. Timeline views of the references revealed that "#0 tau pathology" and "#1 deep learning" are currently the latest research focuses.
CONCLUSION: This study provides an in-depth overview of publications on MRI studies in AD. The United States is the leading country in this field with a concentration of highly productive researchers and high-level institutions. The current research hotspot is deep learning, which is being applied to develop noninvasive diagnosis and safer treatment of AD.}, }
@article {pmid39880699, year = {2025}, author = {Dumurgier, J and Paquet, C and Hugon, J and Planche, V and Gaubert, S and Epelbaum, S and Bombois, S and Teichmann, M and Levy, R and Baudouin, E and Vrillon, A and Hourrègue, C and Cognat, E and Sabia, S and Singh-Manoux, A}, title = {MemScreen: A smartphone application for detection of mild cognitive impairment: A validation study: Smartphone App for MCI Detection.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {3}, pages = {100077}, doi = {10.1016/j.tjpad.2025.100077}, pmid = {39880699}, issn = {2426-0266}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; Female ; *Mobile Applications ; *Smartphone ; Aged ; Male ; Cohort Studies ; Mental Status and Dementia Tests ; Neuropsychological Tests ; Aged, 80 and over ; Sensitivity and Specificity ; }, abstract = {BACKGROUND AND OBJECTIVES: Primary care is often the first point of contact for patients with cognitive complaints, making initial cognitive screening an essential step to avoid delays in diagnosing Alzheimer's disease (AD) at an early stage. We developed MemScreen, a self-administered smartphone application that assesses overall cognition and verbal memory, and evaluated its ability to detect mild cognitive impairment (MCI) in both general and clinical populations.
METHODS: We conducted two validation cohort studies: (1) UK-based Whitehall II cohort study (13th wave, 2018-2022) involving a general population (MCI defined by poor performance on a global cognitive score), and (2) five French memory clinics involving patients without dementia (amnestic MCI defined by the Free and Cued Selective Reminding Test). MemScreen, MMSE, and TMT-A effectiveness was assessed using Area Under the Curve (AUC) values from unadjusted and adjusted logistic regression models.
RESULTS: In Whitehall II (n = 2118, mean age 75.9 years, 23.9 % women, 14.5 % MCI), median MemScreen completion time was 4 min 18 s. MemScreen had the highest AUC (0.87; 95 % CI: 0.82-0.89) for distinguishing MCI, outperforming MMSE (AUC = 0.79; 0.76-0.82; p = 0.018) and TMT-A (AUC = 0.77; 0.74-0.80; p = 0.023). MemScreen sensitivity and specificity were 78.6 % and 78.7 %, respectively. In memory clinics (n = 303, mean age 70.5 years, 53 % women, 46.9 % amnestic MCI), median completion time was 5 min 17 s. MemScreen showed superior performance (AUC = 0.87; 0.83-0.91) compared to MMSE (AUC = 0.72; 0.67-0.78; p < 0.001) and TMT-A (AUC = 0.63; 0.56-0.69; p < 0.001), with 93.0 % sensitivity and 54.0 % specificity for amnestic MCI.
DISCUSSION: MemScreen outperformed traditional tests in identifying MCI in both general and clinical populations. Its self-administration and short completion time suggest potential as an effective screening tool to optimize memory clinic referrals for AD diagnosis and treatment.}, }
@article {pmid39880333, year = {2025}, author = {Izrael, M and Chebath, J and Molakandov, K and Revel, M}, title = {Clinical perspective on pluripotent stem cells derived cell therapies for the treatment of neurodegenerative diseases.}, journal = {Advanced drug delivery reviews}, volume = {218}, number = {}, pages = {115525}, doi = {10.1016/j.addr.2025.115525}, pmid = {39880333}, issn = {1872-8294}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Pluripotent Stem Cells ; Animals ; Cell- and Tissue-Based Therapy/methods ; Stem Cell Transplantation/methods ; Clinical Trials as Topic ; }, abstract = {Self-renewal capacity and potential to differentiate into almost any cell type of the human body makes pluripotent stem cells a valuable starting material for manufacturing of clinical grade cell therapies. Neurodegenerative diseases are characterized by gradual loss of structure or function of neurons, often leading to neuronal death. This results in gradual decline of cognitive, motor, and physiological functions due to the degeneration of the central nervous systems. Over the past two decades, comprehensive preclinical efficacy (proof-of-concept) and safety studies have led to the initiation of First-in-Human phase I-II clinical trials for a range of neurodegenerative diseases. In this review, we explore the fundamentals and challenges of neural-cell therapies derived from pluripotent stem cells for treating neurodegenerative diseases. Additionally, we highlight key preclinical investigations that paved the way for regulatory approvals of these trials. Furthermore, we provide an overview on progress and status of clinical trials done so far in treating neurodegenerative diseases such as spinal cord injury (SCI), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), as well as advances in retina diseases such as Stargardt disease (a.k.a fundus flavimaculatus), retinitis pigmentosa (RP) and age-related macular degeneration (AMD). These trials will pave the way for the development of new cell-based therapies targeting additional neurological conditions, including Alzheimer's disease and epilepsy.}, }
@article {pmid39878947, year = {2025}, author = {Zhang, Y and Sereika, S and Seaman, J and Pettigrew, C and Albert, M and Lingler, J}, title = {Caregivers' Perspectives on Discussions of Medical Treatment Preferences for People Living With Dementia Are Associated With Their Dementia Health Literacy and the Caregiving Relationship.}, journal = {The Gerontologist}, volume = {65}, number = {4}, pages = {}, pmid = {39878947}, issn = {1758-5341}, support = {P50-P50AG033514//University of Wisconsin/ ; P30 AG035982/AG/NIA NIH HHS/United States ; P50-AG005136//University of Washington/ ; //Alzheimer's Disease Research Centers/ ; P30 AG013846/AG/NIA NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; P30-AG010133//Indiana University/ ; 15043228/ALZ/Alzheimer's Association/United States ; P50-AG005131//University of California, San Diego/ ; P50 AG033514/AG/NIA NIH HHS/United States ; P30-AG028383//University of Kentucky/ ; P50-AG016574//Mayo Clinic/ ; P50 AG005131/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; P50-AG005133//University of Pittsburgh/ ; P50 AG005134/AG/NIA NIH HHS/United States ; P30 AG008017/AG/NIA NIH HHS/United States ; P30-AG035982//University of Kansas/ ; P50 AG005133/AG/NIA NIH HHS/United States ; P50-AG005134//Massachusetts General Hospital/Harvard Medical School/ ; P30-AG013846//Boston University/ ; P30-AG008017//Oregon Health Sciences University/ ; P30-AG010161//Rush University Medical Center/ ; P30 AG028383/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Caregivers/psychology ; Female ; Male ; *Dementia/therapy/psychology/nursing ; *Health Literacy ; Aged ; Cross-Sectional Studies ; *Patient Preference ; Middle Aged ; *Advance Care Planning ; Aged, 80 and over ; Health Knowledge, Attitudes, Practice ; Surveys and Questionnaires ; }, abstract = {BACKGROUND AND OBJECTIVES: People living with dementia experience progressive functional decline and increased dependence on caregivers. This study examined the influence of caregivers' dementia health literacy on perceptions of medical care preferences and advance care planning (ACP) in people living with dementia.
RESEARCH DESIGN AND METHODS: This analysis used data from a cross-sectional survey, "Care Planning for Individuals with Dementia," administered nationwide by Alzheimer's Disease Centers. We conducted binary, ordinal, and multinomial logistic regression.
RESULTS: On average, surveyed caregivers (n = 431) were 78.3 years, had 16 years of education, and were mainly White (88.5%). Most lived with (76.8%) and were the designated healthcare proxy (95.1%), with high dementia knowledge scores (mean = 8.4/10). As caregivers' dementia knowledge scores increased, they were 1.27 times more likely (p = .02) to endorse comfort care. Caregivers with greater knowledge about severe dementia were less likely to need further treatment preference-related discussions (knowing a lot: odds ratio [OR] = 0.17, p < .001; knowing some things: OR = 0.37, p = .006). Caregivers live apart from patients were 2.71 times more likely to know about such discussions (p < .001). Caregivers of people in earlier stages endorsed greater needs for further conversations with clinicians (no impairment and mild cognitive impairment [MCI]: OR = 7.38, p = .002; mild impairment: OR = 5.32, p = .005) and their care recipients (no impairment and MCI: OR = 5.24, p = .02).
DISCUSSION AND IMPLICATIONS: These findings highlight the role of dementia-specific education in ACP discussions among people living with dementia, caregivers, and healthcare clinicians. These findings are important because evidence suggests that ACP may promote quality of life, reduce iatrogenic harm, minimize healthcare overutilization, and alleviate care-related burdens.}, }
@article {pmid39878879, year = {2025}, author = {Du, K and Su, Y and Song, Q and Chen, S and Wu, R and Teng, X and Huang, R and Wang, L and Zou, C}, title = {2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione protects against MPP[+]-induced neurotoxicity by ameliorating oxidative stress, apoptosis and autophagy in SH-SY5Y cells.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {113}, pmid = {39878879}, issn = {1573-7365}, support = {2024JJA140684 and 2024JJA141221//the Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation/ ; Guike AB2302602//Guangxi Key Technologies R&D Program/ ; 81971191 and 81670750//National Natural Science Foundation of China/ ; 2014GXNSFDA118030//Guangxi Natural Science Foundation/ ; ZR2019ZD39//Natural Science Foundation of Shandong Province/ ; }, mesh = {Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Autophagy/drug effects ; *Neuroprotective Agents/pharmacology ; Cell Line, Tumor ; *1-Methyl-4-phenylpyridinium/toxicity ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; }, abstract = {2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) is a cyclohexanedione compound extracted from the roots of Averrhoa carambola L. Several studies have documented its beneficial effects on diabetes, Alzheimer's disease, and cancer. However, its potential neuroprotective effects on Parkinson's disease (PD) have not yet been explored. The present study aimed to investigate the protective effects and underlying mechanisms of DMDD in a cellular model of PD. In this study, SH-SY5Y cells were incubated with or without DMDD following intoxication with the parkinsonian neurotoxin 1-methyl-4-phenylpyridine (MPP[+]). Cell viability and apoptosis were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) assay and Hoechst 33,342 staining, respectively. The mitochondrial membrane potential (Δψm) was assessed through the JC-10 assay. The activities of superoxide dismutase (SOD) and the levels of reactive oxygen species (ROS) were measured using WST-8 and DCFH-DA assays. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore significant biological processes and pathways influenced by DMDD. Molecular docking was employed to predict the domains of potential protein targets interacting with DMDD. Western blotting was subsequently conducted to determine the protein expression levels of TH, Nrf2, Bax, Bcl-2, Caspase-3, Beclin-1, PARP, LC3-II, LC3-I, p-PI3K, PI3K, p-mTOR and mTOR. Our study showed that DMDD treatment significantly increased cell viability and reduced apoptosis in MPP[+]-treated SH-SY5Y cells. In addition, DMDD treatment reversed the loss of TH expression and Δψm in MPP[+]-exposed SH-SY5Y cells. Moreover, DMDD treatment reduced MPP+-induced ROS production by promoting SOD activity. Additionally, compared with those in the MPP[+] group, the protein expression levels of Beclin-1, Caspase-3, and PARP and the LC3II/I ratio were significantly decreased, whereas the protein expression levels of Nrf2 and the Bcl-2/Bax, p-PI3K/PI3K, and p-mTOR/mTOR ratios were significantly increased in the DMDD-treated group. In conclusion, DMDD protects against MPP[+]-induced cytotoxicity by mitigating oxidative stress, apoptosis, and autophagy. PI3K/mTOR signaling at least partly mediates the cytoprotective effect of DMDD.}, }
@article {pmid39878109, year = {2025}, author = {Mir, M and Khosravani, P and Ramezannezhad, E and Saadabad, FP and Falahati, M and Ghanbarian, M and Saberian, P and Sadeghi, M and Niknam, N and Ghejelou, SE and Jafari, M and Gulisashvili, D and Mayeli, M}, title = {Association Between Metabolomics Findings and Brain Hypometabolism in Mild Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050350196250110092338}, pmid = {39878109}, issn = {1875-5828}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative condition with rising prevalence due to the aging global population. Existing methods for diagnosing AD are struggling to detect the condition in its earliest and most treatable stages. One early indicator of AD is a substantial decrease in the brain's glucose metabolism. Metabolomics can detect metabolic disturbances in biofluids, which may be advantageous for early detection of some ADrelated changes. The study aims to predict brain hypometabolism in Alzheimer's disease using metabolomics findings and develop a predictive model based on metabolomic data.
METHODS: The data used in this study were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI) project. We conducted a longitudinal cohort study with three assessment time points to investigate the predictive ability of baseline metabolomic data for modeling longitudinal fluorodeoxyglucose-positron emission tomography (FDG-PET) trajectory changes in AD patients. A total number of 44 participants with AD were included. The cognitive abilities of participants were evaluated using the Alzheimer's Disease Assessment Scale (ADAS) and the Mini-Mental State Examination (MMSE), while the overall severity of dementia was measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). We employed the ADNI's FDG MetaROIs (Meta Regions of Interest) dataset to identify AD-associated hypometabolism in the brain. These MetaROIs were selected based on areas frequently mentioned in FDG-PET studies of AD and MCI subjects.
RESULTS: Across models, we observed consistent positive relationships between specific cholesterol esters - CE (20:3) (p = 0.005) and CE (18:3) (p = 0.0039) - and FDG-PET metrics, indicating these baseline metabolites may be valuable indicators of future PET score changes. Selected triglycerides like DG-O (16:0-20:4) also showed time-specific positive associations (p = 0.017).
CONCLUSION: This research provides new insights into the disruptions in the metabolic network linked to AD pathology. These findings could pave the way for identifying novel biomarkers and potential treatment targets for AD.}, }
@article {pmid39878108, year = {2025}, author = {Wang, C and Chen, X and Yu, Z}, title = {Trafficking of Muscarinic 1 Acetylcholine Receptor Regulated by VPS35 in Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050356990250111200217}, pmid = {39878108}, issn = {1875-5828}, abstract = {INTRODUCTION: Muscarinic 1 acetylcholine receptor (M1AChR) is a member of the Gprotein- coupled receptor superfamily, with the dysfunction being linked to the onset of Alzheimer's Disease (AD).
AIMS: Retromer complex with Vacuolar Protein Sorting-35 (VPS35) as the core plays an important role in the transport of biological proteins and has been confirmed to be closely related to the pathogenesis of AD. This study was designed to determine whether VPS35 could affect the trafficking mechanism of M1AChRs.
METHOD: The interaction between VPS35 and M1AChR was studied by co-immunoprecipitation method, and the recycling of M1AChR influence by VPS35 was analyzed using biotinylation technology.
RESULTS: It was found that VPS35 affected the localization of M1AChR on the cell membrane by regulating intracellular M1AChR transport, thus controlling the M1AChR-mediated cholinergic signaling pathway.
CONCLUSION: The findings presented here provide a potential pathogenesis and pathway for the treatment of AD.}, }
@article {pmid39878107, year = {2025}, author = {Mehrabadi, S}, title = {Extracellular Vesicles: A Promising Therapeutic Approach to Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050365314250112042136}, pmid = {39878107}, issn = {1875-5828}, abstract = {Extracellular vesicles (EVs) are nano-sized membranous particles that are secreted by various cell types and play a critical role in intercellular communication. Their unique properties and remarkable ability to deliver bioactive cargo to target cells have made them promising tools in the treatment of various diseases, including Alzheimer's disease (AD). AD is a devastating neurodegenerative disease characterized by progressive cognitive decline and neuropathological hallmarks, such as amyloid-beta plaques and neurofibrillary tangles. Despite extensive research, no disease-modifying therapy for AD is currently available. However, EVs have emerged as a potential therapeutic agent in AD due to their ability to cross the blood-brain barrier, deliver bioactive cargo, and modulate neuroinflammation. This review provides a comprehensive overview of the current knowledge on the role of EVs in AD and discusses their potential as a therapeutic approach. It covers the mechanisms of action, potential therapeutic targets, and challenges and limitations of EV-based therapies for AD.}, }
@article {pmid39877983, year = {2025}, author = {Thirumalai, S and Livesey, FJ and Patani, R and Hung, C}, title = {APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14560}, pmid = {39877983}, issn = {1552-5279}, support = {//Alzheimer's Research UK/ ; }, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects ; *Down Syndrome/metabolism ; *Astrocytes/drug effects/metabolism ; *Mitochondria/drug effects/metabolism ; *Amyloid beta-Protein Precursor/genetics ; *Oligonucleotides, Antisense/pharmacology ; Phenotype ; Cell Differentiation/drug effects ; Alzheimer Disease/metabolism ; Cells, Cultured ; Superoxides/metabolism ; }, abstract = {INTRODUCTION: Antisense oligonucleotides (ASOs) have shown promise in reducing amyloid precursor protein (APP) levels in neurons, but their effects in astrocytes, key contributors to neurodegenerative diseases, remain unclear. This study evaluates the efficacy of APP ASOs in astrocytes derived from an individual with Down syndrome (DS), a population at high risk for Alzheimer's disease (AD).
METHODS: Human induced pluripotent stem cells (hiPSCs) from a healthy individual and an individual with DS were differentiated into astrocytes. Astrocytes were treated with APP ASOs for 10 days, and APP levels were quantified. Mitochondrial morphology and superoxide production in DS astrocytes were analyzed using super-resolution and confocal microscopy.
RESULTS: APP ASOs significantly reduced APP levels in astrocytes from both control and DS individuals. In DS astrocytes, treatment restored mitochondrial health, increasing mitochondrial number and size while reducing superoxide production.
DISCUSSION: APP ASOs effectively reduce APP levels and improve mitochondrial health in astrocytes, suggesting their potential as a therapeutic approach for DS and DS-related AD. Further in vivo studies are required to confirm these findings.
HIGHLIGHTS: APP ASOs reduce APP levels in human iPSC-derived astrocytes. APP ASO treatment rescues mitochondrial phenotypes in trisomy 21 astrocytes. This study supports ASOs as a potential therapy for Down syndrome-related Alzheimer's disease.}, }
@article {pmid39877657, year = {2024}, author = {Wang, J and Bai, X and Chen, X and Liu, S and Sun, M and Li, K and Zheng, Y and Wang, Z}, title = {Effects of acupuncture at the Taichong (LIV3) and Hegu (LI4) points on functional connectivity with the retrosplenial cortex in patients with Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1511183}, pmid = {39877657}, issn = {1662-4548}, abstract = {BACKGROUND: Acupuncture has been demonstrated to have a promising effect on Alzheimer's disease (AD), but the underlying neural mechanisms remain unclear. The retrosplenial cortex (RSC) is one of the earliest brain regions affected in AD, and changes in its functional connectivity (FC) are reported to underlie disease-associated memory impairment. The aim of this study was to examine the effect of acupuncture on FC with the RSC in patients with AD.
METHODS: Demographic data, neuropsychological assessments, and resting-state functional magnetic resonance imaging (fMRI) data were collected from 14 AD patients and 14 normal controls (NCs) matched by age, sex, and educational level at baseline. After the baseline MRI scan, acupuncture stimulation on the Taichong (LIV3) and Hegu (LI4) points was performed for 3 min. Then, another 10 min of fMRI data were acquired after the needle was withdrawn. A dataset that included 100 healthy participants was also included to construct a reliable FC map of the RSC. Two sets of regions of interest (ROIs) in the RSC were selected to assess the sustained effect of acupuncture on FC with the RSC in AD patients and NCs.
RESULTS: Two sets of RSC ROI-based analyses demonstrated robust positive connectivity with the hippocampus (HPC). Furthermore, multiple brain regions, including the bilateral thalamus, bilateral posterior cingulate cortex (PCC), bilateral subcallosal cingulate gyrus (SCG), bilateral orbitofrontal cortex (OFC), and right precuneus, showed decreased FC with the RSC in the AD group and increased FC with the RSC in the NC group after acupuncture compared to that at baseline. Acupuncture also specifically elicited increased FC between the RSC and the HPC as well as between the RSC and the parahippocampal gyrus in AD patients and decreased FC between the RSC and the visual cortices in NCs. Additionally, diminished FC with the RSC was correlated with neuropsychological scale scores in the AD group before acupuncture treatment.
CONCLUSION: These findings confirm and extend previous studies suggesting that acupuncture at Taichong (LIV3) and Hegu (LI4) can exert bidirectional and benign regulatory effects on RSC connectivity in AD patients.}, }
@article {pmid39877076, year = {2024}, author = {Shu, H and Ding, G and Xu, X and Huang, X and He, R}, title = {Association of CSF soluble TREM1 levels with hippocampal atrophy in cognitively impaired older adults.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1481526}, pmid = {39877076}, issn = {1663-4365}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; RF1 AG053303/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; RF1 AG074007/AG/NIA NIH HHS/United States ; U01 AG058922/AG/NIA NIH HHS/United States ; R01 AG044546/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; RF1 AG058501/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Recent studies have shown that cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 1 (sTREM1) are elevated in individuals with Alzheimer's disease (AD), though the relationship between CSF sTREM1 and hippocampal atrophy remains to be elucidated. The primary aim of this study was to investigate the association between CSF sTREM1 levels and longitudinal changes in hippocampal volumes, and to determine if this relationship is moderated by cognitive status.
METHODS: We included 576 participants, comprising 152 cognitively unimpaired (CU) and 424 cognitively impaired (CI) individuals. In the cross-sectional analyses, Pearson's correlation tests were conducted to examine the relationship between baseline CSF sTREM1 levels and hippocampal volumes in both CU and CI participants. For the longitudinal analyses, a linear mixed-effects model was employed to assess the significance of the three-way interaction between CSF sTREM1 levels, cognitive status, and follow-up time on adjusted hippocampal volume (aHV). Further stratified analyses based on cognitive status were performed to dissect the specific effects within each group.
RESULTS: Our findings revealed significantly elevated baseline CSF sTREM1 levels in CI participants compared to CU participants. Cross-sectional analyses demonstrated that CSF sTREM1 levels were negatively associated with hippocampal volumes in both CU and CI participants. In the longitudinal analyses, the three-way interaction between CSF sTREM1 levels, cognitive status, and follow-up time was found to be significant for aHV. Stratified analyses indicated that, in CI participants, higher CSF sTREM1 levels were associated with a more accelerated rate of hippocampal atrophy, whereas no such association was observed in CU participants.
CONCLUSION: These results underscore the complex interplay between neuroinflammation, as reflected by CSF sTREM1 levels, hippocampal atrophy, and cognitive decline. The data suggest that neuroinflammation may contribute differently to hippocampal atrophy rates in CI versus CU individuals, highlighting the potential for targeted anti-inflammatory interventions in the prevention and treatment of AD.}, }
@article {pmid39876884, year = {2025}, author = {Chen, XH and Xia, W and Ma, JB and Chen, J and Hu, J and Shi, X and Yu, JJ and Gong, J and Liu, L and Sun, YA and Liu, ZG}, title = {Rare mixed dementia: A case report.}, journal = {World journal of radiology}, volume = {17}, number = {1}, pages = {102579}, pmid = {39876884}, issn = {1949-8470}, abstract = {BACKGROUND: Autoimmune encephalitis (AE) is a rare and recently described neuroinflammatory disease associated with specific autoantibodies. Anti-leucine-rich glioma inactivated 1 (anti-LGI1) encephalitis is a rare but treatable type of AE discovered in recent years. Alzheimer's disease (AD) is a degenerative brain disease and the most common cause of dementia. AD may undergo a series of pathological physiological changes in brain tissue 20 years before the onset of typical symptoms. The stage of mild cognitive impairment (MCI) that occurs during this process, known as MCI due to AD, is the earliest stage with clinical symptoms. MCI is typically categorized into two subtypes: Amnestic MCI (aMCI) and non-aMCI.
CASE SUMMARY: This report describes a patient with rapid cognitive impairment, diagnosed with anti-LGI1 antibody-mediated AE and aMCI, and treated at Peking University Shenzhen Hospital in March 2023. The patient was hospitalized with acute memory decline for more than 3 months. Both the cerebrospinal fluid and serum were positive for anti-LGI1 antibodies, biomarkers of AD coexisting in the patient's cerebrospinal fluid. Following combination treatment with immunoglobulin therapy and glucocorticoid, plus inhibition of acetylcholinesterase, the patient's cognitive function significantly improved. Throughout the 3-month follow-up period, a sustained improvement in cognitive function was observed. The results of serum anti-LGI1 antibody were negative.
CONCLUSION: This case has raised awareness of the possible interaction between AE and early AD (including MCI due to AD), and alerted clinicians to the possibility of concurrent rare and common diseases in patients presenting with cognitive impairment.}, }
@article {pmid39875073, year = {2025}, author = {Géraudie, A and De Rossi, P and Canney, M and Carpentier, A and Delatour, B}, title = {Effects of blood-brain barrier opening using ultrasound on tauopathies: A systematic review.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {379}, number = {}, pages = {1029-1044}, doi = {10.1016/j.jconrel.2025.01.056}, pmid = {39875073}, issn = {1873-4995}, mesh = {*Blood-Brain Barrier/metabolism ; Humans ; Animals ; *Tauopathies/diagnostic imaging/metabolism ; *tau Proteins/metabolism ; Ultrasonic Therapy/methods ; }, abstract = {UNLABELLED: Blood-brain barrier opening with ultrasound can potentiate drug efficacy in the treatment of brain pathologies and also provides therapeutic effects on its own. It is an innovative tool to transiently, repeatedly and safely open the barrier, with studies showing beneficial effects in both preclinical models for Alzheimer's disease and recent clinical studies. The first preclinical and clinical work has mainly shown a decrease in amyloid burden in mice models and in patients. However, Alzheimer's disease pathology also encompasses tauopathy, which is closely related to cognitive decline, making it a crucial therapeutic target. The effects of blood-brain barrier opening with ultrasound have been rarely assessed on tau and are still unclear.
METHODS: This systematic review, conducted through searches using Pubmed, Embase, Web of Science and Cochrane Central databases, extracted results of 15 studies reporting effects of blood-brain barrier opening using ultrasound on tau proteins.
RESULTS: This review of the literature indicates that blood-brain barrier opening using ultrasound can decrease the extent of the tau pathology or potentialize the effect of a therapeutic drug. However, selected studies report paradoxically that blood-brain barrier opening can increase tau pathology burden and induce brain damage.
DISCUSSION: Apparent discrepancies between reports could originate from the variability in protocols or analytical methods that may impact the effects of blood-brain barrier opening with ultrasound on tauopathies, glial populations, tissue integrity and functional outcomes.
CONCLUSION: This calls for a better standardization effort combined with improved methodologies allowing between-studies comparisons, and for further understanding of the effects of blood-brain barrier opening on tau pathology as an essential prerequisite before translation to clinic.}, }
@article {pmid39875069, year = {2025}, author = {Zuo, Y and Ding, X and Liu, Z and Xie, Y and Liu, G and Liu, C}, title = {Diverse pathways for the treatment of Parkinson's disease: Integration and development of traditional and emerging therapies.}, journal = {Neuroscience}, volume = {568}, number = {}, pages = {388-398}, doi = {10.1016/j.neuroscience.2025.01.045}, pmid = {39875069}, issn = {1873-7544}, mesh = {Humans ; *Parkinson Disease/therapy/metabolism ; *Genetic Therapy/methods ; *Stem Cell Transplantation/methods ; *Immunotherapy/methods/trends ; Animals ; }, abstract = {Parkinson's disease (PD) is the second most common central neurodegenerative disease in the world after Alzheimer's disease (AD), which mainly occurs in middle-aged and elderly people, and is increasing with the aging of the population. With the increasing incidence of PD, it is particularly important to explore its pathology and provide effective interventions and treatments. The pathogenesis of PD involves a variety of factors such as genetics, environment, and age, and is not yet fully understood. The main pathogenic mechanisms include neuronal degeneration, abnormal aggregation of α-synuclein, formation of Lewy bodies and oxidative stress, etc. In recent years, gene therapy, stem cell therapy, and immunotherapy, along with traditional drugs and surgical treatments, have become widely used. Currently, all treatments for PD are symptomatic and there is no radical cure. This paper reviews existing traditional and emerging treatments for PD to provide a theoretical basis for the in-depth study of PD pathogenesis and therapeutic approaches. Meanwhile, the application of gene editing and delivery, stem cell transplantation, immunotherapy and multi-target therapy laid the foundation for the development of safer, more effective and more comprehensive treatments for PD.}, }
@article {pmid39874644, year = {2025}, author = {Park, E and He, C and Abbasi, AZ and Tian, M and Huang, S and Wang, L and Georgiou, J and Collingridge, GL and Fraser, PE and Henderson, JT and Wu, XY}, title = {Brain microenvironment-remodeling nanomedicine improves cerebral glucose metabolism, mitochondrial activity and synaptic function in a mouse model of Alzheimer's disease.}, journal = {Biomaterials}, volume = {318}, number = {}, pages = {123142}, doi = {10.1016/j.biomaterials.2025.123142}, pmid = {39874644}, issn = {1878-5905}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Glucose/metabolism ; *Mitochondria/metabolism/drug effects ; *Disease Models, Animal ; *Brain/metabolism/drug effects/pathology/diagnostic imaging ; *Mice, Transgenic ; Mice ; Nanomedicine/methods ; Nanoparticles/chemistry ; Synapses/metabolism/drug effects ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; }, abstract = {The development of disease-modifying therapeutics for Alzheimer's disease remains challenging due to the complex pathology and the presence of the blood-brain barrier. Previously we have described the investigation of a brain-penetrating multifunctional bioreactive nanoparticle system capable of remodeling the hypoxic and inflammatory brain microenvironment and reducing beta-amyloid plaques improving cognitive function in a mouse model of Alzheimer's disease. Despite the linkage of hypoxia and inflammation to metabolic alteration, the effects of this system on modulating cerebral glucose metabolism, mitochondrial activity and synaptic function remained to be elucidated. To examine this, a transgenic mouse model of Alzheimer's disease (TgCRND8) in vivo were treated intravenously with beta-amyloid antibody-conjugated (Ab), blood-brain barrier-crossing terpolymer (TP) containing polymer-lipid based manganese dioxide nanoparticles (Ab-TP-MDNPs). Alterations in cerebral glucose utilization were determined by [[1][8]F]FDG-PET imaging in vivo, with glucose metabolism and mitochondrial activity analyzed by biomarkers and studies with primary neurons in vitro. Synaptic function was evaluated by both biomarkers and electrophysiologic analysis. Current study shows that intravenously administered Ab-TP-MDNPs enhanced cerebral glucose utilization, improved glucose metabolism, mitochondrial activity, and increased the levels of neprilysin, O-glycosylation. The consequence of this was enhanced glucose and ATP availability, resulting in improved long-term potentiation for promoting neuronal synaptic function. This study highlights the importance of targeting the metabolism of complex disease pathologies in addressing disease-modifying therapeutics for neurodegenerative disorders such as Alzheimer's disease.}, }
@article {pmid39874376, year = {2025}, author = {Lu, H and Ni, X and Man Chan, SS and Cheng, CPW and Chan, W and Lam, LCW}, title = {Pre-treatment subjective sleep quality as a predictive biomarker of tDCS effects in preclinical Alzheimer's disease patients: Secondary analysis of a randomised clinical trial.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0317700}, pmid = {39874376}, issn = {1932-6203}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology/physiopathology ; *Transcranial Direct Current Stimulation/methods ; Male ; Female ; Aged ; *Sleep Quality ; *Cognition/physiology ; Biomarkers ; Memory, Short-Term/physiology ; Middle Aged ; Cognitive Dysfunction/therapy ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {BACKGROUND: Despite transcranial direct current stimulation (tDCS) has demonstrated encouraging potential for modulating the circadian rhythm, little is known about how well and sustainably tDCS might improve the subjective sleep quality in older adults. This study sought to determine how tDCS affected sleep quality and cognition, as well as how well pre-treatment sleep quality predicted tDCS effects on domain-specific cognitive functions in patients with mild neurocognitive disorder due to Alzheimer's disease (NCD-AD).
METHODS: This clinical trial aimed to compare the effectiveness of tDCS and cognitive training in mild NCD-AD patients (n = 201). Over the course of four weeks, patients were randomized to receive either tDCS plus working memory training, or sham tDCS plus working memory training, or tDCS plus controlled cognitive training. The Pittsburgh Sleep Quality Index (PSQI) was used to measured subjective sleep quality. The Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog) was used to evaluate domain-specific cognitive functions.
RESULTS: Recurrent tDCS treatments enhanced subjective sleep quality and cognition considerably. The poor sleepers (i.e., PSQI > 5) who received tDCS treatment had more cognitive benefits (p = 0.031, Cohen's d = 0.605) and sleep improvements (p < 0.001, Cohen's d = 1.209) in comparison to cognitive training. Pre-treatment subjective sleep quality was linked to tDCS-induced improvement in memory function.
CONCLUSION: During the course of two months, repeated tDCS could considerably enhance subjective sleep quality. For the cognitive benefits of the treatments, the status of pre-treatment subjective sleep quality is crucial. More thorough research is necessary to explore an efficient approach to managing comorbidities for preclinical AD patients.}, }
@article {pmid39874173, year = {2025}, author = {Aksu, K and Ayvaz, MÇ and Çelik, ÖF and Serdaroğlu, G and Üstün, E and Kelebekli, L}, title = {Synthesis, Biological Activities, DFT Calculations, and Molecular Docking Studies of O-Methyl-Inositols.}, journal = {Chemistry & biodiversity}, volume = {}, number = {}, pages = {e202402346}, doi = {10.1002/cbdv.202402346}, pmid = {39874173}, issn = {1612-1880}, support = {ODU/BAP Grant AR-1324//Ordu University Scientific Research Projects Coordination Unit/ ; //Scientific and Technological Research Council of Turkey (TUBITAK)/ ; }, abstract = {The concise synthesis of O-methyl-d-inositol derivative and conduritol derivatives was obtained starting from p-benzoquinone. Spectroscopic methods have been performed for the characterization of newly synthesized compounds. Cyclitols are useful molecules with anticancer, antibiotic, antinutrient, and antileukemic activities. Inositol class molecules, known as the most important cyclitol derivatives, were examined in this study for their 1,1-diphenyl-2-picrylhydrazyl (DPPH) and nitric oxide radical scavenging and butyrylcholinesterase (BChE) and glycosidase inhibition activities. It was observed that compound 5, in particular, showed efficacy that competed with the standards in terms of both antioxidant activity and enzyme inhibitor potential. Additionally, compound 5 shows effective antimicrobial activity. The water-soluble characteristics and lipophilic properties of the compounds were also considered and discussed. Moreover, the quantum chemical analyses were performed in light of the DFT/B3LYP/6-311G** level computations to elucidate/compare the studied inositols' possible reactivity directions. Additionally, the interactions of the molecules were analyzed against acetylcholinesterase (AChE), peroxiredoxin 5, and DNA gyrase by molecular docking methods. Cholinesterase inhibitors have an important status as the most important drug group used in the treatment of Alzheimer's disease today. Considering the effects of inhibition of the α-glucosidase enzyme by inhibitors, such molecules can also be used as therapeutic components in the treatment of diabetes.}, }
@article {pmid39873362, year = {2025}, author = {Zhang, L and An, H and Zhen, R and Zhang, T and Ding, M and Zhang, M and Sun, Y and Gu, C}, title = {Di Huang Yi Zhi Fang improves cognitive function in APP/PS1 mice by inducing neuronal mitochondrial autophagy through the PINK1-parkin pathway.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {2}, pages = {372-382}, doi = {10.1177/13872877241299832}, pmid = {39873362}, issn = {1875-8908}, mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Mice, Transgenic ; Mice ; *Mitochondria/drug effects/metabolism ; *Autophagy/drug effects ; *Amyloid beta-Protein Precursor/genetics ; *Protein Kinases/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Neurons/drug effects/metabolism ; *Ubiquitin-Protein Ligases/metabolism/genetics ; Presenilin-1/genetics ; Cognition/drug effects ; Maze Learning/drug effects ; Disease Models, Animal ; Male ; Amyloid beta-Peptides/metabolism ; Signal Transduction/drug effects ; Hippocampus/drug effects/metabolism/pathology ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is an irreversible age-related neurodegenerative condition characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles. Di Huang Yi Zhi (DHYZ) formula, a traditional Chinese herbal compound comprising several prescriptions, demonstrates properties that improve cognitive abilities in clinical. Nonetheless, its molecular mechanisms on treating AD through improving neuron cells mitochondria function have not been deeply investigated.
OBJECTIVE: This study administered DHYZ to APP/PS1 mice to explore its potential therapeutic mechanisms in AD treatment.
METHODS: APP/PS1 transgenic mice were given DHYZ (L, M, H), donepezil, or distilled water for a consecutive 12-week period. The Morris water maze test was used to assess memory capacity, transmission electron microscopy was used to observe mitochondrial and synaptic structures, immunohistochemistry and western blot detected proteins involved in the mitochondrial autophagy pathway, ELISA measured serum Aβ content, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assessed neuronal cell apoptosis.
RESULTS: DHYZ demonstrates a notable therapeutic impact on mice with AD, effectively improving cognitive and memory impairments. DHYZ decreases Aβ accumulation in the hippocampus by reducing BACE1 activity and enhancing Aβ clearance through the blood-brain barrier. Additionally, DHYZ significantly suppresses neuronal apoptosis, enhances synaptic structure, and increases synapse numbers, processes strongly linked to the activation of mitochondrial PINK1-Parkin autophagy.
CONCLUSIONS: DHYZ enhances cognitive function in APP/PS1 mice by stimulating neuronal mitochondrial autophagy through the PINK1-Parkin pathway.}, }
@article {pmid39873275, year = {2025}, author = {Liang, F and Ma, L and Zhang, G and Han, J and Zhu, M and Zhu, C and Jin, Y and Wang, Z}, title = {Mapping of Amyloid-β Aggregates In Vivo by a Fluorescent Probe with Dual Recognition Moieties.}, journal = {Analytical chemistry}, volume = {97}, number = {5}, pages = {3108-3116}, doi = {10.1021/acs.analchem.4c06385}, pmid = {39873275}, issn = {1520-6882}, mesh = {*Fluorescent Dyes/chemistry/chemical synthesis ; *Amyloid beta-Peptides/metabolism/analysis ; Animals ; Mice ; Alzheimer Disease/metabolism/diagnosis/pathology ; Humans ; Brain/diagnostic imaging/metabolism/pathology ; Protein Aggregates ; Peptide Fragments/chemistry/metabolism ; Molecular Structure ; Mice, Transgenic ; Optical Imaging ; }, abstract = {The spontaneous aggregation of amyloid-β (Aβ) leads to neuronal cell death in the brain and causes the development of Alzheimer's disease (AD). The efficient detection of the aggregation state of Aβ holds significant promise for the early diagnosis and subsequent treatment of this neurodegenerative disorder. Currently, most of the fluorescent probes used for the detection of Aβ fibrils share similar recognition moieties, such as the N,N-dimethylamino group, N,N-diethylamino group, and piperidyl group. The development of fluorescent probes incorporating novel recognition groups will, in principle, bring new properties for the detection and imaging of Aβ aggregates. Herein, we designed and synthesized three fluorescent probes (1 CarbCN, 2 NTCN, and 3 NCarbCN) based on dicyanoisophorone. The probe 3 NCarbCN, which integrated two recognition moieties, a carbamate unit (a new recognition group) together with a N,N-dimethylamino group, showed a sensitive turn-on fluorescence response toward the early aggregation state of Aβ, along with a high binding affinity (Kd = 59 nM) and recognition selectivity for Aβ fibrils. Theoretical calculations revealed that the carbamate unit of 3 NCarbCN could provide an additional three hydrogen bonding interaction with Aβ42 fibrils. Furthermore, the probe 3 NCarbCN efficiently crossed the blood-brain barrier and exhibited a higher response in the brains of AD model mice. Co-staining of isolated brain sections with monoclonal antibody further demonstrated specific binding of 3 NCarbCN to Aβ plaques in the brains of AD model mice, thus demonstrating its great potential for the early diagnosis of such neurodegenerative disorders.}, }
@article {pmid39873194, year = {2025}, author = {Kumar, N and Devi, B and Jangid, K and Kumar, V}, title = {Pharmacophore-based virtual screening of the chromone derivatives as potential therapeutic for Alzheimer's disease.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/07391102.2025.2458327}, pmid = {39873194}, issn = {1538-0254}, abstract = {Alzheimer's disease is one of the most complex neurological disorders and millions of people are suffering from this disease all over the world. In the past two decades acetylcholinesterase (AChE) has been the most explored pathological hallmark. The generation of potent AChE inhibitors has grown as a rapid pathological tool for the efficacious treatment of the disease. Hence, AChE enzyme is extensively explored as a drug discovery tool for the development of potent therapeutics. We have used chromone derivatives with known biological activities for developing a Gaussian field-based 3D QSAR pharmacophore model using PHASE module of Schrodinger with statistically significant R[2] and Q[2] values of 0.92 and 0.9209, respectively. ChEMBL and MCULE databases were screened using the best pharmacophore hypothesis model (AAHHRR_4) with features of two hydrogen bond acceptors (A1, A2), two hydrophobic regions (H1, H2), and two aromatic regions (R1, R2). These were subjected to structure-based virtual screening using extra precision, MM/GBSA and ADME calculations for calculating the binding free energies and pharmacokinetic properties, respectively. Subsequently, two hit molecules i.e. CHEMBL1319989 and MCULE-2246633290 were identified. The leads exhibited higher docking score (-8.859 and -9.984 kcal/mol) and ΔGbinding (-57.63 and -56.45 kcal/mol) as compared to the reference (ΔGbinding= -53.79 kcal/mol). MD simulation study exhibited stable interactions with the binding free energy (ΔGMMPBSA) of -27.29 and -21.26 kcal/mol for CHEMBL1319989 and MCULE-2246633290, respectively. So, the generated pharmacophore model may be considered as a valuable tool for the development of potent AChE inhibitors for the treatment of AD.}, }
@article {pmid39873047, year = {2025}, author = {Son, SH and Lee, SW and Chung, G}, title = {Loss of dental pulp potentially increased the risk of Alzheimer's dementia.}, journal = {Journal of dental sciences}, volume = {20}, number = {1}, pages = {310-318}, pmid = {39873047}, issn = {2213-8862}, abstract = {BACKGROUND/PURPOSE: Chronic periodontitis and tooth loss contribute to cognitive decline. Since many biological processes are shared by loss of teeth and loss of pulps, this study investigated the potential association between loss of pulp and the development of dementia.
MATERIALS AND METHODS: A retrospective cohort analysis was conducted to investigate the association between dental treatment and the development of dementia. The records of dental treatment during the 10 years prior to the first diagnosis of dementia were extracted from the Elderly Cohort Database of the National Health Information Sharing Service of Korea. The independence of dementia compared to the number of pulps or teeth removed was evaluated using the chi-squared test. The subjects were grouped by the number of teeth or pulps treated, and their odds ratio for dementia was calculated.
RESULTS: Analysis of 591,592 sessions for pulpectomy and 710,722 sessions for tooth extraction from 558,147 individuals revealed a significant association with Alzheimer's dementia, but not with vascular or unspecified dementia. The number of dementia patients based on the number of pulps or teeth extracted were significantly different across age groups. The odds ratios demonstrated a tendency to increase with the number of dental treatments and decrease with age at the time of diagnosis of dementia. The number of pulps removed to achieve a notable impact on Alzheimer's dementia was found to be lower than the number of teeth extracted.
CONCLUSION: The loss of pulp increased incidence of Alzheimer's dementia, with the impact being more pronounced in younger geriatric groups.}, }
@article {pmid39872995, year = {2024}, author = {Fine, JM and Kosyakovsky, J and Bowe, TT and Faltesek, KA and Stroebel, BM and Abrahante, JE and Kelly, MR and Thompson, EA and Westby, CM and Robertson, KM and Frey, WH and Hanson, LR}, title = {Low-dose intranasal deferoxamine modulates memory, neuroinflammation, and the neuronal transcriptome in the streptozotocin rodent model of Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1528374}, pmid = {39872995}, issn = {1662-4548}, abstract = {INTRODUCTION: Intranasal (IN) deferoxamine (DFO) has emerged over the past decade as a promising therapeutic in preclinical experiments across neurodegenerative and neurovascular diseases. As an antioxidant iron chelator, its mechanisms are multimodal, involving the binding of brain iron and the consequent engagement of several pathways to counter pathogenesis across multiple diseases. We and other research groups have shown that IN DFO rescues cognitive impairment in several rodent models of Alzheimer Disease (AD).
METHODS: This study was designed to probe dosing regimens to inform future clinical trials, while exploring mechanisms within the intracerebroventricular (ICV) streptozotocin (STZ) model.
RESULTS: Five weeks of daily IN dosing of Long Evans rats with 15 μL of a 1% (0.3 mg), but not 0.1% (0.03 mg), solution of DFO rescued cognitive impairment caused by ICV STZ administration as assessed with the Morris Water Maze (MWM) test of spatial memory and learning. Furthermore, IN DFO modulated several aspects of the neuroinflammatory milieu of the ICV STZ model, which was assessed through a novel panel of brain cytokines and immunohistochemistry. Using RNA-sequencing and pathway analysis, STZ was shown to induce several pathways of cell death and neuroinflammation, and IN DFO engaged multiple transcriptomic pathways involved in hippocampal neuronal survival.
DISCUSSION: To our knowledge this study is the first to assess the transcriptomic pathways and mechanisms associated with either the ICV STZ model or DFO treatment, and the first to demonstrate efficacy at this low dose.}, }
@article {pmid39872848, year = {2024}, author = {Wang, X and He, X and Zhong, B}, title = {Oral microbiota: the overlooked catalyst in cancer initiation and progression.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1479720}, pmid = {39872848}, issn = {2296-634X}, abstract = {The advancement of high-throughput sequencing technology in recent decades has led to a greater understanding of the components of the oral microbiota, providing a solid foundation for extensive research in this field. The oral microbiota plays an important role in an individual's overall health. It has been shown to be significantly correlated with chronic human diseases, including diabetes, rheumatoid arthritis, cardiovascular disease, periodontal disease, and Alzheimer's disease. Furthermore, tumor occurrence and development are closely related to the oral microbiome. Specific bacteria, such as Fusobacterium nucleatum (F. nucleatum), Porphyromonas gingivalis (P. gingivalis), Streptococcus, Streptomyces, Prevotella, and Fibrophagy gingivalis, play critical roles in cancer development. The oral microbiota has various oncogenic mechanisms, including bacterial inflammation, immunological suppression, tumor growth mediated by bacterial toxins, antiapoptotic activity, and carcinogenic effects. This paper reviews the role of the oral microbiota in the occurrence and progression of cancer and systematically elucidates the molecular mechanisms by which dysbiosis influences tumorigenesis and tumor progression. This information can provide a theoretical basis for exploring cancer treatment strategies and offer new insights for cancer prevention.}, }
@article {pmid39872720, year = {2025}, author = {Graur, A and Erickson, N and Kabbani, N}, title = {Using Protein Painting Mass Spectrometry to Define Ligand Receptor Interaction Sites for Acetylcholine Binding Protein.}, journal = {Bio-protocol}, volume = {15}, number = {2}, pages = {e5163}, pmid = {39872720}, issn = {2331-8325}, abstract = {Nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gated ion channels expressed in nervous and non-nervous system tissue important for memory, movement, and sensory processes. The pharmacological targeting of nAChRs, using small molecules or peptides, is a promising approach for the development of compounds for the treatment of various human diseases including inflammatory and neurogenerative disorders such as Alzheimer's disease. Using the Aplysia californica acetylcholine binding protein (Ac-AChBP) as an established structural surrogate for human homopentameric α7 nAChRs, we describe an innovative protein painting mass spectrometry (MS) method that can be used to identify interaction sites for various ligands at the extracellular nAChR site. We describe how the use of small molecule dyes can be optimized to uncover contact sites for ligand-protein interactions based on MS detection. Protein painting MS has been recently shown to be an effective tool for the identification of residues within Ac-AChBP involved in the binding of know ligands such as α-bungarotoxin. This strategy can be used with computational structural modeling to identify binding regions involved in drug targeting at the nAChR. Key features • Identify binding ligands of nicotinic receptors based on similarity with the acetylcholine binding protein. • Can be adapted to test various ligands and binding conditions. • Mass spectrometry identification of specific amino acid residues that contribute to protein binding. • Can be effectively coupled to structural modeling analysis.}, }
@article {pmid39871894, year = {2024}, author = {Ren, Y and Chen, M and Wang, Z and Han, JJ}, title = {Oral microbiota in aging and diseases.}, journal = {Life medicine}, volume = {3}, number = {3}, pages = {lnae024}, pmid = {39871894}, issn = {2755-1733}, abstract = {Human microbiomes are microbial populations that form a symbiotic relationship with humans. There are up to 1000 species on the surface of human skin and mucosal system, among which gut microbiota attracts the most interest. As the beginning of the digestive tract, oral cavity is also an important microbial habitat in the human body which is the first line of defense against pathogens entering the body. Many studies have revealed that oral microbial dysbiosis could not only contribute to oral diseases but also whole-body systemic diseases and health status. Oral microorganisms can enter the gastrointestinal tract with saliva and food, or enter the blood circulation through mouth breakage, thus causing systemic inflammation and aging-related diseases including some causal links to Alzheimer's disease. A series of changes take place in oral microbial composition during development, with different age stages marked by different dominant microbial species. Despite a lack of comprehensive studies on aging oral microbiota, through systemic inflammation, oral pathogenic microbes are likely to contribute inflammatory aging. As inflammaging is a key signature and one of the causes for accelerated aging, improving the structure of oral microbiome may be not only a new strategy for disease prevention and treatment, but also for aging intervention.}, }
@article {pmid39871563, year = {2025}, author = {Guo, J and Liu, XY and Yang, SS and Li, Q and Duan, Y and Zhu, SS and Zhou, K and Yan, YZ and Zeng, P}, title = {Roles of C/EBPβ/AEP in Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266357822250119172351}, pmid = {39871563}, issn = {1873-4294}, abstract = {In recent years, an increasing number of studies have shown that increased activation of aspartic endopeptidases (AEPs) is a common symptom in neurodegenerative diseases (NDDs). AEP cleaves amyloid precursor protein (APP), tau (microtubule-associated protein tau), α- synuclein (α-syn), SET (a 39-KDa phosphoprotein widely expressed in various tissues and localizes predominantly in the nucleus), and TAR DNA-binding protein 43 (TDP-43), and promotes their aggregation, contributing to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) pathogenesis. Abundant evidence supports the notion that CCAAT/enhancer-binding protein β (C/EBPβ)/AEP may play an important role in NDDs. Developing its small molecule inhibitors is a promising treatment of NDDs. However, current research suggests that the pathophysiological mechanism of the C/EBPβ/AEP pathway is very complex in NDDs. This review summarizes the structure of C/EBPβ and AEP, their major physiological functions, potential pathogenesis, their small molecule inhibitors, and how C/EBPβ/AEP offers a novel pathway for the treatment of NDDs.}, }
@article {pmid39871559, year = {2025}, author = {Rani, S and Tuteja, M}, title = {Chaperones as Potential Pharmacological Targets for Treating Protein Aggregation Illness.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037338028241230092414}, pmid = {39871559}, issn = {1875-5550}, abstract = {The three-dimensional structure of proteins, achieved through the folding of the nascent polypeptide chain in vivo, is largely facilitated by molecular chaperones, which are crucial for determining protein functionality. In addition to aiding in the folding process, chaperones target misfolded proteins for degradation, acting as a quality control system within the cell. Defective protein folding has been implicated in a wide range of clinical conditions, including neurodegenerative and metabolic disorders. It is now well understood that the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Creutzfeldt-Jakob disease shares a common mechanism: the accumulation of misfolded proteins, which aggregate and become toxic to cells. Among the family of molecular chaperones, Heat Shock Proteins (HSPs) are highly expressed in response to cellular stress and play a pivotal role in preventing protein aggregation. Specific chaperones, particularly HSPs, are now recognized as critical in halting the accumulation and aggregation of misfolded proteins in these conditions. Consequently, these chaperones are increasingly considered promising pharmacological targets for the treatment of protein aggregation-related diseases. This review highlights research exploring the potential roles of specific molecular chaperones in disorders characterized by the accumulation of misfolded proteins.}, }
@article {pmid39871402, year = {2025}, author = {Li, S and Li, M and Li, G and Li, L and Yang, X and Zuo, Z and Zhang, L and Hu, X and He, X}, title = {Physical Exercise Decreases Complement-Mediated Synaptic Loss and Protects Against Cognitive Impairment by Inhibiting Microglial Tmem9-ATP6V0D1 in Alzheimer's Disease.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e14496}, doi = {10.1111/acel.14496}, pmid = {39871402}, issn = {1474-9726}, support = {2024A04J4861//Guangzhou Science and Technology Planning Project/ ; 82272609//National Natural Science Foundation of China/ ; 2022YFC3601200//National Key Research and Development Program of China/ ; }, abstract = {Physical exercise is known to slow synaptic neurodegeneration and cognitive aging in Alzheimer's disease (AD). The benefits of physical exercise are related to reduced amyloid beta (Aβ) deposition and increased synaptic plasticity. Yet little is known about the mechanisms that mediate these effects. Here, we show that physical exercise down-regulated the microglial Tmem9 protein, inhibited C1q activation, and decreased C1q-dependent microglial synapse engulfment, eventually ameliorating cognitive impairment in 5xFAD mice. Furthermore, using oAβ cultured-BV2 in vitro, we show that downregulation of microglial Tmem9 was sufficient to restrain complement activity and decrease microglia-mediated synaptic loss, whereas overexpression of microglial Tmem9 tended to promote complement activation and induced synaptic loss, abolishing exercise-associated protection. Finally, we show that microglial Tmem9 contributed to complement activation by regulating ATP6V0D1, a vesicular (H[+]) ATP-dependent proton pump (V-ATPase) subunit that regulates V-ATPase assembly. Together, our results demonstrate that exercise is a potential treatment for AD patients. In an AD mouse model, it decreased the levels of microglial Tmem9 to inhibit the activation of complement, alleviated complement-dependent synaptic loss, and eventually ameliorated emotional and cognitive disorders.}, }
@article {pmid39871348, year = {2025}, author = {He, S and Xu, Z and Han, X}, title = {Lipidome disruption in Alzheimer's disease brain: detection, pathological mechanisms, and therapeutic implications.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {11}, pmid = {39871348}, issn = {1750-1326}, support = {Methodist Hospital Foundation//Methodist Hospital Foundation/ ; University of Texas Health Science Center at San Antonio//University of Texas Health Science Center at San Antonio/ ; William and Ella Owens Medical Research Foundation//William and Ella Owens Medical Research Foundation/ ; R01 AG085545/AG/NIA NIH HHS/United States ; P30 AG013319/AG/NIA NIH HHS/United States ; R01 AG061872/AG/NIA NIH HHS/United States ; P30 AG044271/AG/NIA NIH HHS/United States ; R01 AG061729/AG/NIA NIH HHS/United States ; Cure Alzheimer's Fund//Cure Alzheimer's Fund/ ; T32 AG021890/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; RF1 AG061872/AG/NIA NIH HHS/United States ; RF1 AG061729/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism ; Humans ; *Brain/metabolism/pathology ; *Lipidomics/methods ; *Lipid Metabolism/physiology ; Animals ; }, abstract = {Alzheimer's disease (AD) is among the most devastating neurodegenerative disorders with limited treatment options. Emerging evidence points to the involvement of lipid dysregulation in the development of AD. Nevertheless, the precise lipidomic landscape and the mechanistic roles of lipids in disease pathology remain poorly understood. This review aims to highlight the significance of lipidomics and lipid-targeting approaches in the diagnosis and treatment of AD. We summarized the connection between lipid dysregulation in the human brain and AD at both genetic and lipid species levels. We briefly introduced lipidomics technologies and discussed potential challenges and areas of future advancements in the lipidomics field for AD research. To elucidate the central role of lipids in converging multiple pathological aspects of AD, we reviewed the current knowledge on the interplay between lipids and major AD features, including amyloid beta, tau, and neuroinflammation. Finally, we assessed the progresses and obstacles in lipid-based therapeutics and proposed potential strategies for leveraging lipidomics in the treatment of AD.}, }
@article {pmid39870228, year = {2025}, author = {Dahiya, M and Kumar, A and Yadav, M and Chauhan, S}, title = {β-pinene ameliorates ICV-STZ induced Alzheimer's pathology via antioxidant, anticholinesterase, and mitochondrial protective effects: In-silico and in-vivo studies.}, journal = {European journal of pharmacology}, volume = {991}, number = {}, pages = {177307}, doi = {10.1016/j.ejphar.2025.177307}, pmid = {39870228}, issn = {1879-0712}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; *Bicyclic Monoterpenes/pharmacology/chemistry ; *Cholinesterase Inhibitors/pharmacology ; *Molecular Docking Simulation ; *Rats, Wistar ; *Antioxidants/pharmacology/chemistry ; *Mitochondria/drug effects/metabolism ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Acetylcholinesterase/metabolism ; Oxidative Stress/drug effects ; Disease Models, Animal ; Behavior, Animal/drug effects ; Galantamine/pharmacology/chemistry ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a leading cause of dementia, characterized by progressive neurodegeneration and cognitive dysfunction. The disease aetiology is closely associated with proteinopathies, mitochondrial abnormalities, and elevated ROS generation, which are some of the primary markers for AD brains.
OBJECTIVES: The current research was intended to elucidate the chemical interaction of β-pinene against potential targets and evaluate its neuroprotective potential in ICV-STZ-induced sAD.
METHODOLOGY: The potential binding interactions of β-pinene and galantamine were evaluated against the active sites of PP2A, SOD1, catalase-3, and AChE using AutoDock vina. Additionally, the β-pinene and galantamine were subjected to tests of their ADMET by employing the Swiss ADME and Protox-II web servers. To assess the neuroprotective potential, β-pinene (50, 100, and 200 mg/kg) and galantamine (2 mg/kg) was administered p.o in ICV-STZ-treated wistar rats for 21 days. Moreover, behavioral parameters (NOR & MWM), biochemical, AChE activities, and mitochondrial complexes were performed.
RESULTS: Molecular docking study showed that β-pinene can interact with human PP2A, SOD1, Catalase-3, and AChE with better ligand efficiency as compared to galantamine. In-vivo data showed that β-pinene treatment (100, and 200 mg/kg) for 21 days exhibited significantly enhanced cognitive performance, as shown in behavioral studies. Additionally, β-pinene treatment significantly re-established antioxidant levels and mitochondrial capacities and attenuated altered AChE activity as compared to ICV-STZ-induced groups.
CONCLUSIONS: In-silico studies revealed that β-pinene shared the same binding pocket as galantamine, supporting its neuroprotective effects in the ICV-STZ-induced animal model by alleviating oxidative stress and mitochondrial dysfunction and reducing AChE activity.}, }
@article {pmid39869613, year = {2025}, author = {Li, X and Gong, B and Chen, X and Li, H and Yuan, G}, title = {Alzheimer's disease image classification based on enhanced residual attention network.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0317376}, pmid = {39869613}, issn = {1932-6203}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis/classification ; Humans ; *Deep Learning ; Early Diagnosis ; Neural Networks, Computer ; Attention ; }, abstract = {With the increasing number of patients with Alzheimer's Disease (AD), the demand for early diagnosis and intervention is becoming increasingly urgent. The traditional detection methods for Alzheimer's disease mainly rely on clinical symptoms, biomarkers, and imaging examinations. However, these methods have limitations in the early detection of Alzheimer's disease, such as strong subjectivity in diagnostic criteria, high detection costs, and high misdiagnosis rates. To address these issues, this study proposes a deep learning model to detect Alzheimer's disease; it is called Enhanced Residual Attention Network (ERAN) that can classify medical images. By combining residual learning, attention mechanism, and soft thresholding, the feature representation ability and classification accuracy of the model have been improved. The accuracy of the model in detecting Alzheimer's disease has reached 99.36%, with a loss rate of only 0.0264. The experimental results indicate that the Enhanced Residual Attention Network has achieved excellent performance on the Alzheimer's disease test dataset, providing strong support for the early diagnosis and treatment of Alzheimer's disease.}, }
@article {pmid39868844, year = {2025}, author = {Elyaman, W and Stern, LJ and Jiang, N and Dressman, D and Bradley, P and Klatzmann, D and Bradshaw, EM and Farber, DL and Kent, SC and Chizari, S and Funk, K and Devanand, D and Thakur, KT and Raj, T and Dalahmah, OA and Sarkis, RA and Weiner, HL and Shneider, NA and Przedborski, S}, title = {Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14548}, pmid = {39868844}, issn = {1552-5279}, support = {T32 AI148099/AI/NIAID NIH HHS/United States ; P01 AI106697/AI/NIAID NIH HHS/United States ; R01AI137198/NH/NIH HHS/United States ; R13 AG090018/AG/NIA NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; R01 AG076018/AG/NIA NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; T32AI148099-4/NH/NIH HHS/United States ; AI106697/NH/NIH HHS/United States ; R01 AG055422/AG/NIA NIH HHS/United States ; R01AG067581/NH/NIH HHS/United States ; R13AG090018-01/NH/NIH HHS/United States ; R01AG076018/NH/NIH HHS/United States ; AG R01AG055422/NH/NIH HHS/United States ; R35GM141457/NH/NIH HHS/United States ; R01 AI137198/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/immunology/therapy ; *Neurodegenerative Diseases/immunology/therapy ; *T-Lymphocytes/immunology ; Immunotherapy/methods ; Brain/pathology/immunology ; }, abstract = {This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of T cells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, T cell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-T cell crosstalk, with a focus on how T cells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory T cell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of T cells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of T cells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study T cells in brain disorders. New technologies allow high-throughput screening of antigen-specific T cells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral T cell responses shape neurological disease pathology. Immunotherapy can induce regulatory T cell responses in neuroinflammatory disorders.}, }
@article {pmid39868840, year = {2025}, author = {Wen, B and Han, X and Gong, J and Wang, P and Sun, W and Xu, C and Shan, A and Wang, X and Luan, H and Li, S and Li, R and Guo, J and Chen, R and Li, C and Sun, Y and Lv, S and Wei, C}, title = {Nutrition: A non-negligible factor in the pathogenesis and treatment of Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14547}, pmid = {39868840}, issn = {1552-5279}, support = {2021ZD0201802//STI2030-Major Projects/ ; 82471450//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Alzheimer Disease ; *Nutritional Status ; *Malnutrition/complications ; Disease Progression ; Risk Factors ; }, abstract = {Alzheimer's disease (AD) is a degenerative disease characterized by progressive cognitive dysfunction. The strong link between nutrition and the occurrence and progression of AD pathology has been well documented. Poor nutritional status accelerates AD progress by potentially aggravating amyloid beta (Aβ) and tau deposition, exacerbating oxidative stress response, modulating the microbiota-gut-brain axis, and disrupting blood-brain barrier function. The advanced stage of AD tends to lead to malnutrition due to cognitive impairments, sensory dysfunctions, brain atrophy, and behavioral and psychological symptoms of dementia (BPSD). This, in turn, produces a vicious cycle between malnutrition and AD. This review discusses how nutritional factors and AD deteriorate each other from the early stage of AD to the terminal stages of AD, focusing on the potential of different levels of nutritional factors, ranging from micronutrients to diet patterns. This review provides novel insights into reducing the risk of AD, delaying its progression, and improving prognosis. HIGHLIGHTS: Two-fifths of Alzheimer's disease (AD) cases worldwide have been attributed to potentially modifiable risk factors. Up to ≈26% of community-dwelling patients with AD are malnourished, compared to 7%∼76% of institutionalized patients. Undernutrition effects the onset, progression, and prognosis of AD through multiple mechanisms. Various levels of nutritional supports were confirmed to be protective factors for AD via specific mechanisms.}, }
@article {pmid39868701, year = {2025}, author = {Keränen, E and Rysä, J and Tiihonen, M and Hartikainen, S and Tolppanen, AM}, title = {HELICOBACTER PYLORI ERADICATION TREATMENTS AND RISK OF ALZHEIMER DISEASE: A CASE-CONTROL STUDY NESTED IN THE FINNISH POPULATION.}, journal = {Epidemiology (Cambridge, Mass.)}, volume = {36}, number = {3}, pages = {327-333}, pmid = {39868701}, issn = {1531-5487}, abstract = {BACKGROUND: Helicobacter pylori (H. pylori) has been inconsistently associated with risk of Alzheimer disease. The exposure assessment period has often overlapped with the prodromal time of Alzheimer disease. Cognitive disorders might increase vulnerability to infectious pathogens, complicating the ascertainment of temporal relationship between H. pylori infection and Alzheimer disease.
METHODS: This Finnish nested case-control study included 70,520 persons with incident Alzheimer disease diagnosed between 2005-2011 and 281,233 age-, sex-, and region of residence-matched controls. We obtained information on comorbidities and drug use from the national healthcare registers. We identified dispensed H. pylori eradication treatments from the Prescription register. We considered exposure at least 5 years before Alzheimer disease diagnosis in the main analysis. We compared risk of Alzheimer disease between H. pylori eradication treatment users and nonusers using confounder-adjusted (comorbidities and other drug use) conditional logistic regression. We assessed cumulative exposure by calculating the number of eradication treatments.
RESULTS: The prevalence of exposure to H. pylori eradication treatment at least 5 years before the outcome was 4.1% in cases and 3.9% in controls. The odds ratio (95% confidence interval) was 1.06 (1.02-1.11) in the crude and 1.03 (0.99-1.07) in the confounder-adjusted model. We observed no association between cumulative exposure and risk of Alzheimer disease.
CONCLUSION: Our results, reflecting diagnosed and treated H. pylori infection late in life, do not support the hypothesis of H. pylori as an independent risk factor for Alzheimer disease. The previously reported association may be explained by reverse association and confounding.}, }
@article {pmid39868614, year = {2025}, author = {Liu, KY and Senn, S and Howard, R}, title = {Avoiding causal fraud in the evaluation of clinical benefits of treatments for Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14457}, pmid = {39868614}, issn = {1552-5279}, support = {MR/S021418/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Randomized Controlled Trials as Topic ; Fraud ; Antibodies, Monoclonal/therapeutic use ; Outcome Assessment, Health Care ; Treatment Outcome ; }, abstract = {Recent regulatory approvals of three amyloid-lowering monoclonal antibody therapies for the treatment of Alzheimer's disease (AD) have triggered a polarizing debate in the field on the clinical meaningfulness of their reported effects. The question of how to define clinical meaningfulness for any treatment that has a modest effect size is important and will likely be subject to influence from interested stakeholders. We warn of claims of evaluating meaningful within-individual change from randomized parallel-group trials of AD treatments, sometimes purportedly assessed by a commonly recognized "responder" analysis approach, and explain why it is likely to mislead and should simply be avoided. The average between-group difference in score change is where the debate and research efforts should be focused to contextualize and evaluate the clinical meaningfulness of the true treatment effect. The statistical and communication principles we consider and would recommend are applicable to the evaluation of most interventions in medicine. HIGHLIGHTS: Dichotomized outcome analysis approaches purporting to evaluate within-individual meaningful change are highly likely to mislead. In our view, the most valid statistical approach to understanding the true treatment effect is to analyze the average between-group difference in outcome scores. The average between-group difference in score change is where the debate and research efforts should be focused to contextualize and evaluate the clinical meaningfulness of the true treatment effect.}, }
@article {pmid39868189, year = {2025}, author = {Kalecký, K and Buitrago, L and Alarcon, JM and Singh, A and Bottiglieri, T and Kaddurah-Daouk, R and Hernández, AI and , }, title = {Rescue of hippocampal synaptic plasticity and memory performance by Fingolimod (FTY720) in APP/PS1 model of Alzheimer's disease is accompanied by correction in metabolism of sphingolipids, polyamines, and phospholipid saturation composition.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39868189}, issn = {2692-8205}, support = {R01 AG046171/AG/NIA NIH HHS/United States ; U19 AG063744/AG/NIA NIH HHS/United States ; RF1 AG059093/AG/NIA NIH HHS/United States ; U01 AG061359/AG/NIA NIH HHS/United States ; RF1 AG058942/AG/NIA NIH HHS/United States ; RF1 AG051550/AG/NIA NIH HHS/United States ; }, abstract = {Previously, our metabolomic, transcriptomic, and genomic studies characterized the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease, and we demonstrated that FTY720, a sphingosine-1-phospahate receptor modulator approved for treatment of multiple sclerosis, recovers synaptic plasticity and memory in APP/PS1 mice. To further investigate how FTY720 rescues the pathology, we performed metabolomic analysis in brain, plasma, and liver of trained APP/PS1 and wild-type mice. APP/PS1 mice showed area-specific brain disturbances in polyamines, phospholipids, and sphingolipids. Most changes were completely or partially normalized in FTY720-treated subjects, indicating rebalancing the "sphingolipid rheostat", reactivating phosphatidylethanolamine synthesis via mitochondrial phosphatidylserine decarboxylase pathway, and normalizing polyamine levels that support mitochondrial activity. Synaptic plasticity and memory were rescued, with spermidine synthesis in temporal cortex best corresponding to hippocampal CA3-CA1 plasticity normalization. FTY720 effects, also reflected in other pathways, are consistent with promotion of mitochondrial function, synaptic plasticity, and anti-inflammatory environment, while reducing pro-apoptotic and pro-inflammatory signals.}, }
@article {pmid39868172, year = {2025}, author = {Rao, SP and Imam-Fulani, AO and Xie, W and Phillip, S and Chennavajula, K and Lind, EB and Zhang, Y and Vince, R and Lee, MK and More, SS}, title = {Oral prodrug of a novel glutathione surrogate reverses metabolic dysregulation and attenuates neurodegenerative process in APP/PS1 mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39868172}, issn = {2692-8205}, support = {R01 AG062469/AG/NIA NIH HHS/United States ; R01 AG077743/AG/NIA NIH HHS/United States ; RF1 AG062135/AG/NIA NIH HHS/United States ; }, abstract = {Glycation-induced oxidative stress underlies the numerous metabolic ravages of Alzheimer's disease (AD). Reduced glutathione levels in AD lead to increased oxidative stress, including glycation-induced pathology. Previously, we showed that the accumulation of reactive 1,2-dicarbonyls such as methylglyoxal, the major precursor of non-enzymatic glycation products, was reduced by the increased function of GSH-dependent glyoxalase-1 enzyme in the brain. In this two-pronged study, we evaluate the therapeutic efficacy of an orally bioavailable prodrug of our lead glyoxalase substrate, pro-ψ-GSH, for the first time in a transgenic Alzheimer's disease mouse model. This prodrug delivers pharmacodynamically relevant brain concentrations of ψ-GSH upon oral delivery. Chronic oral dosing of pro-ψ-GSH effectively reverses the cognitive decline observed in the APP/PS1 mouse model. The prodrug successfully mirrors the robust effects of the parent drug i.e., reducing amyloid pathology, glycation stress, neuroinflammation, and the resultant neurodegeneration in these mice. We also report the first metabolomics study of such a treatment, which yields key biomarkers linked to the reversal of AD-related metabolic dysregulation. Collectively, this study establishes pro-ψ-GSH as a viable, disease-modifying therapy for AD and paves the way for further preclinical advancement of such therapeutics. Metabolomic signatures identified could prove beneficial in the development of treatment-specific clinically translatable biomarkers.}, }
@article {pmid39867586, year = {2025}, author = {Yepes, AF and Cardona-Galeano, W and Herrera-Ramírez, A and Rada, MS and Osorio, E and Gonzalez-Molina, LA and Miranda-Brand, Y and Posada-Duque, R}, title = {Novel multipotent conjugate bearing tacrine and donepezil motifs with dual cholinergic inhibition and neuroprotective properties targeting Alzheimer's disease.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {39867586}, issn = {2632-8682}, abstract = {In this work, we developed potential multifunctional agents to combat Alzheimer's disease. According to our strategy, fragments of tacrine and donepezil were merged in a unique hybrid structure. After successfully synthesizing the compounds, they were evaluated for their dual AChE/BuChE inhibitor potential and neuroprotector response using a glutamate-induced excitotoxicity model. Most of the compounds showed promising activity. Among them, the hybrid with 2,5-dimetoxysubstitution (3b) was the most potent analogue, triggering dual potent AChE/BuChE inhibition with low nanomolar affinity (IC50 ∼ 300 nM) and low toxicity to human liver cancer cells (HepG2). This analogue prevented the glutamate excitotoxic stimulus during pre/post treatment testing, maintained ATP levels, possessed an astrocytic protective response, and abolished the glutamate-induced excitotoxicity. Besides, the hit compound 3b exhibited suitable permeability in the blood-brain barrier (BBB) and low degradability in human blood-plasma. In addition, the docking studies suggested that the neuroprotectant response exhibited by 3b can be related to the direct blockage of the NMDA channel pore. Finally, an ideal neuropharmacokinetic profile was estimated for 3b. Overall, the designed conjugates provide a novel multifunctional molecular scaffold that can be used as a prototype drug in further investigations toward novel multipotent therapeutics for treating AD.}, }
@article {pmid39867516, year = {2025}, author = {Roy, S and Biswas, S and Nandy, A and Guha, D and Dasgupta, R and Bagchi, A and Sil, PC}, title = {An approach to predict and inhibit Amyloid Beta dimerization pattern in Alzheimer's disease.}, journal = {Toxicology reports}, volume = {14}, number = {}, pages = {101879}, pmid = {39867516}, issn = {2214-7500}, abstract = {Alzheimer's Disease (AD) is one of the leading neurodegenerative diseases that affect the human population. Several hypotheses are in the pipeline to establish the commencement of this disease; however, the amyloid hypothesis is one of the most widely accepted ones. Amyloid plaques are rich in Amyloid Beta (Aβ) proteins, which are found in the brains of Alzheimer's patients. They are the spliced product of a transmembrane protein called Amyloid Precursor Protein (APP); when they enter into the amylogenic pathway, they get cleaved simultaneously by Beta and Gamma Secretase and produce Aβ protein. Appearances of Amyloid plaques are the significant clinical hallmarks of this disease. AD is mainly present in two genetically distinct forms; sporadic and familial AD. Sporadic Alzheimer's Disease (sAD) is marked by a later clinical onset of the disease, whereas, familial Alzheimer's Disease (fAD) is an early onset of the disease with mendelian inheritance. Several mutations have been clinically reported in the last decades that have shown a direct link with fAD. Many of those mutations are reported to be present in the APP. In this study, we selected a few significant mutations present in the Aβ stretch of the APP and tried to differentiate the wild-type Aβ dimers formed in sAD and the mutant dimers formed in fAD through molecular modelling as there are no structures available from wet-lab studies till date. We analysed the binding interactions leading to formations of the dimers. Our next aim was to come up with a solution to treat AD using the method of drug repurposing. For that we used virtual screening and molecular docking simulations of the already existing anti-inflammatory drugs and studied their potency in resisting the formation of Aβ dimers. This is the first such report of drug repurposing for the treatment of AD, which might pave new pathways in therapy.}, }
@article {pmid39867382, year = {2025}, author = {Poulet, PE and Tran, M and Tezenas du Montcel, S and Dubois, B and Durrleman, S and Jedynak, B}, title = {Prediction-powered Inference for Clinical Trials.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39867382}, support = {R01 AG021155/AG/NIA NIH HHS/United States ; R01 AG027161/AG/NIA NIH HHS/United States ; R01 EY032284/EY/NEI NIH HHS/United States ; }, abstract = {Prediction-powered inference (PPI) [1] and its subsequent development called PPI++ [2] provide a novel approach to standard statistical estimation leveraging machine learning systems to enhance unlabeled data with predictions. We use this paradigm in clinical trials. The predictions are provided by disease progression models, providing prognostic scores for all the participants as a function of baseline covariates. The proposed method would empower clinical trials by providing untreated digital twins of the treated patients while remaining statistically valid. The potential implications of this new estimator of the treatment effect in a two-arm randomized clinical trial (RCT) are manifold. First, it leads to an overall reduction of the sample size required to reach the same power as a standard RCT. Secondly, it advocates for an imbalance of controls and treated patients, requiring fewer controls to achieve the same power. Finally, this technique directly transfers any disease prediction model trained on large cohorts to practical and scientifically valid use. In this paper, we demonstrate the theoretical properties of this estimator and illustrate them through simulations. We show that it is asymptotically unbiased for the Average Treatment Effect and derive an explicit formula for its variance. An application to an Alzheimer's disease clinical trial showcases the potential to reduce the sample size.}, }
@article {pmid39865978, year = {2025}, author = {Theofanopoulou, C}, title = {Dancing towards speech improvement: Repurposing dance for motor speech deficits in neurodegenerative diseases.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877241313304}, doi = {10.1177/13872877241313304}, pmid = {39865978}, issn = {1875-8908}, abstract = {Dance or rhythmic movement-based training has demonstrated significant efficacy in addressing a range of motor and cognitive deficits associated with neurodegenerative diseases like Parkinson's and Alzheimer's diseases. Leveraging both human and non-human animal behavioral and neurobiological evidence, I hypothesize a possible untapped role of dance training in mitigating impairments in the motor control of speech, a complex sensorimotor behavior affected in these conditions. Here, this hypothesis is supported by an in-depth examination of motor speech deficits in Parkinson's and Alzheimer's diseases, at a behavioral, physiological, and neural level. Additionally, literature on the impact of dance training on behaviors and brain pathways possibly relevant to speech motor control in populations with neurodegenerative diseases is thoroughly reviewed. Synthesizing these findings, I propose repurposing dance as a novel treatment for motor speech deficits and outline specific experiments to test this hypothesis. By comprehensively investigating the full spectrum of the effects of a motor-based training, i.e., dance, on often overlooked motor-based behaviors, such as speech, we may uncover novel therapeutic avenues of a practice that has already shown promising implications.}, }
@article {pmid39865938, year = {2025}, author = {Takeo, Y and Crite, M and Mehmood, K and DiMaio, D}, title = {γ-secretase facilitates retromer-mediated retrograde transport.}, journal = {Journal of cell science}, volume = {138}, number = {4}, pages = {}, pmid = {39865938}, issn = {1477-9137}, support = {R01 AI150897/AI/NIAID NIH HHS/United States ; AI150897//National Institute of Allergy and Infectious Diseases/ ; //Yale University/ ; }, mesh = {Humans ; *trans-Golgi Network/metabolism ; *Protein Transport ; *Endosomes/metabolism ; *Amyloid Precursor Protein Secretases/metabolism/genetics ; Presenilin-1/metabolism/genetics ; Vesicular Transport Proteins/metabolism/genetics ; Receptor, IGF Type 2/metabolism ; HeLa Cells ; rab GTP-Binding Proteins/metabolism/genetics ; rab7 GTP-Binding Proteins ; }, abstract = {Retromer mediates retrograde transport of protein cargoes from endosomes to the trans-Golgi network (TGN). γ-secretase is a protease that cleaves the transmembrane domain of its target proteins. Although retromer can form a stable complex with γ-secretase, the functional consequences of this interaction are not known. Here, we report that retromer-mediated retrograde protein trafficking in cultured human epithelial cells is impaired by the γ-secretase inhibitor XXI or by knockout of PS1 (also known as PSEN1), the catalytic subunit of γ-secretase. These treatments inhibited endosome-to-TGN trafficking of retromer-dependent retrograde cellular cargoes, divalent metal transporter 1 isoform II, cation-independent mannose-6-phosphate receptor and shiga toxin, whereas trafficking of retromer-independent cargoes, cholera toxin and a mutant CIMPR unable to bind retromer was not affected. Moreover, we found that γ-secretase associates with retromer cargoes even in the absence of retromer. XXI treatment and PS1 knockout did not inhibit the ability of retromer or γ-secretase to associate with cargo and did not affect the expression of retromer subunits or Rab7-GTP, which regulates retromer-cargo interaction. These results imply that the γ-secretase-retromer interaction facilitates retromer-mediated retrograde trafficking of cellular transmembrane proteins.}, }
@article {pmid39865820, year = {2025}, author = {Vecchio, I and Colica, C}, title = {New Research on Biomarkers in Alzheimer's Continuum.}, journal = {Reviews on recent clinical trials}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115748871331138250114052615}, pmid = {39865820}, issn = {1876-1038}, abstract = {Alzheimer's disease (AD) is a multifactorial pathology, responsible for neurodegenerative disorders which in more than 60% of patients evolve into dementia. Comprehension of the molecular mechanisms underlying the pathology and the development of reliable diagnostic methods have made new and more effective therapies possible. In recent years, in addition to the classic anticholinesterases (AChEs), which can control the clinical symptoms of the disease, compounds able to reduce deposits of amyloid-β (Aβ) and/or tau (τ) protein aggregates, which are disease-modifying therapeutics (DMTs), have been studied. The results have shown that symptomatic therapy works best when administered in the disease's mild to moderate clinical phase. On the other hand, treatment with DMTs has been found to be more effective in the preclinical stage of AD, when Aβ and τ protein neurofibrillary tangles have not yet been compromised and patients still have a normal quality of life. This innovative approach requires the identification of specific biomarkers predictive of the disease, detectable many years before clinical signs are evident. Biomarkers allow early diagnosis, give indications of the possible development of dementia in the future, and make it possible to study the evolution of the disease. New scenarios, involving different pathways and approaches, could emerge and provide effective therapies to treat the very early stages of the disease and hamper its progression. The specific biomarkers studied so far have been reported here.}, }
@article {pmid39865819, year = {2025}, author = {Zhang, D and Khan, MU and Safir Ullah, }, title = {Harmony in Motion: The Role of Exercise in Orchestrating Neuroprotection for Individuals with Alzheimer's Disease and Diabetes Examined from a Psychological Perspective.}, journal = {Current pharmaceutical biotechnology}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892010340895250119183021}, pmid = {39865819}, issn = {1873-4316}, abstract = {According to epidemiological studies, diabetes is more common in patients with AD, which suggests that diabetes is a significant risk factor for AD. Accelerating brain cell degeneration, worsening cognitive decline, and increasing susceptibility to AD can be attributed to pathogenic mechanisms linked to diabetes, such as impaired insulin signaling in the brain, neuroinflammation, oxidative stress, mitochondrial dysfunction, and vascular impairment. These factors can also lead to the accumulation of β-amyloid and tau protein phosphorylation. New research suggests that certain drugs used to manage diabetes have different levels of effectiveness in treating or preventing Alzheimer's disease. Exercise has numerous advantages, including the reduction of neuroinflammation, alleviation of oxidative stress and mitochondrial dysfunction, improvement of endothelial and cerebrovascular function, stimulation of neurogenesis, and prevention of pathological changes associated with diabetes-related Alzheimer's disease through various internal mechanisms. This study examined the development of Alzheimer's disease (AD) in relation to diabetes, evaluated the ability of specific antidiabetic drugs to prevent and treat AD, and investigated the impacts and underlying processes of exercise interventions in improving AD treatment for individuals with diabetes.}, }
@article {pmid39865687, year = {2025}, author = {Gillman, A and Bourgeat, P and Cox, T and Villemagne, VL and Fripp, J and Huang, K and Williams, R and Shishegar, R and O'Keefe, G and Li, S and Krishnadas, N and Feizpour, A and Bozinovski, S and Rowe, CC and Doré, V}, title = {Digital detector PET/CT increases Centiloid measures of amyloid in Alzheimer's disease: A head-to-head comparison of cameras.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {4}, pages = {1257-1268}, doi = {10.1177/13872877241313063}, pmid = {39865687}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; Female ; Male ; Aged ; *Positron Emission Tomography Computed Tomography/methods/instrumentation ; *Amyloid beta-Peptides/analysis ; Brain/diagnostic imaging/metabolism ; Aged, 80 and over ; Cohort Studies ; }, abstract = {BACKGROUND: The introduction of therapeutics for Alzheimer's disease has led to increased interest in precisely quantifying amyloid-β (Aβ) burden for diagnosis, treatment monitoring, and further clinical research. Recent positron emission tomography (PET) hardware innovations including digital detectors have led to superior resolution and sensitivity, improving quantitative accuracy. However, the effect of PET scanner on Centiloid remains relatively unexplored and is assumed to be minimized by harmonizing PET resolutions.
OBJECTIVE: To quantify the differences in Centiloid between scanners in a paired cohort.
METHODS: 36 participants from the Australian Imaging, Biomarker and Lifestyle study (AIBL) cohort were scanned within a year on two scanners. Each participant underwent [18]F-NAV4694 imaging on two of the three scanners investigated, the Siemens Vision, the Siemens mCT and the Philips Gemini. We compared Aβ Centiloid quantification between scanners and assessed the effectiveness of post-reconstruction PET resolution harmonization. We further compared the scanner differences in target sub-regions and with different reference regions to assess spatial variability.
RESULTS: Centiloid from the Vision camera was found to be significantly higher compared to the Gemini and mCT; the difference was greater at high-Centiloid levels. Post-reconstruction resolution harmonization only accounted for and corrected ∼20% of the Centiloid (CL) difference between scanners. We further demonstrated that residual differences have effects that vary spatially between different subregions of the Centiloid mask.
CONCLUSIONS: We have demonstrated that the type of PET scanner that a participant is scanned on affects Centiloid quantification, even when scanner resolution is harmonized. We conclude by highlighting the need for further investigation into harmonization techniques that consider scanner differences.}, }
@article {pmid39865315, year = {2025}, author = {Lentzen, M and Vairavan, S and Muurling, M and Alepopoulos, V and Atreya, A and Boada, M and de Boer, C and Conde, P and Curcic, J and Frisoni, G and Galluzzi, S and Gjestsen, MT and Gkioka, M and Grammatikopoulou, M and Hausner, L and Hinds, C and Lazarou, I and de Mendonça, A and Nikolopoulos, S and Religa, D and Scebba, G and Jelle Visser, P and Wittenberg, G and Narayan, VA and Coello, N and Brem, AK and Aarsland, D and Fröhlich, H and , }, title = {RADAR-AD: assessment of multiple remote monitoring technologies for early detection of Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {29}, pmid = {39865315}, issn = {1758-9193}, support = {806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; 806999//Innovative Medicines Initiative 2/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis ; Female ; Male ; Aged ; *Early Diagnosis ; Aged, 80 and over ; Remote Sensing Technology/methods/instrumentation ; Machine Learning ; Neuropsychological Tests ; Middle Aged ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide, leading to cognitive and functional decline. Early detection and intervention are crucial for enhancing the quality of life of patients and their families. Remote Monitoring Technologies (RMTs) offer a promising solution for early detection by tracking changes in behavioral and cognitive functions, such as memory, language, and problem-solving skills. Timely detection of these symptoms can facilitate early intervention, potentially slowing disease progression and enabling appropriate treatment and care.
METHODS: The RADAR-AD study was designed to evaluate the accuracy and validity of multiple RMTs in detecting functional decline across various stages of AD in a real-world setting, compared to standard clinical rating scales. Our approach involved a univariate analysis using Analysis of Covariance (ANCOVA) to analyze individual features of six RMTs while adjusting for variables such as age, sex, years of education, clinical site, BMI and season. Additionally, we employed four machine learning classifiers - Logistic Regression, Decision Tree, Random Forest, and XGBoost - using a nested cross-validation approach to assess the discriminatory capabilities of the RMTs.
RESULTS: The ANCOVA results indicated significant differences between healthy and AD subjects regarding reduced physical activity, less REM sleep, altered gait patterns, and decreased cognitive functioning. The machine-learning-based analysis demonstrated that RMT-based models could identify subjects in the prodromal stage with an Area Under the ROC Curve of 73.0 %. In addition, our findings show that the Amsterdam iADL questionnaire has high discriminatory abilities.
CONCLUSIONS: RMTs show promise in AD detection already in the prodromal stage. Using them could allow for earlier detection and intervention, thereby improving patients' quality of life. Furthermore, the Amsterdam iADL questionnaire holds high potential when employed remotely.}, }
@article {pmid39865265, year = {2025}, author = {Kim, BH and Kim, S and Nam, Y and Park, YH and Shin, SM and Moon, M}, title = {Second-generation anti-amyloid monoclonal antibodies for Alzheimer's disease: current landscape and future perspectives.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {6}, pmid = {39865265}, issn = {2047-9158}, support = {RS-2023-00240010//National Research Foundation of Korea/ ; NRF-2022R1A6A3A13053190//National Research Foundation of Korea/ ; RS-2024-00450135//National Research Foundation of Korea/ ; RS-2023-00212388//National Research Foundation of Korea/ ; RS-2023-00273557//National Research Foundation of Korea/ ; RS-2023-KH138733//Korea Health Industry Development Institute/Republic of Korea ; }, mesh = {*Alzheimer Disease/drug therapy/immunology ; Humans ; *Antibodies, Monoclonal/therapeutic use ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors/metabolism ; Antibodies, Monoclonal, Humanized/therapeutic use ; Animals ; }, abstract = {Alzheimer's disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such as amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from the brains of patients with AD, the U.S. Food and Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), and donanemab (Kisunla™). Notably, lecanemab received traditional approval after demonstrating clinical benefit, supporting the Aβ cascade hypothesis. These MABs targeting Aβ are categorized based on their affinity to diverse conformational features of Aβ, including monomer, fibril, protofibril, and plaque forms of Aβ as well as pyroglutamate Aβ. First-generation MABs targeting the non-toxic monomeric Aβ, such as solanezumab, bapineuzumab, and crenezumab, failed to demonstrate clinical benefit for AD in clinical trials. In contrast, second-generation MABs, including aducanumab, lecanemab, donanemab, and gantenerumab directed against pathogenic Aβ species and aggregates have shown that reducing Aβ deposition can be an effective strategy to slow cognitive impairment in AD. In this review, we provide a comprehensive overview of the current status, mechanisms, outcomes, and limitations of second-generation MABs for the clinical treatment of AD. Moreover, we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.}, }
@article {pmid39864933, year = {2025}, author = {Videnovic, A and Cai, A}, title = {Irregular sleep-wake rhythm disorder: From the pathophysiologic perspective to the treatment.}, journal = {Handbook of clinical neurology}, volume = {206}, number = {}, pages = {71-87}, doi = {10.1016/B978-0-323-90918-1.00006-X}, pmid = {39864933}, issn = {0072-9752}, mesh = {Humans ; *Sleep Disorders, Circadian Rhythm/therapy/physiopathology/diagnosis ; Circadian Rhythm/physiology ; }, abstract = {Irregular sleep-wake rhythm disorder (ISWRD) is an intrinsic circadian rhythm disorder caused by loss of the brain's circadian regulation, through changes of the input and/or output to the suprachiasmatic nucleus (SCN), or of the SCN itself. Although there are limited prevalence data for this rare disease, ISWRD is associated with neurodegenerative disorders, including the Alzheimer disease (AD) and the Parkinson disease (PD), which will become increasingly prevalent in an aging population. It additionally presents in childhood developmental disorders, psychiatric disorders, and traumatic brain injury (TBI). Patients present with unpredictable, short sleep periods over a 24-h period, with significant day-to-day and weekly variability. Symptoms manifest as insomnia and excessive daytime sleepiness. Sleep logs and actigraphy monitoring capture rest-activity patterns required for diagnosis. Treatment aims to enhance external circadian cues through timed light therapy, behavioral activity regimens, and melatonin, but efficacy remains quite limited. Pathophysiology of ISWRD in association with various diseases and their specific management are discussed. There is a need for further investigation of disease pathophysiology, development of widely applicable tools for diagnosis, and development of treatments.}, }
@article {pmid39864928, year = {2025}, author = {Liu, YJ and Swaab, DF and Zhou, JN}, title = {Sleep-wake modulation and pathogenesis of Alzheimer disease: Suggestions for postponement and treatment.}, journal = {Handbook of clinical neurology}, volume = {206}, number = {}, pages = {211-229}, doi = {10.1016/B978-0-323-90918-1.00001-0}, pmid = {39864928}, issn = {0072-9752}, mesh = {Humans ; *Alzheimer Disease/therapy ; *Melatonin/metabolism/therapeutic use ; *Circadian Rhythm/physiology ; *Sleep Wake Disorders/therapy/etiology ; *Sleep/physiology ; Animals ; }, abstract = {Sleep-wake disorders are recognized as one of the earliest symptoms of Alzheimer disease (AD). Accumulating evidence has highlighted a significant association between sleep-wake disorders and AD pathogenesis, suggesting that sleep-wake modulation could be a promising approach for postponing AD onset. The suprachiasmatic nucleus (SCN) and the pineal hormone melatonin are major central modulating components of the circadian rhythm system. Cerebrospinal fluid (CSF) melatonin levels are dramatically decreased in AD. Interestingly, the number of neurofibrillary tangles in the hippocampus, which is one of the two major neuropathologic AD biomarkers, increases in parallel with the decrease in CSF melatonin levels. Furthermore, a decrease in salivary melatonin levels in middle-aged persons is a significant risk factor for the onset of the early stages of AD. Moreover, the disappearance of rhythmic fluctuations in melatonin may be one of the best biomarkers for AD diagnosis. Light therapy combined with melatonin supplementation is the recommended first-line treatment for sleep-wake disorders in AD patients and may be beneficial for ameliorating cognitive impairment. Sleep-wake cycle modulation based on AD risk gene presence is a promising early intervention for AD onset postponement.}, }
@article {pmid39864834, year = {2025}, author = {Zhou, Y and Dou, L and Wang, L and Chen, J and Mao, R and Zhu, L and Liu, D and Zheng, K}, title = {Growth and differentiation factor 15: An emerging therapeutic target for brain diseases.}, journal = {Bioscience trends}, volume = {19}, number = {1}, pages = {72-86}, doi = {10.5582/bst.2024.01305}, pmid = {39864834}, issn = {1881-7823}, mesh = {*Growth Differentiation Factor 15/metabolism/genetics ; Humans ; Brain Diseases/metabolism/drug therapy/genetics ; Signal Transduction ; Animals ; Neurodegenerative Diseases/metabolism/drug therapy/genetics ; Glioma/metabolism/genetics/drug therapy/pathology ; }, abstract = {Growth and differentiation factor 15 (GDF15), a member of the transforming growth factor-βsuperfamily, is considered a stress response factor and has garnered increasing attention in recent years due to its roles in neurological diseases. Although many studies have suggested that GDF15 expression is elevated in patients with neurodegenerative diseases (NDDs), glioma, and ischemic stroke, the effects of increased GDF15 expression and the potential underlying mechanisms remain unclear. Notably, many experimental studies have shown the multidimensional beneficial effects of GDF15 on NDDs, and GDF15 overexpression is able to rescue NDD-associated pathological changes and phenotypes. In glioma, GDF15 exerts opposite effects, it is both protumorigenic and antitumorigenic. The causes of these conflicting findings are not comprehensively clear, but inhibiting GDF15 is helpful for suppressing tumor progression. GDF15 is also regarded as a biomarker of poor clinical outcomes in ischemic stroke patients, and targeting GDF15 may help prevent this disease. Thus, we systematically reviewed the synthesis, transcriptional regulation, and biological functions of GDF15 and its related signaling pathways within the brain. Furthermore, we explored the potential of GDF15 as a therapeutic target and assessed its clinical applicability in interventions for brain diseases. By integrating the latest research findings, this study provides new insights into the future treatment of neurological diseases.}, }
@article {pmid39864832, year = {2025}, author = {Kim, JS and Cho, Y and Lee, J and Cho, H and Han, S and Lee, Y and Jeon, Y and Kim, TK and Hong, JM and Im, J and Chae, M and Lee, Y and Kim, H and Park, SY and Kim, SH and Yim, JH and Jo, DG}, title = {N[5]-((perfluorophenyl)amino)glutamine regulates BACE1, tau phosphorylation, synaptic function, and neuroinflammation in Alzheimer's disease models.}, journal = {Bioscience trends}, volume = {19}, number = {1}, pages = {102-115}, doi = {10.5582/bst.2024.01360}, pmid = {39864832}, issn = {1881-7823}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *tau Proteins/metabolism ; *Aspartic Acid Endopeptidases/metabolism ; *Amyloid Precursor Protein Secretases/metabolism ; *Disease Models, Animal ; Mice ; Phosphorylation/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Mice, Transgenic ; Glutamine/metabolism ; Synapses/drug effects/metabolism ; Humans ; Glycogen Synthase Kinase 3 beta/metabolism ; Synaptic Transmission/drug effects ; }, abstract = {Alzheimer's disease (AD) is the most common type of dementia. Its incidence is rising rapidly as the global population ages, leading to a significant social and economic burden. AD involves complex pathologies, including amyloid plaque accumulation, synaptic dysfunction, and neuroinflammation. This study explores the therapeutic potential of N [5] -((perfluorophenyl)amino)glutamine (RA-PF), a derivative of γ-glutamyl-N'-(2-hydroxyphenyl)hydrazide (Ramalin), a compound with antioxidant and anti-inflammatory properties. Administration of RA-PF to 5xFAD mice decreases BACE1, reduces Aβ plaque deposition, inhibits microglial activation, restores synaptic transmission, and improves mitochondrial motility, leading to the recovery of cognitive function. Additionally, RA-PF treatment in 3xTg-AD mice alleviates anxiety-like behaviors, tau phosphorylation via inactivating GSK-3β, and BACE1 expression. Further transcriptomic analysis reveals RA-PF treatment in AD mice models recovers phagosome, inflammation, NOD-like receptor, presynaptic membrane, and postsynaptic membrane related signaling pathways. These findings suggest that RA-PF effectively targets multiple aspects of AD pathology, offering a novel multi-target approach for AD treatment.}, }
@article {pmid39864562, year = {2025}, author = {Hong, X and Chen, T and Liu, Y and Li, J and Huang, D and Ye, K and Liao, W and Wang, Y and Liu, M and Luan, P}, title = {Design, current states, and challenges of nanomaterials in anti-neuroinflammation: A perspective on Alzheimer's disease.}, journal = {Ageing research reviews}, volume = {105}, number = {}, pages = {102669}, doi = {10.1016/j.arr.2025.102669}, pmid = {39864562}, issn = {1872-9649}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; *Nanostructures ; *Neuroinflammatory Diseases/drug therapy/immunology ; Animals ; Amyloid beta-Peptides/metabolism ; Inflammation/drug therapy/metabolism ; }, abstract = {Alzheimer's disease (AD), an age-related neurodegenerative disease, brings huge damage to the society, to the whole family and even to the patient himself. However, until now, the etiological factor of AD is still unknown and there is no effective treatment for it. Massive deposition of amyloid-beta peptide(Aβ) and hyperphosphorylation of Tau proteins are acknowledged pathological features of AD. Recent studies have revealed that neuroinflammation plays a pivotal role in the pathology of AD. With the rise of nanomaterials in the biomedical field, researchers are exploring how the unique properties of these materials can be leveraged to develop effective treatments for AD. This article has summarized the influence of neuroinflammation in AD, the design of nanoplatforms, and the current research status and inadequacy of nanomaterials in improving neuroinflammation in AD.}, }
@article {pmid39863332, year = {2025}, author = {Leng, Y and Ding, H and Ang, TFA and Au, R and Doraiswamy, PM and Liu, C}, title = {Identifying proteomic prognostic markers for Alzheimer's disease with survival machine learning: The Framingham Heart Study.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {2}, pages = {100021}, doi = {10.1016/j.tjpad.2024.100021}, pmid = {39863332}, issn = {2426-0266}, mesh = {Humans ; *Machine Learning ; Female ; Male ; *Alzheimer Disease/diagnosis ; Middle Aged ; *Biomarkers/blood ; *Proteomics ; Prognosis ; Aged ; Adult ; Longitudinal Studies ; Proportional Hazards Models ; }, abstract = {BACKGROUND: Protein abundance levels, sensitive to both physiological changes and external interventions, are useful for assessing the Alzheimer's disease (AD) risk and treatment efficacy. However, identifying proteomic prognostic markers for AD is challenging by their high dimensionality and inherent correlations.
METHODS: Our study analyzed 1128 plasma proteins, measured by the SOMAscan platform, from 858 participants 55 years and older (mean age 63 years, 52.9 % women) of the Framingham Heart Study (FHS) Offspring cohort. We conducted regression analysis and machine learning models, including LASSO-based Cox proportional hazard regression model (LASSO) and generalized boosted regression model (GBM), to identify protein prognostic markers. These markers were used to construct a weighted proteomic composite score, the AD prediction performance of which was assessed using time-dependent area under the curve (AUC). The association between the composite score and memory domain was examined in 339 (of the 858) participants with available memory scores, and in a separate group of 430 participants younger than 55 years (mean age 46, 56.7 % women).
RESULTS: Over a mean follow-up of 20 years, 132 (15.4 %) participants developed AD. After adjusting for baseline age, sex, education, and APOE ε4 + status, regression models identified 309 proteins (P ≤ 0.2). After applying machine learning methods, nine of these proteins were selected to develop a composite score. This score improved AD prediction beyond the factors of age, sex, education, and APOE ε4 + status across 15-25 years of follow-up, achieving its peak AUC of 0.84 in the LASSO model at the 22-year follow-up. It also showed a consistent negative association with memory scores in the 339 participants (beta = -0.061, P = 0.046), 430 participants (beta = -0.060, P = 0.018), and the pooled 769 samples (beta = -0.058, P = 0.003).
CONCLUSION: These findings highlight the utility of machine learning method in identifying proteomic markers in improving AD prediction and emphasize the complex pathology of AD. The composite score may aid early AD detection and efficacy monitoring, warranting further validation in diverse populations.}, }
@article {pmid39863322, year = {2025}, author = {Cox, CG and Brush, BL and Kobayashi, LC and Roberts, JS}, title = {Determinants of dementia diagnosis in U.S. primary care in the past decade: A scoping review.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {2}, pages = {100035}, doi = {10.1016/j.tjpad.2024.100035}, pmid = {39863322}, issn = {2426-0266}, mesh = {Humans ; *Primary Health Care ; United States/epidemiology ; *Dementia/diagnosis/epidemiology ; Alzheimer Disease/diagnosis/epidemiology ; }, abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) are chronically underdiagnosed in the U.S., particularly among minoritized racial and ethnic groups. Primary care providers are at the forefront of diagnosis given the increasing prevalence of cases and shortage of dementia specialists. Advances in policy, detection, and treatment in the past decade necessitate an updated review of the current state of determinants of ADRD diagnosis in U.S. primary care settings.
METHODS: Following Joanna Briggs Institute guidelines, we conducted a scoping literature review on ADRD diagnosis among older adults in U.S. primary care settings. Studies published in English from January 2010 to January 2024 were retrieved from PubMed, PsycINFO, and CINAHL. We extracted primary data on study characteristics and synthesized key findings according to facilitators, barriers, and rates of diagnosis in primary care.
RESULTS: Of 563 articles retrieved, 12 met eligibility criteria. Three studies reported rates of diagnosis, and all but one reported facilitators and/or barriers to diagnosis. ADRD remains underdiagnosed in primary care settings, especially in the earliest symptomatic stage (i.e., mild cognitive impairment). Multi-level barriers and facilitators were identified including individual beliefs about ADRD (e.g., value of early diagnosis), interpersonal relationships between patients and their family members and providers (e.g., importance of an established clinical relationship), and healthcare system limitations (e.g., insufficient resources and training).
CONCLUSION: Despite national policy efforts to improve timely diagnosis of ADRD, underdiagnosis remains a clinical and public health challenge. Increased attention to social and community contexts will be important for future research and intervention.}, }
@article {pmid39863320, year = {2025}, author = {Srisuwan, P and Nakawiro, D and Kuha, O and Kengpanich, S and Gesakomol, K and Chansirikarnjana, S}, title = {Efficacy of a group-based 8-week multicomponent cognitive training on cognition, mood and activities of daily living among healthy older adults: A two-year follow-up of a randomized controlled trial.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {2}, pages = {100033}, doi = {10.1016/j.tjpad.2024.100033}, pmid = {39863320}, issn = {2426-0266}, mesh = {Humans ; Aged ; *Activities of Daily Living ; Female ; Male ; *Affect/physiology ; *Cognition/physiology ; Single-Blind Method ; Follow-Up Studies ; Thailand ; Cognitive Dysfunction/therapy/psychology ; Executive Function/physiology ; Cognitive Behavioral Therapy/methods ; Neuropsychological Tests ; Middle Aged ; Mental Status and Dementia Tests ; Independent Living ; Cognitive Training ; }, abstract = {BACKGROUND: Cognitive training (CT) has been one of the important non-pharmaceutical interventions that could delay cognitive decline. Currently, no definite CT methods are available. Furthermore, little attention has been paid to the effect of CT on mood and instrumental activities of daily living (IADL).
OBJECTIVES: To assess the effectiveness of a multicomponent CT using a training program of executive functions, attention, memory and visuospatial functions (TEAM-V Program) on cognition, mood and instrumental ADL.
DESIGN: A randomized, single-blinded, treatment-as-usual controlled trial.
SETTING: Geriatric clinic in Bangkok, Thailand.
PARTICIPANTS: 80 nondemented community-dwelling older adults (mean age 65.7 ± 4.3 years).
INTERVENTION: The CT (TEAM-V) Program or the treatment-as-usual controlled group. The TEAM-V intervention was conducted over 5 sessions, with a 2-week interval between each session. A total of 80 participants were randomized (n = 40 the TEAM-V Program; n = 40 the control group).
MEASUREMENTS: The Thai version of Montreal Cognitive Assessment (MoCA), The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), Thai version of Hospital Anxiety and Depression Scale (HADS) and The Chula ADL were used to assess at baseline, 6 months, 1 year and 2 years.
RESULTS: Compared with the control arm (n = 36), the TEAM-V Program (n = 39) was associated with significantly improved general cognition (MoCA, P = 0.02) at 2 years. Compared with baseline, participants receiving the TEAM-V Program were associated with significantly improved immediate recall (word recall task, P < 0.001), retrieval and retention of memory processes (word recognition task, P = 0.01) and attention (number cancellation part A, P = 0.01) at 2 years. No training effects on anxiety (P = 0.94), depression (P = 0.093) and IADL (P = 0.48) were detected.
CONCLUSIONS: The TEAM-V Program was effective in improving global cognitive function. Even though, the program did not significantly improve anxiety, depression and IADL compared with the control group, memory and attention improved in the intervention group compared with baseline. Further studies incorporating a larger sample size, longitudinal follow-up and higher-intensity CT should be conducted.}, }
@article {pmid39863318, year = {2025}, author = {LoBue, C and Chiang, HS and Salter, A and McClintock, S and Nguyen, TP and Logan, R and Smernoff, E and Pandya, S and Hart, J}, title = {High definition transcranial direct current stimulation as an intervention for cognitive deficits in Alzheimer's dementia: A randomized controlled trial.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {2}, pages = {100023}, pmid = {39863318}, issn = {2426-0266}, support = {K23 AG075261/AG/NIA NIH HHS/United States ; UL1 TR003163/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Transcranial Direct Current Stimulation/methods ; *Alzheimer Disease/therapy ; Double-Blind Method ; Female ; Male ; Aged ; *Cognitive Dysfunction/therapy ; Pilot Projects ; Prefrontal Cortex ; Neuropsychological Tests ; Executive Function/physiology ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {BACKGROUND: Recent disease-modifying treatments for Alzheimer's disease show promise to slow cognitive decline, but show no efficacy towards reducing symptoms already manifested.
OBJECTIVES: To investigate the efficacy of a novel noninvasive brain stimulation technique in modulating cognitive functioning in Alzheimer's dementia (AD).
DESIGN: Pilot, randomized, double-blind, parallel, sham-controlled study SETTING: Clinical research site at UT Southwestern Medical Center PARTICIPANTS: Twenty-five participants with clinical diagnoses of AD were enrolled from cognition specialty clinics.
INTERVENTION: Treatment consisted of high definition transcranial direct current stimulation (HD-tDCS) delivered for 20 min over the medial prefrontal cortex. Ten sessions of sham, 1 mA, or 2 mA stimulation were received.
MEASUREMENTS: Cognitive outcomes were measured at baseline, after the last HD-tDCS session, and 8-weeks post-treatment. The primary outcome was change in total learning and delayed recall on the Rey Auditory Verbal Learning Test (RAVLT) immediately post-treatment and at 8-weeks. Secondary outcomes included measures of language, processing speed, and executive functioning. A multi-stage approach was used to examine cognitive outcomes, which included evaluation of effect sizes, statistical effects, and rate of clinically meaningful responses.
RESULTS: In this pilot trial, no statistically significant differences on cognitive outcomes were found between sham and active HD-tDCS immediately post-treatment (p's > 0.05). However, moderate-to-large effect sizes were identified for enhanced RAVLT total learning (Cohen's d = 0.69-0.93) and phonemic fluency (d = 1.08-1.49) for both active HD-tDCS conditions compared to sham, with rates of clinically relevant improvement between 25 and 33%. Meaningful enhancement persisted to 8 weeks only for the 1 mA condition.
CONCLUSIONS: Multiple sessions of HD-tDCS over the medial prefrontal cortex appears to have potential to produce meaningful cognitive enhancements in a proportion of patients having AD with improvements maintained for at least 8 weeks in some.
ClinicalTrials.gov (NCT05270408). Registered December 30, 2021.}, }
@article {pmid39862174, year = {2025}, author = {Chekani, F and Mirchandani, K and Zaki, S and Goswami, S and Sharma, M}, title = {Utilization of Potentially Inappropriate Sedative-Hypnotic and Atypical Antipsychotic Medications among Elderly Individuals with Insomnia and Alzheimer's Disease.}, journal = {Sleep}, volume = {}, number = {}, pages = {}, doi = {10.1093/sleep/zsaf003}, pmid = {39862174}, issn = {1550-9109}, abstract = {STUDY OBJECTIVES: This study assessed the utilization of potentially inappropriate medications (PIM) including oral sedative-hypnotic and atypical antipsychotic (OSHAA), healthcare resource utilization (HCRU), and costs among elderly individuals with insomnia and in the subpopulation with Alzheimer's Disease (AD) who also had a diagnosis of insomnia.
METHODS: Using claims database containing International Classification of Diseases, 10th Revision (ICD-10) codes, the cohort included individuals aged ≥ 65 with incident insomnia (EI, N=152,969) and AD insomnia subpopulation (ADI, N=4,888). Proportion of patients utilizing atypical antipsychotics or oral sedative-hypnotic medications, namely z-drugs, benzodiazepines, doxepin, Dual Orexin Receptor Antagonists (DORAs), and melatonin agonists, were assessed. Inappropriate OSHAA utilization was defined as per the American Geriatrics Society (AGS) Beers criteria. Multivariable models were utilized to compare HCRU and costs between PIM-OSHAA and no PIM-OSHAA groups.
RESULTS: Among the EI cohort, z-drugs (13.39%) were the most commonly utilized OSHAA, and in the ADI cohort, it was AAPs (29.97%). PIM-OSHAA was utilized by 20% of the EI and 35% of the ADI cohorts. Patients with PIM-OSHAA use among the EI cohort had a higher annualized adjusted mean HCRU (pharmacy visits: 31.21 vs. 23.68; ambulatory & outpatient visits: 18.55 vs. 16.85) and costs, primarily due to medical costs (mean total cost: $36,676.08 vs. $31,346.54) compared to those without.
CONCLUSIONS: Substantial utilization of PIM-OSHAA was observed in EI and ADI cohorts. PIM-OSHAA use was associated with higher HCRU and costs. These findings underscore the importance of appropriate treatment strategies for insomnia in the elderly population especially in those with concurrent AD.}, }
@article {pmid39862109, year = {2025}, author = {Lu, X and Shan, G}, title = {Adaptive promising zone design for sequential parallel comparison design with continuous outcomes.}, journal = {Clinical trials (London, England)}, volume = {}, number = {}, pages = {17407745241309056}, doi = {10.1177/17407745241309056}, pmid = {39862109}, issn = {1740-7753}, abstract = {INTRODUCTION: The sequential parallel comparison design has emerged as a valuable tool in clinical trials with high placebo response rates. To further enhance its efficiency and effectiveness, adaptive strategies, such as sample size adjustment and allocation ratio modification can be employed.
METHODS: We compared the performance of Jennison and Turnbull's method and the Promising Zone approach for sample size adjustment in a two-phase sequential parallel comparison design study. We also evaluated the impact of allocation ratio adjustments using Neyman and Optimal allocation strategies. Various scenarios were simulated to assess the effects of different design parameters, including weight in the test statistic, initial randomization ratio, and interim analysis timing.
RESULTS: The Promising Zone approach demonstrated superior or comparable power to Jennison and Turnbull's method at equivalent expected sample sizes while maintaining the intuitive property that more promising interim results lead to smaller required follow-up sample sizes. However, the Promising Zone approach may require a larger maximum possible sample size in some cases. The addition of allocation ratio adjustments offered minimal improvements overall, but showed potential benefits when the variance in the treatment group was larger than that in the placebo group. We also applied our findings to a real-world example from the AVP-923 trial in patients with Alzheimer's disease-related agitation, demonstrating the practical implications of adaptive sequential parallel comparison designs in clinical research.
DISCUSSION: Adaptive strategies can significantly enhance the efficiency of sequential parallel comparison designs. The choice between sample size adjustment methods should consider trade-offs between power, expected sample size, and maximum adjusted sample size. Although allocation ratio adjustments showed limited overall impact, they may be beneficial in specific scenarios. Future research should explore the application of these adaptive strategies to binary and survival outcomes in sequential parallel comparison designs.}, }
@article {pmid39862009, year = {2025}, author = {Lu, F and Ma, Q and Shi, C and Yue, W}, title = {Changes in the Parietal Lobe Subregion Volume at Various Stages of Alzheimer's Disease and the Role in Cognitively Normal and Mild Cognitive Impairment Conversion.}, journal = {Journal of integrative neuroscience}, volume = {24}, number = {1}, pages = {25991}, doi = {10.31083/JIN25991}, pmid = {39862009}, issn = {0219-6352}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/physiopathology ; *Cognitive Dysfunction/diagnostic imaging/physiopathology/pathology ; Male ; Female ; *Parietal Lobe/diagnostic imaging/pathology ; Aged ; *Disease Progression ; *Magnetic Resonance Imaging ; Aged, 80 and over ; }, abstract = {BACKGROUND: Volume alterations in the parietal subregion have received less attention in Alzheimer's disease (AD), and their role in predicting conversion of mild cognitive impairment (MCI) to AD and cognitively normal (CN) to MCI remains unclear. In this study, we aimed to assess the volumetric variation of the parietal subregion at different cognitive stages in AD and to determine the role of parietal subregions in CN and MCI conversion.
METHODS: We included 662 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 228 CN, 221 early MCI (EMCI), 112 late MCI (LMCI), and 101 AD participants. We measured the volume of the parietal subregion based on the Human Brainnetome Atlas (BNA-246) using voxel-based morphometry among individuals at various stages of AD and the progressive and stable individuals in CN and MCI. We then calculated the area under the curve (AUC) of the receiver operating characteristic (ROC) curve to test the ability of parietal subregions to discriminate between different cognitive groups. The Cox proportional hazard model was constructed to determine which specific parietal subregions, alone or in combination, could be used to predict progression from MCI to AD and CN to MCI. Finally, we examined the relationship between the cognitive scores and parietal subregion volume in the diagnostic groups.
RESULTS: The left inferior parietal lobule (IPL)_6_5 (rostroventral area 39) showed the best ability to discriminate between patients with AD and those with CN (AUC = 0.688). The model consisting of the left IPL_6_4 (caudal area 40) and bilateral IPL_6_5 showed the best combination for predicting the CN progression to MCI. The left IPL_6_1 (caudal area 39) showed the best predictive power in predicting the progression of MCI to AD. Certain subregions of the volume correlated with cognitive scales.
CONCLUSION: Subregions of the angular gyrus are essential in the early onset and subsequent development of AD, and early detection of the volume of these regions may be useful in identifying the tendency to develop the disease and its treatment.}, }
@article {pmid39862001, year = {2025}, author = {Chen, D and Sun, Y}, title = {Current Status of Plant-Based Bioactive Compounds as Therapeutics in Alzheimer's Diseases.}, journal = {Journal of integrative neuroscience}, volume = {24}, number = {1}, pages = {23090}, doi = {10.31083/JIN23090}, pmid = {39862001}, issn = {0219-6352}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Plants, Medicinal/chemistry ; Animals ; Phytochemicals/pharmacology ; Phytotherapy ; }, abstract = {Alzheimer's disease (AD) is a common central neurodegenerative disease disorder characterized primarily by cognitive impairment and non-cognitive neuropsychiatric symptoms that significantly impact patients' daily lives and behavioral functioning. The pathogenesis of AD remains unclear and current Western medicines treatment are purely symptomatic, with a singular pathway, limited efficacy, and substantial toxicity and side effects. In recent years, as research into AD has deepened, there has been a gradual increase in the exploration and application of medicinal plants for the treatment of AD. Numerous studies have shown that medicinal plants and their active ingredients can potentially mitigate AD by regulating various molecular mechanisms, including the production and aggregation of pathological proteins, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, neurogenesis, neurotransmission, and the brain-gut microbiota axis. In this review, we analyzed the pathogenesis of AD and comprehensively summarized recent advancements in research on medicinal plants for the treatment of AD, along with their underlying mechanisms and clinical evidence. Ultimately, we aimed to provide a reference for further investigation into the specific mechanisms through which medicinal plants prevent and treat AD, as well as for the identification of efficacious active ingredients derived from medicinal plants.}, }
@article {pmid39861773, year = {2025}, author = {Ortiz-Islas, E and Montes, P and Rodríguez-Pérez, CE and Ruiz-Sánchez, E and Sánchez-Barbosa, T and Pichardo-Rojas, D and Zavala-Tecuapetla, C and Carvajal-Aguilera, K and Campos-Peña, V}, title = {Evolution of Alzheimer's Disease Therapeutics: From Conventional Drugs to Medicinal Plants, Immunotherapy, Microbiotherapy and Nanotherapy.}, journal = {Pharmaceutics}, volume = {17}, number = {1}, pages = {}, pmid = {39861773}, issn = {1999-4923}, support = {CF-2023-G-971 and CBF-2023-2024-1982//Ciencia de Frontera/ ; }, abstract = {Alzheimer's disease (AD) represents an escalating global health crisis, constituting the leading cause of dementia among the elderly and profoundly impairing their quality of life. Current FDA-approved drugs, such as rivastigmine, donepezil, galantamine, and memantine, offer only modest symptomatic relief and are frequently associated with significant adverse effects. Faced with this challenge and in line with advances in the understanding of the pathophysiology of this neurodegenerative condition, various innovative therapeutic strategies have been explored. Here, we review novel approaches inspired by advanced knowledge of the underlying pathophysiological mechanisms of the disease. Among the therapeutic alternatives, immunotherapy stands out, employing monoclonal antibodies to specifically target and eliminate toxic proteins implicated in AD. Additionally, the use of medicinal plants is examined, as their synergistic effects among components may confer neuroprotective properties. The modulation of the gut microbiota is also addressed as a peripheral strategy that could influence neuroinflammatory and degenerative processes in the brain. Furthermore, the therapeutic potential of emerging approaches, such as the use of microRNAs to regulate key cellular processes and nanotherapy, which enables precise drug delivery to the central nervous system, is analyzed. Despite promising advances in these strategies, the incidence of Alzheimer's disease continues to rise. Therefore, it is proposed that achieving effective treatment in the future may require the integration of combined approaches, maximizing the synergistic effects of different therapeutic interventions.}, }
@article {pmid39861082, year = {2024}, author = {Chamberlin, SR and Zweig, JA and Neff, CJ and Marney, L and Choi, J and Yang, L and Maier, CS and Soumyanath, A and McWeeney, S and Gray, NE}, title = {Multi-Omics Analysis in Mouse Primary Cortical Neurons Reveals Complex Positive and Negative Biological Interactions Between Constituent Compounds of Centella asiatica.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {1}, pages = {}, pmid = {39861082}, issn = {1424-8247}, support = {U19 AT010829/AT/NCCIH NIH HHS/United States ; S10 OD026922/OD/NIH HHS/United States ; S10 RR027878/RR/NCRR NIH HHS/United States ; U19 AT010829, U19 AT010829-02S1/AT/NCCIH NIH HHS/United States ; K08 AT012477/AT/NCCIH NIH HHS/United States ; }, abstract = {Background: A water extract of the Ayurvedic plant Centella asiatica (L.) Urban, family Apiaceae (CAW), improves cognitive function in mouse models of aging and Alzheimer's disease and affects dendritic arborization, mitochondrial activity, and oxidative stress in mouse primary neurons. Triterpenes (TT) and caffeoylquinic acids (CQA) are constituents associated with these bioactivities of CAW, although little is known about how interactions between these compounds contribute to the plant's therapeutic benefit. Methods: Mouse primary cortical neurons were treated with CAW or equivalent concentrations of four TT combined, eight CQA combined, or these twelve compounds combined (TTCQA). Treatment effects on the cell transcriptome (18,491 genes) and metabolome (192 metabolites) relative to vehicle control were evaluated using RNAseq and metabolomic analyses, respectively. Results: Extensive differentially expressed genes (DEGs) were seen with all treatments, as well as evidence of interactions between compounds. Notably, many DEGs seen with TT treatment were not observed in the TTCQA condition, possibly suggesting CQA reduced the effects of TT. Moreover, additional gene activity seen with CAW as compared to TTCQA indicates the presence of additional compounds in CAW that further modulate TTCQA interactions. Weighted Gene Correlation Network Analysis (WGCNA) identified 4 gene co-expression modules altered by treatments that were associated with extracellular matrix organization, fatty acid metabolism, cellular response to stress and stimuli, and immune function. Compound interaction patterns were seen at the eigengene level in these modules. Interestingly, in metabolomics analysis, the TTCQA treatment saw the highest number of changes in individual metabolites (20), followed by CQA (15), then TT (8), and finally CAW (3). WGCNA analysis found two metabolomics modules with significant eigenmetabolite differences for TT and CQA and possible compound interactions at this level. Conclusions: Four gene expression modules and two metabolite modules were altered by the four treatment types applied. This methodology demonstrated the existence of both negative and positive interactions between TT, CQA, and additional compounds found in CAW on the transcriptome and metabolome of mouse primary cortical neurons.}, }
@article {pmid39860337, year = {2025}, author = {Long, C and Fritts, A and Broadway, J and Brawman-Mintzer, O and Mintzer, J}, title = {Neuroinflammation: A Driving Force in the Onset and Progression of Alzheimer's Disease.}, journal = {Journal of clinical medicine}, volume = {14}, number = {2}, pages = {}, pmid = {39860337}, issn = {2077-0383}, abstract = {Background/Objectives: The goal of this commentary is to highlight several key components of the inflammatory process as it relates to amyloid toxicity in Alzheimer's disease (AD), including the role of neuroinflammatory factors and peripheral inflammatory events. Methods: Google Scholar and PubMed were used to find articles with the following keywords: Alzheimer's disease, amyloids, neuroinflammation, peripheral inflammation, microglia, cytokines, and treatments. Sources that were case reports, not peer-reviewed, or older than 30 years were excluded. Abstracts were reviewed first for their relevance before the full text was considered. Methods sections were reviewed to ensure the interventional papers included were randomized controlled trials, meta-analyses, or systematic reviews; however, several literature reviews were also included due to the relevance of their background information. Results: Based on the literature review, we chose to concentrate on microglia, cytokine signaling, and peripheral inflammation markers. We found that microglia activation and subsequent microglia-driven inflammation play a pivotal role in the pathomechanism of AD. Additionally, cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a) appear to contribute to amyloid accumulation and cell damage. Finally, the increased permeability of the blood-brain barrier (BBB) allows for the peripheral inflammatory process to contribute to the inflammation of the central nervous system (CNS) and amyloid-beta (Aβ) accumulation. Conclusions: Current evidence suggests that the immune system plays a pivotal role in the pathogenesis of AD, both in the CNS and the periphery.}, }
@article {pmid39860128, year = {2025}, author = {Vaz, M and Soares Martins, T and Leandro, K and de Almeida, LP and da Cruz E Silva, OAB and Nunes, A and Henriques, AG}, title = {Fourier Transform Infrared Spectroscopy Analysis as a Tool to Address Aβ Impact on Extracellular Vesicles.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {2}, pages = {}, pmid = {39860128}, issn = {1420-3049}, mesh = {*Extracellular Vesicles/metabolism/chemistry ; Spectroscopy, Fourier Transform Infrared/methods ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/metabolism ; Animals ; Humans ; Mice ; Neurons/metabolism ; Least-Squares Analysis ; Cell Line, Tumor ; }, abstract = {Alzheimer's disease is a challenge in modern healthcare due to its complex etiology and increasing prevalence. Despite advances, further understanding of Alzheimer's disease pathophysiology is needed, particularly the role of Aβ neurotoxic peptide. Fourier transform infrared spectroscopy (FTIR) has shown potential as a screening tool for several pathologies, including Alzheimer's disease. Nonetheless, limited research has explored Aβ direct effects on neurons and extracellular vesicles metabolic profiles. Hence, this study aims to investigate Aβ impact on the spectroscopic profiles of neuronal-like cells (N2a) and N2a-derived extracellular vesicles, employing FTIR spectroscopy and focusing on the 1280-900 cm[-1] region. A comprehensive analysis of spectral data was carried out, including multivariate partial least squares (PLS) analysis and peak intensities analysis. PLS analysis revealed moderate to strong correlations within this spectral region for both N2a and N2a-derived extracellular vesicles. The peak intensity analysis revealed additional peaks with significant differences in EVs' spectra relative to N2a, following Aβ treatment. Specifically, Aβ seems to cause alterations in protein phosphorylation and in the nucleic acids content of extracellular vesicles. These findings support that Aβ's role in Alzheimer's disease pathology may be mediated by extracellular vesicles and highlight FTIR's potential for advancing Alzheimer's disease research and clinical applications.}, }
@article {pmid39860011, year = {2025}, author = {Rubio, C and López-Landa, A and Romo-Parra, H and Rubio-Osornio, M}, title = {Impact of the Ketogenic Diet on Neurological Diseases: A Review.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {39860011}, issn = {2075-1729}, abstract = {BACKGROUND: The ketogenic diet (KD), high in fat and low in carbohydrates, was introduced in the 1920s as a non-pharmacological treatment for refractory epilepsy. Although its mechanism of action is not fully understood, beneficial effects have been observed in neurological diseases such as epilepsy, Alzheimer's disease, and Parkinson's disease.
OBJECTIVE: This review examines the impact of the ketogenic diet and its molecular and neuroglial effects as a complementary therapy for neurological diseases.
DISCUSSION: KD is associated with neuroprotective and antioxidant effects that improve mitochondrial function, regulate neurotransmitter flow, and reduce neuroinflammation and oxidative stress. Glial cells play an essential role in the utilization of ketone bodies (KBs) within the central nervous system's metabolism, particularly during ketosis induced by the KD. Thus, the KD represents a broad and promising strategy that involves both neurons and glial cells, with a molecular impact on brain metabolism and neuroinflammatory homeostasis.
CONCLUSION: Multiple molecular mechanisms have been identified to explain the benefits of the KD in neurological diseases; however, further experimental and clinical studies are needed to address various molecular pathways in order to achieve conclusive results.}, }
@article {pmid39859234, year = {2025}, author = {Jia, C and Zhang, M and Wu, X and Zhang, X and Lv, Z and Zhao, K and Zhang, J and Su, Y and Zhu, F}, title = {HERV-W Env Induces Neuron Pyroptosis via the NLRP3-CASP1-GSDMD Pathway in Recent-Onset Schizophrenia.}, journal = {International journal of molecular sciences}, volume = {26}, number = {2}, pages = {}, pmid = {39859234}, issn = {1422-0067}, support = {Nos. 82272321//National Natural Science Foundation of China/ ; 2042023kf0230//Fundamental Research Funds for the Central Universities/ ; No.06R- 1366//Stanley Foundation from the Stanley Medical Research Institute (SMRI), United States/ ; }, mesh = {Humans ; *Pyroptosis ; *Schizophrenia/metabolism/virology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Endogenous Retroviruses/genetics/metabolism ; *Caspase 1/metabolism/genetics ; *Neurons/metabolism/virology/pathology ; *Signal Transduction ; *Phosphate-Binding Proteins/metabolism/genetics ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Gene Products, env/metabolism/genetics ; Female ; Male ; Adult ; Interleukin-1beta/metabolism ; Gasdermins ; }, abstract = {HERVs (Human endogenous retroviruses) are remnants of ancient exogenous retroviruses that have integrated into the human genome, particularly in germ-line cells. Among these, the envelope protein gene HERV-W env (Human endogenous retroviruses W family envelope protein), located on chromosome 7 and primarily expressed in the human placenta, has been closely linked to various neuropsychiatric disorders, including schizophrenia, as well as autoimmune diseases and cancer. Recent studies have highlighted the abnormal expression of cytokines as a key factor in the pathophysiology of schizophrenia. Notably, elevated serum levels of IL-1β (interleukin 1 beta) in schizophrenia, a cytokine associated with inflammation, are a characteristic feature of pyroptosis-a form of pro-inflammatory programmed cell death. Although previous research has observed significant upregulation of pyroptosis-related genes such as CASP1 (Caspase-1), NLRP3 (NLR family pyrin domain containing 3), and IL1B (interleukin 1 beta) in the serum of schizophrenia patients, and extensive neuron pyroptosis has been documented in various neuropsychiatric disorders, including Alzheimer's disease, epilepsy, and multiple sclerosis, the occurrence of neuron pyroptosis in schizophrenia remains uncertain. Furthermore, the mechanisms underlying pyroptosis in schizophrenia and its potential connection with HERV-W env have yet to be fully elucidated. In this study, we found that the expression levels of pyroptosis-related genes, specifically CASP1, GSDMD (Gasdermin D), and IL1B, were significantly elevated in patients with schizophrenia compared to healthy controls. Furthermore, our analysis revealed a strong positive correlation between HERV-W env expression and the levels of CASP1/GSDMD/IL1B in these patients. Experimental evidence further demonstrated that HERV-W env promoted the activation of Caspase-1 and the cleavage of Gasdermin D, leading to increased release of LDH (lactate dehydrogenase) and IL-1β. Importantly, inhibitors targeting NLRP3, CASP1, and GSDMD significantly reduced the releases of LDH and IL-1β induced by HERV-W env, whereas BID (BH3 interacting domain death agonist) inhibitors did not have a notable effect. This suggests that HERV-W env induces CASP1-GSDMD-dependent pyroptosis through the NLRP3-CASP1-GSDMD signaling pathway. As pyroptosis is increasingly recognized for its connection to neurodegenerative diseases, this study provides insights into the molecular mechanisms of neuronal pyroptosis mediated by the NLRP3 inflammasome in the context of HERV-W env. Additionally, it explores the potential facilitation of HERV-W env in the development of schizophrenia via pyroptosis, proposing that certain pyroptosis indicators could serve as potential biomarkers for schizophrenia. Based on our existing research results and the findings of previous researchers, we infer that HERV-W env acts as a bridge in the onset and progression of schizophrenia. Furthermore, HERV-W env may serve as a potential target for the clinical treatment of schizophrenia, suggesting that monoclonal antibody therapy targeting HERV-W env could represent a novel approach to managing this disease.}, }
@article {pmid39859201, year = {2025}, author = {Barbalho, SM and Laurindo, LF and de Oliveira Zanuso, B and da Silva, RMS and Gallerani Caglioni, L and Nunes Junqueira de Moraes, VBF and Fornari Laurindo, L and Dogani Rodrigues, V and da Silva Camarinha Oliveira, J and Beluce, ME and Penteado Detregiachi, CR and Barbalho Lamas, C and Dos Santos Haber, JF and Cavallari Strozze Catharin, VM and Quesada, K and Tanaka, M and Valenti, VE}, title = {AdipoRon's Impact on Alzheimer's Disease-A Systematic Review and Meta-Analysis.}, journal = {International journal of molecular sciences}, volume = {26}, number = {2}, pages = {}, pmid = {39859201}, issn = {1422-0067}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Adiponectin/metabolism/therapeutic use ; tau Proteins/metabolism ; Receptors, Adiponectin/metabolism/agonists ; Indenes/therapeutic use ; Piperidines/therapeutic use/pharmacology ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) remains a leading cause of cognitive decline and mortality worldwide, characterized by neurodegeneration, synaptic deficiencies, and neuroinflammation. Despite advancements in early detection, diagnosis, and treatment, AD presents substantial challenges due to its complex pathology, heterogeneity, and the limited efficacy of current therapies. Consequently, there is a pressing need for novel therapeutic agents to target the multifaceted aspects of AD pathology, enhance current treatments, and minimize adverse effects. AdipoRon, an adiponectin receptor agonist, has garnered interest for its potential neuroprotective effects, including reducing neuroinflammation, improving mitochondrial function, and mitigating tau hyperphosphorylation. This review aimed to evaluate the effects of AdipoRon-based adiponectin replacement therapy against AD, using a comprehensive approach grounded in the PICO framework-Population, Intervention, Comparison, and Outcomes. A total of six studies were reviewed, including in vitro and in vivo investigations examining AdipoRon's impact on various AD models. These studies involved different cell lines and transgenic mouse models, assessing various outcomes such as cognitive function, neuroinflammation, tau phosphorylation, synaptic deficiencies, and relevant molecular pathways. By synthesizing data from these studies, our review thoroughly explains AdipoRon's neuroprotective effects, mechanisms of action, and potential as a therapeutic agent for AD. This analysis aims to highlight the current state of knowledge, identify gaps in the research, and suggest directions for future studies and clinical applications.}, }
@article {pmid39858890, year = {2025}, author = {Kuziak, A and Heczko, P and Pietrzyk, A and Strus, M}, title = {Iron Homeostasis Dysregulation, Oro-Gastrointestinal Microbial Inflammatory Factors, and Alzheimer's Disease: A Narrative Review.}, journal = {Microorganisms}, volume = {13}, number = {1}, pages = {}, pmid = {39858890}, issn = {2076-2607}, abstract = {Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder that profoundly impacts cognitive function and the nervous system. Emerging evidence highlights the pivotal roles of iron homeostasis dysregulation and microbial inflammatory factors in the oral and gut microbiome as potential contributors to the pathogenesis of AD. Iron homeostasis disruption can result in excessive intracellular iron accumulation, promoting the generation of reactive oxygen species (ROS) and oxidative damage. Additionally, inflammatory agents produced by pathogenic bacteria may enter the body via two primary pathways: directly through the gut or indirectly via the oral cavity, entering the bloodstream and reaching the brain. This infiltration disrupts cellular homeostasis, induces neuroinflammation, and exacerbates AD-related pathology. Addressing these mechanisms through personalized treatment strategies that target the underlying causes of AD could play a critical role in preventing its onset and progression.}, }
@article {pmid39858858, year = {2025}, author = {Onisiforou, A and Charalambous, EG and Zanos, P}, title = {Shattering the Amyloid Illusion: The Microbial Enigma of Alzheimer's Disease Pathogenesis-From Gut Microbiota and Viruses to Brain Biofilms.}, journal = {Microorganisms}, volume = {13}, number = {1}, pages = {}, pmid = {39858858}, issn = {2076-2607}, support = {#101031962//European Commission Marie Skłodowska-Curie fellowship/ ; EXCELLENCE/0421/0543//Research & Innovation Foundation of Cyprus - Excellence Hubs 2021/ ; NA//IDSA Foundation/ ; }, abstract = {For decades, Alzheimer's Disease (AD) research has focused on the amyloid cascade hypothesis, which identifies amyloid-beta (Aβ) as the primary driver of the disease. However, the consistent failure of Aβ-targeted therapies to demonstrate efficacy, coupled with significant safety concerns, underscores the need to rethink our approach to AD treatment. Emerging evidence points to microbial infections as environmental factors in AD pathoetiology. Although a definitive causal link remains unestablished, the collective evidence is compelling. This review explores unconventional perspectives and emerging paradigms regarding microbial involvement in AD pathogenesis, emphasizing the gut-brain axis, brain biofilms, the oral microbiome, and viral infections. Transgenic mouse models show that gut microbiota dysregulation precedes brain Aβ accumulation, emphasizing gut-brain signaling pathways. Viral infections like Herpes Simplex Virus Type 1 (HSV-1) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may lead to AD by modulating host processes like the immune system. Aβ peptide's antimicrobial function as a response to microbial infection might inadvertently promote AD. We discuss potential microbiome-based therapies as promising strategies for managing and potentially preventing AD progression. Fecal microbiota transplantation (FMT) restores gut microbial balance, reduces Aβ accumulation, and improves cognition in preclinical models. Probiotics and prebiotics reduce neuroinflammation and Aβ plaques, while antiviral therapies targeting HSV-1 and vaccines like the shingles vaccine show potential to mitigate AD pathology. Developing effective treatments requires standardized methods to identify and measure microbial infections in AD patients, enabling personalized therapies that address individual microbial contributions to AD pathogenesis. Further research is needed to clarify the interactions between microbes and Aβ, explore bacterial and viral interplay, and understand their broader effects on host processes to translate these insights into clinical interventions.}, }
@article {pmid39858522, year = {2025}, author = {Miliotou, AN and Kotsoni, A and Zacharia, LC}, title = {Deciphering the Role of Adrenergic Receptors in Alzheimer's Disease: Paving the Way for Innovative Therapies.}, journal = {Biomolecules}, volume = {15}, number = {1}, pages = {}, pmid = {39858522}, issn = {2218-273X}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Receptors, Adrenergic/metabolism ; Animals ; Adrenergic Antagonists/therapeutic use ; }, abstract = {Neurodegenerative diseases are currently among the most devastating diseases with no effective disease-modifying drugs in the market, with Alzheimer's disease (AD) being the most prevalent. AD is a complex multifactorial neurodegenerative disorder characterized by progressive and severe cognitive impairment and memory loss. It is the most common cause of progressive memory loss (dementia) in the elderly, and to date, there is no effective treatment to cure or slow disease progression substantially. The role of adrenergic receptors in the pathogenesis of Alzheimer's disease and other tauopathies is poorly understood or investigated. Recently, some studies indicated a potential benefit of drugs acting on the adrenergic receptors for AD and dementias, although due to the heterogeneity of the drug classes used, the results on the whole remain inconclusive. The scope of this review article is to comprehensively review the literature on the possible role of adrenergic receptors in neurodegenerative diseases, stemming from the use of agonists and antagonists including antihypertensive and asthma drugs acting on the adrenergic receptors, but also from animal models and in vitro models where these receptors have been studied. Ultimately, we hope to obtain a better understanding of the role of these receptors, identify the gaps in knowledge, and explore the possibility of repurposing such drugs for AD, given their long history of use and safety.}, }
@article {pmid39857687, year = {2025}, author = {Kim, DU and Kweon, B and Oh, J and Lim, Y and Noh, G and Yu, J and Kang, HR and Kwon, T and Lee, KY and Bae, GS}, title = {A Network Pharmacology Study and Experimental Validation to Identify the Potential Mechanism of Heparan Sulfate on Alzheimer's Disease-Related Neuroinflammation.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857687}, issn = {2227-9059}, support = {2023RIS-008//Ministry of Education/ ; }, abstract = {BACKGROUND/OBJECTIVES: Heparan sulfate (HS) is a polysaccharide that is found on the surface of cells and has various biological functions in the body.
METHODS: The purpose of this study was to predict the pharmacological effects and molecular mechanisms of HS on Alzheimer's disease (AD) and neuroinflammation (NI) through a network pharmacology analysis and to experimentally verify them.
RESULTS: We performed functional enrichment analysis of common genes between HS target genes and AD-NI gene sets and obtained items such as the "Cytokine-Mediated Signaling Pathway", "Positive Regulation Of MAPK Cascade", and "MAPK signaling pathway". To confirm the predicted results, the anti-inflammatory effect of HS was investigated using lipopolysaccharide (LPS)-stimulated BV2 microglia cells. HS inhibited the production of nittic oxide, interleukin (IL)-6, and tumor necrosis factor-α in LPS-stimulated BV2 cells, but not IL-1β. In addition, HS inactivated P38 in the MAPK signaling pathway.
CONCLUSIONS: These findings suggest the potential for HS to become a new treatment for AD and NI.}, }
@article {pmid39855473, year = {2025}, author = {Hansen, N and Teegen, B and Hirschel, S and Fox, J and Fitzner, D and Wiltfang, J and Bartels, C}, title = {Longitudinally persisting KCNA2-autoantibodies in mild amnestic dementia with Alzheimer´s pathology - Report and literature review.}, journal = {Behavioural brain research}, volume = {482}, number = {}, pages = {115437}, doi = {10.1016/j.bbr.2025.115437}, pmid = {39855473}, issn = {1872-7549}, mesh = {Humans ; Male ; Aged ; *Autoantibodies/blood/cerebrospinal fluid/immunology ; *Alzheimer Disease/immunology/blood ; Kv1.2 Potassium Channel/immunology ; Cognitive Dysfunction/immunology/etiology ; tau Proteins/immunology ; Amyloid beta-Peptides/immunology/blood ; Biomarkers/blood ; Amnesia/immunology ; }, abstract = {BACKGROUND: Neural autoantibodies are being increasingly detected in conjunction with neurodegenerative dementias such as Alzheimer's disease dementia (AD), yet their significance is not well clarified. In this case report, we report the previously unreported long-lasting persistence of potassium voltage-gated channel subfamily A member 2 (KCNA2) antibodies in biomarker-supported AD.
METHODS: We report on a 77-year-old, male patient evaluated in our outpatient memory clinic of the Department of Psychiatry and Psychotherapy, University Medical Center Göttingen. Neuropsychological test results and autoantibody testing in serum over a period of 4-5 years is provided.
REPORT: Our patient exhibited mild dementia syndrome and was diagnosed with AD on the basis of a prototypical biomarker profile (reduced Aβ42/40 ratio and elevated p-tau181 protein in cerebrospinal fluid). Within a 5-year follow-up with regular visits to our memory clinic, we observed a nearly stable neuropsychological profile of mild, amnestic variant dementia that did not noticeably progress. KCNA2 autoantibodies were also detectable in serum over 4 years with increasing titers over time. Combined anti-dementia therapy with donepezil, multimodal therapy including non-pharmacological cognitive therapy, and immunotherapy with intravenous methylprednisolone was carried out as an individual treatment approach.
CONCLUSIONS: KCNA2 autoantibody persistence in biomarker-supported AD does not necessarily trigger a poor outcome in the long-term, as cognitive impairment did not progress subsequently. At the same time, mild immunotherapy did not result in less immunoreactivity in conjunction with the detection of KCNA2 autoantibodies. This detection of KCNA2 autoantibodies in AD could provide indices of a potentially benign long-term AD course that should be further evaluated in studies.}, }
@article {pmid39855275, year = {2025}, author = {Zhang, W and Zhang, L and Fu, S and Yan, R and Zhang, X and Song, J and Lu, Y}, title = {Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential.}, journal = {Pharmacology & therapeutics}, volume = {267}, number = {}, pages = {108803}, doi = {10.1016/j.pharmthera.2025.108803}, pmid = {39855275}, issn = {1879-016X}, mesh = {Humans ; *Inflammasomes/metabolism ; Animals ; *Calcium-Binding Proteins/metabolism ; Nervous System Diseases/drug therapy/metabolism/immunology ; Neurodegenerative Diseases/drug therapy/metabolism ; Pyroptosis ; CARD Signaling Adaptor Proteins ; }, abstract = {The nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 4 (NLRC4) inflammasome, a vital component of the innate immune system, is known for defending against bacterial infections. However, recent insights have revealed its significant impact on neurological disorders. This comprehensive review discussed the mechanisms underlying the activation and regulation of the NLRC4 inflammasome, highlighting the complexity of its response to cellular stress and damage signals. The biological functions of NLRC4 were explored, particularly its influence on cytokine production and the induction of pyroptosis, a form of inflammatory cell death. This review further emphasized the role of the NLRC4 inflammasome in brain injuries and neurodegenerative disorders. In the realm of brain injuries such as stroke and traumatic brain injury, as well as in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, the NLRC4 inflammasome played a pivotal role in modulating neuroinflammatory responses, which was crucial for understanding the progression and potential therapeutic targeting of these conditions. The emerging role of NLRC4 in psychiatric disorders and its potential impact on glioma progression were also examined. Additionally, this review presented a thorough summary of the latest research on inhibitors that impeded the assembly and activation of the NLRC4 inflammasome, pointing to new therapeutic possibilities in neurological disorders. In conclusion, by integrating current knowledge on the activation and regulation of NLRC4 with its biological functions and clinical implications, this article underscored the importance of NLRC4 inflammasome in neurological pathologies, which opened new possibilities for the treatment of challenging neurological conditions.}, }
@article {pmid39853846, year = {2025}, author = {Moradi, F and Mokhtari, T}, title = {Role of NLRP3 Inflammasome in Chronic Pain and Alzheimer's Disease-A Review.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {2}, pages = {e70071}, pmid = {39853846}, issn = {1099-0461}, support = {R35 ES030443/ES/NIEHS NIH HHS/United States ; //This study was funded by the Faculty Development Grants from Hubei University of Medicine (No. 2023QDJZR) and partially supported by a grant from the National Institute of Environmental Health Sciences (NIEHS, R35ES030443)./ ; }, mesh = {*Alzheimer Disease/metabolism ; Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Inflammasomes/metabolism ; *Chronic Pain/metabolism/physiopathology ; Animals ; Microglia/metabolism/pathology ; }, abstract = {The coexistence of Alzheimer's disease (AD) and chronic pain (CP) in the elderly population has been extensively documented, and a growing body of evidence supports the potential interconnections between these two conditions. This comprehensive review explores the mechanisms by which CP may contribute to the development and progression of AD, with a particular focus on neuroinflammatory pathways and the role of microglia, as well as the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The review proposes that prolonged pain processing in critical brain regions can dysregulate the activity of the NLRP3 inflammasome within microglia, leading to the overproduction of pro-inflammatory cytokines and excessive oxidative stress in these regions. This aberrant microglial response also results in localized neuroinflammation in brain areas crucial for cognitive function. Additionally, CP as a persistent physiological and psychological stressor may be associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, systemic inflammation, disruption of the blood-brain barrier (BBB), and neuroinflammation. These pathophysiological changes can cause morphological and functional impairments in brain regions responsible for cognition, memory, and neurotransmitter production, potentially contributing to the development and progression of CP-associated AD. Resultant neuroinflammation can further promote amyloid-beta (Aβ) plaque deposition, a hallmark of AD pathology. Potential therapeutic interventions targeting these neuroinflammatory pathways, particularly through the regulation of microglial NLRP3 activation, hold promise for improving outcomes in individuals with comorbid CP and AD. However, further research is required to fully elucidate the complex interplay between these conditions and develop effective treatment strategies.}, }
@article {pmid39853561, year = {2025}, author = {Lee, HH and Chinnameyyappan, A and Feldman, OJ and Marotta, G and Survilla, K and Lanctôt, KL}, title = {Behavioral and Psychological Symptoms (BPSD) in Alzheimer's Disease (AD): Development and Treatment.}, journal = {Current topics in behavioral neurosciences}, volume = {69}, number = {}, pages = {245-273}, pmid = {39853561}, issn = {1866-3370}, mesh = {Humans ; *Alzheimer Disease/therapy/complications/psychology ; *Psychotic Disorders/therapy/etiology ; *Behavioral Symptoms/therapy/etiology ; *Psychomotor Agitation/therapy/etiology ; }, abstract = {Behavioral and psychological symptoms of dementia (BPSD), such as agitation, apathy, and psychosis, are highly prevalent and have a significant impact on patients and their care partners. The neurobiology of BPSD involves a complex interplay of structural brain changes and alterations in the neurotransmitter system. Various genetic and plasma biomarkers have also been studied. Research in BPSD has been limited by heterogeneity in the diagnostic criteria and assessment tools. As such, there have been ongoing efforts to develop a gold-standard assessment tool and diagnostic criteria. Current practice guidelines recommend nonpharmacological therapies as first-line treatments. Pharmacological options are often used when there is an insufficient response to nonpharmacological strategies, but there can be serious adverse effects with existing pharmacological agents. This has resulted in growing efforts to develop novel therapeutics with more favorable tolerability profiles, with some showing promising results. Other biological therapies, such as neurostimulation, have also demonstrated positive results. As our understanding of BPSD evolves, ongoing research efforts in treatment of BPSD are warranted in order to enhance the quality of life for patients and their care partners.}, }
@article {pmid39853424, year = {2025}, author = {Zavarella, M and Cecchetti, G and Rugarli, G and Ghirelli, A and Bottale, I and Orlandi, F and Spinelli, EG and Santangelo, R and Caso, F and Calloni, SF and Vezzulli, PQ and Falini, A and Magnani, G and Agosta, F and Filippi, M}, title = {Favorable long-term cognitive outcomes following recurrent ARIA linked to amyloid-lowering therapies: two cases.}, journal = {Journal of neurology}, volume = {272}, number = {2}, pages = {168}, pmid = {39853424}, issn = {1432-1459}, support = {Project Age-It: "Ageing Well in an Ageing Society"//Ministero dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Cognitive Dysfunction/etiology/drug therapy ; *Antibodies, Monoclonal, Humanized/administration & dosage/adverse effects ; *Alzheimer Disease/drug therapy ; Aged ; Male ; Female ; Recurrence ; Positron-Emission Tomography ; Aged, 80 and over ; Disease Progression ; Follow-Up Studies ; }, abstract = {INTRODUCTION: The large-scale approval of anti-amyloid monoclonal antibodies for treating Alzheimer's disease (AD) has raised concerns about their safety due to treatment-emergent amyloid-related imaging abnormalities (ARIA).
METHODS: We present two cases of patients diagnosed with mild cognitive impairment due to AD who were enrolled in the GRADUATE I clinical trial. They received subcutaneous gantenerumab every two weeks during the study period.
RESULTS: Both patients experienced recurrent ARIA-Effusion/Edema type (ARIA-E). One developed symptomatic and severe ARIA, leading to hospitalization and study withdrawal. We report a long follow-up post-randomization (65 and 54 months), during which the adverse events did not appear to have a negative impact on disease progression. Additionally, one patient had a negative amyloid-PET over a year after treatment cessation.
DISCUSSION: These cases suggest that recurrent ARIA-E do not inevitably lead to accelerated progression, instead, may relate to possible long-term benefits. The mechanisms underlying these findings warrant further real-life evidence.}, }
@article {pmid39852770, year = {2025}, author = {Kala, S and Strutz, AG and Katt, ME}, title = {The Rise of Pluripotent Stem Cell-Derived Glia Models of Neuroinflammation.}, journal = {Neurology international}, volume = {17}, number = {1}, pages = {}, pmid = {39852770}, issn = {2035-8385}, support = {P20 GM109098/GM/NIGMS NIH HHS/United States ; T32 AG052375/AG/NIA NIH HHS/United States ; T32AG052375/GF/NIH HHS/United States ; 5P20GM109098-10/GF/NIH HHS/United States ; }, abstract = {Neuroinflammation is a blanket term that describes the body's complex inflammatory response in the central nervous system (CNS). It encompasses a phenotype shift to a proinflammatory state, the release of cytokines, the recruitment of peripheral immune cells, and a wide variety of other processes. Neuroinflammation has been implicated in nearly every major CNS disease ranging from Alzheimer's disease to brain cancer. Understanding and modeling neuroinflammation is critical for the identification of novel therapeutic targets in the treatment of CNS diseases. Unfortunately, the translation of findings from non-human models has left much to be desired. This review systematically discusses the role of human pluripotent stem cell (hPSC)-derived glia and supporting cells within the CNS, including astrocytes, microglia, oligodendrocyte precursor cells, pericytes, and endothelial cells, to describe the state of the field and hope for future discoveries. hPSC-derived cells offer an expanded potential to study the pathobiology of neuroinflammation and immunomodulatory cascades that impact disease progression. While much progress has been made in the development of models, there is much left to explore in the application of these models to understand the complex inflammatory response in the CNS.}, }
@article {pmid39851568, year = {2025}, author = {Mooradian, AD and Haas, MJ}, title = {Role of Thyroid Hormone in Neurodegenerative Disorders of Older People.}, journal = {Cells}, volume = {14}, number = {2}, pages = {}, pmid = {39851568}, issn = {2073-4409}, mesh = {Humans ; *Thyroid Hormones/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Aged ; }, abstract = {Thyroid dysfunction is associated with a number of neuropsychiatric manifestations. Cognitive decline is a common feature of hypothyroidism and clinical or subclinical hyperthyroidism. In addition, there is a significant association between thyroid hormone (TH) levels and the degree of cognitive impairment in Parkinson's disease (PD). The pathophysiology of TH-related neurodegeneration include changes in the blood-brain barrier, increased cellular stress, altered processing of β-amyloid precursor protein and the effect of TH on neuronal cell viability. The neurotoxicity of TH is partially mediated by the thyroid hormone responsive protein (THRP). This protein is 83% homologous to mouse c-Abl-interacting protein-2 (Abi2), a c-Abl-modulating protein with tumor suppressor activity. In cell cultures, increasing THRP expression either with TH treatment or exogenously through transfecting neuronal or PC 12 cells causes cell necrosis. The expression of exogenous THRP in other cells such as the colonic epithelial cell line Caco-2 and the glial cell line U251 has no effect on cell viability. The effect of THRP on cell viability is not modulated by c-Abl tyrosine kinase. The causal relationship between specific biochemical perturbations in cerebral tissue and thyroid dysfunction remains to be elucidated.}, }
@article {pmid39851526, year = {2025}, author = {Chen, W and Kim, S and Kim, SY and Beheshtian, C and Kim, N and Shin, KH and Kim, RH and Kim, S and Park, NH}, title = {GV1001, hTERT Peptide Fragment, Prevents Doxorubicin-Induced Endothelial-to-Mesenchymal Transition in Human Endothelial Cells and Atherosclerosis in Mice.}, journal = {Cells}, volume = {14}, number = {2}, pages = {}, pmid = {39851526}, issn = {2073-4409}, support = {R21 DE031074/DE/NIDCR NIH HHS/United States ; 441902-19900//University of California System/ ; }, mesh = {*Doxorubicin/pharmacology/adverse effects ; Animals ; *Atherosclerosis/pathology/drug therapy ; Humans ; Mice ; *Epithelial-Mesenchymal Transition/drug effects ; *Telomerase/metabolism ; Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Endothelial Cells/drug effects/metabolism/pathology ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; NF-kappa B/metabolism ; Mice, Inbred C57BL ; Male ; Disease Models, Animal ; Peptide Fragments/pharmacology ; }, abstract = {Doxorubicin is a highly effective anticancer agent, but its clinical use is restricted by severe side effects, including atherosclerosis and cardiomyopathy. These complications are partly attributed to doxorubicin's ability to induce endothelial-to-mesenchymal transition (EndMT) in vascular endothelial cells, a critical process in the initiation and progression of atherosclerosis and cardiomyopathy. GV1001, a multifunctional peptide with anti-inflammatory, anti-cancer, antioxidant, and anti-Alzheimer's properties, has demonstrated inhibition of EndMT. We investigated whether GV1001 could counteract doxorubicin-induced EndMT in endothelial cells and prevent atherosclerosis in a mouse model. The results revealed that GV1001 significantly suppressed EndMT induced by doxorubicin, likely through its protective effects on mitochondria. By mitigating mitochondrial damage, GV1001 reduced the accumulation of mitochondrial and cellular reactive oxygen species (ROS), repressed the activation of nuclear factor kappa B (NF-κB), and reduced the production of proinflammatory cytokines in endothelial cells. Additionally, GV1001 reduced systemic and vascular inflammation, lipid accumulation, and monocyte/macrophage infiltration within arterial walls in mice. In conclusion, GV1001 appears to prevent doxorubicin-induced atherosclerosis by safeguarding vascular endothelial cells from mitochondrial dysfunction, inflammation, and phenotypic changes. These findings suggest the potential of GV1001 as a therapeutic agent to mitigate the long-term cardiovascular side effects associated with doxorubicin treatment in humans.}, }
@article {pmid39851389, year = {2024}, author = {Trinh, DQ and Mai, NH and Pham, TD}, title = {Insufficient Sleep and Alzheimer's Disease: Potential Approach for Therapeutic Treatment Methods.}, journal = {Brain sciences}, volume = {15}, number = {1}, pages = {}, pmid = {39851389}, issn = {2076-3425}, abstract = {The interaction between Alzheimer's disease (AD) and sleep deprivation has recently gained attention in the scientific literature, and recent advances suggest that AD epidemiology management should coincide with the management of sleeping disorders. This review focuses on the aspects of the mechanisms underlying the link between AD and insufficient sleep with progressing age. We also provide information which could serve as evidence for future treatments of AD from the early stages in connection with sleep disorder medication.}, }
@article {pmid39851253, year = {2024}, author = {Sun, Y and Pang, X and Huang, X and Liu, D and Huang, J and Zheng, P and Wei, Y and Pang, C}, title = {Potential mechanisms of non-coding RNA regulation in Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-00696}, pmid = {39851253}, issn = {1673-5374}, abstract = {Alzheimer's disease, a progressively degenerative neurological disorder, is the most common cause of dementia in the elderly. While its precise etiology remains unclear, researchers have identified diverse pathological characteristics and molecular pathways associated with its progression. Advances in scientific research have increasingly highlighted the crucial role of non-coding RNAs in the progression of Alzheimer's disease. These non-coding RNAs regulate several biological processes critical to the advancement of the disease, offering promising potential as therapeutic targets and diagnostic biomarkers. Therefore, this review aims to investigate the underlying mechanisms of Alzheimer's disease onset, with a particular focus on microRNAs, long non-coding RNAs, and circular RNAs associated with the disease. The review elucidates the potential pathogenic processes of Alzheimer's disease and provides a detailed description of the synthesis mechanisms of the three aforementioned non-coding RNAs. It comprehensively summarizes the various non-coding RNAs that have been identified to play key regulatory roles in Alzheimer's disease, as well as how these non-coding RNAs influence the disease's progression by regulating gene expression and protein functions. For example, miR-9 targets the UBE4B gene, promoting autophagy-mediated degradation of Tau protein, thereby reducing Tau accumulation and delaying Alzheimer's disease progression. Conversely, the long non-coding RNA BACE1-AS stabilizes BACE1 mRNA, promoting the generation of amyloid-[2] and accelerating Alzheimer's disease development. Additionally, circular RNAs play significant roles in regulating neuroinflammatory responses. By integrating insights from these regulatory mechanisms, there is potential to discover new therapeutic targets and potential biomarkers for early detection and management of Alzheimer's disease. This review aims to enhance the understanding of the relationship between Alzheimer's disease and non-coding RNAs, potentially paving the way for early detection and novel treatment strategies.}, }
@article {pmid39851113, year = {2025}, author = {Mishra, AS and Vasantham, M and Ghosh, B and Malliappan, SP}, title = {Transforming Alzheimer's Treatment: Unveiling New Potential with Drug Repurposing Strategies.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673341391241231054936}, pmid = {39851113}, issn = {1875-533X}, abstract = {Alzheimer's disease (AD) remains a significant challenge in neurology, marked by progressive cognitive decline and neurodegeneration. Despite extensive research efforts, effective treatments are still lacking. Traditional drug discovery is often slow and costly, frequently resulting in limited success. Drug repurposing, which identifies new therapeutic uses for existing medications, has emerged as a promising approach to expedite AD treatment development. This review examines the potential of drug repurposing to transform AD therapy by utilizing the established safety profiles and known mechanisms of current drugs. We explore various repurposed drugs under investigation for AD, originally intended for cardiovascular, metabolic, and psychiatric conditions. Detailed discussions include how these drugs provide neuroprotective benefits by inhibiting amyloid-beta aggregation, reducing tau phosphorylation, and modulating neuroinflammation. Additionally, we emphasize the benefits of drug repurposing, such as shortened development timelines, lower costs, and increased chances of clinical success. By integrating current research findings, this review offers a thorough overview of the most promising repurposed drug candidates and their potential impact on AD treatment strategies. It stresses the importance of innovative approaches in AD research and calls for greater investment in drug repurposing initiatives. Through these strategies, we aim to accelerate the availability of effective treatments, providing renewed hope and a brighter future for those affected by this devastating disease.}, }
@article {pmid39849525, year = {2025}, author = {Lu, Y and Xu, Y and Zhou, L and Wang, S and Han, Y and Wang, K and Qin, C}, title = {Bone marrow mesenchymal stem cells derived cytokines associated with AKT/IAPs signaling ameliorate Alzheimer's disease development.}, journal = {Stem cell research & therapy}, volume = {16}, number = {1}, pages = {14}, pmid = {39849525}, issn = {1757-6512}, support = {2021-I2M-1-034, 2019-I2M-1-004//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 2022QNRC001//Young Elite Scientitsts Sponsorship Program by CAST/ ; 2023-PT180-01//the Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences/ ; }, mesh = {Animals ; *Alzheimer Disease/therapy/metabolism ; Mice ; *Mesenchymal Stem Cells/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Cytokines/metabolism ; Female ; Signal Transduction ; Disease Models, Animal ; Mesenchymal Stem Cell Transplantation/methods ; Mice, Transgenic ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative condition affecting around 50 million people worldwide. Bone marrow-derived mesenchymal stem cells (BMMSCs) have emerged as a promising source for cellular therapy due to their ability to differentiate into multiple cell types and their paracrine effects. However, the direct injection of BMMSCs can lead to potential unpredictable impairments, prompting a renewed interest in their paracrine effects for AD treatment. The specific mechanism and central role of cytokines in this process have not been fully elucidated.
METHODS: Mouse BMMSCs were isolated, validated, and then transplanted intracerebrally into APP/PS1 female mice. The behavioral tests, including open-field test, novel object recognition test, and Morris water maze were performed, followed by β-amyloidosis plaque and neuron apoptosis analyses. Then the tissue RNA sequencing and mBMMSC cytokine analysis were performed. A cytokine antibody array for BMMSCs and the brain slice models were performed with AD model tissues were used to elucidate the molecular mechanisms. Finally, APP/PS1 mice were administrated with cytokine mixture for cognitive recovery.
RESULTS: Our results demonstrated that BMMSCs significantly improved cognitive function, reduced beta-amyloid plaque deposition, and decreased apoptotic neurons through the activation of the AKT signaling pathway. Using a cytokine antibody array, we identified three highly expressed AKT pathway regulated neuroprotective factors in BMMSCs: IGF1, VEGF, and Periostin2. These cytokines were found to upregulate inhibitors of apoptosis family proteins (IAPs) and suppress Caspase-3 activity in brain slices induced with beta amyloidosis (Aβ), okadaic acid (OA), and lipopolysaccharide (LPS). When injection of this cytokine mixture to APP/PS1 mice also resulted in a mitigation of cognitive impairment.
CONCLUSIONS: These findings suggest that the secretory factors IGF1, VEGF, and Periostin2 derived from BMMSCs play a crucial role in neuroprotection by modulating the AKT/IAPs pathway to restore neuronal function. These cytokine sets could be a potential therapeutic strategy for AD and lay the groundwork for promising clinical applications.}, }
@article {pmid39848035, year = {2025}, author = {Azam, U and Naseer, MM and Rochais, C}, title = {Analysis of skeletal diversity of multi-target directed ligands (MTDLs) targeting Alzheimer's disease.}, journal = {European journal of medicinal chemistry}, volume = {286}, number = {}, pages = {117277}, doi = {10.1016/j.ejmech.2025.117277}, pmid = {39848035}, issn = {1768-3254}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Ligands ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Molecular Structure ; Animals ; tau Proteins/metabolism/antagonists & inhibitors ; }, abstract = {Alzheimer's disease (AD) remains a significant healthcare challenge, necessitating innovative therapeutic approaches to address its complex and multifactorial nature. Traditional drug discovery strategies targeting single molecular targets are not sufficient for the effective treatment of AD. In recent years, MTDLs have emerged as promising candidates for AD therapy, aiming to simultaneously modulate multiple pathological targets. Among the various strategies employed in MTDL design, pharmacophore hybridization offers a versatile approach to integrate diverse pharmacophoric features within a single molecular scaffold. This strategy provides access to a wide array of chemical space for the design and development of novel therapeutic agents. This review, therefore, provides a comprehensive overview of skeletal diversity exhibited by MTDLs designed recently for AD therapy based on pharmacophore hybridization approach. A diverse range of pharmacophoric elements and core scaffolds hybridized to construct MTDLs that has the potential to target multiple pathological features of AD including amyloid-beta aggregation, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress, and neuroinflammation are discussed. Through the comprehensive analysis and integration of structural insights of key biomolecular targets, this review aims to enhance optimization efforts in MTDL design, ultimately striving towards a comprehensive cure for the multifaceted pathophysiology of the disease.}, }
@article {pmid39846361, year = {2025}, author = {Wang, SJ and Wei, LC and Chiu, HJ}, title = {Comment on "Delirium event and associated treatment modifications among older adults with Alzheimer's disease: An interrupted time-series analysis of Medicare data".}, journal = {Pharmacotherapy}, volume = {45}, number = {1}, pages = {70}, doi = {10.1002/phar.4636}, pmid = {39846361}, issn = {1875-9114}, }
@article {pmid39846360, year = {2025}, author = {Aparasu, RR and Talwar, A}, title = {Response to comment on "Delirium event and associated treatment modifications among older adults with Alzheimer's disease: An interrupted time-series analysis of Medicare data".}, journal = {Pharmacotherapy}, volume = {45}, number = {1}, pages = {71}, doi = {10.1002/phar.4637}, pmid = {39846360}, issn = {1875-9114}, }
@article {pmid39846055, year = {2025}, author = {Wei, S and Yang, W and Wang, E and Wang, S and Li, Y}, title = {A 3D decoupling Alzheimer's disease prediction network based on structural MRI.}, journal = {Health information science and systems}, volume = {13}, number = {1}, pages = {17}, pmid = {39846055}, issn = {2047-2501}, abstract = {PURPOSE: This paper aims to develop a three-dimensional (3D) Alzheimer's disease (AD) prediction method, thereby bettering current predictive methods, which struggle to fully harness the potential of structural magnetic resonance imaging (sMRI) data.
METHODS: Traditional convolutional neural networks encounter pressing difficulties in accurately focusing on the AD lesion structure. To address this issue, a 3D decoupling, self-attention network for AD prediction is proposed. Firstly, a multi-scale decoupling block is designed to enhance the network's ability to extract fine-grained features by segregating convolutional channels. Subsequently, a self-attention block is constructed to extract and adaptively fuse features from three directions (sagittal, coronal and axial), so that more attention is geared towards brain lesion areas. Finally, a clustering loss function is introduced and combined with the cross-entropy loss to form a joint loss function for enhancing the network's ability to discriminate between different sample types.
RESULTS: The accuracy of our model is 0.985 for the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset and 0.963 for the Australian Imaging, Biomarker & Lifestyle (AIBL) dataset, both of which are higher than the classification accuracy of similar tasks in this category. This demonstrates that our model can accurately distinguish between normal control (NC) and Alzheimer's Disease (AD), as well as between stable mild cognitive impairment (sMCI) and progressive mild cognitive impairment (pMCI).
CONCLUSION: The proposed AD prediction network exhibits competitive performance when compared with state-of-the-art methods. The proposed model successfully addresses the challenges of dealing with 3D sMRI image data and the limitations stemming from inadequate information in 2D sections, advancing the utility of predictive methods for AD diagnosis and treatment.}, }
@article {pmid39845447, year = {2024}, author = {Zhao, Y and Qiu, C and Lin, P and Yang, M and Huang, L and Zhao, Z and Wu, X and Zhou, D}, title = {Decreased prefrontal activation during verbal fluency task after repetitive transcranial magnetic stimulation treatment for depression in Alzheimer's disease: a functional near-infrared spectroscopy study.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1460853}, pmid = {39845447}, issn = {1663-4365}, abstract = {BACKGROUND: Studies have shown the clinical effects of repetitive transcranial magnetic stimulation (rTMS) on depression in Alzheimer's disease (AD). However, the underlying mechanisms remain poorly understood. The measurement of brain activation links neurobiological and functional aspects but is challenging in patients with dementia. This study investigated the influence of rTMS on cortical activation in patients with AD and depressive symptoms, measured using functional near-infrared spectroscopy (fNIRS) during a verbal fluency task.
METHODS: In this randomized, double-blind study, patients with AD and depression received either active rTMS (n = 17) or sham-rTMS (n = 16). Patients received 4 weeks of bilateral standard rTMS (1 Hz rTMS delivered to the right dorsolateral prefrontal cortex (DLPFC) and 10-Hz rTMS delivered to the left DLPFC).
RESULTS: No significant changes were found in the Mini-Mental State Examination (MMSE) and Modified Barthel Index (MBI); however, significant changes were found for the 17-item Hamilton Depression Rating Scale (HAMD-17) and the depression score of the Neuropsychiatric Inventory (NPI-depression; p < 0.05). The results showed a decrease in the concentration of oxygenated hemoglobin, as measured with fNIRS, from baseline to week 4 in CH41 (in right DLPFC; p = 0.0047, FDR-corrected). There was a negative correlation between the improvement in HAMD-17 severity in these patients and reduced oxygenated hemodynamic response of CH41 (r = - 0.504, p = 0.039).
CONCLUSION: The results indicated a positive effect of rTMS on depression in patients with AD. The underlying cortical changes were imaged using fNIRS. Prefrontal activation measured by fNIRS is a potential biomarker for monitoring the response of patients with depression in AD to rTMS treatment.}, }
@article {pmid39844773, year = {2025}, author = {Xie, Y and Liu, J and Hou, Z and Wang, H and Liu, K and Chen, X and Fan, Z and Li, D and Li, C and Pan, Y and Zhao, Y and Zhu, Y and Hu, B}, title = {CD4-Derived Double-Negative T Cells Ameliorate Alzheimer's Disease-Like Phenotypes in the 5×FAD Mouse Model.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {1}, pages = {e70187}, pmid = {39844773}, issn = {1755-5949}, support = {2021YFA1101400//National Key Research and Development Program of China/ ; ZDBS-LY-SM024//Basic Frontier Science Research Program of CAS/ ; XDA 046205//Strategic Priority Research Program of CAS/ ; }, mesh = {Male ; Female ; Animals ; Mice ; Mice, Inbred C57BL ; Disease Models, Animal ; *CD4-Positive T-Lymphocytes/immunology ; *Alzheimer Disease/genetics/immunology/pathology/therapy ; Space Perception ; Memory ; Cell Transplantation ; Microglia/cytology/immunology/metabolism ; Aging ; Oligodendroglia/cytology/immunology/metabolism ; Neuronal Plasticity ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that is difficult to predict and is typically diagnosed only after symptoms manifest. Recently, CD4[+] T cell-derived double-negative T (DNT) cells have shown strong immuno-regulatory properties in both in vitro and in vivo neuronal inflammation studies. However, the effectiveness of DNT cells in treating on AD are not yet fully understood.
OBJECTIVE: This study's aims were three-fold, to (1) evaluate the efficacy of CD4[+] T cell-derived DNT cells treatment on AD mice, (2) understand how DNT treatment make changes in different cell types of 5FAD mice, (3) identify the side effects of DNT treatment.
METHODS: We performed tail vein injection of transformed and amplified CD4[+] T cell-derived DNT cells into 5 × FAD mice, while using WT mice and saline injection 5FAD mice as controls. DNT suspensions or NaCl alone were administered to 5 × FAD mice at the 6 months of age. For intravenous injection (n = 10 for both DNT and control injections), 5 × FAD mice were injected with a total of 5 × 10[6] DNT cells suspended in 200 μL of 0.9% NaCl or 0.9% NaCl alone via the lateral tail vein. Behavioral tests and pathology tests were carried out 30 days after cell transplantation.
RESULTS: Through qualitative analysis, we identified 6 main themes. DNT from young wild-type mice enhance the capability of spatial learning and memory in AD mice. DNT cell treatment rejuvenates the microglial function. DNT cell treatment improves the state of oligodendrocytes. DNT cell treatment finetunes the activation of the immune system. DNT cell treatment improves the synaptic plasticity and increases the complexity of neurons. DNT cell treatment reduces the density of amyloid Beta plaques deposition in the cortex and hippocampus of 5 × FAD mice.
DISCUSSION: The findings from this study reveal that DNT treatment improved spatial memory and learning abilities, reduced Aβ deposition, and enhanced synaptic plasticity, contrasting with previous reports on thymus-derived DNT cells. Additionally, CD4[+] T cell-derived DNT therapy exhibited anti-inflammatory effects and modulated microglial function, promoting a neuroprotective environment. Notably, DNT treatment also reduced tau pathology by decreasing levels of abnormally phosphorylated tau. These findings suggest that CD4[+] T cell-derived DNT cells hold therapeutic potential for AD, effectively targeting both Aβ and tau pathologies.}, }
@article {pmid39843406, year = {2025}, author = {Islam, MR and Al-Imran, MIK and Zehravi, M and Sweilam, SH and Mortuza, MR and Gupta, JK and Shanmugarajan, TS and Devi, K and Tummala, T and Alshehri, MA and Rajagopal, K and Asiri, M and Ahmad, I and Emran, TB}, title = {Targeting signaling pathways in neurodegenerative diseases: Quercetin's cellular and molecular mechanisms for neuroprotection.}, journal = {Animal models and experimental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/ame2.12551}, pmid = {39843406}, issn = {2576-2095}, abstract = {BACKGROUND: Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, and Huntington's disease, are complex and challenging due to their intricate pathophysiology and limited treatment options.
METHODS: This review systematically sourced articles related to neurodegenerative diseases, neurodegeneration, quercetin, and clinical studies from primary medical databases, including Scopus, PubMed, and Web of Science.
RESULTS: Recent studies have included quercetin to impact the cellular and molecular pathways involved in neurodegeneration. Quercetin, a flavonoid abundant in vegetables and fruits, is gaining attention for its antioxidant, anti-inflammatory, and antiapoptotic properties. It regulates signaling pathways such as nuclear factor-κB (NF-κB), sirtuins, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt). These pathways are essential for cellular survival, inflammation regulation, and apoptosis. Preclinical and clinical studies have shown that quercetin improves symptoms and pathology in neurodegenerative models, indicating promising outcomes.
CONCLUSIONS: The study explores the potential of incorporating laboratory research into practical medical treatment, focusing on quercetin's neuroprotective effects on NDs and its optimal dosage.}, }
@article {pmid39842814, year = {2025}, author = {Ma, YN and Xia, Y and Karako, K and Song, P and Tang, W and Hu, X}, title = {Serum proteomics reveals early biomarkers of Alzheimer's disease: The dual role of APOE-ε4.}, journal = {Bioscience trends}, volume = {19}, number = {1}, pages = {1-9}, doi = {10.5582/bst.2024.01365}, pmid = {39842814}, issn = {1881-7823}, mesh = {*Alzheimer Disease/blood/diagnosis/genetics ; Humans ; *Biomarkers/blood/metabolism ; *Proteomics/methods ; Apolipoprotein E4/genetics ; Amyloid beta-Peptides/blood/metabolism ; Blood-Brain Barrier/metabolism ; }, abstract = {Alzheimer's disease (AD), the leading cause of dementia, significantly impacts global public health, with cases expected to exceed 150 million by 2050. Late-onset Alzheimer's disease (LOAD), predominantly influenced by the APOE-ε4 allele, exhibits complex pathogenesis involving amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), neuroinflammation, and blood-brain barrier (BBB) disruption. Proteomics has emerged as a pivotal technology in uncovering molecular mechanisms and identifying biomarkers for early diagnosis and intervention in AD. This paper reviews the genetic and molecular roles of APOE-ε4 in the pathology of AD, including its effects on Aβ aggregation, tau phosphorylation, neuroinflammation, and BBB integrity. Additionally, it highlights recent advances in serum proteomics, revealing APOE-ε4-dependent and independent protein signatures with potential as early biomarkers for AD. Despite technological progress, challenges such as population diversity, standardization, and distinguishing AD-specific biomarkers remain. Directions for future research emphasize multicenter longitudinal studies, multi-omics integration, and the clinical translation of proteomic findings to enable early detection of AD and personalized treatment strategies. Proteomics advances in AD research hold the promise of improving patient outcomes and reducing the global disease burden.}, }
@article {pmid39842570, year = {2025}, author = {Raj, V and Raorane, CJ and Shastri, D and Kim, JH and Lee, S}, title = {Sulfonic acid functionalized β-amyloid peptide aggregation inhibitors and antioxidant agents for the treatment of Alzheimer's disease: Combining machine learning, computational, in vitro and in vivo approaches.}, journal = {International journal of biological macromolecules}, volume = {299}, number = {}, pages = {140142}, doi = {10.1016/j.ijbiomac.2025.140142}, pmid = {39842570}, issn = {1879-0003}, mesh = {*Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; *Antioxidants/pharmacology/chemistry ; Animals ; *Caenorhabditis elegans/drug effects ; *Sulfonic Acids/chemistry ; *Protein Aggregates/drug effects ; *Machine Learning ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Protein Aggregation, Pathological/drug therapy/metabolism ; Molecular Docking Simulation ; Peptide Fragments/chemistry/pharmacology ; }, abstract = {Alzheimer's disease (AD) is characterized as a neurodegenerative disorder that is caused by plaque formation by accumulating β-amyloid (Aβ), leading to neurocognitive function and impaired mental development. Thus, targeting Aβ represents a promising target for the development of therapeutics in AD management. Several functionalized sulfonic acid molecules have been reported, including tramiprosate prodrug, which is currently in clinical trial III and exhibits a good response in mild to moderate AD patients. Therefore, expanding upon this approach, we hypothesized that the sulfonic acid functionalized aromatic class molecule might demonstrate a good inhibitory effect against β-amyloid aggregation, leading to a decrease in the progression burden of AD. We used computational and in vitro approaches to establish effective compounds. As a result, three potent hit molecules were selected based on binding score as well as availability. In the case of safety profile of compounds, in vitro using human neuroblastoma SH-SY5Y cells and in vivo using C. elegans was performed at doses up to 500 μM; no difference in viability was exhibited between control and treatment groups. However, H2O2-induced ROS stress was significantly reduced in neuroblastoma cells after treatment. The AFM and ThT-embedded β-amyloid1-42 kinetic studies confirmed B-PEA-MBSA and H-HPA-NSA potency. H-HPA-NSA arrested elongation phase of Aβ aggregation in kinetic study at a lower concentration (10 μM), while B-PEA-MBSA reduced the intensity of stationary phase at a dose of 100 μM. Thus, based on the outcomes, it can be suggested that B-PEA-MBSA and H-HPA-NSA can prevent β-amyloid aggregation with mild to moderate AD.}, }
@article {pmid39841316, year = {2025}, author = {Hussain, A and Jairajpuri, DS and Anwar, S and Choudhury, A and Hawwal, MF and Firdous, A and Alajmi, MF and Hassan, MI}, title = {Apigenin-mediated MARK4 inhibition: a novel approach in advancing Alzheimer's disease therapeutics.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {39841316}, issn = {1573-501X}, support = {RSPD2023R980//King Saud University/ ; Grant No. 3-69/2020-CCRUM/Tech//Central Council for Research in Unani Medicine/ ; }, abstract = {Apigenin, a dietary flavonoid with notable anti-cancer properties, has emerged as a promising candidate for the treatment of neurodegenerative disorders, particularly Alzheimer's disease (AD). While extensively studied for its ability to modulate key molecular pathways in cancers, apigenin also exerts neuroprotective effects by reducing neuroinflammation, protecting neurons from oxidative stress, and enhancing neuronal survival and synaptic plasticity. This dual functionality makes apigenin an intriguing therapeutic option for diseases like AD, where kinase dysregulation plays a central role. In this study, we focus on Microtubule Affinity-Regulating Kinase 4 (MARK4), a key enzyme implicated in tauopathies associated with AD, as well as in cancer progression. Through in silico analysis, we explore the interaction between apigenin and MARK4, revealing significant structural changes within the kinase domain upon ligand binding. These computational findings were confirmed via experimental assays using purified recombinant MARK4, where apigenin demonstrated potent inhibition with an IC50 value of 2.39 µM. Fluorescence binding assays further confirmed a strong binding affinity (Ka = 10[8] M[-1]), indicating that apigenin efficiently occupies the MARK4 active site, thereby suppressing its enzymatic activity. These results position apigenin as a potent inhibitor of MARK4, offering a dual therapeutic advantage-both as an anti-cancer agent and as a neuroprotective compound for the potential treatment of AD. This study opens new avenues for the development of apigenin-based therapeutics targeting kinase dysregulation in cancer and neurodegeneration.}, }
@article {pmid39840612, year = {2025}, author = {Saks, DG and Sachdev, PS}, title = {Monogenic causes of cerebral small vessel disease- models for vascular cognitive impairment and dementia?.}, journal = {Current opinion in psychiatry}, volume = {38}, number = {2}, pages = {112-118}, pmid = {39840612}, issn = {1473-6578}, mesh = {Humans ; *Cerebral Small Vessel Diseases/genetics ; *Dementia, Vascular/genetics ; *Cognitive Dysfunction/genetics ; }, abstract = {PURPOSE OF REVIEW: Recent advancements in molecular biomarkers and therapeutic options for Alzheimer's disease have brought into focus the need for greater progress in the second most common cause of dementia, vascular cognitive impairment and dementia (VCID). We examine how the study of monogenic causes of VCID has contributed to the understanding of its pathophysiology and potential biomarker and treatment research.
RECENT FINDINGS: It is widely accepted that conditions which disrupt the cerebral small vessels contribute to vascular pathologies including stroke and cerebral microbleeds, ultimately leading to vascular cognitive impairment and dementia. Among these conditions are a range of monogenic small vessel diseases (SVDs) such as CADASIL, CARASIL, Fabry disease and COL4A-related disorders.
SUMMARY: This review indicates the importance of furthering research into monogenic SVDs in order to gain insight into the pathomechanisms of VCID more broadly. Monogenic conditions are easier to model than sporadic VCID and can serve as a guide for identifying biomarkers for diagnosis, monitoring and intervention outcomes.}, }
@article {pmid39840140, year = {2024}, author = {Ashraf, F and Rasool, FK and Uddin, MMN and Siddiq, MA and Mustafa, MS}, title = {Targeting Beta-Amyloid Protein with Monoclonal Antibodies: A New Hope for Alzheimer's Treatment.}, journal = {Annals of neurosciences}, volume = {31}, number = {4}, pages = {243-245}, pmid = {39840140}, issn = {0972-7531}, }
@article {pmid39839307, year = {2024}, author = {He, J and Xu, P and Xu, T and Yu, H and Wang, L and Chen, R and Zhang, K and Yao, Y and Xie, Y and Yang, Q and Wu, W and Sun, D and Wu, D}, title = {Therapeutic potential of hydrogen-rich water in zebrafish model of Alzheimer's disease: targeting oxidative stress, inflammation, and the gut-brain axis.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1515092}, pmid = {39839307}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder, with amyloid-beta (Aβ) aggregation playing a key role in its pathogenesis. Aβ-induced oxidative stress leads to neuronal damage, mitochondrial dysfunction, and apoptosis, making antioxidative strategies promising for AD treatment. This study investigates the effects of hydrogen-rich water (HRW) in a zebrafish AD model. Zebrafish were exposed to aluminum chloride to induce AD-like pathology and then treated with HRW using a nanobubble device. Behavioral assays, ELISA, Hematoxylin-eosin (H&E) staining, and reactive oxygen species (ROS) and neutrophil fluorescence labeling were employed to assess HRW's impact. Additionally, 16S rRNA sequencing analyzed HRW's effect on gut microbiota. HRW can significantly improve cognitive impairment and depression-like behavior in zebrafish AD model, reduce Aβ deposition (p < 0.0001), regulate liver Soluble epoxide hydrolase (sEH) levels (p < 0.05), reduce neuroinflammation, and reduce oxidative stress. Furthermore, HRW reduced the number of harmful bacteria linked to AD pathology by restoring the balance of microbiota in the gut. These findings suggest that HRW has potential as a therapeutic strategy for AD by targeting oxidative stress, inflammation, and gut-brain axis modulation.}, }
@article {pmid39839126, year = {2024}, author = {Liu, B and Sun, H and Zhao, Q and Li, L and Tian, R and Lui, S and Zhu, H}, title = {Plastic but not progressive changes in cognitive function and hippocampal volume in an adolescent with bipolar disorder: a case report.}, journal = {Frontiers in psychiatry}, volume = {15}, number = {}, pages = {1507333}, pmid = {39839126}, issn = {1664-0640}, abstract = {Bipolar disorder (BD) is a prevalent mood disorder characterized by alternating episodes of depression and mania, often accompanied by varying degrees of cognitive impairment. Cognitive impairments often serve as indicators of a bleak prognosis or the likelihood of progressing to dementia. Additionally, some studies suggest that individuals diagnosed with BD may undergo a decline in hippocampal volume. However, the potential for reversibility of these changes, particularly in adolescents, remains unclear. We present an intriguing case involving an 18-year-old male student who experiences concurrent occurrences of both BD and mild cognitive impairment (MCI), accompanied by a subtle reduction in hippocampal volume. Initially, the individual exhibited impaired general cognitive function, as indicated by an IQ score of 80 on the Standard Raven's Progressive Matrices test, and demonstrated slightly reduced bilateral hippocampal volume compared to the normative reference, as determined through quantitative structural magnetic resonance imaging (qsMRI). The deposition profiles of amyloid beta (Aβ) peptide in the brain were not identified with 18F-AV45 PET/MRI. Following six months of combined psychopharmacological treatment and cognitive behavioral therapy, the individual's psychopathological symptoms improved significantly, leading to a restoration of his IQ score to 116 and normalization of hippocampal volume. This case suggests that the hippocampal volume reduction and cognitive impairment seen in some adolescents with BD may demonstrate greater plasticity compared to neurodegenerative conditions such as Alzheimer's disease (AD). These findings highlight the potential importance of early intervention in young BD patients with cognitive impairments.}, }
@article {pmid39839078, year = {2025}, author = {Underwood, BR and Lourida, I and Gong, J and Tamburin, S and Tang, EYH and Sidhom, E and Tai, XY and Betts, MJ and Ranson, JM and Zachariou, M and Olaleye, OE and Das, S and Oxtoby, NP and Chen, S and Llewellyn, DJ and , }, title = {Data-driven discovery of associations between prescribed drugs and dementia risk: A systematic review.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70037}, pmid = {39839078}, issn = {2352-8737}, support = {R01 AG017644/AG/NIA NIH HHS/United States ; }, abstract = {ABSTRACT: Recent clinical trials on slowing dementia progression have led to renewed focus on finding safer, more effective treatments. One approach to identify plausible candidates is to assess whether existing medications for other conditions may affect dementia risk. We conducted a systematic review to identify studies adopting a data-driven approach to investigate the association between a wide range of prescribed medications and dementia risk. We included 14 studies using administrative or medical records data for more than 130 million individuals and 1 million dementia cases. Despite inconsistencies in identifying specific drugs that may modify Alzheimer's or dementia risk, some themes emerged for drug classes with biological plausibility. Antimicrobials, vaccinations, and anti-inflammatories were associated with reduced risk, while diabetes drugs, vitamins and supplements, and antipsychotics were associated with increased risk. We found conflicting evidence for antihypertensives and antidepressants. Drug repurposing for use in dementia is an urgent priority. Our findings offer a basis for prioritizing candidates and exploring underlying mechanisms.
HIGHLIGHTS: ·We present a systematic review of studies reporting association between drugs prescribed for other conditions and risk of dementia including 139 million people and 1 million cases of dementia.·Our work supports some previously reported associations, for example, showing decreased risk of dementia with drugs to treat inflammatory disease and increased risk with antipsychotic treatment.·Antimicrobial treatment was perhaps more surprisingly associated with decreased risk, supportive of recent increased interest in this potential therapeutic avenue.·Our work should help prioritize drugs for entry into adaptive platform trials in Alzheimer's disease and will serve as a useful resource for those investigating drugs or classes of drugs and risk of dementia.}, }
@article {pmid39838927, year = {2025}, author = {Wang, Z and Sun, Y and Bai, Z and Li, M and Kong, D and Wu, G}, title = {Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {}, number = {}, pages = {}, doi = {10.1002/mds.30123}, pmid = {39838927}, issn = {1531-8257}, support = {SDQLQN2021-01//Qilu Young Scholars Program of Shandong University/ ; 202306352//Taishan Scholar Foundation of Shandong Province/ ; }, abstract = {BACKGROUND: Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study aimed to identify novel biomarkers and drug targets for these diseases through a comprehensive analysis that integrated genome-wide Mendelian randomization (MR) with genes associated with mitochondrial function.
METHODS: Using existing publicly available genome-wide association studies (GWAS) summary statistics and comprehensive data on 1136 mitochondria-related genes, we initially identified a subset of genes related to mitochondrial function that exhibited significant associations with NDDs. We then conducted colocalization and summary-data-based Mendelian randomization (SMR) analyses using expression quantitative trait loci (eQTL) to validate the causal role of these candidate genes. Additionally, we assessed the druggability of the encoded proteins to prioritize potential therapeutic targets for further exploration.
RESULTS: Genetically predicted levels of 10 genes were found to be significantly associated with the risk of NDDs. Elevated DMPK and LACTB2 levels were associated with increased Alzheimer's disease risk. Higher expression of NDUFAF2, BCKDK, and MALSU1, along with lower TTC19, raised Parkinson's disease risk. Higher ACLY levels were associated with both amyotrophic lateral sclerosis and multiple sclerosis (MS) risks, while decreased MCL1, TOP3A, and VWA8 levels raised MS risk. These genes primarily impact mitochondrial function and energy metabolism. Notably, several druggable protein targets identified are being explored for potential NDDs treatment.
CONCLUSIONS: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in NDDs. Additionally, this study identified candidate genes that could serve as potential pharmacological targets for the prevention and treatment of NDDs. © 2025 International Parkinson and Movement Disorder Society.}, }
@article {pmid39838674, year = {2025}, author = {Cheng, M and Gao, Y and Wu, Y and Zhang, L and Xu, B and Lu, X}, title = {Plasmalogens Activate AKT/mTOR Signaling to Attenuate Reactive Oxygen Species Production in Spinal Cord Injury.}, journal = {Current gene therapy}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115665232330349241225074627}, pmid = {39838674}, issn = {1875-5631}, abstract = {BACKGROUND: Plasmalogens, the primary phospholipids in the brain, possess intrinsic antioxidant properties and are crucial components of the myelin sheath surrounding neuronal axons. While their neuroprotective effects have been demonstrated in Alzheimer's disease, their potential benefits in spinal cord injury remain unexplored. This study investigates the reparative effects of plasmalogens on spinal cord injury and the underlying mechanisms.
METHODS: In vitro, we developed dorsal root ganglion (DRG) and RAW 264.7 cell models under high-reactive oxygen species (ROS) conditions to assess ROS levels, neuronal damage, and inflammatory microenvironment changes before and after plasmalogen application. In vivo, we used a complete mouse spinal cord transection model to evaluate changes in ROS levels, neuronal demyelination, and apoptosis following plasmalogen treatment. Additionally, we assessed sensory and motor function recovery and investigated the regulatory effects of plasmalogens on the AKT/mTOR signaling pathway.
RESULTS: In high-ROS cell models, plasmalogens protected DRG neurons (TUJ-1) from axonal damage and modulated the proinflammatory/anti-inflammatory balance in RAW 264.7 cells. In vivo, plasmalogens significantly reduced ROS levels, improved the immune microenvironment, decreased the proinflammatory (iNOS)/anti-inflammatory (ARG-1) ratio, lowered neuronal (TUJ-1) apoptosis (Caspase-3, BAX), and reduced axonal degeneration while promoting myelin (MBP) regeneration, indicating a neuroprotective effect. These findings are linked to the activation of the AKT/mTOR signaling pathway.
CONCLUSION: Plasmalogens reduce ROS levels and regulate inflammation-induced damage, contributing to neuroprotection. This study reveals that plasmalogens promote remyelination, reduce axonal degeneration and neuronal apoptosis, and-used here for the first time in spinal cord injury repair- may protect neurons by reducing ROS levels and activating the AKT/mTOR signaling pathway.}, }
@article {pmid39838656, year = {2025}, author = {Xie, D and Cai, Z and Mao, J and Qu, X and Cao, L and Zhou, J}, title = {High-prediction QSAR Modeling Study Based on the Efficacy of a Novel 6-hydroxybenzothiazole-2-carboxamide Targeted Monoamine Oxidase B in the Treatment of Neurodegenerative Diseases.}, journal = {Medicinal chemistry (Shariqah (United Arab Emirates))}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115734064364749250102024805}, pmid = {39838656}, issn = {1875-6638}, abstract = {BACKGROUND: Neurodegenerative diseases are a group of disorders characterized by progressive neuronal degeneration and death, of which Alzheimer's disease and Parkinson's disease are the most common. These diseases are closely associated with increased expression of monoamine oxidase B (MAO-B), an important enzyme that regulates neurotransmitter concentration, and its overactivity leads to oxidative stress and neurotoxicity, accelerating the progression of neurodegenerative diseases. Therefore, the development of effective MAO-B inhibitors is important for the treatment of neurodegenerative diseases.
OBJECTIVE: This study aims to improve the prediction of the efficacy of novel 6-hydroxybenzothiazole- 2-carboxamide compounds in inhibiting MAO-B by improving the quantitative constitutive effect relationship (QSAR) modeling and to provide a theoretical basis for the discovery of novel neuroprotective drugs.
METHODS: The study first optimized the structures of 36 compounds using the heuristic method (HM) in CODESSA software to construct linear QSAR models. Subsequently, key descriptors were screened by using the gene expression programming (GEP) technique to generate nonlinear QSAR models and validate them.
RESULTS: The R², F-value, and R²cv of the linear model were 0.5724, 10.3752, and 0.4557, respectively, whereas the nonlinear model constructed by the GEP algorithm showed higher prediction accuracies by achieving R² values of 0.89 and 0.82, and mean squared errors (MSE) of 0.0799 and 0.1215 for the training and test sets, respectively. In addition, molecular docking experiments confirmed that the novel compound 31 was tightly bound to the MAO-B active site with significant inhibitory activity.
CONCLUSION: In this study, we successfully improved the prediction ability of the efficacy of novel 6-hydroxybenzothiazole-2-carboxamide compounds to inhibit MAO-B by improving the QSAR model. This not only provides new drug candidates for the treatment of neurodegenerative diseases, but also provides important theoretical guidance for subsequent drug design and development, which can help accelerate the process of new drug discovery and reduce the disease burden of patients.}, }
@article {pmid39838483, year = {2025}, author = {Clemmensen, FK and Gramkow, MH and Simonsen, AH and Ashton, NJ and Huber, H and Blennow, K and Zetterberg, H and Waldemar, G and Hasselbalch, SG and Frederiksen, KS}, title = {Short-term variability of Alzheimer's disease plasma biomarkers in a mixed memory clinic cohort.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {26}, pmid = {39838483}, issn = {1758-9193}, mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; Female ; Male ; Aged ; *Amyloid beta-Peptides/blood ; *tau Proteins/blood ; Cohort Studies ; Middle Aged ; Peptide Fragments/blood ; Aged, 80 and over ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; }, abstract = {BACKGROUND: For clinical implementation of Alzheimer's disease (AD) blood-based biomarkers (BBMs), knowledge of short-term variability, is crucial to ensure safe and correct biomarker interpretation, i.e., to capture changes or treatment effects that lie beyond that of expected short-term variability and considered clinically relevant. In this study we investigated short-term intra- and inter-individual variability of AD biomarkers in the intended use population, memory clinic patients.
METHODS: In a consecutive sample of memory clinic patients (AD n = 27, non-AD n = 20), blood samples were collected on three separate days within a period of 36 days and analysed for plasma Aβ40, Aβ42, p-tau181, p-tau217, p-tau231, T-tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). We measured intra- and inter-individual variability and explored if the variability could be affected by confounding factors. Secondly, we established the minimum change required to detect a difference between two given blood samples that exceeds intra-individual variability and analytical variation (reference change value, RCV). Finally, we tested if classification accuracy varied across the three visits.
RESULTS: Intra-individual variability ranged from ~ 3% (Aβ42/40) to ~ 12% (T-tau). Inter-individual variability ranged from ~ 7% (Aβ40) to ~ 39% (NfL). Adjusting the models for time, eGFR, Hba1c, and BMI did not affect the variation. RCV was lowest for Aβ42/Aβ40 (- ~ 15%/ + ~ 17%) and highest in p-tau181 (- ~ 30/ + ~ 42%). No variation in classification accuracies was found across visits.
CONCLUSION: We found low intra-individual variability, robust to various factors, appropriate to capture individual changes in AD BBMs, while moderate inter-individual variability may give rise to caution in diagnostic contexts. High RCVs may pose challenges for AD BBMs with low fold changes and consequently, short-term variability is important to take into consideration when, e.g., estimating intervention effect and longitudinal changes of AD BBM levels.
TRIAL REGISTRATION: Clinicaltrials.gov (NCT05175664), date of registration 2021-12-01.}, }
@article {pmid39838434, year = {2025}, author = {Kimura, N and Sasaki, K and Masuda, T and Ataka, T and Matsumoto, M and Kitamura, M and Nakamura, Y and Matsubara, E}, title = {Machine learning models for dementia screening to classify brain amyloid positivity on positron emission tomography using blood markers and demographic characteristics: a retrospective observational study.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {25}, pmid = {39838434}, issn = {1758-9193}, mesh = {Humans ; Male ; Female ; Retrospective Studies ; Aged ; *Machine Learning ; *Positron-Emission Tomography/methods ; *Brain/diagnostic imaging/metabolism ; Biomarkers/blood ; Amyloid beta-Peptides/blood/metabolism ; Cognitive Dysfunction/blood/diagnostic imaging/diagnosis ; Aged, 80 and over ; Alzheimer Disease/blood/diagnostic imaging ; Dementia/blood/diagnostic imaging/diagnosis ; Middle Aged ; }, abstract = {BACKGROUND: Intracerebral amyloid β (Aβ) accumulation is considered the initial observable event in the pathological process of Alzheimer's disease (AD). Efficient screening for amyloid pathology is critical for identifying patients for early treatment. This study developed machine learning models to classify positron emission tomography (PET) Aβ-positivity in participants with preclinical and prodromal AD using data accessible to primary care physicians.
METHODS: This retrospective observational study assessed the classification performance of combinations of demographic characteristics, routine blood test results, and cognitive test scores to classify PET Aβ-positivity using machine learning. Participants with mild cognitive impairment (MCI) or normal cognitive function who visited Oita University Hospital or had participated in the USUKI study and met the study eligibility criteria were included. The primary endpoint was assessment of the classification performance of the presence or absence of intracerebral Aβ accumulation using five machine learning models (i.e., five combinations of variables), each constructed with three classification algorithms, resulting in a total of 15 patterns. L2-regularized logistic regression, and kernel Support Vector Machine (SVM) and Elastic Net algorithms were used to construct the classification models using 34 pre-selected variables (12 demographic characteristics, 11 blood test results, 11 cognitive test results).
RESULTS: Data from 262 records (260 unique participants) were analyzed. The mean (standard deviation [SD]) participant age was 73.8 (7.8) years. Using L2-regularized logistic regression, the mean receiver operating characteristic (ROC) area under the curve (AUC) (SD) in Model 0 (basic demographic characteristics) was 0.67 (0.01). Classification performance was similar in Model 1 (basic demographic characteristics and Mini Mental State Examination [MMSE] subscores) and Model 2 (demographic characteristics and blood test results) with a cross-validated mean ROC AUC (SD) of 0.70 (0.01) for both. Model 3 (demographic characteristics, blood test results, MMSE subscores) and Model 4 (Model 3 and ApoE4 phenotype) showed improved performance with a mean ROC AUC (SD) of 0.73 (0.01) and 0.76 (0.01), respectively. In models using blood test results, thyroid-stimulating hormone and mean corpuscular volume tended to be the largest contributors to classification. Classification performances were similar using the SVM and Elastic Net algorithms.
CONCLUSIONS: The machine learning models used in this study were useful for classifying PET Aβ-positivity using data from routine physician visits.
TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000051776, registered on 31/08/2023).}, }
@article {pmid39838228, year = {2025}, author = {Hou, Q and Li, Y}, title = {Dual inhibition of AChE and MAO-B in Alzheimer's disease: machine learning approaches and model interpretations.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {39838228}, issn = {1573-501X}, support = {2021YFA1500300//National Key Research and Development Program of China/ ; 22275027//National Natural Science Foundation of China/ ; }, abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases. Given the multifactorial pathophysiology of AD, monotargeted agents can only alleviate symptoms but not cure AD. Acetylcholinesterase (AChE) and Monoamine oxidase B (MAO-B) are two key targets in the treatment of AD, molecules that inhibiting both targets are considered promising avenue to develop more effective AD therapies. In the present work, a dual inhibition dataset containing 449 molecules was established, based on which five machine learning algorithms (KNN, SVM, RF, GBDT, and LGBM) four fingerprints (MACCS, ECFP4, RDKitFP, PubChemFP) and DRAGON descriptors were combined to develop 25 classification models in which GBDT paired with ECFP4 and RF paired with PubchemFP achieved the same best performance across multiple metrics (Accuracy = 0.92, F1 Score = 0.94, MCC = 0.81). Moreover, based on the curated bioactivity datasets of AChE and MAO-B, regression models were developed to predict pIC50 values. For the AChE inhibition task, GBDT demonstrated the best performance (RMSE = 0.683, MAE = 0.500, R[2] = 0.721). The SVM algorithm emerged as the most effective for MAO-B inhibition (RMSE = 0.668, MAE = 0.507, R[2] = 0.675). The SHAP algorithm was used to interpret the optimal models, identifying and analyzing the key substructures and properties for both dual-target and single-target inhibitors. Moreover, molecules docking process provided potential mechanism and Structure-Activity Relationships (SAR) of dual-target inhibition further.}, }
@article {pmid39837459, year = {2025}, author = {Yang, MX and Wang, ZR and Zhang, YL and Zhang, ZN and Li, YL and Wang, R and Su, Q and Guo, JH}, title = {Albumin antagonizes Alzheimer's disease-related Tau pathology and enhances cognitive performance by inhibiting aberrant Tau aggregation.}, journal = {Experimental neurology}, volume = {386}, number = {}, pages = {115155}, doi = {10.1016/j.expneurol.2025.115155}, pmid = {39837459}, issn = {1090-2430}, mesh = {Animals ; *tau Proteins/metabolism ; *Alzheimer Disease/pathology/metabolism/drug therapy ; Mice ; *Mice, Transgenic ; Humans ; Male ; Female ; Aged ; Cognition/drug effects/physiology ; Protein Aggregation, Pathological/metabolism ; Albumins/metabolism ; Phosphorylation/drug effects ; Aged, 80 and over ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive impairment, for which effective treatments remain lacking. Albumin (ALB) is an essential carrier protein found in various body fluids, playing crucial roles in anti-inflammatory processes, antioxidation, and signal transduction. Recent research indicates that ALB may play a significant role in the development and progression of AD, though its specific function is not yet fully understood. In this study, we observed a link between serum ALB levels and cognitive performance in the elderly. Administration of ALB intranasally was shown to enhance learning and memory in MAPT/P301S transgenic mice, markedly decreasing hyperphosphorylation of Tau protein and reducing neuronal apoptosis. In a neuronal cell model overexpressing Tau, ALB administration in vitro attenuated Tau-induced toxicity and reduced the production of phosphorylated Tau. Additionally, co-incubation of Tau with ALB significantly reduced the formation of neurofibrillary tangles. These results suggest that ALB improves AD-related cognitive function by preventing the pathological aggregation of Tau and reducing its abnormal phosphorylation. Furthermore, ALB's neuroprotective effect helps prevent neuronal apoptosis in the cortex and hippocampus, providing potential targets for AD prevention and treatment.}, }
@article {pmid39835706, year = {2025}, author = {Cacabelos, R and Martínez-Iglesias, O and Cacabelos, N and Carrera, J and Rodríguez, D and Naidoo, V}, title = {The impact of genetic variability on Alzheimer's therapies: obstacles for pharmacogenetic progress.}, journal = {Expert opinion on drug metabolism & toxicology}, volume = {}, number = {}, pages = {1-28}, doi = {10.1080/17425255.2024.2433626}, pmid = {39835706}, issn = {1744-7607}, abstract = {INTRODUCTION: Genetic load influences the therapeutic response to conventional drugs in Alzheimer's disease (AD). Pharmacogenetics (PGx) is the best option to reduce drug-drug interactions and adverse drug reactions in patients undergoing polypharmacy regimens. However, there are important limitations that make it difficult to incorporate pharmacogenetics into routine clinical practice.
AREAS COVERED: This article analyzes the pharmacogenetic apparatus made up of pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes responsible for the efficacy and safety of pharmacological treatment, the impact of genetic load on the outcome of multifactorial treatments, and practical aspects for the effective use of PGx.
EXPERT OPINION: Over 120 genes are closely associated with AD. There is an accumulation of cerebrovascular (CVn) and neurodegenerative (ADn) genes in AD. APOE-4 carriers accumulate more deleterious genetic load related to other CVn and ADn genes, develop the disease earlier, and are at a biological disadvantage compared to APOE-4 non-carriers. CYP2D6-PMs and APOE-4 carriers are the worst responders to anti-dementia drugs. Some limitations hinder the implementation of PGx in clinical practice, including lack of pharmacogenetic information for many drugs, low number of genes in PGx screening protocols, and educational deficiencies in the medical community regarding PGx and genomic medicine.}, }
@article {pmid39835563, year = {2025}, author = {Kushwaha, SK and Ashawat, MS and Arora, R and Baldi, A}, title = {Auranofin-loaded PLGA Nanoparticles for Neuroprotection against Aluminium-induced Alzheimer's Disease.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128336703241202182209}, pmid = {39835563}, issn = {1873-4286}, abstract = {AIM: The aim of the current study was to explore nano-formulation for effective neuroprotection by auranofin.
BACKGROUND: Currently, the treatment options for various CNS disorders, particularly neurodegenerative disorders, are greatly constrained. A significant obstacle in this pursuit is the blood-brain barrier, a shielding covering that hinders the route of numerous biochemical treatments into the brain. To overcome this problem, nanoformulation- based approaches are gaining interest, increasing the compound's BBB penetrability.
OBJECTIVE: The objective of this study was to evaluate whether nanoparticles fabricated from poly(lactic-co-glycolic acid) encapsulated with auranofin could oppose aluminium chloride-induced Alzheimer's disease.
METHOD: Auranofin-encapsulated PLGA nanoparticles were prepared, and their particle size, Entrapment Efficiency (EE), distribution of particles, morphological surface charge, and structural characteristics were characterized. During the in vivo study, rats were orally administered AlCl3 at 100 mg/kg for 21 days. Meanwhile, auranofin and auranofin nanoparticles were orally administered at doses of 5 and 10 mg/kg and 2.5 and 5 mg/kg, respectively, within 2 weeks. After the course therapy, the rats were decapitated, and the hippocampus was collected for the estimated biochemical and neuroinflammatory markers.
RESULTS: The auranofin nanoparticles were characterized, revealing % entrapment efficiency (98%) and % loading dose (76%). The nanoparticles exhibited a morphological surface charge of 27.5 ± 5.10 mV, a polydispersity index of 0.438 ± 0.12, and a mean particle size of 101.5 ± 10.3 nm. In the in vivo study, administering a gold compound (auranofin) and formulation (auranofin nanoparticles) resulted in a significant improvement in cognitive deficits, changes in biochemical parameters, and markers of neuroinflammation triggered with aluminium chloride.
CONCLUSION: The results have suggested that auranofin nanoparticles demonstrate abilities to protect neurons compared to auranofin alone. The noticed therapeutic benefits of the auranofin-encapsulated PLGA nanoparticles can be attributed to modulation in particle size with antioxidative and anti-inflammatory impacts of auranofin. Consequently, the outcome of the research has revealed that gold compound nanoparticles hold the potential to be a promising option for altering the therapeutic course of Alzheimer's disease.}, }
@article {pmid39834810, year = {2024}, author = {Yang, C and Zhao, E and Zhang, H and Duan, L and Han, X and Ding, H and Cheng, Y and Wang, D and Lei, X and Diwu, Y}, title = {Xixin Decoction's novel mechanism for alleviating Alzheimer's disease cognitive dysfunction by modulating amyloid-β transport across the blood-brain barrier to reduce neuroinflammation.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1508726}, pmid = {39834810}, issn = {1663-9812}, abstract = {PURPOSE: Xixin Decoction (XXD) is a classical formula that has been used to effectively treat dementia for over 300 years. Modern clinical studies have demonstrated its significant therapeutic effects in treating Alzheimer's disease (AD) without notable adverse reactions. Nevertheless, the specific mechanisms underlying its efficacy remain to be elucidated. This investigation sought to elucidate XXD's impact on various aspects of AD pathology, including blood-brain barrier (BBB) impairment, neuroinflammatory processes, and amyloid-β (Aβ) deposition, as well as the molecular pathways involved in these effects.
METHODS: In vitro experiments were conducted using hCMEC/D3 and HBVP cell coculture to establish an in vitro blood-brain barrier (BBB) model. BBB damage was induced in this model by 24-h exposure to 1 μg/mL lipopolysaccharide (LPS). After 24, 48, and 72 h of treatment with 10% XXD-medicated serum, the effects of XXD were assessed through Western blotting, RT-PCR, and immunofluorescence techniques. In vivo, SAMP8 mice were administered various doses of XXD via gavage for 8 weeks, including high-dose XXD group (H-XXD) at 5.07 g kg[-1]·d[-1], medium-dose XXD group (M-XXD) at 2.535 g kg[-1]·d[-1], and low-dose XXD group (L-XXD) at 1.2675 g kg[-1]·d[-1]. Cognitive function was subsequently evaluated using the Morris water maze test. BBB integrity was evaluated using Evans blue staining, and protein expression levels were analyzed via ELISA, Western blotting, and immunofluorescence.
RESULTS: In vitro experiments revealed that XXD-containing serum, when cultured for 24, 48, and 72 h, could upregulate the expression of P-gp mRNA and protein, downregulate CB1 protein expression, and upregulate CB2 and Mfsd2a protein expression. In vivo studies demonstrated that XXD improved spatial learning and memory abilities in SAMP8 mice, reduced the amount of Evans blue extravasation in brain tissues, modulated the BBB-associated P-gp/ECS axis, RAGE/LRP1 receptor system, as well as MRP2 and Mfsd2a proteins, and decreased the accumulation of Aβ in the brains of SAMP8 mice. Additionally, XXD upregulated the expression of TREM2, downregulated IBA1, TLR1, TLR2, and CMPK2 expression, and reduced the levels of pro-inflammatory factors NLRP3, NF-κB p65, COX-2, TNF-α, and IL-1β in the hippocampal tissues.
CONCLUSION: XXD may exert its effects by regulating the P-gp/ECS axis, the RAGE/LRP1 receptor system, and the expression of MRP2 and Mfsd2a proteins, thereby modulating the transport function of the BBB to expedite the clearance of Aβ, reduce cerebral Aβ accumulation, and consequently inhibit the activation of microglia induced by Aβ aggregation. This process may suppress the activation of the CMPK2/NLRP3 and TLRs/NF-κB pathways, diminish the production of inflammatory cytokines and chemokines, alleviate neuroinflammation associated with microglia in the brain of AD, and ultimately improve AD pathology.}, }
@article {pmid39834440, year = {2025}, author = {Alkhatabi, HA and Pushparaj, PN}, title = {Untangling the complex mechanisms associated with Alzheimer's disease in elderly patients using high-throughput RNA sequencing data and next-generation knowledge discovery methods: Focus on potential gene signatures and drugs for dementia.}, journal = {Heliyon}, volume = {11}, number = {1}, pages = {e41266}, pmid = {39834440}, issn = {2405-8440}, abstract = {OBJECTIVES: Alzheimer's disease (AD) is a complex neurodegenerative disorder that primarily affects elderly individuals. This study aimed to elucidate the intricate mechanisms underlying AD in elderly patients compared with healthy aged individuals using high-throughput RNA sequencing (RNA-seq) data and next-generation knowledge discovery methods (NGKD), with a focus on identifying potential therapeutic agents.
METHODS: High-throughput RNA-seq data were obtained from the Gene Expression Omnibus (GEO) database (accession number: GSE104704). These data were derived from healthy and diseased human brains (eight young healthy brains [young], 10 aged healthy brains [Old], and 12 aged diseased brains [AD]). We used NGKD tools such as GEO RNA-seq Experiments Interactive Navigator (GREIN) to obtain differentially expressed genes (DEGs) by comparing the AD versus Old RNA-seq data and further filtered and normalized to obtain differentially regulated Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome and Panther pathways using ExpressAnalyst tool. Besides, WebGestalt was used to identify differentially regulated Gene Ontologies (GO) and the pre-ranked Gene Set Enrichment Analysis (GSEA) was performed using GSEA software. The X2K web tool was used to infer upstream regulator networks and X2K Appyter tool for obtaining transcription factors (TFs) and kinase network information. LFW1000 and L1000CDS[2] tools were used to identify specific drugs that reverse AD-associated gene signatures in elderly patients.
RESULTS: Our study revealed significant downregulation of pathways related to neuroactive receptor-ligand interaction, synaptic vesicle cycle, and neuronal system in elderly individuals with AD. GO analysis showed negative enrichment of functions related to cognition, potassium ion transport, receptor-ligand activity, SNARE binding, and primary lysosomes. The transcription factors SUZ12 and REST, along with increased MAPK signaling, were identified as key regulators of downregulated genes. Several drugs and natural products, including dihydroergocristine, mepacrine, gedunin, amlodipine, and disulfiram have been identified as potential therapeutic agents for reversing AD-associated gene signatures.
CONCLUSIONS: This comprehensive analysis of AD in elderly individuals using RNA-seq data and NGKD tools revealed multiple differentially regulated pathways, gene signatures, and potential drugs for dementia treatment. These findings highlight the complex molecular mechanisms underlying AD and provide insights into potential therapeutic strategies. Further research is needed to validate these findings and to develop personalized treatment approaches for AD in elderly patients.}, }
@article {pmid39834035, year = {2025}, author = {Asken, BM and Brett, BL and Barr, WB and Banks, S and Wethe, JV and Dams-O'Connor, K and Stern, RA and Alosco, ML}, title = {Chronic traumatic encephalopathy: State-of-the-science update and narrative review.}, journal = {The Clinical neuropsychologist}, volume = {}, number = {}, pages = {1-25}, doi = {10.1080/13854046.2025.2454047}, pmid = {39834035}, issn = {1744-4144}, support = {R01 AG061028/AG/NIA NIH HHS/United States ; RF1 NS122854/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: The long-recognized association of brain injury with increased risk of dementia has undergone significant refinement and more detailed study in recent decades. Chronic traumatic encephalopathy (CTE) is a specific neurodegenerative tauopathy related to prior exposure to repetitive head impacts (RHI). We aim to contextualize CTE within a historical perspective and among emerging data which highlights the scientific and conceptual evolution of CTE-related research in parallel with the broader field of neurodegenerative disease and dementia.
METHODS: We provide a narrative state-of-the-science update on CTE neuropathology, clinical manifestations, biomarkers, different types and patterns of head impact exposure relevant for CTE, and the complicated influence of neurodegenerative co-pathology on symptoms.
CONCLUSIONS: Now almost 20 years since the initial case report of CTE in a former American football player, the field of CTE continues evolving with increasing clarity but also several ongoing controversies. Our understanding of CTE neuropathology outpaces that of disease-specific clinical correlates or the development of in-vivo biomarkers. Diagnostic criteria for symptoms attributable to CTE are still being validated, but leveraging increasingly available biomarkers for other conditions like Alzheimer's disease may be helpful for informing the CTE differential diagnosis. As diagnostic refinement efforts advance, clinicians should provide care and/or referrals to providers best suited to treat an individual patient's clinical symptoms, many of which have evidence-based behavioral treatment options that are etiologically agnostic. Several ongoing research initiatives and the gradual accrual of gold standard clinico-pathological data will pay dividends for advancing the many existing gaps in the field of CTE.}, }
@article {pmid39833961, year = {2025}, author = {Lin, Y and Luo, X and Wang, F and Cai, H and Lin, Y and Kang, D and Fang, W}, title = {Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice.}, journal = {Biology of sex differences}, volume = {16}, number = {1}, pages = {3}, pmid = {39833961}, issn = {2042-6410}, support = {2023J05136//Natural Science Foundation of Fujian Province/ ; 2022QNA036//Fujian Provincial Health Technology Project/ ; 2023YSJYX-YL-1//Neurosurgery Department, Fujian Neurological Disease Medical Center construction project/ ; }, mesh = {Animals ; *Metformin/pharmacology/therapeutic use ; Female ; Male ; *Anxiety/drug therapy ; *Sex Characteristics ; *Cognition/drug effects ; *Mice, Transgenic ; Hypoglycemic Agents/pharmacology/therapeutic use ; Apolipoprotein E4/genetics ; Aging/drug effects ; Mice ; Phenotype ; Cognitive Dysfunction/drug therapy ; Depression/drug therapy ; Mice, Inbred C57BL ; Blood Glucose ; Apolipoprotein E3/genetics ; }, abstract = {BACKGROUND: Apolipoprotein E4 (ApoE4) is associated with an increased risk of Alzheimer's disease (AD), depression, and anxiety, which were reported to improve after the administration of metformin. However, sex influence on the effect of ApoE4 and metformin on cognition and mental health is poorly understood.
METHODS: ApoE3-TR and apoE4-TR mice of both sexes were randomly assigned to the normal saline and metformin groups from 13 months to 18 months of age. Behavior tests (MWM, EPM, OFT, TST, FST) were conducted to assess cognition, anxiety, and depression-like behaviors. The mice's blood glucose was also recorded.
RESULTS: Male aged apoE4-TR mice are more vulnerable to cognitive decline than females. Metformin improves the spatial memory of female, but not male apoE3-TR mice and female apoE4-TR mice while aggravating the cognitive impairment of male apoE4-TR mice. The anxiety-like phenotypes in male apoE4-TR mice are more severe than in male apoE3-TR mice, while metformin ameliorates the anxiety-like behaviors in the male apoE4-TR mice but not in male apoE3-TR mice. In addition, metformin alleviates depression-like behaviors in male and female apoE4-TR mice. The hypoglycemic effect of metformin is insignificant in both male and female apoE4-TR mice.
CONCLUSIONS: Male sex exacerbates APOE4-related cognitive impairment and anxiety in aged mice and is insensitive to the cognition improvement effect of metformin in the aged apoE3 mice. Male sex with APOE4 may experience more severe cognitive impairment after treatment with metformin while sensitive to the anti-anxiety effects of metformin. These findings identify sex-specific effects on ApoE4-based dementia, anxiety prevention, and therapy, emphasizing the importance of further sex dimension analyses in vivo and clinical studies.}, }
@article {pmid39833898, year = {2025}, author = {Wang, Z and Wang, C and Yuan, B and Liu, L and Zhang, H and Zhu, M and Chai, H and Peng, J and Huang, Y and Zhou, S and Liu, J and Wu, L and Wang, W}, title = {Akkermansia muciniphila and its metabolite propionic acid maintains neuronal mitochondrial division and autophagy homeostasis during Alzheimer's disease pathologic process via GPR41 and GPR43.}, journal = {Microbiome}, volume = {13}, number = {1}, pages = {16}, pmid = {39833898}, issn = {2049-2618}, mesh = {*Propionates/metabolism/pharmacology ; Animals ; *Alzheimer Disease/metabolism/microbiology ; Mice ; *Receptors, G-Protein-Coupled/metabolism ; Humans ; *Gastrointestinal Microbiome ; *Homeostasis ; *Akkermansia ; *Mitochondria/metabolism ; *Autophagy ; *Neurons/metabolism ; Disease Models, Animal ; Male ; Female ; Fatty Acids, Volatile/metabolism ; Aged ; Mitochondrial Dynamics ; Feces/microbiology ; Mitophagy ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disease (ND). In recent years, multiple clinical and animal studies have shown that mitochondrial dysfunction may be involved in the pathogenesis of AD. In addition, short-chain fatty acids (SCFA) produced by intestinal microbiota metabolism have been considered to be important factors affecting central nervous system (CNS) homeostasis. Among the main mediators of host-microbe interactions, volatile fatty acids play a crucial role. Nevertheless, the influence and pathways of microorganisms and their metabolites on Alzheimer's disease (AD) remain uncertain.
RESULTS: In this study, we present distinctions in blood and fecal SCFA levels and microbiota composition between healthy individuals and those diagnosed with AD. We found that AD patients showed a decrease in the abundance of Akkermansia muciniphila and a decrease in propionic acid both in fecal and in blood. In order to further reveal the effects and the mechanisms of propionic acid on AD prevention, we systematically explored the effects of propionic acid administration on AD model mice and cultured hippocampal neuronal cells. Results showed that oral propionate supplementation ameliorated cognitive impairment in AD mice. Propionate downregulated mitochondrial fission protein (DRP1) via G-protein coupled receptor 41 (GPR41) and enhanced PINK1/PARKIN-mediated mitophagy via G-protein coupled receptor 43 (GPR43) in AD pathophysiology which contribute to maintaining mitochondrial homeostasis both in vivo and in vitro. Administered A. muciniphila to AD mice before disease onset showed improved cognition, mitochondrial division and mitophagy in AD mice.
CONCLUSIONS: Taken together, our results demonstrate that A. muciniphila and its metabolite propionate protect against AD-like pathological events in AD mouse models by targeting mitochondrial homeostasis, making them promising therapeutic candidates for the prevention and treatment of AD. Video Abstract.}, }
@article {pmid39832406, year = {2025}, author = {Lee, S and Hahn, C and Seong, E and Choi, HS}, title = {Reactive EEG Biomarkers for Diagnosis and Prognosis of Alzheimer's Disease and Mild Cognitive Impairment.}, journal = {Biosensors & bioelectronics}, volume = {273}, number = {}, pages = {117181}, pmid = {39832406}, issn = {1873-4235}, support = {R01 EB022230/EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Aged ; *Electroencephalography ; *Biomarkers ; Female ; Male ; Prognosis ; Aged, 80 and over ; Biosensing Techniques/methods ; }, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative condition characterized by progressive cognitive decline with currently no effective treatment available. One of the most critical areas in AD research is the identification of reliable biomarkers, which are essential for accurate diagnosis, prognostic assessment, and the development of targeted therapies. In this study, we introduce two novel reactive EEG (rEEG) biomarkers aimed at enhancing the diagnosis of AD and mild cognitive impairment (MCI). These biomarkers, previously unexplored in the literature, offer new insights into differentiating between various cognitive states. The first biomarker demonstrates a significant ability to distinguish between AD patients and normal controls (NC), while also effectively distinguishing MCI patients from NC. The second biomarker is designed to identify a subset of AD patients exhibiting hyperconductivity or hyperactivity, characterized by distinctive neural electrical patterns. A cohort of 90 elderly participants (mean age 76.63 ± 6.08 years) was recruited, including 30 AD patients, 30 individuals with MCI, and 30 NC subjects. Psychiatric diagnoses of participants were made by qualified professionals at Daejeon St. Mary's Hospital, The Catholic University of Korea, utilizing comprehensive neuropsychological assessments. Notably, the rEEG biomarkers achieved accuracies of 95%, 95%, and 98% in distinguishing between AD and NC, AD and MCI, and MCI and NC groups, respectively. These results underscore the potential of rEEG as a highly accurate and reliable diagnostic tool for cognitive impairments, including AD and MCI.}, }
@article {pmid39832109, year = {2025}, author = {Pelczarski, M and Wolaniuk, S and Zaborska, M and Sadowski, J and Sztangreciak-Lehun, A and Bułdak, RJ}, title = {The role of α-tocopherol in the prevention and treatment of Alzheimer's disease.}, journal = {Molecular and cellular biochemistry}, volume = {}, number = {}, pages = {}, pmid = {39832109}, issn = {1573-4919}, abstract = {Scientific reports from various areas of the world indicate the potential role of tocopherols (vitamin E) in particular α-tocopherol in the prevention and therapy of Alzheimer's disease. The current phenomenon is related to the growing global awareness of eating habits and is also determined by the need to develop the prevention, management and therapy of Alzheimer's disease. This article is a review of current research on the action of the active form of vitamin E-α-tocopherol and its impact on the development and course of Alzheimer's disease. Additionally, to contrast this information, selected primary research on this topic was included. The aim of this article is to analyze and summarize the available scientific information on the effects of the active form of vitamin E, α-tocopherol, on the development and course of Alzheimer's disease. In the structure of the review, particular attention was paid to the analysis of the pathophysiological processes of the disease and the biochemical features of the action of α-tocopherol. To discuss the relationship between the effect of α-tocopherol and the occurrence of Alzheimer's disease, a literature review was conducted using the following databases: PubMed, Google Scholar, and Elsevier. During the search process, the following keywords were used: "tocopherols", "vitamin E", "α-tocopherol", "Alzheimer's disease" in various combinations. The process was conducted in accordance with the adopted search strategy taking into account the inclusion and exclusion criteria. Alzheimer's disease (AD) is the most common, irreversible neurodegenerative disease, so many scientists are actively looking for substances and/or strategies to prevent its development and to slow down its course in patients. Alpha-tocopherols (ATF) are a factor that inhibits the pathophysiological processes associated with the development of AD by reducing the formation of atherogenic amyloid B (AB). Additionally, this type of tocopherols has antioxidant and anti-inflammatory properties and has a positive effect on the metabolic functioning of mitochondria. It has been shown that a higher intake of α-tocopherol (ATF) was associated with a reduced risk of developing dementia and the occurrence of mild types of cognitive impairment (MCI). Various sources indicate an insufficient supply of ATF in the diet. ATF supplementation may potentially help to slow down the course of Alzheimer's disease, which is why this substance may be popularized in the treatment of this disease in the future. However, there is a need for further research on this issue.}, }
@article {pmid39832031, year = {2025}, author = {Padti, AC and Bhavi, SM and Thokchom, B and Singh, SR and Bhat, SS and Harini, BP and Sillanpää, M and Yarajarla, RB}, title = {Nanoparticle Interactions with the Blood Brain Barrier: Insights from Drosophila and Implications for Human Astrocyte Targeted Therapies.}, journal = {Neurochemical research}, volume = {50}, number = {1}, pages = {80}, pmid = {39832031}, issn = {1573-6903}, mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Nanoparticles ; *Astrocytes/metabolism ; *Drosophila ; Drug Delivery Systems/methods ; Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {This review explores the intricate connections between Drosophila models and the human blood-brain barrier (BBB) with nanoparticle-based approaches for neurological treatment. Drosophila serves as a powerful model organism due to its evolutionary conservation of key biological processes, particularly in the context of the BBB, which is formed by glial cells that share structural and functional similarities with mammalian endothelial cells. Recent advancements in nanoparticle technology have highlighted their potential for effective drug delivery across the BBB, utilizing mechanisms such as passive diffusion, receptor-mediated transcytosis, and carrier-mediated transport. The ability to engineer nanoparticles with specific physicochemical properties-such as size, surface charge, and functionalization-enhances their targeting capabilities, particularly towards astrocytes, which play a crucial role in maintaining BBB integrity and responding to neuroinflammation. Insights gained from Drosophila studies have informed the design of personalized nanomedicine strategies aimed at treating neurodegenerative diseases, including Alzheimer's, Parkinson's disease etc. As research progresses, the integration of findings from Drosophila models with emerging humanized BBB systems will pave the way for innovative therapeutic approaches that improve drug delivery and patient outcomes in neurological disorders.}, }
@article {pmid39831743, year = {2025}, author = {Maupin, EA and Adams, KL}, title = {Cellular Senescence in Glial Cells: Implications for Multiple Sclerosis.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16301}, pmid = {39831743}, issn = {1471-4159}, support = {TA-2305-41311//National Multiple Sclerosis Society/ ; }, mesh = {Humans ; *Cellular Senescence/physiology ; *Multiple Sclerosis/pathology/metabolism ; *Neuroglia/pathology/metabolism ; Animals ; }, abstract = {Aging is the most common risk factor for Multiple Sclerosis (MS) disease progression. Cellular senescence, the irreversible state of cell cycle arrest, is the main driver of aging and has been found to accumulate prematurely in neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Cellular senescence in the central nervous system of MS patients has recently gained attention, with several studies providing evidence that demyelination induces cellular senescence, with common hallmarks of p16INK4A and p21 expression, oxidative stress, and senescence-associated secreted factors. Here we discuss the current evidence of cellular senescence in animal models of MS and different glial populations in the central nervous system, highlighting the major gaps in the field that still remain. As premature senescence in MS may exacerbate demyelination and inflammation, resulting in inhibition of myelin repair, it is critical to increase understanding of cellular senescence in vivo, the functional effects of senescence on glial cells, and the impact of removing senescent cells on remyelination and MS. This emerging field holds promise for opening new avenues of treatment for MS patients.}, }
@article {pmid39831085, year = {2024}, author = {Kollarik, S and Bimbiryte, D and Sethi, A and Dias, I and Moreira, CG and Noain, D}, title = {Pharmacological enhancement of slow-wave activity at an early disease stage improves cognition and reduces amyloid pathology in a mouse model of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1519225}, pmid = {39831085}, issn = {1663-4365}, abstract = {INTRODUCTION: Improving sleep in murine Alzheimer's disease (AD) is associated with reduced brain amyloidosis. However, the window of opportunity for successful sleep-targeted interventions, regarding the reduction in pathological hallmarks and related cognitive performance, remains poorly characterized.
METHODS: Here, we enhanced slow-wave activity (SWA) during sleep via sodium oxybate (SO) oral administration for 2 weeks at early (6 months old) or moderately late (11 months old) disease stages in Tg2576 mice and evaluated resulting neuropathology and behavioral performance.
RESULTS: We observed that the cognitive performance of 6-month-old Tg2576 mice significantly improved upon SO treatment, whereas no change was observed in 11-month-old mice. Histochemical assessment of amyloid plaques demonstrated that SO-treated 11-month-old Tg2576 mice had significantly less plaque burden than placebo-treated ones, whereas ELISA of insoluble protein fractions from brains of 6-month-old Tg2576 mice indicated lower Aβ-42/Aβ-40 ratio in SO-treated group vs. placebo-treated controls.
DISCUSSION: Altogether, our results suggest that SWA-dependent reduction in brain amyloidosis leads to alleviated behavioral impairment in Tg2576 mice only if administered early in the disease course, potentially highlighting the key importance of early sleep-based interventions in clinical cohorts.}, }
@article {pmid39831016, year = {2025}, author = {Liao, H and Liao, S and Gao, YJ and Wang, X and Guo, LH and Zheng, S and Yang, W and Dai, YN}, title = {Near-infrared brain functional characteristics of mild cognitive impairment with sleep disorders.}, journal = {World journal of psychiatry}, volume = {15}, number = {1}, pages = {97945}, pmid = {39831016}, issn = {2220-3206}, abstract = {BACKGROUND: Mild cognitive impairment (MCI) has a high risk of progression to Alzheimer's disease. The disease is often accompanied by sleep disorders, and whether sleep disorders have an effect on brain function in patients with MCI is unclear.
AIM: To explore the near-infrared brain function characteristics of MCI with sleep disorders.
METHODS: A total of 120 patients with MCI (MCI group) and 50 healthy subjects (control group) were selected. All subjects underwent the functional near-infrared spectroscopy test. Collect baseline data, Mini-Mental State Examination, Montreal Cognitive Assessment scale, fatigue severity scale (FSS) score, sleep parameter, and oxyhemoglobin (Oxy-Hb) concentration and peak time of functional near-infrared spectroscopy test during the task period. The relationship between Oxy-Hb concentration and related indexes was analyzed by Pearson or Spearmen correlation.
RESULTS: Compared with the control group, the FSS score of the MCI group was higher (t = 11.310), and the scores of Pittsburgh sleep quality index, sleep time, sleep efficiency, nocturnal sleep disturbance, and daytime dysfunction were higher (Z = -10.518, -10.368, -9.035, -10.661, -10.088). Subjective sleep quality and total sleep time scores were lower (Z = -11.592, -9.924). The sleep efficiency of the MCI group was lower, and the awakening frequency, rem sleep latency period, total sleep time, and oxygen desaturation index were higher (t = 5.969, 5.829, 2.887, 3.003, 5.937). The Oxy-Hb concentration at T0, T1, and T2 in the MCI group was lower (t = 14.940, 11.280, 5.721), and the peak time was higher (t = 18.800, 13.350, 9.827). In MCI patients, the concentration of Oxy-Hb during T0 was negatively correlated with the scores of Pittsburgh sleep quality index, sleep time, total sleep time, and sleep efficiency (r = -0.611, -0.388, -0.563, -0.356). It was positively correlated with sleep efficiency and total sleep time (r = 0.754, 0.650), and negatively correlated with oxygen desaturation index (r = -0.561) and FSS score (r = -0.526). All comparisons were P < 0.05.
CONCLUSION: Patients with MCI and sleep disorders have lower near-infrared brain function than normal people, which is related to sleep quality. Clinically, a comprehensive assessment of the near-infrared brain function of patients should be carried out to guide targeted treatment and improve curative effect.}, }
@article {pmid39830657, year = {2024}, author = {Nikray, N and Abharian, N and Jafari Ashtiani, S and Kobarfard, F and Faizi, M}, title = {Comparative Evaluation of Aminoguanidine, Semicarbazide and Thiosemicarbazide Treatment for Methylglyoxal-Induced Neurological Toxicity in Experimental Models.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {23}, number = {1}, pages = {e153322}, pmid = {39830657}, issn = {1726-6890}, abstract = {BACKGROUND: Advanced glycation end products (AGEs) are complex compounds that play a critical role in neurological disorders, including the pathogenesis of Alzheimer's disease. Methylglyoxal (MG) is recognized as the primary precursor of AGEs. Methylglyoxal is produced endogenously and also introduced through dietary exposures.
OBJECTIVES: This study aimed to investigate and compare the effects of aminoguanidine (AG), semicarbazide (SC), and thiosemicarbazide (TSC) on MG-induced neurological toxicity in rats.
METHODS: Male Wistar rats were exposed orally to MG, MG + AG, MG + SC, and MG + TSC for 70 days. Neurobehavioral, biochemical, and histopathological changes were evaluated.
RESULTS: The findings indicated that oral administration of MG for 70 days resulted in memory impairment and increased anxiety in neurobehavioral tests. Additionally, MG elevated protein carbonylation in brain tissues. Semicarbazide was found to prevent MG-induced memory problems, while both SC and AG reduced carbonyl content in brain tissues. Aminoguanidine and TSC were effective in alleviating anxiety induced by MG exposure. Histopathological analysis revealed that MG caused cell damage and neuronal necrosis in the hippocampus, particularly in the cornu ammonis 1 and 3 (CA1 and CA3) and AG, SC, and TSC improved neuronal survival specifically in the CA1 and DG areas.
CONCLUSIONS: The data suggest that SC, AG, and TSC may offer neuroprotective effects against MG-induced neurobehavioral toxicity. Further studies are required to explore the mechanisms of action of these compounds.}, }
@article {pmid39830554, year = {2024}, author = {Medel Sánchez, A and Ortiz Hernández, A and Moreno Moreno, RA and Salas López, D and Madrigal Gómez, LE and Dominguez Ibarra, AK and Gutiérrez Rojas, BA and Garcia Navarro, CO and Moreno Becerril, GT and Montelongo Quevedo, M and Flores Valdés, JR}, title = {Aducanumab in Alzheimer's Disease: A Comparative Study of Its Effects on Dementia and Mild Cognitive Impairment.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e75907}, pmid = {39830554}, issn = {2168-8184}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia, characterized by progressive cognitive decline. Cholinesterase inhibitors are commonly used to manage symptoms but have limited efficacy as the disease progresses. Aducanumab, a monoclonal antibody targeting amyloid-β (Aβ) plaques, has emerged as a novel therapeutic approach. Despite its Food and Drug Administration (FDA) approval, its efficacy and safety remain contentious, particularly following the European Medicines Agency's (EMA's) rejection. This systematic review aims to evaluate the efficacy, safety, and clinical outcomes of aducanumab in treating mild AD. Adhering to Preferred Reporting Items for Systematic Reviews (PRISMA) 2020 guidelines, we conducted a comprehensive search of PubMed and Science Direct databases, including randomized controlled trials (RCTs), cohort studies, and case-control studies focusing on aducanumab versus placebo in mild AD. Studies were screened based on predefined inclusion and exclusion criteria, and data were extracted on clinical outcomes, biomarkers, and neuroimaging markers. The risk of bias was assessed using the Cochrane Handbook and Newcastle-Ottawa Scale. Out of 967 identified records, seven studies met the inclusion criteria. Findings indicated a dose-dependent reduction in Aβ plaques with aducanumab, but clinical outcomes varied. High-dose aducanumab (10 mg/kg) demonstrated significant improvements in some studies but not others. Adverse events, notably amyloid-related imaging abnormalities (ARIA), were frequent, especially at higher doses. The studies exhibited heterogeneous treatment effects and underscored the potential of cerebrospinal fluid biomarkers as an alternative to amyloid positron emission tomography (PET) scans. Aducanumab shows promise in reducing Aβ plaques and has potential clinical benefits at high doses; however, its safety profile, particularly concerning ARIA, remains a significant concern. The variability in clinical efficacy highlights the need for further research to optimize dosing regimens and identify patient populations most likely to benefit from treatment. Future studies should focus on refining treatment protocols and exploring alternative biomarkers to improve therapeutic outcomes for AD.}, }
@article {pmid39830039, year = {2024}, author = {Chen, R and Lu, X and Xiao, A and Ma, J}, title = {Role of insulin-like growth factor-2 in Alzheimer's disease induced memory impairment and underlying mechanisms.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1520253}, pmid = {39830039}, issn = {1662-5102}, abstract = {Alzheimer's disease (AD) is the most prevalent type of dementia. Treatments for AD do not reverse the loss of brain function; rather, they decrease the rate of cognitive deterioration. Current treatments are ineffective in part because they do not address neurotrophic mechanisms, which are believed to be critical for functional recovery. Given that structural losses are assumed to be the root cause of cognitive impairment in AD, strengthening neurotrophic pathways may be a useful preventative therapeutic approach. Insulin-like growth factor-2 (IGF2), which is widely expressed in the central nervous system (CNS), has emerged as a crucial mechanism of synaptic plasticity and learning and memory, and many studies have indicated that this neurotrophic peptide is a viable candidate for treating and preventing AD-induced cognitive decline. An increase in IGF2 levels improves memory in healthy animals and alleviates several symptoms associated with neurodegenerative disorders. These effects are primarily caused by the IGF2 receptor, which is widely expressed in neurons and controls protein trafficking, synthesis, and degradation. However, the use of IGF2 as a potential target for the development of novel pharmaceuticals to treat AD-induced memory impairment needs further investigation. We compiled recent studies on the role of IGF2 in AD-associated memory issues and summarized the current knowledge regarding IGF2 expression and function in the brain, specifically in AD-induced memory impairment.}, }
@article {pmid39829171, year = {2025}, author = {Wang, M and Guo, S and Yi, L and Li, Z and Shi, X and Fan, Y and Luo, M and He, Y and Song, W and Du, Y and Dong, Z}, title = {KIF9 Ameliorates Neuropathology and Cognitive Dysfunction by Promoting Macroautophagy in a Mouse Model of Alzheimer's Disease.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e14490}, doi = {10.1111/acel.14490}, pmid = {39829171}, issn = {1474-9726}, support = {CSTB2022NSCQ-LZX0010//Natural Science Foundation of Chongqing Municipality/ ; CSTB2024NSCQ-LZX0008//Natural Science Foundation of Chongqing Municipality/ ; 32371030//National Natural Science Foundation of China/ ; 82071395//National Natural Science Foundation of China/ ; 82371194//National Natural Science Foundation of China/ ; W0044//CQMU Program for Youth Innovation in Future Medicine/ ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting the elderly. The imbalance of protein production and degradation processes leads to the accumulation of misfolded and abnormally aggregated amyloid-beta (Aβ) in the extracellular space and forms senile plaques, which constitute one of the most critical pathological hallmarks of AD. KIF9, a member of the kinesin protein superfamily, mediates the anterograde transport of intracellular cargo along microtubules. However, the exact role of KIF9 in AD pathogenesis remains largely elusive. In this study, we reported that the expression of kinesin family member 9 (KIF9) in the hippocampus of APP23/PS45 double-transgenic AD model mice declined in an age-dependent manner, concurrent with macroautophagy dysfunction. Furthermore, we found that KIF9 mediated the transport of lysosomes through kinesin light chain 1 (KLC1), thereby participating in the degradation of amyloidogenic pathway-related proteins of Aβ precursor protein (APP) in AD model cells through promoting the macroautophagy pathway. Importantly, genetic upregulation of KIF9 via adeno-associated virus (AAV) diminished Aβ deposition and alleviated cognitive impairments in AD model mice by enhancing macroautophagy function. Collectively, our findings underscore the ability of KIF9 to promote macroautophagy through KLC1-mediated anterograde transport of lysosomes, effectively ameliorating cognitive dysfunction in AD model mice. These discoveries suggest that KIF9 may represent a novel therapeutic target for the treatment of AD.}, }
@article {pmid39828895, year = {2025}, author = {Wang, Z and Liang, Q and Lin, Z and Li, H and Chen, X and Zou, Z and Mo, J}, title = {Potential role of formononetin as a novel natural agent in Alzheimer's disease and osteoporosis comorbidity.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {2}, pages = {361-371}, doi = {10.1177/13872877241299104}, pmid = {39828895}, issn = {1875-8908}, mesh = {*Alzheimer Disease/drug therapy/genetics ; *Isoflavones/pharmacology/therapeutic use ; Humans ; *Osteoporosis/drug therapy/genetics ; *Molecular Docking Simulation ; Animals ; Comorbidity ; Mice ; Gene Regulatory Networks/drug effects ; Biological Products/therapeutic use ; Calcium Channels, L-Type/genetics/metabolism ; }, abstract = {BACKGROUND: The growing aging population has led to an increase in the prevalence of Alzheimer's disease (AD) and osteoporosis (OP), both of which significantly impair quality of life. The comorbid nature of these conditions suggests a shared genetic etiology, the understanding of which is crucial for developing targeted therapies.
OBJECTIVE: This study aims to explore the shared genetic etiology underlying AD and OP, using a system biology approach to identify potential therapeutic targets and natural compounds for treatment.
METHODS: We employed Weighted Gene Co-Expression Network Analysis (WGCNA) with molecular docking strategies to uncover the genetic links between AD and OP. MT2A and CACNA1C were identified as key pleiotropic hub genes potentially linking AD and OP. Molecular docking was utilized to screen for compounds with therapeutic potential, leading to the identification of formononetin as a compound with significant binding affinity to these hub genes. Quantitative real-time PCR (qRT-PCR) validation was conducted to confirm the gene expression changes in disease models.
RESULTS: Our study indicate that formononetin exhibits strong binding affinity to the identified hub genes, MT2A and CACNA1C. qRT-PCR validation confirmed the upregulation of these genes in disease models, which was mitigated upon treatment with formononetin, suggesting a reversal of disease markers.
CONCLUSIONS: This study advances our understanding of the genetic intersections between AD and OP and positions formononetin as a promising natural agent for further translational research. Formononetin's multi-target potential makes it a valuable candidate for managing these comorbid conditions, meriting further investigation and development as a therapeutic strategy.}, }
@article {pmid39828502, year = {2025}, author = {Wang, J and Li, X and Pang, H and Bu, S and Zhao, M and Liu, Y and Yu, H and Jiang, Y and Fan, G}, title = {Differential Connectivity Patterns of Mild Cognitive Impairment in Alzheimer's and Parkinson's Disease: A Large-scale Brain Network Study.}, journal = {Academic radiology}, volume = {32}, number = {3}, pages = {1601-1610}, doi = {10.1016/j.acra.2024.09.017}, pmid = {39828502}, issn = {1878-4046}, mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/physiopathology/etiology ; Male ; Female ; *Parkinson Disease/diagnostic imaging/physiopathology/complications ; *Alzheimer Disease/diagnostic imaging/physiopathology ; Aged ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/physiopathology ; Nerve Net/diagnostic imaging/physiopathology ; Middle Aged ; Case-Control Studies ; }, abstract = {RATIONALE AND OBJECTIVES: Cognitive disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), significantly impact the quality of life in older adults. Mild cognitive impairment (MCI) is a critical stage for intervention and can predict the development of dementia. The causes of these two diseases are not fully understood, but there is an overlap in their neuropathology. There is a lack of direct comparison regarding the changes in functional connectivity within and between different brain networks during cognitive impairment in these two diseases.
OBJECTIVE: This study aims to investigate changes in brain network connectivity of AD and PD with mild cognitive impairment, shedding light on the underlying neuropathological mechanisms and potential treatment options.
METHODS: A total of 33 AD-MCI patients, 55 PD-MCI patients, and 34 healthy controls (HCs) underwent resting-state functional MRI and cognitive function assessment using Independent Components Analysis (ICA). We compared intra- and inter-network functional connectivity among the three groups and analyzed the correlation between changes in functional connectivity and cognitive domain performance.
RESULTS: Using ICA, we identified eight functional networks. In the AD-MCI group, reductions in internetwork functional connectivity were mainly around the default mode network (DMN). Intra-network functional connectivity was widely reduced, especially in the DMN, while intra-network functional connectivity in the Salience Network (SN) increased. In contrast, in the PD-MCI group, reductions in internetwork functional connectivity were mainly around the SN. Intra-network functional connectivity in the SN decreased, while intra-network functional connectivity in other networks increased.
CONCLUSION: This study highlights distinct yet overlapping changes in brain network connectivity in AD and PD, providing new insights into the underlying mechanisms of cognitive impairment disorders.}, }
@article {pmid39828086, year = {2025}, author = {Kara, S and Polat, S and Akillioglu, K and Saker, D and Evli Ce, AT and Sencar, L and Aydın, UF and Polat, S}, title = {Effects of TGF-β1 on Aβ-40 and α- β- γ secretase expression in hippocampus and prefrontal cortex in experimental Alzheimer's disease.}, journal = {Behavioural brain research}, volume = {482}, number = {}, pages = {115432}, doi = {10.1016/j.bbr.2025.115432}, pmid = {39828086}, issn = {1872-7549}, mesh = {*Alzheimer Disease/metabolism/drug therapy ; *Prefrontal Cortex/metabolism/drug effects ; *Amyloid Precursor Protein Secretases/metabolism ; *Hippocampus/metabolism/drug effects ; Animals ; *Transforming Growth Factor beta1/metabolism ; Male ; *Amyloid beta-Peptides/metabolism/pharmacology ; *Disease Models, Animal ; *Scopolamine/pharmacology ; Rats ; Peptide Fragments/metabolism/pharmacology ; Rats, Wistar ; Neurons/metabolism/drug effects ; Apoptosis/drug effects/physiology ; }, abstract = {Alzheimer's disease is a chronic complex neurodegenerative disease characterized with amyloid plaques and loss of neurons. TGF-β1 is important growth factor, plays critical roles in cell metabolism, tissue homeostasis, neuronal development, and synaptic plasticity. In this study, we aimed to examine the effect of TGF-β1 on the regulation of α, β, and γ-secretase enzymes, Aβ-40 accumulation, apoptosis, and neuronal damage in an experimental Scopolamine-induced AD-like model. The subjects were divided into 5 groups such as control, sham, TGF-β1 control, Scopolamin group, TGF-β1 treatment groups.Then all groups were divided into 2 subgroups according to 28th-56th days. Except for Morris water maze (MWM) test, hippocampus and prefrontal cortex tissues were taken for light-electron microscopic, immunohistochemical, and biochemical examinations. It was observed that learning and memory abilities, which decreased in the MWM test of the Scopolamine group, increased in the treatment groups. In addition, α-secretase expression decreased in the Scopolamin group, while it increased in the TGF-β1 treatment group. It was determined that Aβ-40 and caspase-3 immunoreactivity, β and γ-secretase enzyme levels increased in the Scopolamin group and decreased in TGF-β1 treatment group. Cellular degenerations were relatively decreased in TGF-β1 treatment group. It was thought that TGF-β1 might have a therapeutic effect on Alzheimer's disease by increasing memory performance and preventing Aβ-40 accumulation in the AD-like model induced by Scopolamine and also, may be effective preventing neuronal damage by down-regulating caspase-3 expression. When all the findings evaluated together, it was concluded that TGF-β1 could be evaluated as a therapeutic agent in Alzheimer's disease.}, }
@article {pmid39828018, year = {2025}, author = {Sharma, D and Singh, V and Kumar, A and Singh, TG}, title = {Genistein: A promising ally in combating neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {991}, number = {}, pages = {177273}, doi = {10.1016/j.ejphar.2025.177273}, pmid = {39828018}, issn = {1879-0712}, mesh = {*Genistein/pharmacology/therapeutic use ; Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative disorders arise when nerve cells in the brain or peripheral nervous system gradually lose functions and eventually die. Although certain therapies may alleviate some of the physical and mental symptoms associated with neurodegenerative disorders, hence slowing their progression, but no sure-shot treatment is currently available. It was shown that the rise in life expectancy and the number of elderly people in the community led to an increasing trend in the incidence and prevalence of neurodegenerative disease. Phytomolecules are demonstrating their effectiveness in combating, regression, and delaying various diseases. Genistein is one of soy isoflavone with antioxidant, anti-inflammatory, and estrogenic effects. Researchers demonstrated that Genistein treatment significantly reduced hyperglycemia, improved cognitive performance by modulating acetylcholinesterase activity and oxidative stress, and alleviated neuroinflammatory conditions in mice. This paper evaluates (in vivo and in vitro) various molecular targets of isoflavones and their ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disorders.}, }
@article {pmid39827439, year = {2025}, author = {Fasth, LM and Kelley, CJ and Colón-Emeric, C and Green, AR and Thorpe, CT and Gilliam, M and Lund, JL and Hanson, LC and Niznik, JD}, title = {How Should Clinicians Discuss Deprescribing with Caregivers of Older Adults Living with Dementia? A Qualitative Study.}, journal = {Drugs & aging}, volume = {42}, number = {2}, pages = {155-164}, pmid = {39827439}, issn = {1179-1969}, support = {K08 AG071794/AG/NIA NIH HHS/United States ; K08AG071794/AG/NIA NIH HHS/United States ; K08AG071794/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Deprescriptions ; *Caregivers/psychology ; Female ; Male ; *Dementia/drug therapy ; *Qualitative Research ; Aged ; Middle Aged ; Physicians/psychology ; Communication ; Diphosphonates/therapeutic use/adverse effects ; Aged, 80 and over ; }, abstract = {BACKGROUND: Preventive medications are potential targets for deprescribing in older adults with dementia as goals of care change from preventive to palliative. Yet, prescribers lack communication guidance to address deprescribing.
OBJECTIVE: Using bisphosphonates as a case example, we sought to characterize and compare communication preferences of prescribers and family/informal caregivers regarding deprescribing.
METHODS: We conducted 23 semi-structured interviews with prescribers (12) and caregivers (11) of older adults with Alzheimer's disease or related dementias (ADRD). Prescribers and caregivers were asked to provide their impressions of seven conversation starters for discussing deprescribing, focusing on a case example using bisphosphonates. These phrases focused on topics including life expectancy, treatment burden, adverse effects, and costs. We used a qualitative framework analysis to identify relevant themes as prescribers and caregivers discussed their general perceptions of the potential benefits and harms of bisphosphonates and experiences with deprescribing.
RESULTS: Among prescribers, there were ten physicians and two nurse practitioners; most (nine) female and white. Among caregivers, eight were female, seven were white, and five were Latino/a. For both prescribers and caregivers, preferred conversation starters initiated a risk versus benefit discussion, emphasizing medication adverse effects and patient-specific factors, such as functional status and indication for treatment. While prescribers emphasized discussing common medication adverse effects, caregivers noted the importance of knowing a medication's potential impact on ADRD. The least preferred conversation starter for deprescribing among both groups focused on the extra effort and cost of continuing bisphosphonates. Discordance between caregivers and prescribers were identified in several phrases; notably, caregivers disliked statements that introduced discussions of prognosis and life expectancy.
CONCLUSIONS: Deprescribing conversations may be best perceived by caregivers when introduced with a discussion of a medication's adverse effects and potential impact on cognition. In addition, deprescribing conversations should be tailored to patient-specific factors, including functional status, goals of care, and the role of their caregiver in medical decision-making. Avoiding discussions of medication cost, pill burden, and life expectancy may help reassure the caregiver that deprescribing is a form of medication optimization and not a withdrawal of care.}, }
@article {pmid39826816, year = {2025}, author = {Chen, L and Zhao, X and Sheng, R and Lazarovici, P and Zheng, W}, title = {Artemisinin alleviates astrocyte overactivation and neuroinflammation by modulating the IRE1/NF-κB signaling pathway in in vitro and in vivo Alzheimer's disease models.}, journal = {Free radical biology & medicine}, volume = {229}, number = {}, pages = {96-110}, doi = {10.1016/j.freeradbiomed.2025.01.027}, pmid = {39826816}, issn = {1873-4596}, mesh = {Animals ; *Astrocytes/metabolism/drug effects/pathology ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *Artemisinins/pharmacology ; *Protein Serine-Threonine Kinases/metabolism/genetics ; *NF-kappa B/metabolism/genetics ; *Signal Transduction/drug effects ; *Disease Models, Animal ; *Amyloid beta-Peptides/metabolism ; *Endoplasmic Reticulum Stress/drug effects ; Humans ; Mice, Transgenic ; Neuroinflammatory Diseases/drug therapy/pathology/metabolism ; Endoribonucleases/metabolism/genetics ; Neurons/metabolism/drug effects/pathology ; Apoptosis/drug effects ; Cells, Cultured ; Neuroprotective Agents/pharmacology ; Peptide Fragments/metabolism/pharmacology ; }, abstract = {Recent studies have shown that neuroinflammation and heightened glial activity, particularly astrocyte overactivation, are associated with Alzheimer's disease (AD). Abnormal accumulation of amyloid-beta (Aβ) induces endoplasmic reticulum (ER) stress and activates astrocytes. Artemisinin (ART), a frontline anti-malarial drug, has been found to have neuroprotective properties. However, its impact on astrocytes remains unclear. In this study, we used Aβ1-42 induced astrocyte cultures and 3 × Tg-AD mice as in vitro and in vivo models, respectively, to investigate the effects of ART on AD related astrocyte overactivation and its underlying mechanisms. ART attenuated Aβ1-42-induced astrocyte activation, ER stress, and inflammatory responses in astrocyte cultures by inhibiting IRE1 phosphorylation and the NF-κB pathway, as evidenced by the overexpression of IRE1 WT and IRE1-K599A (kinase activity invalidated), along with application of activators and inhibitors related to ER stress. Furthermore, ART alleviated the detrimental effects and restored neurotrophic function of astrocytes on co-cultured neurons, preventing neuronal apoptosis during Aβ1-42 treatment. In 3 × Tg-AD mice, ART treatment improved cognitive function and reduced astrocyte overactivation, neuroinflammation, ER stress, and neuronal apoptosis. Moreover, ART attenuated the upregulation of IRE1/NF-κB pathway activity in AD mice. Astrocyte-specific overexpression of IRE1 via adeno-associated virus in AD mice reversed the ameliorating effects of ART. Our findings suggest that ART inhibits astrocyte overactivation and neuroinflammation in both in vitro and in vivo AD models by modulating the IRE1/NF-κB signaling pathway, thereby enhancing neuronal functions. This study underscores the therapeutic potential of ART in AD and highlights the significance of modulating the ER stress-inflammatory cycle and normalizing astrocyte-neuron communication.}, }
@article {pmid39826482, year = {2025}, author = {Zulhafiz, NA and Teoh, TC and Chin, AV and Chang, SW}, title = {Drug repurposing using artificial intelligence, molecular docking, and hybrid approaches: A comprehensive review in general diseases vs Alzheimer's disease.}, journal = {Computer methods and programs in biomedicine}, volume = {261}, number = {}, pages = {108604}, doi = {10.1016/j.cmpb.2025.108604}, pmid = {39826482}, issn = {1872-7565}, mesh = {*Drug Repositioning ; *Alzheimer Disease/drug therapy ; *Molecular Docking Simulation ; Humans ; *Artificial Intelligence ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent form of dementia, remains enigmatic in its origins despite the widely accepted "amyloid hypothesis," which implicates amyloid-beta peptide aggregates in its pathogenesis and progression. Despite advancements in technology and healthcare, the incidence of AD continues to rise. The traditional drug development process remains time-consuming, often taking years to bring an AD treatment to market. Drug repurposing has emerged as a promising strategy for developing cost-effective and efficient therapeutic options by identifying new uses for existing approved drugs, thus accelerating drug development.
OBJECTIVES: This study aimed to examine two key drug repurposing methodologies in general diseases and specifically in AD, which are artificial intelligent (AI) approach and molecular docking approach. In addition, the hybrid approach that integrates AI with molecular docking techniques will be explored too.
METHODOLOGY: This study systematically compiled a comprehensive collection of relevant academic articles, scientific papers, and research studies which were published up until November 2024 (as of the writing of this review paper). The final selection of papers was filtered to include studies related to Alzheimer's disease and general diseases, and then categorized into three groups: AI articles, molecular docking articles, and hybrid articles.
RESULTS: As a result, 331 papers were identified that employed AI for drug repurposing in general diseases, and 58 papers focused specifically in AD. For molecular docking in drug repurposing, 588 papers addressed general diseases, while 46 papers were dedicated to AD. The hybrid approach combining AI and molecular docking in drug repurposing has 52 papers for general diseases and 9 for AD. A comparative review was done across the methods, results, strengths, and limitations in those studies. Challenges of drug repurposing in AD are explored and future prospects are proposed.
DISCUSSION AND CONCLUSION: Drug repurposing emerges as a compelling and effective strategy within AD research. Both AI and molecular docking methods exhibit significant potential in this domain. AI algorithms yield more precise predictions, thus facilitating the exploration of new therapeutic avenues for existing drugs. Similarly, molecular docking techniques revolutionize drug-target interaction modelling, employing refined algorithms to screen extensive drug databases against specific target proteins. This review offers valuable insights for guiding the utilization of AI, molecular docking, or their hybrid in AD drug repurposing endeavors. The hope is to speed up the timeline of drug discovery which could improve the therapeutic approach to AD.}, }
@article {pmid39826392, year = {2025}, author = {Mei, Z and Zhang, Y and Zhao, W and Lam, C and Luo, S and Wang, S and Luo, S}, title = {Music-based interventions for anxiety and depression in older adults with dementia: A systematic review of randomized controlled trials.}, journal = {Complementary therapies in clinical practice}, volume = {59}, number = {}, pages = {101951}, doi = {10.1016/j.ctcp.2025.101951}, pmid = {39826392}, issn = {1873-6947}, abstract = {OBJECTIVE: The objective of this systematic review was to synthesize evidence from randomized controlled trials (RCTs) regarding the efficacy of music-based interventions (MBIs) in improving anxiety and depression in older adults with dementia.
METHODS: Relevant RCTs were identified through searches in electronic databases, including PubMed, Embase, EBSCOhost, Scopus, Web of Science, APA PsycINFO, and Google. The Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) was used to evaluate the risk of bias in the included trials. A narrative synthesis of the included trials was conducted.
RESULTS: Nine RCTs involving 496 patients met the inclusion criteria; five trials evaluated the efficacy of MBIs for anxiety, and six trials evaluated their efficacy for depression in older adults with dementia. Of the nine trials, two reported significant improvements in anxiety in older adults with dementia following MBIs (Cohen's d = -1.71 to -2.48), while one trial reported significant improvements in depression (Cohen's d = -0.66).
CONCLUSIONS: Only a few trials support the efficacy of MBIs in alleviating negative emotions in older adults with dementia, as evidenced by three out of the nine trials. However, due to the small sample sizes and heterogeneity in dementia types, stages, and interventions, quantitative results were not pooled, making it challenging to draw reliable conclusions. Further validation and examination of the findings presented in this study are warranted to strengthen the evidence base for integrating MBIs into dementia care and treatment protocols.}, }
@article {pmid39824583, year = {2025}, author = {Mishra, S and Banerjee, S and Tiwari, BS and Tiwari, AK}, title = {Recent progress in CRISPR-Cas-system for neurological disorders.}, journal = {Progress in molecular biology and translational science}, volume = {210}, number = {}, pages = {231-261}, doi = {10.1016/bs.pmbts.2024.07.017}, pmid = {39824583}, issn = {1878-0814}, mesh = {Humans ; *CRISPR-Cas Systems/genetics ; *Nervous System Diseases/genetics/therapy ; Animals ; Gene Editing ; Genetic Therapy/methods ; }, abstract = {Different neurological diseases including, Parkinson's, Alzheimer's, and Huntington's diseases extant momentous global disease burdens, affecting millions of lives for imposing a heavy disease burden on the healthcare systems. Despite various treatment strategies aimed at alleviating symptoms, treatments remain elusive and ineffective due to the disease's complexity. However, recent advancements in gene therapy via the CRISPR-Cas system offer ground-breaking and targeted treatment options. Based on a bacterial immune mechanism, the CRISPR-Cas system enables precise genome editing, allowing for the alteration of different genetic mutations and the possible cure of genetic diseases. In the context of neurological disorders, the CRISPR-Cas system shows a promising avenue by allowing researchers to conduct genome-editing which is implicated in neurodegenerative disease therapeutics. This book chapter provides an updated overview of the application of the CRISPR-Cas system for addressing target-specific therapeutic approaches for neurodegenerative disorders. Furthermore, we discuss the principles of the CRISPR-Cas mechanism, its role in modeling neurological disorders, identifying molecular targets, and developing gene-based therapies. Additionally, the chapter explores the recent clinical trials and CRISPR-Cas-mediated treatments for neurological conditions. By leveraging the accuracy and versatility of the CRISPR-Cas system, scientists can more effectively handle the genetic underpinnings of neurodegenerative diseases. Furthermore, the chapter extends the critical viewpoints on ethical considerations and technical limitations related to the clinical deployment of this revolutionizing technique.}, }
@article {pmid39824445, year = {2025}, author = {Cardaci, V and Di Pietro, L and Zupan, MC and Sibbitts, J and Privitera, A and Lunte, SM and Caraci, F and Hartley, MD and Caruso, G}, title = {Characterizing oxidative stress induced by Aβ oligomers and the protective role of carnosine in primary mixed glia cultures.}, journal = {Free radical biology & medicine}, volume = {229}, number = {}, pages = {213-224}, pmid = {39824445}, issn = {1873-4596}, support = {K12 GM063651/GM/NIGMS NIH HHS/United States ; P20 GM103638/GM/NIGMS NIH HHS/United States ; P30 GM145499/GM/NIGMS NIH HHS/United States ; T32 GM132061/GM/NIGMS NIH HHS/United States ; }, mesh = {*Carnosine/pharmacology ; *Oxidative Stress/drug effects ; Animals ; *Amyloid beta-Peptides/metabolism ; Rats ; *Reactive Oxygen Species/metabolism ; *Nitric Oxide/metabolism ; Cells, Cultured ; Alzheimer Disease/metabolism/pathology ; Astrocytes/metabolism/drug effects/pathology ; Peptide Fragments/metabolism/pharmacology ; Microglia/metabolism/drug effects ; Neuroglia/metabolism/drug effects/pathology ; Antioxidants/pharmacology ; Neuroprotective Agents/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. A critical aspect of AD pathology is represented by oxidative stress, which significantly contributes to neuronal damage and death. Microglia and astrocytes, the primary glial cells in the brain, are crucial for managing oxidative stress and supporting neuronal function. Carnosine is an endogenous dipeptide possessing a multimodal mechanism of action that includes antioxidant, anti-inflammatory, and anti-aggregant activities. The present study investigated the effects of Aβ1-42 oligomers (oAβ), small aggregates associated with the neurodegeneration observed in AD, on primary rat mixed glia cultures composed of both microglia and astrocytes, focusing on the ability of these detrimental species to induce oxidative stress. We assessed intracellular reactive oxygen species (ROS) and nitric oxide (NO) levels as markers of oxidative stress. Exposure to oAβ significantly elevated both ROS and NO intracellular levels compared to control cells. However, this effect was completely inhibited by the pre-treatment of mixed cultures with carnosine, resulting in ROS and NO levels similar to those observed in untreated (control) cells. Single-cell analysis of cellular responses to oAβ revealed heterogeneous ROS production, resulting in two distinct clusters of cells, one of which was very responsive to the treatment. The presence of carnosine counteracted the overproduction of ROS, also leading to a single, homogeneous cluster, similar to that observed in the case of control cells. Interestingly, unlike ROS response, single-cell analysis of NO production did not show any distinct clusters. Overall, our findings demonstrated the ability of carnosine to mitigate Aβ-induced oxidative stress in mixed glia cells, by rescuing ROS and NO intracellular levels, as well as to normalize the heterogeneous response to the treatment measured in terms of clusters' formation. The present study suggests a therapeutic potential of carnosine in pathologies characterized by oxidative stress including AD.}, }
@article {pmid39823370, year = {2025}, author = {Bell, MB and Kane, MS and Ouyang, X and Young, ME and Jegga, AG and Chatham, JC and Darley-Usmar, V and Zhang, J}, title = {Brain Transcriptome Changes Associated With an Acute Increase of Protein O-GlcNAcylation and Implications for Neurodegenerative Disease.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16302}, pmid = {39823370}, issn = {1471-4159}, support = {R01 HL142216/HL/NHLBI NIH HHS/United States ; R56AG060959/NH/NIH HHS/United States ; T32 HL007457/HL/NHLBI NIH HHS/United States ; I01 BX-004251-01//VA merit award/ ; R56 AG060959/AG/NIA NIH HHS/United States ; P30 AG050886/AG/NIA NIH HHS/United States ; NHLBI HL142216/NH/NIH HHS/United States ; T32 HL007457/NH/NIH HHS/United States ; P30 AG050886/NH/NIH HHS/United States ; }, mesh = {*Brain/metabolism/pathology ; *Transcriptome/drug effects/genetics ; Glycosylation ; *Neurodegenerative Diseases/genetics/metabolism ; *Proteins/metabolism ; Mice, Inbred C57BL ; Animals ; Gene Expression Profiling ; Up-Regulation/drug effects ; Down-Regulation/drug effects ; Metabolic Networks and Pathways/genetics ; Thiazoles/pharmacology ; }, abstract = {Enhancing protein O-GlcNAcylation by pharmacological inhibition of the enzyme O-GlcNAcase (OGA) has been considered as a strategy to decrease tau and amyloid-beta phosphorylation, aggregation, and pathology in Alzheimer's disease (AD). There is still more to be learned about the impact of enhancing global protein O-GlcNAcylation, which is important for understanding the potential of using OGA inhibition to treat neurodegenerative diseases. In this study, we investigated the acute effect of pharmacologically increasing O-GlcNAc levels, using the OGA inhibitor Thiamet G (TG), in normal mouse brains. We hypothesized that the transcriptome signature in response to a 3 h TG treatment (50 mg/kg) provides a comprehensive view of the effect of OGA inhibition. We then performed mRNA sequencing of the brain using NovaSeq PE 150 (n = 5 each group). We identified 1234 significant differentially expressed genes with TG versus saline treatment. Functional enrichment analysis of the upregulated genes identified several upregulated pathways, including genes normally down in AD. Among the downregulated pathways were the cell adhesion pathway as well as genes normally up in AD and aging. When comparing acute to chronic TG treatment, protein autophosphorylation and kinase activity pathways were upregulated, whereas cell adhesion and astrocyte markers were downregulated in both datasets. AMPK subunit Prkab2 was one gene in the kinase activity pathway, and the increase after acute and chronic treatment was confirmed using qPCR. Interestingly, mitochondrial genes and genes normally down in AD were up in acute treatment and down in chronic treatment. Data from this analysis will enable the evaluation of the mechanisms underlying the impact of OGA inhibition in the treatment of AD. In particular, OGA inhibitors appear to have downstream effects related to bioenergetics which may limit their therapeutic benefits.}, }
@article {pmid39822440, year = {2024}, author = {Barnett, C and Morris, K and Shah, Y}, title = {Clinical Diagnoses and Characterization of Patients With Amyloid-Negative Amyloid-Beta, p-Tau, and Neurofilament Light Chain (ATN) Profiles.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e75874}, pmid = {39822440}, issn = {2168-8184}, abstract = {The novel amyloid-beta, p-Tau, and neurofilament light chain (ATN) classification scheme has become a promising system for clinically detecting and diagnosing Alzheimer's disease (AD). In addition to its utility in Alzheimer's diagnosis and treatment, the ATN framework may also have clinical relevance in identifying non-Alzheimer's pathologies. In this study conducted at Broadlawns Geriatric and Memory Center, 92 amyloid-negative profiles out of 182 patients with an ATN framework were categorized into subjective cognitive impairment (SCI), non-amnestic mild cognitive impairment (non-amnestic MCI), amnestic MCI, Alzheimer's dementia, vascular dementia, mixed dementia, unspecified dementia, or other memory changes based on diagnoses written in the chart. Additionally, other secondary diagnoses were found in the differential, including sleep disorders, anxiety, depressive disorders and grief, and cerebrovascular disease. The results are concordant with our expectations that amyloid-negative ATN profiles are associated with mostly non-Alzheimer's cognitive decline. We were also able to demonstrate that amyloid-negative patients have other secondary neurologic or psychiatric diagnoses related to memory or cognitive changes. However, certain enigmatic patient presentations warrant further scrutiny in the medical chart. It is possible that ATN may pose a risk of misclassification in both Alzheimer and non-Alzheimer pathologies, particularly at early stages. Future work may be required to corroborate findings using other new plasma biomarkers, such as p-Tau217. Overall, we hope that this study will provide options for early detection and future treatment of AD and other neurocognitive disorders. We also anticipate that this work will lead to the recognition of other non-neurocognitive conditions comorbid with such neurocognitive disorders.}, }
@article {pmid39822295, year = {2025}, author = {Gleerup, HS and Simonsen, AH and Grötschel, L and Gramkow, MH and Høgh, P and Blennow, K and Zetterberg, H and Ashton, N and Hasselbalch, SG}, title = {Plasma biomarkers of amyloid, tau, astrogliosis, and axonal injury in a mixed memory clinic cohort.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {1}, pages = {e70073}, pmid = {39822295}, issn = {2352-8729}, abstract = {INTRODUCTION: Studies have shown that blood biomarkers can differentiate dementia disorders. However, the diagnosis of dementia still relies primarily on cerebrospinal fluid and imaging modalities. The new disease-modifying treatments call for more widely applicable biomarkers.
METHODS: Plasma samples (n = 250) from two mixed memory clinic were included. Participants were divided into amyloid beta positives (Aβ+) and Aβ negatives (Aβ-). Plasma phosphorylated tau (p-tau) 181, p-tau231, Aβ1-42 (Aβ42), Aβ40, Aβ42/Aβ40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured by single molecule array.
RESULTS: Significant differences were found among cognitively unimpaired, mild cognitive impairment, Alzheimer's disease (AD), and non-AD, and nearly all of the biomarkers were able to predict amyloid status. When combining p-tau181 and p-tau231 they predicted Aβ positivity with an area under the curve (AUC) of 0.75, and when combining all biomarkers an AUC of 0.86 was found.
DISCUSSION: This study supports previous findings on plasma biomarkers, even when investigated in a typical clinical setting in a consecutive, heterogeneous, mixed memory clinic.
HIGHLIGHTS: This study investigated seven plasma biomarkers in a mixed memory clinic, regardless of amyloid co-pathology or atypical phenotypes.These findings support previous promising results on plasma biomarkers, even when investigated in a heterogeneous population.The combination of phosphorylated tau (p-tau)181 and p-231 performed only slightly worse than a panel of multiple biomarkers, aligning with previous studies.Plasma biomarkers show potential for future applications in primary care, treatment monitoring, and trial selection.}, }
@article {pmid39821693, year = {2025}, author = {Caruso, A and Tommonaro, G and Vassallo, A and Paris, D and Monné, M and Catalano, A and Sinicropi, MS and Saturnino, C}, title = {Imino and Thioureidic Derivatives as New Tools for Alzheimer's Disease: Preliminary Studies.}, journal = {Chemical biology & drug design}, volume = {105}, number = {1}, pages = {e70049}, doi = {10.1111/cbdd.70049}, pmid = {39821693}, issn = {1747-0285}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Acetylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis/metabolism ; *Molecular Docking Simulation ; Humans ; *Antioxidants/pharmacology/chemistry ; Structure-Activity Relationship ; }, abstract = {Alzheimer's disease is a neurodegenerative chronic disease with a severe social and economic impact in the societies, which still lacks an efficient therapy. Several pathophysiological events (β-amyloid [Aβ] deposits, τ-protein aggregation, loss of cholinergic activity, and oxidative stress) occurs in the progression of the disease. Therefore, the search for efficient multi-targeted agents for the treatment of Alzheimer's disease becomes indispensable. In this paper we evaluated the AChE inhibition by Ellman's method and antioxidant activity by DPPH assay of nine synthetic compounds: two hydroxy-benzene derivatives (1 and 2), three bis-thioureidic derivatives (3-5), two imidazole derivatives (6 and 7), and two phenylacetamide derivatives (8 and 9). The compound 2, (3s,5s,7s)-adamantan-1-yl 4-(((E)-2,5-dihydroxybenzylidene)amino)benzoate, exhibited the best antioxidant activity (30.00 ± 1.05 μM eq Trolox) and compound 4 showed the highest AChE inhibition value (IC50 [μM] 8.40 ± 0.32). In the search for a compound showing combined activities (antioxidant and AChE inhibition), the compound 4, octane-1,8-diyl-bis-S-amidinothiourea dihydrobromide, (19.02 ± 1.52 μM eq Trolox; IC50 [μM] 8.40 ± 0.32) was chosen to carry out a molecular docking study. The results showed that compound 4 has the ability to bind the active site of acetylcholinesterase with considerable affinity (estimated binding energies of -8.5 kcal/mol). All data indicate that compound 4 has the potential to be further investigated as a possible candidate in the Alzheimer's disease treatment.}, }
@article {pmid40124644, year = {2024}, author = {Gorbunova, V and Seluanov, A}, title = {Hiding in Plain Sight: FDA-Approved Cholesterol Drug Ezetimibe as a Treatment for Alzheimer's.}, journal = {Aging biology}, volume = {2}, number = {}, pages = {}, pmid = {40124644}, issn = {2994-2578}, support = {P01 AG047200/AG/NIA NIH HHS/United States ; }, }
@article {pmid39963030, year = {2024}, author = {Wieczorek, I and Strosznajder, RP}, title = {S1P receptor modulators affect the toxicity of amyloid β oligomers in microglial and neuronal cells.}, journal = {Folia neuropathologica}, volume = {62}, number = {4}, pages = {348-361}, doi = {10.5114/fn.2024.145758}, pmid = {39963030}, issn = {1509-572X}, mesh = {*Microglia/drug effects/metabolism ; *Amyloid beta-Peptides/toxicity/metabolism ; *Neurons/drug effects/metabolism ; Animals ; Cell Survival/drug effects ; Sphingosine 1 Phosphate Receptor Modulators/pharmacology ; Mice ; Receptors, Lysosphingolipid/metabolism ; Alzheimer Disease/metabolism ; }, abstract = {A large body of evidence has shown that the amyloid b peptide oligomers (Abo) are predominantly responsible for the neurodegeneration/cognitive impairments in Alzheimer's disease (AD). Abo cause mitochondrial dysfunctions leading to an imbalance between pro- and antiapoptotic proteins and finally to neuronal apoptosis. Further, Abo trigger overactivation of microglia followed by enhanced release of proinflammatory cytokines, which exacerbates neurotoxicity of Abo. The above-mentioned alterations are accompanied by disturbed metabolism of prosurvival bioactive sphingolipid, sphingosine-1-phosphate (S1P), and S1P-dependent signalling via specific receptors (S1PR1-5). In the present study, we investigated for the first time the influence of selective - ponesimod (S1PR1), CYM5541 (S1PR3), CYM50308 (S1PR4), A971432 (S1PR4), siponimod (S1PR1,5) - and nonselective - phosphorylated fingolimod/pFTY720 (S1PR1,3-5) - S1P receptor modulators on cell viability, mitochondrial membrane potential (MMP) and expression of genes encoding S1P receptors, pro- and antiapoptotic proteins and proinflammatory cytokines in hippocampal neuronal (HT22) and in microglial (BV2) cell lines treated with 1 µM Abo for 24 hours. A significant reduction in the MMP, cell viability and mRNA levels of Bcl2 and Il18 together with increased Il6 expression was observed in HT22 cells after Abo administration. CYM50308 and A971432 restored the Bcl2 mRNA level to control values (those of Abo-untreated cells) and pFTY720 markedly reduced the Il6 expression. In BV2 cells, Abo induced a significant decrease in the MMP, cell viability and expression of S1pr1, Bad, Bcl2, Tnf and Il18, which was not counteracted by any of the modulators used. In turn, mRNA levels of Il1b, Il6, were markedly increased in microglia after Abo treatment and the administration of studied compounds tended to exacerbate the proinflammatory effect of Abo. In conclusion, the toxic effect of Abo is more pronounced in microglia. S1P receptor modulators may to some extent mitigate proapoptotic and proinflammatory effects of Abo in HT22 cells. In contrast, the same compounds tend to enhance Abo-induced inflammatory changes in BV2 cells.}, }
@article {pmid39917255, year = {2023}, author = {Chandra, A and Coile, C and Mommaerts, C}, title = {What Can Economics Say about Alzheimer's Disease?.}, journal = {Journal of economic literature}, volume = {61}, number = {2}, pages = {428-470}, pmid = {39917255}, issn = {0022-0515}, support = {P30 AG012810/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) affects one in ten people aged 65 or older and is the most expensive disease in the United States. We describe the central economic questions raised by AD. Although there is overlap with the economics of aging and health, the defining feature of the "economics of Alzheimer's disease" is an emphasis on choice by cognitively impaired patients that affects health and financial well-being, and situations in which dynamic contracts between patients and caregivers are useful but difficult to enforce. A focus on innovation in AD prevention, treatment, and care is also critical given the enormous social cost of AD and present lack of understanding of its causes, which raises questions of optimal resource allocation and alignment of private and social incentives. The enormous scope for economists to contribute to our understanding of AD-related issues including drug development, efficient care delivery, dynamic contracting, long-term care risk, financial decision-making, and the design of public programs for AD suggests a rich research program for many areas of economics.}, }
@article {pmid40093660, year = {2023}, author = {He, Z and Dieciuc, M and Carr, D and Chakraborty, S and Singh, A and Fowe, IE and Zhang, S and Lustria, MLA and Terracciano, A and Charness, N and Boot, WR}, title = {New Opportunities for the Early Detection and Treatment of Cognitive Decline: Adherence Challenges and the Promise of Smart and Person-Centered Technologies.}, journal = {BMC digital health}, volume = {1}, number = {}, pages = {}, pmid = {40093660}, issn = {2731-684X}, support = {R01 AG064529/AG/NIA NIH HHS/United States ; UL1 TR001427/TR/NCATS NIH HHS/United States ; }, abstract = {Early detection of age-related cognitive decline has transformative potential to advance the scientific understanding of cognitive impairments and possible treatments by identifying relevant participants for clinical trials. Furthermore, early detection is also key to early intervention once effective treatments have been developed. Novel approaches to the early detection of cognitive decline, for example through assessments administered via mobile apps, may require frequent home testing which can present adherence challenges. And, once decline has been detected, treatment might require frequent engagement with behavioral and/or lifestyle interventions (e.g., cognitive training), which present their own challenges with respect to adherence. We discuss state-of-the-art approaches to the early detection and treatment of cognitive decline, adherence challenges associated with these approaches, and the promise of smart and person-centered technologies to tackle adherence challenges. Specifically, we highlight prior and ongoing work conducted as part of the Adherence Promotion with Person-centered Technology (APPT) project, and how completed work will contribute to the design and development of a just-in-time, tailored, smart reminder system that infers participants' contexts and motivations, and how ongoing work might build toward a reminder system that incorporates dynamic machine learning algorithms capable of predicting and preventing adherence lapses before they happen. APPT activities and findings will have implications not just for cognitive assessment and training, but for technology-mediated adherence-support systems to facilitate physical exercise, nutrition, medication management, telehealth, and social connectivity, with the potential to broadly improve the engagement, health, and well-being of older adults.}, }
@article {pmid39820731, year = {2025}, author = {Xiong, R and Liu, H and Zhang, S and Wang, L and Liu, L and Pan, S and Zhang, Y and Zhu, F and Liu, Y and Lai, X}, title = {Integrating network pharmacology and experimental verification to reveal the ferroptosis-associated mechanism of Changpu-Yizhi-Wan in the treatment of Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {106}, pmid = {39820731}, issn = {1573-7365}, support = {2022XQN28//Army Military Medical University/ ; }, mesh = {*Ferroptosis/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Network Pharmacology ; Animals ; Mice ; NF-E2-Related Factor 2/metabolism ; Protein Interaction Maps/drug effects ; }, abstract = {To explore the pharmacological mechanism of Changpu-Yizhi-Wan (CYW) in the treatment of Alzheimer's disease (AD) from the perspective of ferroptosis based on network pharmacology and experimental verification. The Encyclopedia of Traditional Chinese Medicine 2.0 (ETCM2.0) database was used to collect the active components of CYW, and the putative targets were predicted in ETCM2.0 and SwissTargetPrediction database. The AD related targets were collected from GeneCards, comparative toxicogenomics database (CTD), Online Mendelian Inheritance in Man (OMIM), DisGeNET and Therapeutic Target Database (TTD), the ferroptosis related targets were collected from FerrDb V2 database, and the common targets of CYW, AD and ferroptosis were calculated by Venny2.1 platform. Protein-protein interaction (PPI) analysis was performed by STRING database, and the active compounds-target network and the PPI network were constructed using Cytoscape software. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway enrichment analysis were performed through DAVID database. RSL3 was used to induce HT22 cells to establish a neuronal ferroptosis cell model, and the inhibitory effect of CYW on neuronal ferroptosis was evaluated by cell viability assay, intracellular iron assay and lipid peroxidation staining. The ferroptosis-associated key protein expressions of Nrf2, SLC7A11, GPX4 and FTH1 were detected by Western blot. A total of 100 candidate compounds were identified from CYW, and 1129 putative targets were obtained. 3924 AD-related targets and 564 ferroptosis-related targets were collected, respectively. There were 78 common targets between them and CYW targets, which were potential targets for CYW to regulate ferroptosis in the treatment of AD. PPI network analysis identified 10 key targets, including TP53, IL6, STAT3, HIF1A, NFE2L2, and others. GO, KEGG and Reactome enrichment analysis showed that 78 potential targets were involved in the regulation of ferroptosis and Nrf2-mediated gene transcription. Molecular docking showed that some active components of CYW had good affinity with Nrf2. In RSL3-induced HT22 cells, CYW significantly improved cell viability, reduced intracellular iron levels and inhibited lipid peroxidation, and improved the protein expression of Nrf2, SLC7A11, GPX4 and FTH1. The pharmacological mechanism of CYW in the treatment of AD may be related to the regulation of Nrf2/SLC7A11/GPX4/FTH1 axis to inhibit neuronal ferroptosis.}, }
@article {pmid39820594, year = {2025}, author = {Guerguer, FZ and Bouribab, A and Karim, EM and Khedraoui, M and Amegrissi, F and Raouf, YS and Samadi, A and Chtita, S}, title = {Moroccan natural products for multitarget-based treatment of Alzheimer's disease: A computational study.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0313411}, pmid = {39820594}, issn = {1932-6203}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Hesperidin/chemistry/pharmacology/therapeutic use ; Biological Products/chemistry/therapeutic use/pharmacology ; Molecular Dynamics Simulation ; Flavanones/chemistry/therapeutic use/pharmacology ; Morocco ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism/chemistry ; Plants, Medicinal/chemistry ; }, abstract = {Alzheimer's disease is a neurodegenerative disorder that impairs neurocognitive functions. Acetylcholinesterase, Butyrylcholinesterase, Monoamine Oxidase B, Beta-Secretase, and Glycogen Synthase Kinase Beta play central roles in its pathogenesis. Current medications primarily inhibit AChE but fail to halt or reverse disease progression due to the multifactorial nature of Alzheimer's. This underscores the necessity of developing multi-target ligands for effective treatment. This study investigates the potential of phytochemical compounds from Moroccan medicinal plants as multi-target agents against Alzheimer's disease, employing computational approaches. A virtual screening of 386 phytochemical compounds, followed by an assessment of pharmacokinetic properties and ADMET profiles, led to the identification of two promising compounds, naringenin (C23) and hesperetin (C24), derived from Anabasis aretioides. These compounds exhibit favourable pharmacokinetic profiles and strong binding affinities for the five key targets associated with the disease. Density functional theory, molecular dynamics simulations, and MM-GBSA calculations further confirmed their structural stability, with a slight preference for C24, exhibiting superior intermolecular interactions and overall stability. These findings provide a strong basis for further experimental research, including in vitro and in vivo studies, to substantiate their potential efficacy in Alzheimer's disease.}, }
@article {pmid39820472, year = {2025}, author = {Liu, Y and Ding, X and Jia, S and Gu, X}, title = {Current understanding and prospects for targeting neurogenesis in the treatment of cognitive impairment.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-00802}, pmid = {39820472}, issn = {1673-5374}, abstract = {Adult hippocampal neurogenesis is linked to memory formation In the adult brain, with new neurons in the hippocampus exhibiting greater plasticity during their immature stages compared to mature neurons. Abnormal adult hippocampal neurogenesis is closely associated with cognitive impairment in central nervous system diseases. Targeting and regulating adult hippocampal neurogenesis have been shown to improve cognitive deficits. This review aims to expand the current understanding and prospects of targeting neurogenesis in the treatment of cognitive impairment. Recent research indicates the presence of abnormalities in AHN in several diseases associated with cognitive impairment, including cerebrovascular diseases, Alzheimer's disease, aging-related conditions, and issues related to anesthesia and surgery. The role of these abnormalities in the cognitive deficits caused by these diseases has been widely recognized, and targeting AHN is considered a promising approach for treating cognitive impairment. However, the underlying mechanisms of this role are not yet fully understood, and the effectiveness of targeting abnormal adult hippocampal neurogenesis for treatment remains limited, with a need for further development of treatment methods and detection techniques.By reviewing recent studies, we classify the potential mechanisms of adult hippocampal neurogenesis abnormalities into four categories: immunity, energy metabolism, aging, and pathological states. In immunity-related mechanisms, abnormalities in meningeal, brain, and peripheral immunity can disrupt normal adult hippocampal neurogenesis.Lipid metabolism and mitochondrial function disorders are significant energy metabolism factors that lead to abnormal adult hippocampal neurogenesis. During aging, the inflammatory state of the neurogenic niche and the expression of aging-related microRNAs contribute to reduced adult hippocampal neurogenesis and cognitive impairment in older adult patients. Pathological states of the body and emotional disorders may also result in abnormal adult hippocampal neurogenesis. Among the current strategies used to enhance this form of neurogenesis, physical therapies such as exercise, transcutaneous electrical nerve stimulation, and enriched environments have proven effective. Dietary interventions, including energy intake restriction and nutrient optimization, have shown efficacy in both basic research and clinical trials. However, drug treatments, such as antidepressants and stem cell therapy, are primarily reported in basic research, with limited clinical application. The relationship between abnormal adult hippocampal neurogenesis and cognitive impairment has garnered widespread attention, and targeting the former may be an important strategy for treating the latter. However, the mechanisms underlying abnormal adult hippocampal neurogenesis remain unclear, and treatments are lacking. This highlights the need for greater focus on translating research findings into clinical practice.}, }
@article {pmid39820046, year = {2025}, author = {Guo, T and Hayat, MA and Hu, J}, title = {Ferritin nanoparticles: new strategies for the diagnosis and treatment of central nervous system diseases.}, journal = {Biomedical materials (Bristol, England)}, volume = {20}, number = {2}, pages = {}, doi = {10.1088/1748-605X/adab5a}, pmid = {39820046}, issn = {1748-605X}, mesh = {Humans ; *Ferritins/chemistry/metabolism ; *Blood-Brain Barrier/metabolism ; *Nanoparticles/chemistry ; *Central Nervous System Diseases/diagnosis/drug therapy ; Animals ; *Drug Delivery Systems ; Receptors, Transferrin/metabolism ; Drug Carriers/chemistry ; }, abstract = {Ferritin nanoparticles, which can penetrate the blood-brain barrier (BBB), have gained significant research interest for the diagnosis and treatment of central nervous system (CNS) diseases, including gliomas, Alzheimer's disease, and brain metastases. In recent years, ferritin has been proved as a candidate to cross the BBB using receptor-mediated transport (RMT) mechanism through transferrin receptor 1 (TfR1) which is overexpressed in the cells of the BBB. Various types of cargo molecules, including therapeutics, imaging agents, nucleic acids, and metal nanoparticles, have been incorporated into ferritin nanocages for the diagnosis and treatment of CNS diseases. In particular, low immunogenicity of ferritin implies safety for its usage in clinical practices, and high biocompatibility add to the perspectives of its applications. Furthermore, contemporary strides in molecular biology have enabled some alteration in the configuration of the ferritin outer layers and surface characters so as to enhance the drug encapsulation capacity and conjugation affinity. Such modifications not only enhance the property of ferritin in crossing the BBB, but also enhance its efficacy when applied to CNS diseases. In summary, ferritin, as a drug delivery system, shows great potential for the treatment and diagnosis of CNS diseases.}, }
@article {pmid39819742, year = {2025}, author = {Xu, B and Lei, X and Yang, Y and Yu, J and Chen, J and Xu, Z and Ye, K and Zhang, J}, title = {Peripheral proteinopathy in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {2}, pmid = {39819742}, issn = {2047-9158}, support = {82020108012//National Natural Science Foundation of China/ ; 82371250//National Natural Science Foundation of China/ ; LY24H090006//Natural Science Foundation of Zhejiang Province/ ; LZ23H090002//Natural Science Foundation of Zhejiang Province/ ; 2024C03098//Key Research and Development Program of Zhejiang Province/ ; 2024SSYS0018//Key Research and Development Program of Zhejiang Province/ ; ZR2022QH177//Natural Science Foundation of Shandong Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; alpha-Synuclein/metabolism ; }, abstract = {Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases. Investigating how these peripherally derived proteins influence the progression of neurological disorders could open new horizons for achieving early diagnosis and treatment. This review summarizes the distribution, transportation pathways, and pathogenic mechanisms of several neurodegenerative disease-related pathological proteins in the periphery, proposing that targeting these peripheral pathological proteins could be a promising strategy for preventing and managing neurological diseases.}, }
@article {pmid39819531, year = {2025}, author = {Li, C and Chen, Y and Yao, Y and Shang, Y}, title = {Establishment and Validation of the Diagnostic Value of Oligodendrocyte-related Genes in Alzheimer's Disease.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273339310241205055554}, pmid = {39819531}, issn = {1996-3181}, abstract = {BACKGROUND: AD is a demyelinating disease. Myelin damage initiates the pathological process of AD, resulting in abnormal synaptic function and cognitive decline. The myelin sheath formed by oligodendrocytes (OL) is a crucial component of white matter. Investigating AD from the perspective of OL may offer novel diagnostic and therapeutic perspectives.
OBJECTIVES: This study aimed to analyze the association between OL-related genes and Alzheimer's disease (AD) using bioinformatics and verify this association via molecular biology experiments.
METHODS: The AD datasets were acquired from the Gene Expression Omnibus (GEO) database of NCBI. Consensus clustering was employed to determine the subtypes of AD, followed by evaluating the clinical characteristics of these subtypes. Subsequently, immune infiltration analysis of relevant genes and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identify modules and hub genes associated with AD progression. The intersection of genes obtained was analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. To narrow down the scope and identify OL-related genes with diagnostic potential, three machine learning algorithms were utilized. In addition, the eXtreme Sum (XSum) algorithm was used to screen small molecule drug candidates based on the connectivity map (CMAP) database. Finally, these identified genes were validated using Real-time fluorescence quantitative PCR (RT-qPCR).
RESULTS: Among the three subtypes of AD, Cluster A and Cluster C exhibited increased levels of Braak and neurofibrillary tangles compared to Cluster B. The proportion of females was greater than that of males among the three subclasses of AD. There were no significant differences in age among the three subclasses, but significant differences in gene expression existed. Through WGCNA analysis, 108 genes were identified. Among these, 16 genes were identified as shared genes by the least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machines (SVM) algorithms, and logistic regression further determined 11 genes. The establishment of a nomogram demonstrated the significance of these 11 genes in AD. The "XSum" algorithm revealed five drugs with therapeutic potential for AD. qPCR analysis revealed the upregulation and downregulation of the highlighted genes. According to this study, 11 genes related to OL were also found to be associated with immune cell infiltration in AD patients. These genes demonstrated potential diagnostic value for AD. Additionally, we screened five small molecular drugs that exhibit potential therapeutic effects on AD.
CONCLUSION: This research provides a new perspective for personalized clinical management and treatment of AD.}, }
@article {pmid39819417, year = {2025}, author = {Khan, SA and Qamar, Z and Rohilla, A and Singh, PP and Parvez, S and Baboota, S and Ali, J}, title = {Prospective Utilization of Nanocarriers Loaded with Drug Combination for Treating Alzheimer's Disease.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128348877241202053633}, pmid = {39819417}, issn = {1873-4286}, abstract = {Alzheimer's disease (AD) is a debilitating condition that significantly affects the elderly. Early diagnosis is not only critical for improving patient outcomes but also directly influences the success of emerging therapeutic interventions. A therapeutic strategy targeting only one pathogenic mechanism is unlikely to be very effective, as there is increasing evidence that AD does not have a single pathogenic cause. Therefore, combining medications or developing therapies that address multiple pathways may be beneficial. Most clinical trials can be classified under added therapy rather than combination therapy. Effective treatment of AD likely requires targeting multiple mechanisms, such as amyloid-beta (Aβ) and tau pathology. However, many medications face challenges, including poor solubility, low permeability, and the inability to cross the blood- -brain barrier (BBB). This is where nanocarriers come into play, as they can be loaded with these medications to facilitate targeted drug delivery. This approach enhances the pharmacokinetic profile of drugs in both the blood and the brain. Therefore, this paper provides a concise overview of the use of various nanocarriers loaded with drug combinations for treating AD.}, }
@article {pmid39818939, year = {2025}, author = {Bagán, A and López-Ruiz, A and Abás, S and Ruiz-Cantero, MC and Vasilopoulou, F and Taboada-Jara, T and Griñán-Ferré, C and Pallàs, M and Muguruza, C and Diez-Alarcia, R and Callado, LF and Entrena, JM and Cobos, EJ and Pérez, B and Morales-García, JA and Molins, E and De Jonghe, S and Daelemans, D and Brea, J and Val, C and Loza, MI and Hernández-Hernández, E and García-Sevilla, JA and García-Fuster, MJ and Díaz, C and Fernández-Godino, R and Genilloud, O and Beljkaš, M and Oljačić, S and Nikolic, K and Escolano, C}, title = {Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {3}, pages = {2551-2573}, pmid = {39818939}, issn = {1520-4804}, mesh = {Animals ; Humans ; Male ; Mice ; *Alzheimer Disease/drug therapy/metabolism ; *Analgesics/pharmacology/therapeutic use/chemistry/chemical synthesis/pharmacokinetics ; Drug Discovery ; *Imidazoline Receptors/metabolism/agonists ; Ligands ; Structure-Activity Relationship ; *Organophosphonates/chemical synthesis/chemistry/pharmacology ; }, abstract = {Imidazoline I2 receptors (I2-IRs) are altered in Alzheimer's disease (AD) patients and are associated with analgesia. I2-IRs are not structurally described, and their pharmacological characterization relies on their modulation by highly affine ligands. Herein, we describe the synthesis of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates endowed with relevant affinities for I2-IRs in human brain tissues. The optimal ADME and pharmacokinetic profile of a selected compound, 12d, secured its in vivo exploration in a senescence accelerated prone 8 mice revealing improvement in the cognitive impairment and unveiling the mechanism of action by analyzing specific AD biomarkers. The treatment of a capsaicin-induced mechanical hypersensitivity murine model with 12d revealed analgesic properties devoid of motor coordination issues. The target engagement of 12d was demonstrated by suppression of the analgesic effect by pretreatment with idazoxan. Overall, 12d is a putative candidate for advancing preclinical phases and supports the modulation of I2-IRs as an innovative approach for therapeutics.}, }
@article {pmid39818099, year = {2025}, author = {Esandi, J and Renault, P and Capilla-López, MD and Blanch, R and Edo, Á and Ramirez-Gómez, D and Bosch, A and Almolda, B and Saura, CA and Giraldo, J and Chillón, M}, title = {HEBE: A novel chimeric chronokine for ameliorating memory deficits in Alzheimer's disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {183}, number = {}, pages = {117815}, doi = {10.1016/j.biopha.2025.117815}, pmid = {39818099}, issn = {1950-6007}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Memory Disorders/drug therapy ; *tau Proteins/metabolism ; Mice ; *Mice, Transgenic ; Humans ; *Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Male ; Recombinant Fusion Proteins ; Amyloid beta-Protein Precursor/genetics/metabolism ; Phosphorylation ; Memory/drug effects ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-β and Tau protein depositions, with treatments focusing on single proteins have shown limited success due to the complexity of pathways involved. This study explored the potential of chronokines -proteins that modulate aging-related processes- as an alternative therapeutic approach. Specifically, we focused on a novel pleiotropic chimeric protein named HEBE, combining s-KL, sTREM2 and TIMP2, guided by bioinformatic analyses to ensure the preservation of each protein's conformation, crucial for their functions. In vitro studies confirmed HEBE's stability and enzymatic activities, even suggesting it has different activities compared to the individual chronokines. In vivo experiments on APP/Tau mice revealed improved learning and memory functions with HEBE treatment, along with decreased levels of phosphorylated Tau and minor effects on amyloid-β levels. These findings suggest that HEBE is as a promising therapeutic candidate for ameliorating memory deficits and reducing pTau in an AD mouse model.}, }
@article {pmid39818021, year = {2025}, author = {Dawa, Y and Hua, YC and Hu, FD and Chen, J}, title = {Cellulose filter paper immobilized acetylcholinesterase for rapid screening of enzyme inhibitors in Phyllanthus emblica L.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {256}, number = {}, pages = {116669}, doi = {10.1016/j.jpba.2025.116669}, pmid = {39818021}, issn = {1873-264X}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/analysis ; *Acetylcholinesterase/metabolism ; *Plant Extracts/chemistry/pharmacology ; *Phyllanthus emblica/chemistry ; *Molecular Docking Simulation ; *Tandem Mass Spectrometry/methods ; Chromatography, High Pressure Liquid/methods ; *Cellulose/chemistry ; Enzymes, Immobilized/chemistry/antagonists & inhibitors ; Paper ; Fruit/chemistry ; Reproducibility of Results ; Alkaloids ; Sesquiterpenes ; }, abstract = {Acetylcholinesterase (AChE) is widely recognized as a promising therapeutic target enzyme for Alzheimer's disease (AD). The screening of AChE inhibitors (AChEIs) holds great significance for the treatment of AD. In this study, cellulose filter paper (CFP) -immobilized AChE was prepared and firstly applied to screening AChEIs from 30 % ethanol extract of Phyllanthus emblica L. fruits combined with ultra-high performance liquid chromatography quadrupole time-of-fight mass spectrometry (UHPLC-Q-TOF-MS/MS). Using CFP-immobilized AChE as the bait, AChEIs were harvested and the instantaneous separation characteristics of CFP were utilized to further facilitate the separation of the complex from the inactive components. Ultimately, 27 compounds specifically bound with AChE were screened and identified using UHPLC-Q-TOF-MS/MS. Additionally, molecular docking was employed to explore the binding mechanisms between screened potential inhibitors and AChE. The results show that, most of the screened compounds were found to exhibit higher affinity that of the positive control (huperzine A), and all the compounds expect mucic acid to be well embedded into the active pocket of AChE. To verify the reliability of the screening method and molecular docking, two commercial standards geraniin and ellagic acid were experimented with an AChE inhibition assay in vitro. The results showed that both compounds were found to effectively inhibit AChE with IC50 values of 42.42 ± 7.10 μM, 172.43 ± 9.22 μM. The developed method exhibits the advantages of rapidness and effectiveness in screening of AChEIs from complex herbal extracts.}, }
@article {pmid39817315, year = {2025}, author = {Goodwin, GJ and Briley, DA and Singsank, K and Tanner, D and Maloy-Robertson, M and John, SE}, title = {Neuropsychiatric symptoms predict rate of change in executive function in Alzheimer's disease and related dementias.}, journal = {Journal of the International Neuropsychological Society : JINS}, volume = {31}, number = {1}, pages = {22-31}, doi = {10.1017/S1355617724000730}, pmid = {39817315}, issn = {1469-7661}, mesh = {Humans ; *Executive Function/physiology ; Male ; Female ; Aged ; *Alzheimer Disease/physiopathology/complications ; Aged, 80 and over ; *Cognitive Dysfunction/etiology/physiopathology ; Dementia/physiopathology/etiology ; Neuropsychological Tests ; Disease Progression ; Prognosis ; Longitudinal Studies ; Severity of Illness Index ; }, abstract = {OBJECTIVE: Neuropsychiatric symptoms (NPS) are considered diagnostic and prognostic indicators of dementia and are attributable to neurodegenerative processes. Little is known about the prognostic value of early NPS on executive functioning (EF) decline in Alzheimer's disease and related dementias (ADRD). We examined whether baseline NPS predicted the rate of executive function (EF) decline among older adults with ADRD.
METHOD: Older adults (n = 1625) with cognitive impairment were selected from the National Alzheimer's Coordinating Center database. EF was estimated with a latent factor indicated by scores on Number Span Backward, Letter Fluency, and Trail Making-Part B. A curve of factors (CUFF) latent growth curve model was estimated to examine rate of change over four years. Baseline NPS severity was entered as a predictor in the model to examine its influence on the rate of change in EF over time.
RESULTS: The CUFF models exhibited good fit. EF significantly declined over four waves (slope = -.16, p < .001). Initial visit NPS severity predicted decline in EF (slope = .013, p < .001), such that those with greater baseline NPS severity demonstrated a more rapid decline in EF performance over time. Presence of 2 NPS significantly predicted EF decline, and those with medium total NPS severity (NPS score of 2-4) at baseline exhibited a sharper decline in EF.
CONCLUSIONS: Findings underscore the importance of targeting NPS early across ADRD syndromes to minimize EF decline, offering novel insights into how early NPS treatment may alter cognitive trajectories. We provide an innovative, user-friendly web-based application that may be helpful for personalized treatment planning.}, }
@article {pmid39817194, year = {2025}, author = {Wu, CY and Kupferschmid, AC and Chen, L and McManus, AJ and Kivisäkk, P and Galler, JA and Schwab, NA and DesRuisseaux, LA and Williams, VJ and Gerber, J and Riley, M and Young, C and Guzmán-Vélez, E and Dodge, HH and Tanzi, RE and Singer, CM and Arnold, SE}, title = {Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside (NR) supplementation in older adults with subjective cognitive decline and mild cognitive impairment.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70023}, pmid = {39817194}, issn = {2352-8737}, abstract = {INTRODUCTION: Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 g/day) on cognition and plasma AD biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.
METHODS: The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau[217]), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay (z-scores) for cognition and step counts from wearables. Mixed model for repeated measures was used for between-group comparisons; paired t-tests were used for within-individual comparisons.
RESULTS: Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau[217] concentrations after taking NR, while an 18% increase with PBO (p = 0.02). No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores or step counts. For the within-individual comparison, pTau[217] concentrations significantly decreased during the NR phase compared to the PBO (p = 0.02), while step counts significantly increased during the NR phase than PBO (p = 0.04).
DISCUSSION: Eight weeks NR supplementation is safe and lowered pTau[217] concentrations but did not alter cognition as measured by conventional or novel digital assessments. Further research is warranted to validate NR's efficacy in altering pathological brain aging processes.
HIGHLIGHTS: The integrated study design combines a two-arm parallel trial with a crossover phase, offering the opportunity to enhance sample size for within-individual analysis and assess carryover effects.NR is safe but did not alter cognition as measured by multi-modal assessments in SCD/MCI.For between-group comparison, pTau[217] levels decreased with NR and increased with PBO at 8-week follow-up.For within-individual comparison, step counts increased after NR and decreased after PBO.A larger, longer study with pharmacodynamic and pathophysiological biomarkers is needed to assess NR's disease-modifying effects.}, }
@article {pmid39816194, year = {2025}, author = {Yulug, B and Altay, O and Li, X and Hanoglu, L and Cankaya, S and Velioglu, HA and Lam, S and Yang, H and Coskun, E and Idil, E and Bayraktaroglu, Z and Nogaylar, R and Ozsimsek, A and Yildirim, S and Bolat, I and Kiliclioglu, M and Bayram, C and Yuksel, N and Tozlu, OO and Arif, M and Shoaie, S and Hacimuftuoglu, A and Zhang, C and Nielsen, J and Turkez, H and Borén, J and Uhlén, M and Mardinoglu, A}, title = {Multi-omics characterization of improved cognitive functions in Parkinson's disease patients after the combined metabolic activator treatment: a randomized, double-blinded, placebo-controlled phase II trial.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcae478}, pmid = {39816194}, issn = {2632-1297}, abstract = {Parkinson's disease is primarily marked by mitochondrial dysfunction and metabolic abnormalities. We recently reported that the combined metabolic activators improved the immunohistochemical parameters and behavioural functions in Parkinson's disease and Alzheimer's disease animal models and the cognitive functions in Alzheimer's disease patients. These metabolic activators serve as the precursors of nicotinamide adenine dinucleotide and glutathione, and they can be used to activate mitochondrial metabolism and eventually treat mitochondrial dysfunction. Here, we designed a randomized, double-blinded, placebo-controlled phase II study in Parkinson's disease patients with 84 days combined metabolic activator administration. A single dose of combined metabolic activator contains L-serine (12.35 g), N-acetyl-L-cysteine (2.55 g), nicotinamide riboside (1 g) and L-carnitine tartrate (3.73 g). Patients were administered either one dose of combined metabolic activator or a placebo daily for the initial 28 days, followed by twice-daily dosing for the next 56 days. The main goal of the study was to evaluate the clinical impact on motor functions using the Unified Parkinson's Disease Rating Scale and to determine the safety and tolerability of combined metabolic activator. A secondary objective was to assess cognitive functions utilizing the Montreal Cognitive Assessment and to analyse brain activity through functional MRI. We also performed comprehensive plasma metabolomics and proteomics analysis for detailed characterization of Parkinson's disease patients who participated in the study. Although no improvement in motor functions was observed, cognitive function was shown to be significantly improved (P < 0.0000) in Parkinson's disease patients treated with the combined metabolic activator group over 84 days, whereas no such improvement was noted in the placebo group (P > 0.05). Moreover, a significant reduction (P = 0.001) in Montreal Cognitive Assessment scores was observed in the combined metabolic activator group, with no decline (P > 0.05) in the placebo group among severe Parkinson's disease patients with lower baseline Montreal Cognitive Assessment scores. We showed that improvement in cognition was associated with critical brain network alterations based on functional MRI analysis, especially relevant to areas with cognitive functions in the brain. Finally, through a comprehensive multi-omics analysis, we elucidated the molecular mechanisms underlying cognitive improvements observed in Parkinson's disease patients. Our results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson's disease patients as recently shown in Alzheimer's disease patients. The trial was registered in ClinicalTrials.gov NCT04044131 (17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131).}, }
@article {pmid39816083, year = {2024}, author = {Widaja, E and Pawitan, JA}, title = {Integrating epigenetic modification and stem cell therapy strategies: A novel approach for advancing Alzheimer's disease treatment - A literature review.}, journal = {Narra J}, volume = {4}, number = {3}, pages = {e935}, pmid = {39816083}, issn = {2807-2618}, mesh = {*Alzheimer Disease/therapy/genetics/metabolism ; Humans ; *Epigenesis, Genetic ; *Stem Cell Transplantation/methods ; DNA Methylation ; MicroRNAs/genetics/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most frequent form of dementia and represents an increasing global burden, particularly in countries like Indonesia, where the population has begun to age significantly. Current medications, including cholinesterase inhibitors and NMDA receptor antagonists, have modest effects on clinical symptoms in the early to middle stages, but there is no curative treatment available so far despite progress. Activating or repressing epigenetic modifications, including DNA methylation, histone modification and microRNA regulation, appears to play an important role in AD development. These alterations further enact transcriptional changes relevant to the signature AD pathologies of amyloid-β deposition, tau protein malfunctioning, neuroinflammation, and neuronal death. Here, we discuss the feasibility of targeting these epigenetic alterations as a new treatment strategy due to the reversibility of epigenetics and their ability to correct faulty gene expression. We also review the combined promise of stem cell therapies and epigenetic modulation in neurodegeneration, inflammation and cognitive decline. This combined approach may provide a multifaceted strategy to slow disease progression, replace lost neurons, and restore neural function. Despite challenges, including ethical, financial, and methodological barriers, ongoing research in epigenetic modulation and stem cell therapy holds promise for pioneering therapies in AD.}, }
@article {pmid39815655, year = {2025}, author = {Bhattacharya, RS and Singh, R and Panghal, A and Thakur, A and Singh, L and Verma, RK and Singh, C and Goyal, M and Kumar, J}, title = {Multi-Targeting Phytochemicals for Alzheimer's Disease.}, journal = {Phytotherapy research : PTR}, volume = {39}, number = {3}, pages = {1453-1483}, doi = {10.1002/ptr.8435}, pmid = {39815655}, issn = {1099-1573}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Phytochemicals/pharmacology/therapeutic use ; *tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Antioxidants/pharmacology/therapeutic use ; Animals ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a type of neurodegenerative illness in which β-amyloid (Aβ) and tau protein accumulate in neurons in the form of tangles. The pathophysiological pathway of AD consists of Aβ-amyloid peptides, tau proteins, and oxidative stress in neurons and increased neuro-inflammatory response. Food and Drug Administration in the United States has authorized various drugs for the effective treatment of AD, which include galantamine, rivastigmine, donepezil, memantine, sodium oligomannate, lecanemab, and aducanumab. The major disadvantage of these drugs is that they only provide "symptomatic" relief. They are most effective in the early stages or for mild to moderate cases of the disease, but are not suitable for long-term use. Besides conventional therapies, phytochemicals have the potential to stop the progression of AD. According to research, the use of potential phytochemicals against AD has gained attention due to their potent anti-inflammatory, antioxidant, anti-hyperphosphorylation of the tau protein, metal chelation, and anti-amyloid properties. This study seeks to provide an up-to-date compilation of the most current and promising breakthroughs in AD therapy using phytochemicals. It could be concluded that phytochemicals light serve as an effective therapy for AD. However, more mechanistic investigations are needed to determine the clinical implications of phytochemicals in AD treatment.}, }
@article {pmid39815147, year = {2025}, author = {Gao, M and Kong, W and Liu, K and Wen, G and Yu, Y and Zhu, Y and Jiang, Z and Wei, K}, title = {Exploring Brain Imaging and Genetic Risk Factors in Different Progression States of Alzheimer's Disease Through OSnetNMF-Based Methods.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {1}, pages = {7}, pmid = {39815147}, issn = {1559-1166}, mesh = {*Alzheimer Disease/genetics/diagnostic imaging ; Humans ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/metabolism ; Cognitive Dysfunction/diagnostic imaging/genetics ; Algorithms ; Female ; Aged ; Male ; Disease Progression ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with no effective treatment, often preceded by mild cognitive impairment (MCI). Multimodal imaging genetics integrates imaging and genetic data to gain a deeper understanding of disease progression and individual variations. This study focuses on exploring the mechanisms that drive the transition from normal cognition to MCI and ultimately to AD. As an effective joint feature extraction and dimensionality reduction method, non-negative matrix factorization (NMF) and its improved variants, particularly the network-based non-negative matrix factorization (netNMF), have been widely used in multimodal analysis to mine brain imaging and genetic data by considering the interactions between different features. However, many of these methods overlook the importance of the coefficient matrix and do not address issues related to data accuracy and feature redundancy. To address these limitations, we propose an orthogonal sparse network non-negative matrix factorization (OSnetNMF) algorithm, which introduces orthogonal and sparse constraints based on netNMF. By establishing linear relationships between structural magnetic resonance imaging (sMRI) and corresponding gene expression data, OSnetNMF reduces feature redundancy and decreases correlation between data, resulting in more accurate and reliable biomarker extraction. Experiments demonstrate that the OSnetNMF algorithm can accurately identify risk regions of interest (ROIs) and key genes that characterize AD progression, revealing significant trends in ROI pairs such as l4thVen-HIF1A, rBst-MPO, and rBst-PTK2B. Comparative experiments show that the improved algorithm outperforms traditional methods, identifying more disease-related biomarkers and achieving better reconstruction performance.}, }
@article {pmid39814858, year = {2025}, author = {Li, G and Hsu, LM and Wu, Y and Bozoki, AC and Shih, YI and Yap, PT}, title = {Revealing excitation-inhibition imbalance in Alzheimer's disease using multiscale neural model inversion of resting-state functional MRI.}, journal = {Communications medicine}, volume = {5}, number = {1}, pages = {17}, pmid = {39814858}, issn = {2730-664X}, support = {R01 EB008374/EB/NIBIB NIH HHS/United States ; R01EB006733//U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB)/ ; R01 EB006733/EB/NIBIB NIH HHS/United States ; R01EB008374//U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB)/ ; R01 MH125479/MH/NIMH NIH HHS/United States ; R01MH125479//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R21 AG083589/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a serious neurodegenerative disorder without a clear understanding of pathophysiology. Recent experimental data have suggested neuronal excitation-inhibition (E-I) imbalance as an essential element of AD pathology, but E-I imbalance has not been systematically mapped out for either local or large-scale neuronal circuits in AD, precluding precise targeting of E-I imbalance in AD treatment.
METHOD: In this work, we apply a Multiscale Neural Model Inversion (MNMI) framework to the resting-state functional MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify brain regions with disrupted E-I balance in a large network during AD progression.
RESULTS: We observe that both intra-regional and inter-regional E-I balance is progressively disrupted from cognitively normal individuals, to mild cognitive impairment (MCI) and to AD. Also, we find that local inhibitory connections are more significantly impaired than excitatory ones and the strengths of most connections are reduced in MCI and AD, leading to gradual decoupling of neural populations. Moreover, we reveal a core AD network comprised mainly of limbic and cingulate regions. These brain regions exhibit consistent E-I alterations across MCI and AD, and thus may represent important AD biomarkers and therapeutic targets. Lastly, the E-I balance of multiple brain regions in the core AD network is found to be significantly correlated with the cognitive test score.
CONCLUSIONS: Our study constitutes an important attempt to delineate E-I imbalance in large-scale neuronal circuits during AD progression, which may facilitate the development of new treatment paradigms to restore physiological E-I balance in AD.}, }
@article {pmid39814774, year = {2025}, author = {Rajkumar, M and Davis Presley, SI and Thiyagarajulu, N and Girigoswami, K and Janani, G and Kamaraj, C and Madheswaran, B and Prajapati, B and Ali, N and Khan, MR}, title = {Gelatin/PLA-loaded gold nanocomposites synthesis using Syzygium cumini fruit extract and their antioxidant, antibacterial, anti-inflammatory, antidiabetic and anti-Alzheimer's activities.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {2110}, pmid = {39814774}, issn = {2045-2322}, support = {SSN/CE/SRF/2024//SSN College of Engineering/ ; RSPD2024R940//King Saud University/ ; RSPD2024R940//King Saud University/ ; }, mesh = {*Syzygium/chemistry ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Antioxidants/pharmacology/chemistry ; *Plant Extracts/chemistry/pharmacology ; Animals ; *Gold/chemistry ; *Nanocomposites/chemistry ; *Hypoglycemic Agents/chemistry/pharmacology ; *Anti-Inflammatory Agents/pharmacology/chemistry ; *Alzheimer Disease/drug therapy ; *Gelatin/chemistry ; Zebrafish ; Fruit/chemistry ; Humans ; Staphylococcus aureus/drug effects ; Metal Nanoparticles/chemistry ; }, abstract = {Nanotechnology has experienced significant advancements, attracting considerable attention in various biomedical applications. This innovative study synthesizes and characterizes Ge/PLA/AuNCs (gelatin/PLA/gold nanocomposites) using Syzygium cumini extract to evaluate their various biomedical applications. The UV-Visible spectroscopy results in an absorption peak at 534 nm were primarily confirmed by Ge/PLA/AuNCs synthesis. The FTIR spectrum showed various functional groups and the XRD patterns confirmed the crystalline shape and structure of nanocomposites. The FESEM and HRTEM results showed a oval shape of Ge/PLA/AuNCs with an average particle size of 21 nm. The Ge/PLA/AuNC's remarkable antioxidant activity, as evidenced by DPPH (70.84 ± 1.64%), ABTS activity (86.17 ± 1.96%), and reducing power activity (78.42 ± 1.48%) at a concentration of 100 μg/mL was observed. The zone of inhibition against Staphylococcus aureus (19.45 ± 0.89 mm) and Echericia coli (20.83 ± 0.97 mm) revealed the excellent antibacterial activity of Ge/PLA/AuNCs. The anti-diabetic activity of Ge/PLA/AuNCs was supported by inhibition of α-amylase (82.56 ± 1.49%) and α-glucosidase (80.27 ± 1.57%). The anti-Alzheimer activity was confirmed by inhibition of the AChE (76.37 ± 1.18%) and BChE (85.94 ± 1.38%) enzymes. In vivo studies of zebrafish embryos showed that Ge/PLA/AuNCs have excellent biocompatibility and nontoxicity. The SH-SY5Y cell line study demonstrated improved cell viability (95.27 ± 1.62%) and enhanced neuronal cell growth following Ge/PLA/AuNCs treatment. In conclusion, the present study highlights the cost-effective and non-toxic properties of Ge/PLA/AuNCs. Furthermore, it presents an attractive and promising approach for various future biomedical applications.}, }
@article {pmid39814656, year = {2025}, author = {Schöll, M and Vrillon, A and Ikeuchi, T and Quevenco, FC and Iaccarino, L and Vasileva-Metodiev, SZ and Burnham, SC and Hendrix, J and Epelbaum, S and Zetterberg, H and Palmqvist, S}, title = {Cutting through the noise: A narrative review of Alzheimer's disease plasma biomarkers for routine clinical use.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {4}, pages = {100056}, doi = {10.1016/j.tjpad.2024.100056}, pmid = {39814656}, issn = {2426-0266}, mesh = {*Alzheimer Disease/diagnosis/blood ; Humans ; *Biomarkers/blood ; *tau Proteins/blood/cerebrospinal fluid ; Phosphorylation ; }, abstract = {As novel, anti-amyloid therapies have become more widely available, access to timely and accurate diagnosis has become integral to ensuring optimal treatment of patients with early-stage Alzheimer's disease (AD). Plasma biomarkers are a promising tool for identifying AD pathology; however, several technical and clinical factors need to be considered prior to their implementation in routine clinical use. Given the rapid pace of advancements in the field and the wide array of available biomarkers and tests, this review aims to summarize these considerations, evaluate available platforms, and discuss the steps needed to bring plasma biomarker testing to the clinic. We focus on plasma phosphorylated(p)-tau, specifically plasma p-tau217, as a robust candidate across both primary and secondary care settings. Despite the high performance and robustness demonstrated in research, plasma p-tau217, like all plasma biomarkers, can be affected by analytical and pre-analytical variability as well as patient comorbidities, sex, ethnicity, and race. This review also discusses the advantages of the two-point cut-off approach to mitigating these factors, and the challenges raised by the resulting intermediate range measurements, where clinical guidance is still unclear. Further validation of plasma p-tau217 in heterogeneous, real-world cohorts will help to increase confidence in testing and support establishing a standardized approach. Plasma biomarkers are poised to become a more affordable and less invasive alternative to PET and CSF testing. However, understanding the factors that impact plasma biomarker measurement and interpretation is critical prior to their implementation in routine clinical use.}, }
@article {pmid39814340, year = {2025}, author = {Yang, W and Yu, W and Lv, Y}, title = {Neuroprotective effects of chitinase-1 and calcitonin gene-related peptide on Alzheimer's disease by promoting lysosomal function.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {3}, pages = {879-888}, doi = {10.1177/13872877241307257}, pmid = {39814340}, issn = {1875-8908}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Lysosomes/drug effects/metabolism ; Mice ; *Neuroprotective Agents/pharmacology ; *Hippocampus/drug effects/metabolism ; *Mice, Inbred C57BL ; *Calcitonin Gene-Related Peptide/metabolism ; *Neurons/drug effects/metabolism ; Chitinases/metabolism ; Microglia/drug effects/metabolism ; Disease Models, Animal ; Male ; }, abstract = {BACKGROUND: The amyloid cascade hypothesis still dominates in Alzheimer's disease (AD), and the acceleration of the clearance efficiency of amyloid-β (Aβ) has been always considered as an effective treatment option to slow the occurrence and progression of AD.
OBJECTIVE: This study aims to explore the role of zkscan3 and its related pathways in AD of the microglia-mediated pathogenesis, and whether the combined effect of drugs can exert neuroprotective function.
METHODS: N9 mouse microglia and HT-22 mouse hippocampal neurons were randomly divided into 6 groups, qRT-PCR technique was used to detect the gene expression level of zkscan3 and the genes related to lysosome generation and function. Fourteen C57 mice were randomly divided into two groups, and drug intervention model mice were randomly selected to establish from the AD group. Transmission electron microscope was used to detect the cell status and lysosome function in the hippocampus together with the other two groups.
RESULTS: Compared with the AD model group, the gene expression of zkscan3 in the drug intervention group was downregulated, and the degree of neuronal injury in the hippocampus was reduced, the structure and number of synapses were improved, and the function of intracellular lysosome was enhanced.
CONCLUSIONS: Zkscan3 and its related genes play a vital role in the development of AD. CGRP and CHIT-1, as a combined intervention, imparts effects through zkscan3-related pathways to improve lysosomal function and exert certain neuroprotective effects.}, }
@article {pmid39814324, year = {2025}, author = {Fu, Q and Yu, Q and Luo, H and Liu, Z and Ma, X and Wang, H and Cheng, Z}, title = {Protective effects of wogonin in the treatment of central nervous system and degenerative diseases.}, journal = {Brain research bulletin}, volume = {221}, number = {}, pages = {111202}, doi = {10.1016/j.brainresbull.2025.111202}, pmid = {39814324}, issn = {1873-2747}, mesh = {Humans ; *Flavanones/pharmacology/therapeutic use ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; Central Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Wogonin, an O-methylated flavonoid extracted from Scutellaria baicalensis, has demonstrated profound neuroprotective effects in a range of central nervous system (CNS) diseases. This review elucidates the pharmacological mechanisms underlying the protective effects of wogonin in CNS diseases, including ischemic stroke, hemorrhagic stroke, traumatic brain injury, epilepsy, anxiety, neurodegenerative diseases, and CNS infections. Wogonin modulates key signaling pathways, such as the MAPK, NF-κB, and ROS pathways, contributing to its anti-inflammatory, antioxidant, and antiapoptotic properties. In ischemic stroke models, wogonin reduces infarct size and enhances neurological outcomes by mitigating inflammation and oxidative stress. For patients with hemorrhagic stroke and traumatic brain injury, it accelerates hematoma regression, mitigates secondary brain damage, and promotes neurogenesis, making it an entirely new treatment option for patients with limited access to this type of therapy. Its anticonvulsant and anxiolytic effects are mediated through GABA-A receptor modulation. Moreover, wogonin shows promise in treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease by promoting autophagy and reducing neuroinflammation. Additionally, it exhibits antiviral properties, offering potential benefits against CNS infections. Despite extensive preclinical evidence, further clinical studies are warranted to confirm its efficacy and safety in humans. This review highlights the great therapeutic potential of wogonin in terms of CNS protection. However, despite the substantial preclinical evidence, further large-scale clinical studies are necessary. Future researchers need to further explore the long-term efficacy and safety of wogonin in clinical trials and translate it for early application in the clinical treatment of true CNS disorders.}, }
@article {pmid39814203, year = {2025}, author = {Chen, B and Yang, H and Bai, R and Du, X and Gao, Y and Zheng, L}, title = {Engineering silica nanocoated whole-cell asymmetric biocatalyst for efficient preparation of a key chiral intermediate of (S)-Rivastigmine.}, journal = {Journal of biotechnology}, volume = {399}, number = {}, pages = {19-27}, doi = {10.1016/j.jbiotec.2025.01.005}, pmid = {39814203}, issn = {1873-4863}, mesh = {*Silicon Dioxide/chemistry ; *Biocatalysis ; *Rivastigmine/chemistry ; Glucose 1-Dehydrogenase/metabolism/genetics/chemistry ; Molecular Docking Simulation ; Stereoisomerism ; Aldo-Keto Reductases/genetics/metabolism/chemistry ; Escherichia coli/genetics ; }, abstract = {In our previous study, the whole cells containing an aldo-keto reductase (yhdN) and glucose dehydrogenase (GDH) were constructed and applied in a stereoselective carbonyl reduction reaction to prepare (S)-NEMCA-HEPE, being a key chiral intermediate of (S)-Rivastigmine which is widely prescribed for the treatment of Alzheimer's disease. Although the conversion and enantiomeric excess (e.e.) could reach to 78.2 % and 99 %, respectively, ionic liquid as an additive was required to improve the permeability of cell membrane. To further simplify the reaction, the molecular docking and saturation mutagenesis technology were used here to obtain an activity-improved yhdN variant such as G19A. And then, both excellent conversion and e.e. of 99 % for (S)-NEMCA-HEPE could be achieved within 40 min by using only G19A-GDH whole cell as a catalyst without any additive. However, the use of the whole cells still faces the issues of poor operation stability and adverse application prospect. Subsequently, a hydrophobic "cell-in-shell" complex of G19A-GDH@O-Silica was constructed by using a silica nanocoated technology. The obtained G19A-GDH@O-Silica exhibited an excellent conversion towards the asymmetric carbonyl reduction, and a good tolerance in changing thermal, pH, and storage environmental. Giving 76.3 % of reaction conversion even after the 11th cycle of reuse, indicated that G19A-GDH@O-Silica also possessed ideal recyclability. The aim of this study is to provide a rapid, and cost-effective nanocoated whole-cell biocatalyst for efficient preparation of (S)-NEMCA-HEPE. The simplicity and robustness of the immobilization approach may become a powerful tool to utilize whole-cell catalysts towards organic catalysis.}, }
@article {pmid39814004, year = {2025}, author = {Xu, M and Wang, L and Meng, Y and Kang, G and Jiang, Q and Yan, T and Che, F}, title = {The role of lipid metabolism in cognitive impairment.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {1}, pages = {1-13}, pmid = {39814004}, issn = {1678-4227}, support = {2023M732121//China Postdoctoral Science Foundation/ ; ZR2023QH090//Natural Science Foundation of Shandong Province/ ; ZR2022MH119//Natural Science Foundation of Shandong Province/ ; XYFY202343//Development fund of the Affiliated Hospital of Xuzhou Medical University/ ; }, mesh = {Humans ; *Lipid Metabolism/physiology ; *Cognitive Dysfunction/metabolism/physiopathology/etiology ; *Insulin Resistance/physiology ; *Alzheimer Disease/metabolism/physiopathology ; Amyloid beta-Peptides/metabolism ; Apolipoproteins E/metabolism ; Dementia, Vascular/metabolism/physiopathology ; Disease Progression ; tau Proteins/metabolism ; Brain/metabolism ; }, abstract = {Alzheimer's disease (AD), diabetic cognitive impairment (DCI), and vascular dementia (VD) are considered the most common causes of severe cognitive impairment in clinical practice. Numerous factors can influence their progression, and many studies have recently revealed that metabolic disorders play crucial roles in the progression of cognitive impairment. Mounting evidence indicate that the regulation of lipid metabolism is a major factor in maintaining brain homeostasis. Generally, abnormalities in lipid metabolism can affect amyloid-beta (Aβ) deposition, tau hyperphosphorylation, and insulin resistance through lipid metabolic signaling cascades; affect the neuronal membrane structure, neurotransmitter synthesis and release; and promote synapse growth, which can impact neural signal transmission and exacerbate disease progression in individuals with cognitive impairment, including AD, DCI, and VD. Moreover, apolipoprotein E (APOE), a key protein in lipid transport, is involved in the occurrence and development of the aforementioned diseases by regulating lipid metabolism. The present article mainly discusses how lipid metabolic disorders in the brain microenvironment are involved in regulating the progression of cognitive impairment, and it explores the regulatory effects of targeting the key lipid transport protein APOE in the context of the role of lipid metabolism in the common pathogenesis of three diseases-Aβ deposition, tau hyperphosphorylation, and insulin resistance-which will help elucidate the potential of targeting lipid metabolism for the treatment of cognitive impairment.}, }
@article {pmid39813887, year = {2025}, author = {Maji, M and Khajanchi, S}, title = {Mathematical models on Alzheimer's disease and its treatment: A review.}, journal = {Physics of life reviews}, volume = {52}, number = {}, pages = {207-244}, doi = {10.1016/j.plrev.2025.01.004}, pmid = {39813887}, issn = {1873-1457}, mesh = {*Alzheimer Disease/therapy ; Humans ; Animals ; Models, Theoretical ; Oxidative Stress ; Models, Biological ; }, abstract = {Alzheimer's disease is a gradually advancing neurodegenerative disease. According to the report by "World Health Organization (WHO)", there are over 55 million individuals currently living with Alzheimer's disease and other dementia globally, and the number of sufferers is increasing every day. In absence of effective cures and preventive measures, this number is predicted to triple by 2050. The disease's origin is still unclear, and also no such treatment is available for eradicating the disease. Based on the crucial factors that are connected to the disease's progression, the authors developed several types of mathematical models. We review such mathematical models that are utilized to better understand the pathophysiology of Alzheimer's disease. Section-wise, we categorize the mathematical models in terms of different components that might be responsible for Alzheimer's disease. We explain the mathematical models with their descriptions and respective conclusions. In addition to mathematical models, we concentrate on biological aspects of the disease and possible therapeutic targets. We explore the disease's biological basis primarily to understand how proteins, glial cells, cytokines, genes, calcium signaling and oxidative stress contribute to the disease. We go through several treatment targets that might stop the progression of the disease or at least slow it down. We present a table that summarizes the mathematical models in terms of their formalisms, highlighting key components and important remarks.}, }
@article {pmid39813317, year = {2025}, author = {Brandao, W and Jain, N and Yin, Z and Kleemann, KL and Carpenter, M and Bao, X and Serrano, JR and Tycksen, E and Durao, A and Barry, JL and Baufeld, C and Guneykaya, D and Zhang, X and Litvinchuk, A and Jiang, H and Rosenzweig, N and Pitts, KM and Aronchik, M and Yahya, T and Cao, T and Takahashi, MK and Krishnan, R and Davtyan, H and Ulrich, JD and Blurton-Jones, M and Ilin, I and Weiner, HL and Holtzman, DM and Butovsky, O}, title = {Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy.}, journal = {Science translational medicine}, volume = {17}, number = {781}, pages = {eadk3690}, doi = {10.1126/scitranslmed.adk3690}, pmid = {39813317}, issn = {1946-6242}, mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Xenon/pharmacology/administration & dosage ; *Disease Models, Animal ; Administration, Inhalation ; *Tauopathies/drug therapy/pathology ; Mice ; Amyloidosis/drug therapy/pathology ; Mice, Transgenic ; Alzheimer Disease/drug therapy/pathology ; Humans ; Brain/pathology/drug effects/metabolism ; Plaque, Amyloid/pathology ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre-neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.}, }
@article {pmid39812690, year = {2025}, author = {Zhao, C and Li, T and Hao, S and Zhao, L and Han, Y and Cai, Y}, title = {Dysregulation of the molecular clock by blood-borne factors in Alzheimer's disease patients.}, journal = {Journal of neurology}, volume = {272}, number = {2}, pages = {121}, pmid = {39812690}, issn = {1432-1459}, support = {2021YFC2501205//Key Technologies Research and Development Program of Anhui Province/ ; 2021ZD0201101//the STI2030-Major Project/ ; 2022ZD0211800//the STI2030-Major Project/ ; YC202301QX0148//Beijing Translational Medicine Promotion Project/ ; 82020108013//the National Nature Science Foundation of China/ ; }, mesh = {Humans ; *Alzheimer Disease/blood ; Male ; Female ; Aged ; *Cognitive Dysfunction/etiology/blood/physiopathology ; Longitudinal Studies ; Aged, 80 and over ; Circadian Rhythm/physiology ; Middle Aged ; Amyloid beta-Peptides/blood/metabolism ; ARNTL Transcription Factors/genetics ; Nuclear Receptor Subfamily 1, Group D, Member 1/genetics ; Biomarkers/blood ; }, abstract = {BACKGROUND: Circadian disruptions are increasingly recognized in Alzheimer's disease (AD) patients and may influence disease onset and progression. This study examines how AD pathology affects blood-borne factors that regulate circadian rhythms.
METHODS: Eighty-five participants from the Sino Longitudinal Study on Cognitive Decline were enrolled: 35 amyloid-beta negative normal controls (Aβ- NCs), 23 amyloid-beta positive normal controls (Aβ+ NCs), 15 patients with amnestic mild cognitive impairment (aMCI), and 12 with Alzheimer's disease dementia (ADD). Patients with aMCI and ADD were grouped as cognitively impaired (CI). Cellular circadian period length was assessed using a serum-based assay. Expression levels of clock genes in serum-treated cells and in leukocytes of participants were measured via real-time PCR. Plasma biomarkers were quantified using a single-molecule array immunoassay. Pineal parenchymal and hippocampal volumes were determined by magnetic resonance imaging.
RESULTS: The cellular circadian period length was significantly extended by serum from CI patients than by that from Aβ- NCs (p < 0.01). Treatment of cells with serum from the CI patients resulted in suppressed expression of the clock genes Bmal1 and Nr1d1. Strong relationships between the expression levels of clock genes observed in leukocytes of the Aβ- NC group did not appear in those of the Aβ+ NC or CI groups. The significant correlation of cellular circadian period length and the pineal volume was only observed in the Aβ- NC group, but not in the Aβ+ NC or CI groups.
CONCLUSIONS: This study indicates the presence of significant changes in blood-borne factors that could affect the circadian rhythms in AD, starting even at preclinical stages. These alterations could precede cognitive decline and contribute to AD pathogenesis.
TRIAL REGISTRATION: The cohort is registered at ClinicalTrials.gov (SILCODE: NCT03370744; Registered on Mar 15[th], 2017).}, }
@article {pmid39812543, year = {2025}, author = {Zong, NC and Zhang, Y and Huang, Y and Cai, H}, title = {Addressing Healthy Aging: Time to Stop a Tsunami of Rising Alzheimer's Disease.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.1476}, pmid = {39812543}, issn = {2152-5250}, abstract = {Alzheimer's disease [AD] disproportionately affects our seniors, diminishing their health and life expectancy. As the world population grows older, the collective burden of AD has become unsustainable. Globally, there were 43.8 million patients in 2016, with a projection of affecting 152 million by 2050. Recent discoveries have shown that molecular changes characteristic to AD manifested 20 years before discernable neurological phenotypes emerge. It is feasible to halt or reverse this pathological process before reaching an irremediable stage. To take advantage of this treatment window, we need to make rapid progress in early detection and monitoring, targeted implementation of preventative measures, invention of novel therapeutics, and pragmatic ramping-up of relevant supporting policies. PET is a powerful tool for prognosis. The utilization of AI technology, on the other hand, has favorable features of low cost per capita, easy dissemination and broad scale data collection to uncover previously unknown hotspots or risk factors. FDA approved drugs, lecanemab and donanemab, have started to show efficacy to put a pause on AD progression. Additional clinical data will enable comprehensive evaluation of the impacts of these drugs. Gene therapy holds the potential of eliciting long term protection, while several candidate loci have been identified. The urgency of a tsunami of rising AD epidemiology demands rapid actions on all fronts of advanced diagnostics, monitoring, preventative and interventive strategies.}, }
@article {pmid39812538, year = {2025}, author = {Iqbal, Z and El Hamamy, A and Le, NM and Ranjan, A and Zhang, Y and Qi, L and Manwani, B and Tan, C and McCullough, LD and Li, J}, title = {Targeting Astrogliosis in the Retrotrapezoid Nucleus: A Novel Approach to Ameliorate Respiratory Dysfunction and Alzheimer's Pathology in Mice.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.0523}, pmid = {39812538}, issn = {2152-5250}, support = {R35 NS132265/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD), a leading cause of dementia, is associated with significant respiratory dysfunctions. Our study explores the role of astrogliosis in the brainstem retrotrapezoid nucleus (RTN), a key breathing regulatory center, and its impact on breathing control and AD pathology in mice. Using Tg-2576 AD and wild-type mice, we investigated the effect of silencing the transforming growth factor-beta receptor II (TGFβR II) in the RTN. We performed behavioral tests, including the Barnes maze and novel object recognition test, along with whole-body plethysmography to assess breathing disorders. Our results showed that AD mice exhibited increased apneas and cognitive impairment, which were significantly mitigated following TGFβR II gene silencing. Immunohistochemistry revealed elevated levels of GFAP and TGFβR II in the RTN of AD mice, which were reduced post-gene silencing, alongside a decrease in amyloid-beta expression in the cortex and hippocampus. These findings suggest that targeting astrogliosis and improving respiratory control may offer a novel therapeutic avenue for managing Alzheimer's disease. Our study provides the first mechanistic insights into how TGFβ signaling influences both respiratory control and AD pathogenesis, highlighting the potential benefits of stabilizing breathing patterns in AD treatment.}, }
@article {pmid39812537, year = {2025}, author = {Wu, Y and Zhou, YM and Wu, W and Jiang, WR and Zhang, XY and Song, SY and Yao, ZH}, title = {TBC1D15 Inhibits Autophagy of Microglia through Maintaining the Damaged Swelling Lysosome in Alzheimer's Disease.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.1373}, pmid = {39812537}, issn = {2152-5250}, abstract = {Autophagy in microglia is essential for the clearance of amyloid-beta (Aβ) and amyloid plaques in Alzheimer's disease. However, reports regarding the levels of autophagy in microglia have been inconsistent; some studies indicate an early enhancement followed by a subsequent reduction, while others describe a persistently weakened state. Notably, there is a lack of systematic studies documenting the temporal changes in microglial autophagy. TBC1D15, a Rab GTPase, plays a crucial role in lysosomal membrane repair, yet its function in regulating microglial autophagy in Alzheimer's disease remains unexplored. Current research suggests that microglial autophagy is activated in 3-month-old AD mice but gradually decreases by 12 months of age. Furthermore, TBC1D15 levels are significantly elevated in the lysosomes of microglia in Alzheimer's disease. Silencing TBC1D15 markedly inhibits swelling and Aβ phagocytosis in BV2 cells following Aβ treatment while simultaneously promoting autophagy and lysophagy. LIMP II/ATG8-TBC1D15-Dynamin2/RAB7 might participate in lysosome swelling of microglia in AD. These findings indicate that TBC1D15 in microglia is critical for the decline of autophagy in Alzheimer's disease. It is suggested that targeting microglial TBC1D15 may be an important strategy for enhancing autophagy, which facilitates the clearance of amyloid plaques as a therapeutic approach for Alzheimer's disease.}, }
@article {pmid39812331, year = {2025}, author = {Huang, X and Jannu, AJ and Song, Z and Jury-Garfe, N and Lasagna-Reeves, CA and , and Johnson, TS and Huang, K and Zhang, J}, title = {Predicting Alzheimer's disease subtypes and understanding their molecular characteristics in living patients with transcriptomic trajectory profiling.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14241}, pmid = {39812331}, issn = {1552-5279}, support = {5R01NS119280//Indiana University Precision Health Initiative NIH TREAT-AD U54/ ; //Alzheimer's Disease Neuroimaging Initiative/ ; //Alzheimer's Drug Discovery Foundation/ ; U54 AG065181/AG/NIA NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //AbbVie/ ; //F. Hoffmann-La Roche Ltd/ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; R01 NS119280/NS/NINDS NIH HHS/United States ; 5U54AG065181//Indiana University Precision Health Initiative NIH TREAT-AD U54/ ; W81XWH-12-2-0012//Department of Defense/ ; //EuroImmun/ ; //Biogen/ ; //Bristol-Myers Squibb Company/ ; U01 AG024904/AG/NIA NIH HHS/United States ; //Araclon Biotech/ ; U01 AG024904/NH/NIH HHS/United States ; //CereSpir, Inc./ ; //BioClinica, Inc./ ; //Cogstate; Eisai Inc./ ; /EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics ; *Transcriptome ; *Disease Progression ; *Biomarkers/blood ; Female ; Aged ; Gene Expression Profiling ; Male ; Leukocytes, Mononuclear/metabolism ; Cohort Studies ; Prognosis ; Monocytes/metabolism ; }, abstract = {INTRODUCTION: Deciphering the diverse molecular mechanisms in living Alzheimer's disease (AD) patients is a big challenge but is pivotal for disease prognosis and precision medicine development.
METHODS: Utilizing an optimal transport approach, we conducted graph-based mapping of transcriptomic profiles to transfer AD subtype labels from ROSMAP monocyte samples to ADNI and ANMerge peripheral blood mononuclear cells. Subsequently, differential expression followed by comparative pathway and diffusion pseudotime analysis were applied to each cohort to infer the progression trajectories. Survival analysis with real follow-up time was used to obtain potential biomarkers for AD prognosis.
RESULTS: AD subtype labels were accurately transferred onto the blood samples of ADNI and ANMerge living patients. Pathways and associated genes in neutrophil degranulation-like immune process, immune acute phase response, and IL-6 signaling were significantly associated with AD progression.
DISCUSSION: The work enhanced our understanding of AD progression in different subtypes, offering insights into potential biomarkers and personalized interventions for improved patient care.
HIGHLIGHTS: We applied an innovative optimal transport-based approach to map transcriptomic data from different Alzheimer's disease (AD) cohort studies and transfer known AD subtype labels from ROSMAP monocyte samples to peripheral blood mononuclear cell (PBMC) samples within ADNI and ANMerge cohorts. Through comprehensive trajectory and comparative analysis, we investigated the molecular mechanisms underlying different disease progression trajectories in AD. We validated the accuracy of our AD subtype label transfer and identified prognostic genetic markers associated with disease progression, facilitating personalized treatment strategies. By identifying and predicting distinctive AD subtypes and their associated pathways, our study contributes to a deeper understanding of AD heterogeneity.}, }
@article {pmid39811702, year = {2025}, author = {Terao, CM and Alexander, MW and Chalmers, RP and Boshmaf, SZ and Paterson, J and Black, SE and Papp, KV and Sperling, RA and Rabin, JS}, title = {Identifying cognitive test scores associated with early tau burden in Alzheimer's disease.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {1}, pages = {e70052}, pmid = {39811702}, issn = {2352-8729}, support = {R01 AG063689/AG/NIA NIH HHS/United States ; U19 AG010483/AG/NIA NIH HHS/United States ; U24 AG057437/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: This study aimed to identify cognitive tests that optimally relate to tau positron emission tomography (PET) signal in the inferior temporal cortex (ITC), a neocortical region associated with early tau accumulation in Alzheimer's disease (AD).
METHODS: We analyzed cross-sectional data from the harvard aging brain study (HABS) (n = 128) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study (n = 393). We used elastic net regression to identify the most robust cognitive correlates of tau PET signal in the ITC. Secondary analyses examined whether the cognitive correlates remained significantly associated with tau after adjusting for structural brain measures.
RESULTS: Episodic memory measures, including both total and "process" scores, were the most robust correlates of ITC tau across both cohorts. These cognitive test scores remained significant after accounting for structural brain measures.
DISCUSSION: These findings highlight the potential of specific episodic memory test scores to detect and monitor neuropathological changes associated with early AD.
HIGHLIGHTS: Machine learning identified cognitive correlates of early Alzheimer's disease tau burden.Both traditional and process scores predicted early tau burden.Episodic memory scores were among the strongest correlates.Cognitive scores remained significant after accounting for structural brain measures.}, }
@article {pmid39811699, year = {2025}, author = {Blotenberg, I and Wittström, F and Michalowsky, B and Platen, M and Wucherer, D and Teipel, S and Hoffmann, W and Thyrian, JR}, title = {Modifiable risk factors and symptom progression in dementia over up to 8 years-Results of the DelpHi-MV trial.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {1}, pages = {e70050}, pmid = {39811699}, issn = {2352-8729}, abstract = {INTRODUCTION: This study investigated the association between modifiable factors and symptom progression in dementia over up to 8 years.
METHODS: Multilevel growth curve models assessed the role of modifiable risk factors (low education, hearing impairment and its treatment, depression, physical inactivity, diabetes and its treatment, smoking, hypertension and its treatment, obesity, alcohol consumption, social isolation, and visual impairment) on cognitive and functional trajectories in 353 people with dementia.
RESULTS: Higher education was associated with higher initial cognitive status but faster decline. Antidiabetic medication was associated with slower cognitive decline, whereas depression and visual impairment were linked to low baseline functioning and faster cognitive decline.
DISCUSSION: Several modifiable risk factors influenced symptom progression. Education initially had a protective effect, whereas depressive symptoms were linked to worse symptom progression. Treatment of comorbidities (diabetes, visual impairment) could have a positive impact on dementia symptoms. Modifiable risk factors are promising targets for tertiary prevention.
HIGHLIGHTS: Modifiable risk factors were associated with symptom progression in dementia over up to 8 years.More education was associated with higher initial cognitive status but faster decline.Depressive symptoms were linked to less favorable symptom progression.Treatment of comorbidities (diabetes, visual impairment) may positively impact the course of symptoms.Modifiable risk factors are promising targets for tertiary prevention.}, }
@article {pmid39810446, year = {2024}, author = {Biswal, B and Satapathy, BS and Mishra, A and Maharana, L and Pattnaik, S}, title = {Potential of Nanoparticle Based Antimicrobial Drug Repurposing to Efficiently Target Alzheimer's: A Concise Update on Evidence-based Research and Challenges Ahead.}, journal = {Current drug discovery technologies}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115701638329824241220055621}, pmid = {39810446}, issn = {1875-6220}, abstract = {Repurposing of drugs through nanocarriers (NCs) based platforms has been a recent trend in drug delivery research. Various routine drugs are now being repurposed to treat challenging neurodegenerative disorders including Alzheimer disease (AD). AD, at present is one of the challenging neurodegenerative disorders characterized by extracellular accumulation of amyloid-β and intracellular accumulations of neurofibrillary tangles. In spite of catchy progress in drug development, effective treatment outcome in AD patients is far-fetched dream. Out of several proposed hypothesis in the development and progression of AD, potential role of microorganisms causing dementia and AD cannot be ruled out. Several recent researches have been documented a clear correlation in between microbial infection and neuronal damage leading to progression of AD. Thus, antimicrobial drugs repurposing has been emerged as alternate, potential, cost-effective strategy to check progression of AD. Further, for efficient delivery of antimicrobial drugs to brain tissue, novel NCs based platforms are the preferred option to bypass blood-brain barrier. Several polymeric and lipid NCs have been extensively studied over the past years to improve antimicrobial drug delivery to brain. The present review encompasses various repurposing strategy of antimicrobial drugs delivered through various NCs to target AD. Evidence-based research outcome compiled from authentic database like Scopus, PubMed, Web of science have been pooled to provide an updated review. Side by side some light has been thrown on the practical problems faced by nanodrug carriers during technology transfer.}, }
@article {pmid39810384, year = {2025}, author = {Mandal, PK and Maroon, JC and Guha Roy, R and Patira, R and Gogniat, MA and Sindhu, B}, title = {The Missing Link in Antiamyloid Therapy.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {3}, pages = {276-280}, doi = {10.1021/acschemneuro.4c00825}, pmid = {39810384}, issn = {1948-7193}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Oxidative Stress/drug effects/physiology ; Cognitive Dysfunction/metabolism ; Animals ; Antibodies, Monoclonal, Humanized/pharmacology/therapeutic use ; Glutathione/metabolism ; }, abstract = {Alzheimer's disease (AD) impacts millions of elderly adults worldwide causing cognitive decline and severe deterioration of activities of daily life. The popular causal hypotheses for several decades include beta-amyloid (Aβ) deposition and tau hyperphosphorylation. AD research and more than 34% of clinical trials in AD are based on these two hypotheses. A phase-III clinical trial of lecanemab in early AD and mild cognitive impaired (MCI) patients reported a delay in cognitive decline of 27% over an 18-month treatment schedule. This multicenter trial found high specificity of lecanemab toward toxic protofibrils and subsequent clearance of beta-amyloid. There were, however, adverse events, which included cerebral edema and intracerebral hemorrhages in 23.1% of patients compared to 9.3% for those who received a placebo. Suboptimal clinical outcomes, brain volume loss, and adverse events in lecanemab treatment prompted a search for an alternative etiopathogenic explanation. Our research and others have focused on the oxidative stress (OS) hypothesis in AD. Autopsy studies have found significant depletion of the master antioxidant glutathione (GSH) in the hippocampal region, and is believed to be an early event in AD progression. Hippocampal GSH depletion is positively correlated with memory impairment. We have confirmed non-invasively with magnetic resonance spectroscopy (MRS) the depletion of GSH in patients with MCI and AD. We therefore propose a combinational therapy involving oral supplementation of gamma-glutamylcysteine (GGC), an early precursor of glutathione, to replenish brain GSH in addition to lecanemab, potentially to maximize desirable outcomes from combined therapeutic approach.}, }
@article {pmid39809960, year = {2025}, author = {Saunders, MR and Qi, M and Huang, ES and Konetzka, RT}, title = {Trends in Co-morbid Dementia and Chronic Kidney Disease.}, journal = {Journal of general internal medicine}, volume = {}, number = {}, pages = {}, pmid = {39809960}, issn = {1525-1497}, support = {K24AG069080/AG/NIA NIH HHS/United States ; RFIAG069857/AG/NIA NIH HHS/United States ; P50MD17349/MD/NIMHD NIH HHS/United States ; R01DK124597/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Little is known about the population of Medicare beneficiaries with both chronic kidney disease (CKD) and Alzheimer's disease and related dementias (ADRD).
METHODS: Using data from Medicare fee-for-service (FFS) beneficiaries aged 65 and over identified through 2011-2019 Master Beneficiary Summary File (MBSF), we estimated the size, growth, and racial-ethnic characteristics of the ADRD and CKD populations. Individuals were classified as having ADRD and CKD based on CMS Chronic Conditions Data Warehouse (CCW) indicators in the MBSF Chronic Conditions file.
RESULTS: Among FFS beneficiaries, the prevalence of CKD has increased from 17.5% in 2011 to 27.9% in 2019, and the prevalence of ADRD has decreased over that time from 13.3 to 12.5%. The prevalence of individuals with co-morbid ADRD and CKD has risen from 4.4 to 6.3% which represents 1.72 million older adults. Black and Hispanic individuals have the highest prevalence of co-morbid CKD and ADRD, averaging 10.0% and 9.0% in 2019, respectively, compared to other racial-ethnic groups (≤ 7.2% all others). In addition, among those previously diagnosed with ADRD, the proportion with co-morbid CKD has been steadily increasing from 25.5% in 2011 to 44.4% in 2019. While the proportion of individuals with ADRD who have co-morbid CKD has increased across all race-ethnicities, it is highest in Black and Hispanic individuals (56.7 and 51%, respectively in 2019).
CONCLUSION/RELEVANCE: The prevalence of Medicare FFS enrollees with both ADRD and CKD is increasing. Although the ADRD prevalence has declined, there is a rising number of individuals with CKD who are diagnosed with ADRD and a rising proportion of those with ADRD who also have CKD. Due to shared clinical and demographic risk factors, interventions to reduce CKD progression could also delay ADRD onset. In patients with both advanced ADRD and advanced CKD, clinicians and policymakers should focus on treatment options that consider both co-morbidities.}, }
@article {pmid39809015, year = {2025}, author = {Afşar, E and Kantar, D}, title = {How does zinc chelation affect liver sphingolipid metabolism in an Alzheimer's-like model?.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {87}, number = {}, pages = {127589}, doi = {10.1016/j.jtemb.2025.127589}, pmid = {39809015}, issn = {1878-3252}, mesh = {Animals ; *Alzheimer Disease/metabolism ; *Zinc/metabolism ; *Liver/metabolism/drug effects ; *Disease Models, Animal ; Rats ; Male ; *Sphingolipids/metabolism ; Rats, Wistar ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Chelating Agents/pharmacology ; Caspase 3/metabolism ; Glutathione/metabolism ; Aldehydes/metabolism ; }, abstract = {BACKGROUND: The present study aimed to evaluate the impact of Cyclo-Z, a combination of Cyclo (His-Pro) plus zinc, on hepatic sphingolipid (SL) metabolism and antioxidant properties in a rat model of Alzheimer's disease (AD).
METHODS: Alzheimer's disease rat model created via intracerebroventricular (i.c.v.) amyloid beta-42 oligomer (AβO) injection into the lateral ventricles. Cyclo-Z administration was performed with daily gavage for 3 weeks after the AβO injection. Ceramide, ceramide kinase (CERK), sphingosine 1 phosphate (S1P), glutathione (GSH), total oxidant capacity (TOS), 4-hydroxynonenal (HNE) and caspase-3 levels were measured with Elisa kit in liver tissue.
RESULTS: S1P, CERK and GSH levels increased and ceramide, TOS, 4 HNE, and caspase-3 levels decreased in the liver tissues of AD group. Cyclo-Z treatment decreased S1P, CERK, ceramide and caspase-3 levels but increased TOS and 4-HNE levels in the liver tissues of AD group.
CONCLUSION: These results showed that SL metabolism was modulated to generate an anti-apoptotic defense system in liver tissue of AD rats.}, }
@article {pmid39808341, year = {2025}, author = {Gladen-Kolarsky, N and Neff, CJ and Hack, W and Brandes, MS and Wiedrick, J and Meza-Romero, R and Lockwood, DR and Quinn, JF and Offner, H and Vandenbark, AA and Gray, NE}, title = {The CD74 inhibitor DRhQ improves short-term memory and mitochondrial function in 5xFAD mouse model of Aβ accumulation.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {95}, pmid = {39808341}, issn = {1573-7365}, support = {R21NS094881/NH/NIH HHS/United States ; 2I01 BX000226//U.S. Department of Veterans Affairs/ ; P30AG066518/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Mitochondria/drug effects/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Antigens, Differentiation, B-Lymphocyte/metabolism ; *Mice, Transgenic ; Male ; *Amyloid beta-Peptides/metabolism ; Female ; *Disease Models, Animal ; *Memory, Short-Term/drug effects ; Histocompatibility Antigens Class II/metabolism ; Microglia/drug effects/metabolism ; Hippocampus/drug effects/metabolism ; }, abstract = {Neuroinflammation and mitochondrial dysfunction are early events in Alzheimer's disease (AD) and contribute to neurodegeneration and cognitive impairment. Evidence suggests that the inflammatory axis mediated by macrophage migration inhibitory factor (MIF) binding to its receptor, CD74, plays an important role in many central nervous system (CNS) disorders such as AD. Our group has developed DRhQ, a novel CD74 binding construct which competitively inhibits MIF binding, blocks macrophage activation and migration into the CNS, enhances anti-inflammatory microglia cell numbers and reduces pro-inflammatory gene expression. Here, we evaluate its effects in amyloid-β (Aβ) overexpressing mice. 5xFAD mice and their wild type littermates were treated with DRhQ (100 µg) or vehicle for 4 weeks. DRhQ improved cognition and cortical mitochondrial function in both male and female 5xFAD mice. Aβ plaque burden in 5xFAD animals was not robustly impacted by DRhQ treatment in either the hippocampus or the cortex. Cortical microglial activation was similarly not apparently affected by DRhQ treatment, although in the hippocampus there was evidence of a reduction in activated microglia for female 5xFAD mice. Future studies are needed to confirm this possible sex-dependent response on microglial activation, as well as to optimize the dose and timing of DRhQ treatment and gain a better understanding of its mechanism of action in AD.}, }
@article {pmid39808238, year = {2025}, author = {Kumari, S and Bagri, K and Deshmukh, R}, title = {Connecting dots: Preclinical foundations to clinical realities of PDE4 inhibitors in Alzheimer's disease.}, journal = {Inflammopharmacology}, volume = {33}, number = {2}, pages = {593-603}, pmid = {39808238}, issn = {1568-5608}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Phosphodiesterase 4 Inhibitors/pharmacology/therapeutic use ; Humans ; Animals ; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; Neuroprotective Agents/pharmacology ; Cyclic AMP/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's Disease (AD), a progressive and age-associated neurodegenerative disorder, is primarily characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Despite advances in targeting Aβ-mediated neuronal damage with anti-Aβ antibodies, these treatments provide only symptomatic relief and fail to address the multifactorial pathology of the disease. This necessitates the exploration of novel therapeutic approaches and a deeper understanding of molecular signaling mechanisms underlying AD. Phosphodiesterases (PDEs), particularly Phosphodiesterase 4 (PDE4), play a pivotal role in regulating cyclic adenosine monophosphate (cAMP), a key molecule involved in memory consolidation and cognitive function. PDE4 inhibitors have demonstrated potential in enhancing memory and cognition in preclinical models of AD by modulating cAMP signaling. However, their clinical translation has been limited due to challenges such as adverse effects, narrow therapeutic windows, and low specificity in mechanism of action. This review bridges the gap between preclinical discoveries and clinical applications of PDE4 inhibitors in AD. It highlights preclinical evidence supporting the neuroprotective and anti-inflammatory effects of PDE4 inhibitors while addressing challenges in their clinical development, including issues of safety, efficacy, and disease-specific targeting. By integrating findings from both preclinical and clinical studies, we provide a comprehensive understanding of the therapeutic potential of PDE4 inhibitors in AD. Furthermore, this review outlines future research directions aimed at optimizing PDE4 inhibition strategies for AD treatment, offering a roadmap to translate foundational insights into clinical realities.}, }
@article {pmid39807706, year = {2025}, author = {Karakatsani, ME and Nozdriukhin, D and Tiemann, S and Yoshihara, HAI and Storz, R and Belau, M and Ni, R and Razansky, D and Deán-Ben, XL}, title = {Multimodal imaging of murine cerebrovascular dynamics induced by transcranial pulse stimulation.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14511}, pmid = {39807706}, issn = {1552-5279}, support = {RF1 NS126102/NS/NINDS NIH HHS/United States ; RF1-NS126102/NH/NIH HHS/United States ; 51767.1 IP-LS//Innosuisse - Swiss Innovation Agency/ ; }, mesh = {Animals ; Mice ; *Multimodal Imaging ; *Mice, Transgenic ; *Magnetic Resonance Imaging ; *Cerebrovascular Circulation/physiology ; *Alzheimer Disease/therapy/physiopathology ; Disease Models, Animal ; Brain ; Blood-Brain Barrier ; Transcranial Direct Current Stimulation/methods ; Photoacoustic Techniques ; Hemodynamics/physiology ; }, abstract = {INTRODUCTION: Transcranial pulse stimulation (TPS) is increasingly being investigated as a promising potential treatment for Alzheimer's disease (AD). Although the safety and preliminary clinical efficacy of TPS short pulses have been supported by neuropsychological scores in treated AD patients, its fundamental mechanisms are uncharted.
METHODS: Herein, we used a multi-modal preclinical imaging platform combining real-time volumetric optoacoustic tomography, contrast-enhanced magnetic resonance imaging, and ex vivo immunofluorescence to comprehensively analyze structural and hemodynamic effects induced by TPS. Cohorts of healthy and AD transgenic mice were imaged during and after TPS exposure at various per-pulse energy levels.
RESULTS: TPS enhanced the microvascular network, whereas the blood-brain barrier remained intact following the procedure. Notably, higher pulse energies were necessary to induce hemodynamic changes in AD mice, arguably due to their impacted vessels.
DISCUSSION: These findings shed light on cerebrovascular dynamics induced by TPS treatment, and hence are expected to assist improving safety and therapeutic outcomes.
HIGHLIGHTS: ·Transcranial pulse stimulation (TPS) facilitates transcranial wave propagation using short pulses to avoid tissue heating. ·Preclinical multi-modal imaging combines real-time volumetric optoacoustic (OA) tomography, contrast-enhanced magnetic resonance imaging (CE-MRI), and ex vivo immunofluorescence to comprehensively analyze structural and hemodynamic effects induced by TPS. ·Blood volume enhancement in microvascular networks was reproducibly observed with real-time OA imaging during TPS stimulation. ·CE-MRI and gross pathology further confirmed that the brain architecture was maintained intact without blood-brain barrier (BBB) opening after TPS exposure, thus validating the safety of the procedure. ·Higher pulse energies were necessary to induce hemodynamic changes in AD compared to wild-type animals, arguably due to their pathological vessels.}, }
@article {pmid39807644, year = {2025}, author = {Ma, L and Tan, ECK and Goudey, B and Jin, L and Pan, Y}, title = {Unraveling the bidirectional link between cancer and dementia and the impact of cancer therapies on dementia risk: A systematic review and meta-analysis.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14540}, pmid = {39807644}, issn = {1552-5279}, support = {GNT2022203//National Health and Medical Research Council/ ; GNT2007912//National Health and Medical Research Council/ ; GNT2028025//National Health and Medical Research Council/ ; 23AARF-1020292/ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Neoplasms/complications ; *Dementia/epidemiology ; Risk Factors ; Antineoplastic Agents/adverse effects/therapeutic use ; Alzheimer Disease ; }, abstract = {Observational studies on the cancer-dementia relationship have yielded controversial results. This study systematically reviews the evidence to clarify this association. We searched Embase, Global Health, Ovid Medline, and APA PsycInfo. Colorectal and lung cancers showed the greatest risk reduction for all-cause dementia (ACD) and Alzheimer's disease (AD), respectively, while melanoma and colorectal cancers had the largest reduction in vascular dementia (VaD). Prostate cancer survivors on androgen deprivation therapy (ADT) had a higher risk of ACD/AD, while breast cancer patients on tamoxifen had a lower AD risk. Chemotherapy was linked to a reduced AD risk. ACD patients saw a 30% risk reduction for bladder, colorectal, and lung cancers, while AD patients had a ≈ 35% reduction for bladder and lung cancers. Our study urges clinicians to monitor cognitive function in cancer patients, especially those on ADT, tamoxifen, or chemotherapy and highlights the need for research into cancer-dementia mechanisms. HIGHLIGHTS: Cancer survivors have an 8% to 14% lower risk of dementia, while those with dementia have a 25% lower cancer risk. Colorectal and non-melanoma skin cancers were associated with reduced risks of all-cause dementia (ACD; 16%/9%), Alzheimer's disease (AD; 13%/5%), and vascular dementia (VaD; 24%/9%). Lung cancer reduced AD risk by 17%, and melanoma reduced VaD risk by 27%. ACD and AD patients had lower risks of lung (30%/36%), bladder (32%/34%), breast (26%/20%), and colorectal (31%/28%) cancers. Tamoxifen and chemotherapy reduced AD risk, while androgen deprivation therapy increased ACD risk.}, }
@article {pmid39807629, year = {2025}, author = {Feng, Y and Wang, S and Yang, D and Zheng, W and Xia, H and Zhu, Q and Wang, Z and Hu, B and Jiang, X and Qin, X and Ni, C and Pan, W and Zhao, Y and Pan, S and Zhang, Y and Song, W}, title = {Inhibition of IFITM3 in cerebrovascular endothelium alleviates Alzheimer's-related phenotypes.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14543}, pmid = {39807629}, issn = {1552-5279}, support = {82230043//National Natural Science Foundation of China/ ; 82293642//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Membrane Proteins/metabolism/genetics ; Mice ; Humans ; *RNA-Binding Proteins/metabolism ; *Endothelial Cells/metabolism ; *Amyloid Precursor Protein Secretases/metabolism ; *Mice, Transgenic ; Phenotype ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Male ; Endothelium, Vascular/metabolism ; Aspartic Acid Endopeptidases/metabolism ; }, abstract = {INTRODUCTION: Interferon-induced transmembrane protein 3 (IFITM3) modulates γ-secretase in Alzheimer's Disease (AD). Although IFITM3 knockout reduces amyloid β protein (Aβ) production, its cell-specific effect on AD remains unclear.
METHODS: Single nucleus RNA sequencing (snRNA-seq) was used to assess IFITM3 expression. Adeno-associated virus-BI30 (AAV-BI30) was injected to reduce IFITM3 expression in the cerebrovascular endothelial cells (CVECs). The effects on AD phenotypes in cells and AD mice were examined through behavioral tests, two-photon imaging, flow cytometry, Western blot, immunohistochemistry, and quantitative polymerase chain reaction assay (qPCR).
RESULTS: IFITM3 expression was increased in the CVECs of patients with AD. Overexpression of IFITM3 in primary endothelial cells enhanced Aβ generation through regulating beta-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Aβ further increased IFITM3 expression, creating a vicious cycle. Knockdown of IFITM3 in CVECs decreased Aβ accumulation within cerebrovascular walls, reduced Alzheimer's-related pathology, and improved cognitive performance in AD transgenic mice.
DISCUSSION: Knockdown of IFITM3 in CVECs alleviates AD pathology and cognitive impairment. Targeting cerebrovascular endothelial IFITM3 holds promise for AD treatment.
HIGHLIGHTS: Interferon-induced transmembrane protein 3 (IFITM3) expression was increased in the cerebrovascular endothelial cells (CVECs) of patients with Alzheimer's Disease (AD). Cerebrovascular endothelial IFITM3 regulates amyloid β protein (Aβ) generation through regulating beta-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Knockdown of IFITM3 in CVECs reduces Aβ deposits and improves cognitive impairments in AD transgenic mice. Cerebrovascular endothelial IFITM3 could be a potential target for the treatment of AD.}, }
@article {pmid39807622, year = {2025}, author = {Kennedy, JT and Wisch, JK and Dincer, A and Roman, J and Gordon, BA and Handen, B and Benzinger, TLS and Head, E and Mapstone, M and Christian, BT and Tudorascu, DL and Laymon, CL and Hartley, SL and Lao, P and Brickman, AM and Zaman, SH and Ances, BM and , }, title = {Decoding brain structure to stage Alzheimer's disease pathology in Down syndrome.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14519}, pmid = {39807622}, issn = {1552-5279}, support = {//AMED/ ; SG-20-690363-DIAN/ALZ/Alzheimer's Association/United States ; //KHIDI/ ; //DZNE/ ; U19AG032438/AG/NIA NIH HHS/United States ; //FLENI/ ; U19AG068054/AG/NIA NIH HHS/United States ; UF1 AG032438/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; //Paula and Rodger O. Riney fund/ ; //Daniel J Brennan MD fund/ ; //ISCIII/ ; P01 AG003991/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; HI21C0066//KDRC/ ; NIHR203312//NIHR/ ; R01 AG052550/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Down Syndrome/pathology/diagnostic imaging ; *Alzheimer Disease/pathology ; Male ; Female ; *Magnetic Resonance Imaging ; *Brain/pathology/diagnostic imaging ; Middle Aged ; Adult ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) in Down syndrome (DS) is associated with changes in brain structure. It is unknown if thickness and volumetric changes can identify AD stages and if they are similar to other genetic forms of AD.
METHODS: Magnetic resonance imaging scans were collected for 178 DS adults (106 nonclinical, 45 preclinical, and 27 symptomatic). Cortical thickness and subcortical volumes were compared between DS groups and evaluated as a staging metric using receiver operating characteristic analyses. Thickness patterns were compared to those previously reported in autosomal-dominant AD (ADAD).
RESULTS: Decreased parietal and temporal lobe thickness differentiated amyloid positivity (area under the curve [AUC] = 0.83) and impairment (AUC = 0.81), and slightly outperformed subcortical volumes (AUC = 0.8/0.74). Thickness differences in DS were more widespread, severe, and had better discriminative ability than ADAD.
DISCUSSION: Cortical thickness can stage AD pathology in DS. Identification of brain regions affected by AD may aid in tracking disease course and evaluating treatment effects.
HIGHLIGHTS: DSAD is associated with reduced temporal and parietal cortical thickness. DSAD is associated with smaller hippocampal and striatal volumes. Thickness differences can stage DSAD better than other forms of AD. DSAD thickness differences are more extensive and severe than ADAD.}, }
@article {pmid39807377, year = {2024}, author = {Irsal, RAP and Gholam, GM and Dwicesaria, MA and Mansyah, TF and Chairunisa, F}, title = {Computational exploration of palmitoyl-protein thioesterase 1 inhibition by Juniperus phoenicea L. for anti-dementia treatment.}, journal = {Journal of Taibah University Medical Sciences}, volume = {19}, number = {6}, pages = {1165-1180}, pmid = {39807377}, issn = {1658-3612}, abstract = {OBJECTIVES: Dementia, a growing concern globally, affects more than 55 million people-a number projected to rise to 152 million by 2050. Current medications target Alzheimer's disease, the most prevalent form of dementia. This study investigated Juniperus phoenicea L., a plant used in traditional Chinese medicine, as a potential inhibitor of palmitoyl-protein thioesterase 1 (PPT1), an enzyme associated with dementia.
METHODS: J. phoenicea phytochemicals were subjected to in silico docking against PPT1 (PDB ID: 1EH5). Docking simulations were performed in YASARA Structure with VINA scoring. Top-ranked ligands were subjected to ADMET analysis (admetlab 2.0, Protox 3.0) and PASS bioactivity prediction. Stability and reactivity were analyzed with DFT calculations (Gaussian 09), and 500 ns MD simulations (YASARA Structure, AMBER 14 force field) to assess protein-ligand complex stability. MM-PBSA was used to calculate binding free energies.
RESULTS: The docking simulations identified amentoflavone (-9.6 kcal/mol) as the top hit, followed by ferruginol and quercetin 3-O-pentoside. Amentoflavone formed the most interactions (19) with PPT1. In silico toxicity analysis predicted amentoflavone and quercetin 3-O-pentoside to be safe, whereas ferruginol violated the Pfizer rule. The PASS server indicated a higher probability of activity for quercetin 3-O-pentoside (0.423) than amentoflavone (0.287) for dementia treatment. DFT calculations revealed similar electronic properties for both ligands, although amentoflavone showed slightly more favorable values. MD simulations demonstrated that amentoflavone, compared with to galantamine, had superior binding stability in the PPT1 binding pocket.
CONCLUSION: This in silico study was aimed at identifying potential inhibitors of PPT1 from J. phoenicea phytochemicals, given that PPT1 is a target for developing new dementia medications. Our findings identified amentoflavone as a promising candidate for further investigation. These findings warrant further research to validate this compound's potential as a PPT1 inhibitor for dementia treatment.}, }
@article {pmid39807026, year = {2025}, author = {Li, X and Wang, X and Chen, G and Tian, B}, title = {Application trends of hydrogen-generating nanomaterials for the treatment of ROS-related diseases.}, journal = {Biomaterials science}, volume = {13}, number = {4}, pages = {896-912}, doi = {10.1039/d4bm01450b}, pmid = {39807026}, issn = {2047-4849}, mesh = {*Reactive Oxygen Species/metabolism ; *Hydrogen/chemistry/administration & dosage/pharmacology ; Humans ; *Nanostructures/chemistry ; Animals ; Neoplasms/drug therapy ; Neurodegenerative Diseases/drug therapy/metabolism ; Oxidative Stress/drug effects ; Inflammation/drug therapy ; Antioxidants/chemistry/pharmacology/administration & dosage ; }, abstract = {Reactive oxygen species (ROS) play essential roles in both physiological and pathological processes. Under physiological conditions, appropriate amounts of ROS play an important role in signaling and regulation in cells. However, too much ROS can lead to many health problems, including inflammation, cancer, delayed wound healing, neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease), and autoimmune diseases, and oxidative stress from excess ROS is also one of the most critical factors in the pathogenesis of cardiovascular and metabolic diseases such as atherosclerosis. Hydrogen gas effectively removes ROS from the body due to its good antioxidant properties, and hydrogen therapy has become a promising gas therapy strategy due to its inherent safety and stability. The combination of nanomaterials can achieve targeted delivery and effective accumulation of hydrogen, and has some ameliorating effects on diseases. Herein, we summarize the use of hydrogen-producing nanomaterials for the treatment of ROS-related diseases and talk about the prospects for the treatment of other ROS-induced disease models, such as acute kidney injury.}, }
@article {pmid39806956, year = {2025}, author = {Aundhia, C and Parmar, G and Talele, C and Trivedi, R and Kumari, M and Chudasama, J}, title = {Impact and Significance of Viral Vectors for siRNA Delivery in the Treatment of Alzheimer's Disease.}, journal = {Current pharmaceutical biotechnology}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892010334094241112190337}, pmid = {39806956}, issn = {1873-4316}, abstract = {Alzheimer's disease (AD) remains a major challenge in developing effective treatments due to its complex pathophysiology, including the accumulation of amyloid-beta plaques and tau tangles. Small interfering RNA (siRNA) technology offers promise for targeted gene silencing, but effective delivery to the central nervous system remains a significant obstacle. Viral vectors have emerged as potent delivery vehicles for transporting siRNA to neural tissues. This review explores the utilization of viral vectors for siRNA delivery in AD, focusing on delivery strategies and challenges. We discuss the design and optimization of viral vectors, targeting strategies, and safety considerations. Additionally, we examine recent advancements and prospects for enhancing viral vector-mediated siRNA delivery in AD.}, }
@article {pmid39806952, year = {2025}, author = {Li, W and Huang, J and Chen, Z and Zhang, D and He, L and Guo, Y and Zhong, L and Yang, C and Yang, C and Zeng, M and Zhu, J and Cao, Z}, title = {Design, Synthesis, Biological Evaluation and Docking Studies of 2-hydroxy-4-benzyloxy Chalcone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673328877241113091539}, pmid = {39806952}, issn = {1875-533X}, abstract = {OBJECTIVES: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, but no drugs can cure this disease. Chalcones possess good antioxidant activity, anti-neuroinflammatory activity, neuroprotective effects, inhibitory effects on Aβ aggregation, and Aβ disaggregation ability. Therefore, chalcones are ideal lead compounds, and the discovery of novel anti-AD agent-based chalcones is necessary.
METHODS: Hydroxy groups and aryl benzyl ether groups were introduced into chalcone scaffolds to obtain a series of 2-hydroxyl-4-benzyloxy chalcone derivatives. These derivatives were further synthesized, biologically evaluated, and docked.
RESULTS: Most target derivatives exhibited good anti-AD activities. In particular, compound 11d had excellent inhibitory effects on self-induced Aβ1-42 aggregation (90.8% inhibition rate at 25 μM) and Cu2+ induced Aβ1-42 aggregation (93.4% inhibition rate at 25 μM). In addition, it also exhibited good Aβ1-42 fibril disaggregation ability (64.7% at 25 μM), significant antioxidative activity (ORAC = 2.03 Trolox equivalent), moderate MAO-B inhibition (IC50 = 4.81 μM), selective metal chelation, appropriate BBB permeation, and dramatic anti-neuroinflammatory ability. In addition, compound 11d relieved AD symptoms and protected hippocampal neurons in vivo.
CONCLUSION: Compound 11d is a promising multifunctional anti-Aβ agent.}, }
@article {pmid39806490, year = {2025}, author = {Shen, Y and Zhang, X and Liu, S and Xin, L and Xuan, W and Zhuang, C and Chen, Y and Chen, B and Zheng, X and Wu, R and Lin, Y}, title = {CEST imaging combined with [1]H-MRS reveal the neuroprotective effects of riluzole by improving neurotransmitter imbalances in Alzheimer's disease mice.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {20}, pmid = {39806490}, issn = {1758-9193}, support = {240428226498013//Shantou Science and Technology Project/ ; 213769/SNSF_/Swiss National Science Foundation/Switzerland ; 82020108016//National Natural Science Foundation of China/ ; 82071973//National Natural Science Foundation of China/ ; 2023A1515010326//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022ZDZX2020//Key Research Platform and Project of Guangdong University/ ; }, mesh = {Animals ; *Riluzole/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Neuroprotective Agents/pharmacology ; Mice ; *Mice, Transgenic ; *Glutamic Acid/metabolism ; *gamma-Aminobutyric Acid/metabolism ; Proton Magnetic Resonance Spectroscopy/methods ; Brain/drug effects/metabolism/diagnostic imaging ; Disease Models, Animal ; Male ; Magnetic Resonance Imaging/methods ; Neurotransmitter Agents/metabolism ; }, abstract = {BACKGROUND: The imbalance of glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitter system plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Riluzole is a Glu modulator originally approved for amyotrophic lateral sclerosis that has shown potential neuroprotective effects in various neurodegenerative disorders. However, whether riluzole can improve Glu and GABA homeostasis in AD brain and its related mechanism of action remain unknown. This study utilized chemical exchange saturation transfer (CEST) imaging combined with proton magnetic resonance spectroscopy ([1]H-MRS) to monitor the dynamic changes of Glu and GABA in riluzole-treated AD mice, aiming to evaluate the efficacy and mechanism of riluzole in AD treatment.
METHODS: GluCEST, GABACEST and [1]H-MRS were used to longitudinally monitor Glu and GABA levels in 3xTg AD mice treated with riluzole (12.5 mg/kg/day) or vehicle for 20 weeks. Magnetic resonance measurements were performed at baseline, 6, 12, and 20 weeks post-treatment. Cognitive performance was assessed using the Morris Water Maze (MWM) at baseline, 10, and 20 weeks. At the study endpoint, immunohistochemistry, Nissl staining, and Western blot were used to evaluate the brain pathology, neuronal survival, and protein expression.
RESULTS: GluCEST, GABACEST and [1]H-MRS consistently revealed higher levels of Glu and GABA in the brain of riluzole-treated AD mice compared to untreated controls, which were associated with improvements in spatial learning and memory. The cognitive improvements significantly correlated with the increased GluCEST signals and Glu levels. Immunohistochemistry and Nissl staining demonstrated that riluzole treatment reduced amyloid-beta (Aβ) deposition, tau hyperphosphorylation, GFAP-positive astrocyte activation, and prevented neuronal loss. Moreover, riluzole upregulated the expression of excitatory amino acid transporter 2 (EAAT2), glutamic acid decarboxylase 65/67 (GAD65/67), and glutamine synthetase (GS), suggesting enhanced neurotransmitter metabolism.
CONCLUSIONS: CEST imaging combined with [1]H-MRS demonstrated the effectiveness of riluzole in modulating Glu- and GABA-related changes and improving cognitive function in 3xTg AD mice, potentially through regulating key proteins involved in neurotransmitter metabolism. These findings suggest riluzole as a therapeutic agent for Alzheimer's disease and highlight the utility of multimodal MR imaging in monitoring treatment response and exploring disease mechanisms.}, }
@article {pmid39805913, year = {2025}, author = {Sahin, F and Gunel, A and Atasoy, BT and Guler, U and Salih, B and Kuzu, I and Taspinar, M and Cinar, O and Kahveci, S}, title = {Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1165}, pmid = {39805913}, issn = {2045-2322}, mesh = {*Proteasome Endopeptidase Complex/metabolism ; Animals ; Mice ; *Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; Ketamine/pharmacology/therapeutic use ; Memantine/pharmacology/therapeutic use ; Disease Models, Animal ; Humans ; Male ; Mental Disorders/drug therapy/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Brain/metabolism/drug effects ; }, abstract = {NMDAR antagonists, such as memantine and ketamine, have shown efficacy in treating neurodegenerative diseases and major depression. The mechanism by which these drugs correct the aforementioned diseases is still unknown. Our study reveals that these antagonists significantly enhance 20S proteasome activity, crucial for degrading intrinsically disordered, oxidatively damaged, or misfolded proteins, factors pivotal in neurodegenerative diseases like Alzheimer's and Parkinson's. In our mouse model experiment, ketamine administration notably altered brain synaptic protein profiles within two hours, significantly downregulating proteins strongly associated with Alzheimer's and Parkinson's diseases. Furthermore, the altered proteins exhibited enrichment in terms related to plasticity and potentiation, including retrograde endocannabinoid signaling-a pivotal pathway in both short- and long-term plasticity that may elucidate the long-lasting effects of ketamine in major depression. Via the ubiquitin-independent 20S proteasome pathway (UIPS), these drugs maintain cellular protein homeostasis, which is crucial as proteasome activity declines with age, leading to protein aggregation and disease symptoms. Therefore, these findings hold promise for new treatment options not only for brain diseases but also for other systemic conditions associated with unfolded or misfolded proteins.}, }
@article {pmid39805752, year = {2024}, author = {Zhu, FQ and Ma, JY and Zhang, YY and Yu, Y}, title = {[Research progress on mechanisms and pharmacokinetics of ligustilide in treatment of locomotor system diseases].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {49}, number = {24}, pages = {6625-6634}, doi = {10.19540/j.cnki.cjcmm.20240716.701}, pmid = {39805752}, issn = {1001-5302}, mesh = {*4-Butyrolactone/analogs & derivatives/pharmacology/pharmacokinetics/chemistry ; Humans ; Animals ; Drugs, Chinese Herbal/pharmacokinetics/chemistry/pharmacology ; Osteoporosis/drug therapy/metabolism ; Osteoarthritis/drug therapy/metabolism ; Locomotion/drug effects ; Osteosarcoma/drug therapy/metabolism ; }, abstract = {Ligustilide, a phthalide compound extracted from Umbelliferae plants such as Angelica sinensis and Ligusticum chuanxiong, has been proven to possess various pharmacological activities, such as anti-inflammatory, anti-tumor, anti-atherosclerosis, anti-ischemic stroke injury, and anti-Alzheimer's disease properties. In recent years, it has shown great potential, particularly in the treatment of locomotor system diseases. Studies have shown that ligustilide has significant therapeutic effects on various locomotor system diseases, including osteoporosis, osteoarthritis, femoral head necrosis, osteosarcoma, and muscle aging and injury. Its mechanisms of action include enhancing the differentiation ability of osteoblasts(OBs), inhibiting the formation ability of osteoclasts(OCs), downregulating inflammatory factors, promoting the synthesis of extracellular matrix(ECM), improving local blood supply to the femoral head, balancing lipid metabolism, inhibiting the proliferation and migration of osteosarcoma cells, inducing cell cycle arrest, enhancing glucose utilization in skeletal muscle, and regulating autophagy and apoptosis. However, its clinical application is severely limited by drawbacks such as structural instability, poor water solubility, and low bioavailability. Currently, formulation techniques such as dripping pills, micropills, inclusion complexes, and liposomes are being used to improve its stability and water solubility, thereby enhancing its therapeutic efficacy. This article summarized the effects, mechanisms of action, and pharmacokinetics of ligustilide monomers and preparations in the treatment of locomotor system diseases in China and abroad in recent years, aiming to provide reference and guidance for further development and application of ligustilide in this field.}, }
@article {pmid39805666, year = {2025}, author = {Ricaurte-Fajardo, A and Ivanidze, J and Zhang, D and Mahmud, M and Yasen, W and Ravdin, L and Pahlajani, S and de Leon, M and Nordvig, AS and Chiang, GC}, title = {Anti-amyloid therapy and cerebral blood flow changes on Magnetic Resonance Imaging: a potential longitudinal biomarker of treatment response?.}, journal = {AJNR. American journal of neuroradiology}, volume = {}, number = {}, pages = {}, doi = {10.3174/ajnr.A8654}, pmid = {39805666}, issn = {1936-959X}, abstract = {Amyloid-targeting therapy has recently become widely available in the U.S. for the treatment of patients with symptomatic mild Alzheimer's disease (AD). At present, there are no biomarkers that have been clinical validated to assess treatment response in routine clinical practice; longitudinal amyloid PET could play a role but is not cost effective. This report presents a case series of six patients with AD, whose amyloid positivity was confirmed by PET or CSF biomarkers, who underwent baseline and longitudinal arterial spin-labeling magnetic resonance imaging (ASL-MR) as part of FDA-mandated, clinical standard-of-care, non-contrast MR monitoring to assess for amyloid-related imaging abnormalities (ARIA). We and others have previously reported that ASL-MR can screen for neurodegenerative disease, as a proxy for FDG-PET, and can be easily added on as a cost-effective, repeatable method to monitor post-therapy changes. This series highlights varied cerebral blood flow (CBF) changes in response to lecanemab therapy. For instance, Cases 1, 3, and 5 showed increased CBF after multiple infusions, with subjective cognitive improvement in Case 1 and improved MoCA scores in Case 3. Case 2 showed improved CBF initially before the 5[th] infusion, but this returned to baseline on the subsequent study, with no cognitive improvement over the course of therapy. Cases 4 and 6 have demonstrated no significant changes in regional CBF thus far on therapy, with cognitive decline in Case 4. This case series underscores the potential utility of ASL-MR as an adjunct sequence to current imaging protocols to monitor treatment response to anti-amyloid therapy.ABBREVIATIONS: ASL-MR= arterial spin-labeling magnetic resonance imaging; MRI= magnetic resonance imaging; CBF= cerebral blood flow; AD= Alzheimer's disease; PET= positron emission tomography; CSF= cerebrospinal fluid; FDG= fluorodeoxyglucose.}, }
@article {pmid39805473, year = {2025}, author = {Li, SY and Gong, XY and Ndikuryayo, F and Yang, WC}, title = {The emerging role of oxygen redox in pathological progression of disorders.}, journal = {Ageing research reviews}, volume = {104}, number = {}, pages = {102660}, doi = {10.1016/j.arr.2025.102660}, pmid = {39805473}, issn = {1872-9649}, mesh = {Humans ; *Oxidative Stress/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; *Oxidation-Reduction ; *Disease Progression ; *Mitochondria/metabolism/pathology ; Animals ; Oxygen/metabolism ; Antioxidants/metabolism/therapeutic use ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington disease, pose serious threats to human health, leading to substantial economic burdens on society and families. Despite extensive research, the underlying mechanisms driving these diseases remain incompletely understood, impeding effective diagnosis and treatment. In recent years, growing evidence has highlighted the crucial role of oxidative stress in the pathogenesis of various neurodegenerative diseases. However, there is still a lack of comprehensive reviews that systematically summarize the impact of mitochondrial oxidative stress on neurodegenerative diseases. This review aims to address this gap by summarizing the molecular mechanisms by which mitochondrial oxidative stress promotes the initiation and progression of neurodegenerative disorders. Furthermore, it discusses the potential of antioxidant-based therapeutic strategies for the treatment of these diseases. By shedding light on the role of mitochondrial oxidative stress in neurodegenerative diseases, this review not only serves as a valuable reference for further research on the disease mechanisms, but also offers novel perspectives for the treatment of these disorders.}, }
@article {pmid39805463, year = {2025}, author = {Shastri, D and Raorane, CJ and Raj, V and Lee, S}, title = {Human serum albumin-3-amino-1-propanesulfonic acid conjugate inhibits amyloid-β aggregation and mitigates cognitive decline in Alzheimer's disease.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {379}, number = {}, pages = {390-408}, doi = {10.1016/j.jconrel.2025.01.019}, pmid = {39805463}, issn = {1873-4995}, mesh = {*Amyloid beta-Peptides/metabolism ; Animals ; Humans ; *Alzheimer Disease/drug therapy ; Male ; *Serum Albumin, Human/chemistry ; Blood-Brain Barrier/metabolism/drug effects ; Rats, Sprague-Dawley ; Peptide Fragments/administration & dosage/chemistry/pharmacology ; Protein Aggregates/drug effects ; Cognitive Dysfunction/drug therapy ; Reactive Oxygen Species/metabolism ; Brain/metabolism/drug effects ; Neuroprotective Agents/administration & dosage/therapeutic use/chemistry ; Cell Line, Tumor ; Rats ; Sulfonic Acids/administration & dosage/chemistry ; }, abstract = {Alzheimer's disease (AD) is the most commonly occurring brain disorder, characterized by the accumulation of amyloid-β (Aβ) and tau, subsequently leading to neurocognitive decline. 3-Amino-1-propanesulfonic acid (TPS) and its prodrug, currently under clinical trial III, serve as promising therapeutic agents targeting Aβ pathology by specifically preventing monomer-to-oligomer formation. Inspired by the potency of TPS prodrug, we hypothesized that conjugating TPS with human serum albumin (HSA) could enhance brain delivery and synergistically inhibit Aβ aggregation in mild to moderate AD. Thus, we prepared and extensively characterized HSA-TPS (h-TPS) conjugate using an eco-friendly coupling method. In vitro studies on Aβ aggregation kinetics and AFM imaging revealed significant prevention of Aβ aggregation. Additionally, h-TPS significantly reduced Aβ-induced neurotoxicity and H2O2-mediated reactive oxygen species (ROS) stress in SH-SY5Y cells. Moreover, h-TPS administration improved blood-brain barrier permeability and cellular uptake into neuronal cells as well as showed in vivo uptake inside the brain within 1 h. In vivo studies using an Aβ1-42-induced acute AD rat model exhibited a dose-dependent significant reduction in hippocampal Aβ levels and restoration of declined spatial learning and memory with h-TPS treatment. Overall, findings suggest that h-TPS conjugate might be a promising neuroprotective agent for preventing Aβ aggregation in mild to moderate AD.}, }
@article {pmid39805185, year = {2025}, author = {Huang, J and Wu, F and Cao, W and Chen, Y and Yao, Q and Cen, P and Wang, J and Hong, L and Zhang, X and Zhou, R and Jin, C and Tian, M and Zhang, H and Zhong, Y}, title = {Ultrasmall iron-gallic acid coordination polymer nanoparticles for scavenging ROS and suppressing inflammation in tauopathy-induced Alzheimer's disease.}, journal = {Biomaterials}, volume = {317}, number = {}, pages = {123042}, doi = {10.1016/j.biomaterials.2024.123042}, pmid = {39805185}, issn = {1878-5905}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Gallic Acid/pharmacology/chemistry/therapeutic use ; *Reactive Oxygen Species/metabolism ; *Nanoparticles/chemistry ; *Polymers/chemistry ; *Iron/chemistry/metabolism ; *Inflammation/drug therapy/pathology ; Rats, Sprague-Dawley ; Tauopathies/drug therapy ; Rats ; Male ; tau Proteins/metabolism ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/chemistry ; Humans ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder globally, with no effective treatment available yet. A crucial pathological hallmark of AD is the accumulation of hyperphosphorylated tau protein, which is deteriorated by reactive oxygen species (ROS) and neuroinflammation in AD progression. Thus, alleviation of ROS and inflammation has become a potential therapeutic strategy in many studies. Herein, we reported ultrasmall coordination polymer nanoparticles formed by ferric ions and gallic acid (Fe-GA CPNs), which owned antioxidant and anti-inflammation properties for AD therapeutics. The facilely prepared Fe-GA CPNs exhibited remarkable superoxide dismutase-like, peroxidase-like enzyme activity, and ROS eliminating ability with great water solubility, compared with gallic acid. We demonstrated that Fe-GA CPNs effectively relieved oxidative stress, ameliorated inflammation by modulating microglial polarization towards anti-inflammation phenotype, and reduced hyperphosphorylated tau protein levels. Furthermore, Fe-GA CPNs treatment significantly improved cognitive function in tauopathy-induced AD rats, and achieved a neuroprotective effect against AD pathology. This study highlights the potential of coordination polymer nanoparticles as promising therapeutic candidates for AD and other tau-related neurodegenerative diseases.}, }
@article {pmid39804693, year = {2025}, author = {De Silva, U and Madanian, S and Olsen, S and Templeton, JM and Poellabauer, C and Schneider, SL and Narayanan, A and Rubaiat, R}, title = {Clinical Decision Support Using Speech Signal Analysis: Systematic Scoping Review of Neurological Disorders.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e63004}, pmid = {39804693}, issn = {1438-8871}, mesh = {Humans ; *Decision Support Systems, Clinical ; *Nervous System Diseases/physiopathology/diagnosis ; *Speech ; Parkinson Disease/physiopathology ; }, abstract = {BACKGROUND: Digital biomarkers are increasingly used in clinical decision support for various health conditions. Speech features as digital biomarkers can offer insights into underlying physiological processes due to the complexity of speech production. This process involves respiration, phonation, articulation, and resonance, all of which rely on specific motor systems for the preparation and execution of speech. Deficits in any of these systems can cause changes in speech signal patterns. Increasing efforts are being made to develop speech-based clinical decision support systems.
OBJECTIVE: This systematic scoping review investigated the technological revolution and recent digital clinical speech signal analysis trends to understand the key concepts and research processes from clinical and technical perspectives.
METHODS: A systematic scoping review was undertaken in 6 databases guided by a set of research questions. Articles that focused on speech signal analysis for clinical decision-making were identified, and the included studies were analyzed quantitatively. A narrower scope of studies investigating neurological diseases were analyzed using qualitative content analysis.
RESULTS: A total of 389 articles met the initial eligibility criteria, of which 72 (18.5%) that focused on neurological diseases were included in the qualitative analysis. In the included studies, Parkinson disease, Alzheimer disease, and cognitive disorders were the most frequently investigated conditions. The literature explored the potential of speech feature analysis in diagnosis, differentiating between, assessing the severity and monitoring the treatment of neurological conditions. The common speech tasks used were sustained phonations, diadochokinetic tasks, reading tasks, activity-based tasks, picture descriptions, and prompted speech tasks. From these tasks, conventional speech features (such as fundamental frequency, jitter, and shimmer), advanced digital signal processing-based speech features (such as wavelet transformation-based features), and spectrograms in the form of audio images were analyzed. Traditional machine learning and deep learning approaches were used to build predictive models, whereas statistical analysis assessed variable relationships and reliability of speech features. Model evaluations primarily focused on analytical validations. A significant research gap was identified: the need for a structured research process to guide studies toward potential technological intervention in clinical settings. To address this, a research framework was proposed that adapts a design science research methodology to guide research studies systematically.
CONCLUSIONS: The findings highlight how data science techniques can enhance speech signal analysis to support clinical decision-making. By combining knowledge from clinical practice, speech science, and data science within a structured research framework, future research may achieve greater clinical relevance.}, }
@article {pmid39804285, year = {2025}, author = {Yildirim, E and Soncu Buyukiscan, E and Akça Kalem, Ş and Gürvit, H}, title = {Reliability of direct-to-home teleneuropsychological assessment: a within-subject design study.}, journal = {The Clinical neuropsychologist}, volume = {}, number = {}, pages = {1-22}, doi = {10.1080/13854046.2025.2451247}, pmid = {39804285}, issn = {1744-4144}, abstract = {Objective: During the COVID-19 pandemic, the need to continue diagnosis and treatment processes, in addition to scientific research, led to a rapid shift towards direct-to-home tele-neuropsychology administrations, the reliability and validity of which had not been clearly established then. This study, therefore, aimed to examine the reliability of direct-to-home tele-neuropsychological assessment (TNP). Method: The sample included 105 cognitively healthy individuals aged between 50-83 years, and 47 patients diagnosed with neurocognitive disorders (mild cognitive impairment and early-stage Alzheimer's type dementia). All participants underwent both face-to-face and teleneuropsychological assessments in a counterbalanced order. Results: The results revealed that performances across measures of attention, working memory, verbal fluency, verbal and visual memory, and visual perception were comparable across assessment modalities. Intraclass correlation coefficients of the tests ranged from .54 to .92. Conclusions: The findings of the study provide support for direct-to-home teleneuropsychological assessment among patients with neurocognitive disorders. Neuropsychological tests relying on verbal administration and independent of motor performance may represent a reliable alternative for this patient group when administered in settings where external distractions or technological limitations are controlled. For cognitively healthy individuals, on the other hand, the reliability of the TNP application is more questionable for memory and some executive function tests and therefore needs further exploration.}, }
@article {pmid39803455, year = {2024}, author = {Stephenson, RA and Johnson, KR and Cheng, L and Yang, LG and Root, JT and Gopalakrishnan, J and Shih, HY and Narayan, PS}, title = {Triglyceride metabolism controls inflammation and APOE4 -associated disease states in microglia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.04.11.589145}, pmid = {39803455}, issn = {2692-8205}, abstract = {Microglia modulate their cell state in response to various stimuli. Changes to cellular lipids often accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer's disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in cell state but rather necessary for microglial activation. We discovered that both triglyceride biosynthesis and catabolism are needed for the transcription and secretion of proinflammatory cytokines and chemokines in response to extrinsic stimuli. Additionally, we reveal that triglyceride biosynthesis and catabolism are necessary for the activation-associated phagocytosis of multiple substrates including the disease-associated amyloid-beta peptide. In microglia harboring the Alzheimer's disease risk APOE4 genotype, triglyceride-rich lipid droplets accumulate even in the absence of any external stimuli. Inhibiting triglyceride biosynthesis in APOE4 microglia not only modifies the transcription of immune response genes but also attenuates disease-associated transcriptional states. This work establishes that triglyceride metabolism is necessary for microglia to respond to extrinsic activation. In APOE4 microglia, this metabolic process modulates both immune signaling and a disease-associated transcriptional state. Importantly, our work identifies metabolic pathways that can be used to tune microglial immunometabolism in APOE4- associated disease.}, }
@article {pmid39802885, year = {2024}, author = {Buttar, AM and Shaheen, Z and Gumaei, AH and Mosleh, MAA and Gupta, I and Alzanin, SM and Akbar, MA}, title = {Enhanced neurological anomaly detection in MRI images using deep convolutional neural networks.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1504545}, pmid = {39802885}, issn = {2296-858X}, abstract = {INTRODUCTION: Neurodegenerative diseases, including Parkinson's, Alzheimer's, and epilepsy, pose significant diagnostic and treatment challenges due to their complexity and the gradual degeneration of central nervous system structures. This study introduces a deep learning framework designed to automate neuro-diagnostics, addressing the limitations of current manual interpretation methods, which are often time-consuming and prone to variability.
METHODS: We propose a specialized deep convolutional neural network (DCNN) framework aimed at detecting and classifying neurological anomalies in MRI data. Our approach incorporates key preprocessing techniques, such as reducing noise and normalizing image intensity in MRI scans, alongside an optimized model architecture. The model employs Rectified Linear Unit (ReLU) activation functions, the Adam optimizer, and a random search strategy to fine-tune hyper-parameters like learning rate, batch size, and the number of neurons in fully connected layers. To ensure reliability and broad applicability, cross-fold validation was used.
RESULTS AND DISCUSSION: Our DCNN achieved a remarkable classification accuracy of 98.44%, surpassing well-known models such as ResNet-50 and AlexNet when evaluated on a comprehensive MRI dataset. Moreover, performance metrics such as precision, recall, and F1-score were calculated separately, confirming the robustness and efficiency of our model across various evaluation criteria. Statistical analyses, including ANOVA and t-tests, further validated the significance of the performance improvements observed with our proposed method. This model represents an important step toward creating a fully automated system for diagnosing and planning treatment for neurological diseases. The high accuracy of our framework highlights its potential to improve diagnostic workflows by enabling precise detection, tracking disease progression, and supporting personalized treatment strategies. While the results are promising, further research is necessary to assess how the model performs across different clinical scenarios. Future studies could focus on integrating additional data types, such as longitudinal imaging and multimodal techniques, to further enhance diagnostic accuracy and clinical utility. These findings mark a significant advancement in applying deep learning to neuro-diagnostics, with promising implications for improving patient outcomes and clinical practices.}, }
@article {pmid39802402, year = {2024}, author = {Maisto, N and Mango, D}, title = {Nose to brain strategy coupled to nano vesicular system for natural products delivery: Focus on synaptic plasticity in Alzheimer's disease.}, journal = {Journal of pharmaceutical analysis}, volume = {14}, number = {12}, pages = {101057}, pmid = {39802402}, issn = {2214-0883}, abstract = {A wide number of natural molecules demonstrated neuroprotective effects on synaptic plasticity defects induced by amyloid-β (Aβ) in ex vivo and in vivo Alzheimer's disease (AD) models, suggesting a possible use in the treatment of this neurodegenerative disorder. However, several compounds, administered parenterally and orally, are unable to reach the brain due to the presence of the blood-brain barrier (BBB) which prevents the passage of external substances, such as proteins, peptides, or phytocompounds, representing a limit to the development of treatment for neurodegenerative diseases, such as AD. The combination of nano vesicular systems, as colloidal systems, and nose to brain (NtB) delivery depicts a new nanotechnological strategy to overtake this limit and to develop new treatment approaches for brain diseases, including the use of natural molecules in combination therapy for AD. Herein, we will provide an updated overview, examining the literature of the last 20 years and using specific keywords that provide evidence on natural products with the ability to restore synaptic plasticity alterations in AD models, and the possible application using safe and non-invasive strategies focusing on nano vesicular systems for NtB delivery.}, }
@article {pmid39802364, year = {2025}, author = {Fard, TM and Hosseinzadeh, M and Shokri, M and Almasi-Dooghaee, M and Mirfazeli, FS}, title = {When Stroke Disguises as Dementia: A Case of Missed Cerebral Venous Thrombosis.}, journal = {Clinical case reports}, volume = {13}, number = {1}, pages = {e70038}, pmid = {39802364}, issn = {2050-0904}, abstract = {Cerebrovascular thrombosis is among the most critical medical conditions, making early diagnosis and management crucial. Although some symptoms of cerebrovascular thrombosis are typical and lead to early diagnosis, they can sometimes present with rare and unusual symptoms, complicating the diagnostic process. Given the morbidity and mortality associated with these events, it is important to be aware of unexpected symptoms to diagnose and manage these patients more accurately and rapidly. We report a 74-year-old female initially misdiagnosed with Alzheimer's because of cognitive decline and disorganized speech. Her symptoms did not improve with Alzheimer's treatment. She was reevaluated by a neurologist, and her cognitive test results were impaired. Her brain MRI revealed a previously undetected left transverse sinus cerebral venous thrombosis with subcortical white matter lesions. The patient was managed acutely with subcutaneous enoxaparin and transitioned to oral rivaroxaban, resulting in significant improvement. This case report aimed to draw attention to the pitfalls of diagnosing dementia-like syndromes in the elderly, advocating for a systematic approach to differential diagnosis. It emphasizes that a collaborative effort between psychiatrists, neurologists, radiologists, and other healthcare members is essential for accurate diagnosis and timely intervention, which can significantly alter the management and outcome for the patient.}, }
@article {pmid39801712, year = {2025}, author = {Liu, KY and Betts, MJ and Hämmerer, D and Düzel, E and Mather, M and Roiser, JP and Schneider, A and Spottke, A and Rostamzadeh, A and Schott, BH and Rauchmann, BS and Laske, C and Janowitz, D and Spruth, EJ and Ersözlü, E and Lüsebrink, F and Jessen, F and Frommann, I and Kilimann, I and Wiltfang, J and Brustkern, J and Priller, J and Hellman-Regen, J and Buerger, K and Fliessbach, K and Scheffler, K and Kleineidam, L and Stark, M and Ewers, M and Wagner, M and Peters, O and Dechent, P and Perneczky, R and Sodenkamp, S and Hetzer, S and Teipel, S and Glanz, W and Howard, R}, title = {Locus coeruleus signal intensity and emotion regulation in agitation in Alzheimer's disease.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcae457}, pmid = {39801712}, issn = {2632-1297}, abstract = {Hyperphosphorylated tau accumulation is seen in the noradrenergic locus coeruleus from the earliest stages of Alzheimer's disease onwards and has been associated with symptoms of agitation. It is hypothesized that compensatory locus coeruleus-noradrenaline system overactivity and impaired emotion regulation could underlie agitation propensity, but to our knowledge this has not previously been investigated. A better understanding of the neurobiological underpinnings of agitation would help the development of targeted prevention and treatment strategies. Using a sample of individuals with amnestic mild cognitive impairment and probable mild Alzheimer's disease dementia from the German Center for Neurodegenerative Diseases (DZNE)-Longitudinal Cognitive Impairment and Dementia (DELCODE) study cohort (N = 309, aged 67-96 years, 51% female), we assessed cross-sectional relationships between a latent factor representing the functional integrity of an affect-related executive regulation network and agitation point prevalence and severity scores. In a subsample of individuals with locus coeruleus MRI imaging data (N = 37, aged 68-93 years, 49% female), we also investigated preliminary associations between locus coeruleus MRI contrast ratios (a measure of structural integrity, whole or divided into rostral, middle, and caudal thirds) and individual affect-related regulation network factor scores and agitation measures. Regression models controlled for effects of age and clinical disease severity and, for models including resting-state functional MRI connectivity variables, grey matter volume and education years. Agitation point prevalence showed a positive relationship with a latent factor representing the functional integrity (and a negative relationship with a corresponding structural measure) of the affect-related executive regulation network. Locus coeruleus MRI contrast ratios were positively associated with agitation severity (but only for the rostral third, in N = 13) and negatively associated with the functional affect-related executive regulation latent factor scores. Resting-state functional connectivity between a medial prefrontal cortex region and the left amygdala was related to locus coeruleus MRI contrast ratios. These findings implicate the involvement of locus coeruleus integrity and emotion dysregulation in agitation in Alzheimer's disease and support the presence of potential compensatory processes. At the neural level, there may be a dissociation between mechanisms underlying agitation risk per se and symptom severity. Further studies are needed to replicate and extend these findings, incorporating longitudinal designs, measures of autonomic function and non-linear modelling approaches to explore potential causal and context-dependent relationships across Alzheimer's disease stages.}, }
@article {pmid39801412, year = {2025}, author = {Yang, M and Zhao, Y and Yu, H and Chen, S and Gao, G and Li, D and Wu, X and Huang, L and Ye, S}, title = {A Multi-Label Deep Learning Model for Detailed Classification of Alzheimer's Disease.}, journal = {Actas espanolas de psiquiatria}, volume = {53}, number = {1}, pages = {89-99}, pmid = {39801412}, issn = {1578-2735}, mesh = {*Alzheimer Disease/classification/diagnosis ; Humans ; *Deep Learning ; Aged ; Female ; Severity of Illness Index ; Male ; }, abstract = {BACKGROUND: Accurate diagnosis and classification of Alzheimer's disease (AD) are crucial for effective treatment and management. Traditional diagnostic models, largely based on binary classification systems, fail to adequately capture the complexities and variations across different stages and subtypes of AD, limiting their clinical utility.
METHODS: We developed a deep learning model integrating a dot-product attention mechanism and an innovative labeling system to enhance the diagnosis and classification of AD subtypes and severity levels. This model processed various clinical and demographic data, emphasizing the most relevant features for AD diagnosis. The approach emphasized precision in identifying disease subtypes and predicting their severity through advanced computational techniques that mimic expert clinical decision-making.
RESULTS: Comparative tests against a baseline fully connected neural network demonstrated that our proposed model significantly improved diagnostic accuracy. Our model achieved an accuracy of 83.1% for identifying AD subtypes, compared to 72.9% by the baseline. In severity prediction, our model reached an accuracy of 83.3%, outperforming the baseline (73.5%).
CONCLUSIONS: The incorporation of a dot-product attention mechanism and a tailored labeling system in our model significantly enhances the accuracy of diagnosing and classifying AD. This improvement highlights the potential of the model to support personalized treatment strategies and advance precision medicine in neurodegenerative diseases.}, }
@article {pmid39801125, year = {2025}, author = {Abeywickrama, N and Miraval, MNE and Subramaniam, H and Arshad, Q and Pollard, S and Chauhan, G and Jussab, S and Mukaetova-Ladinska, EB}, title = {Efficacy of music-based intervention for people living with dementia in an inpatient setting: A pilot study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {3}, pages = {905-919}, doi = {10.1177/13872877241307311}, pmid = {39801125}, issn = {1875-8908}, mesh = {Humans ; Aged ; Male ; Female ; *Music Therapy/methods ; Pilot Projects ; *Dementia/therapy/psychology ; Aged, 80 and over ; Middle Aged ; *Inpatients ; Quality of Life ; Treatment Outcome ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Pharmacological treatment of behavioral and psychological symptoms of dementia is of limited benefit. The addition of non-pharmacological interventions is often essential for optimal symptom control. Music is a viable way to help patients communicate and improve their quality of life.
OBJECTIVE: This study aims to find the most effective way to use music in a busy dementia ward.
METHODS: 17 inpatients (aged 63-93 years) with a clinical diagnosis of Alzheimer's disease and dementia took part over five weeks. Music lyrics presented via free-field speakers were individualized to personal preferences. Instruments (e.g., maracas) were used in some group sessions. We used the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Music in Dementia Assessment Scales (MiDAS) to evaluate patients' behavior before and after musical intervention.
RESULTS: There was a significant difference in mean NPI-Q scores before and after the music intervention. Specifically, Delusion, Motor Disturbances, and Agitation scores were significantly reduced after music intervention. This was accompanied by significant improvements in Interest, Response, and Enjoyment of MiDAS items during specific intervals.
CONCLUSIONS: Clinical professionals can successfully deliver music-based intervention to inpatients with advanced dementia to help manage their behavioral symptoms in the short term. Music-based interventions' use for inpatient wards must be further investigated as an economical and personalized non-pharmacological therapeutic tool for patients with dementia.}, }
@article {pmid39800469, year = {2025}, author = {Aye, S and Johansson, G and Hock, C and Lannfelt, L and Sims, JR and Blennow, K and Frederiksen, KS and Graff, C and Molinuevo, JL and Scheltens, P and Palmqvist, S and Schöll, M and Wimo, A and Kivipelto, M and Handels, R and Frölich, L and Zilka, N and Tolar, M and Johannsen, P and Jönsson, L and Winblad, B}, title = {Point of view: Challenges in implementation of new immunotherapies for Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {1}, pages = {100022}, doi = {10.1016/j.tjpad.2024.100022}, pmid = {39800469}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy/therapy/immunology ; *Immunotherapy/methods ; Cost-Benefit Analysis ; }, abstract = {The advancement of disease-modifying treatments (DMTs) for Alzheimer's disease (AD), along with the approval of three amyloid-targeting therapies in the US and several other countries, represents a significant development in the treatment landscape, offering new hope for addressing this once untreatable chronic progressive disease. However, significant challenges persist that could impede the successful integration of this class of drugs into clinical practice. These challenges include determining patient eligibility, appropriate use of diagnostic tools and genetic testing in patient care pathways, effective detection and monitoring of side effects, and improving the healthcare system's readiness by engaging both primary care and dementia specialists. Additionally, there are logistical concerns related to infrastructure, as well as cost-effectiveness and reimbursement issues. This article brings together insights from a diverse group of international researchers and dementia experts and outlines the potential challenges and opportunities, urging all stakeholders to prepare for the introduction of DMTs. We emphasize the need to develop appropriate use criteria, including patient characteristics, specifically for the European healthcare system, to ensure that treatments are administered to the most suitable patients. It is crucial to improve the skills and knowledge of physicians to accurately interpret biomarker results, share decision-making with patients, recognize treatment-related side effects, and monitor long-term treatment. We advocate for investment in patient registries and unbiased follow-up studies to better understand treatment effectiveness, evaluate treatment-related side effects, and optimize long-term treatment. Utilizing amyloid-targeting therapies as a starting point for combination therapies should also be a priority.}, }
@article {pmid39800468, year = {2025}, author = {Asken, BM and Cid, REC and Crocco, EA and Armstrong, MJ and Levy, SA and Arias, F and Rosselli, M and Uribe, IV and Barker, WW and Matusz, EF and DeSimone, JC and Wang, WE and Fiala, J and Marsiske, MM and DeKosky, ST and Vaillancourt, DE and Duara, R and Loewenstein, DA and Smith, GE}, title = {Informing etiological heterogeneity of mild cognitive impairment and risk for progression to dementia with plasma p-tau217.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {1}, pages = {100011}, pmid = {39800468}, issn = {2426-0266}, support = {P30 AG066506/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Cognitive Dysfunction/blood/diagnosis ; *Disease Progression ; *tau Proteins/blood ; Female ; Male ; Aged ; *Biomarkers/blood ; Alzheimer Disease/blood/diagnosis ; Dementia/blood/diagnosis ; Middle Aged ; Aged, 80 and over ; }, abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a clinical diagnosis representing early symptom changes with preserved functional independence. There are multiple potential etiologies of MCI. While often presumed to be related to Alzheimer's disease (AD), other neurodegenerative and non-neurodegenerative causes are common. Wider availability of relatively non-invasive plasma AD biomarkers, such as p-tau217, can provide invaluable insights into MCI clinico-pathology and the associated implications for symptom etiology, prognosis (e.g., risk for progression to dementia), and treatment options.
OBJECTIVES: The main goal of this study was to evaluate differences between individuals with MCI with and without plasma p-tau217 biomarker evidence of AD (MCIAD+ and MCIAD-) as well as a control group of clinically normal older adults with negative AD biomarkers (CNAD-). We evaluated group differences in demographics, recruitment, clinical scales, fluid biomarkers, and brain imaging. We further probed these factors as independent contributors to symptoms among MCIAD- participants, for whom symptom etiology is most poorly understood. Lastly, in a subset of participants followed longitudinally, we investigated how these factors related to odds of clinical progression to dementia.
DESIGN: We conducted an observational cross-sectional and longitudinal clinical research study. Study groups were compared cross-sectionally on demographics, recruitment, clinical measures, and biomarkers (chi square analyses, analyses of covariance). Contributors to functional changes were evaluated with multiple linear regression. Factors associated with the odds of progression from MCI to dementia longitudinally were evaluated with binary logistic regression.
SETTING: 1Florida Alzheimer's Disease Research Center.
PARTICIPANTS: Cross-sectional analyses included 378 older adults classified as CNAD- (N = 76, age 66.1 ± 7.2, 63.2% female, 23.7% non-Hispanic/White), MCIAD- (N = 198, age 68.9 ± 7.9, 51.5% female, 29.3% non-Hispanic/White), or MCIAD+ (N = 104, age 73.9 ± 7.4, 52.9% female, 49.0% non-Hispanic/White). Longitudinal analyses focused on 207 participants with MCI (68.5% of cross-sectional MCI sample) followed for an average of 3 years.
MEASUREMENTS: Demographics (age, sex, years of education, self-identified race and ethnicity, primary spoken language), National Alzheimer's Coordinating Center-defined clinical phenotypes (Clinically Normal, Impaired - Not MCI, Amnestic MCI, Nonamnestic MCI, Dementia), recruitment source (clinic-based versus community-based), genetics (APOE genotype), functional evaluation (Clinical Dementia Rating scale), global cognition (Mini Mental State Exam), vascular history (Vascular Burden Score), neuropsychiatric symptoms (NPI-Q Total score), plasma biomarkers (ALZPath p-tau217, Quanterix Simoa-based GFAP and NfL), and brain imaging (grey matter volume in select AD-relevant regions of interest, global white matter hyperintensity volume).
RESULTS: Among those with MCI, 104 (34.4%) had plasma biomarker evidence of AD. MCIAD+ participants were more frequently recruited from clinic-based settings than MCIAD- (74.8% vs. 47.5%, p<.001). Over half (51.5%) of MCIAD+ carried at least one APOE e4 allele compared to 26.6% of MCIAD- and 29.4% of CNAD- (p<.001). Both MCIAD+ (p<.001, Cohen's d = 0.93) and MCIAD- (p<.001, d = 0.75) reported more severe neuropsychiatric symptoms than CNAD. MCIAD+ had higher plasma GFAP and NfL than both MCIAD- (GFAP: p<.001, d = 0.88, NfL: p<.001, d = 0.86) and CNAD- (GFAP: p<.001, d = 0.80; NfL: p<.001, d = 0.89). For the AD signature region of interest, MCIAD+ had lower volume than both CNAD- (p<.001, d = 0.78) and MCIAD- (p=.018, d = 0.39). For the hippocampus, both MCIAD+ (p<.001, d = 0.87) and MCIAD- (p<.001, d = 0.64) had lower volume than CNAD-. Longitudinally, older age (OR=1.14 [1.06-1.22], p<.001), higher levels of p-tau217 (OR=10.37 [3.00-35.02], p<.001) and higher neuropsychiatric symptoms (OR=1.19 [1.02-1.39], p=.023) were associated with higher odds of progression to dementia.
CONCLUSIONS: MCI is etiologically heterogeneous. The presence of Alzheimer's pathology defined by elevated plasma p-tau217 in individuals with MCI significantly worsens prognosis. Neuropsychiatric symptoms may contribute to cognitive complaints and risk for progressive decline irrespective of AD pathology. Plasma p-tau217 can inform our understanding of base rates of different MCI phenotypes on a larger scale. As with other AD biomarkers, frequency of elevated plasma p-tau217 and odds of progression to dementia requires careful consideration of recruitment source (clinic- vs. community-based), especially across ethno-racially diverse older adults. Ongoing integration of emerging neurodegenerative disease biomarkers with detailed clinical evaluations will continue to improve treatment specificity and prognosis.}, }
@article {pmid39800464, year = {2025}, author = {Naik, RA and Rajpoot, R and Koiri, RK and Bhardwaj, R and Aldairi, AF and Johargy, AK and Faidah, H and Babalghith, AO and Hjazi, A and Alsanie, WF and Alamri, AS and Alhomrani, M and Alsharif, A and Shkodina, A and Singh, SK}, title = {Dietary supplementation and the role of phytochemicals against the Alzheimer's disease: Focus on polyphenolic compounds.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {1}, pages = {100004}, doi = {10.1016/j.tjpad.2024.100004}, pmid = {39800464}, issn = {2426-0266}, mesh = {*Alzheimer Disease/drug therapy/prevention & control ; Humans ; *Phytochemicals/therapeutic use/administration & dosage/pharmacology ; *Polyphenols/therapeutic use/pharmacology/administration & dosage ; *Dietary Supplements ; Oxidative Stress/drug effects ; Animals ; }, abstract = {Alzheimer's disease is a complicated, multifaceted, neurodegenerative illness that places an increasing strain on healthcare systems. Due to increasing malfunction and death of nerve cells, the person suffering from Alzheimer's disease (AD) slowly and steadily loses their memories, cognitive functions and even their personality. Although medications may temporarily enhance memory, there are currently no permanent therapies that can halt or cure this irreversible neurodegenerative process. Nonetheless, fast progress in comprehending the cellular and molecular abnormalities responsible for neuronal degeneration has increased confidence in the development of viable prevention and treatments. All FDA-approved anti-AD medications have merely symptomatic effects and cannot cure the illness. This necessitates the pursuit of alternate treatments. Accumulating data shows that systemic neuroinflammation, oxidative stress and associated mitochondrial dysfunction play crucial roles in the etiology of AD and precede its clinical presentation. Therefore, innovative therapeutic approaches targeting these pathophysiological components of Alzheimer's disease are being explored aggressively in the present scenario. Phytochemicals such as resveratrol, curcumin, quercetin, genistein and catechins are prospective therapies owing to their capacity to alter key AD pathogenetic pathways, such as oxidative stress, neuroinflammation, and mitochondrial dysfunction. The use of new phytochemical delivery strategies would certainly provide the possibility to solve several issues with standard anti-AD medicines. In this review, the roles of phytophenolic compound-based treatment strategies for AD are discussed.}, }
@article {pmid39800462, year = {2025}, author = {Farrar, G and Weber, CJ and Rabinovici, GD}, title = {Expert opinion on Centiloid thresholds suitable for initiating anti-amyloid therapy. Summary of discussion at the 2024 spring Alzheimer's Association Research Roundtable.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {1}, pages = {100008}, doi = {10.1016/j.tjpad.2024.100008}, pmid = {39800462}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis ; *Cognitive Dysfunction/drug therapy ; Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; Expert Testimony ; }, abstract = {A 24-30 Centiloid (CL) threshold was collectively considered by a group of global dementia experts as a practical and implementable cut-off for anti-amyloid therapy intervention, in Alzheimer's disease patients who have been diagnosed at the mild cognitive impairment or mild dementia stage of their disease. Though additional validation is needed, knowledge of this threshold would be valuable to those involved in diagnosing and treating patients in the new AD care pathways, as well as entry into clinical trials. Therapy monitoring to determine future treatment response and assess amyloid clearance can be accomplished with amyloid PET with some technical details still to be elucidated.}, }
@article {pmid39800458, year = {2025}, author = {Siemers, E and Feaster, T and Sethuraman, G and Sundell, K and Skljarevski, V and Cline, EN and Zhang, H and Jerecic, J and Honig, LS and Salloway, S and Sperling, R and Trame, MN and Dodds, MG and Johnson, K}, title = {INTERCEPT-AD, a phase 1 study of intravenous sabirnetug in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {1}, pages = {100005}, doi = {10.1016/j.tjpad.2024.100005}, pmid = {39800458}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Cognitive Dysfunction/drug therapy ; Male ; Aged ; Double-Blind Method ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacokinetics/administration & dosage/adverse effects ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Dose-Response Relationship, Drug ; }, abstract = {BACKGROUND: Soluble species of multimeric amyloid-beta including globular amyloid-beta oligomers (AβOs) and linear amyloid-beta protofibrils are toxic to neurons. Sabirnetug (ACU193) is a humanized monoclonal antibody, raised against globular species of soluble AβO, that has over 650-fold greater binding affinity for AβOs over monomers and appears to have relatively little binding to amyloid plaque.
OBJECTIVES: To assess safety, pharmacokinetics, and exploratory measures including target engagement, biomarker effects, and clinical efficacy of sabirnetug in participants with early symptomatic Alzheimer's disease (AD; defined as mild cognitive impairment and mild dementia due to AD).
DESIGN: Randomized, double-blind, placebo-controlled, ascending dose first-in-human phase 1 study.
SETTING: Fifteen study centers in the United States.
PARTICIPANTS: Sixty-five participants with early symptomatic AD.
INTERVENTION: Participants received one infusion of sabirnetug 2 mg/kg, 10 mg/kg, 25 mg/kg, 60 mg/kg, or placebo (Part A) or three infusions of sabirnetug 10 mg/kg, 25 mg/kg, 60 mg/kg, or placebo (Part B).
MEASUREMENTS: Safety, tolerability, serum pharmacokinetics, and central target engagement of single and multiple doses of sabirnetug, cerebrospinal fluid (CSF) concentrations of sabirnetug, and amyloid plaque load, as determined by positron emission tomography.
RESULTS: Sabirnetug was generally well tolerated. A larger percentage of participants receiving sabirnetug (56.3%) versus placebo (42.9%) had at least one treatment emergent adverse event, with approximately 29% in each group considered related to study drug. Most events were mild-to-moderate in severity. Of 48 participants given sabirnetug, five developed amyloid related imaging abnormalities - edema/effusion, including one instance that was mildly symptomatic in a participant who had received one dose sabirnetug 60 mg/kg. Notably, none of the six apolipoprotein E Ɛ4 homozygotes who received sabirnetug developed amyloid related imaging abnormalities - edema/effusion or - hemorrhage/hemosiderin deposition. Infusion reactions, such as rash, pain, or erythema, were not frequent (6.3% for sabirnetug versus 0.0% for placebo). Sabirnetug exposure was dose proportional in both serum and CSF. Target engagement, defined as drug bound to AβOs in CSF, was shown to be dose and exposure dependent. Over three months, approximately 25% and 20% reduction in amyloid plaques, respectively, were observed in participants receiving three infusions of sabirnetug 60 mg/kg every four weeks and 25 mg/kg every two weeks.
CONCLUSIONS: The Phase 1 INTERCEPT-AD study provided safety, tolerability, dosing, and target engagement data that supported the design of the ongoing ALTITUDE-AD study (NCT06335173).}, }
@article {pmid39800452, year = {2025}, author = {Macfarlane, S and Grimmer, T and Teo, K and O'Brien, TJ and Woodward, M and Grunfeld, J and Mander, A and Brodtmann, A and Brew, BJ and Morris, P and Short, C and Kurrle, S and Lai, R and Bharadwaj, S and Drysdale, P and Sturm, J and Lewis, SJG and Barton, D and Kalafatis, C and Sharif, S and Perry, R and Mannering, N and MacSweeney, JE and Pearson, S and Evans, C and Krishna, V and Thompson, A and Munisamy, M and Bhatt, N and Asher, A and Connell, S and Lynch, J and Rutgers, SM and Dautzenberg, PL and Prins, N and Oschmann, P and Frölich, L and Tacik, P and Peters, O and Wiltfang, J and Henri-Bhargava, A and Smith, E and Pasternak, S and Frank, A and Chertkow, H and Ingram, J and Hsiung, GR and Brittain, R and Tartaglia, C and Cohen, S and Villa, LM and Gordon, E and Jubault, T and Guizard, N and Tucker, A and Kaufmann, WE and Jin, K and Chezem, WR and Missling, CU and Sabbagh, MN}, title = {Blarcamesine for the treatment of Early Alzheimer's Disease: Results from the ANAVEX2-73-AD-004 Phase IIB/III trial.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {1}, pages = {100016}, doi = {10.1016/j.tjpad.2024.100016}, pmid = {39800452}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Double-Blind Method ; Male ; Female ; Aged ; Receptors, sigma ; Sigma-1 Receptor ; Amyloid beta-Peptides ; Middle Aged ; Treatment Outcome ; Aged, 80 and over ; }, abstract = {BACKGROUND: There are no approved oral disease-modifying treatments for Alzheimer's disease (AD).
OBJECTIVES: The objective of this study was to assess efficacy and safety of blarcamesine (ANAVEX®2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) in early AD through restoration of cellular homeostasis including autophagy enhancement.
DESIGN: ANAVEX2-73-AD-004 was a randomized, double-blind, placebo-controlled, 48-week Phase IIb/III trial.
SETTING: Multicenter - 52 medical research centers/hospitals in 5 countries.
INTERVENTION: 508 participants with early AD (Stage 3) were randomized to receive either blarcamesine (n = 338) in medium dose group 30 mg or in high dose group 50 mg or placebo (n = 170) oral capsules once daily for 48 weeks. Participants in these groups were offered to enroll into the open-label-extension study ATTENTION-AD, which completed June 2024, ClinicalTrials.gov Identifier NCT04314934.
MEASUREMENTS: The co-primary cognitive and functional outcomes were assessed as change in ADAS-Cog13 and ADCS-ADL from baseline to 48 weeks. The outcomes include the secondary outcome CDR-SB and biomarkers from the A/T/N spectrum, plasma Aβ42/40-ratio and global brain volume changes measured by MRI. All clinical endpoints were analyzed using mixed model for repeated measures (MMRM), plasma biomarker measurements were analyzed by Welch's t-test, and volumetric MRI scans were analyzed by general linear model.
RESULTS: Among 462 randomized participants in the intent-to-treat population (mean age, 73.7 years; 225 [48.7%] women), 338 (73.2%) completed the trial. The co-primary outcome was met under the multiplicity control rule, since the differences in the least-squares mean (LSM) change from baseline to 48 weeks between the prespecified blarcamesine and placebo groups for ADAS-Cog13 was significant at a level of P < 0.025 and for CDR-SB was significant at a level of P < 0.025, while ADCS-ADL did not reach significance at Week 48 (ADAS-Cog13 difference of -2.027 [95% CI -3.522 to -0.533]; P = 0.008; CDR-SB difference of -0.483 [95% CI -0.853 to -0.114]; P = 0.010; ADCS-ADL difference of 0.775 [95%CI -0.874 to 2.423]; P = 0.357). Plasma Aβ42/40-ratio increased significantly with blarcamesine group vs. placebo, (P = 0.048) and whole brain volume loss was significantly decreased (P = 0.002). Participants in the full safety population with ≥1 serious treatment-emergent adverse events (TEAEs) occurred in 56 participants (16.7%) in the blarcamesine and 17 (10.1%) in the placebo group. Common TEAEs included dizziness, which was transient and mostly mild to moderate in severity. One death in the blarcamesine group and 1 in the placebo group were both not considered treatment related.
CONCLUSIONS: Blarcamesine, demonstrating a safety profile with no associated neuroimaging adverse events, significantly slowed clinical progression by 36.3% at 48 weeks with blarcamesine group as well as the individual 30 mg (by 34.6%) and 50 mg (by 38.5%) blarcamesine groups vs. placebo on the prespecified primary cognitive endpoint ADAS-Cog13. The prespecified secondary endpoint CDR-SB, which is used as the sole primary endpoint in recent successful AD drug submissions, is significantly improved at Week 48 with blarcamesine relative to placebo. The findings are supported by biomarkers from the A/T/N spectrum, including plasma Aβ42/40-ratio and reduction of whole brain atrophy. Additionally, the prespecified SIGMAR1 gene variant subgroup analysis confirmed beneficial clinical effect of blarcamesine group through upstream SIGMAR1 activation - subjects with the common SIGMAR1 wild-type gene (excluding carriers of the mutated SIGMAR1 rs1800866 variant) experienced an even greater significant clinical benefit with slowed clinical progression by 49.8% at 48 weeks on the prespecified primary cognitive endpoint ADAS-Cog13. Oral once daily blarcamesine could represent a novel treatment in early AD and be complementary or alternative to anti-beta amyloid drugs.}, }
@article {pmid39800193, year = {2025}, author = {Ji, HL and Liu, C and Zhang, JJ and Lin, L and Yang, Q and Yang, Y and Dong, CC and He, YB and Shao, CW}, title = {Molecular cloning, expression, and functional analyses of plasmanylethanolamine desaturase gene of Takifugu rubripes.}, journal = {Gene}, volume = {953}, number = {}, pages = {149242}, doi = {10.1016/j.gene.2025.149242}, pmid = {39800193}, issn = {1879-0038}, mesh = {Cloning, Molecular/methods ; Animals ; Humans ; HEK293 Cells ; *Takifugu/genetics/metabolism ; *Oxidoreductases/genetics/metabolism ; Brain/metabolism ; Plasmalogens/metabolism/biosynthesis ; *Fish Proteins/genetics/metabolism ; Amino Acid Sequence ; Open Reading Frames ; }, abstract = {The aging population has led to a significant increase in neurodegenerative diseases, particularly Alzheimer's disease (AD), which adversely affects the quality of life and longevity of the elderly. Abnormal plasmalogen metabolism plays a crucial role in the pathogenesis of AD. This study focused on tmem189, a key gene involved in plasmalogen synthesis. We successfully cloned and characterized the open reading frame (ORF) of tmem189 in Takifugu rubripes, revealing that it encodes a protein consisting of 275 amino acids. Notably, tmem189 expression was found to be higher in brain compared to other tissues. We transfected a GFP-tagged eukaryotic expression vector into 293 T cells, confirming successful expression of tmem189 with increased expression levels. Additionally, liquid chromatography-mass spectrometry (LC-MS) analysis demonstrated that tmem189 promotes plasmalogen synthesis in the transfected 293T cells. Our findings suggest that tmem189 could serve as a potential target for the treatment of neurodegenerative diseases, providing new insights into the promotion of plasmalogen synthesis.}, }
@article {pmid39799838, year = {2025}, author = {Nair, AC and Kuriakose, BB and Biju, A and Surendran, S and Sudheesh, MS and Lakshmi, PK}, title = {Pharmacological effects of herbal ingredients of Manasamitra vatakam in the treatment of Alzheimer's disease: A review.}, journal = {Journal of Ayurveda and integrative medicine}, volume = {16}, number = {1}, pages = {101041}, pmid = {39799838}, issn = {0975-9476}, abstract = {Multi-targeted drug therapy has received substantial attention for the treatment of diseases of multi-factorial origin, including neurodegenerative and autoimmune diseases. It seems reasonable to argue that the complex pathology of neurodegenerative diseases (ND) cannot be reduced to a single target to modulate a broad range of cellular signaling, associated pathologies, and symptoms. It is this idea that has brought the attention of the scientific world towards phytochemicals and traditional drugs that are notoriously multi-targeted. A systematic study of these formulations and establishing the molecular pathways of individual molecules can lead to a standardized multi-component product that can modulate a broad range of activities on different targets of ND. This could provide an accessible and affordable solution to the significant disease burden of ND. With this idea in mind, a systematic review was carried out on an Ayurvedic product Manasamitra Vatakam (MMV), known to be a neuroprotective formulation and highly effective against Alzheimer's disease. MMV can be a source of phytomolecules for treating neurodegenerative diseases. The multifactorial nature of these diseases makes them suitable candidates for testing phytochemicals due to the inherent multitargeting capabilities of these compounds. The primary objective of this review is to provide a comprehensive understanding of the phytomolecules from MMV that are responsible for its multitargeted effect against neurodegenerative diseases. From the reported literature, it is clear that many phytoconstituents and extracts of the herbal ingredients from MMV have demonstrated their efficacy against AD models. However, the combination of these molecules in AD models has never been tested. Scientific studies should be done to explore the bioactive compounds in the formulation and the druggability of these identified compounds can be evaluated using experimental methods.}, }
@article {pmid39799559, year = {2025}, author = {Üremiş, N and Üremiş, MM}, title = {Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {1}, pages = {e70133}, pmid = {39799559}, issn = {1099-0461}, support = {//This research was supported by the Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (grant number: TUB1)./ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Apoptosis ; *Oxidative Stress ; *Nitrosative Stress ; *Oxidation-Reduction ; Animals ; *Signal Transduction ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases are significant health concerns that have a profound impact on the quality and duration of life for millions of individuals. These diseases are characterized by pathological changes in various brain regions, specific genetic mutations associated with the disease, deposits of abnormal proteins, and the degeneration of neurological cells. As neurodegenerative disorders vary in their epidemiological characteristics and vulnerability of neurons, treatment of these diseases is usually aimed at slowing disease progression. The heterogeneity of genetic and environmental factors involved in the process of neurodegeneration makes current treatment methods inadequate. However, the existence of common molecular mechanisms in the pathogenesis of these diseases may allow the development of new targeted therapeutic strategies. Oxidative and nitrosative stress damages membrane components by accumulating ROS and RNS and disrupting redox balance. This process results in the induction of apoptosis, which is important in the pathogenesis of neurodegenerative diseases through oxidative stress. Studies conducted using postmortem human samples, animal models, and cell cultures have demonstrated that oxidative stress, nitrosative stress, and apoptosis are crucial factors in the development of diseases such as Alzheimer's, Parkinson's, Multiple Sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. The excessive production of reactive oxygen and nitrogen species, elevated levels of free radicals, heightened mitochondrial stress, disturbances in energy metabolism, and the oxidation and nitrosylation of cellular macromolecules are recognized as triggers for neuronal cell death. Challenges in managing and treating neurodegenerative diseases require a better understanding of this field at the molecular level. Therefore, this review elaborates on the molecular mechanisms by which oxidative and nitrosative stress are involved in neuronal apoptosis.}, }
@article {pmid39799207, year = {2025}, author = {Shen, D and Agarwal, A and Misra, V and Schelter, B and Shah, D and Shiells, H and Wischik, C}, title = {Obtaining personalized predictions from a randomized controlled trial on Alzheimer's disease.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1671}, pmid = {39799207}, issn = {2045-2322}, mesh = {*Alzheimer Disease/therapy ; Humans ; *Randomized Controlled Trials as Topic ; *Precision Medicine/methods ; Clinical Trials, Phase III as Topic ; }, abstract = {The purpose of this article is to infer patient level outcomes from population level randomized control trials (RCTs). In this pursuit, we utilize the recently proposed synthetic nearest neighbors (SNN) estimator. At its core, SNN leverages information across patients to impute missing data associated with each patient of interest. We focus on two types of missing data: (i) unrecorded outcomes from discontinuing the assigned treatments and (ii) unobserved outcomes associated with unassigned treatments. Data imputation in the former powers and de-biases RCTs, while data imputation in the latter simulates "synthetic RCTs" to predict the outcomes for each patient under every treatment. The SNN estimator is interpretable, transparent, and causally justified under a broad class of missing data scenarios. Relative to several standard methods, we empirically find that SNN performs well for the above two applications using Phase 3 clinical trial data on patients with Alzheimer's Disease. Our findings directly suggest that SNN can tackle a current pain point within the clinical trial workflow on patient dropouts and serve as a new tool towards the development of precision medicine. Building on our insights, we discuss how SNN can further generalize to real-world applications.}, }
@article {pmid39798939, year = {2025}, author = {Magavern, EF and Deshmukh, H and Asselin, G and Theusch, E and Trompet, S and Li, X and Noordam, R and Chen, YI and Seeman, TE and Taylor, KD and Post, WS and Tardif, JC and Paul, DS and Benjamin, EJ and Heard-Costa, NL and Vasan, RS and Rotter, JI and Krauss, RM and Jukema, JW and Ridker, PM and Munroe, PB and Caulfield, MJ and Chasman, DI and Dubé, MP and Hitman, GA and Warren, HR and , }, title = {GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study.}, journal = {Pharmacological research}, volume = {212}, number = {}, pages = {107575}, doi = {10.1016/j.phrs.2024.107575}, pmid = {39798939}, issn = {1096-1186}, mesh = {Humans ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use/pharmacology ; *Genome-Wide Association Study ; *Apolipoproteins E/genetics ; *C-Reactive Protein/genetics/metabolism ; Polymorphism, Single Nucleotide ; Female ; Male ; Hepatocyte Nuclear Factor 1-alpha ; }, abstract = {Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response. CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts. Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer's and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered. The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer's, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.}, }
@article {pmid39798853, year = {2025}, author = {Guan, D and Liang, C and Zheng, D and Liu, S and Luo, J and Cai, Z and Zhang, H and Chen, J}, title = {The role of mitochondrial remodeling in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {183}, number = {}, pages = {105927}, doi = {10.1016/j.neuint.2024.105927}, pmid = {39798853}, issn = {1872-9754}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Mitochondrial Dynamics/physiology ; Energy Metabolism/physiology ; }, abstract = {Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.}, }
@article {pmid39798677, year = {2025}, author = {Meng, X and Zhao, W and Yang, R and Xu, SQ and Wang, SY and Li, MM and Jiang, YK and Hao, ZC and Guan, W and Kuang, HX and Chen, QS and Yao, HY and Yan, JJ and Yang, BY and Liu, Y}, title = {Lignans from Schisandra chinensis (Turcz.) Baill ameliorates cognitive impairment in Alzheimer's disease and alleviates ferroptosis by activating the Nrf2/FPN1 signaling pathway and regulating iron levels.}, journal = {Journal of ethnopharmacology}, volume = {341}, number = {}, pages = {119335}, doi = {10.1016/j.jep.2025.119335}, pmid = {39798677}, issn = {1872-7573}, mesh = {Animals ; *Ferroptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Lignans/pharmacology/therapeutic use/isolation & purification ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; *Schisandra/chemistry ; *Signal Transduction/drug effects ; *Iron/metabolism ; Male ; *Cognitive Dysfunction/drug therapy/metabolism ; Cell Line ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/isolation & purification ; }, abstract = {Schisandra chinensis (Turcz.) Baill (S. chinensis), first recorded in Shennong's Classic of the Materia Medica, is described as a "top grade medicine". As a traditional Chinese medicine of tonifying the kidneys and the brain, S. chinensis is widely used to treat diseases such as amnesia and dementia. Alzheimer's disease (AD) is a neurodegenerative disease, and ferroptosis is one of the essential causes of AD. Although previous studies have suggested that the lignans of S. chinensis (SCL) have neuroprotective effects, it is unclear whether SCL can alleviate AD pathology by inhibiting ferroptosis.
AIM OF THE STUDY: To investigate the effect of SCL on AD caused by ferroptosis and its possible molecular mechanism.
MATERIALS AND METHODS: This study was based on SAMR1/SAMP8 mouse models along with Erastin-induced HT22 cell lines to examine the influence of SCL on ferroptosis in AD. The S. chinensis was extracted via 75% EtOH-H2O and identified by HPLC/UPLC-QTOF-MS. MWM assessed spatial learning, while HE staining, biochemical detection, IHC, and WB analyzed AD pathology and iron metabolism. Mitochondrial changes were evaluated by TEM, and confocal imaging post-SCL treatment analyzed ROS, MMP, and Fe[2+] levels in HT22 cells. IF determined the expression levels and localization of Nrf2 and FPN1. CETSA was deployed to study the interaction between SCL and Nrf2.
RESULTS: Treatment with SCL mitigated cognitive dysfunction and reduced p-Tau as well as neuronal loss in AD model mice. Additionally, the administration of SCL alleviated oxidative stress and maintained relatively intact mitochondrial ridges and membranes, decreased TFR and DMT1 protein expression, and upregulated FTH1. Consistent with the in vivo results, SCL inhibited Erastin-induced ferroptosis in HT22 cells. SCL promoted Nrf2 nuclear translocation and upregulated FPN1, SLC7A11, and GPX4 protein expressions while decreasing FACL4. The improvement of ferroptosis by SCL was associated with the regulation of the Nrf2/FPN1 signaling pathway.
CONCLUSION: The novel discoveries of this study suggest that SCL can suppress ferroptosis in the brains of AD model mice and exerts a partial protective effect against Erastin-induced ferroptosis in HT22 cells, in which the Nrf2/FPN1 signaling pathway plays a crucial role.}, }
@article {pmid39798452, year = {2025}, author = {Kumar, V and Jangid, K and Kumar, V and Kumar, N and Mishra, J and Arora, T and Dwivedi, AR and Kumar, P and Bhatti, JS and Parkash, J and Kumar, V}, title = {In vitro and in vivo Investigations of 4-Substituted 2-Phenylquinazoline derivatives as multipotent ligands for the treatment of Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {155}, number = {}, pages = {108126}, doi = {10.1016/j.bioorg.2025.108126}, pmid = {39798452}, issn = {1090-2120}, mesh = {Animals ; Humans ; *Acetylcholinesterase/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Dose-Response Relationship, Drug ; Ligands ; Molecular Docking Simulation ; Molecular Structure ; Monoamine Oxidase/metabolism ; Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Peptide Fragments/antagonists & inhibitors/metabolism ; *Quinazolines/pharmacology/chemistry/chemical synthesis ; Reactive Oxygen Species/metabolism ; Structure-Activity Relationship ; *Zebrafish ; }, abstract = {The pathology of Alzheimer's disease (AD) is complex due to its multifactorial nature and single targeting drugs proved inefficient. A series of novel 4-N-substituted-2-phenylquinazoline derivatives was designed and synthesized as potential multi-target directed ligands (MTDLs) through dual inhibition of AChE and MAO-B enzymes along with Aβ42 aggregation inhibition for the treatment of AD. Two compounds in the series, VAV-8 and VAV-19 were found to be the most potent inhibitors of both AChE and MAO-B enzymes and moderate inhibitor of Aβ42, with good thermodynamic stability at the binding pocket of the enzymes. Both the ligands showed moderate ROS inhibition and neuroprotection potential and found to be permeable to the blood-brain barrier. Furthermore, VAV-8 was subjected to toxicity evaluation and in vivo investigation using a zebrafish model. In adult zebrafish, VAV-8 (5 μM, and 10 μM) was found to be effective in reducing cognitive deterioration, neurodegeneration, and oxidative stress induced by scopolamine. Thus, these quinazoline derivatives have the potential to be developed as MTDLs for the treatment of Alzheimer's disease.}, }
@article {pmid39798400, year = {2025}, author = {Xun, QQ and Zhang, J and Li, YP and Li, Y and Ma, YY and Chen, ZB and Ding, LP and Shi, XL}, title = {Synthesis and biological evaluation of novel pyrrolo[2,3-b]pyridine derivatives as potent GSK-3β inhibitors for treating Alzheimer's disease.}, journal = {European journal of medicinal chemistry}, volume = {285}, number = {}, pages = {117236}, doi = {10.1016/j.ejmech.2025.117236}, pmid = {39798400}, issn = {1768-3254}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Animals ; *Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism ; *Pyridines/pharmacology/chemical synthesis/chemistry ; *Zebrafish ; Structure-Activity Relationship ; *Pyrroles/pharmacology/chemistry/chemical synthesis ; Mice ; Molecular Structure ; Protein Kinase Inhibitors/pharmacology/chemical synthesis/chemistry ; Dose-Response Relationship, Drug ; Cell Line, Tumor ; }, abstract = {The development of potent glycogen synthase kinase-3β (GSK-3β) inhibitor has been increasingly recognized as the candidate treatment against the multifactorial pathogenic mechanism of Alzheimer's disease (AD). This study prepared various new pyrrolo[2,3-b]pyridine derivatives, evaluated the anti-AD activities and detected the security based on the structure-guided rational design. Our results indicated that many pyrrolo[2,3-b]pyridine derivatives had strong GSK-3β inhibitory activities, particularly compounds 41, 46 and 54, with the half maximal inhibitory concentrations (IC50) of 0.22, 0.26 and 0.24 nM, respectively, and each of them generally possessed GSK-3β selectivity over 24 structurally similar kinases. In addition, further targeting studies at the cellular level revealed that compound 41 increased GSK-3β phosphorylation at Ser9 site dose-dependently for inhibiting GSK-3β activity, therefore inhibiting the hyperphosphorylation of tau protein by decreasing the p-tau-Ser396 abundance. Moreover, 41 up-regulated β-catenin and neurogenesis-related markers (GAP43 and MAP-2), thereby promoting neurite outgrowth of neurons in SH-SY5Y cells. According to the in vitro cells assay, 41 showed the lower cytotoxicity to SH-SY5Y cells with a survival rate of over 70 % at the concentration of 100 μM. In vivo efficacy and acute toxicity experiments showed that, 41 effectively ameliorated the dyskinesia in AlCl3-induced zebrafish AD models and exhibited its low-toxicity nature in C57BL/6 mice. Overall, the pyrrolo[2,3-b]pyridine derivative 41 could serve as a promising GSK-3β inhibitor for treating AD.}, }
@article {pmid39797567, year = {2025}, author = {Bhattacharya, K and Bhattacharjee, A and Chakraborty, M and Das, D and Paudel, KR}, title = {From Antipsychotic to Neuroprotective: Computational Repurposing of Fluspirilene as a Potential PDE5 Inhibitor for Alzheimer's Disease.}, journal = {Journal of computational chemistry}, volume = {46}, number = {2}, pages = {e70029}, doi = {10.1002/jcc.70029}, pmid = {39797567}, issn = {1096-987X}, mesh = {*Alzheimer Disease/drug therapy ; *Phosphodiesterase 5 Inhibitors/pharmacology/chemistry ; Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism/chemistry ; *Antipsychotic Agents/pharmacology/chemistry ; *Molecular Docking Simulation ; Molecular Dynamics Simulation ; Drug Repositioning ; Molecular Structure ; }, abstract = {Phosphodiesterase 5 (PDE5) inhibitors have shown great potential in treating Alzheimer's disease by improving memory and cognitive function. In this study, we evaluated fluspirilene, a drug commonly used to treat schizophrenia, as a potential PDE5 inhibitor using computational methods. Molecular docking revealed that fluspirilene binds strongly to PDE5, supported by hydrophobic and aromatic interactions. Molecular dynamics simulations confirmed that the fluspirilene-PDE5 complex is stable and maintains its structural integrity over time. Binding energy calculations further highlighted favorable interactions, indicating that the drug forms a strong and stable bond with PDE5. Additional analyses, including studies of protein dynamics and energy landscape mapping, revealed how the drug interacts dynamically with PDE5, adapting to different conformations and maintaining stability. These findings suggest that fluspirilene may modulate PDE5 activity, potentially offering therapeutic benefits for Alzheimer's disease. This study provides strong evidence for repurposing fluspirilene as a treatment for Alzheimer's and lays the foundation for further experimental and clinical investigations.}, }
@article {pmid39796582, year = {2024}, author = {Gentili, V and Schiuma, G and Dilliraj, LN and Beltrami, S and Rizzo, S and Lara, D and Giovannini, PP and Marti, M and Bortolotti, D and Trapella, C and Narducci, M and Rizzo, R}, title = {DAG-MAG-ΒHB: A Novel Ketone Diester Modulates NLRP3 Inflammasome Activation in Microglial Cells in Response to Beta-Amyloid and Low Glucose AD-like Conditions.}, journal = {Nutrients}, volume = {17}, number = {1}, pages = {}, pmid = {39796582}, issn = {2072-6643}, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Humans ; *Microglia/drug effects/metabolism ; *Inflammasomes/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism ; Cell Line ; Glucose/metabolism ; Ketones/pharmacology ; Cell Survival/drug effects ; Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: A neuroinflammatory disease such as Alzheimer's disease, presents a significant challenge in neurotherapeutics, particularly due to the complex etiology and allostatic factors, referred to as CNS stressors, that accelerate the development and progression of the disease. These CNS stressors include cerebral hypo-glucose metabolism, hyperinsulinemia, mitochondrial dysfunction, oxidative stress, impairment of neuronal autophagy, hypoxic insults and neuroinflammation. This study aims to explore the efficacy and safety of DAG-MAG-ΒHB, a novel ketone diester, in mitigating these risk factors by sustaining therapeutic ketosis, independent of conventional metabolic pathways.
METHODS: We evaluated the intestinal absorption of DAG-MAG-ΒHB and the metabolic impact in human microglial cells. Utilizing the HMC3 human microglia cell line, we examined the compound's effect on cellular viability, Acetyl-CoA and ATP levels, and key metabolic enzymes under hypoglycemia. Additionally, we assessed the impact of DAG-AG-ΒHB on inflammasome activation, mitochondrial activity, ROS levels, inflammation and phagocytic rates.
RESULTS: DAG-MAG-ΒHB showed a high rate of intestinal absorption and no cytotoxic effect. In vitro, DAG-MAG-ΒHB enhanced cell viability, preserved morphological integrity, and maintained elevated Acetyl-CoA and ATP levels under hypoglycemic conditions. DAG-MAG-ΒHB increased the activity of BDH1 and SCOT, indicating ATP production via a ketolytic pathway. DAG-MAG-ΒHB showed remarkable resilience against low glucose condition by inhibiting NLRP3 inflammasome activation.
CONCLUSIONS: In summary, DAG-MAG-ΒHB emerges as a promising treatment for neuroinflammatory conditions. It enhances cellular health under varying metabolic states and exhibits neuroprotective properties against low glucose conditions. These attributes indicate its potential as an effective component in managing neuroinflammatory diseases, addressing their complex progression.}, }
@article {pmid39796199, year = {2025}, author = {Zhang, J and Tsui, KC and Lee, HY and Aquili, L and Wong, KH and Kocabicak, E and Temel, Y and Lu, Z and Fung, ML and Kalueff, A and Lim, LW}, title = {Data Mining Approach to Melatonin Treatment in Alzheimer's Disease: New Gene Targets MMP2 and NR3C1.}, journal = {International journal of molecular sciences}, volume = {26}, number = {1}, pages = {}, pmid = {39796199}, issn = {1422-0067}, mesh = {*Alzheimer Disease/drug therapy/genetics/metabolism ; *Melatonin/pharmacology/therapeutic use ; Humans ; *Matrix Metalloproteinase 2/genetics/metabolism ; *Data Mining ; *Protein Interaction Maps ; Gene Regulatory Networks/drug effects ; Gene Ontology ; Signal Transduction/drug effects ; }, abstract = {Melatonin is a hormone released by the pineal gland that regulates the sleep-wake cycle. It has been widely studied for its therapeutic effects on Alzheimer's disease (AD), particularly through the amyloidosis, oxidative stress, and neuroinflammation pathways. Nevertheless, the mechanisms through which it exerts its neuroprotective effects in AD are still largely unknown. Data mining was used to identify potential gene targets that link melatonin's effects to AD pathways, yielding a comprehensive view of the underlying molecular mechanisms. We identified 3397 genes related to AD from DisGeNet and 329 melatonin gene targets from ChEMBL, which revealed 223 overlapping genes and the potential shared pathways. These genes were used to construct a protein-protein interaction (PPI) network comprising 143 nodes and 823 edges, which demonstrated significant PPI enrichment. A cluster analysis highlighted two key clusters centered on MMP2 and NR3C1, with both genes playing crucial roles in steroid hormone signaling, apoptosis, and monoamine neurotransmission. Gene Ontology (GO) enrichment and KEGG pathway analyses further elucidated their involvement in critical pathways, for instance, steroid hormone signaling and apoptosis regulation, significantly influencing AD pathology through mechanisms such as extracellular matrix remodeling, epigenetic modifications, and neuroinflammation. Our findings emphasize MMP2 and NR3C1 as important gene targets for future research on melatonin treatment in AD, paving the way for further investigations into their roles in AD pathophysiology.}, }
@article {pmid39796097, year = {2024}, author = {Mohd Murshid, N and Mohd Sahardi, NFN and Makpol, S}, title = {Advancing Alzheimer's Disease Modelling by Developing a Refined Biomimetic Brain Microenvironment for Facilitating High-Throughput Screening of Pharmacological Treatment Strategies.}, journal = {International journal of molecular sciences}, volume = {26}, number = {1}, pages = {}, pmid = {39796097}, issn = {1422-0067}, support = {FRGS/1/2024/SKK10/UKM/01/1//Malaysia Ministry of Higher Education Fundamental Research Grant Scheme/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Brain/metabolism/drug effects/pathology ; *High-Throughput Screening Assays/methods ; Animals ; Biomimetics/methods ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Disease Models, Animal ; Drug Evaluation, Preclinical/methods ; Drug Discovery/methods ; }, abstract = {Alzheimer's disease (AD) poses a significant worldwide health challenge, requiring novel approaches for improved models and treatment development. This comprehensive review emphasises the systematic development and improvement of a biomimetic brain environment to address the shortcomings of existing AD models and enhance the efficiency of screening potential drug treatments. We identify drawbacks in traditional models and emphasise the necessity for more physiologically accurate systems through an in-depth analysis of current literature. This review aims to study the development of an advanced AD model that accurately replicates key AD pathophysiological aspects using cutting-edge biomaterials and microenvironment design. Incorporating biomolecular elements like Tau proteins and beta-amyloid (Aβ) plaques improve the accuracy of illustrating disease mechanisms. The expected results involve creating a solid foundation for high-throughput screening with enhanced scalability, translational significance, and the possibility of speeding up drug discovery. Thus, this review fills the gaps in AD modelling and shows potential for creating precise and efficient drug treatments for AD.}, }
@article {pmid39796014, year = {2024}, author = {Ogos, M and Stary, D and Bajda, M}, title = {Recent Advances in the Search for Effective Anti-Alzheimer's Drugs.}, journal = {International journal of molecular sciences}, volume = {26}, number = {1}, pages = {}, pmid = {39796014}, issn = {1422-0067}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Ligands ; Animals ; Plaque, Amyloid/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Drug Design ; }, abstract = {Alzheimer's disease, the most common form of dementia, is characterized by the deposition of amyloid plaques and neurofibrillary tangles in the brain, leading to the loss of neurons and a decline in a person's memory and cognitive function. As a multifactorial disease, Alzheimer's involves multiple pathogenic mechanisms, making its treatment particularly challenging. Current drugs approved for the treatment of Alzheimer's disease only alleviate symptoms but cannot stop the progression. Moreover, these drugs typically target a single pathogenic mechanism, leaving other contributing factors unaddressed. Recent advancements in drug design have led to the development of multi-target-directed ligands (MTDLs), which have gained popularity for their ability to simultaneously target multiple pathogenic mechanisms. This paper focuses on analyzing the activity, mechanism of action, and binding properties of the anti-Alzheimer's MTDLs developed between 2020 and 2024.}, }
@article {pmid39795532, year = {2024}, author = {Benredjem, S and Mekhaznia, T and Rawad, A and Turaev, S and Bennour, A and Sofiane, B and Aborujilah, A and Al Sarem, M}, title = {Parkinson's Disease Prediction: An Attention-Based Multimodal Fusion Framework Using Handwriting and Clinical Data.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {39795532}, issn = {2075-4418}, abstract = {BACKGROUND: Neurodegenerative diseases (NGD) encompass a range of progressive neurological conditions, such as Alzheimer's disease (AD) and Parkinson's disease (PD), characterised by the gradual deterioration of neuronal structure and function. This degeneration manifests as cognitive decline, movement impairment, and dementia. Our focus in this investigation is on PD, a neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the brain, leading to motor disturbances. Early detection of PD is paramount for enhancing quality of life through timely intervention and tailored treatment. However, the subtle nature of initial symptoms, like slow movements, tremors, muscle rigidity, and psychological changes, often reduce daily task performance and complicate early diagnosis.
METHOD: To assist medical professionals in timely diagnosis of PD, we introduce a cutting-edge Multimodal Diagnosis framework (PMMD). Based on deep learning techniques, the PMMD framework integrates imaging, handwriting, drawing, and clinical data to accurately detect PD. Notably, it incorporates cross-modal attention, a methodology previously unexplored within the area, which facilitates the modelling of interactions between different data modalities.
RESULTS: The proposed method exhibited an accuracy of 96% on the independent tests set. Comparative analysis against state-of-the-art models, along with an in-depth exploration of attention mechanisms, highlights the efficacy of PMMD in PD classification.
CONCLUSIONS: The obtained results highlight exciting new prospects for the use of handwriting as a biomarker, along with other information, for optimal model performance. PMMD's success in integrating diverse data sources through cross-modal attention underscores its potential as a robust diagnostic decision support tool for accurately diagnosing PD.}, }
@article {pmid39795159, year = {2024}, author = {Tareen, FK and Catenacci, L and Perteghella, S and Sorrenti, M and Bonferoni, MC}, title = {Carvacrol Essential Oil as a Neuroprotective Agent: A Review of the Study Designs and Recent Advances.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {1}, pages = {}, pmid = {39795159}, issn = {1420-3049}, mesh = {*Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; *Oils, Volatile/therapeutic use/chemistry/pharmacology ; *Cymenes/therapeutic use/pharmacology/chemistry ; Humans ; Animals ; Neurodegenerative Diseases/drug therapy ; }, abstract = {Neurodegenerative diseases were mostly perceived as diseases of ageing populations, but now-a-days, these diseases pose a threat to populations of all age groups despite significant improvements in quality of life. Almost all essential oils (EOs) have been reported to have some neuroprotective abilities and have been used as supplements for good mental health over the centuries. This review highlights the therapeutic potential of one such monoterpene phenolic EO, carvacrol (CV), that has the potential to be used as a main therapeutic intervention for neurodegenerative disorders. Three libraries, Google Scholar, PubMed, and ScienceDirect, were explored for research studies related to the neuroprotective roles of CV. All the research articles from these libraries were sorted out, with the first article tracing back to 2009, and the latest article was published in 2024. The positive effects of CV in the treatment of Alzheimer's and Parkinson's Diseases, multiple sclerosis, ischemia, and behavioural disorders have been supported with evidence. This review not only focused on study designs and the pharmacological pathways taken by CV for neuroprotection but also focused on demographics, illustrating the trend of CV research studies in certain countries and the preferences for the use of in vitro or in vivo models in studies. Our review provides useful evidence about the neuroprotective potential of CV; however, a lack of studies was observed regarding CV encapsulation in proper dosage forms, in particular nanoparticles, which could be further explored for CV delivery to the central nervous system.}, }
@article {pmid39794687, year = {2025}, author = {Barisch-Fritz, B and Shah, J and Krafft, J and Geda, YE and Wu, T and Woll, A and Krell-Roesch, J}, title = {Physical activity and the outcome of cognitive trajectory: a machine learning approach.}, journal = {European review of aging and physical activity : official journal of the European Group for Research into Elderly and Physical Activity}, volume = {22}, number = {1}, pages = {1}, pmid = {39794687}, issn = {1813-7253}, abstract = {BACKGROUND: Physical activity (PA) may have an impact on cognitive function. Machine learning (ML) techniques are increasingly used in dementia research, e.g., for diagnosis and risk stratification. Less is known about the value of ML for predicting cognitive decline in people with dementia (PwD). The aim of this study was to use an ML approach to identify variables associated with a multimodal PA intervention that may impact cognitive changes in PwD, i.e., by distinguishing between cognitive decliners and non-decliners.
METHODS: This is a secondary, exploratory analysis using data from a Randomized Controlled Trial that included a 16-week multimodal PA intervention for the intervention group (IG) and treatment as usual for the control group (CG) in nursing homes. Predictors included in the ML models were related to the intervention (e.g., adherence), physical performance (e.g., mobility, balance), and pertinent health-related variables (e.g., health status, dementia form and severity). Primary outcomes were global and domain-specific cognitive performance (i.e., attention/ executive function, language, visuospatial skills, memory) assessed by standardized tests. A Support Vector Machine model was used to perform the classification of each primary outcome into the two classes of decline and non-decline. GridSearchCV with fivefold cross-validation was used for model training, and area under the ROC curve (AUC) and accuracy were calculated to assess model performance.
RESULTS: The study sample consisted of 319 PwD (IG, N = 161; CG, N = 158). The proportion of PwD experiencing cognitive decline, in the different domains measured, ranged from 27-48% in CG, and from 23-49% in IG, with no statistically significant differences and no time*group effects. ML models showed accuracy and AUC values ranging from 40.6-75.6. The strongest predictors of cognitive decline or non-decline were performance of activities of daily living in IG and CG, and adherence and mobility in IG.
CONCLUSIONS: ML models showed moderate performance, suggesting that the selected variables only had limited value for classification, with adherence and performance of activities of daily living appearing to be predictors of cognitive decline. While the study provides preliminary evidence of the potential use of ML approaches, larger studies are needed to confirm our observations and to include other variables in the prediction of cognitive decline, such as emotional health or biomarker abnormalities.}, }
@article {pmid39793907, year = {2025}, author = {Zheng, N and Cao, RL and Liu, DY and Liu, P and Zhao, XY and Zhang, SX and Huang, M and Zheng, ZH and Chen, GL and Zou, LB}, title = {OAB-14 alleviates mitochondrial impairment through the SIRT3-dependent mechanism in APP/PS1 transgenic mice and N2a/APP cells.}, journal = {Free radical biology & medicine}, volume = {228}, number = {}, pages = {360-378}, doi = {10.1016/j.freeradbiomed.2025.01.014}, pmid = {39793907}, issn = {1873-4596}, mesh = {Animals ; *Sirtuin 3/metabolism/genetics ; Mice ; *Mitochondria/metabolism/drug effects/pathology ; *Mice, Transgenic ; *Alzheimer Disease/metabolism/drug therapy/pathology/genetics ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Presenilin-1/genetics/metabolism ; Humans ; Hippocampus/metabolism/pathology/drug effects ; Disease Models, Animal ; Mitophagy/drug effects ; DNA, Mitochondrial/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Mitochondrial Dynamics/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive degenerative disease that affects a growing number of elderly individuals worldwide. OAB-14, a novel chemical compound developed by our research group, has been approved by the China Food and Drug Administration (FDA) for clinical trials in patients with AD (approval no. YD-OAB-220210). Previous studies have shown that OAB-14 enhances cognitive function in APP/PS1 transgenic mice and ameliorates abnormal mitochondrial morphology in the hippocampus. Mitochondrial dysfunction is a major risk factor for the development of AD, and maintaining healthy mitochondrial morphology and function is essential for improving the pathological changes and symptoms of AD. However, the protective effects of OAB-14 on mitochondria in AD and the underlying mechanisms remain unclear. This study aimed to investigate the protective effects of OAB-14 on the mitochondria of APP/PS1 transgenic mice and N2a/APP cells. Treatment with OAB-14 restored impaired mitochondrial function, mitochondrial dynamics, mitophagy, and mitochondrial DNA (mtDNA) in APP/PS1 transgenic mice and N2a/APP cells. In APP/PS1 transgenic mice and N2a/APP cells, OAB-14-treated elevated the expression and activity of SIRT3, decreased mitochondrial acetylation, and reduced mitochondrial reactive oxygen species (mtROS) levels. OAB-14 also attenuated mitochondrial acetylation, improved mitochondrial dynamics and mitophagy, and mitigated mtDNA damage in a SIRT3-dependent manner. In addition, OAB-14 suppressed mitochondrial Aβ accumulation in the hippocampus of APP/PS1 transgenic mice. This study provides further clarification on the potential therapeutic mechanisms of OAB-14 in the treatment of AD and lays the groundwork for future drug applications.}, }
@article {pmid39793847, year = {2025}, author = {Shinde, U and Balasinor, NH and Ravichandran, V and Kumar, AS and Gunasekaran, VP}, title = {"Extracellular Vesicle DNA: Advances and Applications as a Non-Invasive Biomarker in Disease Diagnosis and Treatment".}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {568}, number = {}, pages = {120125}, doi = {10.1016/j.cca.2025.120125}, pmid = {39793847}, issn = {1873-3492}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/analysis/metabolism ; *DNA ; Cardiovascular Diseases/diagnosis/metabolism ; Neoplasms/diagnosis/genetics/therapy ; Neurodegenerative Diseases/diagnosis/metabolism ; }, abstract = {Extracellular vesicles (EVs) are nanoscale, membrane-enclosed structures released by cells into the extracellular milieu. These vesicles encapsulate a diverse array of molecular constituents, including nucleic acids, proteins, and lipids, which provide insights into the physiological or pathological conditions of their parent cells. Despite their potential, the study of EV-derived DNA (EV-DNA) has gathered relatively limited attention. This review aims to present a thorough examination of the emerging knowledge surrounding the utility of EV-DNA as a non-invasive biomarker across a spectrum of diseases. The review delves into various mechanisms underlying DNA packaging within EVs and the prevalent methodologies employed for extraction of EV-DNA. The relevance of EV-DNA is assessed across numerous health conditions, notably cancer, cardiovascular diseases, neurodegenerative disorders, infectious diseases, and pregnancy-related complications. The use of EV-DNA for cancer mutation detection has demonstrated remarkable sensitivity and specificity, thereby enhancing both diagnostic accuracy and therapeutic monitoring. In the context of cardiovascular diseases, EV-DNA serves as a predictive marker for events such as myocardial infarctions and shows a correlation with the severity of the disease. With respect to neurodegenerative conditions, including Parkinson's and Alzheimer's, EV-DNA contributes to the understanding of disease mechanisms and progression. Additionally, it plays an essential role in modulating immune tolerance and facilitating communication between maternal and fetal systems. Although there is a pressing need for standardized protocols for EV isolation and DNA analysis to facilitate clinical implementation, the prospect of EV-DNA as a non-invasive biomarker for diagnostic and prognostic purposes across diverse pathological conditions is considerable.}, }
@article {pmid39793029, year = {2025}, author = {Tiwari, A and Singh, R and Kumar, S and Sunkaria, A and Jain, A}, title = {From Plant to Pathway: Molecular Mechanisms of Ruscogenin in Preventing Amyloid-Beta Aggregation through Computational and Experimental Approaches.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {3}, pages = {500-512}, doi = {10.1021/acschemneuro.4c00745}, pmid = {39793029}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism ; *Spirostans/pharmacology/chemistry ; Humans ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; Alzheimer Disease/metabolism ; Protein Aggregates/drug effects ; Sapogenins/pharmacology/chemistry ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, extracellular amyloid-β (Aβ) plaque accumulation, and intracellular neurofibrillary tangles. Recent efforts to find effective therapies have increased interest in natural compounds with multifaceted effects on AD pathology. This study explores natural compounds for their potential to mitigate AD pathology using molecular docking, ADME screening, and in vitro assays, with ruscogenin─a steroidal sapogenin from Ruscus aculeatus─emerging as a promising candidate. Ruscogenin, known for its antioxidant and anti-inflammatory properties, was investigated for its effects on Aβ aggregation, a critical process in AD progression. In vitro assays demonstrated that ruscogenin inhibits Aβ oligomerization at equimolar and higher molar ratios. Molecular dynamics (MD) simulations further revealed that ruscogenin targets aggregation-prone regions, reducing noncovalent interactions and the solvent-accessible surface area of Aβ aggregates. These effects were concentration-dependent, with higher concentrations yielding optimal inhibition, pointing to a multiphasic behavior in ruscogenin's modulation of Aβ aggregation. This study highlights ruscogenin's potential as a natural therapeutic agent for AD, capable of addressing both oxidative stress and inflammation. The findings lay the groundwork for further exploration of ruscogenin-based interventions and underscore the broader potential of natural compounds in AD treatment strategies.}, }
@article {pmid39793012, year = {2025}, author = {Ye, BS and Chang, KW and Kang, S and Jeon, S and Chang, JW}, title = {Repetitive and extensive focused ultrasound-mediated bilateral frontal blood-brain barrier opening for Alzheimer's disease.}, journal = {Journal of neurosurgery}, volume = {}, number = {}, pages = {1-8}, doi = {10.3171/2024.8.JNS24989}, pmid = {39793012}, issn = {1933-0693}, abstract = {OBJECTIVE: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is safe and potentially beneficial in patients with Alzheimer's disease (AD) for the removal of amyloid-beta (Aβ) plaques. However, the optimal BBB opening intervals and number of treatment sessions for clinical improvement remain undefined. Therefore, the aim of this study was to evaluate the safety and benefits of repeated and more extensive BBB opening alone.
METHODS: In this open-label prospective study, 6 patients with AD were enrolled from June 2022 to July 2023. FUS-mediated BBB opening was performed three times at 2-month intervals targeting the bilateral frontal lobes. 18F-florbetaben positron emission tomography (FBB-PET) was performed before the first procedure and after the third procedure. Patients were administered neuropsychological and neuropsychiatric evaluations.
RESULTS: All 6 participants completed the study without any acute treatment-related adverse events. An extensive area of BBB opening (mean 43.1 cm3), more than twice as large as the opening volume (mean 20 cm3) in the authors' previous study, was confirmed by contrast-enhanced MRI. FBB-PET scans demonstrated a 14.9-Centiloid average decrease in Aβ plaques in 4 of the 6 participants (67%), but the Aβ plaques increased in 2 participants after BBB opening, compared with baseline. No significant changes were observed in the Korean version of the Mini-Mental State Examination in either group. Caregiver-Administered Neuropsychiatric Inventory scores improved in 5 of 6 participants (83%), indicating an improvement in neuropsychiatric symptoms.
CONCLUSIONS: This study confirmed the safety and efficacy of more frequent and extensive bilateral frontal BBB opening over multiple sessions in patients with AD. Furthermore, this is the first clinical trial to demonstrate improvement in neuropsychiatric symptoms through BBB opening alone, without concurrent administration of antibody medications.}, }
@article {pmid39792646, year = {2025}, author = {Waller, SE and Stockwell, JB and Fung, VSC and Anstey, KJ and Colebatch, JG and Markoulli, M and Krishnan, AV}, title = {Topical review: Ocular surface abnormalities in neurodegenerative disorders.}, journal = {Optometry and vision science : official publication of the American Academy of Optometry}, volume = {102}, number = {2}, pages = {68-77}, doi = {10.1097/OPX.0000000000002215}, pmid = {39792646}, issn = {1538-9235}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Tears/metabolism/physiology ; *Microscopy, Confocal ; Cornea/metabolism/diagnostic imaging ; Corneal Diseases/diagnosis/metabolism ; Biomarkers/metabolism ; }, abstract = {SIGNIFICANCE: In an aging population, the number of people living with neurodegenerative disease is projected to increase. It is vital to develop reliable, noninvasive biomarkers to detect disease onset and monitor progression, and there is a growing body of research into the ocular surface as a potential source of such biomarkers.
BACKGROUND: This article reviews the potential of in vivo corneal confocal microscopy and tear fluid analysis as tools for biomarker development. Corneal confocal microscopy, traditionally used for studying corneal health, offers high-resolution imaging of corneal nerves and has shown promise for examining systemic diseases such as Alzheimer disease and Parkinson's disease. Complementarily, tear fluid analysis, known for its ease of collection, reflects systemic changes in neurodegenerative conditions.
CONCLUSION: Together, these noninvasive techniques provide insights into disease onset and progression and hold potential for advancing diagnostic and treatment strategies.}, }
@article {pmid39792495, year = {2024}, author = {Espay, AJ}, title = {From Europe to the World: EMA's Leadership in Alzheimer Disease Treatment.}, journal = {American journal of therapeutics}, volume = {31}, number = {6}, pages = {e686-e688}, doi = {10.1097/MJT.0000000000001840}, pmid = {39792495}, issn = {1536-3686}, }
@article {pmid39792490, year = {2024}, author = {Necula, BR and Necula, RD and Petric, PS and Ifteni, PI and Irimie, M and Dima, L}, title = {EGb761 Trials for Mild-to-Moderate Dementia-What Have We Learned in the Past 18 years?.}, journal = {American journal of therapeutics}, volume = {31}, number = {6}, pages = {e645-e651}, doi = {10.1097/MJT.0000000000001849}, pmid = {39792490}, issn = {1536-3686}, mesh = {Humans ; *Ginkgo biloba ; *Plant Extracts/therapeutic use/adverse effects ; *Alzheimer Disease/drug therapy/psychology ; *Randomized Controlled Trials as Topic ; Dementia, Vascular/drug therapy ; Neuroprotective Agents/therapeutic use ; Treatment Outcome ; Mental Status and Dementia Tests/standards ; Dementia/drug therapy ; Ginkgo Extract ; }, abstract = {BACKGROUND: Dementia leads to cognitive decline affecting memory, thinking, and behavior. Current pharmaceutical treatments are symptomatic, with limited efficacy and significant drawbacks. Ginkgo biloba extract (EGb761) is being explored as an adjuvant therapy for dementia because of its potential neuroprotective effects.Areas of Uncertainty:Despite decades of study, EGb761 has not been incorporated into treatment guidelines for these conditions. This review evaluates research futility in EGb761 trials for dementia, analyzing efficacy and methodological challenges to inform future research directions.
DATA SOURCES: In this review, we investigate the efficacy and adverse reactions of Ginkgo biloba extract (EGb761) as a treatment for Alzheimer disease or vascular dementia. We searched the randomized controlled trials published between 2006 and 2023 on PubMed and ScienceDirect.
RESULTS: The 7 selected studies have shown that the degree of improvement in standard cognitive assessment scores [Mini-Mental State Examination (MMSE), short cognitive performance test (SKT), neuropsychiatric inventory (NPI)] was not significant enough for a substantial proportion of patients. Improvements of the SKT score with at least 3 points in the Alzheimer disease/vascular dementia groups were found only in 2 out of 7 studies, changes of less than 2 points in MMSE score were found in 2 of the studies, while an improvement of at least 4 points in NPI scores was reported in 4 out of 7 studies. We aim to understand why this extract has not reached the level of evidence to be included in guideline recommendation despite extensive research and what have we learned from systematic reviews performed since 2010? Studies included in this review have shown some improvement in outcome scores with EGb761 treatment compared with placebo, but these improvements did not reach the threshold for clinically significant enhancement in MMSE/SKT/NPI scores. Limitations such as small sample sizes, minimal score changes, predominantly placebo comparisons, and short follow-up durations make it challenging to determine the usefulness of EGb761 in dementia treatment. The changes observed and methodological constraints underscore the uncertainty surrounding the efficacy of EGb761.
CONCLUSION: The findings do not consistently demonstrate the clinical utility of EGb761, and improved scores on cognitive and neuropsychiatric assessments may not necessarily translate into meaningful clinical outcomes for patients with dementia. Starting from the question "What have we learned in the past 18 years?", the answer would be: not much. Consequently, the question raised is: how long should we go on with the same conclusion, continuing to spend time and financial resources to replicate these results? Research strategies should be refined to optimize decision making and advance evidence-based care for neurocognitive disorders.}, }
@article {pmid39791382, year = {2025}, author = {Xing, H and Kant, S and Kanuparthy, M and Harris, D and Stone, C and Broadwin, M and Zhang, Z and Pearson, E and Hu, J and Sauer, A and Princiotto, A and Harrington, EO and de la Monte, SM and Sellke, F and Feng, J}, title = {Impaired cerebral microvascular reactivity and endothelial SK channel activity in a streptozotocin-treated mouse model of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {4}, pages = {1112-1125}, pmid = {39791382}, issn = {1875-8908}, support = {R01 HL046716/HL/NHLBI NIH HHS/United States ; R01 AA028408/AA/NIAAA NIH HHS/United States ; P20 GM103652/GM/NIGMS NIH HHS/United States ; R01 AA011431/AA/NIAAA NIH HHS/United States ; R01 HL136347/HL/NHLBI NIH HHS/United States ; R01 HL127072/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Small-Conductance Calcium-Activated Potassium Channels/metabolism ; Mice ; *Streptozocin/pharmacology ; *Disease Models, Animal ; *Endothelial Cells/metabolism/drug effects ; *Microvessels/drug effects ; *Amyloid beta-Peptides/metabolism ; Male ; Humans ; Mice, Inbred C57BL ; Indoles/pharmacology ; Peptide Fragments/pharmacology ; Brain/metabolism ; Oximes ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disease marked by increased amyloid-β (Aβ) deposition, tau hyperphosphorylation, impaired energy metabolism, and chronic ischemia-type injury. Cerebral microvascular dysfunction likely contributes to AD pathology, but its precise pathogenic role has been poorly defined.
OBJECTIVE: To examine microvascular reactivity to endothelium-dependent vasodilators and small conductance calcium-activated potassium (SK) channel activity in an intracerebral streptozotocin (STZ)-induced AD mouse model.
METHODS: Control and STZ-AD mice underwent Morris Water Maze and Barnes testing, after which cerebral microvascular and brain microvascular endothelial cells (MBMECs) were dissected to assess microvascular reactivity, responses to SK channel activator NS309, and ion-channel current recordings using whole-cell patch clamp methodology. Control mouse cerebral microvascular and human brain microvascular endothelial cells (HBMECs) were treated with soluble Aβ1-42 peptide to characterize microvascular reactivity and endothelial potassium currents.
RESULTS: STZ-AD mice exhibited impaired performance vs control mice in behavioral testing. STZ-AD mice also exhibited diminished cerebral microvascular responsiveness and MBMECs potassium current augmentation in response to NS309 compared with control mice. Incubation of control mouse cerebral micro-vessels and HBMECs with soluble Aβ (1 µM) for 2 h attenuated relaxation responses to NS309 and diminished NS309-sensitive endothelial potassium currents.
CONCLUSIONS: STZ-AD mice exhibited impaired microvascular relaxation responses to endothelium-dependent vasodilators; SK/IK channel dysfunction may be involved in the mechanism of this impairment. Acute treatment with Aβ produced dysregulated cerebrovascular endothelial SK/IK channels. Further elucidation of the role of microvascular dysfunction in AD is needed to prevent the chronic ischemia-type injury that contributes to cognitive decline.}, }
@article {pmid39791373, year = {2025}, author = {Xu, F and Shi, J}, title = {Insulin signaling and oxidative stress: Bridging the gap between type 2 diabetes mellitus and Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {4}, pages = {994-1004}, doi = {10.1177/13872877241307404}, pmid = {39791373}, issn = {1875-8908}, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Oxidative Stress/physiology ; *Diabetes Mellitus, Type 2/metabolism ; *Insulin/metabolism ; Animals ; *Signal Transduction/physiology ; *Insulin Resistance/physiology ; Hypoglycemic Agents/therapeutic use/pharmacology ; Brain/metabolism/pathology ; }, abstract = {BACKGROUND: Type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD) are two prevalent chronic diseases that pose significant global health challenges. Increasing evidence suggests a complex bidirectional relationship between these conditions, where T2D elevates the risk of AD, and AD exacerbates glucose metabolism abnormalities in T2D.
OBJECTIVE: This review explores the molecular mechanisms linking T2D and AD, focusing on the role of insulin signaling pathways and oxidative stress.
METHODS: A comprehensive literature search from PubMed, Web of Science, and other relevant databases was conducted and analyzed.
RESULTS: Insulin resistance in T2D leads to impaired insulin signaling in the brain, contributing to cognitive decline and the development of AD. Hyperglycemia-induced oxidative stress exacerbates neuronal damage, promoting the formation of amyloid-β plaques and neurofibrillary tangles characteristic of AD. Clinically antidiabetic drugs such as metformin show potential against AD in preclinical studies; Many natural products such as Dendrobium nobile Lindl. have anti-T2D efficacy and are also effective against AD in various in vivo and in vitro models.
CONCLUSIONS: Improving insulin resistance and reducing oxidative stress are important strategies in the treatment of T2D and AD. To understand the bridging role of insulin singling and oxidative stress in T2D and AD will provide insights and broader applications in alleviating T2D and AD.}, }
@article {pmid39791204, year = {2025}, author = {Wan, T and Wang, C}, title = {SMOC2 promotes microglia activity and neuroinflammation in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {3}, pages = {941-950}, doi = {10.1177/13872877241307337}, pmid = {39791204}, issn = {1875-8908}, mesh = {*Microglia/metabolism ; *Alzheimer Disease/metabolism/pathology ; *Phagocytosis ; Animals ; *Calcium-Binding Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Neuroinflammatory Diseases/metabolism ; Humans ; Mice ; NF-kappa B/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), the leading cause of dementia, is characterized by cognitive decline and the accumulation of amyloid-β (Aβ). It affects millions, with numbers expected to double by 2050. SMOC2, implicated in inflammation and fibrosis, may play a role in AD pathogenesis, particularly in microglial cell function, offering a potential therapeutic target.
OBJECTIVE: Alzheimer's disease (AD) leads to neurodegeneration, affecting cognition, language, and personality, underscoring the urgency for effective treatments. Our study investigates the role of secreted modular calcium-binding protein 2 (SMOC2) in microglial cells and its impact on AD pathology.
METHODS: We introduced SMOC2 overexpression and interference vectors into microglial cells treated with Aβ. Activity and phagocytosis were assessed using CCK8 and flow cytometry. SMOC2 mRNA levels were quantified by qPCR, and protein levels of SMOC2, TGF-β1, p-NF-κB/NF-κB were analyzed by western blot. Aβ content was determined by ELISA, and immunofluorescence detected TNF-α, IL-1β, CD163, and CD206.
RESULTS: Aβ treatment inhibited microglial activity and phagocytosis, but SMOC2 disruption enhanced these functions (p < 0.05). SMOC2 overexpression increased its expression and Aβ levels, while interference reduced them (p < 0.001). SMOC2 overexpression also decreased TGF-β1, CD163, and CD206, and increased p-NF-κB/NF-κB, TNF-α, and IL-1β (p < 0.05).
CONCLUSIONS: SMOC2 plays a crucial role in microglial cell activity, phagocytosis, and polarization, potentially through the TGF-β1/NF-κB pathway, offering insights into AD pathogenesis.}, }
@article {pmid39791155, year = {2025}, author = {Chen, H and Chang, X and Zhou, J and Zhang, G and Cheng, J and Zhang, Z and Xing, J and Yan, C and Liu, Z}, title = {Anti-neuroinflammatory and Neuroprotective Effects of T-006 on Alzheimer's Disease Models by Modulating TLR4-Mediated MyD88/ NF-κB Signaling.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273337232241121113048}, pmid = {39791155}, issn = {1996-3181}, abstract = {INTRODUCTION: Neuroinflammation derived from the activation of the microglia is considered a vital pathogenic factor of Alzheimer's Disease (AD). T-006, a tetramethylpyrazine derivative, has been found to alleviate cognitive deficits via inhibiting tau expression and phosphorylation in AD transgenic mouse models. Recently, T-006 has been proven to dramatically decrease the levels of total Amyloid β (Aβ) peptide and Glial Fibrillary Acidic Protein (GFAP) and suppress the expression of ionized calcium binding adaptor molecule-1 (Iba-1) in APP/PS1 mice. Therefore, we have further investigated the effects of T-006 on neuroinflammation in AD-like pathology.
METHODS: The anti-inflammatory effects of T-006 and its underlying mechanisms were evaluated in Lipopolysaccharide (LPS)-induced AD rats. The potential protective effects against LPS-activated microglia-mediated neurotoxicity were also measured.
RESULTS: T-006 significantly improved the cognitive impairment in LPS-induced AD rats by inhibiting the microglia/astrocyte activation. Further cellular assays found that T-006 significantly reserved the anomalous elevation of inflammatory cytokines in LPS-induced BV2 microglial cells in a concentration-dependent manner, while T-006 treatment alone showed no effects on the normal cultured cells. T-006 also reduced the levels of Toll-like Receptor 4 (TLR4)/Myeloid Differentiation protein-88 (MyD88)/NF-κB signaling-related proteins in BV2 cells exposed to LPS stimulation. TAK242, which selectively inhibits TLR4, slightly lessened the effects of T-006 in LPS-treatment BV2 cells without significance. Importantly, T-006 protected neurons against LPS-induced neuroinflammation by inhibiting the Reactive Oxygen Species (ROS) production and maintaining mitochondrial function.
CONCLUSION: T-006 inhibited TLR4-mediated MyD88/NF-κB signaling pathways to suppress neuroinflammation in the LPS-induced AD rat model.}, }
@article {pmid39791140, year = {2025}, author = {Alghamdi, A and de Vos, S and Bos, JH and Schuiling-Veninga, CC and van Munster, BC and Mubarik, S and Luijendijk, HJ and Hak, E}, title = {A matched case-control study on polypharmacy and co-medications one year before drug treatment for Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {3}, pages = {706-713}, doi = {10.1177/13872877241305799}, pmid = {39791140}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy/epidemiology ; Male ; Female ; *Polypharmacy ; Aged ; Case-Control Studies ; Aged, 80 and over ; Cross-Sectional Studies ; Comorbidity ; Prevalence ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by amyloid-β plaques and neurofibrillary tangles. With an aging population, both AD and comorbidities are increasingly common. Managing comorbidities often requires multiple medications, leading to polypharmacy, defined as the concurrent use of five or more medications.
OBJECTIVE: This study aimed to estimate and compare the prevalence of polypharmacy one-year prior AD diagnosis compared to non-AD individuals.Methods: A matched cross-sectional design used data from the IADB.nl prescription database (1994-2021), including individuals aged 65 and older with at least one AD medication prescription within a year. Controls were matched by age and sex at a 9:1 ratio. Analyses were stratified by time period (≤2010 and >2010) and further by sex and age.
RESULTS: 4150 AD individuals were included and matched with 37,350 controls. AD individuals had a higher prevalence of polypharmacy compared to controls, ≤ 2010 (OR: 1.15, 95% CI: 1.03-1.29), > 2010 (OR: 1.25, 95% CI: 1.16-1.36). Females with AD had slightly higher odds of polypharmacy than males. The prevalence was consistent across different time periods and age groups, with the highest odds in individuals aged 65-74.
CONCLUSIONS: AD individuals in the Netherlands exhibit a significantly higher prevalence of polypharmacy in a year pre-AD diagnosis. The findings highlight the complexity of managing multiple comorbid conditions in AD individuals, emphasizing the need for regular review and optimization of medication regimens and the inclusion of non-pharmacological interventions to minimize adverse outcomes and improve quality of life.}, }
@article {pmid39790124, year = {2025}, author = {Sharma, A and Rudrawar, S and Bharate, SB and Jadhav, HR}, title = {Recent advancements in the therapeutic approaches for Alzheimer's disease treatment: current and future perspective.}, journal = {RSC medicinal chemistry}, volume = {16}, number = {2}, pages = {652-693}, pmid = {39790124}, issn = {2632-8682}, abstract = {Alzheimer's disease (AD) is a complex, incurable neurological condition characterized by cognitive decline, cholinergic neuron reduction, and neuronal loss. Its exact pathology remains uncertain, but multiple treatment hypotheses have emerged. The current treatments, single or combined, alleviate only symptoms and struggle to manage AD due to its multifaceted pathology. The developmental drugs target pivotal disease factors involved in the envisaged hypotheses and include targets such as amyloid aggregation, hyperphosphorylated tau proteins, and receptors like cholinergic, adrenergic, etc. Present-day research focuses on multi-target directed ligands (MTDLs), which inhibit multiple factors simultaneously, helping slow the disease's progression. This review attempts to collate the recent information related to proposed hypotheses for AD etiology. It systematically organizes the advances in various therapeutic options for AD, with a particular emphasis on clinical candidates. Also, it is expected to help medicinal chemists design novel AD treatments based on available information, which could be helpful to AD patients.}, }
@article {pmid39788884, year = {2025}, author = {Pawlosky, R and Demarest, TG and King, MT and Estrada, D and Veech, RL and Bohr, VA}, title = {Effect of Dietary Ketosis and Nicotinamide Riboside on Hippocampal Krebs Cycle Intermediates and Mitochondrial Energetics in a DNA Repair-Deficient 3xTg/POLβ[+/-] Alzheimer Disease Mouse Model.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16295}, pmid = {39788884}, issn = {1471-4159}, support = {/AA/NIAAA NIH HHS/United States ; /AG/NIA NIH HHS/United States ; }, mesh = {*Ketosis/blood/metabolism/pathology ; *Hippocampus/metabolism/pathology ; *Citric Acid Cycle/drug effects ; *Mitochondria/drug effects/metabolism ; *Energy Metabolism/drug effects ; *DNA Repair/drug effects ; Mice, Transgenic ; Animals ; *Alzheimer Disease/metabolism/pathology ; Disease Models, Animal ; DNA Polymerase beta/deficiency ; Niacinamide/pharmacology ; Diet ; Male ; Female ; Mice, Inbred C57BL ; Blood Glucose/metabolism ; Ketones/blood ; Glycolysis/drug effects ; Sex Factors ; NAD/metabolism ; Ubiquinone/metabolism ; Aging/pathology ; Body Weight ; }, abstract = {Alzheimer disease is a neurodegenerative pathology-modifying mitochondrial metabolism with energy impairments where the effects of biological sex and DNA repair deficiencies are unclear. We investigated the therapeutic potential of dietary ketosis alone or with supplemental nicotinamide riboside (NR) on hippocampal intermediary metabolism and mitochondrial bioenergetics in older male and female wild-type (Wt) and 3xTgAD-DNA polymerase-β-deficient (3xTg/POLβ[+/-]) (AD) mice. DNA polymerase-β is a key enzyme in DNA base excision repair (BER) of oxidative damage that may also contribute to mitochondrial DNA repair. Metabolic alterations imparted by ketosis and/or NR were assessed in 16 male and female groups, 4 Wt and 4 AD. At 73 weeks of age, mice were divided into: (A) carbohydrate diet (Carb); (B) Carb diet with NR (Carb-NR); (C) Ket diet (Ket); and (D) Ket diet with NR (Ket-NR) groups and remained on their respective treatments for 12 weeks. Mice were euthanized and hippocampi were rapidly removed and frozen. Glycolytic and TCA cycle intermediates were determined by quantitative GC-MS and the ratios of the mitochondrial free [NADox]/[NADHred] and coenzyme ubiquinone (CoQ/CoQH2) couples and the Gibbs free energy of the Complex I-II system of the electron transport chain (ETC) (∆ G mitochondrial Complex I - II ' $$ \Delta {G}_{\mathrm{mitochondrial}\ \mathrm{Complex}\ \mathrm{I}-\mathrm{II}}^{\prime } $$) were calculated from selected metabolites. Mice in Groups C and D had elevated blood ketones (1-2 mM). In most groupings, male mice had higher concentrations of TCA cycle intermediates than females. Moreover, higher concentrations of fumarate in Wt males were associated with elevations in the ΔG' of Complex I-II compared to females. In Wt males, NR treatments were associated with elevated concentrations of α-ketoglutarate and malate and linked to increased energy of Complex I-II. In AD males, both NR treatment and dietary ketosis restored the ΔG' of Complex I-II, where the ratio of the CoQ/CoQH2 couple was oxidized and the [NADox]/[NADHred] couple was reduced. In AD females, only mice in the Ket diet group had a sufficiently reduced [NADox]/[NADHred] couple to restore the free energy profile.}, }
@article {pmid39788499, year = {2024}, author = {Pan, Q and Hu, X and Guo, K}, title = {Beta-amyloid protein regulates miR-15a and activates Bag5 to influence neuronal apoptosis in Alzheimer's disease.}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {49}, number = {7}, pages = {1109-1119}, pmid = {39788499}, issn = {1672-7347}, mesh = {*MicroRNAs/genetics/metabolism ; Animals ; *Alzheimer Disease/metabolism/genetics ; *Apoptosis ; Rats ; *Amyloid beta-Peptides/metabolism ; *Neurons/metabolism ; *Rats, Sprague-Dawley ; Humans ; Disease Models, Animal ; Brain/metabolism/pathology ; Caspase 3/metabolism ; Cell Proliferation ; Cell Line, Tumor ; Male ; }, abstract = {OBJECTIVES: The prevalence of Alzheimer's disease (AD) is increasing globally, however its pathogenesis is still unclear. The evidence showed that the progression of AD was closely related to the apoptosis of nerve cells. This study amis to explore the role and specific mechanism of miR-15a and Bag5 in the apoptosis of nerve cells induced by beta-amyloid protein (Aβ) in AD.
METHODS: The AD rat model was constructed by injecting Aβ42 into SD rat brain and the AD cell model was constructed by treating SH-SY5Y cells with Aβ42. The learning and memory ability of rats was detected by Morris Water Maze. Hematoxylin and eosin (HE) staining was used to detect the pathological changes of brain tissues. Nissl staining was used to detect the changes of cell morphology and number in brain tissues. The upstream miRNA that interacted with Bag5 were screened by bioinformatics analysis. Methyl thiazolyl tetrazolium (MTT) assay was used to detect cell proliferation. Flow cytometry was used to detect the apoptosis rate of cells. Real-time reverse transcription PCR (real-time RT-PCR) was used to detect the mRNA levels of miR-15a and Bag5. Western blotting was used to detect the protein expression levels of Bag5, Bax and Caspase-3. MiR-15a knockdown or overexpression vectors or Bag5 knockdown vectors were transfected into AD rat model and AD cell models, respectively. Luciferase reporter assay was used to verify the binding relationship between miR-15a and Bag5.
RESULTS: Morris Water Maze, HE staining and Nissl staining showed that the rat model of AD was established successfully, and Aβ could induce neuronal apoptosis and inhibit the expression of miR-15a in AD rats. Compared with normal cells, Aβ treatment significantly increased apoptosis rate and Bag5 expression, and weakened cell proliferation and miR-15a (all P<0.01). Overexpression of miR-15a further enhanced the effect of Aβ on cell proliferation and apoptosis, while knockdown of miR-15a expression had the opposite effect (all P<0.01). Luciferase reporter assay confirmed that there was a negative targeting relationship between miR-15a and Bag5. Compared with Bag5 knockdown alone, the co-transfection of miR-15a inhibitor and si-Bag5 significantly increased the cell proliferation ability and mRNA and protein levels of Bag5, and significantly reduced the cell apoptosis rate and the expression of Bax and Caspase-3, animal studies have also shown consistent results (all P<0.01).
CONCLUSIONS: Aβ can inhibit the expression of miR-15a, thereby inducing the expression of Bag5 and activating the protective mechanism of Bag5 against Aβ induced apoptosis.}, }
@article {pmid39788493, year = {2024}, author = {Zhang, T and Wang, P and Li, R and Wang, Y and Yan, S}, title = {Correlation between obesity and Alzheimer's disease and the mechanisms.}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {49}, number = {7}, pages = {1052-1061}, pmid = {39788493}, issn = {1672-7347}, support = {232102310431//the Henan Province Science and Technology Research Project/ ; }, mesh = {*Alzheimer Disease/etiology/metabolism ; Humans ; *Obesity/complications ; Risk Factors ; Inflammation ; Leptin/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive central neurodegenerative disorder with an insidious onset. With global aging, the incidence and mortality of AD have been steadily increasing, yet effective treatments remain elusive. Obesity, characterized by excessive or abnormal fat accumulation, is a complex metabolic disorder and a confirmed risk factor for numerous diseases. Both obesity and AD have become major public health concerns, posing significant threats to human health and economic development. Studies have revealed a strong correlation between obesity and AD, with multiple contributing factors, including metabolic abnormalities of endocrine factors, inflammatory responses, and genetic interactions. Exploring the correlation and mechanisms between obesity and AD provides important insights and new strategies for the prevention and treatment of AD.}, }
@article {pmid39788400, year = {2025}, author = {Sadat Razavi, Z and Sina Alizadeh, S and Sadat Razavi, F and Souri, M and Soltani, M}, title = {Advancing neurological disorders therapies: Organic nanoparticles as a key to blood-brain barrier penetration.}, journal = {International journal of pharmaceutics}, volume = {670}, number = {}, pages = {125186}, doi = {10.1016/j.ijpharm.2025.125186}, pmid = {39788400}, issn = {1873-3476}, mesh = {*Blood-Brain Barrier/metabolism ; Humans ; *Nanoparticles ; Animals ; *Drug Delivery Systems/methods ; Drug Carriers/chemistry ; Biological Transport ; Nervous System Diseases/drug therapy ; }, abstract = {The blood-brain barrier (BBB) plays a vital role in protecting the central nervous system (CNS) by preventing the entry of harmful pathogens from the bloodstream. However, this barrier also presents a significant obstacle when it comes to delivering drugs for the treatment of neurodegenerative diseases and brain cancer. Recent breakthroughs in nanotechnology have paved the way for the creation of a wide range of nanoparticles (NPs) that can serve as carriers for diagnosis and therapy. Regarding their promising properties, organic NPs have the potential to be used as effective carriers for drug delivery across the BBB based on recent advancements. These remarkable NPs have the ability to penetrate the BBB using various mechanisms. This review offers a comprehensive examination of the intricate structure and distinct properties of the BBB, emphasizing its crucial function in preserving brain balance and regulating the transport of ions and molecules. The disruption of the BBB in conditions such as stroke, Alzheimer's disease, and Parkinson's disease highlights the importance of developing creative approaches for delivering drugs. Through the encapsulation of therapeutic molecules and the precise targeting of transport processes in the brain vasculature, organic NP formulations present a hopeful strategy to improve drug transport across the BBB. We explore the changes in properties of the BBB in various pathological conditions and investigate the factors that affect the successful delivery of organic NPs into the brain. In addition, we explore the most promising delivery systems associated with NPs that have shown positive results in treating neurodegenerative and ischemic disorders. This review opens up new possibilities for nanotechnology-based therapies in cerebral diseases.}, }
@article {pmid39788398, year = {2025}, author = {Otaegui, L and Urgin, T and Zaiter, T and Zussy, C and Vitalis, M and Pellequer, Y and Acar, N and Vigor, C and Galano, JM and Durand, T and Givalois, L and Béduneau, A and Desrumaux, C}, title = {Nose-to-brain delivery of DHA-loaded nanoemulsions: A promising approach against Alzheimer's disease.}, journal = {International journal of pharmaceutics}, volume = {670}, number = {}, pages = {125125}, doi = {10.1016/j.ijpharm.2024.125125}, pmid = {39788398}, issn = {1873-3476}, mesh = {*Alzheimer Disease/drug therapy ; *Docosahexaenoic Acids/administration & dosage/chemistry/pharmacology ; Animals ; *Administration, Intranasal ; *Mice, Transgenic ; *Brain/metabolism/drug effects ; *Emulsions ; *Nanoparticles/administration & dosage ; Disease Models, Animal ; Mice ; Oxidative Stress/drug effects ; Male ; Humans ; Amyloid beta-Peptides/metabolism/administration & dosage ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {Reduced docosahexaenoic acid (DHA) concentrations seem to be associated with an increased risk of Alzheimer's disease (AD), and DHA accretion to the brain across the blood-brain-barrier (BBB) can be modulated by various factors. Therefore, there is an urgent need to identify an efficient and non-invasive method to ensure brain DHA enrichment. In the present study, a safe and stable DHA-enriched nanoemulsion, designed to protect DHA against oxidation, was designed and administered intranasally in a transgenic mouse model of AD, the J20 mice. Intranasal treatment with nanoformulated DHA significantly improved well-being and working spatial memory in six-months-old J20 mice. These behavioral effects were associated with a reduction of amyloid deposition, oxidative stress, and neuroinflammation in brain tissues, which may be partially due to DHA-induced inactivation of the pleiotropic kinase GSK3β. In conclusion, intranasal DHA administration exhibited strong therapeutic effects and disease-modifying benefits in the J20 AD model. Given that DHA has already shown safety and tolerability in healthy human subjects, our results further support the need for clinical trials to assess the potential of this approach in Alzheimer's patients.}, }
@article {pmid39787544, year = {2024}, author = {Belojević, G}, title = {Sound and Alzheimer's Disease-From Harmful Noise to Beneficial Soundscape Augmentation and Music Therapy.}, journal = {Noise & health}, volume = {26}, number = {123}, pages = {445-448}, pmid = {39787544}, issn = {1998-4030}, mesh = {Humans ; *Music Therapy/methods ; *Alzheimer Disease/therapy ; *Noise/adverse effects ; Hearing Loss, Noise-Induced/prevention & control/therapy ; }, abstract = {Exposure to sound energy may be a risk factor or a therapeutic intervention for Alzheimer's disease (AD). On one hand, noise has a harmful effect on people with AD by contributing to hearing loss, sleep disturbance, oxidative stress, inflammation, and excitotoxicity. But on the other hand, clinical trials and nursing home interventions with soundscape augmentation involving natural sounds have shown promising results in alleviating psychophysiological symptoms in people with AD. Music therapy, an emerging non-pharmacological treatment, can improve cognition, reduce anxiety and depression, and enhance self-awareness in patients with AD. To ensure that music does not become noise in clinical trials, only favorite music at levels safe for hearing should be used. From a public health standpoint, noise countermeasures, soundscape augmentation with natural sounds, and active or passive engagement with music may be regarded as potentially powerful strategies for the prevention of AD.}, }
@article {pmid39786589, year = {2025}, author = {Zarneshan, SN and Arkan, E and Kiani, A and Hosseini, SZ and Abbaszadeh, F and Fakhri, S}, title = {Protective effects of polydatin amphiphilic chitosan nanocarriers against an aluminum chloride-induced model of Alzheimer's disease in rats: relevance to its anti-inflammatory and antioxidant effects.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {39786589}, issn = {1432-1912}, support = {4020128//Kermanshah University of Medical Sciences/ ; }, abstract = {Alzheimer's disease (AD) is the most frequent cause of dementia. Since there are complex pathophysiological mechanisms behind AD, and there is no effective treatment strategy, it is necessary to introduce novel multi-targeting agents with fewer side effects and higher efficacy. Polydatin (PD) is a naturally occurring resveratrol glucoside employing multiple mechanisms toward neuroprotection. In the current study, the anti-AD mechanisms of a novel amphiphilic chitosan nanocarrier formulation (ACN) of PD (NPD) were studied. After preparing the amphiphilic chitosan nanoformulation (i.e., NPD), physicochemical properties were assessed, including particle size, zeta potential, drug loading, drug release, MTT, Fourier transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM). For in vivo analysis, aluminum chloride (AlCl3) was injected intraperitoneally for 14 days to induce AD in male Albino Wistar rats. To examine the anti-AD mechanisms of NPD, a total of 36 rats were divided into six groups of six. Behavioral tests, including open field, Y-maze, elevated plus maze, and shuttle box were done on days 7, 8, 14, and 15. Additionally, zymography, biochemical analysis, and histological studies were done. NPD, as a newly synthesized formulation for PD, potentially improved memory and cognitive behavioral parameters and reduced the activity of inflammatory matrix metalloproteinase 9 (MMP9) and serum nitrite levels, while increasing anti-inflammatory MMP2, antioxidant catalase, and glutathione. NPD also prevented morphological changes and increased neuronal survival in the CA2, CA4, and DG regions of the rat hippocampus. In conclusion, NPD is a novel formulation against AD through anti-inflammatory, antioxidant, and neuroprotective mechanisms.}, }
@article {pmid39784680, year = {2025}, author = {Su, S and Huang, R and Liu, Y}, title = {The effects of transcranial direct current stimulation on global cognition in patients with Alzheimer's disease: An update meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {1}, pages = {19-37}, doi = {10.1177/13872877241298303}, pmid = {39784680}, issn = {1875-8908}, mesh = {*Alzheimer Disease/therapy/psychology ; *Transcranial Direct Current Stimulation/methods ; Humans ; *Cognition/physiology ; Randomized Controlled Trials as Topic ; Quality of Life/psychology ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease. At present, there are currently no drugs that can cure AD.
OBJECTIVE: A number of empirical studies have shown that transcranial direct current stimulation (tDCS) may be used to treat cognitive abnormalities in patients with AD. We will through meta-analysis reviews tDCS overall research on the effects of cognitive function in patients with AD.
METHODS: Systematic searches were performed in the PubMed, Embase, and Cochrane Library databases from their creation until 8 March 2024. Using a fixed effect model and random effect model to evaluate the average difference between the treatment group and control group (MD) and its 95% confidence interval (CI).
RESULTS: The study included 10 randomized controlled trials (Nactive = 165, Nsham = 167). The results of the overall analysis showed that tDCS did not significantly improve the overall cognitive function (SMD = 0.17; 95%CI = -0.05, 0.39; p = 0.14; I² = 51%). Quality of life of AD patients after treatment was also evaluated, but no improvement was seen. Subgroup analysis showed no significant improvement in global cognitive function after tDCS treatment. The sensitivity analysis to confirm the reliability of the data, risk assessment did not find any high-risk projects.
CONCLUSIONS: The tDCS treatment did not improve cognitive function in patients with AD. Further empirical research in the future will help to explore new schemes for tDCS to improve cognitive function of patients.}, }
@article {pmid39781179, year = {2024}, author = {Babu, B and Parvathy, G and Mohideen Bawa, FS and Gill, GS and Patel, J and Sibia, DS and Sureddi, J and Patel, V}, title = {Comparing the Artificial Intelligence Detection Models to Standard Diagnostic Methods and Alternative Models in Identifying Alzheimer's Disease in At-Risk or Early Symptomatic Individuals: A Scoping Review.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e75389}, pmid = {39781179}, issn = {2168-8184}, abstract = {Alzheimer's disease (AD) and other neurodegenerative illnesses place a heavy strain on the world's healthcare systems, particularly among the aging population. With a focus on research from January 2022 to September 2023, this scoping review, which adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-Scr) criteria, examines the changing landscape of artificial intelligence (AI) applications for early AD detection and diagnosis. Forty-four carefully chosen articles were selected from a pool of 2,966 articles for the qualitative synthesis. The research reveals impressive advancements in AI-driven approaches, including neuroimaging, genomics, cognitive tests, and blood-based biomarkers. Notably, AI models focusing on deep learning (DL) algorithms demonstrate outstanding accuracy in early AD identification, often even before the onset of clinical symptoms. Multimodal approaches, which combine information from various sources, including neuroimaging and clinical assessments, provide comprehensive insights into the complex nature of AD. The study also emphasizes the critical role that blood-based and genetic biomarkers play in strengthening AD diagnosis and risk assessment. When combined with clinical or imaging data, genetic variations and polygenic risk scores help to improve prediction models. In a similar vein, blood-based biomarkers provide non-invasive instruments for detecting metabolic changes linked to AD. Cognitive and functional evaluations, which include neuropsychological examinations and assessments of daily living activities, serve as essential benchmarks for monitoring the course of AD and directing treatment interventions. When these evaluations are included in machine learning models, the diagnosis accuracy is improved, and treatment monitoring is made more accessible. In addition, including methods that support model interpretability and explainability helps in the thorough understanding and valuable implementation of AI-driven insights in clinical contexts. This review further identifies several gaps in the research landscape, including the need for diverse, high-quality datasets to address data heterogeneity and improve model generalizability. Practical implementation challenges, such as integrating AI systems into clinical workflows and clinician adoption, are highlighted as critical barriers to real-world application. Moreover, ethical considerations, particularly surrounding data privacy and informed consent, must be prioritized as AI adoption in healthcare accelerates. Performance metrics (e.g., sensitivity, specificity, and area under the curve (AUC)) for AI-based approaches are discussed, with a need for clearer reporting and comparative analyses. Addressing these limitations, alongside methodological clarity and critical evaluation of biases, would strengthen the credibility of AI applications in AD detection. By expanding its scope, this study highlights areas for improvement and future opportunities in early detection, aiming to bridge the gap between innovative AI technologies and practical clinical utility.}, }
@article {pmid39780269, year = {2025}, author = {Li, X and Ding, Q and Wan, X and Wu, Q and Ye, S and Lou, Y}, title = {Fecal microbiota transplantation attenuates Alzheimer's disease symptoms in APP/PS1 transgenic mice via inhibition of the TLR4-MyD88-NF-κB signaling pathway-mediated inflammation.}, journal = {Behavioral and brain functions : BBF}, volume = {21}, number = {1}, pages = {2}, pmid = {39780269}, issn = {1744-9081}, support = {Grant No. Y20220029//Health Project of the Science and Technology Department of Wenzhou/ ; 231104408302408//Industry-university Cooperative education program of Ministry of Education/ ; First Class, Category A//the Key Discipline of Zhejiang Province in Medical Technology/ ; }, mesh = {Animals ; *Fecal Microbiota Transplantation/methods ; *Myeloid Differentiation Factor 88/metabolism ; Mice ; *Alzheimer Disease/therapy/microbiology ; *Mice, Transgenic ; *Toll-Like Receptor 4/metabolism ; *NF-kappa B/metabolism ; *Signal Transduction/physiology ; *Presenilin-1/genetics ; Amyloid beta-Protein Precursor/genetics ; Gastrointestinal Microbiome/physiology ; Inflammation/therapy/metabolism ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) is a prevalent and progressive neurodegenerative disorder that is the leading cause of dementia. The underlying mechanisms of AD have not yet been completely explored. Neuroinflammation, an inflammatory response mediated by certain mediators, has been exhibited to play a crucial role in the pathogenesis of AD. Additionally, disruption of the gut microbiota has been found to be associated with AD, and fecal microbiota transplantation (FMT) has emerged as a potential therapeutic approach. However, the precise mechanism of FMT in the treatment of AD remains elusive. In this study, FMT was performed by transplanting fecal microbiota from healthy wild-type mice into APP/PS1 mice (APPswe, PSEN1dE9) to assess the effectiveness of FMT in mitigating AD-associated inflammation and to reveal its precise mechanism of action. The results demonstrated that FMT treatment improved cognitive function and reduced the expression levels of inflammatory factors by regulating the TLR4/MyD88/NF-κB signaling pathway in mice, which was accompanied by the restoration of gut microbial dysbiosis. These findings suggest that FMT has the potential to ameliorate AD symptoms and delay the disease progression in APP/PS1 mice.}, }
@article {pmid39780249, year = {2025}, author = {Cummings, JL and Atri, A and Feldman, HH and Hansson, O and Sano, M and Knop, FK and Johannsen, P and León, T and Scheltens, P}, title = {evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {14}, pmid = {39780249}, issn = {1758-9193}, mesh = {Humans ; *Glucagon-Like Peptides/therapeutic use/adverse effects ; *Alzheimer Disease/drug therapy ; Double-Blind Method ; Aged ; Female ; Male ; Middle Aged ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {BACKGROUND: Disease-modifying therapies targeting the diverse pathophysiology of Alzheimer's disease (AD), including neuroinflammation, represent potentially important and novel approaches. The glucagon-like peptide-1 receptor agonist semaglutide is approved for the treatment of type 2 diabetes and obesity and has an established safety profile. Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes. Large randomized controlled trials are needed to assess the efficacy and safety of semaglutide in early-stage symptomatic AD.
METHODS: evoke and evoke+ are randomized, double-blind, placebo-controlled phase 3 trials investigating the efficacy, safety, and tolerability of once-daily oral semaglutide versus placebo in early-stage symptomatic AD. Eligible participants were men or women aged 55-85 years with mild cognitive impairment or mild dementia due to AD with confirmed amyloid abnormalities (assessed by positron emission tomography or cerebrospinal fluid [CSF] analysis). After a maximum 12-week screening phase, an anticipated 1840 patients in each trial are randomized (1:1) to semaglutide or placebo for 156 weeks (104-week main treatment phase and 52-week extension). Randomized participants follow an 8-week dose escalation regimen (3 mg [weeks 0-4], 7 mg [weeks 4-8], and 14 mg [weeks 8-156]). The primary endpoint is the semaglutide-placebo difference on change from baseline to week 104 in the Clinical Dementia Rating - Sum of Boxes score. Analyses of plasma biomarkers, collected from all participants, and a CSF sub-study (planned n = 210) will explore semaglutide effects on AD biomarkers and neuroinflammation.
RESULTS: Enrollment was undertaken between May 18, 2021, and September 8, 2023. Completion of the trials' main phase is expected in September 2025, and the 52-week extension (in which participants and investigators remain blinded to treatment assignment) will continue to October 2026.
CONCLUSION: evoke and evoke+ are the first large-scale trials to investigate the disease-modifying potential of semaglutide in participants with early-stage symptomatic AD, including exploration of effects on AD biomarkers and neuroinflammation. The trials will provide data on the potential disease-modifying effects of semaglutide and will be important in evaluating its utility in the treatment of early-stage symptomatic AD.
TRIAL REGISTRATION: Clinicaltrials.gov, NCT04777396 and NCT04777409. Date: 02/03/2021.}, }
@article {pmid39780222, year = {2025}, author = {Xing, X and Zhang, X and Wang, K and Wang, Z and Feng, Y and Li, X and Hua, Y and Zhang, L and Dong, X}, title = {Post-marketing safety concerns with lecanemab: a pharmacovigilance study based on the FDA Adverse Event Reporting System database.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {15}, pmid = {39780222}, issn = {1758-9193}, mesh = {Humans ; United States/epidemiology ; *Adverse Drug Reaction Reporting Systems/statistics & numerical data ; *Pharmacovigilance ; *United States Food and Drug Administration ; Male ; Female ; Aged ; Middle Aged ; Product Surveillance, Postmarketing/statistics & numerical data/methods ; Databases, Factual ; Alzheimer Disease ; Aged, 80 and over ; Adult ; Drug-Related Side Effects and Adverse Reactions/epidemiology ; }, abstract = {BACKGROUND: The safety data of lecanemab in the post-marketing period has yet to be fully investigated in the current literature. We aimed to identify and characterise the safety profile of lecanemab in the post-marketing period.
METHODS: We searched and reviewed the reports submitted to the FDA's Adverse Event Reporting System (FAERS). We used a case/non-case approach to estimate the reporting odds ratio (ROR) and information component (IC) with 95% confidence intervals (CI) for lecanemab-related adverse events (AEs) reported at least four counts. We compared the difference between serious and non-serious reports using non-parametric tests.
RESULTS: The FAERS recorded 1,986 lecanemab-related AEs affecting 868 patients. Two hundred and three patients experienced serious AEs, including 22 deaths. The most frequently reported AEs were headache (n = 193), chills (n = 100), fatigue (n = 93), and amyloid-related imaging abnormality-oedema/effusion (ARIA-E) (n = 91). Safety signals were detected, such as headache (ROR: 10.4, 95%CI: 8.97, 12.07; IC: 3.25, 95%CI: 2.97, 3.40), ARIA-E (ROR: 18,299.69, 95%CI: 14,001.27, 23,917.73; IC: 13.37, 95%CI: 6.15, 6.87), and infusion-related reaction (ROR: 35.25, 95CI 27.58, 45.07; IC: 5.09, 95CI 4.15, 4.87). We also identified several new AEs, such as migraine and pancreatic carcinoma. Patients with serious AEs were more likely to be on polypharmacy for Alzheimer's disease and use aspirin, acid-suppressing medications, statins, antidepressants, or benzodiazepines compared to those with non-serious AEs.
CONCLUSIONS: Lecanemab may have a significant potential for AEs. Our results provide evidence for healthcare professionals and patients to weigh the risks and benefits of lecanemab treatment. Further prospective studies are needed to explore rare and unexpected AEs.}, }
@article {pmid39780188, year = {2025}, author = {Zhang, J and Zhang, Y and Liu, L and Zhang, M and Zhang, X and Deng, J and Zhao, F and Lin, Q and Zheng, X and Fu, B and Zhao, Y and Wang, X}, title = {Chemerin-9 is neuroprotective in APP/PS1 transgenic mice by inhibiting NLRP3 inflammasome and promoting microglial clearance of Aβ.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {5}, pmid = {39780188}, issn = {1742-2094}, support = {2024QNB012//Health science and technology project of Fujian Province/ ; 82401653//National Natural Science Foundation of China/ ; 81974158//National Natural Science Foundation of China/ ; 82071288//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Mice, Transgenic ; Mice ; *Microglia/drug effects/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors ; *Amyloid beta-Peptides/metabolism ; *Presenilin-1/genetics ; *Inflammasomes/metabolism ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Humans ; Neuroprotective Agents/pharmacology/therapeutic use ; Intercellular Signaling Peptides and Proteins/metabolism/genetics ; Mice, Inbred C57BL ; Chemokines/metabolism ; Cells, Cultured ; Male ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder worldwide, and microglia are thought to play a central role in neuroinflammatory events occurring in AD. Chemerin, an adipokine, has been implicated in inflammatory diseases and central nervous system disorders, yet its precise function on microglial response in AD remains unknown.
METHODS: The APP/PS1 mice were treated with different dosages of chemerin-9 (30 and 60 µg/kg), a bioactive nonapeptide derived from chemerin, every other day for 8 weeks consecutively. The primary mouse microglia were stimulated by amyloid beta 42 (Aβ42) oligomers followed by treatment with chemerin-9 in vitro. ChemR23 inhibitor α-NETA was further used to investigate whether the effects of chemerin-9 were ChemR23-dependent.
RESULTS: We found that the expression of chemerin and ChemR23 was increased in AD. Intriguingly, treatment with chemerin-9 significantly ameliorated Aβ deposition and cognitive impairment of the APP/PS1 mice, with decreased microglial proinflammatory activity and increased phagocytic activity. Similarly, chemerin-9-treated primary microglia showed increased phagocytic ability and decreased NLRP3 inflammasome activation. However, the ChemR23 inhibitor α-NETA abolished the neuroprotective microglial response of chemerin-9.
CONCLUSIONS: Collectively, our data demonstrate that chemerin-9 ameliorates cognitive deficits in APP/PS1 transgenic mice by boosting a neuroprotective microglial phenotype.}, }
@article {pmid39779882, year = {2025}, author = {Neth, BJ and Huynh, K and Giles, C and Wang, T and Mellett, NA and Duong, T and Blach, C and Schimmel, L and Register, TC and Blennow, K and Zetterberg, H and Batra, R and Schweickart, A and Dilmore, AH and Martino, C and Arnold, M and Krumsiek, J and Han, X and Dorrestein, PC and Knight, R and Meikle, PJ and Craft, S and Kaddurah-Daouk, R}, title = {Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer's disease in humans.}, journal = {Communications medicine}, volume = {5}, number = {1}, pages = {11}, pmid = {39779882}, issn = {2730-664X}, support = {R01 AG046171/AG/NIA NIH HHS/United States ; U19 AG063744/AG/NIA NIH HHS/United States ; R01AG046171, RF1AG051550, RF1AG057452, R01AG059093, RF1AG058942, U01AG061359, U19AG063744//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; UL1 TR001420/TR/NCATS NIH HHS/United States ; RF1 AG059093/AG/NIA NIH HHS/United States ; U01 AG061359/AG/NIA NIH HHS/United States ; RF1 AG057452/AG/NIA NIH HHS/United States ; R01 AG069901/AG/NIA NIH HHS/United States ; P30 AG013319/AG/NIA NIH HHS/United States ; P30 AG049638/AG/NIA NIH HHS/United States ; #DAOU16AMPA//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; RF1 AG058942/AG/NIA NIH HHS/United States ; RF1 AG051550/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear.
METHOD: In this post-hoc analysis of a randomized crossover study of 20 elderly adults, we investigated the effects of a modified Mediterranean ketogenic diet (MMKD) on the plasma lipidome in the context of AD biomarkers, analyzing 784 lipid species across 47 classes using a targeted lipidomics platform.
RESULTS: Here we identified substantial changes in response to MMKD intervention, aside from metabolic changes associated with a ketogenic diet, we identified a a global elevation across all plasmanyl and plasmenyl ether lipid species, with many changes linked to clinical and biochemical markers of AD. We further validated our findings by leveraging our prior clinical studies into lipid related changeswith AD (n = 1912), and found that the lipidomic signature with MMKD was inversely associated with the lipidomic signature of prevalent and incident AD.
CONCLUSIONS: Intervention with a MMKD was able to alter the plasma lipidome in ways that contrast with AD-associated patterns. Given its low risk and cost, MMKD could be a promising approach for prevention or early symptomatic treatment of AD.}, }
@article {pmid39778970, year = {2025}, author = {Rabinovici, GD and Knopman, DS and Arbizu, J and Benzinger, TLS and Donohoe, KJ and Hansson, O and Herscovitch, P and Kuo, PH and Lingler, JH and Minoshima, S and Murray, ME and Price, JC and Salloway, SP and Weber, CJ and Carrillo, MC and Johnson, KA}, title = {Updated Appropriate Use Criteria for Amyloid and Tau PET: A Report from the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging Workgroup.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.124.268756}, pmid = {39778970}, issn = {1535-5667}, abstract = {The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. Methods: The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered. A modified Delphi approach was used to rate each scenario by consensus as "rarely appropriate," "uncertain," or "appropriate." Ratings were performed separately for amyloid and tau PET as stand-alone modalities. Results: For amyloid PET, 7 scenarios were rated as appropriate, 2 as uncertain, and 8 as rarely appropriate. For tau PET, 5 scenarios were rated as appropriate, 6 as uncertain, and 6 as rarely appropriate. Conclusion: AUC for amyloid and tau PET provide expert recommendations for clinical use of these technologies in the evolving landscape of diagnostics and therapeutics for Alzheimer's disease.}, }
@article {pmid39778694, year = {2025}, author = {Wang, N and Li, J and Guo, Y and Zhang, P and You, F and Wang, Z and Wang, Z and Hong, X}, title = {Neural mechanisms of non-pharmacological interventions in patients with mild cognitive impairment and Alzheimer's disease: An ALE meta-analysis.}, journal = {Experimental gerontology}, volume = {200}, number = {}, pages = {112678}, doi = {10.1016/j.exger.2025.112678}, pmid = {39778694}, issn = {1873-6815}, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology ; *Cognitive Dysfunction/therapy/physiopathology ; Exercise Therapy/methods ; Brain/physiopathology/diagnostic imaging ; Cognitive Behavioral Therapy/methods ; Neuroimaging ; Likelihood Functions ; Aged ; }, abstract = {Non-pharmacologic interventions are effective for persons showing mild cognitive impairment (MCI) and Alzheimer's disease (AD). We used activation likelihood estimation (ALE) meta-analysis to systematically quantify the results of 19 neuroimaging studies in order to identify brain regions in which patients showed stable increases or decreases in activation after interventions. We also tested the moderating effects of disease stage (MCI vs. AD) and intervention modality (cognitive training vs. exercise intervention). The results showed increased activation in the cuneus, precuneus and medial frontal gyrus in the combined groups after treatment, whereas the anterior cingulate gyrus showed decreased activation. Secondly, in the MCI group there was increased activation in the precuneus and precentral gyrus after treatment, whereas there was decreased activation in the anterior cingulate gyrus; in the AD group there was only increased activation after treatment, including in the lingual gyrus and bilateral superior temporal gyrus. Finally, the bilateral cuneus and precentral gyrus showed increased activation after cognitive training, while bilateral insula, among others, showed decreased activation. This suggests that there are brain activation changes after non-pharmacological treatments for MCI and AD patients, but that the treatment mechanisms are moderated by stage and intervention modality. Future studies could continue to explore specific neural mechanisms involved in different intervention conditions for these patients.}, }
@article {pmid39778593, year = {2025}, author = {Chen, Q and Chen, G and Wang, Q}, title = {Application of Network Pharmacology in the Treatment of Neurodegenerative Diseases with Traditional Chinese Medicine.}, journal = {Planta medica}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2512-8928}, pmid = {39778593}, issn = {1439-0221}, support = {2023AFB677//the Natural Science Foundation of Hubei Province/ ; 2024AFB578//the Natural Science Foundation of Hubei Province/ ; 2023LYYYGZRP0003//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; 2023LYYYSZRP0001//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; }, abstract = {In recent years, the incidence of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, has exhibited a steadily rising trend, which has posed a major challenge to the global public health. Traditional Chinese medicine, with its multicomponent and multitarget characteristics, offers a promising approach to treating neurodegenerative diseases. However, comprehensively elucidating the complex mechanisms underlying traditional Chinese medicine formulations remains challenging. As an emerging systems biology method, network pharmacology has provided a vital tool for revealing the multitarget mechanisms of traditional Chinese medicine through high-throughput technologies, molecular docking, and network analysis. This paper reviews the advancements in the application of network pharmacology in treating neurodegenerative diseases using traditional Chinese medicine, analyzes the current status of relevant databases and technological methods, discusses the limitations, and proposes future directions to promote the modernization of traditional Chinese medicine and the development of precision medicine.}, }
@article {pmid39778561, year = {2025}, author = {Kwon, HS and Koh, SH}, title = {Monoclonal Antibodies-A New Horizon in Alzheimer's Treatment.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {21}, number = {1}, pages = {1-2}, pmid = {39778561}, issn = {1738-6586}, }
@article {pmid39778487, year = {2025}, author = {Nguyen, VTT and Slotos, RS and Guilherme, MDS and Nguyen, TT and Weisenburger, S and Lehner, MD and Endres, K}, title = {Ginkgo biloba extract EGb 761® ameliorates cognitive impairment and alleviates TNFα response in 5xFAD Alzheimer's disease model mice.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {136}, number = {}, pages = {156327}, doi = {10.1016/j.phymed.2024.156327}, pmid = {39778487}, issn = {1618-095X}, mesh = {Animals ; *Ginkgo biloba/chemistry ; *Plant Extracts/pharmacology ; *Alzheimer Disease/drug therapy ; *Disease Models, Animal ; Male ; *Cognitive Dysfunction/drug therapy ; Female ; *Mice, Transgenic ; Mice ; *Tumor Necrosis Factor-alpha/metabolism ; *Microglia/drug effects ; Plaque, Amyloid/drug therapy ; Anti-Inflammatory Agents/pharmacology ; Brain/drug effects/metabolism ; Mice, Inbred C57BL ; Cognition/drug effects ; Ginkgo Extract ; }, abstract = {BACKGROUND: Ginkgo biloba leaf extract EGb 761® has shown clinical efficacy in patients with mild cognitive impairment and dementia. However, the pharmacological action of EGb 761® in Alzheimer's disease (AD) remains unclear and molecular mechanisms targeted in the brain are not completely understood.
HYPOTHESIS/PURPOSE: We aimed to investigate 1) the potential sex-dependent effects of oral administration of EGb 761® in 5xFAD mice, an AD mouse model, and 2) the underlying microglial subtype responsible for the observed anti-inflammatory effects in the brain.
METHODS: Eight-week old 5xFAD and wild type mice received EGb 761®-supplemented diet or control diet for eight weeks. The study investigated changes in cognitive function as well as amyloid plaque load, expression of AD-related genes, and anti-inflammatory effects. Moreover, we used organotypic brain slices for confirmation and assessment of concentration-dependency of the observed EGb 761® effects and performed single cell RNA sequencing on the prefrontal cortex of male mice with focus on microglia.
RESULTS: We demonstrate that EGb 761® treatment improves cognitive function in 5xFAD mice in several behavioral tests. Analysis of the brain tissue from these animals indicated a reduction in amyloid plaque load in the prefrontal cortex (PFC). This brain area was further investigated to assess the molecular changes that occurred following EGb 761® intake. Alterations in the expression of genes related to AD were highly sex-specific with effects on the cholinergic system, the γ-secretase complex, and neuroinflammation. Anti-inflammatory effects of EGb 761® with a particularly pronounced reduction of the TNFα-response could be shown for the PFC but also peripherally in the serum of 5xFAD mice of both sexes. Single-cell RNA sequencing revealed that EGb761® mainly affected disease-associated microglia stage 2 (DAM2), which are thought to have a detrimental role in AD.
CONCLUSIONS: EGb 761® shows efficacy in the treatment of cognitive deficits in the 5xFAD mouse model via multimodal activity, including sex-specific and sex-unrelated mechanisms including the normalization of neuroinflammatory parameters.}, }
@article {pmid39777990, year = {2025}, author = {Huang, KL and Hsiao, IT and Huang, CW and Huang, CG and Chang, HI and Huang, SH and Lin, KJ and Ma, MC and Huang, CC and Chang, CC}, title = {The Taiwan-ADNI workflow toward integrating plasma p-tau217 into prediction models for the risk of Alzheimer's disease and tau burden.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14297}, pmid = {39777990}, issn = {1552-5279}, support = {NSTC112-2321-B-182A-004//National Science and Technology Council/ ; NSTC112-2314-B-182-053//National Science and Technology Council/ ; NSTC113-2314-B-182-042-MY2//National Science and Technology Council/ ; NSTC113-2321-B-182A-005//National Science and Technology Council/ ; NSTC110-2314-B-182A-073-MY3//National Science and Technology Council/ ; CORPG8N0041//Chang Gung Memorial Hospital/ ; CMRPG8J0524//Chang Gung Memorial Hospital/ ; CMRPG8J0843//Chang Gung Memorial Hospital/ ; CMRPG3P0861//Chang Gung Memorial Hospital/ ; CMRPD1N0401//Chang Gung Memorial Hospital/ ; BMRP-488//Chang Gung Memorial Hospital/ ; CMRPG8K1533//Chang Gung Memorial Hospital/ ; }, mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *tau Proteins/blood ; Male ; *Biomarkers/blood ; Female ; Aged ; *Positron-Emission Tomography ; Taiwan ; *Amyloid beta-Peptides/blood ; Workflow ; Phosphorylation ; Middle Aged ; Aged, 80 and over ; }, abstract = {INTRODUCTION: We integrated plasma biomarkers from the Taiwan Alzheimer's Disease Neuroimaging Initiative and propose a workflow to identify individuals showing amyloid-positive positron emission tomography (PET) with low/intermediate tau burden based on [18F]Florzolotau PET-based quantification.
METHODS: We assessed 361 participants across the Alzheimer's disease (AD) and non-AD continuum and measured plasma phosphorylated tau (p-tau)217, p-tau181, amyloid beta (Aβ)42/40 ratio, neurofilament light chain, and glial fibrillary acidic protein levels at two medical centers. We evaluated the diagnostic potential of these biomarkers.
RESULTS: Among all plasma biomarkers, p-tau217 had the highest consistency with amyloid PET results (area under the curve = 0.94), and a cutoff value could have reduced the number of confirmatory amyloid PET scans by 57.5%. In amyloid PET-positive cases intending to use anti-amyloid therapy, p-tau217 level, along with clinical parameters, had the highest predictive ability for low/intermediate tau burden.
DISCUSSION: A two-step workflow based on p-tau217 and confirmatory amyloid PET could accurately classify AD patients showing low/intermediate tau burden.
HIGHLIGHTS: The emergence of anti-amyloid therapy increases the need to accurately diagnose Alzheimer's disease (AD). The use of plasma biomarkers, especially phosphorylated tau 217 (p-tau217), can help in the diagnosis of AD. P-tau217 is a better predictor of amyloid positron emission tomography (PET) positivity than other core biomarkers. In amyloid PET-positive individuals, p-tau217 can predict tau burden. We propose a two-step workflow to identify AD cases suitable for treatment.}, }
@article {pmid39777099, year = {2024}, author = {Wang, C and Ren, J}, title = {Ultrasound blood-brain barrier opening: A new era of treatment for Alzheimer's disease?.}, journal = {Aging medicine (Milton (N.S.W))}, volume = {7}, number = {6}, pages = {673-675}, pmid = {39777099}, issn = {2475-0360}, }
@article {pmid39776809, year = {2025}, author = {Xiong, W and She, W and Liu, Y and Zhou, H and Wang, X and Li, F and Li, R and Wang, J and Qin, D and Jing, S and Duan, X and Jiang, C and Xu, C and He, Y and Wang, Z and Ye, Q}, title = {Clinical-grade human dental pulp stem cells improve adult hippocampal neural regeneration and cognitive deficits in Alzheimer's disease.}, journal = {Theranostics}, volume = {15}, number = {3}, pages = {894-914}, pmid = {39776809}, issn = {1838-7640}, mesh = {Animals ; *Dental Pulp/cytology ; *Alzheimer Disease/therapy/physiopathology ; Humans ; *Hippocampus ; *Mice, Transgenic ; Mice ; *Disease Models, Animal ; Stem Cell Transplantation/methods ; Nerve Regeneration/physiology ; Stem Cells/physiology/cytology ; Cell Differentiation ; Cognitive Dysfunction/therapy ; Male ; Neurons/physiology ; Wnt Signaling Pathway ; }, abstract = {Background: Disrupted hippocampal functions and progressive neuronal loss represent significant challenges in the treatment of Alzheimer's disease (AD). How to achieve the improvement of pathological progression and effective neural regeneration to ameliorate the intracerebral dysfunctional environment and cognitive impairment is the goal of the current AD therapy. Methods: We examined the therapeutic potential of clinical-grade human derived dental pulp stem cells (hDPSCs) in cognitive function and neuropathology in AD. Specifically, we investigated the effect of neural crest-specific derived hDPSCs on endogenous neural regeneration and long-term efficacy following a single transplantation in the triple-transgenic mouse model (3xTg-AD). Results: Our research demonstrated that a single administration of clinical-grade hDPSCs yielded dramatic short-term therapeutic benefits (5 weeks) and sustained partial efficacy (6 months) with respect to improving cognitive impairment and delaying typical pathological progression in 3xTg-AD mice. Intriguingly, exogenous hDPSCs were robustly self-differentiated into newborn functional neurons in the hippocampus of 3xTg-AD mice. The foremost evidence is provided that hDPSCs promote endogenic neural regeneration by enhancing the activation of the Wnt/β-catenin pathway, which may contribute to stabilizing the hippocampal neural network to reverse memory deficits. Conclusion: These findings highlight the multifunctional potential of hDPSCs in AD treatment, which enhances cognition through alleviating neuropathology and providing neural regenerative driving force. Understanding these multiplicity effects is critical to advancing the clinical translation of stem cell-based therapies for AD.}, }
@article {pmid39776697, year = {2024}, author = {Usuda, D and Sugita, M and Shen, P and Umehara, T and Kitamoto, T}, title = {Leaky Gut Syndrome Along With Clostridium perfringens Bacteremia in a Neurodegenerative Disease Patient: A Case Report.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e75290}, pmid = {39776697}, issn = {2168-8184}, abstract = {Leaky gut syndrome (LGS) is caused by intestinal epithelial injury and increased intestinal permeability due to a variety of factors, including chronic stress, inflammatory bowel disease, diabetes, surgery, and chemotherapy, resulting in an increased influx of matter from the intestinal lumen causing constipation and bacteremia. To our knowledge, this is the first known case of LGS along with Clostridium perfringens (C. perfringens) bacteremia in a neurodegenerative disease patient. The patient was an 81-year-old male with a history of Alzheimer's disease, cerebral infarction, and diverticulitis in a psychiatric hospital, fed via a nasogastric tube. During hospitalization, he developed a 37.4℃ temperature and disturbance of consciousness evaluated as 3 points on the Glasgow Coma Scale. A follow-up blood examination revealed a white blood cell count of 29,000/µL and a C-reactive protein value of 11.2 mg/dL. Computed tomography revealed an increased concentration of peripheral adipose tissue from the sigmoid colon to the rectum and significant quantities of stool in the rectum. Treatment was initiated with doripenem (DRPM) for sepsis of unknown focus. C. perfringens was subsequently identified in both two blood culture tests. He improved with decreased inflammatory response; DRPM was terminated after 14 days. He remains free of recurrence. We speculate that the LGS in this case may have developed from dopaminergic neuronal decrease and impaired amino acid metabolism caused by chronic hypo-inflammation due to neurodegenerative disease (Alzheimer's disease). We report the first known case of LGS along with C. perfringens bacteremia in a neurodegenerative disease patient.}, }
@article {pmid39776249, year = {2025}, author = {Rabinovici, GD and Knopman, DS and Arbizu, J and Benzinger, TLS and Donohoe, KJ and Hansson, O and Herscovitch, P and Kuo, PH and Lingler, JH and Minoshima, S and Murray, ME and Price, JC and Salloway, SP and Weber, CJ and Carrillo, MC and Johnson, KA}, title = {Updated appropriate use criteria for amyloid and tau PET: A report from the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging Workgroup.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14338}, pmid = {39776249}, issn = {1552-5279}, mesh = {Humans ; *Positron-Emission Tomography/standards ; *Alzheimer Disease/diagnostic imaging/metabolism ; *tau Proteins/metabolism ; Nuclear Medicine/standards ; Amyloid/metabolism ; Molecular Imaging/standards/methods ; Societies, Medical ; }, abstract = {INTRODUCTION: The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET.
METHODS: The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered. A modified Delphi approach was used to rate each scenario by consensus as "rarely appropriate," "uncertain," or "appropriate." Ratings were performed separately for amyloid and tau PET as stand-alone modalities.
RESULTS: For amyloid PET, seven scenarios were rated as appropriate, two as uncertain, and eight as rarely appropriate. For tau PET, five scenarios were rated as appropriate, six as uncertain, and six as rarely appropriate.
DISCUSSION: AUC for amyloid and tau PET provide expert recommendations for clinical use of these technologies in the evolving landscape of diagnostics and therapeutics for Alzheimer's disease.
HIGHLIGHTS: A multidisciplinary workgroup convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging updated the appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. The goal of these updated AUC is to assist clinicians in identifying clinical scenarios in which amyloid or tau PET may be useful for guiding the diagnosis and management of patients who have, or are at risk for, cognitive decline These updated AUC are intended for dementia specialists who spend a significant proportion of their clinical effort caring for patients with cognitive complaints, as well as serve as a general reference for a broader audience interested in implementation of amyloid and tau PET in clinical practice.}, }
@article {pmid39776239, year = {2025}, author = {Li, S and Li, S and Semde, R and Teng, H and Shi, M and Huang, L and Lou, X and Jia, B and Zhu, H and Zhao, Y}, title = {Protocatechuic Acid Improves Alzheimer's Disease by Regulating the Cholinergic Synaptic Signaling Pathway.}, journal = {Chemistry & biodiversity}, volume = {}, number = {}, pages = {e202402771}, doi = {10.1002/cbdv.202402771}, pmid = {39776239}, issn = {1612-1880}, support = {20220204076YY//Jilin Provincial Scientific and Technology Plan Projects/ ; 20230204099YY//Jilin Provincial Scientific and Technology Plan Projects/ ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by memory decline and cognitive impairments. The clinical treatments for AD have numerous adverse effects; hence, the exploration of natural products for AD therapy is of significant importance. Protocatechuic acid (PA), a natural phenolic acid, has been shown to possess various pharmacological activities, including anti-inflammatory, antioxidant, and antitumor effects. However, the mechanisms underlying its therapeutic potential for AD remain elusive. This study utilized a β-amyloid (Aβ) injection into the hippocampus of mice as an AD model and L-glu-induced HT-22 cell neurotoxicity and lipopolysaccharides (LPS)-induced cellular neuroinflammation models to assess reactive oxygen species (ROS), JC-1, and relevant biochemical markers. This study examined behavioral, pathological, and inflammatory factors and investigated the molecular mechanisms through transcriptomics, western blot, and molecular docking studies. This study's findings reveal that high-dose PA (50 mg/kg) improves symptoms in AD mice through the cholinergic synaptic signaling pathway. This study indicates that PA is a potential candidate for AD treatment targeting the cholinergic synaptic signaling pathway, providing a lead compound for AD therapy.}, }
@article {pmid39776027, year = {2025}, author = {Komal, K and Ghosh, R and Sil, D and Sharma, R and Kumar, S and Pandey, P and Kumar, M}, title = {Advancements in nose-to-brain drug targeting for Alzheimer's disease: a review of nanocarriers and clinical insights.}, journal = {Inflammopharmacology}, volume = {33}, number = {2}, pages = {605-626}, pmid = {39776027}, issn = {1568-5608}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Drug Delivery Systems/methods ; *Administration, Intranasal/methods ; *Brain/metabolism/drug effects ; *Drug Carriers ; Animals ; *Nanoparticles/administration & dosage ; Nasal Mucosa/metabolism/drug effects ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD) is a type of neurodegenerative disease that describes cognitive decline and memory loss resulting in disability in movement, memory, speech etc. Which first affects the hippocampal and entorhinal cortex regions of brain. Pathogenesis of AD depends on Amyloid-β, hyper-phosphorylation of tau protein, mitochondrial dysfunction, cholinergic hypothesis and oxidative stress. In comparison with males, females are more prone to AD due to reduced estrogen level. Some of the FDA-approved drugs and their conventional formulations available in the market are discussed in this review. Nose-to-brain delivery system provides the target specific drug delivery via olfactory and trigeminal nerve (active and passive drug targeting strategies) and bypassing the Blood Brain Barrier. Mucoadhesive agents and permeation enhancers are mostly utilized to enhance the retention time and bioavailability of the drugs. Liposomes, niosomes, cubosomes, solid lipid nanoparticles, nanoemulsions, micelles, and many more nanocarriers for nose-to-brain delivery of drugs are also described thoroughly in this review. It also covers the clinical trials and patents for nose-to-brain delivery. In this article, we investigate the nose-to-brain pathways for AD treatment strategies.}, }
@article {pmid39775804, year = {2025}, author = {Chu, C and Wang, Y and Wang, Y and Fowler, C and Zisis, G and Masters, CL and Doecke, JD and Goudey, B and Jin, L and Pan, Y and , }, title = {Development and Validation of a Tool to Predict Onset of Mild Cognitive Impairment and Alzheimer Dementia.}, journal = {JAMA network open}, volume = {8}, number = {1}, pages = {e2453756}, doi = {10.1001/jamanetworkopen.2024.53756}, pmid = {39775804}, issn = {2574-3805}, mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Female ; Aged ; Male ; Aged, 80 and over ; *Age of Onset ; Prognosis ; Australia ; Cohort Studies ; }, abstract = {IMPORTANCE: The ability to predict the onset of mild cognitive impairment (MCI) and Alzheimer dementia (AD) could allow older adults and clinicians to make informed decisions about dementia care.
OBJECTIVE: To assess whether the age at onset of MCI and AD can be predicted using a statistical modeling approach.
This prognostic study used data from 2 aging and dementia cohort studies-the Australian Imaging, Biomarker and Lifestyle (AIBL) study and the Alzheimer's Disease Neuroimaging Initiative (ADNI)-for model development and validation of the Florey Dementia Index (FDI), a tool used to predict the age at onset of MCI and AD in older adults. Data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study were used for a simulated trial. Data were collected from 1665 AIBL participants, 2029 ADNI participants, and 93 A4 participants from October 1, 2004, to March 1, 2023. The data analysis was conducted between January and August 2024.
MAIN OUTCOMES AND MEASURES: Predicted age at onset compared with clinically observed age at onset.
RESULTS: Among the 1665 AIBL participants (741 [44.5%] female) and 2029 ADNI participants (925 [45.6%] female), the mean (SD) age at first evaluation was 71.8 (7.1) years and 74.5 (6.7) years, respectively. The FDI achieved mean absolute errors of 2.78 (95% CI, 2.63-2.93) years for predicting MCI onset and 1.48 (95% CI, 1.32-1.65) years for predicting AD onset. In the simulated trial with 93 A4 participants (48 [51.6%] female; mean [SD] age at baseline, 73.4 [5.1] years), the FDI achieved mean absolute errors of 1.57 (95% CI, 1.41-1.71) years for predicting MCI onset and 0.70 (95% CI, 0.53-0.88) years for predicting AD onset.
CONCLUSIONS AND RELEVANCE: In this prognostic study, the FDI was developed and validated to predict the onset age of MCI and AD. This tool may be useful in organizing health care for older adults with cognitive decline or dementia and in the future may help prioritize patients for the use of disease-modifying monoclonal antibody drugs.}, }
@article {pmid39775196, year = {2025}, author = {Padhy, DS and Aggarwal, P and Velayutham, R and Banerjee, S}, title = {Aerobic exercise and metformin attenuate the cognitive impairment in an experimental model of type 2 diabetes mellitus: focus on neuroinflammation and adult hippocampal neurogenesis.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {92}, pmid = {39775196}, issn = {1573-7365}, support = {5/4/5-11/Diab./20-NCD-III//Indian Council of Medical Research/ ; 5/4/5-11/Diab./20-NCD-III//Indian Council of Medical Research/ ; 5/4/5-11/Diab./20-NCD-III//Indian Council of Medical Research/ ; 5/4/5-11/Diab./20-NCD-III//Indian Council of Medical Research/ ; }, mesh = {Animals ; *Metformin/pharmacology/therapeutic use ; *Cognitive Dysfunction/drug therapy ; *Hippocampus/metabolism/drug effects ; *Neurogenesis/drug effects ; *Diabetes Mellitus, Type 2/metabolism/complications ; *Physical Conditioning, Animal/physiology ; Rats ; Male ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Diabetes Mellitus, Experimental/complications/metabolism ; Hypoglycemic Agents/pharmacology/therapeutic use ; Rats, Wistar ; Diet, High-Fat/adverse effects ; }, abstract = {Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that increases the prevalence of cognitive impairment in the geriatric population. Aerobic exercise is an excellent non-pharmacological therapeutic strategy to prevent Alzheimer's disease, the most common form of dementia. The exact molecular mechanism of aerobic exercise (Exe) as an intervention to counter cognitive decline is far from clear. Metformin is a first-line agent against T2DM with neuroprotective properties. The present study assessed the role of treadmill exercise in combination with a low dose of metformin (Met; 70 mg/kg) in cognitive impairment and its associated molecular mechanism in T2DM rats. The experimental model of T2DM-associated cognitive decline was created by administration of a high-fat diet (HFD) with a low dose of streptozotocin (STZ; 35 mg/kg). Neurobehavioral assessments were performed to evaluate spatial recognition and fear-conditioned memory across the groups: control, HFD + STZ, HFD + STZ + Exe, and HFD + STZ + Exe + Met. In addition, we performed immunohistochemistry and western blotting on the rat hippocampal tissue from the above groups for protein expression studies. T2DM rats showed a significant cognitive decline compared to the control group, which improved in the long-term exercise and metformin co-administered animals. The level of neuroinflammation was significantly elevated in the hippocampal tissue of T2DM rats compared to the control and lowered after exercise and metformin treatment. T2DM reduced mature neurons and neurogenesis while increasing astrogliosis and microgliosis, ameliorated by exercise and metformin treatment. Moreover, T2DM impaired hippocampal neurogenesis by reducing the canonical Wnt/β-catenin pathway, which got upregulated in exercise and metformin-co-administered rats. Long-term aerobic exercise with metformin treatment ameliorated neuroinflammation and promoted adult hippocampal neurogenesis via upregulating the canonical Wnt/β-catenin pathway in T2DM rats.}, }
@article {pmid39774759, year = {2025}, author = {Reimers-Wessberg, M and Xu, H and Fastbom, J and Seiger, Å and Eriksdotter, M}, title = {Cholinesterase inhibitors and reduced risk of hospitalization and mortality in patients with Alzheimer's dementia and heart failure.}, journal = {European heart journal. Cardiovascular pharmacotherapy}, volume = {11}, number = {1}, pages = {22-33}, pmid = {39774759}, issn = {2055-6845}, support = {//Stockholm County Council/ ; 975207//Karolinska Institutet/ ; 2020-02014//Swedish Medical Research Council/ ; //Johanniterorden/ ; 963369//CIMED/ ; }, mesh = {Humans ; Female ; Male ; *Heart Failure/mortality/drug therapy/diagnosis ; *Cholinesterase Inhibitors/therapeutic use/adverse effects ; *Hospitalization ; *Alzheimer Disease/mortality/drug therapy/diagnosis ; Aged ; Aged, 80 and over ; Sweden/epidemiology ; Donepezil/therapeutic use/adverse effects ; Risk Factors ; Registries ; Rivastigmine/therapeutic use/adverse effects ; Propensity Score ; Indans/therapeutic use/adverse effects ; Galantamine/therapeutic use/adverse effects ; Treatment Outcome ; Piperidines/therapeutic use/adverse effects ; }, abstract = {AIMS: Cholinesterase inhibitors (ChEIs) have beneficial effects on the heart. Associations between ChEI-use and reduced mortality and cardiovascular events in Alzheimer's disease (AD) have been shown. Whether these associations exist in those with both heart failure (HF) and AD is unknown.
METHODS AND RESULTS: A propensity score (PS) matched cohort with patients with HF and AD was obtained through linking registers for cognitive/dementia disorders, comorbidities, drug prescription, and death, in Sweden, to analyse associations between ChEI-use and risk of mortality or hospitalization for HF, stroke, or myocardial infarction, were examined. In 455 patients with and 455 without ChEI treatment, ChEI use was associated with reductions of mortality and hospitalization due to HF by 21% [0.79; (confidence interval) CI 0.66-0.96] and 47% (0.53; CI 0.38-0.75), respectively. Donepezil and galantamine but not rivastigmine were associated with a lower risk of death compared with non-users. Donepezil was associated with a lower risk of hospitalization due to HF compared with non-users. There was no significant difference in hospitalization for bradycardia, AV block, or implantation of pacemaker between ChEI use and non-use.
CONCLUSION: This study suggests that in persons with HF and AD, treatment with ChEIs is associated with improved survival and a decreased risk of hospital care for HF, but results due to the type of ChEI vary.}, }
@article {pmid39773090, year = {2025}, author = {Wang, X and Chen, L and Li, W and He, Z and Jiang, H}, title = {Association of dipeptidyl peptidase-4 with Alzheimer's disease: A new therapeutic prospect.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {2}, pages = {319-332}, doi = {10.1177/13872877241304673}, pmid = {39773090}, issn = {1875-8908}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; *Dipeptidyl Peptidase 4/metabolism ; *Diabetes Mellitus, Type 2/drug therapy/complications ; Animals ; }, abstract = {Alzheimer's disease (AD) is the most common disease associated with cognitive dysfunction, which is closely associated with type 2 diabetes mellitus (T2DM) in clinical manifestations, pathological changes and prevention. Inhibition of dipeptidyl peptidase 4 (DPP-4) can lower blood glucose levels by stimulating insulin secretion. Besides, it can affect cognitive function through the neuroprotective effect of DPP-4 substrates, such as glucose-dependent insulin peptide and glucagon-like peptide-1, the proteolytic effect on amyloid-β and the protective effect on neuronal structure. This review discusses the relationship between cognitive impairment in T2DM and in AD, summarizes the effect of DPP-4 inhibitor (DPP-4i) on improving cognitive impairment in these two diseases based on the current studies. Given the lack of clinical randomized trials that evaluate the effect of DPP-4i on AD, this review is expected to provide preclinical evidence for DPP-4i as a potential therapy for the treatment and prevention of AD.}, }
@article {pmid39772836, year = {2025}, author = {Wang, P and Dong, YL and Li, SS and Jin, Y and Sun, WL and Zhao, BS and Li, QB and Chen, X}, title = {Integrating network pharmacology and component analysis to investigate the potential mechanisms of Sheng-Hui-Yi-Zhi decoction in the treatment of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {3}, pages = {666-678}, doi = {10.1177/13872877241305744}, pmid = {39772836}, issn = {1875-8908}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Mice ; *Network Pharmacology ; *Hippocampus/drug effects/metabolism ; Male ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Maze Learning/drug effects ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment.
OBJECTIVE: To elucidate the potential mechanisms of Sheng-Hui-Yi-Zhi (SHYZ) for the treatment of AD and explore the effective substances of SHYZ.
METHODS: Liquid chromatography-mass spectrometry (LC-MS) was used to identify the active components of SHYZ. Network pharmacology was employed to predict the potential targets and pathways of SHYZ in the treatment of AD. SAMP8 mice were used as a model for AD and were treated with SHYZ. The Morris water maze was utilized to assess the learning and memory capabilities of mice. Additionally, the levels of TNF-α, IL-1β, and IL-6 in the brain hippocampus of mice were quantified using ELISA. The protein expression of PI3 K/p-PI3 K, AKT/p-AKT, MAPK38/p-MAPK38, and NFκB p65/p-NFκB p65 in the hippocampus was analyzed using Western blotting. Additionally, qRT-PCR was employed to assess the gene expressions of TNF-α, IL-1β, and IL-6 in the hippocampus.
RESULT: The network pharmacological prediction results showed that the treatment of AD with SHYZ was closely related to the inhibition of inflammatory response. Behavioral experiments revealed that SHYZ significantly reduced the time taken to escape, increased the number of times the platform was crossed, and prolonged the residence time in the target quadrant. Meanwhile, SHYZ treatment suppressed the expression of Aβ1-42 protein and inflammatory factors. SHYZ significantly inhibited the expression of proteins of PI3 K, AKT, MAPK p38, and NF-κB p65.
CONCLUSIONS: SHYZ has been shown to effectively ameliorate learning and memory impairment in SAMP8 AD mice by inhibiting the expression of Aβ1-42 and reducing the increase of inflammatory factors.}, }
@article {pmid39772767, year = {2025}, author = {Levine, DA and Sussman, JB and Hayward, RA and Gałecki, AT and Whitney, RT and Briceño, EM and Gross, AL and Giordani, BJ and Elkind, MS and Gottesman, RF and Gaskin, DJ and Sidney, S and Yaffe, K and Burke, JF}, title = {The potential impact of optimal blood pressure treatment intensity to reduce disparities in dementia between Black and White individuals.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {2}, pages = {506-518}, doi = {10.1177/13872877241302506}, pmid = {39772767}, issn = {1875-8908}, mesh = {Humans ; *Dementia/ethnology/epidemiology ; *White People ; Male ; Female ; Aged ; Middle Aged ; *Black or African American ; *Blood Pressure/physiology ; *Hypertension/ethnology/drug therapy ; Antihypertensive Agents/therapeutic use ; Health Status Disparities ; Aged, 80 and over ; Adult ; Healthcare Disparities ; United States/epidemiology ; White ; }, abstract = {BACKGROUND: Black adults have higher dementia risk than White adults. Whether tighter population-level blood pressure (BP) control reduces this disparity is unknown.
OBJECTIVE: Estimate the impact of optimal BP treatment intensity on racial disparities in dementia.
METHODS: A microsimulation study of US adults ≥18 across a life-time policy-planning horizon. BP treatment strategies were the Systolic Blood Pressure Intervention Trial (SPRINT) protocol, the Eighth Joint National Committee (JNC-8) recommendations, and usual care (non-intervention control). Outcomes were all-cause dementia, atherosclerotic cardiovascular disease (ASCVD), stroke, myocardial infarction, non-ASCVD death, global cognitive performance, and optimal brain health (being free of dementia, cognitive impairment, or stroke). Population-level and individual-level effects stratified by race were estimated.
RESULTS: Optimal population-level implementation of a SPRINT-based BP treatment strategy, compared to usual care, would increase average annual dementia incidence in White, but not Black, adults (1% versus 0%), due to hypertensive individuals' greater survival, and reduce annual ASCVD events more in Black than White adults (13% versus 5%). Under a SPRINT-based strategy, individuals with hypertension gained more years lived without dementia, ASCVD, myocardial infarction, or stroke and more years lived in optimal brain health. A SPRINT-based strategy did not attenuate individual-level race disparities in outcomes, except stroke. Due to longer life expectancy, a SPRINT-based strategy did not substantially reduce lifetime dementia risk in either group. The JNC-8-based strategy had similar but smaller effects as the SPRINT-based strategy.
CONCLUSIONS: Our results suggest that tighter population-level BP control would not reduce population-level disparities in dementia between US Black and White adults.}, }
@article {pmid39771275, year = {2024}, author = {Georgiev, B and Sidjimova, B and Berkov, S}, title = {Phytochemical and Cytotoxic Aspects of Amaryllidaceae Alkaloids in Galanthus Species: A Review.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {24}, pages = {}, pmid = {39771275}, issn = {2223-7747}, abstract = {The genus Galanthus (Amaryllidaceae) currently contains 25 plant species naturally occurring in Europe and the Middle East region. These perennial bulbous plants possess well-known medicinal and ornamental qualities. Alkaloid diversity is their most distinctive phytochemical feature. A total of 127 compounds (≈20% of all known Amaryllidaceae alkaloids) grouped in 16 structural types have been previously found in Galanthus extracts. Some structural types like galanthindole, graciline and plicamine were first discovered in Galanthus plants. Nine Galanthus species, however, remain unstudied regarding their alkaloid patterns. Intraspecific variability has only been studied in G. nivalis and G. elwesii. Amaryllidaceae alkaloids are molecules with anticholinesterase, antibacterial, antifungal, antiviral and anticancer properties. Galanthamine, isolated for the first time from Galanthus woronowii Losinsk., stands out as an acetylcholinesterase inhibitor approved for medical use by the FDA for the treatment of symptoms of Alzheimer's disease. Lycorine, narciclasine and pancratistatin are noteworthy cytotoxic and antitumor alkaloids. Structural types like galanthamine, homolycorine and haemanthamine are fairly well studied in anticancer research, but little to no information is available on galanthindole, graciline and other types. This review aims to present an update on the alkaloid diversity of Galanthus spp. and highlight the need for further research on the antitumor potential of these molecules.}, }
@article {pmid39770989, year = {2024}, author = {Pekdemir, B and Raposo, A and Saraiva, A and Lima, MJ and Alsharari, ZD and BinMowyna, MN and Karav, S}, title = {Mechanisms and Potential Benefits of Neuroprotective Agents in Neurological Health.}, journal = {Nutrients}, volume = {16}, number = {24}, pages = {}, pmid = {39770989}, issn = {2072-6643}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; Brain/drug effects/metabolism ; Animals ; Flavonoids/pharmacology/therapeutic use ; Apoptosis/drug effects ; Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {The brain contains many interconnected and complex cellular and molecular mechanisms. Injury to the brain causes permanent dysfunctions in these mechanisms. So, it continues to be an area where surgical intervention cannot be performed except for the removal of tumors and the repair of some aneurysms. Some agents that can cross the blood-brain barrier and reach neurons show neuroprotective effects in the brain due to their anti-apoptotic, anti-inflammatory and antioxidant properties. In particular, some agents act by reducing or modulating the accumulation of protein aggregates in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and prion disease) caused by protein accumulation. Substrate accumulation causes increased oxidative stress and stimulates the brain's immune cells, microglia, and astrocytes, to secrete proinflammatory cytokines. Long-term or chronic neuroinflammatory response triggers apoptosis. Brain damage is observed with neuronal apoptosis and brain functions are impaired. This situation negatively affects processes such as motor movements, memory, perception, and learning. Neuroprotective agents prevent apoptosis by modulating molecules that play a role in apoptosis. In addition, they can improve impaired brain functions by supporting neuroplasticity and neurogenesis. Due to the important roles that these agents play in central nervous system damage or neurodegenerative diseases, it is important to elucidate many mechanisms. This review provides an overview of the mechanisms of flavonoids, which constitute a large part of the agents with neuroprotective effects, as well as vitamins, neurotransmitters, hormones, amino acids, and their derivatives. It is thought that understanding these mechanisms will enable the development of new therapeutic agents and different treatment strategies.}, }
@article {pmid39770582, year = {2024}, author = {Hayden, MR and Tyagi, N}, title = {Sodium Thiosulfate: An Innovative Multi-Target Repurposed Treatment Strategy for Late-Onset Alzheimer's Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {12}, pages = {}, pmid = {39770582}, issn = {1424-8247}, abstract = {Late-onset Alzheimer's disease (LOAD) is a chronic, multifactorial, and progressive neurodegenerative disease that associates with aging and is highly prevalent in our older population (≥65 years of age). This hypothesis generating this narrative review will examine the important role for the use of sodium thiosulfate (STS) as a possible multi-targeting treatment option for LOAD. Sulfur is widely available in our environment and is responsible for forming organosulfur compounds that are known to be associated with a wide range of biological activities in the brain. STS is known to have (i) antioxidant and (ii) anti-inflammatory properties; (iii) chelation properties for calcium and the pro-oxidative cation metals such as iron and copper; (iv) donor properties for hydrogen sulfide production; (v) possible restorative properties for brain endothelial-cell-derived bioavailable nitric oxide. Thus, it becomes apparent that STS has the potential for neuroprotection and neuromodulation and may allow for an attenuation of the progressive nature of neurodegeneration and impaired cognition in LOAD. STS has been successfully used to prevent cisplatin oxidative-stress-induced ototoxicity in the treatment of head and neck and solid cancers, cyanide and arsenic poisoning, and fungal skin diseases. Most recently, intravenous STS has become part of the treatment plan for calciphylaxis globally due to vascular calcification and ischemia-induced skin necrosis and ulceration. Side effects have been minimal with reports of metabolic acidosis and increased anion gap; as with any drug treatment, there is also the possibility of allergic reactions, possible long-term osteoporosis from animal studies to date, and minor side-effects of nausea, headache, and rhinorrhea if infused too rapidly. While STS poorly penetrates the intact blood-brain barrier(s) (BBBs), it could readily penetrate BBBs that are dysfunctional and disrupted to deliver its neuroprotective and neuromodulating effects in addition to its ability to penetrate the blood-cerebrospinal fluid barrier of the choroid plexus. Novel strategies such as the future use of nano-technology may be helpful in allowing an increased entry of STS into the brain.}, }
@article {pmid39770430, year = {2024}, author = {Bures, J and Novak, M and Radochova, V and Kohoutova, D and Prchal, L and Martinek, J and Mares, J and Cerny, J and Suchanek, S and Pejchal, J and Voxova, B and Urbanek, P and Zavoral, M and Soukup, O}, title = {The Effect of Tacrine on Functional Response of the Lower Oesophageal Sphincter Assessed by Endoscopic Luminal Impedance Planimetry in Experimental Pigs.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {12}, pages = {}, pmid = {39770430}, issn = {1424-8247}, support = {23-07570S//Czech Science Foundation/ ; }, abstract = {Background/Objectives: Tacrine is a centrally active non-competitive reversible acetylcholinesterase inhibitor. It also exerts antagonising activity against N-methyl-D-aspartate receptors. Tacrine was approved for the treatment of Alzheimer's disease in 1993, but was withdrawn from clinical use in 2013 because of its hepatotoxicity and gastrointestinal side effects. Nevertheless, tacrine is currently facing a renewed wave of interest primarily due to several new tacrine-incorporated hybrids and derivates. There were two specific aims for this study: firstly, to explain the mechanisms of the adverse action of tacrine, as a distinctive example of a highly effective acetylcholinesterase inhibitor; and secondly to check whether luminal impedance planimetry is feasible for preclinical testing of possible side effects of compounds potentially toxic to the gastrointestinal tract. Methods: Six experimental pigs were used as the animal model in this study. Five major parameters were evaluated: luminal pressure (mmHg), estimated diameter (mm), cross-sectional area (mm[2]), distensibility (mm[2]/mmHg), and zone compliance (mm[3]/mmHg). All measurements were performed before and 360 min after intragastric administration of 200 mg tacrine (at the porcine tacrine Tmax). Results: This study consistently demonstrated an increase in luminal pressure (a directly measured indicator) for the particular balloon filling volumes used, and inversely a reciprocal decrease in the other parameters after tacrine administration. Conclusions: Endoscopic luminal impedance planimetry is a feasible method to evaluate functional response of the lower oesophageal sphincter to tacrine in experimental pigs. Tacrine did not compromise the function of the lower oesophageal sphincter either toward oesophageal spasms or, in contrast, decreased competence of the lower oesophageal sphincter.}, }
@article {pmid39769442, year = {2024}, author = {Yang, H and Yang, J and Park, N and Hwang, DS and Park, SY and Kim, S and Bae, H}, title = {Adoptive Transfer of CX3CR1-Transduced Tregs Homing to the Forebrain in Lipopolysaccharide-Induced Neuroinflammation and 3xTg Alzheimer's Disease Models.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769442}, issn = {1422-0067}, support = {RS-2023-00208347//National Research Foundation of Korea/ ; }, mesh = {Animals ; *Alzheimer Disease/therapy/genetics/metabolism/immunology ; *CX3C Chemokine Receptor 1/metabolism/genetics ; *Lipopolysaccharides ; *T-Lymphocytes, Regulatory/immunology/metabolism ; Mice ; *Disease Models, Animal ; *Neuroinflammatory Diseases/metabolism ; Prosencephalon/metabolism/immunology ; Microglia/metabolism/immunology ; Adoptive Transfer/methods ; Mice, Transgenic ; Male ; }, abstract = {CX3CR1-transduced regulatory T cells (Tregs) have shown potential in reducing neuroinflammation by targeting microglial activation. Reactive microglia are implicated in neurological disorders, and CX3CR1-CX3CL1 signaling modulates microglial activity. The ability of CX3CR1-transduced Tregs to inhibit LPS-induced neuroinflammation was assessed in animal models. CX3CR1 Tregs were administered to LPS-induced and 3xTg Alzheimer's mouse models, resulting in reduced proinflammatory marker expression in both the cortices and hippocampi. In the 3xTg Alzheimer's model, neuroinflammation was significantly reduced, demonstrating the efficacy of CX3CR1 Tregs even in chronic neuroinflammatory conditions. These findings highlight the therapeutic potential of CX3CR1 Treg therapy in modulating microglial activity and offer promising treatment strategies for neurodegenerative diseases.}, }
@article {pmid39769398, year = {2024}, author = {Testa, G and Giannelli, S and Staurenghi, E and Cecci, R and Floro, L and Gamba, P and Sottero, B and Leonarduzzi, G}, title = {The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer's Disease: A Possible Target for the Disease Treatment.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769398}, issn = {1422-0067}, support = {LEOG_RILO_23_01; GAMP_RILO_23_01; SOTB_RILO_23_01; LEOG_RF_CLINIC_23_01//University of Turin/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/etiology/pathology/drug therapy ; *Proprotein Convertase 9/metabolism ; Animals ; Brain/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; PCSK9 Inhibitors ; Cholesterol/metabolism ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease mainly caused by β-amyloid (Aβ) accumulation in the brain. Among the several factors that may concur to AD development, elevated cholesterol levels and brain cholesterol dyshomeostasis have been recognized to play a relevant role. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein primarily known to regulate plasma low-density lipoproteins (LDLs) rich in cholesterol and to be one of the main causes of familial hypercholesterolemia. In addition to that, PCSK9 is also recognized to carry out diverse important activities in the brain, including control of neuronal differentiation, apoptosis, and, importantly, LDL receptors functionality. Moreover, PCSK9 appeared to be directly involved in some of the principal processes responsible for AD development, such as inflammation, oxidative stress, and Aβ deposition. On these bases, PCSK9 management might represent a promising approach for AD treatment. The purpose of this review is to elucidate the role of PCSK9, whether or not cholesterol-related, in AD pathogenesis and to give an updated overview of the most innovative therapeutic strategies developed so far to counteract the pleiotropic activities of both humoral and brain PCSK9, focusing in particular on their potentiality for AD management.}, }
@article {pmid39769243, year = {2024}, author = {Paoletti, I and Coccurello, R}, title = {Irisin: A Multifaceted Hormone Bridging Exercise and Disease Pathophysiology.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769243}, issn = {1422-0067}, mesh = {Humans ; *Fibronectins/metabolism ; *Exercise/physiology ; Animals ; Alzheimer Disease/metabolism ; Muscle, Skeletal/metabolism/physiopathology ; }, abstract = {The fibronectin domain-containing protein 5 (FNDC5), or irisin, is an adipo-myokine hormone produced during exercise, which shows therapeutic potential for conditions like metabolic disorders, osteoporosis, sarcopenia, obesity, type 2 diabetes, and neurodegenerative diseases, including Alzheimer's disease (AD). This review explores its potential across various pathophysiological processes that are often considered independent. Elevated in healthy states but reduced in diseases, irisin improves muscle-adipose communication, insulin sensitivity, and metabolic balance by enhancing mitochondrial function and reducing oxidative stress. It promotes osteogenesis and mitigates bone loss in osteoporosis and sarcopenia. Irisin exhibits anti-inflammatory effects by inhibiting NF-κB signaling and countering insulin resistance. In the brain, it reduces amyloid-β toxicity, inflammation, and oxidative stress, enhancing brain-derived neurotrophic factor (BDNF) signaling, which improves cognition and synaptic health in AD models. It also regulates dopamine pathways, potentially alleviating neuropsychiatric symptoms like depression and apathy. By linking physical activity to systemic health, irisin emphasizes its role in the muscle-bone-brain axis. Its multifaceted benefits highlight its potential as a therapeutic target for AD and related disorders, with applications in prevention, in treatment, and as a complement to exercise strategies.}, }
@article {pmid39769209, year = {2024}, author = {Xing, C and Chen, H and Bi, W and Lei, T and Hang, Z and Du, H}, title = {Targeting 5-HT Is a Potential Therapeutic Strategy for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769209}, issn = {1422-0067}, support = {32300682//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Serotonin/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; Alzheimer Disease/metabolism/drug therapy ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Parkinson Disease/metabolism/drug therapy ; Receptors, Serotonin/metabolism ; }, abstract = {There is increasing interest in the potential therapeutic role of 5-HT (serotonin) in the treatment of neurodegenerative diseases, which are characterized by the progressive degeneration and death of nerve cells. 5-HT is a vital neurotransmitter that plays a central role in regulating mood, cognition, and various physiological processes in the body. Disruptions in the 5-HT system have been linked to several neurological and psychiatric disorders, making it an attractive target for therapeutic intervention. Although the exact causes of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are not fully understood, researchers believe that regulating the 5-HT system could help alleviate symptoms and potentially slow the progression of these diseases. Here, we delve into the potential of harnessing 5-HT as a therapeutic target for the treatment of neurodegenerative diseases. It is important to note that the current clinical drugs targeting 5-HT are still limited in the treatment of these complex diseases. Therefore, further research and clinical trials are needed to evaluate the feasibility and effectiveness of its clinical application.}, }
@article {pmid39769187, year = {2024}, author = {O'Day, DH}, title = {The Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769187}, issn = {1422-0067}, mesh = {Animals ; Humans ; alpha-Synuclein/metabolism ; Alzheimer Disease/metabolism/pathology/drug therapy/therapy ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Calmodulin/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; Parkinson Disease/metabolism/pathology/therapy ; Protein Glutamine gamma Glutamyltransferase 2 ; RNA-Binding Protein FUS/metabolism/genetics ; tau Proteins/metabolism ; Transglutaminases/metabolism ; }, abstract = {The predominant neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention. First, they all form toxic aggregates prior to taking on their final forms as contributors to plaques, neurofibrillary tangles, Lewy bodies, and other protein deposits. Second, the primary enzyme that directs their aggregation is transglutaminase 2 (TGM2), a brain-localized enzyme involved in neurodegeneration. Third, TGM2 binds to calmodulin, a regulatory event that can increase the activity of this enzyme threefold. Fourth, the most common mixed pathology toxic biomarkers (Aβ, pTau, αSyn, nHtt) also bind calmodulin, which can affect their ability to aggregate. This review examines the potential therapeutic routes opened up by this knowledge. The end goal reveals multiple opportunities that are immediately available for universal therapeutic treatment of the most devastating neurodegenerative diseases facing humankind.}, }
@article {pmid39769066, year = {2024}, author = {Toader, C and Dumitru, AV and Eva, L and Serban, M and Covache-Busuioc, RA and Ciurea, AV}, title = {Nanoparticle Strategies for Treating CNS Disorders: A Comprehensive Review of Drug Delivery and Theranostic Applications.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769066}, issn = {1422-0067}, mesh = {Humans ; *Central Nervous System Diseases/drug therapy/diagnosis ; *Theranostic Nanomedicine/methods ; *Nanoparticles/chemistry ; *Drug Delivery Systems/methods ; Animals ; *Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {This review aims to address the significant challenges of treating central nervous system (CNS) disorders such as neurodegenerative diseases, strokes, spinal cord injuries, and brain tumors. These disorders are difficult to manage due to the complexity of disease mechanisms and the protective blood-brain barrier (BBB), which restricts drug delivery. Recent advancements in nanoparticle (NP) technologies offer promising solutions, with potential applications in drug delivery, neuroprotection, and neuroregeneration. By examining current research, we explore how NPs can cross the BBB, deliver medications directly to targeted CNS regions, and enhance both diagnostics and treatment. Key NP strategies, such as passive targeting, receptor-mediated transport, and stimuli-responsive systems, demonstrate encouraging results. Studies show that NPs may improve drug delivery, minimize side effects, and increase therapeutic effectiveness in models of Alzheimer's, Parkinson's, stroke, and glioblastoma. NP technologies thus represent a promising approach for CNS disorder management, combining drug delivery and diagnostic capabilities to enable more precise and effective treatments that could significantly benefit patient outcomes.}, }
@article {pmid39769034, year = {2024}, author = {Oxenkrug, G}, title = {Anthranilic Acid-G-Protein Coupled Receptor109A-Cytosolic Phospholipase A2-Myelin-Cognition Cascade: A New Target for the Treatment/Prevention of Cognitive Impairment in Schizophrenia, Dementia, and Aging.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769034}, issn = {1422-0067}, mesh = {Humans ; *Schizophrenia/metabolism/drug therapy ; *Cognitive Dysfunction/metabolism/drug therapy/etiology/prevention & control ; *ortho-Aminobenzoates/pharmacology/therapeutic use ; Animals ; *Aging/metabolism ; Myelin Sheath/metabolism ; Phospholipases A2, Cytosolic/metabolism ; Dementia/metabolism/drug therapy/prevention & control/etiology ; Receptors, G-Protein-Coupled/metabolism ; Cognition/drug effects ; Signal Transduction/drug effects ; }, abstract = {Cognitive impairment is a core feature of neurodevelopmental (schizophrenia) and aging-associated (mild cognitive impairment and Alzheimer's dementia) neurodegenerative diseases. Limited efficacy of current pharmacological treatments warrants further search for new targets for nootropic interventions. The breakdown of myelin, a phospholipids axonal sheath that protects the conduction of nerve impulse between neurons, was proposed as a neuropathological abnormality that precedes and promotes the deposition of amyloid-β in neuritic plaques. The present review of the recent literature and our own pre- and clinical data suggest (for the first time) that the anthranilic acid (AA)-induced activation of microglial-expressed G-protein coupled receptor (GPR109A) inhibits cytosolic phospholipase A2 (cPLA2), an enzyme that triggers the degradation of myelin and consequently attenuates cognitive impairment. The present review suggests that the up-regulation of AA formation is a sex-specific compensatory (adaptive) reaction aimed to prevent/treat cognitive impairment. The AA-GPR109A-cPLA2-myelin-cognition cascade suggests new nootropic interventions, e.g., the administration of pegylated kynureninase, an enzyme that catalyzes AA formation from Kynurenine (Kyn), a tryptophane catabolite; pegylated interferon-alpha; central and peripheral Kyn aminotransferase inhibitors that increase availability of Kyn as a substrate for AA formation; and vagus nerve stimulation. The cascade predicts nootropic activity of exogenous GPR109A agonists that were designed and underwent clinical trials (unsuccessful) as anti-dyslipidemia agents. The proposed cascade might contribute to the pathogenesis of cognitive impairment. Data on AA in neurodegenerative disorders are scarce, and the proposed cascade needs further exploration in pre- and clinical studies.}, }
@article {pmid39768683, year = {2024}, author = {Świetlik, D}, title = {Deep Brain Stimulation Combined with NMDA Antagonist Therapy in the Treatment of Alzheimer's Disease: In Silico Trials.}, journal = {Journal of clinical medicine}, volume = {13}, number = {24}, pages = {}, pmid = {39768683}, issn = {2077-0383}, support = {SPR0001//GENELYTICA SP. z o.o./ ; }, abstract = {Background: Deep brain stimulation (DBS) is employed to adjust the activity of impaired brain circuits. The variability in clinical trial outcomes for treating Alzheimer's disease with memantine is not yet fully understood. We conducted a randomized in silico study comparing virtual DBS therapies with treatment involving an NMDA antagonist combined with DBS in patients with Alzheimer's disease. Methods: Neural network models representing Alzheimer's disease (AD) patients were randomly assigned to four groups: AD, memantine treatment, DBS, and DBS and memantine. Out of 100 unique neural networks created to model moderate and severe AD with varying hippocampal synaptic loss, 20 were randomly selected to represent AD patients. Virtual treatments-memantine, DBS, and DBS and memantine-were applied, resulting in a total of 80 simulations. Results: The normalized mean number of spikes in the CA1 region among the virtual AD hippocampi treated with memantine, DBS therapy, and DBS and memantine differed significantly (p < 0.0001). The normalized mean number of spikes in the virtual AD hippocampi was 0.33 (95% CI, 0.29-0.36) and was significantly lower compared to the number of spikes in the virtual AD hippocampi treated with memantine, which was 0.53 (95% CI, 0.48-0.59) (p = 0.0162), and in the DBS and memantine group, which was 0.67 (95% CI, 0.57-0.78) (p = 0.0001). Conclusions: Our simulation results indicate the effectiveness of virtual memantine and DBS therapy compared to memantine monotherapy for Alzheimer's disease.}, }
@article {pmid39768369, year = {2024}, author = {Adel, E and Nicolas, M}, title = {Potential Regulation of the Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript1 by Estrogen in Parkinson's Disease.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {12}, pages = {}, pmid = {39768369}, issn = {2075-1729}, abstract = {Parkinson's disease (PD) is the second-leading cause of death among neurodegenerative disease after Alzheimer's disease (AD), affecting around 2% of the population. It is expected that the incidence of PD will exceed 12 million by 2040. Meanwhile, there is a recognized difference in the phenotypical expression of the disease and response to treatment between men and women. Men have twice the incidence of PD compared to women, who have a late onset and worse prognosis that is usually associated with menopause. In addition, the incidence of PD in women is associated with the cumulative estrogen levels in their bodies. These differences are suggested to be due to the protective effect of estrogen on the brain, which cannot be given in clinical practice to improve the symptoms of the disease because of its peripheral side effects, causing cancer in both males and females in addition to the feminizing effect it has on males. As PD pathophysiology involves alteration in the expression levels of multiple LncRNAs, including metastatic-associated lung adenocarcinoma transcript 1 (MALAT1), and as estrogen has been illustrated to control the expression of MALAT1 in multiple conditions, it is worth investigating the estrogen-MALAT1 interaction in Parkinson's disease to mimic its protective effect on the brain while avoiding its peripheral side effects. The following literature review suggests the potential regulation of MALAT1 by estrogen in PD, which would enhance our understanding of the pathophysiology of the disease, improving the development of more tailored and effective treatments.}, }
@article {pmid39768263, year = {2024}, author = {Cacabelos, R and Martínez-Iglesias, O and Cacabelos, N and Carrera, I and Corzo, L and Naidoo, V}, title = {Therapeutic Options in Alzheimer's Disease: From Classic Acetylcholinesterase Inhibitors to Multi-Target Drugs with Pleiotropic Activity.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {12}, pages = {}, pmid = {39768263}, issn = {2075-1729}, abstract = {Alzheimer's disease (AD) is a complex/multifactorial brain disorder involving hundreds of defective genes, epigenetic aberrations, cerebrovascular alterations, and environmental risk factors. The onset of the neurodegenerative process is triggered decades before the first symptoms appear, probably due to a combination of genomic and epigenetic phenomena. Therefore, the primary objective of any effective treatment is to intercept the disease process in its presymptomatic phases. Since the approval of acetylcholinesterase inhibitors (Tacrine, Donepezil, Rivastigmine, Galantamine) and Memantine, between 1993 and 2003, no new drug was approved by the FDA until the advent of immunotherapy with Aducanumab in 2021 and Lecanemab in 2023. Over the past decade, more than 10,000 new compounds with potential action on some pathogenic components of AD have been tested. The limitations of these anti-AD treatments have stimulated the search for multi-target (MT) drugs. In recent years, more than 1000 drugs with potential MT function have been studied in AD models. MT drugs aim to address the complex and multifactorial nature of the disease. This approach has the potential to offer more comprehensive benefits than single-target therapies, which may be limited in their effectiveness due to the intricate pathology of AD. A strategy still unexplored is the combination of epigenetic drugs with MT agents. Another option could be biotechnological products with pleiotropic action, among which nosustrophine-like compounds could represent an attractive, although not definitive, example.}, }
@article {pmid39767773, year = {2024}, author = {Shrivastava, P and Lu, Y and Su, S and Kobayashi, Y and Zhao, Y and Lien, N and Masoud, AR and Lukiw, WJ and Hong, S}, title = {Maresin-like 1 Ameliorates Neuropathology of Alzheimer's Disease in Brains of a Transgenic Mouse Model.}, journal = {Biomedicines}, volume = {12}, number = {12}, pages = {}, pmid = {39767773}, issn = {2227-9059}, support = {R21 AG066119/AG/NIA NIH HHS/United States ; R21 AG060430/AG/NIA NIH HHS/United States ; R21AG060430/NH/NIH HHS/United States ; 1R21AG068756/NH/NIH HHS/United States ; R21AG066119/NH/NIH HHS/United States ; R21 AG068756/AG/NIA NIH HHS/United States ; }, abstract = {(1) Background: Impeded resolution of inflammation contributes substantially to the pathogenesis of Alzheimer's disease (AD); consequently, resolving inflammation is pivotal to the amelioration of AD pathology. This can potentially be achieved by the treatment with specialized pro-resolving lipid mediators (SPMs), which should resolve neuroinflammation in brains. (2) Methods: Here, we report the histological effects of long-term treatment with an SPM, maresin-like 1 (MarL1), on AD pathogenesis in a transgenic 5xFAD mouse model. (3) Results: MarL1 treatment reduced Aβ overload, curbed the loss of neurons in brains especially cholinergic neurons associated with cleaved-caspase-3-associated apoptotic degeneration, reduced microgliosis and the pro-inflammatory M1 polarization of microglia, curbed the AD-associated decline in anti-inflammatory Iba1[+]Arg-1[+]-M2 microglia, inhibited phenotypic switching to pro-inflammatory N1 neutrophils, promoted the blood-brain barrier-associated tight-junction protein claudin-5 and decreased neutrophil leakage in 5xFAD brains, and induced the switch of neutrophils toward the inflammation-resolving N2 phenotype. (4) Conclusions: Long-term administration of MarL1 mitigates AD-related neuropathogenesis in brains by curbing neuroinflammation and neurodegeneration, based on the histological results. These findings provide preclinical leads and mechanistic insights for the development of MarL1 into an effective modality to ameliorate AD pathogenesis.}, }
@article {pmid39767690, year = {2024}, author = {Zhang, Y and Liao, X and Xu, J and Yin, J and Li, S and Li, M and Shi, X and Zhang, S and Li, C and Xu, W and Yu, X and Yang, Y}, title = {The Promising Potency of Sodium-Glucose Cotransporter 2 Inhibitors in the Prevention of and as Treatment for Cognitive Impairment Among Type 2 Diabetes Patients.}, journal = {Biomedicines}, volume = {12}, number = {12}, pages = {}, pmid = {39767690}, issn = {2227-9059}, support = {81974114//National Natural Science Foundation of China/ ; }, abstract = {Type 2 diabetes mellitus (T2DM), accounting for the majority of diabetes mellitus prevalence, is associated with an increased risk of cognition decline and deterioration of cognition function in diabetic patients. The sodium-glucose cotransporter 2 (SGLT2), located in the renal proximal tubule, plays a role in urine glucose reabsorption. SGLT2 inhibitors (SGLT2i), have shown potential benefits beyond cardiac and renal improvement in preventing and treating cognitive impairment (CI), including mild cognitive impairment, Alzheimer's disease and vascular dementia in T2DM patients. Studies suggest that SGLT2i may ameliorate diabetic CI through metabolism pathways, inflammation, oxidative stress, neurotrophic factors and AChE inhibition. Clinical trials and meta-analyses have reported significant and insignificant results. Given their vascular effects, SGLT2i may offer unique protection against vascular CI. This review compiles mechanisms and clinical evidence, emphasizing the need for future analysis, evaluation, trials and meta-analyses to verify and recommend optimal SGLT2i selection and dosage for specific patients.}, }
@article {pmid39767653, year = {2024}, author = {Neațu, M and Ioniță, I and Jugurt, A and Davidescu, EI and Popescu, BO}, title = {Exploring the Complex Relationship Between Antidepressants, Depression and Neurocognitive Disorders.}, journal = {Biomedicines}, volume = {12}, number = {12}, pages = {}, pmid = {39767653}, issn = {2227-9059}, abstract = {The coexistence of dementia and depression in older populations presents a complex clinical challenge, with each condition often exacerbating the other. Cognitive decline can intensify mood disturbances, and untreated or recurring depression accelerates neurodegenerative processes. As depression is a recognized risk factor for dementia, it is crucial to address both conditions concurrently to prevent further deterioration. Antidepressants are frequently used to manage depression in dementia patients, with some studies suggesting they offer neuroprotective benefits. These benefits include promoting neurogenesis, enhancing synaptic plasticity, and reducing neuroinflammation, potentially slowing cognitive decline. Additionally, antidepressants have shown promise in addressing Alzheimer's-related pathologies by reducing amyloid-beta accumulation and tau hyperphosphorylation. However, treatment-resistant depression remains a significant challenge, particularly in older adults with cognitive impairment. Many do not respond well to standard antidepressant therapies due to advanced neurodegenerative changes. Conflicting findings from studies add to the uncertainty, with some research suggesting that antidepressants may increase dementia risk, especially when used in patients with undiagnosed early-stage dementia. This article aims to explore the intricate relationship between depression and dementia, examining the benefits and risks of antidepressant use. We highlight the urgent need for personalized, comprehensive treatment strategies that balance mental health improvement with cognitive protection.}, }
@article {pmid39767605, year = {2024}, author = {Wang, P and Okada-Rising, S and Scultetus, AH and Bailey, ZS}, title = {The Relevance and Implications of Monoclonal Antibody Therapies on Traumatic Brain Injury Pathologies.}, journal = {Biomedicines}, volume = {12}, number = {12}, pages = {}, pmid = {39767605}, issn = {2227-9059}, abstract = {Traumatic brain injury (TBI) is a global public health concern. It remains one of the leading causes of morbidity and mortality. TBI pathology involves complex secondary injury cascades that are associated with cellular and molecular dysfunction, including oxidative stress, coagulopathy, neuroinflammation, neurodegeneration, neurotoxicity, and blood-brain barrier (BBB) dysfunction, among others. These pathological processes manifest as a diverse array of clinical impairments. They serve as targets for potential therapeutic intervention not only in TBI but also in other diseases. Monoclonal antibodies (mAbs) have been used as key therapeutic agents targeting these mechanisms for the treatment of diverse diseases, including neurological diseases such as Alzheimer's disease (AD). MAb therapies provide a tool to block disease pathways with target specificity that may be capable of mitigating the secondary injury cascades following TBI. This article reviews the pathophysiology of TBI and the molecular mechanisms of action of mAbs that target these shared pathological pathways in a wide range of diseases. Publicly available databases for various applications of mAb therapy were searched and further classified to assess relevance to TBI pathology and evaluate current stages of development. The authors intend for this review to highlight the potential impact of current mAb technology within pathological TBI processes.}, }
@article {pmid39767596, year = {2024}, author = {Boboc, IKS and Dumitrelea, PD and Meca, AD and Mititelu-Tartau, L and Bogdan, M}, title = {Exploring the Impact of Semaglutide on Cognitive Function and Anxiety-Related Behaviors in a Murine Model of Alzheimer's Disease.}, journal = {Biomedicines}, volume = {12}, number = {12}, pages = {}, pmid = {39767596}, issn = {2227-9059}, abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by progressive cognitive decline and behavioral disturbances, with an increasing incidence as the global population ages. This study investigates the effects of semaglutide (SEM), a glucagon-like peptide-1 analog, on cognitive function and anxiety-like behavior in a transgenic murine model of AD.
METHODS: 20 mice were randomly distributed into the following groups (n = 5): (WT + VEH) group: C57BL/6J + saline, (WT + SEM) group: C57BL/6J + semaglutide, (AD + VEH) group: AD + saline, (AD + SEM) group: AD + semaglutide. The animals underwent a four-week treatment, during which we monitored blood glucose levels, body weight, and responses in an open field test, novel object recognition test, social chamber test, and 0-maze test.
RESULTS: Post-treatment, SEM significantly reduced blood glucose levels in AD mice, aligning them with those of wild-type controls. Cognitive assessments indicated an improvement in the investigation index for SEM-treated mice compared to those receiving a vehicle, suggesting cognitive benefits. Although SEM did not significantly enhance motor and exploratory activities, it displayed a potential anxiolytic effect, particularly evident in the combined anxiety index, with notable differences observed before and after treatment in the AD group.
CONCLUSIONS: The findings of this pilot study suggest that SEM may play a dual role in managing AD by improving glycemic control and potentially enhancing cognitive function. As the landscape of AD treatment evolves, the comprehensive approach of utilizing SEM could pave the way for innovative interventions targeting the complex interplay of metabolic and cognitive dysfunctions in this challenging neurodegenerative disorder.}, }
@article {pmid39767175, year = {2024}, author = {Kolanek, A and Cemaga, R and Maciejczyk, M}, title = {Role and Diagnostic Significance of Apolipoprotein D in Selected Neurodegenerative Disorders.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {14}, number = {24}, pages = {}, pmid = {39767175}, issn = {2075-4418}, abstract = {The World Health Organization in 2021 ranked Alzheimer's disease and other dementias as the seventh leading cause of death globally. Neurodegenerative disorders are progressive, intractable, and often fatal diseases. Early diagnosis may allow patients to enjoy prolonged survival with attenuated symptomatology because of early intervention. Hence, further research on finding non-invasive biomarkers of neurodegenerative diseases is warranted. Apolipoprotein D (ApoD) is a glycoprotein involved in lipid metabolism, oxidative stress regulation, and inflammation. It is expressed in various body fluids and regions of the central nervous system. ApoD's roles in neuroprotection, lipid transport, and anti-inflammatory processes are crucial as far as the prevention of neurodegenerative pathologies is concerned. This review aims to summarize the background knowledge on ApoD, and it covers studies indexed in the PubMed, Scopus, and Web of Science databases. It discusses the evidence for the multifaceted roles of ApoD in the mechanisms and pathogenesis of multiple sclerosis, Alzheimer's disease, and Parkinson's disease. ApoD may be a specific, sensitive, easily obtained, cost-effective biomarker for neurodegenerative diseases and its applications in diagnostic practices, treatment strategies, and advancing neurodegenerative disorders' management.}, }
@article {pmid39767131, year = {2024}, author = {Dubey, Y and Bhongade, A and Palsodkar, P and Fulzele, P}, title = {Efficient Explainable Models for Alzheimer's Disease Classification with Feature Selection and Data Balancing Approach Using Ensemble Learning.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {14}, number = {24}, pages = {}, pmid = {39767131}, issn = {2075-4418}, abstract = {Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia. Early diagnosis of Alzheimer's disease is critical for better management and treatment outcomes, but it remains a challenging task due to the complex nature of the disease. Clinical data, including a range of cognitive, functional, and demographic variables, play a crucial role in Alzheimer's disease classification. Also, challenges such as data imbalance and high-dimensional feature sets often hinder model performance. Objective: This paper aims to propose a computationally efficient, reliable, and transparent machine learning-based framework for the classification of Alzheimer's disease patients. This framework is interpretable and helps medical practitioners learn complex patterns in patients. Method: This study addresses these issues by employing boosting algorithms, for enhanced classification accuracy. To mitigate data imbalance, a random sampling technique is applied, ensuring a balanced representation of Alzheimer's and healthy cases. Extensive feature analysis was conducted to identify the most impactful clinical features followed by feature reduction techniques to focus on the most informative clinical features, reducing model complexity and overfitting risks. Explainable AI tools, such as SHAP, LIME, ALE, and ELI5 are integrated to provide transparency into the model's decision-making process, highlighting key features influencing the classification and allowing clinicians to understand and trust the key features driving the predictions. Results: This approach results in a robust, interpretable, and clinically relevant framework for Alzheimer's disease diagnosis. The proposed approach achieved the best accuracy of 95%, demonstrating its effectiveness and potential for reliable early diagnosis of Alzheimer's disease. Conclusions: This study demonstrates that integrating ensemble learning algorithms and explainable AI, while using a balanced dataset with feature selection, improves quantitative results and interpretability. This approach offers a promising method for early and better-informed clinical decisions.}, }
@article {pmid39766465, year = {2024}, author = {Kumar, R and Waisberg, E and Ong, J and Paladugu, P and Amiri, D and Saintyl, J and Yelamanchi, J and Nahouraii, R and Jagadeesan, R and Tavakkoli, A}, title = {Artificial Intelligence-Based Methodologies for Early Diagnostic Precision and Personalized Therapeutic Strategies in Neuro-Ophthalmic and Neurodegenerative Pathologies.}, journal = {Brain sciences}, volume = {14}, number = {12}, pages = {}, pmid = {39766465}, issn = {2076-3425}, abstract = {Advancements in neuroimaging, particularly diffusion magnetic resonance imaging (MRI) techniques and molecular imaging with positron emission tomography (PET), have significantly enhanced the early detection of biomarkers in neurodegenerative and neuro-ophthalmic disorders. These include Alzheimer's disease, Parkinson's disease, multiple sclerosis, neuromyelitis optica, and myelin oligodendrocyte glycoprotein antibody disease. This review highlights the transformative role of advanced diffusion MRI techniques-Neurite Orientation Dispersion and Density Imaging and Diffusion Kurtosis Imaging-in identifying subtle microstructural changes in the brain and visual pathways that precede clinical symptoms. When integrated with artificial intelligence (AI) algorithms, these techniques achieve unprecedented diagnostic precision, facilitating early detection of neurodegeneration and inflammation. Additionally, next-generation PET tracers targeting misfolded proteins, such as tau and alpha-synuclein, along with inflammatory markers, enhance the visualization and quantification of pathological processes in vivo. Deep learning models, including convolutional neural networks and multimodal transformers, further improve diagnostic accuracy by integrating multimodal imaging data and predicting disease progression. Despite challenges such as technical variability, data privacy concerns, and regulatory barriers, the potential of AI-enhanced neuroimaging to revolutionize early diagnosis and personalized treatment in neurodegenerative and neuro-ophthalmic disorders is immense. This review underscores the importance of ongoing efforts to validate, standardize, and implement these technologies to maximize their clinical impact.}, }
@article {pmid39766385, year = {2024}, author = {Kraybill, EP and Mojabi, FS and Heath, AM and Spikes, CR and Beard, C and McNerney, MW}, title = {rTMS Modulation of Behavioral and Biological Measures in 3xTg-AD Mice.}, journal = {Brain sciences}, volume = {14}, number = {12}, pages = {}, pmid = {39766385}, issn = {2076-3425}, support = {IK2 BX004105/BX/BLRD VA/United States ; 5IK2BX004105//Department of Veterans Affairs, BLR&D/ ; }, abstract = {BACKGROUND/OBJECTIVES: The biological basis for behavioral manifestations of Alzheimer's disease remains unclear. Emotional and behavioral alterations of Alzheimer's disease can result in substantial caregiver burden and lack effective management. This study expands upon previous work investigating behavioral alterations in mice with Alzheimer's disease and a potential treatment of increasing brain-derived neurotrophic factor (BDNF) using repetitive transcranial magnetic stimulation (rTMS).
METHODS: A total of 47 3xTg-AD (Alzheimer's) and 53 B6 (wildtype) mice were administered ANA12 (an antagonist of TrkB receptor) or Vehicle (saline) and then rTMS or Sham treatment daily. After 14 days of treatments and injections, mouse behavior was assessed under various behavioral cognitive tests. Mice were then perfused, and brain samples were processed for histology and protein assays. Brain homogenates were analyzed for BDNF and its downstream signaling molecules.
RESULTS: Open field testing demonstrated that 3xTg-AD mice spent more time in the center than B6 mice. 3xTg-AD-Sham mice injected with ANA12 were the only group to travel significantly less distance than B6-ANA12-Sham or B6-Vehicle-Sham mice (p < 0.05), while 3xTg-AD-rTMS mice (irrespective of injection) were not significantly different from B6 mice. 3xTg-AD mice had significantly greater measured levels of BDNF and TrkB than the wild-type mice.
CONCLUSIONS: Treatment of Alzheimer's disease using rTMS positively affects elements of hypoactivity, but not all behavioral abnormalities. rTMS shifted 3xTg-AD open field behavioral test measures, generating significant differences between untreated 3xTg-AD and B6 genotypes. Despite its benefit, further investigation of rTMS as a treatment for Alzheimer's disease as well as its biological underpinnings are needed.}, }
@article {pmid39765138, year = {2025}, author = {Zheng, Y and An, S and Kim, GY and Park, GD and Yoo, BH and Kim, KN and Lee, TK}, title = {Treatment with soybean lecithin-derived α-GPC (SHCog™) improves scopolamine-induced cognitive declines in mice via regulating cholinergic neurotransmission and enhancing neural plasticity in the hippocampus.}, journal = {Tissue & cell}, volume = {93}, number = {}, pages = {102705}, doi = {10.1016/j.tice.2024.102705}, pmid = {39765138}, issn = {1532-3072}, mesh = {Animals ; *Scopolamine/pharmacology ; *Neuronal Plasticity/drug effects ; *Hippocampus/drug effects/metabolism ; *Synaptic Transmission/drug effects ; *Glycine max/chemistry ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism ; Male ; Lecithins/pharmacology ; Mice, Inbred C57BL ; Brain-Derived Neurotrophic Factor/metabolism ; Glycerylphosphorylcholine/pharmacology/metabolism ; Disks Large Homolog 4 Protein/metabolism ; Cognition/drug effects ; Choline O-Acetyltransferase/metabolism ; Acetylcholinesterase/metabolism ; }, abstract = {Mild cognitive impairment is a diagnostic category marked by declines in memory and cognitive function that are less severe than those observed in Alzheimer's disease. Previous studies have indicated that individuals with mild cognitive impairment have an elevated risk of progressing to Alzheimer's disease. The hippocampus is well known to play pivotal roles in memory and cognitive functions. Scopolamine (Sco) disrupts cholinergic neurotransmission in the hippocampus and triggers functional declines in memory and cognition. SHCog™ is a commercially available alpha glycerophosphorylcholine (α-GPC) derived from soybean lecithin. The objective of the present study was to examine whether SHCog™ can alleviate memory and cognitive dysfunctions in a mouse model of cognitive impairments induced by Sco. In this study, C57BL/6 J mice were subjected to the passive avoidance and Morris water maze tests to investigate short-term and spatial memory functions, respectively. This study also examined cellular morphology and distribution by cresyl violet staining and investigated changes in acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) as cholinergic enzymes through immunohistochemical staining of the hippocampus. Additionally, we examined changes in postsynaptic density protein 95 (PSD-95) and brain-derived neurotrophic factor (BDNF) related to neural plasticity in the hippocampus. Treatment with SHCog™ (125 mg/kg and 250 mg/kg) brought functional recovery in short-term and spatial memory against Sco-induced memory and cognitive impairments. Changes in cellular morphology and distribution in the hippocampus were not detected following the administration of Sco and/or SHCog™. Treatment with SHCog™ reduced AChE elevated by Sco, whereas SHCog™ administration increased ChAT decreased by Sco. Furthermore, SHCog™ restored PSD-95 and BDNF in the mouse hippocampus reduced by Sco. Specifically, SHCog™ modulated cholinergic neurotransmission and enhanced neural plasticity in the hippocampus. Taken together, we suggest that SHCog™ can be a valuable ingredient in functional foods or supplements for improving memory and cognitive functions.}, }
@article {pmid39764533, year = {2025}, author = {Bai, H and Feng, XF}, title = {Searching for new drugs to treat Alzheimer's disease dementia through multiple pathways.}, journal = {World journal of clinical cases}, volume = {13}, number = {1}, pages = {100833}, pmid = {39764533}, issn = {2307-8960}, abstract = {Dementia is a group of diseases, including Alzheimer's disease (AD), vascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease dementia, metabolic dementia and toxic dementia. The treatment of dementia mainly includes symptomatic treatment by controlling the primary disease and accompanying symptoms, nutritional support therapy for repairing nerve cells, psychological auxiliary treatment, and treatment that improves cognitive function through drugs. Among them, drug therapy to improve cognitive function is important. This review focuses on introducing and commenting on some recent progress in exploring drugs to improve cognitive function, especially the new progress in drug treatment for AD. We mainly discuss the opportunities and challenges in finding and developing new therapeutic drugs from the aspects of acetylcholinesterase, N-methyl-D-aspartate glutamate receptor, amyloid protein, tau protein and chronic immune inflammation.}, }
@article {pmid39764140, year = {2024}, author = {Akif, A and My Nguyen, TT and Liu, L and Xu, X and Kulkarni, A and Jiang, J and Zhang, Y and Hao, J}, title = {Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39764140}, issn = {2693-5015}, support = {R01 NS105787/NS/NINDS NIH HHS/United States ; R21 NS133895/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.
METHODS: In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50[th] day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA.
RESULTS: AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood.
CONCLUSIONS: The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.}, }
@article {pmid39764113, year = {2024}, author = {Orlunwo, PO and Onuodu, FE}, title = {Comparison of Ensemble Techniques for Early Prediction of Alzhiemer Disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39764113}, issn = {2693-5015}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a progressive neurological condition characterized by a loss in cognitive functions, with no disease-modifying medication now available. It is crucial for early detection and treatment of Alzheimer's disease before clinical manifestation. The stage between cognitively healthy older persons and AD is known as mild cognitive impairment (MCI). To predict the transition from one-stage MCI to probable AD, five ensemble learning approach was used (Stacking, Gradient boost Bagging, Adaptive boost and Voting), an integrated model that combines not only cross-sectional neuroimaging biomarkers at baseline but also longitudinal cerebrospinal fluid (CSF) and cognitive performance biomarkers from the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI). The adaptive boost, stacking and bagging ensemble approach has shown potential to identify those at risk of developing Alzheimer's disease, this would benefit them the most from a clinical trial or to use as a stratification approach inside clinical trials.}, }
@article {pmid39763832, year = {2024}, author = {Friday, CM and Stephens, IO and Smith, CT and Lee, S and Satish, D and Devanney, NA and Cohen, S and Morganti, JM and Gordon, SM and Johnson, LA}, title = {APOE4 alters the lipid droplet proteome and modulates droplet dynamics.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.12.16.628710}, pmid = {39763832}, issn = {2692-8205}, support = {R01 AG081421/AG/NIA NIH HHS/United States ; }, abstract = {Excess lipid droplet (LD) accumulation is associated with several pathological states, including Alzheimer's disease (AD). However, the mechanism(s) by which changes in LD composition and dynamics contribute to pathophysiology of these disorders remains unclear. Apolipoprotein E (ApoE) is a droplet associated protein with a common risk variant (E4) that confers the largest increase in genetic risk for late-onset AD. E4 is associated with both increased neuroinflammation and excess LD accumulation. In the current study, we sought to quantitatively profile the lipid and protein composition of LDs between the 'neutral' E3 and risk variant E4, to gain insight into potential LD-driven contributions to AD pathogenesis. Targeted replacement mice expressing human E3 or E4 were injected with saline or lipopolysaccharide (LPS), and after 24 hours, hepatic lipid droplets were isolated for proteomic and lipidomic analyses. Lipidomics revealed a shift in the distribution of glycerophospholipids in E4 LDs with a concomitant increase in phosphatidylcholine species, and overall, the baseline profile of E4 LDs resembled that of the LPS-treated groups. Quantitative proteomics showed that LDs from E4 mice are enriched for proteins involved in protein/vesicle transport but have decreased levels of proteins involved in fatty acid β-oxidation. Interestingly, proteins associated with LDs showed substantial overlap with previously published lists of AD postmortem tissue and microglia 'omics studies, suggesting a potential role for LDs in modulating AD risk or progression. Given this, we exposed primary microglia from the same E3 or E4 mice to exogenous lipid, inflammatory stimulation, necroptotic N2A cells (nN2A), or a combination of treatments to evaluate LD formation and its impact on the cells' immune state. Microglia from E4 mice accumulated more LDs in every condition tested - at baseline and following addition of fatty acids, LPS stimulation, or nN2As. E4 microglia also secreted significantly more cytokines (TNF, IL-1β, IL-10) than E3 microglia in the control, oleic acid, and nN2A treatment conditions, yet showed a blunted response to LPS. In sum, these results suggest that E4 microglia accumulate more LDs compared to E3 microglia and that E4 is associated with a basal LD composition that resembles a pro-inflammatory cell. Together with the high overlap of the LD proteome with established AD-associated datasets, these data further support the idea that alterations in LD dynamics, particularly within microglia, may contribute to the increased risk for AD associated with APOE4 .}, }
@article {pmid39763821, year = {2024}, author = {Kline-Schoder, AR and Tsitsos, FN and Batts, AJ and DiBenedetto, MR and Liu, K and Bae, S and Konofagou, EE}, title = {Response of Serum-isolated Extracellular Vesicles to Focused Ultrasound Blood-Brain Barrier Opening.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.12.17.629012}, pmid = {39763821}, issn = {2692-8205}, abstract = {The blood-brain barrier (BBB) limits drug delivery to the brain and the movement of neurological biomarkers between the brain and blood. Focused ultrasound-mediated blood-brain barrier opening (FUS-BBBO) noninvasively opens the BBB, allowing increased molecular transport to and from the brain parenchyma. Despite being initially developed as a drug delivery method, FUS-BBBO has shown promise both as a neuroimmunotherapeutic modality, and as a way of improving neurological disease diagnosis via amplification of disease biomarker circulation. Recently, the role of extracellular vesicles (EVs) in modulating the neuroimmune system and in improving biomarker detection has sparked research interest. However, despite their potential role in modulating FUS-BBBO-induced neuroimmunotherapy and their ability to improve biomarker specificity after treatment, the EV response to FUS-BBBO had not been extensively characterized prior to this study. In this study, we investigated the effect of FUS-BBBO on EV concentration and content in the serum of mice and Alzheimer's Disease (AD) patients. We observed a 164% increase in murine EV concentration one hour after treatment, as well as an increase in EV RNA associated with FUS-BBBO neuroimmunotherapy. Patient EV concentration also increased one hour after treatment and was dependent on the volume of BBB opening three days post-treatment. Furthermore, EV isolation was found to significantly enhance the amplification of AD biomarker detection by FUS-BBBO. Overall, we present the first evidence of altered murine and AD patient EV concentration and content in response to FUS-BBBO, providing evidence of EVs' role within FUS-BBBO neuroimmunotherapy as well as their utility in improving FUS-BBBO biomarker amplification.}, }
@article {pmid39763748, year = {2024}, author = {Dunlop, BW and Cha, J and Mayberg, HS and Choi, KS and Edward Craighead, W and MahmoudianDehkordi, S and Bhattacharyya, S and John Rush, A and Kaddurah-Daouk, R}, title = {Association of Bile Acids with Connectivity of Executive Control and Default Mode Networks in Patients with Major Depression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.12.20.629637}, pmid = {39763748}, issn = {2692-8205}, abstract = {OBJECTIVE: Bile acids may contribute to pathophysiologic markers of Alzheimer's disease, including disruptions of the executive control network (ECN) and the default mode network (DMN). Cognitive dysfunction is common in major depressive disorder (MDD), but whether bile acids impact these networks in MDD patients is unknown.
METHODS: Resting state functional magnetic resonance imaging (fMRI) scans and blood measures of four bile acids from 74 treatment-naïve adults with MDD were analyzed. Dorsolateral prefrontal cortex (DLPFC) seeds were used to examine connectivity of the ECN and posterior cingulate cortex (PCC) seeds were used for the DMN. Using a whole-brain analysis, the functional connectivity of these seeds was correlated with serum levels chenodeoxycholic acid (CDCA) and its bacterially-derived secondary bile acid, lithocholic acid (LCA).
RESULTS: CDCA levels were strongly and inversely correlated with connectivity between DLPFC regions of the ECN (R [2] = .401, p<.001). LCA levels were strongly and positively correlated with connectivity of the DLPFC and left inferior temporal cortex of the ECN (R [2] =.263, p<.001). The LCA/CDCA ratio was strongly and positively correlated with connectivity of the DLPFC with two components of the ECN: bilateral inferior temporal cortex and the left superior and inferior parietal lobules (all R [2] >.24, all p<.001). For the DMN, the LCA/CDCA ratio was strongly and negatively correlated with connectivity of the PCC with multiple bilateral insula regions (all R [2] >0.25, all p<.001).
CONCLUSIONS: The relationship between LCA and CDCA levels and functional connectivity of the ECN and DMN suggests potential shared pathophysiologic processes between Alzheimer's disease and MDD.}, }
@article {pmid39763617, year = {2024}, author = {Jodeiri Farshbaf, M and Matos, TA and Niblo, K and Alokam, Y and Ables, JL}, title = {STZ-induced hyperglycemia differentially influences mitochondrial distribution and morphology in the habenulointerpeduncular circuit.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1432887}, pmid = {39763617}, issn = {1662-5102}, support = {P30 DK020541/DK/NIDDK NIH HHS/United States ; R01 DA059455/DA/NIDA NIH HHS/United States ; }, abstract = {INTRODUCTION: Diabetes is a metabolic disorder of glucose homeostasis that is a significant risk factor for neurodegenerative diseases, such as Alzheimer's disease, as well as mood disorders, which often precede neurodegenerative conditions. We examined the medial habenulainterpeduncular nucleus (MHb-IPN), as this circuit plays crucial roles in mood regulation, has been linked to the development of diabetes after smoking, and is rich in cholinergic neurons, which are affected in other brain areas in Alzheimer's disease.
METHODS: This study aimed to investigate the impact of streptozotocin (STZ)-induced hyperglycemia, a type 1 diabetes model, on mitochondrial and lipid homeostasis in 4% paraformaldehyde-fixed sections from the MHb and IPN of C57BL/6 J male mice, using a recently developed automated pipeline for mitochondrial analysis in confocal images. We examined different time points after STZ-induced diabetes onset to determine how the brain responded to chronic hyperglycemia, with the limitation that mitochondria and lipids were not examined with respect to cell type or intracellular location.
RESULTS: Mitochondrial distribution and morphology differentially responded to hyperglycemia depending on time and brain area. Six weeks after STZ treatment, mitochondria in the ventral MHb and dorsal IPN increased in number and exhibited altered morphology, but no changes were observed in the lateral habenula (LHb) or ventral IPN. Strikingly, mitochondrial numbers returned to normal dynamics at 12 weeks. Both blood glucose level and glycated hemoglobin (HbA1C) correlated with mitochondrial dynamics in ventral MHb, whereas only HbA1C correlated in the IPN. We also examined lipid homeostasis using BODIPY staining for neutral lipids in this model given that diabetes is associated with disrupted lipid homeostasis. BODIPY staining intensity was unchanged in the vMHb of STZ-treated mice but increased in the IPN and VTA and decreased in the LHb at 12 weeks. Interestingly, areas that demonstrated changes in mitochondria had little change in lipid staining and vice versa.
DISCUSSION: This study is the first to describe the specific impacts of diabetes on mitochondria in the MHb-IPN circuit and suggests that the cholinergic MHb is uniquely sensitive to diabetesinduced hyperglycemia. Further studies are needed to understand the functional and behavioral implications of these findings.}, }
@article {pmid39763548, year = {2024}, author = {Wang, L and Venkatesh, S and Morris, M and Li, M and Srivastava, R and Visweswaran, S and Lopez, O and Xia, Z and Cai, T}, title = {Stratification of Alzheimer's Disease Patients Using Knowledge-Guided Unsupervised Latent Factor Clustering with Electronic Health Record Data.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.12.23.24319588}, pmid = {39763548}, abstract = {BACKGROUND: People with Alzheimer's disease (AD) exhibit varying clinical trajectories. There is a need to predict future AD-related outcomes such as morbidity and mortality using clinical profile at the point of care.
OBJECTIVE: To stratify AD patients based on baseline clinical profiles (up to two years prior to AD diagnosis) and update the model after AD diagnosis to prognosticate future AD-related outcomes.
METHODS: Using the electronic health record (EHR) data of a large healthcare system (2011-2022), we first identified patients with ≥1 diagnosis code for AD or related dementia and applied a validated unsupervised phenotyping algorithm to assign AD diagnosis status. Next, we applied an unsupervised latent factor clustering approach, guided by knowledge graph embeddings of relevant EHR features up to the baseline, to cluster patients into two groups at AD diagnosis. We then prognosticated the risk of two readily ascertainable and clinically relevant AD-related outcomes (i.e., nursing home admission indicating greater need for assistance and mortality), adjusting for baseline confounders (e.g., age, gender, race, ethnicity, healthcare utilization, and comorbidities). For patients remaining at risk one year post-diagnosis, we updated their group membership and repeated the prognostication.
RESULTS: We stratified 16,411 algorithm-identified AD patients into two groups based on their baseline clinical profiles (41% Group 1, 59% Group 2). Patients in Group 1 were marginally older at AD diagnosis (age Mean [SD]: 81.4 [9.3] vs 81.0 [8.7], p =.007), exhibited greater comorbidity burden (Elixhauser comorbidity index Mean [SD]: 11.3 [10.3] vs 7.5 [8.6], p <.0001), and more frequently received AD-related medications (47.7% vs 40.9%, p <.0001) than those in Group 2. Compared to Group 1, Group 2 had a lower risk of nursing home admission (HR [95% CI]=0.804 [0.765, 0.844], p <.001), while the two groups had similar mortality risk (HR [95% CI]=1.008 [0.963, 1.056], p =.733). One year after AD diagnosis, 12,606 patients remained at risk (45.7% Group 1, 54.3% Group 2). Consistent with baseline findings, Group 2 had a lower risk of nursing home admission than (HR [95% CI]=0.815 [0.766, 0.868], p <.001) and similar mortality risk as (HR [95% CI]=0.977 [0.922, 1.035], p =0.430) Group 1 in the updated model.
CONCLUSIONS: It is feasible to stratify patients based on readily available clinical profiles before AD diagnosis and crucially to update the model one year after diagnosis to effectively prognosticate future AD-related outcomes.
SHORT ABSTRACT: Prognostication for people with Alzheimer's disease (AD) at the point of care could improve clinical management. Applying a novel unsupervised latent factor clustering approach guided by knowledge graph embeddings of relevant clinical features from electronic health records, we stratified 16,411 AD patients into two groups at diagnosis and prognosticated their risk of AD-related outcomes (i.e., nursing home admission, mortality), adjusting for baseline confounders. To reflect real-world evolution in clinical trajectories, we updated patient stratification for 12,606 AD patients remaining at risk 1-year post-diagnosis and repeated prognostication. At both timepoints, one group had a higher nursing home admission risk and exhibited characteristics suggesting greater symptom burden, but the mortality risk remained comparable between groups. This study supports that patient stratification can enable outcome prognosis for AD patients. While baseline prognostication can guide early treatment and tailored management, dynamic prognostication may inform more timely interventions to improve long-term outcomes.}, }
@article {pmid39762936, year = {2025}, author = {Carles, A and Freyssin, A and Guehairia, S and Reguero, T and Vignes, M and Hirbec, H and Rubinstenn, G and Maurice, T}, title = {Neuroprotection by chronic administration of Fluoroethylnormemantine (FENM) in mouse models of Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {7}, pmid = {39762936}, issn = {1758-9193}, support = {0682//SATT AXLR/ ; 0682//SATT AXLR/ ; 0682//SATT AXLR/ ; 0682//SATT AXLR/ ; 0682//SATT AXLR/ ; 0682//SATT AXLR/ ; 0682//SATT AXLR/ ; 0682//SATT AXLR/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; *Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; Mice ; *Peptide Fragments/toxicity ; Memantine/pharmacology/administration & dosage/pharmacokinetics ; Amyloid beta-Protein Precursor/genetics ; Male ; Mice, Inbred C57BL ; Hippocampus/drug effects/metabolism ; }, abstract = {BACKGROUND: Fluoroethylnormemantine (FENM), a new Memantine (MEM) derivative, prevented amyloid-β[25-35] peptide (Aβ25-35)-induced neurotoxicity in mice, a pharmacological model of Alzheimer's disease (AD) with high predictive value for drug discovery. Here, as drug infusion is likely to better reflect drug bioavailability due to the interspecies pharmacokinetics variation, we analyzed the efficacy of FENM after chronic subcutaneous (SC) infusion, in comparison with IP injections in two AD mouse models, Aβ25-35-injected mice and the transgenic APPswe/PSEN1[∂E9] (APP/PS1) line.
METHODS: In Aβ25-35-treated mice, FENM was infused at 0.03-0.3 mg/kg/day during one week after Aβ25-35 injection. For comparison, FENM and MEM were administered IP daily at 0.03-0.3 mg/kg. In 10-month-old APP/PS1 mice, FENM was administered during four weeks by daily IP injections at 0.3 mg/kg or chronic SC infusion at 0.1 mg/kg/day. Memory deficits, spatial working memory and recognition memory, were analysed. Markers of neuroinflammation, apoptosis, oxidative stress, and amyloid burden in APP/PS1 mice, were quantified. Markers of synaptic plasticity such as PSD-95 and GluN2A/B/D subunits expression in hippocampus homogenates or synaptosomes were quantified in Aβ25-35-treated mice and synaptic long-term potentiation (LTP) in hippocampal slices was analysed in APP/PS1 mice.
RESULTS: Deficits in spontaneous alternation and object recognition in Aβ25-35 mice were prevented by infused FENM at all doses tested. Similar effects were observed with the daily FENM or MEM treatments. Animals infused with 0.1 mg/kg/day FENM showed prevention of Aβ25-35-induced neuroinflammation, oxidative stress and apoptosis. FENM infusion restored Aβ25-35-induced alterations in synaptosomal PSD-95, GluN2A and P-GluN2B levels. GluN2D levels were unchanged whatever the treatment. In APP/PS1 mice, FENM infused or administered IP alleviated spontaneous alternation deficits, neuroinflammation, increases in Aβ1-40/Aβ1-42 and hippocampal LTP alteration.
CONCLUSION: These data confirmed the neuroprotective potential of FENM in the pharmacological Aβ25-35 and transgenic APP/PS1 mouse models of AD, with a superiority to MEM, and showed that the drug can be efficiently infused chronically.}, }
@article {pmid39761836, year = {2025}, author = {Mo, Y and He, X and Cui, H and Cheng, Y and Zhou, M and Cui, X and Zhang, T}, title = {Gut microbiota: A new key of understanding for Panax notoginseng against multiple disorders and biotransformation.}, journal = {Journal of ethnopharmacology}, volume = {341}, number = {}, pages = {119306}, doi = {10.1016/j.jep.2024.119306}, pmid = {39761836}, issn = {1872-7573}, mesh = {Humans ; *Gastrointestinal Microbiome/drug effects ; *Panax notoginseng ; *Biotransformation ; Animals ; Drugs, Chinese Herbal/pharmacology ; }, abstract = {Panax notoginseng (Burkill) F.H.Chen(P. notoginseng) has been widely used as an herbal medicine for reducing swelling, relieving pain, promoting blood circulation and stopping bleeding, with notable therapeutic effects on obesity, liver diseases, colitis, Alzheimer's disease, chronic kidney disease and other diseases.
AIM OF THE STUDY: This review highlighted the close link and bidirectional effects between P. notoginseng and gut microbiota, with the ultimate aim of providing new insights into the potential mechanisms of pharmacological effects of P. notoginseng in the treatment of different diseases and PNS transformation.
MATERIALS AND METHODS: By means of some reputable databases (PubMed, China National Knowledge Infrastructure (CNKI), Google Scholar, etc.), we screened the published articles related to P. notoginseng from 1998 to 2024, including original research, clinical trials and review on raw materials and chemical constituents of P. notoginseng. Then, we employed the keywords "gut microbiota", "intestinal microbiota", "gut biotransformation" and "intestinal" to exclude the articles that do not in line with our topic. Plant information was obtained from www.worldfloraonline.org using "Panax notoginseng (Burkill) F.H.Chen" as the keyword.
RESULTS: P. notoginseng elevated certain probiotics including Lactobacillus, Bifidobacterium and Akkermansia, while simultaneously reducing pathogenic bacteria such as Prevotellaceae, Enterococcus, Enterobacter and Helicobacter, to fight various diseases. Meanwhile, considering to the low oral bioavailability and degradable properties of Panax notoginseng saponin (PNS), gut microbiota converted it into protopanaxatriol(PPT) and protopanaxadiol(PPD) mainly through deglycosylation reactions to enhance the bioactivity.
CONCLUSION: Increasing evidences suggest that gut microbiota may play a vital role for P. notoginseng exerting on beneficial effects on the prevention and treatment of metabolic disorders, liver diseases, neurological diseases, chronic kidney diseases, vascular diseases, colitis, and other diseases, as well as for biotransformation of P. notoginseng.}, }
@article {pmid39761259, year = {2025}, author = {Policarpo, R and Wolfs, L and Martínez-Montero, S and Vandermeulen, L and Royaux, I and Van Peer, G and Mestdagh, P and De Strooper, B and Sierksma, A and d'Ydewalle, C}, title = {The MIR-NAT MAPT-AS1 does not regulate Tau expression in human neurons.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0314973}, pmid = {39761259}, issn = {1932-6203}, mesh = {*tau Proteins/metabolism/genetics ; Humans ; *Neurons/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Gene Expression Regulation ; Cell Line, Tumor ; MicroRNAs/genetics/metabolism ; RNA, Antisense/genetics ; Brain/metabolism ; RNA, Messenger/genetics/metabolism ; }, abstract = {The MAPT gene encodes Tau protein, a member of the large family of microtubule-associated proteins. Tau forms large insoluble aggregates that are toxic to neurons in several neurological disorders, and neurofibrillary Tau tangles represent a key pathological hallmark of Alzheimer's disease (AD) and other tauopathies. Lowering Tau expression levels constitutes a potential treatment for AD but the mechanisms that regulate Tau expression at the transcriptional or translational level are not well understood. Natural antisense transcripts (NATs) are a particular class of long non-coding RNAs (lncRNAs) that can regulate expression of their overlapping protein-coding genes at the epigenetic, transcriptional, or translational level. We and others identified a long non-coding RNA associated with the MAPT gene, named MAPT antisense 1 (MAPT-AS1). We confirmed that MAPT-AS1 is expressed in neurons in human post mortem brain tissue. To study the role of MAPT-AS1 on MAPT expression regulation, we modulated the expression of this lncRNA in human neuroblastoma cell lines and in human induced pluripotent stem cell (iPSC) derived neurons. In contrast to previous reports, we observed no changes on MAPT mRNA or Tau protein levels upon modulation of MAPT-AS1 levels in these cellular models. Our data suggest that MAPT-AS1 does not regulate Tau expression levels in human neurons in vitro. Thus, MAPT-AS1 does not represent a valuable therapeutic target to lower Tau expression in patients affected by tauopathies including AD.}, }
@article {pmid39760900, year = {2025}, author = {Chew, CS and Lee, JY and Ng, KY and Koh, RY and Chye, SM}, title = {Resilience mechanisms underlying Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {86}, pmid = {39760900}, issn = {1573-7365}, mesh = {Animals ; Humans ; *Alzheimer Disease/genetics/metabolism/pathology/psychology ; Brain/metabolism/pathology ; Brain-Derived Neurotrophic Factor/genetics/metabolism ; *Resilience, Psychological ; }, abstract = {Alzheimer's disease (AD) consists of two main pathologies, which are the deposition of amyloid plaque as well as tau protein aggregation. Evidence suggests that not everyone who carries the AD-causing genes displays AD-related symptoms; they might never acquire AD as well. These individuals are referred to as non-demented individuals with AD neuropathology (NDAN). Despite the presence of extensive AD pathology in their brain, it was found that NDAN had better cognitive function than was expected, suggesting that they were more resilient (better at coping) to AD due to differences in their brains compared to other demented or cognitively impaired patients. Thus, identification of the mechanisms underlying resilience is crucial since it represents a promising therapeutic strategy for AD. In this review, we will explore the molecular mechanisms underpinning the role of genetic and molecular resilience factors in improving resilience to AD. These include protective genes and proteins such as APOE2, BDNF, RAB10, actin network proteins, scaffolding proteins, and the basal forebrain cholinergic system. A thorough understanding of these resilience mechanisms is crucial for not just comprehending the development of AD but may also open new treatment possibilities for AD by enhancing the neuroprotective pathway and targeting the pathogenic process.}, }
@article {pmid39760845, year = {2025}, author = {Baranowski, R and Amschler, J and Wittwer, D and Arendash, GW}, title = {Memory enhancement by transcranial radiofrequency wave treatment occurs without appreciably increasing brain temperature.}, journal = {Physical and engineering sciences in medicine}, volume = {}, number = {}, pages = {}, pmid = {39760845}, issn = {2662-4737}, support = {9R44AG073096-02A1//National Institute of Health/ ; }, abstract = {We have previously shown in small studies that full brain Transcranial Radiofrequency Wave Treatment (TRFT) to subjects with Alzheimer's Disease could stop and reverse their cognitive decline. An 8-emitter head device, the "MemorEM", was used in these studies to provide TRFT at 915 MHz frequency and power level of 1.6 W/kg Specific Absorption Rate (SAR) during daily 1-hour treatments. Although no deleterious side effects during up to 2.5 years of treatment were reported, it is important to rule out the possibility that brain heating will occur during TRFT in humans at a higher power level of 4.0 W/kg SAR, which is anticipated for future clinical testing in order to increase treatment intensity/efficacy to deep sub-cortical areas. To examine if brain heating occurs during a single 1-hour treatment at 4 W/kg SAR, a hollow human head phantom filled with brain-analogous gel and with an attached MemorEM head device was utilized. Brain temperatures were taken at 64 specific coordinates within the brain gel before and immediately following one-hour of TRFT. Results revealed none of the 64 sites having a temperature increase after TRFT of 1 °C or more. Indeed, 45 of the 64 sites exhibited a temperature rise of less than 0.5 °C, with just three sites exhibiting an increase between 0.75 and 0.9 °C. These results demonstrate that TRFT in a human head phantom that mimics the electromagnetic properties of the human head, does not appreciably increase brain temperature (i.e., is non-thermal) at 915 MHz frequency and 4 W/kg SAR power level. Thus, TRFT would appear to be safe at 4 W/kg for long-term daily treatments.}, }
@article {pmid39760808, year = {2025}, author = {Huang, C and Liu, Y and Wang, S and Xia, J and Hu, D and Xu, R}, title = {From Genes to Metabolites: HSP90B1's Role in Alzheimer's Disease and Potential for Therapeutic Intervention.}, journal = {Neuromolecular medicine}, volume = {27}, number = {1}, pages = {6}, pmid = {39760808}, issn = {1559-1174}, support = {2022YQB041//Scientific research foundation for young doctors of the Second Affiliated Hospital, AMU/ ; }, mesh = {*Alzheimer Disease/genetics/metabolism/drug therapy ; Animals ; Humans ; Mice ; *Hippocampus/metabolism ; *HSP90 Heat-Shock Proteins/genetics/biosynthesis ; *Disease Models, Animal ; *Machine Learning ; *Biomarkers ; Male ; Amyloid beta-Peptides/metabolism/genetics ; MicroRNAs/genetics/biosynthesis ; Gene Expression Regulation/drug effects ; Mice, Transgenic ; Aged ; Cell Survival/drug effects ; Female ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) is a prototypical neurodegenerative disorder, predominantly affecting individuals in the presenile and elderly populations, with an etiology that remains elusive. This investigation aimed to elucidate the alterations in anoikis-related genes (ARGs) in the AD brain, thereby expanding the repertoire of biomarkers for the disease. Using publically available gene expression data for the hippocampus from both healthy and AD subjects, differentially expressed genes (DEGs) were identified. Subsequent intersection with a comprehensive list of 575 ARGs yielded a subset for enrichment analysis. Machine learning algorithms were employed to identify potential biomarker, which was validated in an AD animal model. Additionally, gene set enrichment analysis was conducted on the biomarker and its interacting genes and microRNAs were predicted through online databases. To assess its biological functions, the expression of the marker was suppressed in an in vitro model to examine cell viability and inflammation-related indicators. Furthermore, following treatment with the inhibitor, the dysregulated metabolites in the hippocampus of the model mice were evaluated. Forty-seven ARGs were ultimately identified, with HSP90B1 emerging as a central marker. HSP90B1 was found to be significantly up-regulated in AD hippocampal samples and its inhibition conferred increased cell viability and reduced levels of inflammatory factors in amyloid β-protein (Aβ)-treated cells. A total of 24 differentially expressed metabolites were confidently identified between model mice and those with low HSP90B1 expression, with bioinformatics analysis shedding light on the molecular underpinnings of HSP90B1's involvement in AD. Collectively, these findings may inform novel insights into the pathogenesis, mechanisms, or therapeutic strategies for AD.}, }
@article {pmid39760610, year = {2025}, author = {Sabatini, S and Hawes, F and Eluigwe, K and Tang, EYH}, title = {Identifying Challenges Related to the Management of Comorbidities in People with Dementia in Residential Care: Expert Delphi Consensus Exercise.}, journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society}, volume = {}, number = {}, pages = {7334648241309734}, doi = {10.1177/07334648241309734}, pmid = {39760610}, issn = {1552-4523}, abstract = {Improving early detection, management, and treatment of comorbid conditions to dementia in residential care could slow down cognitive and functional decline, and increase residents' quality of life. We conducted a Delphi study comprising three rounds (two surveys and an interview) to identify the most difficult dementia comorbidities to deal with in residential care and related issues. Participants were 15 UK-based experts including academics, residential care workers, geriatricians, and neuropsychologists. In the first-round of the Delphi, experts mentioned 15 comorbid health conditions to dementia and 19 issues. In the following rounds of the Delphi mental illnesses, delirium, and sensory impairments were identified as the most difficult comorbidities to dementia to deal with. Medication management, symptom management, shortage of staff, lack of training among staff, and limited resources from the broader healthcare system were identified as the most difficult issues when dealing with dementia comorbidities.}, }
@article {pmid39760003, year = {2025}, author = {Qin, G and Cui, W and Song, R}, title = {Shen Zhi Ling oral liquid improve neuroinflammation against Alzheimer's disease via the PI3K/Akt pathway.}, journal = {3 Biotech}, volume = {15}, number = {1}, pages = {29}, pmid = {39760003}, issn = {2190-572X}, abstract = {The etiology and pathogenesis of Alzheimer's disease (AD) are complex, and currently, no comprehensive treatment measures exist. In this study, we initially utilized ultra-high-performance liquid chromatography with quadrupole orbitrap mass spectrometry (UHPLC-QE-MS) to profile the bioactive constituents of SZLOL present in the bloodstream. Subsequent Y-maze experimental data demonstrated that SZLOL could ameliorate short-term memory deficits in APP/PS1 mice. Furthermore, micro-positron emission tomography (Micro-PET) experiments revealed that SZLOL enhanced glucose metabolism in the cerebral cortex of the mice. To model AD in vitro, we utilized Aβ42-induced SH-SY5Y cells and assessed the effects of SZLOL-containing serum on cell growth and migration using immunofluorescence and wound-healing assays. Both in vivo and in vitro Western blot analyses indicated that SZLOL and SZLOL-containing serum were capable of activating the PI3K/Akt signaling pathway, which modulates the expression of inflammatory mediators. In future studies, we will validate our findings in more animal and cell models.}, }
@article {pmid39759457, year = {2024}, author = {Ahmad, SR and Zeyaullah, M and Khan, MS and AlShahrani, AM and Altijani, AAG and Ali, H and Dawria, A and Mohieldin, A and Alam, MS and Mohamed, AOA}, title = {Pharmacogenomics for neurodegenerative disorders - a focused review.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1478964}, pmid = {39759457}, issn = {1663-9812}, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by the progressive degeneration of neuronal structure and function, leading to severe cognitive and motor impairments. These conditions present significant challenges to healthcare systems, and traditional treatments often fail to account for genetic variability among patients, resulting in inconsistent therapeutic outcomes. Pharmacogenomics aims to tailor medical treatments based on an individual's genetic profile, thereby improving therapeutic efficacy and reducing adverse effects. This focused review explores the genetic factors influencing drug responses in neurodegenerative diseases and the potential of pharmacogenomics to revolutionize their treatment. Key genetic markers, such as the APOE ε4 allele in AD and the CYP2D6 polymorphisms in PD, are highlighted for their roles in modulating drug efficacy. Additionally, advancements in pharmacogenomic tools, including genome-wide association studies (GWAS), next-generation sequencing (NGS), and CRISPR-Cas9, are discussed for their contributions to personalized medicine. The application of pharmacogenomics in clinical practice and its prospects, including ethical and data integration challenges, are also examined.}, }
@article {pmid39759399, year = {2024}, author = {Chen, G and Xi, E and Gu, X and Wang, H and Tang, Q}, title = {The study on cuproptosis in Alzheimer's disease based on the cuproptosis key gene FDX1.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1480332}, pmid = {39759399}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory and cognitive impairments. Previous studies have shown neuronal death in the brains of AD patients, but the role of cuproptosis and its associated genes in AD neurons remains unclear.
METHODS: Intersection analysis was conducted using the AD transcriptome dataset GSE63060, neuron dataset GSE147528, and reported cuproptosis-related genes to identify the cuproptosis key gene FDX1 highly expressed in AD. Subsequently, cell experiments were performed by treating SH-SY5Y cells with Aβ25-35 to establish AD cell model. The real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blotting (WB) assays were employed to detect the expression levels of FDX1, DLAT, and DLST. Cell proliferation was analyzed by counting Kit-8 (CCK8), mitochondrial ROS levels were analyzed using flow cytometry. shRNA was used to downregulate FDX1 expression, followed by repetition of the aforementioned experiments. Clinical experiments utilized qPCR to detect FDX1 mRNA levels in peripheral venous blood of patients, and analyzed FDX1 expression differences in different APOE genotypes of AD patients. Finally, a protein-protein interaction (PPI) network of FDX1 was constructed based on the GeneMANIA database, immune infiltration analysis was conducted using R language, and transcription factors prediction for FDX1 was performed based on the ENCODE database.
RESULTS: The cuproptosis key gene FDX1 showed significantly higher expression in peripheral blood and neuron models of AD compared to non-AD individuals, with significantly higher expression in APOE ε4/ε4 genotype than other APOE genotype of AD patients. Knockdown of FDX1 expression reduced the lipidation levels of DLAT and DLST in neurons, alleviated ROS accumulation in mitochondria, improved cell viability, and mitigated cuproptosis. Immune infiltration analysis results indicated a high enrichment of peripheral blood γδ-T lymphocytes in AD, and FDX1 was significantly associated with the infiltration of four immune cells and may be regulated by three transcription factors.
CONCLUSION: The cuproptosis key gene FDX1 is highly expressed in AD and may promote cuproptosis in AD neurons by regulating the lipidation levels of DLAT and DLST, thereby participating in the onset and development of AD. This provides a potential target for the diagnosis and treatment of AD.}, }
@article {pmid39758929, year = {2025}, author = {Shakir, SA and Rashid, U and Marryum, and Fatima, N and Ejaz, SA and Fayyaz, A and Ullah, MZ and Saeed, A and Khan, A and Al Harrasi, A and Mumtaz, A}, title = {Exploration of novel triazolo-thiadiazine hybrids of deferasirox as multi-target-directed anti-neuroinflammatory agents with structure-activity relationship (SAR): a new treatment opportunity for Alzheimer's disease.}, journal = {RSC advances}, volume = {15}, number = {1}, pages = {101-118}, pmid = {39758929}, issn = {2046-2069}, abstract = {It is believed that inflammation influences several physiological processes, including the function of the central nervous system. Moreover, the impairment of lipid mechanisms/pathways is associated with neurodegenerative disorders and onset of Alzheimer's disease (AD). AD is a chronic neurodegenerative disease representing the major cause of dementia worldwide. In this case, the overexpression of different pharmacological targets has been confirmed to address neuronal inflammation and AD, with acetylcholinesterase (AChE), monoamine oxidase-B (MAO-B), cyclooxygenase-2 (COX-2) and 5-lipoxygenase (LOX-5) being the most explored targets. Currently, the available treatments are only capable of alleviating the symptoms and not capable of delivering disease-modifying effects. Thus, the current research objective is to synthesize triazolo-thiadiazine derivatives of the deferasirox drug as multi-target compounds that could concurrently inhibit ChEs, MAOs, LOX-5 and COX-2. The synthesized derivatives were confirmed by FTIR, [1]H NMR, [13]C NMR and DEPT-135 spectroscopic techniques. During in vitro investigations, compound 11 was found to be the most potent inhibitor of all the targeted enzymes. Briefly, this compound exhibited inhibitory values (IC50 ± SEM) of 0.31 ± 0.16, 0.13 ± 0.16 and 0.94 ± 0.16 μM against AChE, MAO-B and COX-2, respectively, suggesting that it is a lead molecule for the synthesis of more potential multi-targeted inhibitors. Several compounds, such as compound 9 and 13, showed dual inhibition potential in comparison to standard drugs. Furthermore, molecular docking analysis was performed to validate the in vitro results, where the potent compounds showed some significant interactions with the key amino acids present in the active site of the targeted enzymes. Furthermore, molecular dynamics (MD) simulation data and physicochemical properties supported deferasirox-substituted triazolo-thiadiazine as a promising horizon for the discovery and development of new molecules to treat multifactorial diseases associated with neuro-inflammation, such as AD.}, }
@article {pmid39758348, year = {2024}, author = {Tu, W and Xu, F and Li, J and Tian, X and Cao, L and Wang, L and Qu, Y}, title = {Studying targeted oxidation in diabetic cognitive dysfunction based on scientometrics analysis: research progress of natural product approaches.}, journal = {Frontiers in endocrinology}, volume = {15}, number = {}, pages = {1445750}, pmid = {39758348}, issn = {1664-2392}, mesh = {Animals ; Humans ; *Antioxidants/therapeutic use/pharmacology ; *Bibliometrics ; *Biological Products/therapeutic use/pharmacology ; *Cognitive Dysfunction/drug therapy/metabolism ; *Diabetes Complications/drug therapy/metabolism ; *Oxidative Stress/drug effects ; }, abstract = {PURPOSE: The aim is to provide new insights for researchers studying the pathogenesis of diabetic cognitive dysfunction and promoting the wider use of natural products in their treatment.
METHOD: First, the Web of Science Core Collection was selected as the data source for a computerized literature search on oxidative stress and diabetic cognitive dysfunction (DCD). Next, Biblimetrix and VOSviewer performed statistical analysis focusing on publication countries, institutions, authors, research hotspots, and emerging directions in the field. Then, through the analysis of keywords and key articles, the forefront of the field is identified. Finally, we discussed the pathogenesis of DCD, the influence of oxidative stress on DCD and the antioxidant effect of natural products on DCD.
RESULT: 293 valid papers were obtained. Bibliometrics showed that oxidative stress, diabetes, Alzheimer's disease (AD), cognitive decline, insulin resistance and quercetin were the key words of the symbiotic network.
CONCLUSION: The antioxidant effects of natural products in improving DCD have been extensively studied in preclinical studies, providing potential for their treatment in DCD, but their evaluation in clinical trials is currently uncommon.}, }
@article {pmid39758321, year = {2024}, author = {Li, R and Wang, H and Wang, Q and Zhang, Z and Wang, L}, title = {Acid-assisted polysaccharides extracted from Asparagus cochinchinensis protect against Alzheimer's disease by regulating the microbiota-gut-brain axis.}, journal = {Frontiers in nutrition}, volume = {11}, number = {}, pages = {1496306}, pmid = {39758321}, issn = {2296-861X}, abstract = {In this study, an acid-assisted extraction strategy was used to extract a novel polysaccharide (ACP) from Asparagus cochinchinensis, after which this polysaccharide was purified and subjected to extensive characterization. ACP was determined to have an average molecular weight of 15,580 Da in structural characterization studies, and it was found to primarily consist of glucose, galactose, L-fucose, and fructose at an 82.14:12.23:2.61:2.49 ratio. Trace amounts of xylose, arabinose, and rhamnose were also detected in ACP preparations at a 0.48:0.04:0.02 ratio. GC-MS analyses identified eight different sugar linkages within ACP, including Glcp-(1→, →2)-Glcp-(1→, →6)-Glcp-(1→, →4)-Glcp-(1→, →3, 4)-Glcp-(1→, →2,4) -Galp-(1→, →4,6)-Galp-(1→, and →3,4,6)-Galp-(1 → linkages present at 23.70:1.30:3.55:50.77:6.91:1.10:11.50:1.18 molar percent ratios. One-dimensional NMR, two-dimensional NMR, and methylation analyses ultimately revealed that the polysaccharide is mainly composed of →4)-β-D-Glcp-(1 → and a small amount→4,6)-α-D-Galp-(1 → and →3,4)-α-D-Glcp-(1 → and so on. Branched chain is mainly composed of α-D-Glcp-(1 → 4)-β-D-Glcp-(1 → connected to the sugar residues α-D-Glcp-(1 → 4)-β-D-Glcp-(1 → O-4 position or sugar residues of α-D-Glcp-(1 → 4)-β-D-Glcp-(1 → O-3 position. ACP treatment in SAMP8 mice was associated with reductions in oxidative stress and brain pathology together with enhanced cognitive function. ACP treated SAMP8 mice also presented with increases in Bacteroidota abundance and reduced Firmicutes, Patescibacteria, Actinobacteriota, and Campilobacterota abundance. Thus, ACP can prevent Alzheimer's disease by modulating the microbe-gut-brain axis.}, }
@article {pmid39758054, year = {2025}, author = {Chiu, YL and Yan, SH and Fan, YT and Chang, CF and Hung, RW and Liu, YC and Yang, TO and Chuang, YF}, title = {Aβ-reactive T cell polyfunctionality response as a new biomarker for mild cognitive impairment.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {1}, pages = {e70042}, pmid = {39758054}, issn = {2352-8729}, abstract = {INTRODUCTION: Alzheimer's disease (AD) involves neuroinflammation and amyloid plaque deposition, yet the role of amyloid-reactive immune response in neurodegeneration remains unclear. We investigate amyloid-reactive T cell levels in the Epidemiology of Mild Cognitive Impairment Study in Taiwan (EMCIT) and Taiwan Precision Medicine Initiative of Cognitive Impairment and Dementia (TPMIC) cohorts.
METHOD: Using diverse amyloid peptide formulations, we established a polyfunctionality assay for five T cell functions and compared mild cognitive impairment (MCI) patients to control subjects in both cohorts.
RESULTS: In both cohorts, MCI individuals exhibit higher amyloid-reactive T cell responses than controls. In the TPMIC cohort, CD4+ and CD8+ total response frequencies are notably elevated in MCI (CD4: 1.3%, CD8: 1.91%) versus controls (CD4: 0.15%, CD8: 0.28%; both p < 0.001). Amyloid-reactive T cell response outperforms plasma phosphorylated tau 181 (p-tau181) in discriminating MCI (area under the receiver operating characteristic curve CD4+: 0.97; CD8+: 0.96; p-tau181: 0.72; both p < 0.001).
DISCUSSION: Amyloid-reactive T cell polyfunctional response distinguishes MCI from normal aging and could serve as a novel MCI biomarker.
HIGHLIGHTS: Amyloid-reactive polyfunctional T cell responses can be detected in the peripheral circulation.Amyloid-reactive T cell response is significantly enhanced in individuals with mild cognitive impairment compared to age-matched, cognitively unimpaired individuals.The unique discriminative accuracy of amyloid-reactive T cell response is significantly higher than phosphorylated tau181 and is not a result of overall T cell hyperreactivity.Future studies are needed to determine the predictive role of amyloid-reactive T cell responses in disease progression and if the amyloid-reactive immune response could be a therapeutic target for the treatment of neurodegeneration.}, }
@article {pmid39758048, year = {2025}, author = {Huang, S and Nunez, J and Toresco, DL and Wen, C and Slotabec, L and Wang, H and Zhang, H and Rouhi, N and Adenawoola, MI and Li, J}, title = {Alterations in the inflammatory homeostasis of aging-related cardiac dysfunction and Alzheimer's diseases.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {39}, number = {1}, pages = {e70303}, doi = {10.1096/fj.202402725RR}, pmid = {39758048}, issn = {1530-6860}, support = {R33AG071249//National Institute of Health Sciences/ ; I01CX002406//U.S. Department of Veterans Affairs (VA)/ ; P30GM149404//National Institute of Health Sciences/ ; I01BX005625//U.S. Department of Veterans Affairs (VA)/ ; P30 GM149404/GM/NIGMS NIH HHS/United States ; R01AG088199//National Institute of Health Sciences/ ; R01HL158515//National Institute of Health Sciences/ ; P20GM104357//National Institute of Health Sciences/ ; }, mesh = {Animals ; Humans ; *Aging/metabolism ; *Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; *Heart Diseases/metabolism/pathology ; Homeostasis ; *Inflammation/metabolism/pathology ; Neuroinflammatory Diseases/metabolism/pathology ; Oxidative Stress ; }, abstract = {Alzheimer's disease (AD) is well known among the elderly and has a profound impact on both patients and their families. Increasing research indicates that AD is a systemic disease, with a strong connection to cardiovascular disease. They share common genetic factors, such as mutations in the presenilin (PS1 and PS2) and the apolipoprotein E (APOE) genes. Cardiovascular conditions can lead to reduced cerebral blood flow and increased oxidative stress. These factors contribute to the accumulation of Aβ plaques and the formation of abnormal tau protein tangles, which are both key pathological features of AD. Additionally, Aβ deposits and abnormal protein responses have been observed in cardiomyocytes as well as in peripheral tissues. The toxic Aβ deposition intensifies damage to the microvascular structure associated with blood-brain barrier disruption and the initiation of neuroinflammation, which may accelerate the onset of neurocognitive deficits and cardiovascular dysfunction. Thus, we discuss the main mechanisms linking AD and cardiac dysfunction to enhance our understanding of these conditions. Ultimately, insights into the brain-heart axis may help us develop effective treatment strategies in the future.}, }
@article {pmid39757645, year = {2025}, author = {Hu, X and Luo, R and Lei, F and Li, X and Luo, Y and Li, Q and Yi, L and Zhang, X and Polyak, A and Tao, Y and Jiang, R}, title = {Therapeutic Potential of Dexmedetomidine in Neuropsychiatric Disorders: From the Bench to the Clinic.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X349530241123140415}, pmid = {39757645}, issn = {1875-6190}, abstract = {Neuropsychiatric disease encompasses a range of conditions resulting from various dysfunctions within the nervous system, manifesting in diverse neurological impairments. These disorders, including depression, schizophrenia, anxiety, and Alzheimer's disease, impose significant economic and psychological burdens on both individuals and society overall. Recent clinical and preclinical studies have highlighted the potential therapy of dexmedetomidine (Dex), a highly selective α2 adrenergic receptor agonist, not only as an effective sedation but also as a neuroprotective agent. Dex exhibits anti-inflammatory and anti-apoptotic effects, as well as contributes to maintaining the integrity of the blood-brain barrier. Clinical observations also supports the application of Dex for the management of neuropsychiatric disorders. Importantly, its side effects in rodents and humans studies are less than those of antipsychotics. In this review, we present a comprehensive overview of the preclinical and clinical evidence supporting the therapeutic efficacy of Dex in neuropsychiatric disorders. We then discussed underlying mechanisms of its effect. Last, we point out future research directions of Dex in the treatment of neuropsychiatric disorders.}, }
@article {pmid39757626, year = {2024}, author = {Li, K and Gao, Y and Liu, M and Chen, Y}, title = {Advances in Alzheimer's Disease Biomarkers.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050366767241223050957}, pmid = {39757626}, issn = {1875-5828}, abstract = {Alzheimer's disease (AD) is a neurodegenerative condition characterized by gradual onset and complex pathological mechanisms. Clinically, it presents with progressive cognitive decline and behavioral impairments, making it one of the most common causes of dementia. The intricacies of its pathogenesis are not fully understood, and current treatment options are limited, with diagnosis typically occurring at intermediate to advanced stages. The development of new biomarkers offers a crucial avenue for the early diagnosis of AD and improving patient outcomes. Several biomarkers with high specificity have been identified. This article reviews biomarkers related to tau protein, β-amyloid, and blood cells to deepen our understanding of AD and emphasize the advantages and disadvantages of various biomarkers in order to explore further and mine new biomarkers for AD diagnosis.}, }
@article {pmid39757620, year = {2024}, author = {Verma, M and Usman Ms, M and Singh, NK}, title = {Neuroactive Phytoconstituents of Glycyrrhiza glabra for the Treatment of Alzheimer's Disease.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266357793241223100307}, pmid = {39757620}, issn = {1873-4294}, abstract = {Alzheimer's Disease (AD), a prevalent neurodegenerative disorder, poses a significant global health challenge with complicated pathogenesis. Pathological characteristics of AD include increasing loss of cholinergic neurons, oxidative stress, mitochondrial dysfunction, and amyloid beta accumulation. Due to the limited availability of effective therapeutic options with only symptomatic relief and their severe adverse effects, there is a significant need to search and explore new agents for the management of AD. Recently, natural products and/or phytoconstituents of plants have gained notable attention as potential sources of neuroprotective agents due to their diverse chemical constituents, mechanism of action, and relatively safe profiles. In view of this, Glycyrrhiza glabra has been recognized for its several therapeutic properties in traditional medicine systems for centuries. Further, neuroactive phytoconstituents of this plant, including glycyrrhizin, liquiritigenin, isoliquiritigenin, glabridin, and glycyrrhizic acid, exhibit significant pharmacological advantages along with potential neuroprotective effects against AD. Glycyrrhiza glabra and its phytoconstituents have gained significant interest due to its ability to exert a neuroprotective impact by influencing multiple signaling pathways, inhibiting AChE and BACE1 activity, reducing Aβ accumulation, plaque formation, and tau phosphorylation, and quenching the free radical in experimentally-induced AD-like brain. The present review summarizes available in vitro and in vivo preclinical studies that have been performed to evaluate the beneficial neuroprotective effect of Glycyrrhiza glabra and its phytoconstituents against AD-like pathology. Based on available facts, it can be concluded that neuroactive phytoconstituents of Glycyrrhiza glabra could be significant lead molecules for the drug discovery of anti-AD medicines in the future.}, }
@article {pmid39757300, year = {2025}, author = {Atef, F and Abdelkawy, MA and Eltanany, BM and Pont, L and Fayez, AM and Abdelhameed, MF and Benavente, F and Younis, IY and Otify, AM}, title = {A comprehensive investigation of Clerodendrum Infortunatum Linn. using LC-QTOF-MS/MS metabolomics as a promising anti-alzheimer candidate.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {859}, pmid = {39757300}, issn = {2045-2322}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Clerodendrum/chemistry ; *Plant Extracts/pharmacology/therapeutic use/chemistry ; Rats ; *Metabolomics/methods ; *Tandem Mass Spectrometry/methods ; Male ; Chromatography, Liquid/methods ; Acetylcholinesterase/metabolism ; Scopolamine ; Hippocampus/drug effects/metabolism ; Disease Models, Animal ; Cholinesterase Inhibitors/pharmacology/therapeutic use ; }, abstract = {Alzheimer's disease (AD) poses a global health challenge, demanding innovative approaches for effective treatments. Clerodendrum infortunatum Linn. (Lamiaceae) is a shrub traditionally used as a medicinal plant to treat inflammation, skin diseases, and bronchitis. This study aims to identify the main bioactive metabolites in C. infortunatum using LC-QTOF-MS/MS and investigate its potential in protecting against cognitive decline in rats with scopolamine-induced AD disease. Metabolite profiling was performed on the methanol extract of the plant's aerial parts using LC-QTOF-MS/MS. The inhibitory activity of the acetylcholinesterase enzyme was measured in vitro. To evaluate the cognitive effects, the methanol extract was orally administered at three doses (100, 200, and 400 mg/kg) to scopolamine-induced AD rats, and their cognitive functions were assessed using the novel object recognition test. Additionally, acetylcholinesterase enzyme activity, as well as the levels of acetylcholine, dopamine, noradrenaline, glutathione, malondialdehyde, tumor necrosis factor-α, interleukin-1β, and amyloid-β in the rat hippocampus, were measured using ELISA, followed by histopathological evaluation. A total of 79 metabolites, spanning various chemical classes, such as organic acids, phenolic acids, phenylpropanoids and phenylethanoids, flavonoids, coumarins, other phenolics, and fatty acids and their derivatives, were identified. The results showed that the extract promoted enhanced cognitive functions in the novel object recognition test. Scopolamine administration significantly altered the acetylcholinesterase enzyme activity and biomarker levels in the rat's hippocampus. However, treatment with C. infortunatum at 200 and 400 mg/kg almost restored these neurotransmitter levels to normal, which was further confirmed by histopathological analysis. This study demonstrates the therapeutic potential of C. infortunatum in mitigating cognitive decline in AD, with its first metabolite profiling revealing a range of bioactive compounds. The extract improved cognitive function in scopolamine-induced AD rats, restored acetylcholinesterase activity, normalized neurotransmitter levels, and reduced oxidative stress and inflammation. These findings suggest that C. infortunatum is a promising candidate for the development of natural therapies targeting AD.}, }
@article {pmid39757213, year = {2025}, author = {Dabaghkar, Y and Eghlima, G and Behboudi, H and Ebrahimi, M and Ghorbanpour, M}, title = {Agro-morphological characterization and assessment of metabolic profiling and anticancer activities in various tribulus (Tribulus terrestris L.) populations.}, journal = {BMC plant biology}, volume = {25}, number = {1}, pages = {20}, pmid = {39757213}, issn = {1471-2229}, mesh = {*Tribulus/chemistry ; Humans ; Plant Extracts/pharmacology ; Iran ; Antineoplastic Agents, Phytogenic/pharmacology ; PC-3 Cells ; Phytochemicals/pharmacology/metabolism/chemistry ; Metabolome ; Saponins/pharmacology/metabolism ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Plant Leaves/chemistry/metabolism ; }, abstract = {Tribulus terrestris L. from the family of Zygophyllaceae, which is rich in saponin compounds, especially diosgenin, has various biological properties, such as anti-inflammation, anti-Alzheimer, anti-obesity, anti-diabetes, anti-leukemia, and anti-cancer activities, due to these compounds. This research aimed to study the diversity of agro-morphological and phytochemical traits and anti-proliferative activity against human prostate cancer cells (PC3) of T. terrestris collected from 24 geographical regions in Iran and to select the superior populations for future domestication and breeding projects. The highest coefficient of variations was related to the fruit dry weight (104.77%), shoot dry weight (104.62%), and leaf dry weight (99.83%). Maximum plant height (113.96 cm), leaf length (49.39 mm), leaf width (23.48 mm), fruit diameter (11.42 mm), and fruit dry weight (34.11 g/plant) were recorded in SBU population. Gallic acid, 3.4dhb, rutin, salicylic acid, quercetin, kaempferol, apigenin, chlorogenic acid, caffeic acid, p-coumarin, ferulic acid, and rosmarinic acid were identified as the main phenolic compounds by HPLC. The highest total saponin content was observed in the RAF population (9.46 µg OCE/g DW) and the lowest in the KER population (4.75 µg OCE/g DW). The minimum (0.65 mg/g DW) and maximum (7.49 mg/g DW) diosgenin content was observed in KHA and PAN populations, respectively. The results of the MTT assay demonstrated the significant anti-proliferative activity of the T. terrestris extracts against the PC3 cancer cell line. IC50 calculated for the T. terrestris extracts in the 24-h treatment was from 15.02 to 27.11 µg/ml, implying that all samples had considerable cytotoxicity activity against the PC3 cells. The diversity observed among the T. terrestris populations in the studied traits shows its high potential for selecting and using the best populations in domestication, breeding, and cultivation projects.}, }
@article {pmid39756554, year = {2025}, author = {Jiang, M and Chi, J and Qiao, Y and Wang, J and Zhang, Z and Liu, J and Sheng, X and Yuan, L}, title = {Ginsenosides Rg1, Rb1 and rare ginsenosides: Promising candidate agents for Parkinson's disease and Alzheimer's disease and network pharmacology analysis.}, journal = {Pharmacological research}, volume = {212}, number = {}, pages = {107578}, doi = {10.1016/j.phrs.2025.107578}, pmid = {39756554}, issn = {1096-1186}, mesh = {*Ginsenosides/pharmacology/therapeutic use ; Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Parkinson Disease/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Network Pharmacology ; }, abstract = {Ginseng has been commonly used as a traditional Chinese medicine in Asian countries for thousands of years. Ginsenosides are the main pharmacologically active ingredients isolated from ginseng and have neuroprotective effects in the treatment of neurodegenerative disorders, such as Parkinson's disease (PD) and Alzheimer's disease (AD). To summarise and investigate the protective roles of ginsenosides and their underlying mechanisms in PD and AD, we used ''Ginsenoside", ''Parkinson's disease", ''Alzheimer's disease", ''anti-inflammatory", ''antioxidant", and ''apoptosis" as keywords to search and extract relevant literature information from scientific databases such as Elsevier, PubMed, and Google Scholar databases. In particular, we used network pharmacology to identify the potential targets of ginsenosides Rg1 and Rb1 in PD and AD. By analysing the existing research advances and network pharmacology results, we found that the neuroprotective effects of ginsenosides, primarily mediated through anti-inflammation, anti-apoptosis and anti-oxidative stress, etc, may be associated with the PI3K/Akt, BDNF/TrkB, MAPKs, NF-κB, Nrf2 and Wnt/β-catenin signalling pathways. This review systematically summarises the different roles and mechanisms of ginsenosides Rg1, Rb1, and rare ginsenosides in PD and AD and provides new strategies for the treatment of neurodegenerative disorders. Network pharmacology provides a new research paradigm for the treatment of PD and AD using Rg1 and Rb1.}, }
@article {pmid39756421, year = {2025}, author = {Wang, L and Sheng, J and Zhang, Q and Song, Y and Zhang, Q and Wang, B and Zhang, R}, title = {Diagnosis of Alzheimer's disease using FusionNet with improved secretary bird optimization algorithm for optimal MK-SVM based on imaging genetic data.}, journal = {Cerebral cortex (New York, N.Y. : 1991)}, volume = {35}, number = {2}, pages = {}, doi = {10.1093/cercor/bhae498}, pmid = {39756421}, issn = {1460-2199}, support = {LTGY23F020004//Natural Science Foundation of Zhejiang Province/ ; 62271177//National Natural Science Foundations of China/ ; LZ24F010007//Key Program of the Natural Science Foundation of Zhejiang Province/ ; }, mesh = {*Alzheimer Disease/genetics/diagnostic imaging ; Humans ; *Support Vector Machine ; *Magnetic Resonance Imaging/methods ; *Neuroimaging/methods ; Algorithms ; Polymorphism, Single Nucleotide ; Neural Networks, Computer ; Aged ; Brain/diagnostic imaging ; Female ; }, abstract = {Alzheimer's disease is an irreversible central neurodegenerative disease, and early diagnosis of Alzheimer's disease is beneficial for its prevention and early intervention treatment. In this study, we propose a novel framework, FusionNet-ISBOA-MK-SVM, which integrates a fusion network (FusionNet) and improved secretary bird optimization algorithm to optimize multikernel support vector machine for Alzheimer's disease diagnosis. The model leverages multimodality data, including functional magnetic resonance imaging and genetic information (single-nucleotide polymorphisms). Specifically, FusionNet employs U-shaped hierarchical graph convolutional networks and sparse graph attention networks to select feature effectively. Extensive validation using the Alzheimer's Disease Neuroimaging Initiative dataset demonstrates the model's superior interpretability and classification performance. Compared to other state-of-the-art machine learning methods, FusionNet-ISBOA-MK-SVM achieves classification accuracies of 98.6%, 95.7%, 93.0%, 91.8%, 93.1%, and 95.4% for HC vs. AD, EMCI vs. AD, LMCI vs. AD, EMCI vs. AD, HC vs. EMCI, and HC vs. LMCI, respectively. Moreover, the proposed model identifies affected brain regions and pathogenic genes, offering deeper insights into the mechanisms and progression of Alzheimer's disease. These findings provide valuable scientific evidence to support early diagnosis and preventive strategies for Alzheimer's disease.}, }
@article {pmid39755189, year = {2025}, author = {Wu, X and Qiu, X and Wang, S and Zhang, N and An, L and Song, P and Li, X and Gao, W}, title = {Xinnaoxin capsule alleviates neuropathological changes and cognitive deficits in Alzheimer's disease mouse model induced by D-galactose and aluminum chloride via reducing neuroinflammation and protecting synaptic proteins.}, journal = {Journal of ethnopharmacology}, volume = {341}, number = {}, pages = {119323}, doi = {10.1016/j.jep.2025.119323}, pmid = {39755189}, issn = {1872-7573}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/psychology ; *Galactose ; Male ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Disease Models, Animal ; *Cognitive Dysfunction/drug therapy/metabolism ; Mice ; *Neuroinflammatory Diseases/drug therapy ; *Aluminum Chloride ; Hippocampus/drug effects/metabolism/pathology ; Mice, Inbred C57BL ; Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Maze Learning/drug effects ; Spatial Memory/drug effects ; }, abstract = {Originally formulated to mitigate high-altitude sickness, Xinnaoxin capsules (XNX) are composed of three traditional Chinese medicines (Rhodiola rosea L., Lycium barbarum L. and Hippophae rhamnoides) with properties of anti-hypoxia, anti-fatigue, and anti-aging. Emerging evidence now suggests that XNX may also offer therapeutic benefits in Alzheimer's disease (AD), highlighting its potential significance in the development of novel AD treatments.
AIM OF THE STUDY: This study aims to investigate whether XNX improves AD-related behavioral and cognitive deficits by enhancing antioxidant defenses, reducing peripheral and neuroinflammation, and protecting neurons.
MATERIALS AND METHODS: The AD mouse model was established using D-galactose and aluminum chloride. Spatial memory and anxiety-like behaviors were assessed via the Morris water maze and open field tests to evaluate the therapeutic effects of XNX. Biochemical markers in hippocampal tissue and serum were measured using ELISA kits, while serum chemical composition was analyzed by LC-MS. Histopathological changes and amyloid-β deposition in the hippocampus were examined through hematoxylin-eosin (HE) staining and immunofluorescence. Additionally, hippocampal expression of apoptotic proteins Bax and Caspase-3, anti-apoptotic protein Bcl-2, and synaptic proteins PSD-95 and Syn were assessed via Western blot.
RESULTS: Behavioral tests demonstrated that XNX significantly improved spatial learning and memory abilities, as well as reduced anxiety-like behaviors in AD mice. XNX also modulated inflammatory cytokines and oxidative stress markers in hippocampal tissue and serum, while reducing amyloid-β deposition. Further LC-MS analysis of serum revealed a marked upregulation of compounds such as adenosine following treatment, with key metabolic pathways affected, including linoleic acid metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis. HE staining and immunofluorescence indicated that XNX ameliorated neuronal damage and decreased amyloid-β accumulation. Western blot analysis confirmed that XNX inhibited neuronal apoptosis and preserved synaptic proteins in the hippocampus.
CONCLUSION: XNX mitigates AD-induced behavioral and cognitive deficits by enhancing antioxidant defenses, reducing peripheral and neuroinflammation, and protecting neurons. Our findings provide valuable data and a theoretical foundation for the potential therapeutic application of XNX in AD treatment and its further development.}, }
@article {pmid39755187, year = {2025}, author = {Su, W and Du, Y and Wang, W and Li, Q and Zhang, J and He, W}, title = {Dihuang Yinzi improves scopolamine-induced learning and memory impairment by regulating plasma exosome-derived BDNF.}, journal = {Journal of ethnopharmacology}, volume = {341}, number = {}, pages = {119322}, doi = {10.1016/j.jep.2025.119322}, pmid = {39755187}, issn = {1872-7573}, mesh = {Animals ; *Scopolamine ; *Brain-Derived Neurotrophic Factor/metabolism ; *Exosomes/metabolism/drug effects ; Male ; *Mice, Inbred C57BL ; *Drugs, Chinese Herbal/pharmacology ; *Memory Disorders/drug therapy/chemically induced ; Mice ; *Rats, Sprague-Dawley ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Rats ; Cognitive Dysfunction/drug therapy/chemically induced ; Memory/drug effects ; }, abstract = {Dihuang Drink (DHD), formulated by Liu Hejian during the Yuan Dynasty, is listed as one of the first ancient classical prescriptions by the National Medical Products Administration of China. It is commonly used for the prevention and treatment of Alzheimer's disease (AD). This study further investigates the therapeutic effects and potential mechanisms of DHD in AD.
AIM OF THE STUDY: This study aimed to evaluate the cognitive improvement effects of DHD on scopolamine (SCOP)-induced memory impairment in mice and to explore its anti-AD mechanisms mediated by exosomes.
MATERIALS AND METHODS: A cognitive impairment model was established in C57BL/6J mice via intraperitoneal injection of SCOP (1 mg/kg) for 21 consecutive days, followed by DHD intervention to assess its effects on learning, memory, hippocampal synaptic density, and the cholinergic system. SD rats were gavaged with DHD (22.00 g/kg) for 7 days, and plasma exosomes were extracted. These exosomes were injected into SCOP-treated mice (2 mg/kg, every other day for 14 days, 7 injections) to verify the role of exosomes in improving cognitive function. Behavioral performance and brain ChAT and BDNF levels were measured.
RESULTS: DHD improved learning and memory in SCOP model mice, attenuated neuronal loss and decreases in dendritic spines induced by scopolamine, and modulated the expression of BDNF, SYN-1, PSD95, and M1 mAChR. DHD-derived plasma exosomes further enhanced learning and memory function and significantly increased brain ChAT activity and BDNF levels.
CONCLUSIONS: DHD may alleviate cognitive impairment in SCOP model mice, potentially through exosome-mediated neuroprotection.}, }
@article {pmid39754674, year = {2025}, author = {Chunhui, G and Yanqiu, Y and Jibing, C and Ning, L and Fujun, L}, title = {Exosomes and non-coding RNAs: bridging the gap in Alzheimer's pathogenesis and therapeutics.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {84}, pmid = {39754674}, issn = {1573-7365}, support = {Key Project with Chinese Medicine Characteristics and Advantages, Ruikang Hospital, 2024//the Chinese Medicine Service System and Capacity Building/ ; 2023JJA140082//the Guangxi Natural Science Foundation/ ; }, mesh = {*Alzheimer Disease/metabolism/genetics/therapy ; Humans ; *Exosomes/metabolism ; *RNA, Untranslated/genetics/metabolism ; Animals ; RNA, Long Noncoding/genetics/metabolism ; Blood-Brain Barrier/metabolism ; MicroRNAs/metabolism/genetics ; RNA, Circular/genetics/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that primarily affects the elderly population and is the leading cause of dementia. Meanwhile, the vascular hypothesis suggests that vascular damage occurs in the early stages of the disease, leading to neurodegeneration and hindered waste clearance, which in turn triggers a series of events including the accumulation of amyloid plaques and Tau protein tangles. Non-coding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), have been found to be involved in the regulation of AD. Furthermore, lncRNAs and circRNAs can act as competitive endogenous RNAs to inhibit miRNAs, and their interactions can form a complex regulatory network. Exosomes, which are extracellular vesicles (EVs), are believed to be able to transfer ncRNAs between cells, thus playing a regulatory role in the brain by crossing the blood-brain barrier (BBB). Exosomes are part of the intercellular carrier system; therefore, utilizing exosomes to deliver drugs to recipient cells might not activate the immune system, making it a potential strategy to treat central nervous system diseases. In this review, we review that AD is a multifactorial neurological disease and that ncRNAs can regulate its multiple pathogenic mechanisms to improve our understanding of the etiology of AD and to simultaneously regulate multiple pathogenic mechanisms of AD through the binding of ncRNAs to exosomes to improve the treatment of AD.}, }
@article {pmid39754267, year = {2025}, author = {Huang, YL and Tsai, TH and Shen, ZQ and Chan, YH and Tu, CW and Tung, CY and Wang, PN and Tsai, TF}, title = {Transcriptomic predictors of rapid progression from mild cognitive impairment to Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {3}, pmid = {39754267}, issn = {1758-9193}, mesh = {Humans ; *Cognitive Dysfunction/genetics/diagnosis ; *Alzheimer Disease/genetics/diagnosis ; *Disease Progression ; Female ; Male ; *Transcriptome ; Aged ; Longitudinal Studies ; Machine Learning ; Biomarkers/blood ; Aged, 80 and over ; }, abstract = {BACKGROUND: Effective treatment for Alzheimer's disease (AD) remains an unmet need. Thus, identifying patients with mild cognitive impairment (MCI) who are at high-risk of progressing to AD is crucial for early intervention.
METHODS: Blood-based transcriptomics analyses were performed using a longitudinal study cohort to compare progressive MCI (P-MCI, n = 28), stable MCI (S-MCI, n = 39), and AD patients (n = 49). Statistical DESeq2 analysis and machine learning methods were employed to identify differentially expressed genes (DEGs) and develop prediction models.
RESULTS: We discovered a remarkable gender-specific difference in DEGs that distinguish P-MCI from S-MCI. Machine learning models achieved high accuracy in distinguishing P-MCI from S-MCI (AUC 0.93), AD from S-MCI (AUC 0.94), and AD from P-MCI (AUC 0.92). An 8-gene signature was identified for distinguishing P-MCI from S-MCI.
CONCLUSIONS: Blood-based transcriptomic biomarker signatures show great utility in identifying high-risk MCI patients, with mitochondrial processes emerging as a crucial contributor to AD progression.}, }
@article {pmid39753993, year = {2025}, author = {Cheng, L and Liu, Z and Shen, C and Xiong, Y and Shin, SY and Hwang, Y and Yang, SB and Chen, Z and Zhang, X}, title = {A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {1}, pages = {e70208}, pmid = {39753993}, issn = {1755-5949}, support = {20224BAB216045//Youth Foundation of Natural Science Foundation of Jiangxi Province/ ; GJJ211812//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; GJJ211813//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; 202131084//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; 202211982//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; RZYB202201//Research project of Cognitive Science and Transdisciplinary Studies Center of Jiangxi Province/ ; 20224BAB206040//Provincial Natural Science Foundation of Jiangxi Province/ ; 202411843024//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; S202411843050//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; 2022B1010//Administration of Traditional Chinese Medicine of Jiangxi Province/ ; }, mesh = {*Adenosine Deaminase/genetics/metabolism ; Humans ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; *Central Nervous System Diseases/genetics/metabolism/therapy ; RNA Editing ; }, abstract = {BACKGROUND: Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double-stranded RNA (dsRNA) molecules into inosine in a process known as A-to-I RNA editing. ADAR1 regulates gene expression output by interacting with RNA and other proteins; plays important roles in development, including growth; and is linked to innate immunity, tumors, and central nervous system (CNS) diseases.
RESULTS: In recent years, the role of ADAR1 in tumors has been widely discussed, but its role in CNS diseases has not been reviewed. It is worth noting that recent studies have shown ADAR1 has great potential in the treatment of neurodegenerative diseases, but the mechanisms are still unclear. Therefore, it is necessary to elaborate on the role of ADAR1 in CNS diseases.
CONCLUSIONS: Here, we focus on the effects and mechanisms of ADAR1 on CNS diseases such as Aicardi-AicardiGoutières syndrome, Alzheimer's disease, Parkinson's disease, glioblastoma, epilepsy, amyotrophic lateral sclerosis, and autism. We also evaluate the impact of ADAR1-based treatment strategies on these diseases, with a particular focus on the development and treatment strategies of new technologies such as microRNAs, nanotechnology, gene editing, and stem cell therapy. We hope to provide new directions and insights for the future development of ADAR1 gene editing technology in brain science and the treatment of CNS diseases.}, }
@article {pmid39752841, year = {2025}, author = {Huang, J and Xu, J and Gu, Y and Sun, H and Liu, H and He, Y and Li, M and Gao, X and Tang, Z and Wang, H}, title = {Tea consumption and cognitive health in Chinese older adults: A propensity score matching and weighting analysis.}, journal = {Archives of gerontology and geriatrics}, volume = {131}, number = {}, pages = {105735}, doi = {10.1016/j.archger.2024.105735}, pmid = {39752841}, issn = {1872-6976}, mesh = {Humans ; *Tea ; Male ; *Propensity Score ; Female ; Aged ; China/epidemiology ; *Cognition ; *Cognitive Dysfunction/epidemiology ; Longitudinal Studies ; Mental Status and Dementia Tests ; Aged, 80 and over ; East Asian People ; }, abstract = {BACKGROUND: The association between tea consumption, especially different types, and cognitive function has not been adequately explored. This study aimed to investigate the associations of tea consumption, including status, frequency, and type, with cognitive function, considering selection bias.
METHODS: We used data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) in 2018(N = 8498). Cognitive function was measured by Mini-Mental State Examination (MMSE). Logistic and linear regression were applied to assess the associations of tea consumption with cognitive impairment and cognitive scores, respectively. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to balance characteristic differences between groups.
RESULTS: The characteristics of tea consumption status, frequency and type were well balanced between groups after using PSM and IPTW. Drinking tea was associated with less cognitive impairment (ORadjusted:0.84, ORPSM:0.84, ORIPTW:0.87) and higher cognitive scores (Coefficientadjusted:0.29, CoefficientPSM:0.33, CoefficientIPTW:0.29). Regular tea drinkers may have better cognitive function than those who never or rarely consumed (Ptrend < 0.05 for both methods). Green tea drinkers had lower prevalence of cognitive impairment (ORadjusted:0.71, ORIPTW:0.75) and higher cognitive scores (Coefficientadjusted:0.45, CoefficientIPTW:0.54). Men, uneducated, and those with annual income>10,000 RMB were more likely to benefit from flower tea. Significant interactions of tea consumption with age, education and income were observed.
CONCLUSIONS: Tea consumption, especially regular and green tea consumption, was associated with less cognitive impairment and higher cognitive scores, even after PSM and IPTW adjustments. Flower teas may have potential protective effect that is worth further study. Age, education and income have synergistic effects with tea consumption on cognitive function.}, }
@article {pmid39752365, year = {2025}, author = {Isei, MO and Crockett, M and Chen, E and Rodwell-Bullock, J and Carroll, T and Girardi, PA and Nehrke, K and Johnson, GVW}, title = {Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0307358}, pmid = {39752365}, issn = {1932-6203}, support = {R01 AG067617/AG/NIA NIH HHS/United States ; }, mesh = {*Oxidative Stress/drug effects ; Animals ; *Mitophagy/drug effects ; *tau Proteins/metabolism ; Phosphorylation ; Mice ; *Tacrolimus Binding Proteins/metabolism ; *Paraquat/pharmacology ; Mitochondria/metabolism/drug effects ; Humans ; Neurons/metabolism/drug effects ; Hippocampus/metabolism ; Cell Line ; }, abstract = {Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimer's disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles are selectively removed from the mitochondrial network. The precise mechanism through which this occurs remains unclear. Previously, we showed that tau which has been mutated at Thr-231 to glutamic acid to mimic an Alzheimer's-relevant phospho-epitope expressed early in disease selectively inhibits oxidative stress-induced mitophagy in Caenorhabditis elegans. Here, we use immortalized mouse hippocampal neuronal cell lines to extend that result into mammalian cells. Specifically, we show that phosphomimetic tau at Ser-396/404 (EC) or Thr-231/Ser-235 (EM) partly inhibits mitophagy induction by paraquat, a potent inducer of mitochondrial oxidative stress. Moreover, a combination of immunologic and biochemical approaches demonstrates that the levels of the mitophagy receptor FKBP8, significantly decrease in response to paraquat in cells expressing EC or EM tau mutants, but not in cells expressing wildtype tau. In contrast, paraquat treatment results in a decrease in the levels of the mitophagy receptors FUNDC1 and BNIP3 in the presence of both wildtype tau and the tau mutants. Interestingly, FKBP8 is normally trafficked to the endoplasmic reticulum during oxidative stress induced mitophagy, and our results support a model where this trafficking is impacted by disease-relevant tau, perhaps through a direct interaction. We provide new insights into the molecular mechanisms underlying tau pathology in Alzheimer's disease and highlight FKBP8 receptor as a potential target for mitigating mitochondrial dysfunction in neurodegenerative diseases.}, }
@article {pmid39752040, year = {2025}, author = {Joodi, SA and Ibrahim, WW and Khattab, MM}, title = {Drugs repurposing in the experimental models of Alzheimer's disease.}, journal = {Inflammopharmacology}, volume = {33}, number = {1}, pages = {195-214}, pmid = {39752040}, issn = {1568-5608}, mesh = {*Drug Repositioning/methods ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Animals ; Disease Models, Animal ; Oxidative Stress/drug effects ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {The currently approved drugs for Alzheimer's disease (AD) are only for symptomatic treatment in the early stages of the disease but they could not halt the neurodegeneration, additionally, the safety profile of the recently developed immunotherapy is a big issue. This review aims to explain the importance of the drugs repurposing technique and strategy to develop therapy for AD. We illustrated the biological alterations in the pathophysiology of AD including the amyloid pathology, the Tau pathology, oxidative stress, mitochondrial dysfunction, neuroinflammation, glutamate-mediated excitotoxicity, insulin signaling impairment, wingless-related integration site/β-catenin signaling, and autophagy. Additionally, we demonstrated the different repurposed drugs in the experimental models of AD including the anti-inflammatory, anti-hypertensive, anti-diabetic, antiepileptic, antidepressant and anticancer drugs. Further, we showed the pipeline and FDA approved drugs for AD. The repurposed drugs have a promising therapeutic activity against AD, confirming the value of the drugs repurposing technique to elucidate curative therapy for AD.}, }
@article {pmid39751972, year = {2025}, author = {Liu, X and Lv, Z and Huang, Q and Lei, Y and Liu, H and Xu, P}, title = {The Role of Oligodendrocyte Lineage Cells in the Pathogenesis of Alzheimer's Disease.}, journal = {Neurochemical research}, volume = {50}, number = {1}, pages = {72}, pmid = {39751972}, issn = {1573-6903}, support = {82060218//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/pathology/metabolism ; Humans ; *Oligodendroglia/metabolism/pathology ; Animals ; *Cell Lineage ; Myelin Sheath/pathology/metabolism ; Oligodendrocyte Precursor Cells/metabolism/pathology ; Oxidative Stress/physiology ; Blood-Brain Barrier/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a central nervous system degenerative disease with a stealthy onset and a progressive course characterized by memory loss, cognitive dysfunction, and abnormal psychological and behavioral symptoms. However, the pathogenesis of AD remains elusive. An increasing number of studies have shown that oligodendrocyte progenitor cells (OPCs) and oligodendroglial lineage cells (OLGs), especially OPCs and mature oligodendrocytes (OLGs), which are derived from OPCs, play important roles in the pathogenesis of AD. OLGs function mainly by myelinating axons, transmitting electrical signals, and regulating neural development. In addition to myelin, OPCs and OLGs can also participate in AD pathogenesis in other ways. This review summarizes the mechanisms by which OPCs and OLGs affect myelin formation, oxidative stress, neuroinflammation, the blood-brain barrier, synaptic function, and amyloid-beta protein and further elucidates the mechanisms by which oligodendrocyte lineage cells participate in AD pathogenesis and treatment, which is highly important for clarifying the pathogenesis of AD, clinical treatment, and prevention.}, }
@article {pmid39751741, year = {2025}, author = {Zeng, T and Zhang, C and Sun, L and Xu, H}, title = {Water-Soluble Ginseng Oligosaccharides Prevent Scopolamine-Induced Cholinergic Dysfunction and Inflammatory Cytokine Overexpression.}, journal = {Cell biochemistry and biophysics}, volume = {}, number = {}, pages = {}, pmid = {39751741}, issn = {1559-0283}, support = {JJKH20211230KJ//The Education Department of Jilin Province/ ; 2020SCZT048//The Jilin Provincial Health Special Project of China/ ; }, abstract = {Cholinergic deficiency and neuroinflammation are the two main factors of Alzheimer's disease. Recent studies have shown that water-soluble ginseng oligosaccharides (WGOS) derived from Panax ginseng roots can protect against scopolamine-induced impairments in learning and memory. However, the fundamental mechanisms remain unclear for the most part. The purpose of this study was to examine the effect of WGOS on cholinergic function and protein levels of proinflammatory cytokines in the hippocampus of mice. Mice were first pretreated with WGOS or saline, and then treated with scopolamine to establish an Alzheimer's disease model. The cognition memory of the mice was assessed through the behavioral test. The effect of WGOS on the cholinergic system was evaluated by measuring acetylcholine (ACh) neurotransmitter concentration and acetylcholinesterase (AChE) activity in the hippocampus. Using ELISA, the inflammatory cytokines IL-1β and TNF-α in the hippocampus were identified. This study found that WGOS treatment prevented the scopolamine-induced impairment of mice's recognition memory, as seen by their enhanced object recognition. In addition, WGOS prevented the scopolamine-induced decrease in ACh concentration and increase in AChE activity. Moreover, WGOS treatment inhibited scopolamine-induced upregulation of the inflammatory proteins IL-1β and TNF-α. These findings suggest that the amelioration of scopolamine-induced cognitive impairment in mice by WGOS was a consequence of the control of cholinergic function and inflammatory response in the hippocampus. Our findings suggest that WGOS should be investigated as a dietary supplement or medication for the treatment of learning and memory disorders in humans.}, }
@article {pmid39749958, year = {2025}, author = {Xu, Y and Chen, J and Zhou, L and Zhao, Y and He, N and Xu, Q and Zhao, J and Liu, Y}, title = {GASTRODIN PROTECTS AGAINST SEPSIS-ASSOCIATED ENCEPHALOPATHY BY SUPPRESSING FERROPTOSIS.}, journal = {Shock (Augusta, Ga.)}, volume = {63}, number = {4}, pages = {628-637}, doi = {10.1097/SHK.0000000000002542}, pmid = {39749958}, issn = {1540-0514}, mesh = {Animals ; *Benzyl Alcohols/pharmacology/therapeutic use ; *Ferroptosis/drug effects ; Mice ; *Sepsis-Associated Encephalopathy/drug therapy/metabolism ; *Glucosides/pharmacology/therapeutic use ; Male ; Mice, Inbred C57BL ; Sepsis/drug therapy/metabolism/complications ; }, abstract = {Background: Sepsis-associated encephalopathy (SAE) represents a severe complication of sepsis, substantially elevating both mortality and healthcare costs for patients. Gastrodin (GAS), a principal bioactive constituent of Gastrodia elata Blume, is neuroprotective in various neurological disorders, including ischemic stroke, epilepsy, Alzheimer's disease, and neuropathic pain. In this study, we sought to investigate whether GAS could serve as a protective agent against SAE. Methods: Mice were subjected to cecal ligation and puncture (CLP) or the murine brain microvascular endothelial cell bEnd.3 was exposed to lipopolysaccharide (LPS) and subsequently treated with GAS. We assessed neurological deficits, blood-brain barrier (BBB) integrity, neuroinflammation, and the state of ferroptosis to evaluate the regulation of GAS on SAE. Mechanistically, we utilized glutathione peroxidase 4 (GPX4) knockout mice to delineate the crucial role of GPX4 and examined the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway to uncover the upstream signaling of GPX4. Results: GAS mitigated neurological deficits in SAE mice and reduced BBB disruption and neuroinflammation both in vivo and in vitro . Functionally, the neuroprotective effects of GAS were realized through the inhibition of ferroptosis. Furthermore, we demonstrated that GPX4 played a pivotal role in this process. Lastly, we found that the COX-2/PGE2 pathway was activated following GAS treatment in SAE mice, thereby increasing the expression level of GPX4. Conclusions: Our study elucidated that GAS offers protection against SAE by suppressing ferroptosis through the activation of the COX-2/PGE2/GPX4 axis. This research validates the therapeutic potential of GAS and provides novel insights into potential therapeutic strategies for the management of SAE.}, }
@article {pmid39749582, year = {2025}, author = {Li, Z and Wang, T and Du, S and Miao, Z and Zhao, Y and Tang, Y and Meng, X and Yu, S and Zhang, D and Jiang, H and Du, K and Wei, W and Deng, H}, title = {Tgm2-Catalyzed Covalent Cross-Linking of IκBα Drives NF-κB Nuclear Translocation to Promote SASP in Senescent Microglia.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e14463}, doi = {10.1111/acel.14463}, pmid = {39749582}, issn = {1474-9726}, support = {82172556//National Natural Science Foundation of China/ ; T2293763//National Natural Science Foundation of China/ ; ZYYCXTD-C-202210//the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine/ ; 2021YFA1302601//National Key Research and Development Program of China/ ; }, abstract = {Microglia, as resident immune cells in the central nervous system (CNS), play a crucial role in maintaining homeostasis and phagocytosing metabolic waste in the brain. Senescent microglia exhibit decreased phagocytic capacity and increased neuroinflammation through senescence-associated secretory phenotype (SASP). This process contributes to the development of various neurodegenerative diseases, including Alzheimer's disease (AD). In this study, we found that SASP was elevated in senescent microglia, and proteomics showed that Tgm2 was upregulated. Mechanistically, we revealed that Tgm2-catalyzed covalent cross-linking of IκBα at K22 and Q248 residues in the cytoplasm of microglia, resulting in the reduction of IκBα and nuclear translocation of NF-κB to promote SASP production. Treatment of senescent microglia with Tgm2 inhibitors (Tg2-IN1 and Cys-D) resulted in reduced NF-κB nuclear translocation and decreased SASP. Additionally, oral administration of Cys-D significantly improved the aging phenotype in aged mice. To summarize, Tgm2 is a potential target for antiaging, and inhibitors of Tgm2 can serve as novel prophylactics or senomorphics.}, }
@article {pmid39749254, year = {2024}, author = {Zhen, W and Wang, Y and Zhen, H and Zhang, W and Shao, W and Sun, Y and Qiao, Y and Jia, S and Zhou, Z and Wang, Y and Chen, L and Zhang, J and Peng, D}, title = {Association between Alzheimer's disease pathologic products and age and a pathologic product-based diagnostic model for Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1513930}, pmid = {39749254}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) has a major negative impact on people's quality of life, life, and health. More research is needed to determine the relationship between age and the pathologic products associated with AD. Meanwhile, the construction of an early diagnostic model of AD, which is mainly characterized by pathological products, is very important for the diagnosis and treatment of AD.
METHOD: We collected clinical study data from September 2005 to August 2024 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Using correlation analysis method like cor function, we analyzed the pathology products (t-Tau, p-Tau, and Aβ proteins), age, gender, and Minimum Mental State Examination (MMSE) scores in the ADNI data. Next, we investigated the relationship between pathologic products and age in the AD and non-AD groups using linear regression. Ultimately, we used these features to build a diagnostic model for AD.
RESULTS: A total of 1,255 individuals were included in the study (mean [SD] age, 73.27 [7.26] years; 691male [55.1%]; 564 female [44.9%]). The results of the correlation analysis showed that the correlations between pathologic products and age were, in descending order, Tau (Corr=0.75), p-Tau (Corr=0.71), and Aβ (Corr=0.54). In the AD group, t-Tau protein showed a tendency to decrease with age, but it was not statistically significant. p-Tau protein levels similarly decreased with age and its decrease was statistically significant. In contrast to Tau protein, in the AD group, Aβ levels increased progressively with age. In the non-AD group, the trend of pathologic product levels with age was consistently opposite to that of the AD group. We finally screened the optimal AD diagnostic model (AUC=0.959) based on the results of correlation analysis and by using the Xgboost algorithm and SVM algorithm.
CONCLUSION: In a novel finding, we observed that Tau protein and Aβ had opposite trends with age in both the AD and non-AD groups. The linear regression curves of the AD and non-AD groups had completely opposite trends. Through a machine learning approach, we constructed an AD diagnostic model with excellent performance based on the selected features.}, }
@article {pmid39749010, year = {2025}, author = {Fertan, E and Hung, C and Danial, JSH and Lam, JYL and Preman, P and Albertini, G and English, EA and Böken, D and Livesey, FJ and De Strooper, B and Patani, R and Klenerman, D}, title = {Clearance of beta-amyloid and tau aggregates is size dependent and altered by an inflammatory challenge.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcae454}, pmid = {39749010}, issn = {2632-1297}, abstract = {Extracellular beta-amyloid aggregation and inflammation are in a complex and not fully understood interplay during hyperphosphorylated tau aggregation and pathogenesis of Alzheimer's disease. Our group has previously shown that an immune challenge with tumour necrosis factor alpha can alter extracellular beta-sheet containing aggregates in human-induced pluripotent stem cell-derived cortical neurons carrying familial Alzheimer's disease-related presenilin 1 mutations. Here, using single-molecule detection and super-resolution imaging techniques, we quantified and characterized the intra- and extracellular beta-amyloid and AT8-positive tau aggregates. Our results indicate a pre-existing Alzheimer's disease-like pathology caused by the presenilin 1 mutation, with increased beta-amyloid aggregates in both the cell lysate and conditioned media compared to isogenic controls and also increased intracellular tau aggregates. The main effect of tumour necrosis factor alpha treatment on presenilin 1 neurons was the formation of larger intracellular beta-amyloid aggregates. In contrast, isogenic controls showed more significant changes with tumour necrosis factor alpha treatment with an increase in beta-amyloid aggregates in the media but not intracellularly and an increase in tau aggregates in both the media and cell lysate, suggesting a chronic inflammation-driven mechanism for the development of sporadic Alzheimer's disease. Remarkably, we also found significant morphological differences between intra- and extracellular beta-amyloid and tau aggregates in human-induced pluripotent stem cell-derived cortical neurons, suggesting these neurons can only clear aggregates when small, and that larger aggregates stay inside the neurons. While majority of the beta-amyloid aggregates were cleared into the media, a greater portion of the tau aggregates remained intracellular. This size-dependent aggregate clearance was also shown to be conserved in vivo, using soaked and homogenized mouse and human post-mortem Alzheimer's disease brain samples. As such, our results are proposing a previously unknown, size-dependent aggregate clearance mechanism, which can possibly explain the intracellular aggregation of tau and extracellular aggregation of beta-amyloid.}, }
@article {pmid39748851, year = {2024}, author = {Kielbasa, W and Goldsmith, P and Donnelly, KB and Nuthall, HN and Shcherbinin, S and Fleisher, AS and Hendle, J and DuBois, SL and Lowe, SL and Zhang, FF and Woerly, EM and Dreyfus, NJ and Evans, D and Gilmore, J and Mancini, M and Constantinescu, CC and Gunn, RN and Russell, DS and Collins, EC and Brys, M and Hutton, ML and Mergott, DJ}, title = {Discovery and clinical translation of ceperognastat, an O-GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {10}, number = {4}, pages = {e70020}, pmid = {39748851}, issn = {2352-8737}, abstract = {INTRODUCTION: The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O-GlcNAcylation, an important post-translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O-GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models. O-GlcNAcase (OGA) catalyzes the removal of O-GlcNAc from tau thereby driving interest in OGA inhibition as a potential therapeutic approach to reduce tau pathology and slow the progression of AD.
METHODS: A multidisciplinary approach was used to identify ceperognastat (LY3372689) as a potent OGA inhibitor, including an extensive discovery effort with synthetic chemistry, structure-based drug design, and in vivo OGA enzyme occupancy studies. Preclinical studies assessed the target engagement, inhibition of OGA enzyme activity, OGA enzyme occupancy, and changes in tau O-GlcNAc. Four clinical Phase 1 studies of ceperognastat in healthy participants were performed to assess clinical safety and tolerability, pharmacokinetics (PK), and enzyme occupancy.
RESULTS: Ceperognastat is a potent, central nervous system (CNS)-penetrant, low-dose inhibitor of OGA, which can achieve > 95% OGA enzyme occupancy in animal and human brain. Overall, ceperognastat had an acceptable safety profile in Phase 1 clinical studies with no serious adverse events reported following single and multiple dosing. The PK, enzyme occupancy, and safety profile supported Phase 2 development of ceperognastat.
DISCUSSION: Ceperognastat is an orally available, highly potent, CNS-penetrant OGA inhibitor that achieved high (> 80%) OGA enzyme occupancy and increased brain O-GlcNAc-tau preclinically. Ceperognastat demonstrated > 95% OGA enzyme occupancy in Phase 1 trials. These occupancy data informed the dose selection for the Phase 2 clinical program.
HIGHLIGHTS: Ceperognastat is a highly potent, CNS-penetrant OGA inhibitor.Ceperognastat is both orally available and CNS-penetrant even when given at low doses.Ceperognastat can achieve > 95% OGA enzyme occupancy in the animal and human brain.Ceperognastat had an acceptable safety profile in Phase 1 clinical studies.}, }
@article {pmid39748848, year = {2024}, author = {Hlávka, JP and Kinoshita, AT and Jeyasingh, D and Huang, C and Mirsafian, L and Jacobson, M}, title = {Emerging Alzheimer's disease treatment paradigms: A late-stage clinical trial review.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {10}, number = {4}, pages = {e70022}, pmid = {39748848}, issn = {2352-8737}, abstract = {INTRODUCTION: Without disease-modifying interventions, Medicare and Medicaid spending on Alzheimer's disease (AD) management is expected to reach 637 billion USD annually by 2050. The recent advent of promising AD therapies after decades of a near-total failure rate in clinical trials suggests that more disease-modifying therapies are on the horizon. In this review, we assess the late-stage pipeline of disease-modifying candidates for AD and offer a novel classification of intervention candidates by treatment paradigms-groups of candidates that share an underlying biological mechanism of action and general disease target.
METHODS: We extracted data from the National Library of Medicine clinical trials database regarding Phase 2 and 3 trials of disease-modifying AD therapies. We categorized trials into eight unique treatment paradigms, which we defined by combinations of therapy (biologic, small molecule, cell and gene therapy, other) and target (amyloid, tau, other). We analyzed primary endpoints, eligibility criteria including clinical ratings of cognition, trial phase and length, and funding sources.
RESULTS: We identified 123 unique disease-modifying intervention candidates in 175 late-stage clinical trials. Biologic and small molecule drugs comprised 30% and 54% of trials, respectively. Eligibility criteria favored patients between the ages of 60 and 80 years with mild cognitive impairment. Including multi-phase trials, 81% of studies were engaged in Phase 2 and 27% in Phase 3. Notably, within the Biologic-Amyloid paradigm, 64% of trials were engaged in Phase 3.
DISCUSSION: Current studies of disease-modifying therapies for AD comprise a diverse set of approaches to treating the disease. However, effort is largely concentrated in a few treatment paradigms and a narrow patient population, causing varying rates of progress among treatment paradigms in the late-stage clinical trial pipeline. Strategies may be warranted to accelerate successes in the most promising therapeutical paradigms and nurture growth within nascent areas lacking resources but not potential.
HIGHLIGHTS: An analysis of Alzheimer's disease trial treatment paradigms was conducted.From April 2021 to March 2023, 175 trials of 123 unique candidates were reviewed.Biologic and small molecule drugs comprised 30% and 54% of trials, respectively.Eligibility criteria favored ages 60 through 80 with mild cognitive impairment.}, }
@article {pmid39748842, year = {2024}, author = {Bakker, A and Rani, N and Mohs, R and Gallagher, M}, title = {The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non-carriers with mild cognitive impairment due to Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {10}, number = {4}, pages = {e70004}, pmid = {39748842}, issn = {2352-8737}, abstract = {INTRODUCTION: Hippocampal hyperactivity is a hallmark of prodromal Alzheimer's disease (AD) that predicts progression in patients with amnestic mild cognitive impairment (aMCI). AGB101 is an extended-release formulation of levetiracetam in the dose range previously demonstrated to normalize hippocampal activity and improve cognitive performance in aMCI. The HOPE4MCI study was a 78-week trial to assess the progression of MCI due to AD. As reported in Mohs et al., the decline in the Clinical Dementia Rating Sum of Boxes score (CDR-SB) was reduced by 40% in apolipoprotein E (APOE) ε4 non-carriers over the 78-week duration of the study with a negligible effect in carriers. Here we report an exploratory analysis of the effects of AGB101 on neuroimaging and biomarker measures in the 44 APOE ε4 non-carriers who completed the 78-week protocol.
METHODS: Structural magnetic resonance imaging scans obtained at baseline and after 78 weeks were analyzed using the Automated Segmentation of Hippocampal Subfields software providing volume measures of key structures of the medial temporal lobe relevant to AD progression. Blood samples collected at 78 weeks in the study were analyzed for plasma biomarkers.
RESULTS: Treatment with AGB101 significantly reduced atrophy of the left entorhinal cortex (ERC) compared to placebo. This reduction in atrophy was correlated with less decline in the CDR-SB score over 78 weeks and with lower neurofilament light chain (NfL), a marker of neurodegeneration.
DISCUSSION: The HOPE4MCI study showed that APOE ε4 non-carriers treated with AGB101 demonstrated a substantially more favorable treatment effect compared to carriers. Here we report that treatment with AGB101 in non-carriers of APOE ε4 significantly reduced atrophy of the left ERC over 78 weeks. That reduction in atrophy was closely coupled with the change in CDR-SB and with plasma NfL indicative of neurodegeneration in the brain. These exploratory analyses are consistent with a reduction in neurodegeneration in APOE ε4 non-carriers treated with AGB101 before a clinical diagnosis of dementia.
HIGHLIGHTS: AGB101 slows entorhinal cortex (ERC) atrophy in apolipoprotein E (APOE) ε4 non-carriers with mild cognitive impairment (MCI) due to Alzheimer's disease (AD).Slowing ERC atrophy by AGB101 is associated with less Clinical Dementia Rating Sum of Boxes decline.Slowing ERC atrophy by AGB101 is associated with lower neurofilament light chain.AGB101 treatment reduces neurodegeneration in APOE ε4 non-carriers with MCI due to AD.}, }
@article {pmid39748839, year = {2024}, author = {Van Eldik, LJ and Siemers, ER and Collins, EC and Gold, M and Henley, D and Johannsen, P and Möbius, HJ and Shulman, M and Zhou, J and Carrillo, M and Weber, C}, title = {Understanding recent advances in non-amyloid/non-tau (NANT) biomarkers and therapeutic targets in Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {10}, number = {4}, pages = {e70014}, pmid = {39748839}, issn = {2352-8737}, abstract = {UNLABELLED: The Alzheimer's disease (AD) research community continues to make great strides in expanding approaches for early detection and treatment of the disease, including recent advances in our understanding of fundamental AD pathophysiology beyond the classical targets: beta-amyloid and tau. Recent clinical trial readouts implicate a variety of non-amyloid/non-tau (NANT) approaches that show promise in slowing cognitive decline for people with AD. The Alzheimer's Association Research Roundtable (AARR) meeting held on December 13-14, 2022, reviewed the current state of NANT targets on underlying AD pathophysiology and their contribution to cognitive decline, the current data on a diverse range of NANT biomarkers and therapeutic targets, and the integration of NANT concepts in clinical trial designs. Participants also discussed the current definition of therapies that target underlying AD pathophysiology, what endpoints best define what is considered a meaningful change beyond the current approved definition for clinical efficacy, and how the recent NANT findings should inform the development of future guidelines for AD classification and personalized treatment strategies.
HIGHLIGHTS: The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government to review the current state of non-beta amyloid and non-tau (NANT) targets on underlying Alzheimer's disease (AD) pathophysiology.The totality of scientific and clinical evidence supports the hypothesis that emerging NANT targets play a role in cognitive decline and neurodegeneration in AD. New biomarkers based on NANT targets must be globally developed and implemented with specific consideration of fluid biomarkers as a cost-effective clinical option, to ensure better, more equitable treatment options for AD.}, }
@article {pmid39748838, year = {2024}, author = {Weninger, S and Irizarry, MC and Fleisher, AS and León, T and Maruff, P and Miller, DS and Seleri, S and Carrillo, MC and Weber, CJ}, title = {Alzheimer's disease drug development in an evolving therapeutic landscape.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {10}, number = {4}, pages = {e70015}, pmid = {39748838}, issn = {2352-8737}, abstract = {UNLABELLED: The Alzheimer's disease (AD) research field has entered a new era, where our fundamental understanding of the pathophysiology of AD and advances in biomarkers have not only allowed for earlier, timely, and accurate detection and diagnosis of the disease, but that amyloid removal has been shown to be associated with signals of slowing cognitive and functional decline. Although recent FDA-approved amyloid plaque-lowering monoclonal antibody therapies have shifted the trajectory of AD, additional treatment options will be key to further slowing clinical decline or stopping disease progression. Thus, new and emerging therapies for AD have created an evolving therapeutic landscape. The Alzheimer's Association Research Roundtable (AARR) Spring meeting held on May 23-34, 2023, brought together a broad array of scientific leaders from the AARR membership, academia, industry, and government and regulatory agencies to discuss the future of clinical trials in an era of regulator-approved amyloid-targeting therapies. Participants discussed lessons learned from other neurological diseases where disease-modifying treatments were first approved and key considerations for future clinical trials, for example, trial population real-world representativeness, duration, biomarker screening, efficacy endpoints, combination therapy, as well as overall trial design and the ethical and equity concerns that clinicians, patients, and their families face when considering clinical trial participation.
HIGHLIGHTS: The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry and academia, as well as patients, clinicians, and government and regulatory agency scientists to discuss the topic, "Alzheimer's Disease Drug Development in an Evolving Therapeutic Landscape."While recently approved amyloid-targeting therapies show great promise in providing clinically meaningful outcomes for patients and families, additional treatments, and a better understanding of dosing and administration of these approved treatments, are needed to further slow and eventually prevent clinical decline in AD.Approved therapies will impact many aspects of clinical trial design including the use of placebo-controls, participant re-enrollment, safety monitoring, as well as biomarker selection.This exciting new era in AD research represents a hopeful future for clinicians, patients, and their care partners.}, }
@article {pmid39748776, year = {2025}, author = {Singh Gautam, A and Panda, ES and Balki, S and Pandey, SK and Tiwari, A and Singh, RK}, title = {Therapeutic potential of chrysin in regulation of interleukin-17 signaling in a repeated intranasal amyloid-beta-induced Alzheimer's disease model.}, journal = {Food & function}, volume = {16}, number = {2}, pages = {731-749}, doi = {10.1039/d4fo05278a}, pmid = {39748776}, issn = {2042-650X}, mesh = {Animals ; *Flavonoids/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism ; *Interleukin-17/metabolism ; Male ; Mice ; *Mice, Inbred BALB C ; *Disease Models, Animal ; *Signal Transduction/drug effects ; Administration, Intranasal ; Peptide Fragments ; Brain/metabolism/drug effects ; Humans ; }, abstract = {Objective: The aim of the current study was to study the therapeutic potential of chrysin against repeated intranasal amyloid-beta (Aβ)-induced interleukin-17 (IL-17) signaling in a mouse model of AD. Methods: Male BALB/c mice were daily exposed to intranasal Aβ1-42 (10 μg/10 μL) for seven consecutive days. Chrysin was orally administered at doses of 25, 50 and 100 mg kg[-1] in 0.5% sodium carboxy methyl cellulose suspension from day 5 of Aβ1-42 administration for seven days. Following the treatment, the memory of the animals was appraised using Morris water maze, novel object recognition and passive avoidance tests. Further, the effects of chrysin on Aβ1-42-induced IL-17 signaling and redox levels were evaluated in the cortex and hippocampus regions of the mouse brain through western blot and immunohistochemistry. Results: The exposure to Aβ1-42 through the intranasal route induced a significant decline in the spatial, learning and cognitive memory of the animals, and most interestingly, exposure to Aβ1-42 triggered IL-17-mediated signaling, which resulted in a significant increase in the expression of IL-17RA, Act1 and TRAF6. Furthermore, Aβ1-42 impaired the tissue redox level and inflammatory cytokines in the mouse brain. Alternatively, treatment with chrysin at 25, 50 and 100 mg kg[-1] oral doses alleviated Aβ1-42-mediated memory decline, impaired redox levels and inflammation. Specifically, chrysin downregulated the expression of IL-17 and mediated signaling in the brain regions of the mice. Conclusion: Chrysin was evidenced to be a potent antioxidant and anti-inflammatory agent, clearly showing a protective role against Aβ1-42-induced IL-17-mediated inflammation in the brain of the mice.}, }
@article {pmid39748632, year = {2025}, author = {Rolan, P and Seckl, J and Taylor, J and Harrison, J and Maruff, P and Woodward, M and Mills, R and Jaros, M and Hilt, D}, title = {Clinical Pharmacology and Approach to Dose Selection of Emestedastat, a Novel Tissue Cortisol Synthesis Inhibitor for the Treatment of Central Nervous System Disease.}, journal = {Clinical pharmacology in drug development}, volume = {14}, number = {2}, pages = {105-115}, pmid = {39748632}, issn = {2160-7648}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Hydrocortisone/cerebrospinal fluid ; *11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors/metabolism ; *Dose-Response Relationship, Drug ; *Positron-Emission Tomography/methods ; Cognition/drug effects ; Brain/metabolism/diagnostic imaging/drug effects ; Central Nervous System Diseases/drug therapy/metabolism ; Models, Biological ; Enzyme Inhibitors/administration & dosage/pharmacokinetics/pharmacology ; }, abstract = {This review demonstrates the value of central pharmacodynamics (PD), including positron emission tomography (PET) and computerized cognitive testing, to supplement pharmacokinetic (PK) and peripheral PD for determining the target dose range for clinical efficacy testing of emestedastat, an 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitor. Combined data from 6 clinical trials in cognitively normal volunteers and patients with Alzheimer disease included a population PK model, endocrine PD, a human PET trial (11β-HSD1 brain imaging), and computerized cognitive testing. PK and PET findings were similar in volunteers and patients with Alzheimer disease. PK modeling suggested that 20 mg daily would be optimal to maintain cerebrospinal fluid concentrations above the brain half maximal inhibitory concentration. However, subsequent PET scanning suggested that emestedastat doses of 10 or even 5 mg daily may be sufficient to adequately inhibit 11β-HSD1. With once-daily doses of 5-20 mg in cognitively normal, older volunteers, a consistent pattern of pro-cognitive benefit, without dose-response, was seen as improvement in attention and working memory but not episodic memory. Thus, emestedastat therapeutic activity might be attained at doses lower than those predicted from cerebrospinal fluid drug levels. Doses as low as 5 mg daily may be efficacious and were studied in subsequent trials.}, }
@article {pmid39748415, year = {2025}, author = {Sheng, Z and Wang, L and Chen, M and Zhong, F and Wu, S and Liang, S and Song, J and Chen, L and Chen, Y and Chen, S and Yu, W and Lü, Y}, title = {Cerebrospinal fluid β2-microglobulin promotes the tau pathology through microglia-astrocyte communication in Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {2}, pmid = {39748415}, issn = {1758-9193}, support = {KJZD-K202200405//Key Project of Science and Technology Research Program of Chongqing Municipal Education Commission/ ; 2022YSZX-JSX0002CSTB//Science Innovation Programs Led by the Academicians in Chongqing under Project/ ; W0166//Program for Youth Innovation in Future Medicine, Chongqing Medical University/ ; No. 2021ZD0201802//STI2030-Major Projects/ ; cstc2022ycjh-bgzxm0184//Chongqing Talent Plan/ ; U01 AG024904/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/pathology ; *tau Proteins/cerebrospinal fluid ; Female ; Male ; Aged ; *beta 2-Microglobulin/cerebrospinal fluid/blood ; *Microglia/metabolism/pathology ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid/blood ; *Astrocytes/metabolism/pathology ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Aged, 80 and over ; Receptors, Immunologic ; Peptide Fragments/cerebrospinal fluid ; Middle Aged ; Cell Communication ; Membrane Glycoproteins/cerebrospinal fluid ; }, abstract = {BACKGROUND: Cerebrospinal fluid (CSF) β2-microglobulin (β2M) has been demonstrated as an important factor in β-amyloid (Aβ) neurotoxicity and a potential target for Alzheimer's disease (AD). However, more investigation is required to ascertain the relationship between β2M and glial activities in AD pathogenesis.
METHODS: In this study, 211 participants from the Alzheimer's disease Neuroimaging Initiative (ADNI) with CSF and Plasma β2M, CSF glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), Aβ42, phosphorylated-tau (P-tau) and total tau (T-tau) were divided into four groups, stage 0, 1, 2, and suspected non-AD pathology (SNAP) based on the National Institute on Aging- Alzheimer's Association (NIA-AA) criteria. Multiple linear regression, linear mixed effects models, and causal mediation analyses bootstrapped 10,000 iterations were used to investigate the underlying associations among β2M and CSF biomarkers at baseline and during a longitudinal visit.
RESULTS: CSF β2M concentration decreased with amyloid in stage 1 compared with stage 0 and increased with tau pathology and neurodegeneration in stage 2 and SNAP compared with stage 1. Moreover, CSF β2M level was positively correlated with the Aβ42 (β = 0.230), P-tau (β = 0.564), T-tau (β = 0.603), GFAP (β = 0.552), and sTREM2 (β = 0.641) (all P < 0.001). CSF β2M was only longitudinally correlated with T-tau change. The correlation of CSF β2M with P-tau (proportion = 25.4%, P < 0.001) and T-tau (proportion = 26.7%, P < 0.001) was partially mediated by GFAP in total participants, reproduced in late-life individuals. Furthermore, the astrocyte cascade also partially mediated the pathological relationship between CSF β2M and tau pathology (β2M → GFAP → YKL-40 → P-tau/T-tau, IE: 0.424-0.435, all P < 0.001). Nevertheless, the mediation effects of sTREM2 were not significant. Additionally, there was no association between plasma β2M and CSF biomarkers.
CONCLUSIONS: CSF β2M is dynamic in AD pathology and associated with neuroinflammation. CSF GFAP might mediate the association between β2M and tau pathology, complementing the existing research on the effect of β2M in AD pathology and providing a new perspective on treatment.}, }
@article {pmid39747869, year = {2025}, author = {Wu, W and Zhao, Y and Cheng, X and Xie, X and Zeng, Y and Tao, Q and Yang, Y and Xiao, C and Zhang, Z and Pang, J and Jin, J and He, H and Lin, Y and Li, B and Ma, J and Ye, X and Lin, WJ}, title = {Modulation of glymphatic system by visual circuit activation alleviates memory impairment and apathy in a mouse model of Alzheimer's disease.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {63}, pmid = {39747869}, issn = {2041-1723}, support = {81972967//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82172526//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82272586//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32271068//National Natural Science Foundation of China (National Science Foundation of China)/ ; 202007030001//Guangzhou Science and Technology Program key projects/ ; 202007030001//Guangzhou Science and Technology Program key projects/ ; 202007030001//Guangzhou Science and Technology Program key projects/ ; }, mesh = {Animals ; *Alzheimer Disease/therapy/metabolism ; *Disease Models, Animal ; Mice ; *Mice, Transgenic ; *Aquaporin 4/metabolism/genetics ; *Memory Disorders/therapy/metabolism ; *Amyloid beta-Peptides/metabolism ; *Glymphatic System/metabolism ; Apathy ; Hippocampus/metabolism ; Male ; Light ; Humans ; }, abstract = {Alzheimer's disease is characterized by progressive amyloid deposition and cognitive decline, yet the pathological mechanisms and treatments remain elusive. Here we report the therapeutic potential of low-intensity 40 hertz blue light exposure in a 5xFAD mouse model of Alzheimer's disease. Our findings reveal that light treatment prevents memory decline in 4-month-old 5xFAD mice and motivation loss in 14-month-old 5xFAD mice, accompanied by restoration of glial water channel aquaporin-4 polarity, improved brain drainage efficiency, and a reduction in hippocampal lipid accumulation. We further demonstrate the beneficial effects of 40 hertz blue light are mediated through the activation of the vLGN/IGL-Re visual circuit. Notably, concomitant use of anti-Aβ antibody with 40 hertz blue light demonstrates improved soluble Aβ clearance and cognitive performance in 5xFAD mice. These findings offer functional evidence on the therapeutic effects of 40 hertz blue light in Aβ-related pathologies and suggest its potential as a supplementary strategy to augment the efficacy of antibody-based therapy.}, }
@article {pmid39746896, year = {2025}, author = {Wu, Z and Liu, X and Wang, Y and Zeng, Z and Chen, W and Li, H}, title = {Pseudogene Lamr1-ps1 Aggravates Early Spatial Learning Memory Deficits in Alzheimer's Disease Model Mice.}, journal = {Neuroscience bulletin}, volume = {41}, number = {4}, pages = {600-614}, pmid = {39746896}, issn = {1995-8218}, mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/pathology ; *Pseudogenes/genetics ; Mice ; *Memory Disorders/genetics/metabolism ; MicroRNAs/metabolism/genetics ; Disease Models, Animal ; *Spatial Learning/physiology ; Mice, Transgenic ; Presenilin-1/genetics ; Male ; Amyloid Precursor Protein Secretases/metabolism ; Mice, Inbred C57BL ; Aspartic Acid Endopeptidases/metabolism ; }, abstract = {Alzheimer's disease (AD), a neurodegenerative disorder with complex etiologies, manifests through a cascade of pathological changes before clinical symptoms become apparent. Among these early changes, alterations in the expression of non-coding RNAs (ncRNAs) have emerged as pivotal events. In this study, we focused on the aberrant expression of ncRNAs and revealed that Lamr1-ps1, a pseudogene of the laminin receptor, significantly exacerbates early spatial learning and memory deficits in APP/PS1 mice. Through a combination of bioinformatics prediction and experimental validation, we identified the miR-29c/Bace1 pathway as a potential regulatory mechanism by which Lamr1-ps1 influences AD pathology. Importantly, augmenting the miR-29c-3p levels in mice ameliorated memory deficits, underscoring the therapeutic potential of targeting miR-29c-3p in early AD intervention. This study not only provides new insights into the role of pseudogenes in AD but also consolidates a foundational basis for considering miR-29c as a viable therapeutic target, offering a novel avenue for AD research and treatment strategies.}, }
@article {pmid39746645, year = {2025}, author = {Rajab, HA and Al-Kuraishy, HM and Shokr, MM and Al-Gareeb, AI and Al-Harchan, NA and Alruwaili, M and Papadakis, M and Alexiou, A and Batiha, GE}, title = {Statins for vascular dementia: A hype or hope.}, journal = {Neuroscience}, volume = {567}, number = {}, pages = {45-55}, doi = {10.1016/j.neuroscience.2024.12.059}, pmid = {39746645}, issn = {1873-7544}, mesh = {Humans ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; *Dementia, Vascular/drug therapy ; Animals ; }, abstract = {Vascular dementia (VaD) is a second most common type of dementia subsequent to Alzheimer disease (AD). VaD is characterized by cognitive impairment and memory loss that may progress due to the development of cerebral amyloid angiopathy (CAA) a hallmark of AD. CAA triggers the progression of ischemic and hemorrhagic strokes with the subsequent the development of VaD and mixed dementia. Early diagnosis of patients with appropriate use of anti-inflammatory can prevent CAA-related inflammation and VaD development. Currently, there are no effective drugs in the management of VaD. Of note, cholesterol-lowering agent statins which are commonly used in patients with vascular diseases and dyslipidemia may affect the progression of VaD. Many previous studies highlighted the potential therapeutic efficacy of statins in treating VaD. Though, the underlying mechanisms of statins in prevention and treatment of VaD are not fully clarified. Consequently, this review aims to discuss the mechanistic role of statins in the management of VaD, and how statins may adversely affect the cognitive function in VaD patients.}, }
@article {pmid39746450, year = {2024}, author = {Guan, DX and Peters, ME and Pike, GB and Ballard, C and Creese, B and Corbett, A and Pickering, E and Roach, P and Smith, EE and Ismail, Z}, title = {Cognitive, Behavioral, and Functional Outcomes of Suspected Mild Traumatic Brain Injury in Community-Dwelling Older Persons Without Mild Cognitive Impairment or Dementia.}, journal = {Journal of the Academy of Consultation-Liaison Psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaclp.2024.12.004}, pmid = {39746450}, issn = {2667-2960}, abstract = {BACKGROUND: Traumatic brain injury is associated with greater risk and earlier onset of dementia.
OBJECTIVE: This study investigated whether later-life changes in subjective cognition and behavior - potential markers of Alzheimer disease - could be observed in cognitively unimpaired older persons with a history of suspected mild traumatic brain injury (smTBI) earlier in life and whether changes in cognition and behavior mediated the link between smTBI and daily function.
METHODS: Data for 1392 participants from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging were analyzed. A validated self-reported brain injury screening questionnaire was used to determine the history of smTBI. Outcomes were measured using the Everyday Cognition scale (for subjective cognitive decline [SCD]), Mild Behavioral Impairment (MBI) Checklist, and Standard Assessment of Global Everyday Activities (for function). Inverse probability of treatment weighted logistic and negative binomial regressions were used to model smTBI (exposure) associations with SCD and MBI statuses, and Everyday Cognition-II and MBI Checklist total scores, respectively. Mediation analyses were conducted using bootstrapping.
RESULTS: History of smTBI was linked to higher odds of SCD (odds ratio = 1.45, 95% confidence interval: [1.14-1.84]) or MBI (odds ratio = 1.75, 95% confidence interval: [1.54-1.98]), as well as 24% (95% confidence interval: [18%-31%]) higher Everyday Cognition-II and 52% (95% confidence interval: [41%-63%]) higher MBI Checklist total scores. Finally, SCD and MBI mediated approximately 45% and 56%, respectively, of the association between smTBI history and poorer function, as indicated by higher Standard Assessment of Global Everyday Activities total scores.
CONCLUSIONS: smTBI at any point in the life course is linked to poorer cognition and behavior even in community-dwelling older persons without MCI or dementia. Older persons with smTBI may benefit from early dementia risk assessment using tools that measure changes in cognition and behavior. Interventions for declining cognition and behavior may also be beneficial in this population to address functional impairment.}, }
@article {pmid39746296, year = {2025}, author = {Newman, JL and Brook, Z and Cox, SJ and Phillips, JS}, title = {Towards the automatic detection of activities of daily living using eye-movement and accelerometer data with neural networks.}, journal = {Computers in biology and medicine}, volume = {186}, number = {}, pages = {109607}, doi = {10.1016/j.compbiomed.2024.109607}, pmid = {39746296}, issn = {1879-0534}, mesh = {Humans ; *Activities of Daily Living ; *Neural Networks, Computer ; *Accelerometry/methods ; Eye Movements/physiology ; Male ; Female ; }, abstract = {Early diagnosis of neurodegenerative diseases, such as Alzheimer's disease, improves treatment and care outcomes for patients. Early signs of cognitive decline can be detected using functional scales, which are written records completed by a clinician or carer, detailing a patient's capability to perform routine activities of daily living. For example, tasks requiring planning, such as meal preparation, are some of the earliest affected by early mild cognitive impairment. In this article, we describe work towards the development of a system to automatically discriminate and objectively quantify activities of daily living. We train a selection of neural networks to discriminate a novel list of 14 activities, specially selected to overlap with those measured by existing functional scales. Our dataset consists of eight hours of development data captured from four individuals wearing the Continuous Ambulatory Vestibular Assessment (CAVA) device, which was originally developed to aid the diagnosis of vertigo. Using frequency domain recognition features derived from eye-movement and accelerometer data, we compare several classification approaches, including three bespoke neural networks, and two established network architectures commonly applied to time-series classification problems. In 10-fold cross-validation experiments, a peak mean accuracy of 64.1% is obtained. The highest accuracy across all folds is 75.3%, produced by networks comprising Gated Recurrent Units. The addition of eye-movement data is shown to improve discrimination compared to using accelerometer data alone, by close to 9%. Classification accuracy is shown to degrade if the system is trained such that test subjects are excluded from the training data, with the small size of the dataset given as a likely explanation. Our findings demonstrate that the addition of eye-movement data can significantly improve the discrimination of daily activities, and that neural networks are well suited to this task.}, }
@article {pmid39745072, year = {2025}, author = {Dengiz, A and Cetisli-Korkmaz, N and Kitis, A}, title = {Effect of the strategy game Mangala on cognitive function, anxiety, depression, and fine motor skills in individuals with Alzheimer's disease: A randomized controlled trial.}, journal = {Applied neuropsychology. Adult}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/23279095.2024.2448503}, pmid = {39745072}, issn = {2327-9109}, abstract = {Cognitive impairment, changes in mood, and decrease in fine motor skills are some of the most common symptoms experienced by individuals with Alzheimer's Disease (AD). This study aimed to investigate the effects of the Turkish intelligence and strategy game Mangala on cognitive functions, anxiety, depression, and fine motor skills in individuals with AD. In this randomized controlled study, 37 participants were divided into Mangala Group (MG) and Control Group (CG). Both the MG (n = 18) and the CG (n = 19) attended daily physiotherapy and rehabilitation sessions. Additionally, the MG played Mangala 2 sessions/week for six weeks. The mood state was evaluated using the Hospital Anxiety and Depression Scale (HAD), cognitive functions were examined using the Montreal Cognitive Assessment Scale (MoCA), and fine motor skills were measured using the Nine Hole Peg Test (NHPT). There was no significant difference between the groups pretreatment in terms of MoCA, depression and NHPT values (p > .05), except anxiety levels (p= .009) The MG showed significant improvement post-treatment in terms of MoCA and HAD anxiety (p =.0001 and p =.0008), HAD depression and fine motor skills (p =.043 and p =.0001). There were significant improvements in favor of MG in MoCA (p =.014) and NHPT (p =.004), but not in HAD anxiety (p =.782) and depression (p =.514) scores in terms of delta (difference between pre and post treatment) values. To prevent cognitive decline, reduce depression, and improve fine motor skills in patients with AD, The Mangala game may be a good alternative.}, }
@article {pmid39744933, year = {2025}, author = {Meise, E and Corbett, J and Meyer, A and Grevelding, P and Hrdlicka, HC}, title = {Construct Validity, Criterion Validity, and Internal Consistency of GOT-Cog©, a Novel Occupational Therapy Cognitive Screen.}, journal = {The American journal of occupational therapy : official publication of the American Occupational Therapy Association}, volume = {79}, number = {1}, pages = {}, doi = {10.5014/ajot.2025.050832}, pmid = {39744933}, issn = {0272-9490}, mesh = {Humans ; *Occupational Therapy/methods ; Female ; Male ; Reproducibility of Results ; Middle Aged ; *Cross-Over Studies ; Aged ; Cognition ; Adult ; Neuropsychological Tests ; }, abstract = {IMPORTANCE: No single cognitive screen adequately captures the cognitive domains needed for inpatient occupational therapy treatment planning.
OBJECTIVE: To assess the construct validity of the Gaylord Occupational Therapy Cognitive (GOT-Cog©) screen, a novel comprehensive cognitive screen that evaluates functional cognition.
DESIGN: Randomized crossover controlled study design using the St. Louis University Mental Status (SLUMS) exam as a comparator.
SETTING: Long-term acute-care hospital.
PARTICIPANTS: Participants were inpatients admitted to Gaylord Hospital who were ages 18 yr or older, prescribed occupational therapy services, with no documented history of dementia, Alzheimer's, or preexisting intellectual disability and no present aphasia.
INTERVENTION: During participants' initial occupational therapy evaluation, either the SLUMS or GOT-Cog were randomly delivered; the screen that was not delivered on admission was delivered 22 to 26 hr later by the same or a different clinician.
OUTCOMES AND MEASURES: GOT-Cog and SLUMS total scores and individual item and domain scores.
RESULTS: Ninety-eight participants yielded sufficient data for analysis. Total GOT-Cog and SLUMS scores positively correlated (p < .0001). All shared domains between GOT-Cog and SLUMS were significantly correlated (p ≤ .0155); similarly, all unique domains showed significant correlations with both GOT-Cog and SLUMS total scores (p ≤ .0194). No ordering effects were observed (p ≥ .8081). Despite having 11 more items, GOT-Cog took only 6 min longer to complete (10 vs. 16 min; p < .0001). Both demonstrated adequate internal consistency.
CONCLUSIONS AND RELEVANCE: The GOT-Cog has overall strong construct and criterion validity. Going forward, we will evaluate the rater reliability and responsiveness of the GOT-Cog. Plain-Language Summary: Occupational therapists evaluate clients' cognitive strengths and limitations in relation to activities of daily living and instrumental activities of daily living. Occupational therapists use this evaluation to help clients identify strategies to adapt to their specific environments, support their independence, and improve their ability to perform tasks. No cognitive screen currently exists that adequately evaluates a person's cognitive domains as part of treatment planning for inpatient occupational therapy. This study reviewed the construct validity, criterion validity, and internal consistency of the Gaylord Occupational Therapy Cognitive screen (GOT-Cog), a new comprehensive cognitive screen. The GOT-Cog was used with inpatients at a long-term acute-care hospital as part of their initial occupational therapy evaluation. The study found that the GOT-Cog has overall strong construct and criterion validity. Future studies will evaluate the interrater and intrarater reliability and responsiveness of this new cognitive screen.}, }
@article {pmid39744681, year = {2025}, author = {Park, M and Ryu, H and Heo, S and Kim, B and Park, J and Lim, KH and Han, SB and Park, H}, title = {Targeted demethylation of cathepsin D via epigenome editing rescues pathology in Alzheimer's disease mouse model.}, journal = {Theranostics}, volume = {15}, number = {2}, pages = {428-438}, pmid = {39744681}, issn = {1838-7640}, mesh = {Animals ; *Alzheimer Disease/genetics/therapy/metabolism ; *Disease Models, Animal ; Mice ; *Amyloid beta-Peptides/metabolism ; *Cathepsin D/metabolism/genetics ; *Gene Editing/methods ; *Mice, Transgenic ; *Epigenome ; Neurons/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Humans ; Brain/metabolism/pathology ; Genetic Therapy/methods ; CRISPR-Cas Systems/genetics ; Male ; }, abstract = {Background: Cathepsin D (Ctsd) has emerged as a promising therapeutic target for Alzheimer's disease (AD) due to its role in degrading intracellular amyloid beta (Aβ). Enhancing Ctsd activity could reduce Aβ42 accumulation and restore the Aβ42/40 ratio, offering a potential AD treatment strategy. Methods: This study explored Ctsd demethylation in AD mouse models using dCas9-Tet1-mediated epigenome editing. We identified dCas9-Tet1 as an effective tool for demethylating the endogenous Ctsd gene in primary neurons and in vivo brains. Results: Treatment with Ctsd-targeted dCas9-Tet1 in primary neurons overexpressing mutant APP (mutAPP) reduced Aβ peptide levels and the Aβ42/40 ratio. Additionally, in vivo demethylation of Ctsd via dCas9-Tet1 in 5xFAD mice significantly altered Aβ levels and alleviated cognitive and behavioral deficits. Conclusion: These findings offer valuable insights into developing epigenome editing-based gene therapy strategies for AD.}, }
@article {pmid39744037, year = {2024}, author = {Reitere, Ē and Duhovska, J and Karkou, V and Mārtinsone, K}, title = {Telehealth in arts therapies for neurodevelopmental and neurological disorders: a scoping review.}, journal = {Frontiers in psychology}, volume = {15}, number = {}, pages = {1484726}, pmid = {39744037}, issn = {1664-1078}, abstract = {BACKGROUND: Arts therapies, encompassing art therapy, music therapy, drama therapy, and dance movement therapy with the broader practice of expressive arts therapies, have demonstrated positive outcomes in the treatment of neurodevelopmental and neurological disorders (NNDs). Integrating arts therapies into telehealth has become increasingly important to improve accessibility for people with mobility impairments or those living in remote areas. This study aims to map the existing body of literature to provide an in-depth overview of telehealth in arts therapies for individuals with NNDs.
METHODOLOGY: This scoping review followed the PRISMA guidelines. Six databases were systematically searched, with 2,888 articles screened for eligibility. Inclusion criteria focused on primary research peer-reviewed articles in English that addressed telehealth arts therapies for NNDs.
RESULTS: Seventeen telehealth studies published between 2009 and March 2024 were included, with a notable increase in publications after 2020. The studies covered various neurodevelopmental disorders, including autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), Rett syndrome, and neurological disorders such as stroke, epilepsy, cerebral palsy, central nervous system (CNS) tumors, dementia, Alzheimer's disease, Parkinson's disease, spinal cord injuries, and mild cognitive impairment. Music therapy was the most widely studied modality. Interventions ranged from therapeutic singing and songwriting to virtual reality experiences. Different platforms and specialized virtual environments were used alongside pre-recorded sessions. Positive benefits included psychological enrichment, social connectivity, cognitive improvements, and brain changes, although some studies reported mixed or no significant effects in certain areas.
CONCLUSION: Telehealth in arts therapies significantly benefits individuals with NNDs, improving accessibility and providing psychological, emotional, social, and cognitive benefits. The positive benefits observed highlight the potential of these interventions to improve overall well-being and daily functioning. Future research may focus on high-quality qualitative studies and neuroimaging assessments to further validate the impact of telehealth arts therapies.}, }
@article {pmid39743075, year = {2025}, author = {Ding, X and Zuo, Y and Liu, Z and Sun, Y and Wang, L and Xie, Y and Liu, G and Liu, C}, title = {Recombinant neurotrophin-3 with the ability to penetrate the blood-brain barrier: A new strategy against Alzheimer's disease.}, journal = {International journal of biological macromolecules}, volume = {293}, number = {}, pages = {139359}, doi = {10.1016/j.ijbiomac.2024.139359}, pmid = {39743075}, issn = {1879-0003}, mesh = {*Neurotrophin 3/genetics/metabolism ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Blood-Brain Barrier/metabolism ; Animals ; Mice ; *Recombinant Proteins/pharmacology/genetics ; Humans ; Hippocampus/metabolism/pathology ; Oxidative Stress/drug effects ; Disease Models, Animal ; Apoptosis/drug effects ; Neurons/metabolism/drug effects ; }, abstract = {This study aims to develop and evaluate a novel therapeutic strategy for Alzheimer's disease (AD) by overcoming the blood-brain barrier (BBB) limitations of Neurotrophin-3 (NT-3). NT-3, a critical neurotrophic factor, plays essential roles in hippocampal neuron growth, survival, and synaptic plasticity, making it a promising candidate for AD treatment. However, its clinical application is hindered by its inability to cross the BBB. To address this, we utilized genetic engineering techniques to fuse the TAT transmembrane peptide with NT-3, producing a recombinant NT-3 (T-NT-3) with enhanced membrane-penetrating capability. Protein characterization confirmed that T-NT-3 possesses good stability and the ability to cross the BBB. In vitro experiments demonstrated that T-NT-3 inhibits oxidative stress, apoptosis, and inflammatory responses in neural cells by activating TrkC receptors and suppressing M1 microglial activation. In vivo, T-NT-3 improved cognitive and memory impairments in APP/PS1 mice and reduced AD-associated pathological changes. These findings highlight the mechanisms by which T-NT-3 alleviates hippocampal neurotoxicity, providing a foundation for its future application as a recombinant protein therapy for AD.}, }
@article {pmid39743062, year = {2025}, author = {Shao, X and Fan, T and Yan, C and Cao, X and Wang, C and Wang, X and Guan, P and Fan, L and Hu, X}, title = {Multifunctional selenium-doped carbon dots for modulating Alzheimer's disease related toxic ions, inhibiting amyloid aggregation and scavenging reactive oxygen species.}, journal = {International journal of biological macromolecules}, volume = {293}, number = {}, pages = {139333}, doi = {10.1016/j.ijbiomac.2024.139333}, pmid = {39743062}, issn = {1879-0003}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Carbon/chemistry ; *Selenium/chemistry/pharmacology ; *Reactive Oxygen Species/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; Humans ; *Copper/chemistry ; Protein Aggregates/drug effects ; Quantum Dots/chemistry/toxicity ; Oxidative Stress/drug effects ; Free Radical Scavengers/pharmacology/chemistry ; Animals ; Ions ; }, abstract = {β-Amyloid (Aβ) protein deposition, oxidative stress, and metal ion imbalance are established pathological features of Alzheimer's disease (AD), highlighting the imperative to efficiently reduce Aβ aggregates formation, alleviate oxidative stress, and chelate metal ions. Existing research indicates the necessity of developing multifunctional nanomaterials to facilitate multi-target therapy. In this work, we designed and prepared multifunctional selenium-doped carbonized polymer dots (SeCDs), and examined the multifunctionality at inhibiting Aβ, cleaning reactive oxygen species (ROS), and modulating copper ions. SeCDs exhibit efficient clearance of active hydroxyl radicals and superoxide anion radicals. In addition, SeCDs can chelate Cu ions, therefore reducing the cytotoxicity linked to the Aβ-Cu complex. More importantly, SeCDs can effectively reduce the level of intracellular reactive oxygen species. This study demonstrates the potential of carbon dots as a multifunctional β-sheet disruptor, while multifunctional SeCDs offer promising avenues for further research in the multi-target treatment of Alzheimer's disease. Meanwhile, this strategy provides a new perspective on the development of zero-dimensional carbon materials in Alzheimer's therapy.}, }
@article {pmid39742695, year = {2025}, author = {Tan, JH and Laurell, AA and Sidhom, E and Rowe, JB and O'Brien, JT}, title = {The effect of Amyloid and Tau Co-pathology on disease progression in Lewy body dementia: A systematic review.}, journal = {Parkinsonism & related disorders}, volume = {131}, number = {}, pages = {107255}, doi = {10.1016/j.parkreldis.2024.107255}, pmid = {39742695}, issn = {1873-5126}, mesh = {Humans ; *Lewy Body Disease/pathology ; *Disease Progression ; *tau Proteins/cerebrospinal fluid/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; }, abstract = {Co-morbid Alzheimer's disease (AD) pathology (amyloid-beta and tau) is commonly observed in Lewy body dementia (LBD), and this may affect clinical outcomes. A systematic review of the effect of AD co-pathology on longitudinal clinical outcomes in LBD was conducted. A search of MEDLINE and EMBASE (October 2024) yielded n = 3558 records that were screened by two independent reviewers. Included studies (n = 31) assessed AD co-pathology in LBD by neuropathologic examination (n = 10), positron emission tomography (PET) imaging (n = 7), cerebrospinal fluid (CSF) (n = 8) or plasma biomarkers (n = 6); and reported longitudinal clinical outcomes including cognitive and functional decline, mortality, or treatment response. Most neuropathology, PET and plasma studies reviewed demonstrated poorer prognosis in LBD + compared to LBD-, but discrepant findings were seen among CSF studies. No included study reported better outcomes in LBD+. The risk of bias was assessed with the Quality in Prognosis Studies tool. All studies rated as low risk of bias (n = 12) reported that the presence of AD co-pathology in LBD (LBD+) was associated with accelerated cognitive decline (n = 7/7), accelerated functional decline (n = 3/3), greater mortality (n = 2/2) and poorer response to treatment (n = 1/1). Among these studies, LBD+ was associated with an additional decline of -0.53 to -2.9 MMSE points/year compared to LBD-, while one study reported an adjusted hazard ratio for mortality in LBD + as 3.70. We conclude that AD co-pathology is associated with worse clinical outcomes in LBD whether assessed by greater cognitive decline, increased mortality or greater decline on functional assessment scales.}, }
@article {pmid39742273, year = {2024}, author = {Van Gaever, F and Mingneau, F and Vanherle, S and Driege, Y and Haegman, M and Van Wonterghem, E and Xie, J and Vandenbroucke, RE and Hendriks, JJA and Beyaert, R and Staal, J}, title = {The phytohormone abscisic acid enhances remyelination in mouse models of multiple sclerosis.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1500697}, pmid = {39742273}, issn = {1664-3224}, mesh = {Animals ; *Abscisic Acid/pharmacology/metabolism ; Mice ; *Multiple Sclerosis/drug therapy/metabolism ; *Disease Models, Animal ; *Remyelination/drug effects ; Mice, Inbred C57BL ; Plant Growth Regulators/pharmacology ; Myelin Sheath/metabolism/drug effects ; Microglia/drug effects/metabolism ; Encephalomyelitis, Autoimmune, Experimental/drug therapy/immunology/metabolism ; Female ; }, abstract = {INTRODUCTION: Over the past few decades, there has been a sudden rise in the incidence of Multiple Sclerosis (MS) in Western countries. However, current treatments often show limited efficacy in certain patients and are associated with adverse effects, which highlights the need for safer and more effective therapeutic approaches. Environmental factors, particularly dietary habits, have been observed to play a substantial role in the development of MS. In this study, we are the first to investigate the potential protective effect of the phytohormone abscisic acid (ABA) in MS. ABA, which is abundant in fruits such as figs, apricots and bilberries, is known to cross the blood-brain barrier and has demonstrated neuroprotective effects in conditions like depression and Alzheimer's disease.
METHODS: In this study, we investigated whether ABA supplementation enhances remyelination in both ex vivo and in vivo mouse models.
RESULTS: Our results indicated that ABA enhanced remyelination and that this enhanced remyelination is associated with increased lipid droplet load, reduced levels of degraded myelin, and a higher abundance of F4/80+ cells in the demyelinated brain of mice treated with ABA. In in vitro models, we further demonstrated that ABA treatment elevates lipid droplet formation by enhancing the phagocytic capacity of macrophages. Additionally, in a mouse model of microglial activation, we showed that ABA-treated mice maintain a less inflammatory microglial phenotype.
CONCLUSION: Our findings highlight a crucial role for macrophages and microglia in enabling ABA to enhance the remyelination process. Furthermore, ABA's ability to improve remyelination together with its ability to reduce microglial activation, make ABA a promising candidate for modulating macrophage phenotype and reducing neuroinflammation in MS.}, }
@article {pmid39742156, year = {2024}, author = {Meng, L and Gu, T and Yu, P and Zhang, Z and Wei, Z}, title = {The role of microglia in Neuroinflammation associated with cardiopulmonary bypass.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1496520}, pmid = {39742156}, issn = {1662-5102}, abstract = {Cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) are indispensable core techniques in cardiac surgery. Numerous studies have shown that cardiopulmonary bypass and deep hypothermic circulatory arrest are associated with the occurrence of neuroinflammation, accompanied by the activation of microglia. Microglia, as macrophages in the central nervous system, play an irreplaceable role in neuroinflammation. Current research on neuroinflammation induced by microglia activation mainly focuses on neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, neuropathic pain, acquired brain injury, and others. However, there is relatively limited research on microglia and neuroinflammation under conditions of cardiopulmonary bypass and deep hypothermic circulatory arrest. The close relationship between cardiopulmonary bypass, deep hypothermic circulatory arrest, and cardiac surgery underscores the importance of identifying targets for intervening in neuroinflammation through microglia. This could greatly benefit cardiac surgery patients during cardiopulmonary bypass and the perioperative period, significantly improving patient prognosis. This review article provides the first comprehensive discussion on the signaling pathways associated with neuroinflammation triggered by microglia activation, the impact of cardiopulmonary bypass on microglia, as well as the current status and advancements in cardiopulmonary bypass animal models. It provides new insights and methods for the treatment of neuroinflammation related to cardiopulmonary bypass and deep hypothermic circulatory arrest, holding significant importance for clinical treatment by cardiac surgeons, management strategies by cardiopulmonary bypass physicians, and the development of neurologically related medications.}, }
@article {pmid39741520, year = {2024}, author = {Wei, Y and Du, X and Guo, H and Han, J and Liu, M}, title = {Mitochondrial dysfunction and Alzheimer's disease: pathogenesis of mitochondrial transfer.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1517965}, pmid = {39741520}, issn = {1663-4365}, abstract = {In recent years, mitochondrial transfer has emerged as a universal phenomenon intertwined with various systemic physiological and pathological processes. Alzheimer's disease (AD) is a multifactorial disease, with mitochondrial dysfunction at its core. Although numerous studies have found evidence of mitochondrial transfer in AD models, the precise mechanisms remain unclear. Recent studies have revealed the dynamic transfer of mitochondria in Alzheimer's disease, not only between nerve cells and glial cells, but also between nerve cells and glial cells. In this review, we explore the pathways and mechanisms of mitochondrial transfer in Alzheimer's disease and how these transfer activities contribute to disease progression.}, }
@article {pmid39740882, year = {2025}, author = {Negru, DC and Bungau, SG and Radu, A and Tit, DM and Radu, AF and Nistor-Cseppento, DC and Negru, PA}, title = {Evaluation of the Alkaloids as Inhibitors of Human Acetylcholinesterase by Molecular Docking and ADME Prediction.}, journal = {In vivo (Athens, Greece)}, volume = {39}, number = {1}, pages = {236-250}, pmid = {39740882}, issn = {1791-7549}, mesh = {*Molecular Docking Simulation ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Humans ; *Acetylcholinesterase/metabolism/chemistry ; *Alkaloids/chemistry/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Ligands ; Blood-Brain Barrier/metabolism ; Protein Binding ; }, abstract = {BACKGROUND/AIM: Alzheimer's disease is a complex, incurable to date, multifactorial disease, which suggests the need for continued development of pharmacotherapy.
MATERIALS AND METHODS: A comprehensive literature search was conducted to identify known ligands with anticholinesterase activity, resulting in the discovery of over 100 alkaloids that are also available in the PubChem database. Subsequently, the ligands underwent molecular docking to evaluate their affinity for the target enzyme. The ligands with the greatest affinity were selected for ligand-based virtual screening.
RESULTS: Three potential compounds were identified for further investigation: ZINC000055042508, ZINC000096316348, and ZINC000067 446933. Computational models of absorption, distribution, metabolism, and excretion (ADME) properties prediction using SwissADME suggested that ZINC000055042508 and ZINC000067446933 can permeate the blood-brain barrier and exhibit non-substrate behavior with respect to P-glycoprotein. In contrast, the ProTox-III prediction indicated the potential for all three compounds to penetrate the blood-brain barrier.
CONCLUSION: These alkaloid derivatives warrant further investigation as potential acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.}, }
@article {pmid39740766, year = {2025}, author = {Zullo, AR and Riester, MR and Varma, H and Daiello, LA and Gerlach, LB and Coe, AB and Thomas, KS and Joshi, R and Zhang, T and Shireman, TI and Bynum, JPW}, title = {Effects of Nursing Home Changes in Antipsychotic Use on Outcomes among Residents with Dementia.}, journal = {Journal of the American Medical Directors Association}, volume = {26}, number = {3}, pages = {105439}, pmid = {39740766}, issn = {1538-9375}, support = {RF1 AG089541/AG/NIA NIH HHS/United States ; R01 AG065722/AG/NIA NIH HHS/United States ; R01 AG088522/AG/NIA NIH HHS/United States ; P01 AG027296/AG/NIA NIH HHS/United States ; R01 AG077620/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Nursing Homes ; *Antipsychotic Agents/therapeutic use ; Male ; Female ; *Dementia/drug therapy ; Aged, 80 and over ; United States ; Aged ; *Hospitalization/statistics & numerical data ; Medicare ; }, abstract = {OBJECTIVES: Little information exists on whether nationwide efforts to reduce antipsychotic use among nursing home (NH) residents with Alzheimer's disease and related dementias improved mortality and hospitalization outcomes for residents. Our objective was to examine the effect of NH decreases in antipsychotic use on outcomes for residents with Alzheimer's disease and related dementias.
DESIGN: Observational nationwide study that emulated a series of cluster randomized trials.
SETTING AND PARTICIPANTS: Long-stay NH residents with Alzheimer's disease and related dementias in US NHs.
METHODS: The study used data from Medicare claims to emulate cluster randomized trials in which NHs were assigned to either decrease or maintain/increase antipsychotic use. Outcome ascertainment for the first trial began on April 1, 2012 (ie, following the announcement of the National Partnership to Improve Dementia Care in NHs). The last day of follow-up was December 31, 2017. Outcomes measured included 12-month all-cause mortality, all-cause hospitalization, and hospitalization for stroke, myocardial infarction, fracture, and psychiatric conditions. Use of other psychotropic medications was also evaluated. Inverse-probability-of-treatment-weighted pooled Poisson regression models estimated covariate-adjusted risk ratios (RRs).
RESULTS: The adjusted risks of death (RR, 1.01; 95% CLs, 1.00, 1.01), all-cause hospitalization (RR, 1.00; 95% CLs, 1.00, 1.01), and hospitalization for specific causes were similar between resident-trials in NHs that decreased vs maintained/increased antipsychotic use. Use of antidepressants, anxiolytic/sedative-hypnotics, anticonvulsant/mood stabilizers, and antidementia medications was slightly higher among resident-trials in NHs that decreased antipsychotic use.
CONCLUSIONS AND IMPLICATIONS: Decreases in NH antipsychotic use do not appear to improve resident outcomes. Intensive initiatives focused predominantly on achieving a decrease in antipsychotic use may not be effective at improving mortality and hospitalization outcomes for residents with Alzheimer's disease and related dementias. These findings suggest the need for better strategies that incorporate safe and effective nonpharmacological or pharmacological alternatives for managing neuropsychiatric symptoms of dementia.}, }
@article {pmid39740737, year = {2025}, author = {Kaur, R and Pandey, S and Gupta, S and Singh, J}, title = {Harnessing the potential of long non-coding RNAs in the pathophysiology of Alzheimer's disease.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115134}, doi = {10.1016/j.expneurol.2024.115134}, pmid = {39740737}, issn = {1090-2430}, mesh = {*Alzheimer Disease/genetics/metabolism/physiopathology ; *RNA, Long Noncoding/genetics/metabolism ; Humans ; Animals ; Biomarkers/metabolism ; }, abstract = {Alzheimer's disease (AD), a diverse neurodegenerative disease, is the leading cause of dementia, accounting for 60-80 % of all cases. The pathophysiology of Alzheimer's disease is unknown, and there is no cure at this time. Recent developments in transcriptome-wide profiling have led to the identification of a number of non-coding RNAs (ncRNAs). Among these, long non-coding RNAs (lncRNAs)-long transcripts that don't seem to be able to code for proteins-have drawn attention because they function as regulatory agents in a variety of biological processes. Recent research suggests that lncRNAs play a role in the pathogenesis of Alzheimer's disease by modulating tau hyperphosphorylation, amyloid production, synaptic impairment, neuroinflammation, mitochondrial dysfunction, and oxidative stress, though their precise effects on the disorder are unknown. The biology and modes of action of the best-characterized lncRNAs in AD will be outlined here, with an emphasis on their possible involvement in the pathophysiology of the disease. As lncRNAs may offer prospective prognostic/diagnostic biomarkers and therapeutic targets for the treatment of AD, a greater comprehension of the molecular processes and the intricate network of interactions in which they are implicated could pave the way for future research.}, }
@article {pmid39740711, year = {2025}, author = {Dileep, KV and Sakai, N and Ihara, K and Nakata, A and Ito, A and Sivaraman, DM and Yip, CW and Shin, JW and Yoshida, M and Shirouzu, M and Zhang, KYJ}, title = {Identification of benzimidazole-6-carboxamide based inhibitors of secretory glutaminyl cyclase for the treatment of Alzheimer's disease.}, journal = {International journal of biological macromolecules}, volume = {293}, number = {}, pages = {139320}, doi = {10.1016/j.ijbiomac.2024.139320}, pmid = {39740711}, issn = {1879-0003}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Aminoacyltransferases/antagonists & inhibitors/chemistry/metabolism ; *Benzimidazoles/chemistry/pharmacology ; *Enzyme Inhibitors/chemistry/pharmacology ; Cell Line, Tumor ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors/chemistry ; Molecular Docking Simulation ; }, abstract = {The formation of the pyroglutamate variant of amyloid beta (pGlu-Aβ), which is extremely hydrophobic, rapidly aggregating, and highly neurotoxic, is mediated by the action of secretory glutaminyl cyclase (sQC). The pGlu-Aβ often acts as a seed for the aggregation of the full length Aβ and contributes to the overall load of Aβ plaques in Alzheimer's disease (AD). Therefore, inhibiting sQC is a potential approach to limit the formation of pGlu-Aβ and to modify the progression of AD. This study presents two novel molecules containing benzimidazole-6-carboxamide, namely LSB-09 and LSB-24, as promising sQC inhibitors. These inhibitors demonstrated moderate toxicity in human neuroblastoma cell lines and possessed IC50 values in the micromolar range (40 and 4 μM for LSB-09 and LSB-24, respectively). Additionally, the X-ray crystal structure of the sQC-LSB-09 complex revealed a unique binding mode, and a systematic computational investigation elucidated the binding mode for LSB-24. The binding mode of these two benzimidazole-6-carboxamide inhibitors offers a potential platform for designing attractive lead candidates against sQC.}, }
@article {pmid39740290, year = {2025}, author = {Yang, Y and Drake, SA and Wang, J and Shen, GC and Miao, H and Morgan, RO and Du, XL and Lairson, DR}, title = {Comparing total medical costs of surgical treatment versus nonoperative care for femoral neck fractures among Alzheimer's disease patients: A retrospective cohort study.}, journal = {Geriatric nursing (New York, N.Y.)}, volume = {61}, number = {}, pages = {499-505}, doi = {10.1016/j.gerinurse.2024.12.023}, pmid = {39740290}, issn = {1528-3984}, mesh = {Humans ; Retrospective Studies ; *Femoral Neck Fractures/surgery/economics ; Male ; Female ; *Alzheimer Disease/economics ; Aged ; Aged, 80 and over ; Health Care Costs ; Comorbidity ; }, abstract = {OBJECTIVES: To compare the total medical costs associated with operative versus non-operative medical procedures for femoral neck fractures in older adults with Alzheimer's disease (AD).
METHODS: This retrospective cohort study examined 4,157 Optum beneficiaries diagnosed with AD who filed an initial claim for femoral neck fracture between January 1, 2012, and December 31, 2017. Generalized linear regression with Gamma log link function was performed to evaluate total medical costs between surgical treatment and non-operative care while controlling for covariates.
RESULTS: The adjusted total medical costs per patient for arthroplasty and internal fixation were $207,392 and $170,210, exceeding the total medical costs for non-operative cases ($63,041). Comorbidities such as history of falls, sarcopenia/muscle weakness, abnormal weight loss, depression, and fatigue also had a significant impact on the overall medical costs.
CONCLUSIONS: Surgical intervention for femoral neck fractures incurs higher costs but offers better clinical outcomes than non-operative care.}, }
@article {pmid39740121, year = {2025}, author = {Erickson, CM and Largent, EA and O'Brien, KS}, title = {Paving the way for Alzheimer's disease blood-based biomarkers in primary care.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14203}, pmid = {39740121}, issn = {1552-5279}, support = {//Greenwall Foundation/ ; }, mesh = {*Alzheimer Disease/diagnosis ; Humans ; *Biomarkers/blood ; *Primary Health Care ; }, abstract = {Blood-based biomarkers (BBBMs) for Alzheimer's disease (AD) have the potential to revolutionize the detection and management of cognitive impairment. AD BBBMs are not currently recommended for use in primary care but may soon be as research demonstrates their clinical utility for differential diagnosis and patient management. To prepare for the incorporation of AD BBBMs into primary care, several practical challenges must be addressed. Here, we describe four immediate challenges: (1) preparing primary care providers to order and disclose AD BBBMs, (2) expanding the dementia-capable workforce, (3) ensuring equitable uptake of AD BBBM testing, and (4) securing access to AD treatment. We conclude by discussing future directions and challenges for use of AD BBBMs in primary care, including screening for preclinical AD and dementia detection algorithms. HIGHLIGHTS: Alzheimer's disease (AD) blood-based biomarkers (BBBMs) may be well suited for primary care. Many changes are needed to prepare the workforce and ensure patient access. Paving the way for AD BBBMs in primary care will require a multi-pronged approach.}, }
@article {pmid39740107, year = {2025}, author = {Karneboge, J and Haberstroh, J and Geschke, K and Perry, J and Radenbach, K and Jessen, F and Rostamzadeh, A}, title = {Facing the new diagnostic and treatment options of Alzheimer's disease: The necessity of informed consent.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14204}, pmid = {39740107}, issn = {1552-5279}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/drug therapy ; *Informed Consent ; *Biomarkers ; Cognitive Dysfunction/diagnosis/therapy ; Decision Making ; Mental Competency ; }, abstract = {With advances in biomarker-based detection of Alzheimer's disease (AD) and new treatment options with disease-modifying treatments (DMTs), we are heading toward a new conceptualization of diagnostics and therapy in the early stages of AD. Yet consensus guidelines on best clinical practices in predictive AD diagnostics are still developing. Currently, there is a knowledge gap regarding counseling and disclosure practices in early symptomatic disease stages, its implications for dementia risk estimation, and DMTs with associated risks and benefits. The crucial feature is the capacity of patients with (mild) cognitive impairment, eligible for DMTs, to consent. This perspective aims to (1) discuss the current challenges in assessing capacity to consent and (2) highlight the importance of a supported (informed) decision-making process. Measures to facilitate informed decision-making of patients constitute an ethical approach to enhancing the quality of care in this evolving therapeutic landscape. HIGHLIGHTS: This perspective: Explores biomarker-based early symptomatic AD detection and the implications for patient care. Emphasizes supported decision-making in DMTs for MCI and dementia patients. Discusses the need for standardized tools to assess the capacity to consent. Aligns diagnostic and treatment approaches with ethical care standards. Enhances patient autonomy in the evolving AD therapeutic landscape.}, }
@article {pmid39740074, year = {2025}, author = {VandeVrede, L and Schindler, SE}, title = {Clinical use of biomarkers in the era of Alzheimer's disease treatments.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14201}, pmid = {39740074}, issn = {1552-5279}, support = {R01 AG070941/AG/NIA NIH HHS/United States ; R01AG070941/AG/NIA NIH HHS/United States ; K23AG073514/AG/NIA NIH HHS/United States ; K23 AG073514/AG/NIA NIH HHS/United States ; //Barnes-Jewish Hospital Foundation/ ; }, mesh = {*Alzheimer Disease/diagnosis/therapy ; Humans ; *Biomarkers/cerebrospinal fluid ; Brain/metabolism/pathology ; Cognitive Dysfunction/diagnosis ; }, abstract = {With the advent of treatments that specifically target Alzheimer's disease brain pathology, biomarker tests will become an increasingly important part of the routine clinical evaluation of cognitive impairment and guide clinical decision making. Clinicians must ensure they are using accurate and well-validated biomarker tests and select the most appropriate testing modality for each patient based on individual and practical considerations. The interpretation of test results may be complex and depends on the pre-test probability and test-specific factors. Biomarker results must be presented and discussed with patients in a process that is sensitive to the major implications of the results and is carefully connected to diagnosis, prognosis, and management. Advances in treatments for Alzheimer's disease will likely require non-dementia specialists to use biomarkers, necessitating major educational efforts. In the new era of Alzheimer's disease treatments, biomarkers are essential tools that will be integrated into all aspects of dementia diagnosis and care.}, }
@article {pmid39739455, year = {2024}, author = {Ebrahimi, F and Kumari, A and Ghadami, S and Al Abdullah, S and Dellinger, K}, title = {The Potential for Extracellular Vesicles in Nanomedicine: A Review of Recent Advancements and Challenges Ahead.}, journal = {Advanced biology}, volume = {}, number = {}, pages = {e2400623}, doi = {10.1002/adbi.202400623}, pmid = {39739455}, issn = {2701-0198}, support = {2302452//Directorate for Engineering/ ; R16GM149496-01/GM/NIGMS NIH HHS/United States ; }, abstract = {Extracellular vesicles (EVs) have emerged as promising tools in diagnostics and therapy for chronic diseases, including cancer and Alzheimer's. Small EVs, also called exosomes, are lipid-bound particles (≈30-150 nm) that play a role in healthy and pathophysiological interactions, including intercellular communication, by transporting bioactive molecules, including proteins, lipids, and nucleic acids. Their ability to cross biological barriers, such as the blood-brain barrier, makes them ideal candidates for targeted therapeutic interventions. In the context of chronic diseases, exosomes can be engineered to deliver active agents, including small molecules and siRNAs to specific target cells, providing a novel approach to precision medicine. Moreover, exosomes show great promise as repositories for diagnostic biomarkers. Their cargo can reflect the physiological and pathological status of the parent cells, making them valuable indicators of disease progression and response to treatment. This paper presents a comprehensive review of the application of exosomes in four chronic diseases: cancer, cardiovascular disease, neurodegenerative disease, and orthopedic disease, which significantly impact global public health due to their high prevalence and associated morbidity and mortality rates. Furthermore, the potential of exosomes as valuable tools for theranostics and disease management is highlighted. Finally, the challenges associated with exosomes and their demonstrated potential for advancing future nanomedicine applications are discussed.}, }
@article {pmid39737997, year = {2024}, author = {Bagherpoor Helabad, M and Matlahov, I and Kumar, R and Daldrop, JO and Jain, G and Weingarth, M and van der Wel, PCA and Miettinen, MS}, title = {Integrative determination of atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington disease.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10793}, pmid = {39737997}, issn = {2041-1723}, support = {R01 GM112678/GM/NIGMS NIH HHS/United States ; INFRAIA-2016-1-73089//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; contract A-17778//CHDI Foundation (CHDI Foundation, Inc.)/ ; 86110//Volkswagen Foundation (VolkswagenStiftung)/ ; }, mesh = {*Huntingtin Protein/genetics/metabolism/chemistry ; *Huntington Disease/genetics/metabolism/pathology ; Humans ; *Molecular Dynamics Simulation ; *Exons/genetics ; *Peptides/chemistry/metabolism ; Mutation ; Amyloid/chemistry/metabolism ; Magnetic Resonance Spectroscopy ; }, abstract = {Neurodegeneration in Huntington's disease (HD) is accompanied by the aggregation of fragments of the mutant huntingtin protein, a biomarker of disease progression. A particular pathogenic role has been attributed to the aggregation-prone huntingtin exon 1 (HTTex1), generated by aberrant splicing or proteolysis, and containing the expanded polyglutamine (polyQ) segment. Unlike amyloid fibrils from Parkinson's and Alzheimer's diseases, the atomic-level structure of HTTex1 fibrils has remained unknown, limiting diagnostic and treatment efforts. We present and analyze the structure of fibrils formed by polyQ peptides and polyQ-expanded HTTex1 in vitro. Atomic-resolution perspectives are enabled by an integrative analysis and unrestrained all-atom molecular dynamics (MD) simulations incorporating experimental data from electron microscopy (EM), solid-state NMR, and other techniques. Alongside the use of prior data, we report magic angle spinning NMR studies of glutamine residues of the polyQ fibril core and surface, distinguished via hydrogen-deuterium exchange (HDX). Our study provides a molecular understanding of the structure of the core as well as surface of aggregated HTTex1, including the fuzzy coat and polyQ-water interface. The obtained data are discussed in context of their implications for understanding the detection of such aggregates (diagnostics) as well as known biological properties of the fibrils.}, }
@article {pmid39737667, year = {2025}, author = {Chandler, HL and Wheeler, J and Escott-Price, V and Murphy, K and Lancaster, TM}, title = {Non-APOE variants predominately expressed in smooth muscle cells contribute to the influence of Alzheimer's disease genetic risk on white matter hyperintensities.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14455}, pmid = {39737667}, issn = {1552-5279}, support = {PNU-80762-CU-14//European Regional Development Fund/ ; UKDRI-3003//UK Dementia Research Institute/ ; WT224267//Wellcome/ ; /WT_/Wellcome Trust/United Kingdom ; MR/L010305/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; Male ; *Polymorphism, Single Nucleotide ; Female ; Aged ; *White Matter/pathology/diagnostic imaging ; *Myocytes, Smooth Muscle/pathology ; *Genetic Predisposition to Disease/genetics ; Middle Aged ; Aged, 80 and over ; Apolipoproteins E/genetics ; Magnetic Resonance Imaging ; Multifactorial Inheritance/genetics ; Risk Factors ; }, abstract = {INTRODUCTION: White matter hyperintensity volumes (WMHVs) are disproportionally prevalent in individuals with Alzheimer's disease (AD), potentially reflecting neurovascular injury. We quantify the association between AD polygenic risk score (AD-PRS) and WMHV, exploring single-nucleotide polymorphisms (SNPs) that are proximal to genes overexpressed in cerebrovascular cell species.
METHODS: In a UK-Biobank sub-sample (mean age = 64, range = 45-81 years), we associate WMHV with (1) AD-PRS estimated via SNPs across the genome (minus apolipoprotein E [APOE] locus) and (2) AD-PRS estimated with SNPs proximal to specific genes that are overexpressed in cerebrovascular cell species.
RESULTS: We observed a positive association between non-APOE-AD-PRS and WMHVs. We further demonstrate an association between WMHVs and AD-PRS constructed with SNPs that are proximal to genes over-represented in smooth muscles cells (SMCs; β = 0.135, PFWE < 0.01) and internally replicated (PDISCOVERY+REPLICATION < 0.01).
DISCUSSION: Common AD genetic risk could explain physiological processes underlying vascular pathology in AD. SMC function may offer a treatment target to prevent WMHV-related AD pathophysiology prior to the onset of symptoms.
HIGHLIGHTS: Alzheimer's disease (AD) risk factors such as apolipoprotein E (APOE) ε4, link to increased white matter hyperintensity volume (WMHV). WMHVs indicate vascular risk and neurovascular injury in AD. The broader genetic link between AD risk and WMHV is not fully understood. We quantify AD polygenic risk score (PRS) associations with WMHV, excluding APOE. AD-PRS in smooth muscle cells (SMCs) shows a significant association with increased WMHV.}, }
@article {pmid39737527, year = {2025}, author = {Yang, S and Xue, J and Li, Z and Zhang, S and Zhang, Z and Huang, Z and Yung, KKL and Lai, KWC}, title = {Deep Learning-Based Ion Channel Kinetics Analysis for Automated Patch Clamp Recording.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {12}, pages = {e2404166}, doi = {10.1002/advs.202404166}, pmid = {39737527}, issn = {2198-3844}, support = {T42-717/20-R//Hong Kong Special Administrative Region Government/ ; C7174-20G//Hong Kong Special Administrative Region Government/ ; }, mesh = {*Deep Learning ; *Ion Channels/metabolism ; *Patch-Clamp Techniques/methods ; Kinetics ; Humans ; Neurons/metabolism/physiology ; Alzheimer Disease/metabolism ; }, abstract = {The patch clamp technique is a fundamental tool for investigating ion channel dynamics and electrophysiological properties. This study proposes the first artificial intelligence framework for characterizing multiple ion channel kinetics of whole-cell recordings. The framework integrates machine learning for anomaly detection and deep learning for multi-class classification. The anomaly detection excludes recordings that are incompatible with ion channel behavior. The multi-class classification combined a 1D convolutional neural network, bidirectional long short-term memory, and an attention mechanism to capture the spatiotemporal patterns of the recordings. The framework achieves an accuracy of 97.58% in classifying 124 test datasets into six categories based on ion channel kinetics. The utility of the novel framework is demonstrated in two applications: Alzheimer's disease drug screening and nanomatrix-induced neuronal differentiation. In drug screening, the framework illustrates the inhibitory effects of memantine on endogenous channels, and antagonistic interactions among potassium, magnesium, and calcium ion channels. For nanomatrix-induced differentiation, the classifier indicates the effects of differentiation conditions on sodium and potassium channels associated with action potentials, validating the functional properties of differentiated neurons for Parkinson's disease treatment. The proposed framework is promising for enhancing the efficiency and accuracy of ion channel kinetics analysis in electrophysiological research.}, }
@article {pmid39736972, year = {2024}, author = {Safiri, S and Ghaffari Jolfayi, A and Fazlollahi, A and Morsali, S and Sarkesh, A and Daei Sorkhabi, A and Golabi, B and Aletaha, R and Motlagh Asghari, K and Hamidi, S and Mousavi, SE and Jamalkhani, S and Karamzad, N and Shamekh, A and Mohammadinasab, R and Sullman, MJM and Şahin, F and Kolahi, AA}, title = {Alzheimer's disease: a comprehensive review of epidemiology, risk factors, symptoms diagnosis, management, caregiving, advanced treatments and associated challenges.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1474043}, pmid = {39736972}, issn = {2296-858X}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired reasoning. It is the leading cause of dementia in older adults, marked by the pathological accumulation of amyloid-beta plaques and neurofibrillary tangles. These pathological changes lead to widespread neuronal damage, significantly impacting daily functioning and quality of life.
OBJECTIVE: This comprehensive review aims to explore various aspects of Alzheimer's disease, including its epidemiology, risk factors, clinical presentation, diagnostic advancements, management strategies, caregiving challenges, and emerging therapeutic interventions.
METHODS: A systematic literature review was conducted across multiple electronic databases, including PubMed, MEDLINE, Cochrane Library, and Scopus, from their inception to May 2024. The search strategy incorporated a combination of keywords and Medical Subject Headings (MeSH) terms such as "Alzheimer's disease," "epidemiology," "risk factors," "symptoms," "diagnosis," "management," "caregiving," "treatment," and "novel therapies." Boolean operators (AND, OR) were used to refine the search, ensuring a comprehensive analysis of the existing literature on Alzheimer's disease.
RESULTS: AD is significantly influenced by genetic predispositions, such as the apolipoprotein E (APOE) ε4 allele, along with modifiable environmental factors like diet, physical activity, and cognitive engagement. Diagnostic approaches have evolved with advances in neuroimaging techniques (MRI, PET), and biomarker analysis, allowing for earlier detection and intervention. The National Institute on Aging and the Alzheimer's Association have updated diagnostic criteria to include biomarker data, enhancing early diagnosis.
CONCLUSION: The management of AD includes pharmacological treatments, such as cholinesterase inhibitors and NMDA receptor antagonists, which provide symptomatic relief but do not slow disease progression. Emerging therapies, including amyloid-beta and tau-targeting treatments, gene therapy, and immunotherapy, offer potential for disease modification. The critical role of caregivers is underscored, as they face considerable emotional, physical, and financial burdens. Support programs, communication strategies, and educational interventions are essential for improving caregiving outcomes. While significant advancements have been made in understanding and managing AD, ongoing research is necessary to identify new therapeutic targets and enhance diagnostic and treatment strategies. A holistic approach, integrating clinical, genetic, and environmental factors, is essential for addressing the multifaceted challenges of Alzheimer's disease and improving outcomes for both patients and caregivers.}, }
@article {pmid39736920, year = {2024}, author = {Bianchetti, ME and Ferreira, AFF and Britto, LRG}, title = {Inhibition of neuroinflammation by GIBH-130 (AD-16) reduces neurodegeneration, motor deficits, and proinflammatory cytokines in a hemiparkinsonian model.}, journal = {Frontiers in neuroanatomy}, volume = {18}, number = {}, pages = {1511951}, pmid = {39736920}, issn = {1662-5129}, abstract = {Parkinson's disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) of the brain, manifesting itself with both motor and non-motor symptoms. A critical element of this pathology is neuroinflammation, which triggers a harmful neurotoxic cycle, exacerbating cell death within the central nervous system. AD-16 (also known as GIBH-130) is a recently identified compound capable of reducing the expression of pro-inflammatory cytokines while increasing the expression of anti-inflammatory cytokines in Alzheimer's disease models. Here, for the first time, we sought to comprehend the potential impact of orally administered AD-16 in mitigating neurodegeneration and subsequent disease progression in PD. To accomplish this, 6- hydroxydopamine (6-OHDA) unilateral striatal injections were employed to induce a PD model in male C57BL/6 mice. Cylinder and apomorphine-induced rotation behavior tests were conducted to assess motor behavior and validate the PD model 3 days after the injection. AD-16 was administered via gavage daily between days 3 and 9 after surgery. On the last day of treatment, motor tests were performed again. All animals were euthanized on day 10 and immunohistochemistry techniques were performed to detect tyrosine hydroxylase (TH) and Iba-1 and thus label dopaminergic neurons and microglia in the SNc and striatum (CPu). These same regions were collected for ELISA assays to assess different cytokine concentrations. Our results revealed an enhancement in the motor function of the AD-16-treated animals, as well as reduced nigrostriatal neurodegeneration. In addition, AD-16 reduced the increase in microglia density and prevented the changes in its morphology observed in the PD animal models. Furthermore, AD-16 was able to avoid the increase of pro-inflammatory cytokines levels that were present in 6-OHDA-injected animals who received vehicle. Consequently, AD-16 emerges as a compound with significant potential for negative modulation of neurodegeneration and neuroinflammation suppression in the 6-OHDA animal model of Parkinson's disease.}, }
@article {pmid39736372, year = {2025}, author = {Tian, Y and Li, W and Zhang, Y}, title = {3-N-Butylphthalide alleviate Aβ-induced cellular senescence through the CDK2-pRB1-Caspase3 axis.}, journal = {Brain research}, volume = {1849}, number = {}, pages = {149435}, doi = {10.1016/j.brainres.2024.149435}, pmid = {39736372}, issn = {1872-6240}, mesh = {Humans ; *Benzofurans/pharmacology ; *Cellular Senescence/drug effects/physiology ; *Cyclin-Dependent Kinase 2/metabolism ; *Apoptosis/drug effects ; *Amyloid beta-Peptides/metabolism ; *Caspase 3/metabolism ; Cell Line, Tumor ; Retinoblastoma Protein/metabolism ; Signal Transduction/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Senescence-Associated Secretory Phenotype/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) and leading to cellular senescence and cognitive deficits. Cellular senescence contributes significantly to the pathogenesis of AD through the senescence-associated secretory phenotype (SASP), exacerbating Aβ deposition. This study investigates the protective effects of 3-N-Butylphthalide (NBP), a compound derived from Apium graveolens Linn (Chinese celery), on Aβ-induced cellular senescence in U87 cells. Using RNA-sequencing and biochemical assays, we demonstrate that NBP ameliorate Aβ oligomer-induced cellular senescence and apoptosis, and regulated the expression of cyclin-dependent kinase inhibitor 2A (CDKN2A) and components of the cyclin-dependent kinase 2 (CDK2)- phosphorylated retinoblastoma 1 (pRB1)-Caspase3 pathway. Moreover, NBP was shown to suppress the expression of SASP-related genes. These findings suggest that NBP rescues U87 cells from Aβ oligomer-induced senescence and apoptosis through modulating the CDK2-pRB1-Caspase3 axis and SASP expression. Our results underscore the potential of NBP as a senostatic agent for AD which have not been reported in previous studies, offering insights into its mechanisms of action and paving the way for future studies on its efficacy in vivo and in clinical settings. Thus, we contribute to growing evidence supporting the use of senolytic and senostatic agents in the treatment of AD.}, }
@article {pmid39735856, year = {2024}, author = {Abdalla, M and Khalid, A and Hedayati, J and Ghayur, MN}, title = {Cholinesterase Inhibitory Activity of Paeoniflorin: Molecular Dynamics Simulation, and In Vitro Mechanistic Investigation.}, journal = {Biochemistry research international}, volume = {2024}, number = {}, pages = {9192496}, pmid = {39735856}, issn = {2090-2247}, abstract = {Alzheimer's disease (AD), a neurological disorder, is one of the major reasons for memory loss in the world. AD is characterized by a sequela of cognitive and functional decline caused by brain cell degeneration. Paeoniflorin is a monoterpenoid glycoside found in plants of the Paeoniaceae family, which are known for their medicinal properties including dementia. In this project, we report actions of paeoniflorin on the two related cholinesterases (ChE): acetylChE (AChE) and butyrylChE (BuChE). Paeoniflorin, in a dose-dependent (maximum inhibition at 1 mg/mL) manner, inhibited both AChE (0.06-1 mg/mL) and BuChE (0.007-1 mg/mL) enzymes with maximum inhibition of AChE enzyme at 90.3 ± 1.4%, while 99.4 ± 0.3% for BuChE enzyme. The EC50 value for the inhibitory effect of the compound against AChE was 0.52 mg/mL (0.18-1.52), while against BuChE was 0.13 mg/mL (0.08-0.21). The observed ani-ChE action was like an effect also mediated by the known ChE blocker physostigmine. Molecular interactions between paeoniflorin and both ChE enzymes were additionally sought via molecular docking and molecular dynamics simulations for 100 ns, that showed paeoniflorin interacted with the active-site gorge of AChE and BuChE via hydrogen bonds and water bridging with the many amino acids of the AChE and BuChE enzymes. This study presents the ChE inhibitory potential of paeoniflorin against both AChE and BuChE enzymes. With this kind of inhibitory activity, the chemical can potentially increase ACh levels and may have use in the treatment of dementia of AD.}, }
@article {pmid39735485, year = {2024}, author = {Öztürk, B}, title = {Cardiac effects and comorbidities of neurological diseases.}, journal = {Turkish journal of medical sciences}, volume = {54}, number = {7}, pages = {1428-1437}, pmid = {39735485}, issn = {1303-6165}, mesh = {Humans ; *Comorbidity ; *Nervous System Diseases/epidemiology/physiopathology ; *Cardiovascular Diseases/epidemiology ; Parkinson Disease/complications/epidemiology/physiopathology ; Risk Factors ; Multiple Sclerosis/epidemiology/complications/physiopathology ; }, abstract = {Neurological disorders encompass a complex and heterogeneous spectrum of diseases affecting the brain, spinal cord, and peripheral nervous system, each presenting unique challenges that extend well beyond primary neurological symptoms. These disorders profoundly impact cardiovascular health, prompting an intensified exploration into the intricate interconnections between the neurological and cardiovascular systems. This review synthesizes current insights and research on cardiovascular comorbidities associated with major neurological conditions, including stroke, epilepsy, Parkinson's disease, multiple sclerosis, and Alzheimer's disease. The cardiovascular sequelae of these neurological disorders are multifactorial. For instance, strokes not only predispose individuals to arrhythmia and heart failure but also exacerbate preexisting cardiovascular risk factors. Similarly, epilepsy is associated with autonomic dysregulation and an elevated risk of sudden cardiac death, underscoring the necessity for vigilant cardiac monitoring in affected individuals. Parkinson's disease manifests with orthostatic hypotension and cardiac sympathetic denervation, significantly contributing to morbidity. Additionally, multiple sclerosis and Alzheimer's disease exhibit cardiovascular autonomic dysfunction and heightened cardiovascular risk, underscoring the need for proactive management strategies. Mechanistically, these conditions disrupt autonomic nervous system regulation, induce chronic inflammation, and may share genetic susceptibilities, each contributing to cardiovascular pathology. Effective management of these complexities requires an integrative approach that includes risk factor modification, pharmacotherapy, lifestyle interventions, and comprehensive patient education. Future research directions include identifying novel therapeutic targets, conducting large-scale clinical trials, and investigating genetic biomarkers to individualize treatment strategies. By addressing the multifaceted interactions between neurological disorders and cardiovascular health, healthcare providers can optimize patient care, reducing cardiovascular morbidity and mortality in this vulnerable population.}, }
@article {pmid39734765, year = {2024}, author = {Dabravolski, SA and Churov, AV and Elizova, NV and Ravani, AL and Karimova, AE and Sukhorukov, VN and Orekhov, AN}, title = {Association between atherosclerosis and the development of multi-organ pathologies.}, journal = {SAGE open medicine}, volume = {12}, number = {}, pages = {20503121241310013}, pmid = {39734765}, issn = {2050-3121}, abstract = {Atherosclerosis is a chronic inflammatory disease affecting the vascular system, characterised by the accumulation of modified lipoproteins, immune cell aggregation and the development of fibrous tissue within blood vessel walls. As atherosclerosis impacts blood vessels, its adverse effects may manifest across various tissues and organs. In this review, we examine the association of atherosclerosis with Alzheimer's disease, stroke, pancreatic and thyroid dysfunction, kidney stones and chronic kidney diseases. In several cases, the reciprocal causative effect of these diseases on the progression of atherosclerosis is also discussed. Particular attention is given to common risk factors, biomarkers and identified molecular mechanisms linking the pathophysiology of atherosclerosis to the dysfunction of multiple tissues and organs. Understanding the role of atherosclerosis and its associated microenvironmental conditions in the pathology of multi-organ disorders may unveil novel therapeutic avenues for the prevention and treatment of cardiovascular and associated diseases.}, }
@article {pmid39734634, year = {2024}, author = {Wang, C and Wu, B and Lin, R and Cheng, Y and Huang, J and Chen, Y and Bai, J}, title = {Vagus nerve stimulation: a physical therapy with promising potential for central nervous system disorders.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1516242}, pmid = {39734634}, issn = {1664-2295}, abstract = {The diseases of the central nervous system (CNS) often cause irreversible damage to the human body and have a poor prognosis, posing a significant threat to human health. They have brought enormous burdens to society and healthcare systems. However, due to the complexity of their causes and mechanisms, effective treatment methods are still lacking. Vagus nerve stimulation (VNS), as a physical therapy, has been utilized in the treatment of various diseases. VNS has shown promising outcomes in some CNS diseases and has been approved by the Food and Drug Administration (FDA) in the United States for epilepsy and depression. Moreover, it has demonstrated significant potential in the treatment of stroke, consciousness disorders, and Alzheimer's disease. Nevertheless, the exact efficacy of VNS, its beneficiaries, and its mechanisms of action remain unclear. This article discusses the current clinical evidence supporting the efficacy of VNS in CNS diseases, providing updates on the progress, potential, and potential mechanisms of action of VNS in producing effects on CNS diseases.}, }
@article {pmid39734582, year = {2024}, author = {Jimenez-García, AM and Villarino, M and Arias, N}, title = {A systematic review and meta-analysis of basal microbiota and cognitive function in Alzheimer's disease: A potential target for treatment or a contributor to disease progression?.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {16}, number = {4}, pages = {e70057}, pmid = {39734582}, issn = {2352-8729}, abstract = {UNLABELLED: A systematic review and meta-analysis examined the impact of gut microbiota in Alzheimer's disease (AD) pathogenesis. Dysbiosis may influence neurodegeneration by affecting gut permeability and neurotrophic factors, leading to cognitive decline. The study analyzed microbiome differences between patients with AD and healthy individuals, as well as the impact of various interventions in both preclinical and clinical studies. Of 60 studies reviewed, 12 were excluded from the meta-analysis due to unsuitable data or lack of control groups. Meta-analyses revealed significant cognitive impairment in AD patients and animal models, with specific tests identifying these deficits. Notably, Bacteroides levels were higher in patients with AD, whereas probiotics improved Prevotella levels. Natural treatments increased Bacteroidetes and reduced Firmicutes in animal models. The findings emphasize the need for standardized methods to develop therapies targeting the gut microbiota to restore cognition in AD. Understanding individual dysbiosis could further clarify the cognitive effects of the gut-brain axis.
HIGHLIGHTS: Dysbiosis in the gut microbiota is linked to cognitive decline in Alzheimer's disease (AD).Patients with AD show significant differences in Bacteroides levels compared to healthy individuals.Probiotic treatments increase Prevotella levels in AD animal models.Natural agents boost Bacteroidetes and reduce Firmicutes in AD animal models.Human studies show no consistent effects of gut microbiota interventions on cognitive function in AD.}, }
@article {pmid39734227, year = {2024}, author = {Zhao, G and Zhang, H and Xu, Y and Chu, X}, title = {Research on magnetic resonance imaging in diagnosis of Alzheimer's disease.}, journal = {European journal of medical research}, volume = {29}, number = {1}, pages = {632}, pmid = {39734227}, issn = {2047-783X}, support = {ZR2022MH124//Natural Science Foundation of Shandong Province/ ; 202,201-105//Youth Science Foundation of Shandong First Medical University/ ; 202,103,070,325//Shandong Medical and Health Technology Development Fund/ ; M-2, 022,216//Shandong Province Traditional Chinese Medicine Science and Technology Project/ ; 23DZ2291500//Shanghai Science and Technology Innovation Action Plan/ ; }, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Magnetic Resonance Imaging/methods ; Diagnosis, Differential ; Brain/diagnostic imaging/pathology ; }, abstract = {As a common disease in the elderly, the diagnosis of Alzheimer's disease (AD) is of great significance to the treatment and prognosis of the patients. Studies have found that magnetic resonance imaging plays an important role in the early diagnosis of Alzheimer's disease. This article tries to review the application of magnetic resonance imaging in the diagnosis and differential diagnosis of Alzheimer's disease.}, }
@article {pmid39733876, year = {2025}, author = {Wang, N and Liu, Y and Yang, C and Du, J and Yu, D and He, P and Xu, H and Li, L and Zhao, P and Li, Y}, title = {Molecular insights into vasicine and butyrylcholinesterase interactions: A complimentary biophysical, multi-spectroscopic, and computational study.}, journal = {International journal of biological macromolecules}, volume = {292}, number = {}, pages = {139253}, doi = {10.1016/j.ijbiomac.2024.139253}, pmid = {39733876}, issn = {1879-0003}, mesh = {*Butyrylcholinesterase/chemistry/metabolism ; *Quinazolines/chemistry/pharmacology ; *Molecular Docking Simulation ; Cholinesterase Inhibitors/pharmacology/chemistry ; Protein Binding ; Alkaloids/chemistry/pharmacology ; Animals ; Thermodynamics ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Spectrometry, Fluorescence ; }, abstract = {Butyrylcholinesterase (BChE) plays a pivotal role in regulating acetylcholine (ACh) levels during the progression of Alzheimer's disease (AD), so emerged as an attractive target in AD treatment. Vasicine, a naturally occurring pyrroloquinazoline alkaloid, was identified as a natural BChE inhibitor (IC50 = 1.47 ± 0.37 μM) from Traditional Chinese Medicine database. No any detailed research concerning the binding behavior of BChE with small molecule. As the first case, the inhibitory mechanism of vasicine on BChE was investigated using multi-spectroscopic methods (including fluorescence quenching, ANS fluorescence probe, three-dimensional fluorescence, time-resolved fluorescence, circular dichroism), isothermal titration calorimetry, surface plasmon resonance, and computational approaches. As a reversible and mixed inhibitor, vasicine displayed moderate affinity for BChE with an affinity constant KD of 2.111 μM, its binding process was characterized as a spontaneous exothermic reaction with reduced entropy, primarily driven by hydrogen bonding interactions. Vasicine quenched the fluorescence of BChE through both static and dynamic quenching mechanisms, leading to an increase in the α-helix content and surface hydrophobicity of BChE. Furthermore, the fluctuation of the skeleton atoms in the vasicine-BChE complex system remained stable, indicating good stability within the simulated physiological environment. In addition, vasicine exerted good safety for PC12 cells. Above findings provide molecular insights into the inhibitory mechanism of vasicine against BChE for the first time, and offer valuable information for future structure modification and therapeutic applications of vasicine as a BChE inhibitor.}, }
@article {pmid39733799, year = {2025}, author = {Zhang, Y and Liu, S and Cao, D and Zhao, M and Lu, H and Wang, P}, title = {Rg1 improves Alzheimer's disease by regulating mitochondrial dynamics mediated by the AMPK/Drp1 signaling pathway.}, journal = {Journal of ethnopharmacology}, volume = {340}, number = {}, pages = {119285}, doi = {10.1016/j.jep.2024.119285}, pmid = {39733799}, issn = {1872-7573}, mesh = {*Ginsenosides/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Signal Transduction/drug effects ; *Mice, Transgenic ; Mice ; *Mitochondrial Dynamics/drug effects ; Amyloid beta-Peptides/metabolism ; Male ; Amyloid beta-Protein Precursor/genetics/metabolism ; AMP-Activated Protein Kinases/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; Humans ; Mitochondria/drug effects/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by a complex pathogenesis that includes Aβ deposition, abnormal phosphorylation of tau protein, chronic neuroinflammation, and mitochondrial dysfunction. In traditional medicine, ginseng is revered as the 'king of herbs'. Ginseng has the effects of greatly tonifying vital energy, strengthening the spleen and benefiting the lungs, generating fluids and nourishing the blood, and calming the mind while enhancing intelligence. Ginsenoside Rg1 (Rg1) is a well-defined major active component found in ginseng, known for its relatively high content. It has been demonstrated to exhibit neuroprotective effects in both in vivo and in vitro models, capable of ameliorating Aβ and tau pathology, regulating synaptic function, and reducing inflammation, oxidative stress, and apoptosis. However, the potential of Rg1 to improve AD pathology through the regulation of mitochondrial dynamics is still uncertain.
AIM OF THE STUDY: Despite the active research efforts on drugs for AD, the currently available anti-AD medications can only slow disease progression and manage symptoms, yet unable to provide a cure for AD. Furthermore, some anti-AD drugs failed phase III and IV clinical trials due to significant side effects. Therefore, there is an urgent need to further investigate the pathogenesis of AD, to identify new therapeutic targets, and to explore more effective therapies. The aim of this study is to evaluate the potential therapeutic effects of Rg1 on APP/PS1 double transgenic mice and Aβ42-induced HT22 cell models, and to investigate the potential mechanisms through which it provides neuroprotective effects.
MATERIALS AND METHODS: This study investigates the effects of Rg1 in treating AD on APP/PS1 double transgenic mice and Aβ42-induced HT22 cells. In the in vivo experiments, APP/PS1 mice were divided into a model group, Rg1-L group, Rg1-H group, and donepezil group, with C57BL/6 mice serving as the control group (n = 12 per group). The Rg1-L and Rg1-H groups were administered Rg1 at doses of 5 mg/kg/d and 10 mg/kg/d, respectively, while the donepezil group received donepezil at a dose of 1.3 mg/kg/d. Both the control and model groups received an equal volume of physiological saline daily for 28 days. Learning and spatial memory were assessed by the Morris water maze (MWM) and novel object recognition (NOR) tests, and neuronal damage by Nissl staining. Aβ deposition was analyzed through immunohistochemistry and Western blot, while the expression levels of synaptic proteins PSD95 and SYN were evaluated via immunofluorescence staining and Western blot. The dendritic spines of neurons was observed by Golgi staining.The ultrastructure of neuronal mitochondria and synapses was examined by transmission electron microscopy (TEM). Mitochondrial function was assessed through measurements of Reactive oxygen species (ROS), Superoxide Dismutase (SOD), and Adenosine Triphosphate (ATP), and Western blot analysis was performed to detect the expression levels of AMPK, p-AMPK, Drp1, p-Drp1, OPA1, Mfn1, and Mfn2, thereby investigating the protective effects of Rg1 on mitochondrial dysfunction and cognitive impairment in APP/PS1 double transgenic mice. In vitro experiments, HT22 cells were treated with Aβ42 of 10 μM for 24 h to verify the therapeutic effects of Rg1. Flow cytometry was used to detect ROS and JC-1, biochemical methods were employed to measure SOD and ATP, immunofluorescence staining was used to detect the expression levels of PSD95 and SYN, and Western blot analysis was conducted to elucidate its potential mechanisms of action.
RESULTS: The findings suggest that after 28 days of Rg1 treatment, cognitive dysfunction in APP/PS1 mice was improved. Pathological and immunohistochemical analyses demonstrated that Rg1 treatment significantly reduced Aβ deposition and neuronal loss. Rg1 can improve synaptic dysfunction and mitochondrial function in APP/PS1 mice. Rg1 activated AMPK, enhanced p-AMPK expression, inhibited Drp1, and reduced p-Drp1 levels, which led to increased expression of OPA1, Mfn1, and Mfn2, thereby inhibiting mitochondrial fission and facilitating mitochondrial fusion. Additionally, Rg1 effectively reversed the decrease in mitochondrial membrane potential (MMP) and the increase in ROS production induced by Aβ42 in HT22 cells, restoring SOD and ATP levels. Furthermore, Rg1 regulated mitochondrial fission mediated by the AMPK/Drp1 signaling pathway, promoting mitochondrial fusion and improving synaptic dysfunction.
CONCLUSION: Our research provides evidence for the neuroprotective mechanisms of Rg1 in AD models. Rg1 modulates mitochondrial dynamics through the AMPK/Drp1 signaling pathway, thereby reducing synaptic and mitochondrial dysfunction in APP/PS1 mice and AD cell models.}, }
@article {pmid39733760, year = {2025}, author = {Rodrigues, B and Ventura, E and Moreira, P and Resende, R and Bicker, J and Santos, AE and Pereira, CF and Cruz, MT and Robalo, MP and Silva, A and Silva, S}, title = {New low-dose curcumin derivative with therapeutic potential in Alzheimer's disease: Results from an in vitro and in vivo study in mice.}, journal = {Neurobiology of aging}, volume = {147}, number = {}, pages = {105-123}, doi = {10.1016/j.neurobiolaging.2024.12.005}, pmid = {39733760}, issn = {1558-1497}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Curcumin/administration & dosage/analogs & derivatives/pharmacology/therapeutic use ; *Mice, Transgenic ; *Disease Models, Animal ; *Amyloid beta-Peptides/metabolism ; *NF-E2-Related Factor 2/metabolism ; Nitric Oxide/metabolism ; Interleukin-1beta/metabolism ; Antioxidants/administration & dosage ; Cyclooxygenase 2/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Hippocampus/metabolism/drug effects ; Anti-Inflammatory Agents/administration & dosage ; Heme Oxygenase-1/metabolism ; Male ; }, abstract = {Curcumin has been proposed as a potential treatment for Alzheimer's disease (AD) due to its ability to inhibit amyloid-β (Aβ) peptide aggregates and to destabilise pre-formed ones. Derivative 27 was synthesized to improve low-dose efficacy in the context of AD. Its anti-inflammatory, antioxidant and anti-amyloidogenic activities were evaluated in chemico, in vitro using AD and neuroinflammation cell models, and in vivo using the double-transgenic APP/PS1 mice. In vitro, this curcumin derivative significantly reduced nitric oxide (NO) production and levels of pro-inflammatory proteins, inducible NO synthase, pro-interleukin-1β (Pro-IL-1β) and cyclooxygenase-2. Furthermore, Derivative 27 activated nuclear factor erythroid 2-related factor 2 transcription factor (Nrf2) and significantly increased Nrf2 and heme-oxygenase-1 protein levels in the nucleus and in the cytoplasm, respectively. In one-year-old APP/PS1 mice, orally administered-Derivative 27 (50 mg/Kg/day) for 28 days improved spatial short-term memory and significantly decreased hippocampal Pro-IL-1β and amyloid precursor protein levels, as well as Aβ levels in the hippocampus and plasma. This study supports developing new chemical approaches to alter curcumin molecule, enabling lower doses, while increasing the effectiveness in AD treatment.}, }
@article {pmid39733087, year = {2024}, author = {Ju, Y and Li, S and Kong, X and Zhao, Q}, title = {Exploring fatty acid metabolism in Alzheimer's disease: the key role of CPT1A.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {31483}, pmid = {39733087}, issn = {2045-2322}, support = {20230204099YY//Department of Science and Technology of Jilin Province/ ; 20230402012GH//Department of Science and Technology of Jilin Province/ ; }, mesh = {*Alzheimer Disease/metabolism/genetics/pathology ; *Carnitine O-Palmitoyltransferase/metabolism/genetics ; *Fatty Acids/metabolism ; *Astrocytes/metabolism ; Humans ; Lipid Metabolism ; Male ; Oxidation-Reduction ; }, abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disease, and the most common type of dementia, with symptoms of progressive cognitive dysfunction and behavioral impairment. Studying the pathogenesis of AD and exploring new targets for the prevention and treatment of AD is a very worthwhile challenge. Accumulating evidence has highlighted the effects of fatty acid metabolism on AD. In this study, fatty acid metabolism was used as an entry point to understand the pathogenesis of AD and identify new targets. After identifying differentially expressed genes, multiple machine learning algorithms, carnitine palmitoyltransferase 1 A (CPT1A) was identified as the key gene for fatty acid metabolism in AD. Further single nucleus RNA sequencing analysis were performed, and the GSEA results showed that the fatty acid β-oxidation pathway was enriched only in astrocytes, and the fatty acid β-oxidation pathway was down-regulated in the AD astrocytes compared to the CN astrocytes, while CPT1A was specifically downregulated in astrocytes of AD, which was confirmed in vitro experiment subsequently, and decreased expression level of CPT1A would lead to abnormal lipid metabolism, which shapes astrocyte reactivity and injury, neuroinflammatory, and thus affects AD pathogenesis. Our findings report the involvement of CPT1A in AD. We confirm that the primary role of astrocytes for fatty acid β-oxidation, and CPT1A is localized in astrocytes. Downregulated CPT1A could be a novel potential target for the prevention and treatment of AD. Our study provides strong evidence for the involvement of fatty acid metabolism in the pathogenesis of AD.}, }
@article {pmid39732824, year = {2024}, author = {Levendowski, DJ and Tsuang, D and Chahine, LM and Walsh, CM and Berka, C and Lee-Iannotti, JK and Salat, D and Fischer, C and Mazeika, G and Boeve, BF and Strambi, LF and Lewis, SJG and Neylan, TC and Louis, EKS}, title = {Concordance and test-retest consistency of sleep biomarker-based neurodegenerative disorder profiling.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {31234}, pmid = {39732824}, issn = {2045-2322}, support = {1195830//National Health and Medical Research Council/ ; R01 AG060477/AG/NIA NIH HHS/United States ; R44AG050326/NH/NIH HHS/United States ; RO1AG060477/NH/NIH HHS/United States ; U19 AG071754/NH/NIH HHS/United States ; RR024150-01/NH/NIH HHS/United States ; R33AG064271/NH/NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers ; Aged ; Female ; Male ; *Neurodegenerative Diseases/diagnosis ; *Lewy Body Disease/diagnosis/physiopathology ; Middle Aged ; REM Sleep Behavior Disorder/diagnosis ; Machine Learning ; Alzheimer Disease/diagnosis/physiopathology ; Sleep/physiology ; Aged, 80 and over ; Cognitive Dysfunction/diagnosis ; Parkinson Disease/diagnosis/physiopathology ; Algorithms ; }, abstract = {Biomarkers that aid in early detection of neurodegeneration are needed to enable early symptomatic treatment and enable identification of people who may benefit from neuroprotective interventions. Increasing evidence suggests that sleep biomarkers may be useful, given the bi-directional relationship between sleep and neurodegeneration and the prominence of sleep disturbances and altered sleep architectural characteristics in several neurodegenerative disorders. This study aimed to demonstrate that sleep can accurately characterize specific neurodegenerative disorders (NDD). A four-class machine-learning algorithm was trained using age and nine sleep biomarkers from patients with clinically-diagnosed manifest and prodromal NDDs, including Alzheimer's disease dementia (AD = 27), Lewy body dementia (LBD = 18), and isolated REM sleep behavior disorder (iRBD = 15), as well as a control group (CG = 58). The algorithm was validated in a total of 381 recordings, which included the training data set plus an additional AD = 10, iRBD = 18, Parkinson disease without dementia (PD = 29), mild cognitive impairment (MCI = 78) and CG = 128. Test-retest consistency was then assessed in LBD = 10, AD = 9, and CG = 46. The agreement between the NDD profiles and their respective clinical diagnoses exceeded 75% for the AD, LBD, and CG, and improved when NDD participants classified Likely Normal with NDD indications consistent with their clinical diagnosis were considered. Profiles for iRBD, PD and MCI participants were consistent with the heterogeneity of disease severities, with the majority of overt disagreements explained by normal sleep characterization in 27% of iRBD, 21% of PD, and 26% of MCI participants. For test-retest assignments, the same or similar NDD profiles were obtained for 88% of LBD, 86% in AD, and 98% of CG participants. The potential utility for NDD subtyping based on sleep biomarkers demonstrates promise and requires further prospective development and validation in larger NDD cohorts.}, }
@article {pmid39732343, year = {2025}, author = {Erboz, A and Kesekler, E and Gentili, PL and Uversky, VN and Coskuner-Weber, O}, title = {Electromagnetic radiation and biophoton emission in neuronal communication and neurodegenerative diseases.}, journal = {Progress in biophysics and molecular biology}, volume = {195}, number = {}, pages = {87-99}, doi = {10.1016/j.pbiomolbio.2024.12.004}, pmid = {39732343}, issn = {1873-1732}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Neurons/metabolism ; Animals ; Electromagnetic Radiation ; Photons ; Cell Communication ; Oxidative Stress ; Brain/metabolism ; }, abstract = {The intersection of electromagnetic radiation and neuronal communication, focusing on the potential role of biophoton emission in brain function and neurodegenerative diseases is an emerging research area. Traditionally, it is believed that neurons encode and communicate information via electrochemical impulses, generating electromagnetic fields detectable by EEG and MEG. Recent discoveries indicate that neurons may also emit biophotons, suggesting an additional communication channel alongside the regular synaptic interactions. This dual signaling system is analyzed for its potential in synchronizing neuronal activity and improving information transfer, with implications for brain-like computing systems. The clinical relevance is explored through the lens of neurodegenerative diseases and intrinsically disordered proteins, where oxidative stress may alter biophoton emission, offering clues for pathological conditions, such as Alzheimer's and Parkinson's diseases. The potential therapeutic use of Low-Level Laser Therapy (LLLT) is also examined for its ability to modulate biophoton activity and mitigate oxidative stress, presenting new opportunities for treatment. Here, we invite further exploration into the intricate roles the electromagnetic phenomena play in brain function, potentially leading to breakthroughs in computational neuroscience and medical therapies for neurodegenerative diseases.}, }
@article {pmid39732222, year = {2025}, author = {Calvin-Dunn, KN and Mcneela, A and Leisgang Osse, A and Bhasin, G and Ridenour, M and Kinney, JW and Hyman, JM}, title = {Electrophysiological insights into Alzheimer's disease: A review of human and animal studies.}, journal = {Neuroscience and biobehavioral reviews}, volume = {169}, number = {}, pages = {105987}, doi = {10.1016/j.neubiorev.2024.105987}, pmid = {39732222}, issn = {1873-7528}, support = {P20 GM109025/GM/NIGMS NIH HHS/United States ; }, mesh = {*Alzheimer Disease/physiopathology ; Humans ; Animals ; *Electroencephalography ; Magnetoencephalography ; Brain/physiopathology ; Electrophysiological Phenomena/physiology ; }, abstract = {This review highlights the crucial role of neuroelectrophysiology in illuminating the mechanisms underlying Alzheimer's disease (AD) pathogenesis and progression, emphasizing its potential to inform the development of effective treatments. Electrophysiological techniques provide unparalleled precision in exploring the intricate networks affected by AD, offering insights into the synaptic dysfunction, network alterations, and oscillatory abnormalities that characterize the disease. We discuss a range of electrophysiological methods, from non-invasive clinical techniques like electroencephalography and magnetoencephalography to invasive recordings in animal models. By drawing on findings from these studies, we demonstrate how electrophysiological research has deepened our understanding of AD-related network disruptions, paving the way for targeted therapeutic interventions. Moreover, we underscore the potential of electrophysiological modalities to play a pivotal role in evaluating treatment efficacy. Integrating electrophysiological data with clinical neuroimaging and longitudinal studies holds promise for a more comprehensive understanding of AD, enabling early detection and the development of personalized treatment strategies. This expanded research landscape offers new avenues for unraveling the complexities of AD and advancing therapeutic approaches.}, }
@article {pmid39732217, year = {2025}, author = {Li, L and Zhang, J and Zhang, Y and Zhao, R and Yang, F and Yan, Y and Wang, Q and Xie, M}, title = {Biofilm-modified Prussian blue improves memory function in late-stage Alzheimer's disease mice with triple therapy.}, journal = {International journal of pharmaceutics}, volume = {670}, number = {}, pages = {125112}, doi = {10.1016/j.ijpharm.2024.125112}, pmid = {39732217}, issn = {1873-3476}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Ferrocyanides/chemistry/pharmacology ; Mice ; *Reactive Oxygen Species/metabolism ; *Nanoparticles ; *Amyloid beta-Peptides/metabolism ; Male ; Blood-Brain Barrier/metabolism/drug effects ; Disease Models, Animal ; Memory/drug effects ; Copper/chemistry/administration & dosage ; Photothermal Therapy/methods ; Oxidative Stress/drug effects ; Macrophages/drug effects ; Chelating Agents/chemistry/pharmacology/administration & dosage ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that is significantly characterized by cognitive and memory impairments, which worsen significantly with age. In the late stages of AD, metal ion disorders and an imbalance of reactive oxygen species (ROS) levels occur in the brain microenvironment, which causes abnormal aggregation of β-amyloid (Aβ), leading to a significant worsening of the AD symptoms. Therefore, we designed a composite nanomaterial of macrophage membranes-encapsulated Prussian blue nanoparticles (PB NPs/MM). Prussian blue nanoparticles (PB NPs) are capable of chelating Cu[2+] and reducing ROS. Macrophage membranes (MM) have advantages over liposomal and erythrocyte membrane carriers, including inflammatory targeting capabilities and more effective immune evasion. Concurrently, the excellent photothermal ability of PB NPs can briefly open the blood-brain barrier (BBB) under near-infrared laser irradiation, which improves the transport efficiency of PB NPs/MM across the BBB and ablates Aβ deposition, thus achieving optimal therapeutic efficacy. In vitro experiments demonstrated that PB NPs/MM is a multifunctional nanosystem, which can effectively inhibit Cu[2+]-induced Aβ monomers aggregation, photothermally depolymerize Aβ fibrils, and attenuate oxidative stress through the combined treatment of chelating metals, photothermal therapy and scavenging ROS. In behavioral experiments, it also significantly improved the cognitive and learning deficits in late-stage APP/PS1 mice, thereby providing new ideas for the treatment of late-stage AD and other neurodegenerative diseases.}, }
@article {pmid39731791, year = {2025}, author = {Fayed, EA and El-Sebaey, SA and Ebrahim, MA and Abu-Elfotuh, K and El-Sayed Mansour, R and Mohamed, EK and Hamdan, AME and Al-Subaie, FT and Albalawi, GS and Albalawi, TM and Hamdan, AM and Mohammed, AA and Ramsis, TM}, title = {Discovery of novel bicyclic and tricyclic cyclohepta[b]thiophene derivatives as multipotent AChE and BChE inhibitors, in-Vivo and in-Vitro assays, ADMET and molecular docking simulation.}, journal = {European journal of medicinal chemistry}, volume = {284}, number = {}, pages = {117201}, doi = {10.1016/j.ejmech.2024.117201}, pmid = {39731791}, issn = {1768-3254}, mesh = {Animals ; Humans ; Male ; Rats ; *Acetylcholinesterase/metabolism ; Alzheimer Disease/drug therapy/metabolism ; *Butyrylcholinesterase/metabolism ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; Dose-Response Relationship, Drug ; Drug Discovery ; *Molecular Docking Simulation ; Molecular Structure ; Structure-Activity Relationship ; *Thiophenes/pharmacology/chemistry/chemical synthesis ; Heterocyclic Compounds, 3-Ring/chemical synthesis/chemistry/pharmacology ; }, abstract = {Alzheimer's disease (AD) is primarily caused by oxidative stress, hyperphosphorylated τ-protein aggregation, and amyloid-β deposition. Changes in dopaminergic and serotoninergic neurotransmitter pathways are linked to certain symptoms of AD. Derivatives of bicyclic and tricyclic cyclohepta[b]thiophene were developed to identify new potential candidates as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors for the treatment of AD. All synthesized compounds exhibited AChE inhibition with IC50 values below 15 μM, while all compounds exhibited BChE inhibition with IC50 values below 25 μM. Compounds 9 and 12 exhibited AChE inhibitory activities with IC50 values of 0.51 μM and 0.55 μM, respectively. Compounds 5 and 9 demonstrated excellent inhibitory activity against BChE with IC50 values of 2.9 μM and 2.48 μM, respectively. Compounds 9, 13, and 14 were found to be the most active in terms of the decrease in the escape latency time, with values comparable to that of Donepezil. Compounds 10, 11, and 12 exhibited promising effects on learning and memory. Compounds 5, 10, 11, and 12 exhibited promising SAP values of 70.67 %, 71.5 %, 74.33 % and 73.83 %, respectively. Other biomarkers were evaluated in rat brains including TAC, MDA, SOD, BDNF, IL-β and TNF-α. Fundamental features of ADMET have been computed in-silico for synthesized compounds. Molecular docking was performed to confirm the binding of the novel compounds to the targets.}, }
@article {pmid39731365, year = {2024}, author = {Kurishev, AO and Golimbet, VE}, title = {[Neuronal models based on olfactory epithelial cells in the study of the pathogenesis of mental disorders].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {12}, pages = {20-25}, doi = {10.17116/jnevro202412412120}, pmid = {39731365}, issn = {1997-7298}, mesh = {Humans ; *Olfactory Mucosa/metabolism/cytology ; *Mental Disorders/metabolism ; *Schizophrenia/metabolism/physiopathology ; Alzheimer Disease/metabolism ; DNA Methylation ; Bipolar Disorder/metabolism ; Epithelial Cells/metabolism ; Epigenesis, Genetic ; Neurons/metabolism ; }, abstract = {Mental disorders are complex illnesses with multifactorial etiologies involving genetic and environmental components. This review focuses on cellular models derived from the olfactory epithelium as a promising tool to study the molecular mechanisms of some neuropsychiatric diseases. The authors consider cell lines allowing the identification of potential biomarkers and pathogenetic mechanisms of schizophrenia, bipolar disorder, and Alzheimer's disease. Advantages of these models include the preservation of epigenetic modifications, the possibility of studying intercellular interactions, and conducting personalized studies. Particular emphasis is placed on state-of-the-art analytical techniques, such as single-cell RNA sequencing and DNA methylation analysis, as well as non-invasive methods of obtaining cellular material. The use of these models opens up new perspectives for the development of personalized therapeutic approaches and optimizing existing treatment regimens for psychiatric disorders.}, }
@article {pmid39731272, year = {2025}, author = {Gaur, A and Singh, YP and Sharma, R and Bainsal, N}, title = {Deoxyvasicinone hybrids in the management of Alzheimer's disease: Recent advances on manmade derivatives, pharmacological activities, and structure-activity relationship.}, journal = {Archiv der Pharmazie}, volume = {358}, number = {1}, pages = {e2400742}, doi = {10.1002/ardp.202400742}, pmid = {39731272}, issn = {1521-4184}, support = {//None/ ; }, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Structure-Activity Relationship ; Animals ; Molecular Structure ; Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Alkaloids ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurological illness that affects over 80% of aged adults globally in cases of dementia. Although the exact pathophysiological causes of AD remain unclear, its pathogenesis is primarily driven by several distinct biochemical alterations: (i) the accumulation of toxic Aβ plaques, (ii) the hyperphosphorylation of tau proteins, (iii) oxidative stress resulting in cell death, and (iv) an imbalance between the two main neurotransmitters, glutamate and acetylcholine (ACh). Currently, there are very few medications available and no treatment. Presently marketed medications include memantine, an N-methyl-d-aspartate receptor (NMDA) antagonist, and acetylcholinesterase (AChE) inhibitors: rivastigmine, donepezil, and galantamine. Unfortunately, these medications are only useful in the initial stages of AD. The mentioned medications only provide symptomatic relief and do not slow down the disease progression in the advanced stages. Therefore, there is an urgent need to develop potential candidates to treat AD, symptomatically and therapeutically. Many research groups focus on natural products due to their diverse therapeutic profiles and easy availability. One such natural product is deoxyvasicinone, isolated from Adhatoda vasica. Given its broad pharmacological profile, various researchers have developed semisynthetic hybrids of deoxyvasicinone to address multifaceted diseases like AD. In this review article, we tried to summarize the semisynthetic hybrids of deoxyvasicinone developed over the past decade (2014-2024) for managing AD. We focus on their design, pharmacological activity, and structure-activity relationship (SAR) analysis. We hope this review enhances the reader's understanding of future exploratory options for deoxyvasicinone hybrids in AD management.}, }
@article {pmid39730451, year = {2024}, author = {Wang, F and Liang, Y and Wang, QW}, title = {Interpretable machine learning-driven biomarker identification and validation for Alzheimer's disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {30770}, pmid = {39730451}, issn = {2045-2322}, support = {LQ23H090003//Natural Science Foundation of Zhejiang Province/ ; 2023KY1135//Zhejiang Medical and Health Technology Project/ ; 2024C03101//Zhejiang Province Key program/ ; 32171035//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/genetics/diagnosis/metabolism ; Humans ; *Machine Learning ; *Biomarkers/metabolism ; *Protein Interaction Maps/genetics ; Gene Expression Profiling/methods ; Computational Biology/methods ; Gene Regulatory Networks ; Transcriptome ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by limited effective treatments, underscoring the critical need for early detection and diagnosis to improve intervention outcomes. This study integrates various bioinformatics methodologies with interpretable machine learning to identify reliable biomarkers for AD diagnosis and treatment. By leveraging differentially expressed genes (DEGs) analysis, weighted gene co-expression network analysis (WGCNA), and construction of Protein-Protein Interaction (PPI) Networks, we meticulously analyzed the AD dataset from the GEO database to pinpoint Hub genes. Subsequently, various machine learning algorithms were employed to construct diagnostic models, which were then elucidated using SHapley Additive exPlanations (SHAP). To visualize our findings, we generated an insightful bioinformatics map of 10 Hub genes. We then conducted experimental validation on less-studied Hub genes, revealing significant differential mRNA expression of MYH9 and RHOQ in an AD cell model. Finally, we explored the biological significance of these two genes at the single-cell transcriptome level. This study not only introduces interactive SHAP panels for precise decision-making in AD but also offers novel insights into the identification of AD biomarkers through interpretable machine learning diagnostic models. Particularly, MYH9 has emerged as a promising new potential biomarker, pointing the way towards enhanced diagnostic accuracy and personalized therapeutic strategies for AD. Although the mRNA expression patterns of RHOQ are opposite in AD cell models and human brain tissue samples, the role of RHOQ in AD remains worthy of further exploration due to the diversity and complexity of biological molecular regulation.}, }
@article {pmid39727960, year = {2024}, author = {Akgöl, J and Kutlay, Ö and Keskin Aktan, A and Fırat, F}, title = {Assessment of Modified Citrus Pectin's Effects on Dementia in the Scopolamine-Induced Alzheimer's Model in Adult Male Wistar Rats.}, journal = {Current issues in molecular biology}, volume = {46}, number = {12}, pages = {13922-13936}, pmid = {39727960}, issn = {1467-3045}, support = {Project No: 21. General. 021//Afyonkarahisar Health Sciences University Scientific Research Projects Coordination Unit/ ; }, abstract = {Modified citrus pectin (MCP) modulates galectin-3, a key player in neuroinflammation linked to Alzheimer's disease. By inhibiting galectin-3, MCP reduces the brain's inflammatory response and may alleviate cognitive decline. This study examines MCP's impact on neuroinflammation, cognitive function, and its role in galectin-3 inhibition in a dementia model. Male Wistar rats were assigned to four groups: control (n = 6), scopolamine (SCP) (n = 7), SCP + MCP (n = 7), and MCP only (n = 7). MCP was administered orally at 100 mg/kg/day via drinking water for six weeks. SCP was injected intraperitoneally at 1 mg/kg for seven days to induce an Alzheimer's-type dementia model. The researchers assessed cognitive performance through the Morris Water Maze (MWM) test. After behavioral tests, blood and brain tissues, including the hippocampus, were collected and stored at -80 °C for analysis. Immunohistochemistry was used to evaluate superoxide dismutase (SOD) activity, malondialdehyde (MDA) levels, brain-derived neurotrophic factor (BDNF), and inflammatory markers (IL-1β, IL-6, TNF-α, and galectin-3). The data were analyzed with SPSS 22. SCP treatment increased lipid peroxidation (MDA) and elevated inflammatory markers (TNF-α, IL-6, and galectin-3), while reducing BDNF and impairing spatial memory. Co-administering MCP with SCP significantly reduced TNF-α, IL-6, and galectin-3 levels; increased BDNF; and improved memory performance. Although MCP did not lower MDA levels, it boosted SOD activity, suggesting antioxidant effects. Modified citrus pectin (MCP) alleviated cognitive impairments and reduced neuroinflammation in Alzheimer's-type dementia by inhibiting galectin-3. MCP also exhibited antioxidant potential, underscoring its therapeutic promise for neurodegenerative diseases.}, }
@article {pmid39727954, year = {2024}, author = {Kot, A and Koszewska, D and Ochman, B and Świętochowska, E}, title = {Clinical Potential of Misshapen/NIKs-Related Kinase (MINK) 1-A Many-Sided Element of Cell Physiology and Pathology.}, journal = {Current issues in molecular biology}, volume = {46}, number = {12}, pages = {13811-13845}, pmid = {39727954}, issn = {1467-3045}, abstract = {Misshapen/NIKs-related kinase (MINK) 1 belongs to the mammalian germinal center kinase (GCK) family. It contains the N-terminal, conserved kinase domain, a coiled-coil region, a proline-rich region, and a GCK, C-terminal domain with the Citron-NIK-Homology (CNH) domain. The kinase is an essential component of cellular signaling pathways, which include Wnt signaling, JNK signaling, pathways engaging Ras proteins, the Hippo pathway, and STRIPAK complexes. It thus contributes to regulating the cell cycle, apoptosis, cytoskeleton organization, cell migration, embryogenesis, or tissue homeostasis. MINK1 plays an important role in immunological responses, inhibiting Th17 and Th1 cell differentiation and regulating NLRP3 inflammasome function. It may be considered a link between ROS and the immunological system, and a potential antiviral target for human enteroviruses. The kinase has been implicated in the pathogenesis of sepsis, rheumatoid arthritis, asthma, SLE, and more. It is also involved in tumorigenesis and drug resistance in cancer. Silencing MINK1 reduces cancer cell migration, suggesting potential for new therapeutic approaches. Targeting MINK1 could be a promising treatment strategy for patients insensitive to current chemotherapies, and could improve their prognosis. Moreover, MINK1 plays an important role in the nervous system and the cardiovascular system development and function. The modulation of MINK1 activity could influence the course of neurodegenerative diseases, including Alzheimer's disease. Further exploration of the activity of the kinase could also help in gaining more insight into factors involved in thrombosis or congenital heart disease. This review aims to summarize the current knowledge on MINK1, highlight its therapeutic and prognostic potential, and encourage more studies in this area.}, }
@article {pmid39727881, year = {2024}, author = {Mohamed, M and Mohamed, N and Kim, JG}, title = {P300 Latency with Memory Performance: A Promising Biomarker for Preclinical Stages of Alzheimer's Disease.}, journal = {Biosensors}, volume = {14}, number = {12}, pages = {}, pmid = {39727881}, issn = {2079-6374}, support = {S1601-20-1016//Ministry of Science and ICT/ ; NRF-2016M3C7A1905475//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Alzheimer Disease ; Male ; *Biomarkers ; Female ; *Event-Related Potentials, P300/physiology ; *Memory ; Middle Aged ; Aged ; Neuropsychological Tests ; Electroencephalography ; }, abstract = {Detecting and tracking the preclinical stages of Alzheimer's disease (AD) is now of particular interest due to the aging of the world's population. AD is the most common cause of dementia, affecting the daily lives of those afflicted. Approaches in development can accelerate the evaluation of the preclinical stages of AD and facilitate early treatment and the prevention of symptom progression. Shifts in P300 amplitude and latency, together with neuropsychological assessments, could serve as biomarkers in the early screening of declines in cognitive abilities. In this study, we investigated the ability of the P300 indices evoked during a visual oddball task to differentiate pre-clinically diagnosed participants from normal healthy adults (HCs). Two preclinical stages, named asymptomatic AD (AAD) and prodromal AD (PAD), were included in this study, and a total of 79 subjects participated, including 35 HCs, 22 AAD patients, and 22 PAD patients. A mixed-design ANOVA test was performed to compare the P300 indices among groups during the processing of the target and non-target stimuli. Additionally, the correlation between these neurophysiological variables and the neuropsychological tests was evaluated. Our results revealed that neither the peak amplitude nor latency of P300 can distinguish AAD from HCs. Conversely, the peak latency of P300 can be used as a biomarker to differentiate PAD from AAD and HCs. The correlation results revealed a significant relationship between the peak latency of P300 and memory domain tasks, showing that less time-demanding neuropsychological assessments can be used. In summary, our findings showed that a combination of P300 latency and memory-requiring tasks can be used as an efficient biomarker to differentiate individuals with AAD from HCs.}, }
@article {pmid39726994, year = {2025}, author = {Wu, S and Qi, Y and Jiang, C and Zheng, J}, title = {Mining and analysis of adverse events associated with aducanumab: a real-world study using FDA Adverse Event Reporting System database.}, journal = {Expert opinion on drug safety}, volume = {24}, number = {4}, pages = {469-478}, doi = {10.1080/14740338.2024.2448205}, pmid = {39726994}, issn = {1744-764X}, mesh = {Humans ; *Adverse Drug Reaction Reporting Systems/statistics & numerical data ; *Data Mining ; United States ; Male ; *United States Food and Drug Administration ; *Antibodies, Monoclonal, Humanized/adverse effects/administration & dosage ; *Alzheimer Disease/drug therapy ; Female ; Aged ; *Databases, Factual ; Middle Aged ; Aged, 80 and over ; Adult ; }, abstract = {BACKGROUND: Aducanumab, a monoclonal antibody, received approval for the treatment of Alzheimer's disease in 2021. However, it remains controversial over the security of this drug. In this study, aducanumab-related adverse events (AEs) were evaluated through data mining based on the FDA Adverse Event Reporting System (FAERS) database.
RESEARCH DESIGN AND METHODS: The AE reports induced by aducanumab as the primary suspected drug were extracted from the FAERS database. The clinical characteristics of aducanumab-associated reports were analyzed. The potential new AE signals of aducanumab were explored using four disproportionality analysis methods. Furthermore, the difference in aducanumab-associated AE signals was investigated concerning sex, age, weight, dose, onset time, and continent.
RESULTS: In total, 328 reports and 793 AEs associated with aducanumab were identified. Six new AEs were identified. No significant sex and weight difference in aducanumab-related signals was found. Notably, nervous system disorders, especially 'amyloid related imaging abnormality-edema/effusion' and 'amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits,' were more frequently to be reported within 121-240 days, particularly in Europe.
CONCLUSIONS: This study contributes real-world evidence regarding the safety of aducanumab.}, }
@article {pmid39725376, year = {2025}, author = {Gutierre, RC and Rocha, PR and Graciani, AL and Coppi, AA and Arida, RM}, title = {Tau, amyloid, iron, oligodendrocytes ferroptosis, and inflammaging in the hippocampal formation of aged rats submitted to an aerobic exercise program.}, journal = {Brain research}, volume = {1850}, number = {}, pages = {149419}, doi = {10.1016/j.brainres.2024.149419}, pmid = {39725376}, issn = {1872-6240}, mesh = {Animals ; *Hippocampus/metabolism ; *Physical Conditioning, Animal/physiology/methods ; Rats ; *Ferroptosis/physiology ; *Oligodendroglia/metabolism ; *Iron/metabolism ; *tau Proteins/metabolism ; *Aging/physiology ; Male ; Rats, Wistar ; Neurons/metabolism ; Alzheimer Disease/metabolism/pathology ; Inflammation/metabolism ; Amyloid/metabolism ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disease affecting memory, language, and thinking with no curative treatment. Symptoms appear gradually, and pathological brain changes may occur twenty years before the physical and psychological signs, pointing to the urgent development of preventive interventions. Physical activity has been investigated as a preventive tool to defeat the main biological features of AD: pathological amyloid protein plaques, tau tangles, myelin degeneration, and iron deposits in the brain. This work quantifies tau tangles, amyloid, iron, and ferroptosis in oligodendrocytes in the aged rat hippocampal formation and statistically correlates neuron-neuron, neuron-glia, and glia-glia crosstalk and the effect of physical exercise on it. Our results indicate that iron overload in the oligodendrocytes is an inducer of ferroptosis; physical exercise reduces inflammaging, and improves axon-myelin volume relations; tau, amyloid, iron, and hippocampal formation cells present statistical correlations. Our data suggest the beneficial effects of physical exercise in AD and a mathematical relationship between the hippocampal formation cells in sedentary and active individuals, which should be considered in human and animal studies as a guide to a better understanding of crosstalk physiology.}, }
@article {pmid39724945, year = {2025}, author = {Song, X and Wang, C and Ding, Q and Li, P and Sun, S and Wei, W and Zhang, J and Sun, R and Yin, L and Liu, S and Pu, Y}, title = {Modulation of β secretase and neuroinflammation by biomimetic nanodelivery system for Alzheimer's disease therapy.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {378}, number = {}, pages = {735-749}, doi = {10.1016/j.jconrel.2024.12.060}, pmid = {39724945}, issn = {1873-4995}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; *Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; *Curcumin/administration & dosage/pharmacology/therapeutic use/chemistry ; Humans ; Neuroinflammatory Diseases/drug therapy ; Neuroprotective Agents/administration & dosage/therapeutic use ; MicroRNAs/administration & dosage ; Biomimetic Materials/administration & dosage/chemistry ; Microglia/drug effects/metabolism ; Mice ; Nanoparticles/administration & dosage/chemistry ; Neurons/metabolism/drug effects ; Biomimetics ; Male ; Anti-Inflammatory Agents/administration & dosage/therapeutic use ; Blood-Brain Barrier/metabolism ; }, abstract = {Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. The vicious circle between amyloid-β peptide (Aβ) overgeneration and microglial dysfunction is an important pathological event that promotes AD progression. However, therapeutic strategies toward only Aβ or microglial modulation still have many problems. Herein, inspired by the Aβ transportation, an Aβ-derived peptide (CKLVFFAED) engineered biomimetic nanodelivery system (MK@PC-R NPs) is reported for realizing BBB penetration and reprogram neuron and microglia in AD lesion sites. This hollow mesoporous Prussian blue-based MK@PC-R NPs carrying curcumin and miRNA-124 can down-regulate β secretase expression, thereby inhibiting Aβ production and reducing Aβ-induced neurotoxicity. Meanwhile, MK@PC-R NPs with excellent antioxidant and anti-inflammatory properties could normalize the microglial phenotype and promote Aβ degradation, providing neuroprotection. As expected, after treatment with MK@PC-R NPs, the Aβ burdens, neuron damages, neuroinflammation, and memory deficits of transgenic AD mice (APP/PS1 mice) are significantly attenuated. Overall, this biomimetic nanodelivery system with anti-Aβ and anti-inflammatory properties provides a promising strategy for the multi-target therapy of early AD.}, }
@article {pmid39722372, year = {2025}, author = {Fang, C and Chen, Q and Zheng, G and Zhang, F and Li, Z and Mei, J and Wu, X and Chen, X and Zeng, K and Yang, L}, title = {Cellulose-like chitosan microfibrils facilitate targeted release and enhance the prolonged residence time of quercetin-selenium nanoparticles for Alzheimer's disease treatment.}, journal = {International journal of pharmaceutics}, volume = {670}, number = {}, pages = {125129}, doi = {10.1016/j.ijpharm.2024.125129}, pmid = {39722372}, issn = {1873-3476}, mesh = {Animals ; *Chitosan/chemistry/administration & dosage ; *Quercetin/administration & dosage/pharmacology/chemistry/pharmacokinetics ; *Nanoparticles/administration & dosage ; *Gastrointestinal Microbiome/drug effects ; Mice ; Male ; *Selenium/chemistry/administration & dosage ; *Alzheimer Disease/drug therapy ; *Cellulose/chemistry ; Drug Liberation ; Nanofibers/administration & dosage ; Drug Carriers/chemistry ; Brain/metabolism/drug effects ; Liver/metabolism/drug effects ; Povidone/chemistry/administration & dosage ; Mice, Inbred C57BL ; Nanoparticle Drug Delivery System/chemistry ; }, abstract = {The effect of digestion on nanocarriers will affect the release and pharmacological effects of bioactive compounds in delivery systems. The digestion of cellulose is limited to gut microbiota, which offers a new research strategy for targeted delivery of bioactive compounds. Herein, positively charged cellulose-like chitosan/polyvinylpyrrolidone nanofiber was prepared to improve the residence time, colon target and gut microbiota regulation activity of quercetin decorated selenium nanoparticles (QUE@SeNPs/CS/PVPNFs). Selenium nanoparticles block the degradation of quercetin and QUE@SeNPs/CS/PVPNFs only decompose when caused by chitosanase secretion from gut microbiota. In vivo imaging showed that the residence time of QUE@SeNPs/CS/PVPNFs was longer than that of QUE@SeNPs. Thus, it significantly decreased the lipid concentrations in liver, which further inhibited insulin resistance in mice. Moreover, QUE@SeNPs/CS/PVPNFs treatment improves gut barrier integrity, increased the relative abundance of anti-obesity and anti-inflammation related bacterial including Akkermansia, Lactobacillus and Bacteroides. Consequently, the inflammatory factor (IL-β and TNF-α) levels in gut, liver and brain were also decreased. Nissl and PSD-95 staining indicated that QUE@SeNPs/CS/PVPNFs ameliorated synapse dysfunction in the brain. Therefore, QUE@SeNPs/CS/PVPNFs has a greater effect than QUE@SeNPs in improving cognitive ability in Morris water maze. Overall, QUE@SeNPs/CS/PVPNFs with prolonged residence time attenuates cognitive disorder via gut-liver-brain axis in AD.}, }
@article {pmid39722311, year = {2025}, author = {Wang, R and Azad, AK and Sheikh, AM and Tabassum, S and Zhang, Y and Zhou, X and Bhuiya, J and Binte Abdullah, F and Yano, S and Ikeue, T and Nagai, A}, title = {Carboxylated Zn-phthalocyanine attenuates brain Aβ in AD model mouse.}, journal = {Brain research}, volume = {1850}, number = {}, pages = {149422}, doi = {10.1016/j.brainres.2024.149422}, pmid = {39722311}, issn = {1872-6240}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *Disease Models, Animal ; Mice ; *Isoindoles/pharmacology ; *Indoles/pharmacology ; *Brain/drug effects/metabolism ; *Organometallic Compounds/pharmacology ; *Zinc Compounds/pharmacology ; Neurons/drug effects/metabolism ; Male ; Microglia/drug effects/metabolism ; Mice, Transgenic ; Maze Learning/drug effects ; Hippocampus/drug effects/metabolism ; }, abstract = {The deposition of aggregated amyloid β (Aβ) is considered as a key factor for Alzheimer's Disease (AD). Previously, we demonstrated that a carboxylated Zn-phthalocyanine (ZnPc) inhibits Aβ fibril formation, consequently protects neurons in culture. This study evaluated the effects of ZnPc on pathological changes in an AD mouse model (J20). Nine-month-old J20 mice received weekly intraperitoneal injection of ZnPc (2 and 4 mg/kg) for 12 weeks. Cognitive performance was assessed using Y-maze and open field tests. ZnPc levels in the tissues were evaluated using near-infrared microscopy and spectroscopy. ZnPc accumulated primarily in the liver and kidney. A considerable amount was also detected in brain tissue, where it co-localized with neurons, microglia, and extracellularly deposited Aβ. ZnPc treatment (2 mg/kg) significantly improved cognitive functions of J20 mice. Immunostaining results showed that Aβ was positive intracellularly in neurons, and extracellularly around the vessels and parenchyma in the cortex and hippocampus of PBS-treated J20 mice, which was significantly decreased in ZnPc-treated J20 mice in a dose-dependent manner. Nissl staining demonstrated that neuronal numbers were increased both in the cortex and hippocampus. GFAP-positive astrocytes and Iba-1 positive microglia were decreased by ZnPc treatment. Also, vessel numbers were increased in ZnPc-treated groups. In PBS-treated group, aquaporin 4 immunopositive area extended beyond STL-positive vessels into the parenchyma, which was confined primarily around the vessels in the ZnPc-treated group. Claudin 5 levels were increased in ZnPc-treated group. Therefore, ZnPc can decrease brain Aβ deposition in J20 mice, suggesting it as a potential therapeutic agent for AD.}, }
@article {pmid39721955, year = {2024}, author = {Yang, F and Gao, W and Wang, J and Li, X and Li, H}, title = {Progress of Chinese Medicine in Regulating Microglial Polarization against Alzheimer's Disease.}, journal = {The American journal of Chinese medicine}, volume = {52}, number = {8}, pages = {2255-2275}, doi = {10.1142/S0192415X24500873}, pmid = {39721955}, issn = {1793-6853}, mesh = {*Alzheimer Disease/drug therapy/therapy ; *Microglia/metabolism ; Humans ; *Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use ; Animals ; Neuroinflammatory Diseases/drug therapy ; }, abstract = {Alzheimer's disease (AD), the predominant form of dementia, is a neurodegenerative disorder of the central nervous system (CNS) characterized by a subtle onset and a spectrum of cognitive and functional declines. The clinical manifestation of AD encompasses memory deficits, cognitive deterioration, and behavioral disturbances, culminating in a severe impairment of daily living skills. Despite its high prevalence, accounting for 60-70% of all dementia cases, there remains an absence of curative therapeutics. Microglia (MG), the resident immune cells of the CNS, exhibit a bifurcated role in AD pathogenesis. Functioning in a neuroprotective capacity, MGs express scavenger receptors, facilitating the clearance of [Formula: see text]-amyloid protein (A[Formula: see text]) and cellular debris. Conversely, aberrant activation of MGs can lead to the secretion of pro-inflammatory cytokines, thereby propagating neuroinflammatory responses that are detrimental to neuronal integrity. The dynamics of MG activation and the ensuing neuroinflammation are pivotal in the evolution of AD. Chinese medicine (CM), a treasure trove of traditional Chinese cultural practices, has demonstrated significant potential in the therapeutic management of AD. Over the past triennium, CM has garnered considerable research attention for its multifaceted approaches to AD, including the regulation of MG polarization. This review synthesizes current knowledge on the origins, polarization dynamics, and mechanistic interplay of MG with AD pathology. It further explores the nexus between MG polarization and cardinal pathological hallmarks of AD, such as A[Formula: see text] plaque deposition, hyperphosphorylation of tau, synaptic plasticity impairments, neuroinflammation, and brain-gut-axis dysregulation. The review also encapsulates the therapeutic strategies of CM, which encompass monomers, formulae, and acupuncture. These strategies modulate MG polarization in the context of AD treatment, thereby providing a robust theoretical framework in which to conduct future investigative endeavors in both the clinical and preclinical realms.}, }
@article {pmid39721456, year = {2025}, author = {Li, X and Pan, J and Liu, X and Li, M and Zhuang, L and Jiang, P and Wang, S and Guan, W and Xue, S and Chen, Q and Zhang, L and Kuang, H and Yang, B and Liu, Y}, title = {The total withanolides from the leaves of Datura stramonium L. Improves Alzheimer's disease pathology by restraining neuroinflammation through NLRP3/IL-1β/IL1R1/TOM 1 pathway.}, journal = {International immunopharmacology}, volume = {146}, number = {}, pages = {113893}, doi = {10.1016/j.intimp.2024.113893}, pmid = {39721456}, issn = {1878-1705}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Plant Leaves/chemistry ; *Mice, Transgenic ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Mice ; *Signal Transduction/drug effects ; *Withanolides/pharmacology/therapeutic use ; *Interleukin-1beta/metabolism ; Receptors, Interleukin-1 Type I/metabolism ; Microglia/drug effects/metabolism ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Humans ; Disease Models, Animal ; Cell Line ; Neuroinflammatory Diseases/drug therapy/immunology ; Amyloid beta-Peptides/metabolism ; Lipopolysaccharides ; Male ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta-amyloid (Aβ) peptides. Microglia-mediated neuroinflammation is one of the primary contributors to the pathogenesis of AD. Withanolides, the main constituents in the leaves of Datura stramonium L., exhibit anti-neuroinflammatory activity. It is unknown if total withanolide from Datura stramonium L. leaves (TWD) reduces nerve inflammation and potentially mitigates the pathogenic elements of AD. This study examined the potential effects of TWD on neuroinflammation in triple transgenic AD (3 × Tg-AD) mice and LPS-induced BV-2, as well as associated signaling pathways. HPLC-Q-TOF-MS/MS was used in this study to examine the main chemical components of the TWD extract. 3 × Tg-AD as in vivo AD models and LPS induce BV-2 cells in vitro AD models. The molecular process was investigated by ELISA, WB, IHC, and IF. In 3 × Tg-AD mice, TWD dramatically ameliorates cognitive impairment. Treatment with TWD can counteract the increased activation of microglia and Aβ deposits observed in 3 × Tg-AD mice. Further research indicates that TWD can enhance TOM 1 and mitigate inflammatory responses by reducing the levels of IL-1β, TNF-α, IL-6, IL1R1, and IL-18. Additionally, TWD may inhibit neuroinflammation through the pathways of IL1R1/MyD88/NF-κB and NLRP3/IL-1β/IL1R1. In summary, this study reveals for the first time that TWD effectively improves cognitive deficits in 3 × Tg-AD mice by modulating the IL1R1/MyD88/NF-κB and NLRP3/IL-1β/IL1R1 pathways. It also alleviates excessive activation of microglia and suppresses Aβ accumulation. Therefore, TWD has the potential as a therapeutic agent for AD.}, }
@article {pmid39721106, year = {2025}, author = {Peng, W and Ma, Y and Li, C and Dai, W and Fu, X and Liu, L and Liu, L and Liu, J}, title = {Fusion of brain imaging genetic data for alzheimer's disease diagnosis and causal factors identification using multi-stream attention mechanisms and graph convolutional networks.}, journal = {Neural networks : the official journal of the International Neural Network Society}, volume = {184}, number = {}, pages = {107020}, doi = {10.1016/j.neunet.2024.107020}, pmid = {39721106}, issn = {1879-2782}, mesh = {*Alzheimer Disease/genetics/diagnostic imaging/diagnosis ; Humans ; *Neural Networks, Computer ; *Brain/diagnostic imaging/physiopathology ; *Magnetic Resonance Imaging/methods ; Polymorphism, Single Nucleotide ; Aged ; Neuroimaging/methods ; Male ; Female ; }, abstract = {Correctly diagnosing Alzheimer's disease (AD) and identifying pathogenic brain regions and genes play a vital role in understanding the AD and developing effective prevention and treatment strategies. Recent works combine imaging and genetic data, and leverage the strengths of both modalities to achieve better classification results. In this work, we propose MCA-GCN, a Multi-stream Cross-Attention and Graph Convolutional Network-based classification method for AD patients. It first constructs a brain region-gene association network based on brain region fMRI time series and gene SNP data. Then it integrates the absolute and relative positions of the brain region time series to obtain a new brain region time series containing temporal information. Then long-range and local association features between brain regions and genes are sequentially aggregated by multi-stream cross-attention and graph convolutional networks. Finally, the learned brain region and gene features are input to the fully connected network to predict AD types. Experimental results on the ADNI dataset show that our model outperforms other methods in AD classification tasks. Moreover, MCA-GCN designed a multi-stage feature scoring process to extract high-risk genes and brain regions related to disease classification.}, }
@article {pmid39720940, year = {2024}, author = {Alfayez, F and Rozov, S and El Tokhy, MS}, title = {Accurate and Efficient Algorithm for Detection of Alzheimer Disability Based on Deep Learning.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {58}, number = {6}, pages = {739-755}, doi = {10.33594/000000746}, pmid = {39720940}, issn = {1421-9778}, mesh = {Humans ; *Deep Learning ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Algorithms ; *Support Vector Machine ; *Neural Networks, Computer ; Aged ; Male ; Female ; Diagnosis, Computer-Assisted/methods ; }, abstract = {BACKGROUND/AIMS: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that severely affects cognitive functions and memory. Early detection is crucial for timely intervention and improved patient outcomes. However, traditional diagnostic tools, such as MRI and PET scans, are costly and less accessible. This study aims to develop an automated, cost-effective digital diagnostic approach using deep learning (DL) and computer-aided detection (CAD) methods for early AD identification and classification.
METHODS: The proposed framework utilizes pretrained convolutional neural networks (CNNs) for feature extraction, integrated with two classifiers: multi-class support vector machine (MSVM) and artificial neural network (ANN). A dataset categorized into four groups-non-demented, very mild demented, mild demented, and moderate demented-was employed for evaluation. To optimize the classification process, a texture-based algorithm was applied for feature reduction, enhancing computational efficiency and reducing processing time.
RESULTS: The system demonstrated high statistical performance, achieving an accuracy of 91%, precision of 95%, and recall of 90%. Among the initial set of twenty-two texture features, seven were identified as particularly effective in differentiating normal cases from mild AD stages, significantly streamlining the classification process. These results validate the robustness and efficacy of the proposed DL-based CAD system.
CONCLUSION: This study presents a reliable and affordable solution for early AD detection and diagnosis. The proposed system outperforms existing state-of-the-art models and offers a valuable tool for timely treatment planning. Future research should explore its application to larger, more diverse datasets and investigate integration with other imaging modalities, such as MRI, to further enhance diagnostic precision.}, }
@article {pmid39720194, year = {2024}, author = {Varlibas, FB and Domac, FM and Yuksel, G and Akhan, O and Ercin, E}, title = {Prevalance of Non-Provoke Generalize Tonic-Clonic Seizure in Sporadic Alzheimer's Disease.}, journal = {Journal of epilepsy research}, volume = {14}, number = {2}, pages = {66-72}, pmid = {39720194}, issn = {2233-6249}, abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD) and epileptic seizure are among the most common health problems in the elderly population. This study aimed to estimate the prevalence rate and predictors of seizures in sporadic AD patients.
METHODS: The study was conducted by retrospectively for a period of 10 years examining the file records. Patients were selected among the patients diagnosed with probable sporadic late onset AD according to the National Institute of Neurological Communicative Disorders and Stroke AD and related disorders association criteria and the diagnostic and statistical manual of mental disorders (n=451). In our 213 sporadic AD patients who were followed up regularly and had a follow up examination in the last 6 months, the file records were examined, scanned and questioned for the presence of epileptic seizures.
RESULTS: The prevalence of non provoked generalized tonic clonic seizures in sporadic AD was found to be 6.57% (n=14). Neuroleptic use, presence of diabetes mellitus (DM) and/or treatment, presence of ischemic heart disease (IHD) and/or treatment were found to be 2.99 times, 1.91 times and 3.09 times higher in our patients who had seizures, respectively. When the factors that can affect seizures were examined, the use of neuroleptics and the presence of IHD and/or treatment were found to be statistically significant in terms of the risk of seizure in AD.
CONCLUSIONS: The use of neuroleptics, the presence of IHD and DM and/or their medications could facilitate the development of unprovoked generalized tonic clonic seizures in sporadic AD. It is doubtful whether the seizures are primary or secondary generalized.}, }
@article {pmid39720065, year = {2024}, author = {Agnihotri, SK and Cai, J and Wang, Z}, title = {Exploring the synchronization of cortical networks via entrainment to intrinsic frequencies.}, journal = {Heliyon}, volume = {10}, number = {24}, pages = {e41034}, pmid = {39720065}, issn = {2405-8440}, abstract = {INTRODUCTION: Transcranial electrical stimulation (tES), including transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS), is widely studied for its potential to modulate brain oscillations and connectivity, offering treatment options for neurological disorders like Alzheimer's, Parkinson's, and insomnia. In this study, we focus on investigating the efficacy of tACS and tDCS in entraining intrinsic cortical network oscillations through a computational model.
MATERIALS AND METHODS: We developed a 2D computational cortical neuron model with 2000 neurons (1600 pyramidal and 400 inhibitory), based on the Izhikevich neuron model. The network was structured to generate low-frequency oscillations, particularly within the delta (4 Hz) range. Both tACS and tDCS were simulated to assess their effect on network synchronization. An algorithm was employed to extract the network's intrinsic frequency and align stimulation frequencies accordingly.
RESULTS: Our model successfully generated 4 Hz oscillations, characteristic of delta waves, associated with sleep states. t-ACS stimulation enhanced the power of the 4 Hz frequency, achieving effective synchronization with the intrinsic network dynamics. In contrast, tDCS failed to increase the power of 4 Hz oscillations and disrupted the excitatory-inhibitory balance of the network, reducing connectivity and synchronization. Our results demonstrate that tACS effectively enhances network synchronization and maintains excitatory-inhibitory balance by aligning with the network's intrinsic oscillatory frequency. In contrast, tDCS disrupts these dynamics, reducing connectivity and failing to entrain the target frequency. These findings suggest that tACS may hold greater potential for applications requiring precise network synchronization, while tDCS may have distinct but more limited efficacy in influencing oscillatory activity.
CONCLUSION: The study demonstrates the superior efficacy of tACS over tDCS in enhancing the synchronization of cortical networks by entraining intrinsic frequencies. Future research may extend this model by incorporating long-term plasticity mechanisms to better understand tES effects over longer time scales.}, }
@article {pmid39719687, year = {2025}, author = {Guenoun, D and Blaise, N and Sellam, A and Roupret-Serzec, J and Jacquens, A and Steenwinckel, JV and Gressens, P and Bokobza, C}, title = {Microglial Depletion, a New Tool in Neuroinflammatory Disorders: Comparison of Pharmacological Inhibitors of the CSF-1R.}, journal = {Glia}, volume = {73}, number = {4}, pages = {686-700}, pmid = {39719687}, issn = {1098-1136}, support = {//Institut National de la Santé et de la Recherche Médicale/ ; ANR-22-CE37-0019//Agence Nationale de la Recherche/ ; Investissement d'Avenir-ANR-11-INBS-0011-NeurATR//Agence Nationale de la Recherche/ ; //Fondation de France/ ; PREMSTEM-874721//Horizon 2020 Framework Programme/ ; //Université Sorbonne Paris Cité/ ; //Fondation des Gueules Cassées/ ; //Assistance Publique - Hôpitaux de Paris/ ; }, mesh = {*Microglia/drug effects/metabolism ; Animals ; Humans ; *Neuroinflammatory Diseases/drug therapy ; Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors/metabolism ; Aminopyridines/pharmacology/therapeutic use ; Pyrroles/pharmacology ; Anisoles ; Organic Chemicals ; Pyrimidines ; }, abstract = {A growing body of evidence highlights the importance of microglia, the resident immune cells of the CNS, and their pro-inflammatory activation in the onset of many neurological diseases. Microglial proliferation, differentiation, and survival are highly dependent on the CSF-1 signaling pathway, which can be pharmacologically modulated by inhibiting its receptor, CSF-1R. Pharmacological inhibition of CSF-1R leads to an almost complete microglial depletion whereas treatment arrest allows for subsequent repopulation. Microglial depletion has shown promising results in many animal models of neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease, or multiple sclerosis) where transitory microglial depletion reduced neuroinflammation and improved behavioral test results. In this review, we will focus on the comparison of three different pharmacological CSF-1R inhibitors (PLX3397, PLX5622, and GW2580) regarding microglial depletion. We will also highlight the promising results obtained by microglial depletion strategies in adult models of neurological disorders and argue they could also prove promising in neurodevelopmental diseases associated with microglial activation and neuroinflammation. Finally, we will discuss the lack of knowledge about the effects of these strategies on neurons, astrocytes, and oligodendrocytes in adults and during neurodevelopment.}, }
@article {pmid39719647, year = {2024}, author = {Yan, L and Song, YS and Zhou, J and Zhu, L and Shi, TW and Yu, HQ and Dong, ZQ and Wang, W and Long, T and Liu, HY and Shi, ZY and Li, JG}, title = {Expression of nicastrin, NICD1, and Hes1 in NCSTN knockout mice: implications for hidradenitis suppurativa, Alzheimer's, and liver cancer.}, journal = {European journal of medical research}, volume = {29}, number = {1}, pages = {622}, pmid = {39719647}, issn = {2047-783X}, support = {81773344//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Transcription Factor HES-1/genetics/metabolism ; *Amyloid Precursor Protein Secretases/genetics/metabolism ; *Mice, Knockout ; *Alzheimer Disease/genetics/metabolism ; Mice ; *Hidradenitis Suppurativa/genetics ; Female ; Male ; *Liver Neoplasms/genetics/pathology ; *Membrane Glycoproteins/genetics/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Receptor, Notch1/genetics ; }, abstract = {BACKGROUND: Nicastrin, a subunit of the γ-secretase complex, is encoded by the NCSTN gene and regulates notch signaling, it is involved in the pathogenesis of hidradenitis suppurativa (HS), Alzheimer disease (AD), and liver cancer. However, the animal models for studying HS are relatively scarce.
METHODS: CRISPR/Cas-mediated genetic engineering was used to generate targeted knockout offspring mice (C57BL/6J). Different doses (10 mg/kg, 20 mg/kg, and 30 mg/kg) and injection methods (subcutaneous/intraperitoneal/gavage injection) of tamoxifen were used to induce the construction of NCSTN knockout mice (mice model). The expressions of nicastrin, NICD1, hes1 in skin, brain, and liver tissue in mice model and wild-type (WT) mice were measured by qRT-PCR and IHC.
RESULTS: The construction of mice model was successfully induced by tamoxifen, knockout efficiency was 93%, there was no difference in knockout efficiency among three doses, injection methods, genders (P > 0.05). HS-like lesions appeared on the skin of NCSTN knockout mice after 1 month of treatment with tamoxifen, male mice had a higher number of skin lesions compared to female mice (male vs female = 76.5% vs 41.7%, P = 0.027). Compared with WT mice, the expressions of nicastrin (skin P = 0.0009, brain P = 0.0194, liver P = 0.0066), NICD1 (skin P = 0.0115, brain P = 0.0307, liver P = 0.008), hes1 (skin P = 0.0476, brain P = 0.0143, liver P = 0.0003) in mice model all decreased.
CONCLUSIONS: The NCSTN knockout mouse might be employed as HS animal model; Reducing nicastrin may affect the expression of notch1-hes1 pathway molecules in skin, brain, and liver tissues; low dose (10 mg/kg/d) tamoxifen could be used to induce the deletion of the target gene in mice.}, }
@article {pmid39719518, year = {2024}, author = {Alsaleem, MA and Al-Kuraishy, HM and Al-Gareeb, AI and Albuhadily, AK and Alrouji, M and Yassen, ASA and Alexiou, A and Papadakis, M and Batiha, GE}, title = {Molecular Signaling Pathways of Quercetin in Alzheimer's Disease: A Promising Arena.}, journal = {Cellular and molecular neurobiology}, volume = {45}, number = {1}, pages = {8}, pmid = {39719518}, issn = {1573-6830}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Quercetin/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment and memory deficit. Even with extensive research and studies, presently, there is no effective treatment for the management of AD. Besides, most of drugs used in the treatment of AD did not avert the AD neuropathology, and the disease still in a progressive status. For example, acetyl cholinesterase inhibitors are associated with many adverse effects, such as insomnia and nightmares. As well, acetylcholinesterase inhibitors augment cholinergic neurotransmission leading to the development of adverse effects related to high acetylcholine level, such as salivation, rhinorrhea, vomiting, loss of appetite, and seizure. Furthermore, tacrine has poor bioavailability and causes hepatotoxicity. These commonly used drugs do not manage the original causes of AD. For those reasons, natural products were repurposed for the treatment of AD and neurodegenerative diseases. It has been shown that phytochemicals produce neuroprotective effects against the development and progression of neurodegenerative diseases by different mechanisms, including antioxidant and anti-inflammatory effects. Quercetin (QCN) has been reported to exert an effective neuroprotective effect against AD and other neurodegenerative diseases by lessening oxidative stress. In this review, electronic databases such as PubMed, Scopus, and Web of Science were searched for possible relevant studies and article linking the effect of QCN on AD. Findings from this review highlighted that many studies highlighted different mechanistic signaling pathways regarding the neuroprotective effect of QCN in AD. Nevertheless, the precise molecular mechanism of QCN in AD was not completely clarified. Consequently, this review aims to discuss the molecular mechanism of QCN in AD.}, }
@article {pmid39718338, year = {2025}, author = {Knopman, DS}, title = {Precision diagnosis of cognitive impairment due to Alzheimer's disease for therapeutic interventions.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14043}, pmid = {39718338}, issn = {1552-5279}, support = {//NIH/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; *Cognitive Dysfunction/diagnosis/therapy ; Precision Medicine ; Antibodies, Monoclonal/therapeutic use ; Amyloid beta-Peptides ; Biomarkers ; }, abstract = {With the advent of anti-amyloid monoclonal antibody (AAMA) therapy, precision diagnosis is necessary for identifying appropriate patients with cognitive disorders due to Alzheimer's disease. Therapy with AAMAs requires that candidates be diagnosed with mild cognitive impairment or mild dementia, have elevated brain amyloid-β, have good physical, psychiatric, and medical health, and lack clinical or biomarker evidence of potentially impactful non-Alzheimer brain disorders. The first three diagnostic activities are the core of the Clinical Practice Guidelines, but the last element of the precision diagnosis requires new decision-making tools for recognizing multi-etiology cognitive impairment. Within the context of shared decision-making between clinician, patient, and family, proper diagnosis is essential. In addition to discussing the benefits and risks of AAMA therapy, the experienced clinician must empathetically assist in bridging the gap between expectations of benefit and the patient's overall diagnostic suitability for AAMA therapy. HIGHLIGHTS: In order to prescribe an anti-amyloid monoclonal antibody (AAMA) to the right patients, those selected for treatment should be diagnosed with mild cognitive impairment or mild dementia, have elevated brain amyloid-β (Aβ), and have good physical, psychiatric, or medical health. Persons with Alzheimer's biology as the primary etiology are the ideal AAMA treatment recipients. A novel activity necessary to optimize therapeutic response is to exclude persons with clinical or biomarker evidence of alternative contributory brain disorders. While mild clinical severity and elevated brain amyloid-β are essential elements for selecting patients for AAMA treatment, clinical judgment is required to weigh the implications of more advanced disease severity, other medical co-morbidities, and the presence of other contributory neuropathologies.}, }
@article {pmid39717968, year = {2024}, author = {Vergini, DE and Hadjipavlou-Litina, D}, title = {"A patent review on arachidonic acid lipoxygenase (LOX) inhibitors for the treatment of neurodegenerative diseases (2018-present)".}, journal = {Expert opinion on therapeutic patents}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/13543776.2024.2447067}, pmid = {39717968}, issn = {1744-7674}, abstract = {INTRODUCTION: Neuroinflammation is correlated to neurodegenerative diseases like Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Huntington Disease (HD), and Parkinson's disease (PD). A lot of recent research and patents are focused on the design and synthesis of arachidonic acid lipoxygenase (ALOX) inhibitors for the treatment of neurodegenerative diseases.
AREAS COVERED: The survey covers natural products, synthesis, hybrids, and assessments of biological effects in biological studies as ALOX inhibitors. A survey of patent publications from 2018 to present, taken from Google Scholar, Espanet, Web of Science, Drugbank, Scopus, or PubMed is analyzed.
EXPERT OPINION: The authors suggest that (i) numerous areas of biology-pharmacology need to be considered: selectivity, in vivo studies, toxicity, bioavailability, and drug-likeness, the mechanism of action in different animals and humans, evaluation of more efficient and selective biological tests; (ii) synthetic method outbalance in the discovery and production of ALOX inhibitors with greater selectivity. Several ALOX inhibitors show promising results for the treatment of neurological disorders. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action and their bioavailability are well defined can be used as lead compounds for the treatment of neurodegenerative diseases.}, }
@article {pmid39717698, year = {2024}, author = {Kashyap, B and Hanson, LR and Gustafson, SK and Barclay, T and Howe, CM and Sherman, SJ and Hungs, M and Rosenbloom, MH}, title = {Open label pilot of personalized, neuroimaging-guided theta burst stimulation in early-stage Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1492428}, pmid = {39717698}, issn = {1662-4548}, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by cerebral amyloid plaques and neurofibrillary tangles and disruption of large-scale brain networks (LSBNs). Transcranial magnetic stimulation (TMS) has emerged as a potential non-invasive AD treatment that may serve as an adjunct therapy with FDA approved medications.
METHODS: We conducted a 10-subject open label, single site study evaluating the effect of functional connectivity-resting state functional MRI guided-approach to TMS targeting with dysfunctional LSBNs in subjects with biomarker-confirmed early-stage AD (https://clinicaltrials.gov/study/NCT05292222). Subjects underwent pre-post imaging and testing to assess connectivity dysfunction and cognition. All participants received intermittent theta burst stimulation [(iTBS), (80% motor threshold; 5 sessions per day; 5 days; 3 targets; 18,000 pulses/day)] over 2 weeks. Three Human Connectome Project (HCP) defined parcellations were targeted, with one common right temporal area G dorsal (RTGd) target across all subjects and two personalized.
RESULTS: We identified the following parcellations to be dysfunctional: RTGd, left area 8A ventral (L8Av), left area 8B lateral (L8BL), and left area 55b (L55b). There were no changes in these parcellations after treatment, but subjects showed improvement on the Repeatable Battery for the Assessment of Neuropsychological Status attention index (9.7; p = 0.01). No subject dropped out of the treatment, though 3 participants were unable to tolerate the RTGd target due to facial twitching (n = 2) and anxiety (n = 1).
CONCLUSION: Accelerated iTBS protocol was well-tolerated and personalized target-based treatment is feasible in early-stage AD. Further sham-controlled clinical trials are necessary to determine if this is an effective adjunctive treatment in early-stage AD.}, }
@article {pmid39717696, year = {2024}, author = {Perini, HF and Matos, BS and de Oliveira, CJF and da Silva, MV}, title = {Biomimetic nanocarriers: integrating natural functions for advanced therapeutic applications.}, journal = {Beilstein journal of nanotechnology}, volume = {15}, number = {}, pages = {1619-1626}, pmid = {39717696}, issn = {2190-4286}, abstract = {Biomimetic nanocarriers, engineered to mimic the characteristics of native cells, offer a revolutionary approach in the treatment of various complex human diseases. This strategy enhances drug delivery by leveraging the innate properties of cellular components, thereby improving biocompatibility and targeting specificity. Biomimetic nanocarriers demonstrate significant advancements in drug delivery systems against cancer therapy, Alzheimer's disease, autoimmune diseases, and viral infections such as COVID-19. Here, we address the therapeutic applications of biomimetic nanocarriers and their promising strategy for personalized medicine.}, }
@article {pmid39717614, year = {2024}, author = {Defrancesco, M and Post, F and Hofer, A and Jehle, J}, title = {Psychological telephone triage system for outpatient memory clinics - a way for adaptation to new challenges of increasing dementia prevalence and new treatment options?.}, journal = {International journal of clinical and health psychology : IJCHP}, volume = {24}, number = {4}, pages = {100530}, pmid = {39717614}, issn = {2174-0852}, abstract = {BACKGROUND: The increasing prevalence of dementia and new therapeutic developments for Alzheimer's disease (AD) have created an urgent need for rapid and cost-effective methods to diagnose those affected in the early stages of the disease. Unlike emergency departments, memory clinics lack triage systems, e.g. the Manchester Triage System.
METHOD: This retrospective, observational study evaluated the effects of a psychological telephone triage (PTT) system for people requesting an initial assessment at a specialized outpatient memory clinic over a 15-months period in terms of waiting times, staff resources, and as a screening method for cognitive disorders. The PTT consisted of an interdisciplinary pre-screening of available preliminary patient information prior to telephone contact, a semi-structured interview of approximately 30 min with a clinical psychologist, and telephone psychological counseling if there was no indication for an on-site dementia assessment. Based on the PTT interview, patients were triaged using a 4-level priority system (red = acute, yellow = subacute, green = not acute, blue = no indication/counseling). The results were compared with data from the two years prior to the introduction of PTT.
RESULTS: The data of 612 people (327 before and 285 after the introduction of PTT) who called the secretary's office between January 1, 2021 and April 30, 2024 and requested an initial assessment were analyzed. Of the original sample who called after the introduction of PTT, 66.7% had an indication for an on-site visit and were invited to do so. This was accepted by 51.6%. A further 14% received psychological telephone counseling, resulting in a 34% reduction in on-site visits. Patients triaged as acute cases had the shortest waiting time and presented with the most severe cognitive and functional symptoms at the on-site visit.
DISCUSSION: Our study shows that PTT is an effective method to identify patients with urgent need for an initial dementia assessment and to provide psychological counseling as an alternative to on-site visits. We expect that this will reduce the number of emergency admissions and thus the burden on caregivers and the healthcare system. This PTT concept can thus help to better manage the increasing need for initial assessments in the context of new therapies for AD and the increasing prevalence of dementia in general.}, }
@article {pmid39717593, year = {2024}, author = {Vahid, ZF and Eskandani, M and Dadashi, H and Vandghanooni, S and Rashidi, MR}, title = {Recent advances in potential enzymes and their therapeutic inhibitors for the treatment of Alzheimer's disease.}, journal = {Heliyon}, volume = {10}, number = {23}, pages = {e40756}, pmid = {39717593}, issn = {2405-8440}, abstract = {Alzheimer's disease (AD), a chronic neurodegenerative disease, is clinically characterized by loss of memory and learning ability among other neurological deficits. Amyloid plaques, hyperphosphorylated tau protein, and neurofibrillary tangles involve in AD etiology. Meanwhile, enzymes and their inhibitors have become the focus of research in AD treatment. In this review, the molecular mechanisms involved in the pathogenesis of AD were overviewed and various enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase, γ-secretase, monoamine oxidase (MAO), and receptor of advanced glycation end products (RAGE) were highlighted as potential targets for AD treatment. Several hybrid molecules with essential substructures derived from various chemotypes have demonstrated desired pharmacological activity. It is envisioned that the development of new drugs that inhibit enzymes involved in AD is a future trend in the management of the disease.}, }
@article {pmid39716798, year = {2024}, author = {Ansari, SA and Alshanberi, AM and Satar, R and Abujamai, J and Ashraf, GM}, title = {Current Updates on Nanotechnology-based Drug Delivery Platforms for Treating Alzheimer's with Herbal Drugs.}, journal = {Pharmaceutical nanotechnology}, volume = {}, number = {}, pages = {}, doi = {10.2174/0122117385335626241204165702}, pmid = {39716798}, issn = {2211-7393}, abstract = {Alzheimer's disease (AD) is an irreversible brain disorder that led to memory loss and disrupts daily life. Earlier strategies to treat AD such as acetylcholinesterase inhibitor (AChEI) drugs are not showing effectiveness due to the inability to cross the blood-brain barrier. Moreover, traditional AChEI provides limited efficacy in terms of bioavailability and solubility for treating AD treatment. Many of the current drugs such as donepezil taken to treat the disease exhibited harmful side effects. Hence, researchers are keen to find the alternative effective therapeutic agents for treating AD. This review summarizes the recent advancement in nanotechnology-based drug delivery systems of herbal drugs such as Curcumin, Ginkgo biloba, Salvia officinalis, etc for the prevention and cure of AD. Herbal drugs proved useful in treating neuronal disorders such as AD but exhibited some limitations like low bioavailability via oral drug delivery. Such limitations were overcome by tagging these drugs by nanoparticles which enables them to cross the blood-brain barrier and offer the delivery of greater concentration of herbal drugs to the brain. Inorganic nanoparticle-based drugdelivery systems such as gold nanoparticles and magnetic nanoparticles, organic nanoparticulate systems like polymeric micelles and dendrimers, and solid polymeric nanoparticles were some of the effective methods that have earlier shown potential for enhancing the delivery of herbal drugs to the brain. Long-term repeated injection of drugs loaded on nanomaterials can lead to the accumulation of nanomaterials in the body without timely and effective degradation which can cause serious issues to the brain. Hence, nanotechnology-based strategies should involve the formulation of nontoxic nanoparticles in such a way that they can significantly transport the drugs across the BBB followed by effective degradation of nanoparticles.}, }
@article {pmid39716791, year = {2025}, author = {Tripathi, S and Sharma, Y and Kumar, D}, title = {Exploring New Structures of Kinase Inhibitors and Multitarget Strategies in Alzheimer's Disease Treatment.}, journal = {Protein and peptide letters}, volume = {32}, number = {1}, pages = {2-17}, pmid = {39716791}, issn = {1875-5305}, mesh = {*Alzheimer Disease/drug therapy/metabolism/enzymology ; Humans ; *Protein Kinase Inhibitors/chemistry/therapeutic use/pharmacology ; Animals ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) treatments currently available have ineffective results. Previously employed Acetylcholine esterase inhibitors and memantine, an NMDA receptor antagonist, target a single target structure that plays a complex role in the multifactorial progression of disease. Memantine moderates the toxic effects of excessive glutamate activity by blocking NMDA receptors, which decreases neurotoxicity in AD, while acetylcholine esterase inhibitors function by blocking cholinergic receptors (muscarinic and nicotinic), preventing the breakdown of acetylcholine, thereby enhancing cholinergic transmission, thus improving cognitive functions in mild to moderate stages of AD. Every drug class targets a distinct facet of the intricate pathophysiology of AD, indicating the diverse strategy required to counteract the advancement of this neurodegenerative disorder. Thus, patients are currently not getting much benefit from current drugs. A closer look at the course of AD revealed several potential target structures for future drug discovery. AD drug development strategies focus on developing new target structures in addition to well-established ones for combination treatment regimens, ideally with a single drug that can target two different target structures. Because of their roles in AD progression pathways like pathologic tau protein phosphorylations as well as amyloid β toxicity, protein kinases have been identified as potential targets. This review will give a quick rundown of the first inhibitors of single protein kinases, such as glycogen synthase kinase (gsk3) β, along with cyclin-dependent kinase 5. We will also look into novel inhibitors that target recently identified protein kinases in Alzheimer's disease, such as dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Additionally, multitargeting inhibitors, which target multiple protein kinases as well as those thought to be involved in other processes related to AD will be discussed. This kind of multitargeting offers prospective hope for improved patient outcomes down the road since it is the most effective way to impede multifactorial disease development.}, }
@article {pmid39716790, year = {2024}, author = {Bhattacharya, K and Sungoh, D and Kharmujai, D and Islam, A and Das, D and Jha, SK and Chanu, NR and Kashyap, B and Bora, NS and Sahariah, BJ and Deka, S and Khanal, P}, title = {Exploring the Therapeutic Potential of 8-Prenyldaidzein: A Comprehensive Study of its Multi-Target Efficacy in Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {21}, number = {8}, pages = {578-598}, doi = {10.2174/0115672050358848241211080546}, pmid = {39716790}, issn = {1875-5828}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Molecular Docking Simulation ; Humans ; *Isoflavones/pharmacology/chemistry ; *Molecular Dynamics Simulation ; *Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; Acetylcholinesterase/metabolism ; Aspartic Acid Endopeptidases/metabolism/antagonists & inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is marked by cognitive decline, amyloid plaques, neurofibrillary tangles, and cholinergic loss. Due to the limited success of amyloid-targeted therapies, attention has shifted to new non-amyloid targets like phosphodiesterases (PDE). This study investigates the potential of Flemingia vestita (FV) phytomolecules and derivatives, particularly 8-Prenyldaidzein, in AD treatment.
MATERIALS AND METHODS: Phytocompounds and derivatives were screened for drug-likeness, toxicity, BBB permeability, and ADME profiles. Molecular docking was conducted with PDE5A, BACE-1, and AChE, followed by molecular dynamics (MD) simulations on the best binding complexes.
RESULTS: 8-Prenyldaidzein, a derivative of daidzein, demonstrated favorable drug-likeness and ADME properties. It exhibited strong binding to PDE5A, BACE-1, and AChE, with MD simulations confirming stable protein-ligand interactions.
DISCUSSION: The multi-target potential of 8-Prenyldaidzein, particularly through non-amyloid pathways, offers a promising approach to AD therapy. Its inhibition of PDE5A, BACE-1, and AChE could address multiple aspects of AD pathology.
CONCLUSION: 8-Prenyldaidzein shows strong potential as a multi-target inhibitor for AD treatment. While in-silico findings are promising, further experimental validation is needed to confirm its clinical applicability.}, }
@article {pmid39716787, year = {2024}, author = {Wu, D and Zhang, B and Chang, Y and Huang, S}, title = {Apathy Associated with Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {21}, number = {8}, pages = {527-537}, doi = {10.2174/0115672050350970241216072400}, pmid = {39716787}, issn = {1875-5828}, support = {(No. 2019BJP02)//Heilongjiang University of Chinese Medicine/ ; (No. 81873108)//National Natural Science Foundation of China (NSFC)/ ; }, mesh = {*Apathy/physiology ; Humans ; *Alzheimer Disease/psychology ; Brain/pathology ; }, abstract = {INTRODUCTION/OBJECTIVE: Apathy is a multidimensional and complex disease that is the primary neuropsychiatric symptom among those diagnosed with Alzheimer's disease (AD). Yet, apathy in AD is sometimes underestimated.
METHODS: A systematic literature review was conducted using databases such as PubMed, Scopus, and Web of Science. The search utilized specific keywords related to apathy and Alzheimer's disease (e.g., "apathy," "Alzheimer's disease," "neuropsychiatric symptoms," "front-striatal circuitry"). The studies were selected based on pre-defined criteria, including publication date (within the last 10 years), peer-reviewed status, and relevance to neurobiological, neurochemical, and behavioral aspects of apathy in AD. The articles were screened through title and abstract reviews, followed by full-text evaluations to ensure they met the inclusion criteria, such as relevance to apathy in Alzheimer's patients, study design rigor, and methodological quality.
RESULTS: Some research on the behavioral and neurobiological characteristics of apathy in AD points to the role of the front-striatal circuitry, particularly the anterior cingulate cortex (ACC). In addition, we reviewed the neurochemical, neuropsychological, and neuropathological characteristics believed to be associated with apathy symptoms.
CONCLUSION: The findings indicate that understanding the intricate neurobiological underpinnings of apathy in AD is crucial for developing targeted interventions. Our analysis suggests that a multimodal approach, incorporating both pharmacological and personalized non-pharmacological strategies, could enhance therapeutic efficacy and improve patient outcomes. This highlights the need for future research to explore these combined treatment modalities and their potential to alleviate apathy in AD patients.}, }
@article {pmid39716786, year = {2024}, author = {Bolshakova, OI and Slobodina, AD and Slepneva, EE and Sarantseva, SV}, title = {Acetyl-L-Carnitine Aids in Preservation of Cholinergic Neurons and Memory in the Drosophila melanogaster Model of Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {21}, number = {8}, pages = {557-565}, doi = {10.2174/0115672050347906241203075930}, pmid = {39716786}, issn = {1875-5828}, mesh = {Animals ; *Drosophila melanogaster ; *Alzheimer Disease/drug therapy/metabolism ; *Cholinergic Neurons/drug effects/metabolism ; *Acetylcarnitine/pharmacology ; *Disease Models, Animal ; *Amyloid beta-Peptides/metabolism ; Neuroprotective Agents/pharmacology ; Animals, Genetically Modified ; Brain/drug effects/metabolism ; Peptide Fragments/metabolism ; Memory/drug effects ; }, abstract = {BACKGROUND: The lack of effective therapy for the treatment of Alzheimer's disease demands both the search for new drugs and the reconsideration of already known substances currently used in other areas of medicine. Drosophila melanogaster offers the potential to model features of Alzheimer's disease, study disease mechanisms, and conduct drug screening.
OBJECTIVES: The purpose of this work was to analyze the neuroprotective properties of the drug "carnicetine", which is an acetylated form of the natural low molecular weight compound L-carnitine. The drug is able to cross the blood-brain barrier and is currently used as a means of improving cellular metabolism.
METHODS: Using tissue-specific drivers, direct expression of amyloid beta peptide (42 amino acids) was exhibited in certain groups of neurons in the Drosophila melanogaster brain, namely in dopaminergic and cholinergic neurons. The effect of acetyl-L-carnitine (carnicetine) on the death of these neurons and the memory of flies was analyzed.
RESULTS: The expression of amyloid beta peptide in dopaminergic or cholinergic neurons resulted in neurodegeneration of cholinergic neurons in the Drosophila brain and memory impairment. The use of carnicetine added to animal food made it possible to treat these disorders. At the same time, no effect on dopaminergic neurons was noted.
CONCLUSION: The data obtained confirmed the neuroprotective properties of the drug under study, demonstrating its participation in the restoration of the cholinergic system and the feasibility of using carnicetine for the treatment of Alzheimer's disease.}, }
@article {pmid39716330, year = {2024}, author = {Dong, J and Tong, W and Liu, M and Liu, M and Liu, J and Jin, X and Chen, J and Jia, H and Gao, M and Wei, M and Duan, Y and Zhong, X}, title = {Endosomal traffic disorders: a driving force behind neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {66}, pmid = {39716330}, issn = {2047-9158}, support = {No.81901309//the National Natural Science Foundation of China/ ; No.2023JH2/20200039//the Science and technology funding project to support the high-quality development of China Medical University/ ; No.LJKZ0775//the Basic Scientific Research Project of Institutions of Higher Learning of Liaoning Province/ ; No.2023-MSLH-369//the Joint plan of science and technology plan of Liaoning Province/ ; No.CXTD2022007//the Science and Technology Innovation Team Project of China Medical University/ ; }, mesh = {*Endosomes/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Protein Transport/physiology ; Endocytosis/physiology ; Biological Transport/physiology ; }, abstract = {Endosomes are crucial sites for intracellular material sorting and transportation. Endosomal transport is a critical process involved in the selective uptake, processing, and intracellular transport of substances. The equilibrium between endocytosis and circulation mediated by the endosome-centered transport pathway plays a significant role in cell homeostasis, signal transduction, and immune response. In recent years, there have been hints linking endosomal transport abnormalities to neurodegenerative diseases, including Alzheimer's disease. Nonetheless, the related mechanisms remain unclear. Here, we provide an overview of endosomal-centered transport pathways and highlight potential physiological processes regulated by these pathways, with a particular focus on the correlation of endosomal trafficking disorders with common pathological features of neurodegenerative diseases. Additionally, we summarize potential therapeutic agents targeting endosomal trafficking for the treatment of neurodegenerative diseases.}, }
@article {pmid39716328, year = {2024}, author = {Li, Z and Lin, C and Cai, X and Lv, F and Yang, W and Ji, L}, title = {Anti-diabetic agents and the risks of dementia in patients with type 2 diabetes: a systematic review and network meta-analysis of observational studies and randomized controlled trials.}, journal = {Alzheimer's research & therapy}, volume = {16}, number = {1}, pages = {272}, pmid = {39716328}, issn = {1758-9193}, support = {7202216//Natural Science Foundation of Beijing Municipality/ ; 81970698//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Dementia/epidemiology/etiology/prevention & control ; *Diabetes Mellitus, Type 2/complications/drug therapy ; *Hypoglycemic Agents/therapeutic use ; Network Meta-Analysis ; Observational Studies as Topic ; Randomized Controlled Trials as Topic ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; }, abstract = {OBJECTIVE: To evaluate the association between anti-diabetic agents and the risks of dementia in patients with type 2 diabetes (T2D).
METHODS: Literature retrieval was conducted in PubMed, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov between January 1995 and October 2024. Observational studies and randomized controlled trials (RCTs) in patients with T2D, which intercompared anti-diabetic agents or compared them with placebo, and reported the incidence of dementia were included. Conventional and network meta-analyses of these studies were implemented. Results were exhibited as the odds ratio (OR) or risk ratio (RR) with 95% confidence interval (CI).
RESULTS: A total of 41 observational studies (3,307,483 participants) and 23 RCTs (155,443 participants) were included. In the network meta-analysis of observational studies, compared with non-users, sodium glucose cotransporter-2 inhibitor (SGLT-2i) (OR = 0.56, 95%CI, 0.45 to 0.69), glucagon-like peptide-1 receptor agonist (GLP-1RA) (OR = 0.58, 95%CI, 0.46 to 0.73), thiazolidinedione (TZD) (OR = 0.68, 95%CI, 0.57 to 0.81) and metformin (OR = 0.89, 95%CI, 0.80 to 0.99) treatments were all associated with reduced risk of dementia in patients with T2D. The surface under the cumulative ranking curve (SUCRA) evaluation conferred a rank order as SGLT-2i > GLP-1RA > TZD > dipeptidyl peptidase-4 inhibitor (DPP-4i) > metformin > α-glucosidase inhibitor (AGI) > glucokinase activator (GKA) > sulfonylureas > glinides > insulin in terms of the cognitive benefits. Meanwhile, compared with non-users, SGLT-2i (OR = 0.43, 95%CI, 0.30 to 0.62), GLP-1RA (OR = 0.54, 95%CI, 0.30 to 0.96) and DPP-4i (OR = 0.73, 95%CI, 0.57 to 0.93) were associated with a reduced risk of Alzheimer's disease while a lower risk of vascular dementia was observed in patients receiving SGLT-2i (OR = 0.42, 95%CI, 0.22 to 0.80) and TZD (OR = 0.52, 95%CI, 0.36 to 0.75) treatment. In the network meta-analysis of RCTs, the risks of dementia were comparable among anti-diabetic agents and placebo.
CONCLUSION: Compared with non-users, SGLT-2i, GLP-1RA, TZD and metformin were associated with the reduced risk of dementia in patients with T2D. SGLT-2i, and GLP-1RA may serve as the optimal choice to improve the cognitive prognosis in patients with T2D.}, }
@article {pmid39715923, year = {2024}, author = {Shapira, G and Karmon, G and Hacohen-Kleiman, G and Ganaiem, M and Shazman, S and Theotokis, P and Grigoriadis, N and Shomron, N and Gozes, I}, title = {ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {39715923}, issn = {1476-5578}, abstract = {Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical for neurogenesis and cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism and somatic ADNP mutations parallel Alzheimer's disease progression. Furthermore, clinical trials with the ADNP fragment NAP (the investigational drug davunetide) showed efficacy in women suffering from the tauopathy progressive supranuclear palsy and differentially boosted memory in men (spatial) and women (verbal), exhibiting prodromal Alzheimer's disease. While autism is more prevalent in boys and Alzheimer's disease in women, both involve impaired neurogenesis. Here, we asked whether ADNP sex-dependently regulates neurogenesis. Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, we identified two-fold higher labeling in the hippocampal sub-ventricular zone of ADNP-intact male versus female mice. Adnp haplo-insufficient (Adnp[+/-]) mice or mice CRSIPR/Cas9-edited to present the most prevalent neurodevelopmental ADNP syndrome mutation, p.Tyr718* (Tyr) showed dramatic reductions in male BrdU incorporation, resulting in mutated females presenting higher labeling than males. Treatment with NAP compensated for the male reduction of BrdU labeling. Mechanistically, hippocampal RNAseq revealed male-specific Tyr down-regulation of endoplasmic reticulum unfolded protein response genes critical for sex-dependent organogenesis. Newly discovered mitochondrial accessibility of ADNP was inhibited by the Tyr718* mutation further revealing female-specific Tyr downregulation of mitochondrial ATP6. NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes. Thus, ADNP is a key regulator of sex-dependent neurogenesis that acts by controlling canonical pathways, with NAP compensating for fundamental ADNP deficiencies, striding toward clinical development targeting the ADNP syndrome and related neurodevelopmental/neurodegenerative diseases.}, }
@article {pmid39715912, year = {2025}, author = {Syed, YY}, title = {Xanomeline/Trospium Chloride: First Approval.}, journal = {Drugs}, volume = {85}, number = {1}, pages = {103-109}, pmid = {39715912}, issn = {1179-1950}, mesh = {Humans ; *Schizophrenia/drug therapy ; *Nortropanes/pharmacology/therapeutic use ; *Benzilates/pharmacology/therapeutic use ; *Drug Approval ; *Muscarinic Agonists/pharmacology/therapeutic use ; *Pyridines/pharmacology/therapeutic use/adverse effects ; Muscarinic Antagonists/pharmacology/therapeutic use/adverse effects ; Thiophenes/pharmacology/therapeutic use/adverse effects ; Drug Combinations ; Alzheimer Disease/drug therapy ; Antipsychotic Agents/therapeutic use/pharmacology/adverse effects ; United States ; Thiadiazoles ; }, abstract = {Xanomeline/trospium chloride (COBENFY™), formerly KarXT, is a first-in-class, oral, fixed-dose muscarinic agonist/antagonist combination being developed for use in schizophrenia and Alzheimer's disease psychosis. Xanomeline is thought to confer efficacy by acting as an agonist at M1 and M4 muscarinic acetylcholine receptors in the brain, and trospium chloride reduces the peripheral cholinergic adverse events associated with xanomeline. Xanomeline/trospium chloride received its first approval on 26 September 2024 in the USA for the treatment of schizophrenia in adults. This article summarizes the milestones in the development of xanomeline/trospium chloride leading to this first approval for schizophrenia.}, }
@article {pmid39715167, year = {2024}, author = {Lee, GB and Jeong, YJ and Kang, DY and Yun, HJ and Yoon, M}, title = {Multimodal feature fusion-based graph convolutional networks for Alzheimer's disease stage classification using F-18 florbetaben brain PET images and clinical indicators.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0315809}, pmid = {39715167}, issn = {1932-6203}, mesh = {*Alzheimer Disease/diagnostic imaging/classification ; Humans ; *Positron-Emission Tomography/methods ; Male ; Aged ; Female ; *Brain/diagnostic imaging/pathology ; *Stilbenes ; *Aniline Compounds ; Neural Networks, Computer ; Neuroimaging/methods ; Aged, 80 and over ; }, abstract = {Alzheimer's disease (AD), the most prevalent degenerative brain disease associated with dementia, requires early diagnosis to alleviate worsening of symptoms through appropriate management and treatment. Recent studies on AD stage classification are increasingly using multimodal data. However, few studies have applied graph neural networks to multimodal data comprising F-18 florbetaben (FBB) amyloid brain positron emission tomography (PET) images and clinical indicators. The objective of this study was to demonstrate the effectiveness of graph convolutional network (GCN) for AD stage classification using multimodal data, specifically FBB PET images and clinical indicators, collected from Dong-A University Hospital (DAUH) and Alzheimer's Disease Neuroimaging Initiative (ADNI). The effectiveness of GCN was demonstrated through comparisons with the support vector machine, random forest, and multilayer perceptron across four classification tasks (normal control (NC) vs. AD, NC vs. mild cognitive impairment (MCI), MCI vs. AD, and NC vs. MCI vs. AD). As input, all models received the same combined feature vectors, created by concatenating the PET imaging feature vectors extracted by the 3D dense convolutional network and non-imaging feature vectors consisting of clinical indicators using multimodal feature fusion method. An adjacency matrix for the population graph was constructed using cosine similarity or the Euclidean distance between subjects' PET imaging feature vectors and/or non-imaging feature vectors. The usage ratio of these different modal data and edge assignment threshold were tuned by setting them as hyperparameters. In this study, GCN-CS-com and GCN-ED-com were the GCN models that received the adjacency matrix constructed using cosine similarity (CS) and the Euclidean distance (ED) between the subjects' PET imaging feature vectors and non-imaging feature vectors, respectively. In modified nested cross validation, GCN-CS-com and GCN-ED-com respectively achieved average test accuracies of 98.40%, 94.58%, 94.01%, 82.63% and 99.68%, 93.82%, 93.88%, 90.43% for the four aforementioned classification tasks using DAUH dataset, outperforming the other models. Furthermore, GCN-CS-com and GCN-ED-com respectively achieved average test accuracies of 76.16% and 90.11% for NC vs. MCI vs. AD classification using ADNI dataset, outperforming the other models. These results demonstrate that GCN could be an effective model for AD stage classification using multimodal data.}, }
@article {pmid39715098, year = {2025}, author = {Liu, X and Wu, W and Li, X and Wang, C and Chai, K and Yuan, F and Zheng, H and Yao, Y and Li, C and Ye, ZC and Zha, D}, title = {The compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one alleviates neuroinflammation and cognitive impairment in a mouse model of Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3330-3344}, pmid = {39715098}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202511000-00034/figure1/v/2024-12-20T164640Z/r/image-tiff Previous studies have shown that the compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one (D30), a pyromeconic acid derivative, possesses antioxidant and anti-inflammatory properties, inhibits amyloid-β aggregation, and alleviates scopolamine-induced cognitive impairment, similar to the phase III clinical drug resveratrol. In this study, we established a mouse model of Alzheimer's disease via intracerebroventricular injection of fibrillar amyloid-β to investigate the effect of D30 on fibrillar amyloid-β-induced neuropathology. Our results showed that D30 alleviated fibrillar amyloid-β-induced cognitive impairment, promoted fibrillar amyloid-β clearance from the hippocampus and cortex, suppressed oxidative stress, and inhibited activation of microglia and astrocytes. D30 also reversed the fibrillar amyloid-β-induced loss of dendritic spines and synaptic protein expression. Notably, we demonstrated that exogenous fibrillar amyloid-β introduced by intracerebroventricular injection greatly increased galectin-3 expression levels in the brain, and this increase was blocked by D30. Considering the role of D30 in clearing amyloid-β, inhibiting neuroinflammation, protecting synapses, and improving cognition, this study highlights the potential of galectin-3 as a promising treatment target for patients with Alzheimer's disease.}, }
@article {pmid39714723, year = {2025}, author = {Das, A and Balakrishnan, P}, title = {Mechanisms and clinical applications of palmitoylethanolamide (PEA) in the treatment of neuropathic pain.}, journal = {Inflammopharmacology}, volume = {33}, number = {1}, pages = {121-133}, pmid = {39714723}, issn = {1568-5608}, mesh = {*Palmitic Acids/therapeutic use/pharmacology ; *Ethanolamines/pharmacology/therapeutic use/administration & dosage ; Humans ; *Amides/pharmacology ; *Neuralgia/drug therapy ; Animals ; Analgesics/pharmacology/therapeutic use ; Inflammation/drug therapy ; Endocannabinoids/metabolism ; }, abstract = {Palmitoylethanolamide (PEA) is emerging as a promising therapeutic agent for neuropathic and other pain-related conditions. This naturally occurring fatty acid has drawn interest because of its ability to regulate pain and inflammation. Initially identified in food sources, PEA has been the subject of extensive research to elucidate its properties, efficacy, and clinical applications. PEA primarily exerts its effects through interaction with its primary receptor PPAR α, this interaction influences pain signalling pathways and neuroinflammatory processes by modulating the synthesis of pro-inflammatory cytokines, mast cell degranulation, microglial activation, and decrease of oxidative stress. PEA's interaction with endocannabinoid receptors decreases the inflammatory cytokine and chemokine production and thereby a descending pain sensation. The pharmacological and pharmacokinetic characteristics of PEA are examined in this paper, along with its potential for efficiency when used in in combination additional therapies in a variety of neurodegenerative disease models, including multiple sclerosis, Parkinson's disease, and Alzheimer's. Experimental evidence shows that PEA not only reduces pain and inflammation but also lowers the need for higher dosages of other drugs hence minimizing the risk of drug toxicity. The bioavailability of PEA has been enhanced by recent technological developments, which emphasize continuous research efforts to maximize PEA's therapeutic potential in pain treatment and associated medical sectors.}, }
@article {pmid39714451, year = {2025}, author = {Ma, M and Wang, J and Guo, K and Zhong, W and Cheng, Y and Lin, L and Zhao, Y}, title = {A Self-Reinforced "Microglia Energy Modulator" for Synergistic Amyloid-β Clearance in Alzheimer's Disease Model.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {64}, number = {8}, pages = {e202420547}, doi = {10.1002/anie.202420547}, pmid = {39714451}, issn = {1521-3773}, support = {NRF-CRP26-2021-0002//National Research Foundation Singapore/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism ; *Microglia/metabolism/drug effects ; Animals ; Mice ; Disease Models, Animal ; Phagocytosis/drug effects ; Humans ; Adenosine Triphosphate/metabolism ; }, abstract = {Microglial phagocytosis is a highly energy-consuming process that plays critical roles in clearing neurotoxic amyloid-β (Aβ) in Alzheimer's disease (AD). However, microglial metabolism is defective overall in AD, thereby undermining microglial phagocytic functions. Herein, we repurpose the existing antineoplastic drug lonidamine (LND) conjugated with hollow mesoporous Prussian blue (HMPB) as a "microglial energy modulator" (termed LND@HMPB-T7) for safe and synergistic Aβ clearance. The modified blood-brain barrier penetrating heptapeptide (T7) enables efficient transport of LND@HMPB-T7 to the AD brain. LND in LND@HMPB-T7 could fuel Aβ phagocytosis by stimulating microglial adenosine triphosphate (ATP) production, whereas HMPB with catalase and superoxide dismutase-mimicking activities substantially alleviates the mitochondrial side effects commonly associated with LND and thus further enhances ATP production. The synergism of LND and nanozyme affords a high microglial Aβ clearance efficacy without triggering mitochondrial dysfunction. In vivo experiments ascertain that LND@HMPB-T7 could synergistically promote phagocytic clearance of Aβ, relieve neuroinflammation and ameliorate cognitive function in AD mice. These findings indicate that LND@HMPB-T7 holds tremendous clinical potential as a repurposed drug for AD treatment.}, }
@article {pmid39714110, year = {2025}, author = {Achmad, NA and Tuna, RW and Kurniawan, I and Khairiyah, and Asaf, MB and Rahman, L and Manggau, MA and Aliyah, and Dominguez-Robles, J and Aswad, M and Permana, AD}, title = {Development of Thermosensitive Mucoadhesive Gel Based Encapsulated Lipid Microspheres as Nose-to-Brain Rivastigmine Delivery System.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {41}, number = {1}, pages = {314-328}, doi = {10.1021/acs.langmuir.4c03530}, pmid = {39714110}, issn = {1520-5827}, mesh = {*Rivastigmine/pharmacokinetics/chemistry/administration & dosage ; *Gels/chemistry ; *Microspheres ; Animals ; *Brain/metabolism/drug effects ; *Lipids/chemistry ; Temperature ; Rats ; Administration, Intranasal ; Drug Delivery Systems ; Cholinesterase Inhibitors/pharmacokinetics/chemistry/administration & dosage ; Particle Size ; Nasal Mucosa/metabolism/drug effects ; Drug Carriers/chemistry ; }, abstract = {Alzheimer's disease (ALZ) is a neurodegenerative disease that damages neuronal cells and causes decline in cognitive abilities. Administration of cholinesterase inhibitor compounds is the primary choice in the treatment of ALZ, one of which is rivastigmine (RVT). Several routes of administration of RVT are available, such as oral and transdermal. However, in the oral route, RVT has low bioavailability, undergoes first-pass metabolism, and the presence of the blood-brain barrier (BBB) reduces the therapeutic concentration of RVT. The transdermal route is nonselective target in the brain. This study aims to combine thermosensitive mucoadhesive gel (TG) and lipid microspheres (LM) as a drug delivery system to improve the efficacy of RVT. Combining these will prevent systemic side effects of RVT and increase drug concentration in the brain. LM was formulated with varying concentrations of Compritol polymer. The results of LM evaluation showed the values of particle size, PDI, and %EE and %DL were 8.519 μm, 0.018 ± 0.004, 72.54%, and 76.43%, respectively. The TG formulation can provide a liquid form at room temperature (25 °C) and a gel at nasal temperature (35 °C). Hemolytic and HET-CAM tests confirmed TG RVT LM's safety for use. Ex vivo studies showed controlled and sustained release of TG RVT LM, and in vivo studies showed TG RVT LM a higher pharmacokinetic profile in the brain than oral formulations and injections. The Cmax was found to be 7.05 ± 0.55 μg/cm[3], Tmax was 24 h, and AUC0-24, which is related to the effectiveness of brain targeting, was 225.73 μg/cm[3]. In conclusion, this study shows the successful development of TG RVT LM, as evidenced by improved drug delivery to the brain, which is characterized by higher concentrations of RVT in the brain compared with oral and injectable RVT, this delivery system shows potential as a future treatment for Alzheimer's disease.}, }
@article {pmid39713873, year = {2025}, author = {Hammers, DB and Eloyan, A and Taurone, A and Thangarajah, M and Gao, S and Beckett, L and Polsinelli, AJ and Kirby, K and Dage, JL and Nudelman, K and Aisen, P and Reman, R and La Joie, R and Lagarde, J and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, I and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Womack, K and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, SJ and Turner, RS and Wingo, TS and Wolk, DA and Carrillo, MC and Rabinovici, GD and Dickerson, BC and Apostolova, LG and , }, title = {Longitudinal cognitive performance of participants with sporadic early onset Alzheimer's disease from LEADS.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14439}, pmid = {39713873}, issn = {1552-5279}, support = {R56 AG057195/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; P30AG066506/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; LDRFP-21-818464/ALZ/Alzheimer's Association/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; P50AG047366/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; P50 AG005146/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; K23 AG080071/AG/NIA NIH HHS/United States ; U01 AG016976/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; AARG-22-926940/ALZ/Alzheimer's Association/United States ; K23AG080071/AG/NIA NIH HHS/United States ; P50 AG047366/AG/NIA NIH HHS/United States ; LEADS GENETICS-19-639372/ALZ/Alzheimer's Association/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; U01AG6057195/AG/NIA NIH HHS/United States ; U24AG021886/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease ; Male ; Female ; Longitudinal Studies ; *Neuropsychological Tests/statistics & numerical data ; Middle Aged ; Executive Function/physiology ; Cognitive Dysfunction ; Aged ; Cognition/physiology ; Disease Progression ; Age of Onset ; }, abstract = {INTRODUCTION: Early-onset Alzheimer's disease (EOAD) manifests prior to the age of 65, and affects 4%-8% of patients with Alzheimer's disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early-onset dementia.
METHODS: Data from 307 cognitively normal (CN) volunteer participants and those with amyloid-positive EOAD or amyloid-negative cognitive impairment (EOnonAD) were compared. Cognitive trajectories across a comprehensive cognitive battery spanning 42 months were examined using mixed-effects modeling.
RESULTS: The EOAD group displayed worse cognition at baseline relative to EOnonAD and CN groups, and more aggressive declines in cognition over time. The largest effects were observed on measures of executive functioning domains, while memory declines were blunted in EOAD.
DISCUSSION: EOAD declined 2-4× faster than EOnonAD, and EOAD pathology is not restricted to memory networks. Early identification of deficits is critical to ensure that individuals with sporadic EOAD can be considered for treatment using disease-modifying medications.
HIGHLIGHTS: Represents the most comprehensive longitudinal characterization of sporadic EOAD to date. The trajectory of cognitive declines was steep for EOAD participants and worse than for other groups. Executive functioning measures exhibited the greatest declines over time in EOAD.}, }
@article {pmid39713820, year = {2025}, author = {Qian, W and Liu, D and Liu, J and Liu, M and Ji, Q and Zhang, B and Yang, Z and Cheng, Y and Zhou, S}, title = {The Mitochondria-Targeted Micelle Inhibits Alzheimer's Disease Progression by Alleviating Neuronal Mitochondrial Dysfunction and Neuroinflammation.}, journal = {Small (Weinheim an der Bergstrasse, Germany)}, volume = {21}, number = {6}, pages = {e2408581}, doi = {10.1002/smll.202408581}, pmid = {39713820}, issn = {1613-6829}, support = {2023-ZDYJSY-001//Key Laboratory of New Drug Delivery System and New Technology for Formulation, Shaanxi Administration of Traditional Chinese Medicine/ ; 2023-JC-QN-0988//Natural Science Foundation of Shaanxi Province/ ; 2021ZDLSF03-08//Key Science and Technology Program of Shaanxi Province/ ; 2023-YBSF-221//Key Science and Technology Program of Shaanxi Province/ ; 2024SF-YBXM-026//Key Science and Technology Program of Shaanxi Province/ ; 82073775//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Micelles ; *Mitochondria/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Neurons/drug effects/metabolism/pathology ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Mice ; Disease Progression ; Microglia/drug effects/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Cyclosporine/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Blood-Brain Barrier/drug effects/metabolism/pathology ; Oligopeptides ; }, abstract = {Mitochondrial dysfunction plays an important role in neuroinflammation and cognitive impairment in Alzheimer's disease (AD). Herein, this work designs a mitochondria-targeted micelle CsA-TK-SS-31 (CTS) to block the progression of AD by simultaneously alleviating mitochondrial dysfunction in microglia and neurons. The mitochondria-targeted peptide SS-31 drives cyclosporin A (CsA) to penetrate the blood-brain barrier (BBB) and delivers CsA to mitochondria of microglia and neurons in the brains of 5 × FAD mice. Under the high level of reactive oxygen species (ROS) environment in damaged mitochondria of microglia and neurons, the linker (thioketal, TK) between CsA and SS-31 is broken and CsA and SS-31 are released while consuming ROS in the microenvironment. The released CsA and SS-31 synergistically restore the mitochondrial membrane potential and the balance between the fission and fusion of mitochondria, which subsequently protect neurons from apoptosis and reduce the activation of microglia in the brains of 5 × FAD mice. Ultimately, the neuroinflammation and cognitive impairment of 5 × FAD mice are ameliorated. This research provides a synergistic treatment strategy for AD through alleviating mitochondrial dysfunction to reduce neuroinflammation and restore the function of neurons simultaneously.}, }
@article {pmid39713353, year = {2024}, author = {Li, Y and Serras, CP and Blumenfeld, J and Xie, M and Hao, Y and Deng, E and Chun, YY and Holtzman, J and An, A and Yoon, SY and Tang, X and Rao, A and Woldemariam, S and Tang, A and Zhang, A and Simms, J and Lo, I and Oskotsky, T and Keiser, MJ and Huang, Y and Sirota, M}, title = {Data-driven discovery of cell-type-directed network-correcting combination therapy for Alzheimer's disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39713353}, issn = {2692-8205}, support = {R01 AG060393/AG/NIA NIH HHS/United States ; R01 AG078164/AG/NIA NIH HHS/United States ; P01 AG073082/AG/NIA NIH HHS/United States ; R01 AG057683/AG/NIA NIH HHS/United States ; RF1 AG076647/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were identified as a potential combination therapy, each targeting AD-related gene expression changes in neurons and glial cells, respectively. In an AD mouse model, this combination therapy significantly improved memory function and reduced AD-related pathologies compared to vehicle and single-drug treatments. Single-nuclei transcriptomic analysis confirmed that the therapy reversed disease-associated gene networks in a cell-type-specific manner. These results highlight the promise of cell-type-directed combination therapies in addressing multifactorial diseases like AD and lay the groundwork for precision medicine tailored to patient-specific transcriptomic and clinical profiles.}, }
@article {pmid39713140, year = {2024}, author = {Zou, P and He, Q and Xia, H and Zhong, W}, title = {Ferroptosis and its impact on common diseases.}, journal = {PeerJ}, volume = {12}, number = {}, pages = {e18708}, pmid = {39713140}, issn = {2167-8359}, mesh = {*Ferroptosis ; Humans ; Neoplasms/metabolism/pathology ; Lipid Peroxidation ; Reperfusion Injury/pathology/metabolism ; Cardiovascular Diseases/pathology/metabolism ; Inflammatory Bowel Diseases/metabolism/pathology/therapy/physiopathology ; Alzheimer Disease/pathology/metabolism ; Iron/metabolism ; Acute Kidney Injury/metabolism/pathology ; Stroke/pathology/metabolism ; Animals ; }, abstract = {Ferroptosis is a novel form of programmed cell death characterized by iron accumulation, lipid peroxidation, and a decline in antioxidant capacity, all of which are regulated by gene expression. The onset of numerous diseases is closely associated with ferroptosis. Common diseases affect a large population, reduce the quality of life, and impose an increased burden on the healthcare system. The role of ferroptosis in common diseases, its therapeutic potential, and even its translation into clinical drug treatments are currently significant research topics worldwide. This study preliminarily explores the theoretical basis of ferroptosis, its mechanism and treatment prospect in common diseases including ischaemia-reperfusion injury, inflammatory bowel diseases, liver fibrosis, acute kidney injury, diabetic kidney disease, stroke, Alzheimer's disease, cardiovascular disease, immune and cancer. This review provides a theoretical foundation for the further study and development of ferroptosis, as well as for the prevention and treatment of common diseases.}, }
@article {pmid39712854, year = {2024}, author = {Mansoor, S and Jindal, A and Badu, NYA and Katiki, C and Ponnapalli, VJS and Desai, KJ and Nassar, ST}, title = {Role of Neurotrophins in the Development and Treatment of Neurodegenerative Diseases: A Systematic Review.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e74048}, pmid = {39712854}, issn = {2168-8184}, abstract = {A considerable amount of morbidity and disability are caused by a wide variety of neurological illnesses together referred to as neurodegenerative diseases. Among them, Alzheimer's and Parkinson's diseases are the most prevalent and have been thoroughly studied. The development of intervention techniques that focus on the unfavorable elements of these diseases, particularly those that could help halt their course, has become increasingly important. This study aims to explain the most current findings about the function of neurotrophins, the signaling pathways they follow in neurodegenerative illnesses, and their possible therapeutic applications. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 criteria served as the foundation for this systematic review. In April 2024, a thorough search was conducted through the Cochrane Library, Google Scholar, PubMed, PubMed Central, and ScienceDirect databases. The predetermined criteria used to choose the research were the English language, narrative and systematic reviews, observational studies, and randomized and non-randomized clinical trials published within the last ten years. Subsequently, each study type-specific quality assessment was conducted utilizing the available assessment method. Of the 3,322 studies found during the first search, 15 were ultimately chosen for inclusion in the final selection. One cohort, one non-randomized clinical trial, one randomized clinical trial, three meta-analyses and systematic reviews, and nine narrative reviews were included. This review has explained in detail the current understanding of how neurotrophins play an essential role in neuroplasticity and neurogenesis, as well as their complex downstream signaling that leads to the process of neurodegeneration. Our study has also highlighted previous studies showing the efficacy of neurotrophins in clinical trials, but the data is limited; more preclinical and clinical studies are needed in this regard. These have also drawn our attention to future clinical trials that will address the challenges faced in their delivery and associated complications. Altogether, neurotrophins could serve as promising targets for therapeutic intervention that could stop or even reverse the development of neuropathology associated with neurodegenerative illnesses.}, }
@article {pmid39712748, year = {2024}, author = {Kalchev, E}, title = {Rethinking Arterial Spin Labeling Perfusion in Neurodegeneration Considering Global and Regional Changes.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e74188}, pmid = {39712748}, issn = {2168-8184}, abstract = {Recent advancements in arterial spin labeling (ASL) MRI have significantly improved our understanding of cerebral perfusion in neurodegenerative diseases. Traditionally, the focus has been on regional perfusion deficits corresponding to specific neural pathologies. However, this localized approach may overlook the influence of global cerebral blood flow alterations. This manuscript proposes a nuanced perspective that considers the interplay between global and regional changes. By integrating a broader view of cerebral perfusion, we can enhance diagnostic accuracy, uncover new patterns in disease progression, and potentially refine treatment strategies. We advocate for a collaborative effort to validate and implement this comprehensive approach in clinical and research settings.}, }
@article {pmid39712494, year = {2024}, author = {Fontán-Baselga, T and Cañeque-Rufo, H and Rivera-Illades, E and Gramage, E and Zapico, JM and de Pascual-Teresa, B and Ramos-Álvarez, MDP and Herradón, G and Vicente-Rodríguez, M}, title = {Pharmacological inhibition of receptor protein tyrosine phosphatase β/ζ decreases Aβ plaques and neuroinflammation in the hippocampus of APP/PS1 mice.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1506049}, pmid = {39712494}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder that courses with chronic neuroinflammation. Pleiotrophin (PTN) is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ which is upregulated in different neuroinflammatory disorders of diverse origin, including AD. To investigate the role of RPTPβ/ζ in neuroinflammation and neurodegeneration, we used eight-to ten-month-old APP/PS1 AD mouse model. They were administered intragastrically with MY10, an inhibitor of RPTPβ/ζ, at different doses (60 and 90 mg/kg) every day for 14 days. Treatment with 90 mg/kg MY10 significantly reduced the number and size of amyloid beta (Aβ) plaques in the dorsal subiculum of the hippocampus of APP/PS1 mice. In addition, we observed a significant decrease in the number and size of astrocytes in both sexes and in the number of microglial cells in a sex-dependent manner. This suggests that RPTPβ/ζ plays an important role in modulating Aβ plaque formation and influences glial responses, which may contribute to improved Aβ clearance. In addition, MY10 treatment decreased the interaction of glial cells with Aβ plaques in the hippocampus of APP/PS1 mice. Furthermore, the analysis of proinflammatory markers in the hippocampus revealed that MY10 treatment decreased the mRNA levels of Tnfa and Hmgb1. Notably, treatment with MY10 increased Bace1 mRNA expression, which could be involved in enhancing Aβ degradation, and it decreased Mmp9 levels, which might reflect changes in the neuroinflammatory environment and impact Aβ plaque dynamics. These results support the therapeutic potential of inhibition of RPTPβ/ζ in modulating Aβ pathology and neuroinflammation in AD.}, }
@article {pmid39712107, year = {2024}, author = {Tseriotis, VS and Vavougios, G and Tsolaki, M and Spilioti, M and Kosmidis, EK}, title = {Electroencephalogram criticality in cognitive impairment: a monitoring biomarker?.}, journal = {Cognitive neurodynamics}, volume = {18}, number = {6}, pages = {3679-3689}, pmid = {39712107}, issn = {1871-4080}, abstract = {UNLABELLED: Critical states present scale-free dynamics, optimizing neuronal complexity and serving as a potential biomarker in cognitively impaired patients. We explored electroencephalogram (EEG) criticality in amnesic Mild Cognitive Impairment patients with clinical improvement in working memory, verbal memory, verbal fluency and overall executive functions after the completion of a 6-month prospective memory training. We compared "before" and "after" stationary resting-state EEG records of right-handed MCI patients (n = 17; 11 females), using the method of critical fluctuations and Haar wavelet analysis. Improvement of criticality indices was observed in most electrodes, with mean values being higher after prospective memory training. Significant criticality enhancement was found in the subgroup analysis of frontotemporal electrodes [mean dif: 0.10; Z = 7, p = 0.019]. In the isolated electrode signal analysis, significant post-intervention improvement was noted in pooled criticality indices of electrodes T6 [mean dif: 0.204; t(10) = -2.3, p = 0.044] and F4 [mean dif: 0.0194; t(10) = -2.82; p = 0.018]. EEG criticality agreed with clinical improvement, consisting a possible quantifiable and easy-to-obtain biomarker in MCI and Alzheimer's disease (AD), especially in patients under cognitive training/rehabilitation. We highlight the role of EEG in prognostication, monitoring and potentially early treatment optimization in MCI or AD patients. Further standardization of the methodology in larger patient cohorts could be valuable for AD theragnostics in patients receiving disease-modifying treatments by providing insights regarding synaptic brain plasticity.
GRAPHICAL ABSTRACT: Critical states' scale-free dynamics optimize neuronal complexity, emerging as biomarkers in cognitive neuroscience. Applying the method of critical fluctuations and Haar wavelet analysis in stationary EEG time-series, we demonstrate criticality enhancement in the frontotemporal electroencephalographic (EEG) recordings of mild cognitive impairment (MCI) patients after a 6-month prospective memory training, suggesting EEG criticality as a possible monitoring biomarker in MCI and Alzheimer's disease.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11571-024-10155-4.}, }
@article {pmid39711499, year = {2025}, author = {Kloske, CM and Forner, S and Meyers, EA and Towers, AE and Snyder, HM and Carrillo, MC}, title = {Alzheimer's Association's funding portfolio: Insights from the International Alzheimer's and Related Dementias Research Portfolio (IADRP).}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14354}, pmid = {39711499}, issn = {1552-5279}, support = {N/A/ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Alzheimer Disease/economics ; *Biomedical Research/economics ; Dementia/economics/therapy ; Research Support as Topic ; Organizations, Nonprofit/economics ; Societies, Medical ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) and related dementias (ADRD) present significant health challenges. Understanding their underlying biology, advancing existing and new therapies, and enhancing care for patients and caregivers are critical priorities.
METHODS: This article utilizes data from the International Alzheimer's and Related Dementias Research Portfolio (IADRP) to analyze funding patterns from the Alzheimer's Association over the past decade.
RESULTS: As the largest nonprofit funder of AD/ADRD research globally, the Alzheimer's Association has committed over $430 million, supporting a diverse range of studies across the entire spectrum of dementia-related science. The funding landscape has evolved, reflecting new areas of investigation and collaboration with broader research initiatives.
DISCUSSION: This article highlights the dynamic nature of the Association's funding strategies and ongoing efforts to connect funding with additional supportive resources, thereby enhancing the overall research ecosystem Highlights As the world's largest nonprofit funder of Alzheimer's disease and dementia science, the Alzheimer's Association's funding activities are strategically designed in partnership with the global research community to address scientific gaps in our knowledge to advance research. A large part of the Association's funding portfolio depends on key partnerships and collaborations. From 2019 to 2023, the Alzheimer's Association has allocated funding for more than 850 new research studies. The diversity of areas funded is clear across the Association's portfolio. Beyond the Association's strong emphasis on supporting research through grant funding, there are also efforts to ensure the necessary ecosystem to support the career development of researchers and clinicians, maintaining ongoing support for current and future awardees, including convening and the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART).}, }
@article {pmid39711283, year = {2025}, author = {Song, D and Zhang, J and Hu, X and Liu, X}, title = {Progress in the treatment of Alzheimer's disease based on nanosized traditional Chinese medicines.}, journal = {Journal of materials chemistry. B}, volume = {13}, number = {5}, pages = {1548-1572}, doi = {10.1039/d4tb02062f}, pmid = {39711283}, issn = {2050-7518}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Medicine, Chinese Traditional ; *Drugs, Chinese Herbal/chemistry/therapeutic use/pharmacology ; Animals ; Nanoparticles/chemistry ; Blood-Brain Barrier/metabolism/drug effects ; Drug Carriers/chemistry ; Drug Delivery Systems ; }, abstract = {Traditional Chinese medicine (TCM) has been employed for centuries in treating and managing Alzheimer's disease (AD). However, their effective delivery to target sites can be a major challenge. This is due to their poor water solubility, low bioavailability, and potential toxicity. Furthermore, the blood-brain barrier (BBB) is a major obstacle to effective TCM delivery, significantly reducing efficacy. Advancements in nanotechnology and its applications in TCM (nano-TCM) can deliver active ingredients or components of TCM across the BBB to the targeted brain area. This review summarizes the recent advances in nanocarrier-based delivery systems for different types of active constituents of TCM for AD, including terpenoids, polyphenols, alkaloids, flavonoids, and quinones. Besides, the main challenges and opportunities for the future development of these advanced TCM nanocarriers are emphasized. In conclusion, this review provides valuable insights and guidance for utilizing nanocarriers to shape future TCM drug delivery.}, }
@article {pmid39711134, year = {2024}, author = {Mamgain, R and Mishra, G and Kriti, S and Singh, FV}, title = {Organoselenium compounds beyond antioxidants.}, journal = {Future medicinal chemistry}, volume = {16}, number = {24}, pages = {2663-2685}, pmid = {39711134}, issn = {1756-8927}, mesh = {Animals ; Humans ; Anti-Infective Agents/chemical synthesis/pharmacology ; Anti-Inflammatory Agents/chemical synthesis/pharmacology ; Antineoplastic Agents/chemical synthesis/pharmacology ; Antioxidants/chemical synthesis/pharmacology ; Antiviral Agents/chemical synthesis/pharmacology ; Hypoglycemic Agents/chemical synthesis/pharmacology ; *Organoselenium Compounds/chemical synthesis/pharmacology ; }, abstract = {Organoselenium chemistry has become a significant field due to its role in synthesizing numerous biologically active and therapeutic compounds. In early phase, researchers focused on designing organoselenium compounds with antioxidant properties and were quite successful. In last two decades, synthetic chemists shifted their focus toward synthesis of organoselenium compounds with biological properties, moving beyond their traditional antioxidant properties. The review includes synthesis and study of organo-selenium compounds as anticancer, antimicrobial, antiviral, antidiabetic, antithyroid, anti-inflammatory therapies, contributing to disease treatment. This review covers the synthesis and medicinal applications of synthetic organoselenium compounds over the past 10 years, thus making it a valuable resource for researchers in the field of medicinal chemistry.}, }
@article {pmid39710907, year = {2025}, author = {Olivares Ordoñez, MA and Smith, RC and Yiu, G and Liu, YA}, title = {Retinal Microstructural and Microvascular Changes in Alzheimer Disease: A Review.}, journal = {International ophthalmology clinics}, volume = {65}, number = {1}, pages = {59-67}, pmid = {39710907}, issn = {1536-9617}, support = {R01 EY032238/EY/NEI NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Tomography, Optical Coherence/methods ; *Retinal Vessels/diagnostic imaging/pathology ; Retinal Diseases/diagnostic imaging/etiology/diagnosis ; Microvessels/diagnostic imaging/pathology ; Fluorescein Angiography/methods ; Retina/diagnostic imaging/pathology ; }, abstract = {"The eyes are a window to the brain," prompting the investigation of whether retinal biomarkers can indicate Alzheimer disease (AD) and cognitive impairment. AD is a neurodegenerative condition with a lengthy preclinical phase where pathologic changes in the central nervous system (CNS) occur before clinical symptoms. Mild cognitive impairment (MCI) often precedes AD. As part of the CNS, the retina exhibits similar pathologic changes related to AD as those seen in the brains of patients with MCI. Noninvasive imaging technologies such as optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) allow high-resolution visualization of the retina, providing an opportunity to screen and monitor AD noninvasively. In this review, we summarize the relationship between AD and retinal pathology detected by OCT and OCTA. The most common findings in patients with AD include peripapillary retinal nerve fiber layer thinning, decreased macular thickness, an enlarged foveal avascular zone, and decreased vascular densities in the superficial and deep capillary plexuses. These retinal changes correlate with magnetic resonance imaging (MRI) findings of cerebral atrophy, positron emission tomography (PET) findings of increased amyloid load, and neuropsychological testing results suggesting cognitive dysfunction. We conclude that retinal microstructural and microvascular abnormalities may serve as biomarkers for the early detection and clinical monitoring of AD and as tools for evaluating potential treatment effects. Future studies should focus on standardizing protocols for in vivo ophthalmic imaging to measure retinal pathology in AD and MCI.}, }
@article {pmid39710054, year = {2025}, author = {Yang, Q and Chen, T and Li, S and Yang, C and Zheng, X and Mao, S and Liu, N and Mo, S and Li, D and Yang, M and Lu, Z and Tang, L and Huang, X and Liu, X and Jian, C and Yin, Y and Shang, J}, title = {Inhibition of autophagy attenuates cognitive decline and mitochondrial dysfunction in an Alzheimer's disease mouse model with chronic cerebral hypoperfusion.}, journal = {Brain research}, volume = {1850}, number = {}, pages = {149416}, doi = {10.1016/j.brainres.2024.149416}, pmid = {39710054}, issn = {1872-6240}, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Autophagy/physiology ; *Disease Models, Animal ; *Cognitive Dysfunction/metabolism ; Mice ; *Mitochondria/metabolism ; *Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; Mitochondrial Dynamics/physiology ; Male ; Adenine/analogs & derivatives/pharmacology ; Brain Ischemia/metabolism ; }, abstract = {This study aimed to investigate the impact of chronic cerebral hypoperfusion (CCH) on cognitive function, amyloid-β (Aβ) deposition, cellular autophagy, and mitochondrial dynamics in an Alzheimer's disease (AD) mouse model, and to evaluate the intervention effects of autophagy modulation on these outcomes. Utilizing the APP/PS1 mouse model combined with CCH, we assessed cognitive function, Aβ deposition, and the expression levels of relevant proteins through behavioral tests and immunohistochemical analysis. Our findings revealed pronounced cognitive deficits and increased Aβ deposition in the AD + CCH group mice, along with upregulation of mitochondrial fission proteins (Drp1, Fis1) and downregulation of mitochondrial fusion proteins (Opa1, Mfn1), indicating a shift towards mitochondrial fission and promoting cell apoptosis. Additionally, alterations were observed in the expression levels of cellular autophagy-related proteins (LC3-II, P62), which were reversed by treatment with autophagic inhibitor 3-methyladenine (3-MA). Furthermore, the expression of mitochondrial autophagy-related proteins PINK1 and Parkin was affected, with 3-MA alleviating this effect. In summary, our study elucidates the complex interplay among cognitive decline, increased Aβ deposition, and mitochondrial dysfunction in the AD + CCH model, and suggests that modulating autophagy could be a potential therapeutic strategy for treating the AD + CCH model.}, }
@article {pmid39708879, year = {2025}, author = {Wang, W and Wu, X and Zhang, Q and Zhang, T and Jiang, L and Qu, L and Lu, F and Liu, F}, title = {Tetrahydrofolic acid accelerates amyloid fibrillization, decreases cytotoxic oligomers and suppresses their toxicity.}, journal = {International journal of biological macromolecules}, volume = {290}, number = {}, pages = {139041}, doi = {10.1016/j.ijbiomac.2024.139041}, pmid = {39708879}, issn = {1879-0003}, mesh = {*Amyloid/chemistry/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism/toxicity/chemistry ; *Caenorhabditis elegans/drug effects ; *alpha-Synuclein/metabolism/chemistry ; Humans ; Protein Aggregates/drug effects ; Protein Multimerization/drug effects ; }, abstract = {Soluble cytotoxic oligomers produced during the fibrillation of both α-synuclein (αS) and amyloid-β protein (Aβ) are key pathogenic factors in Parkinson's disease (PD) and Alzheimer's disease (AD). Reducing toxic oligomers by regulating the aggregation process of αS and Aβ is an important strategy for the treatment of PD and AD. Herein, tetrahydrofolic acid (THF) is found to accelerate amyloid fibrillization, decreases cytotoxic oligomers and suppresses their toxicity. Thioflavin T and atomic force microscopy assays results showed that THF was able to accelerate the formation of dense fibrils from αS and Aβ in a dose-dependent manner. Strikingly, this was accompanied by a reduction in the abundance of toxic oligomers, and these results were confirmed by DB. Meanwhile, MTT and FDA/PI assays demonstrated that THF-induced accelerated fibril formation was accompanied by a reduction in αS- and Aβ-induced cytotoxicity. In addition, the lifespan of genetically modified αS and Aβ expressing C. elegans was extended by feeding THF, although plaque deposits of αS and Aβ increased. These findings suggest that THF enhances the conversion of αS and Aβ oligomers into less toxic fibrils and is a potential therapeutic agent for PD and AD.}, }
@article {pmid39708551, year = {2025}, author = {Shaaban, AE and Ali, AR and Ayyad, SN and Badria, FA}, title = {Multi-target directed ligands inspired natural products as an effective approach for the treatment of complex chronic health disorders.}, journal = {Bioorganic chemistry}, volume = {154}, number = {}, pages = {108075}, doi = {10.1016/j.bioorg.2024.108075}, pmid = {39708551}, issn = {1090-2120}, mesh = {*Biological Products/chemistry/pharmacology/therapeutic use ; Humans ; Ligands ; Chronic Disease/drug therapy ; Molecular Structure ; Animals ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Complex diseases involve multifaceted etiological components, which limit the effectiveness of conventional targeted therapies. Therefore, standard medicinal treatments often face significant challenges and failures when addressing these disease conditions. Furthermore, the growing interest in multidrug resistance (MDR), the occurrence of adverse drug reactions related to use traditional approaches, and the limited clinical efficacy of single-target drug therapy have increased the demand for innovative drug treatments. In this rapidly evolving era, the exploration of multi-target directed ligands (MTDLs) derived from natural products has granted us access to a wide range of compounds with medicinal properties. The allure of these MTDLs lies in their unique ability to minimize side effects from using two medicinal agents, establishing them as the preferred choice for drug developers. MTDLs have been recognized for their extraordinary capacity to collectively hinder multiple pathways implicated in the development of intricate diseases by merging or linking active molecules obtained from these sources. This review delves into promising MTDLs derived from natural products, which modulates diverse biological pathways implicated in complex diseased conditions particularly Alzheimer's disease, diabetes, cardiac disorders and inflammatory conditions.}, }
@article {pmid39708491, year = {2025}, author = {Cai, Y and Li, Y and Wang, Y and Xu, Y and Chen, T and Xue, R and Liu, Y and Chen, W and Yang, X and Liu, Z and Bao, X and Huang, Z}, title = {Triple-mode sensing platform for acetylcholinesterase activity monitoring and anti-Alzheimer's drug screening based on a highly stable Cu (I) compound.}, journal = {Biosensors & bioelectronics}, volume = {271}, number = {}, pages = {117078}, doi = {10.1016/j.bios.2024.117078}, pmid = {39708491}, issn = {1873-4235}, mesh = {*Acetylcholinesterase/chemistry/metabolism ; *Alzheimer Disease/drug therapy/diagnosis ; *Cholinesterase Inhibitors/analysis/pharmacology/chemistry ; *Biosensing Techniques ; *Copper/chemistry ; Humans ; Fluorescent Dyes/chemistry ; Colorimetry/methods ; Manganese Compounds/chemistry ; Limit of Detection ; Spectrometry, Fluorescence/methods ; Oxides/chemistry ; Smartphone ; Drug Evaluation, Preclinical ; Acetylthiocholine/chemistry/analogs & derivatives ; }, abstract = {Acetylcholinesterase (AChE) and AChE inhibitors play critical roles in the early diagnosis and treatment of Alzheimer's disease (AD). Herein, a fluorescence/colorimetry/smartphone triple-mode sensing platform was constructed for both AChE activity monitoring and AChE inhibitor screening by exploring a Cu (I) compound, Cu3I (SR)2 (R = CH2CH2NH2), as a fluorescent probe. In comparison of most other fluorescent probes, Cu3I (SR)2 presented exceptional stability against pH, temperature, UV irradiation, redox agents, and metal ions, as well as good recyclability due to its unique chemical structure. We further found the fluorescence emission of Cu3I (SR)2 could be quenched by MnO2 nanosheet (NS) via inner filter effect, and restored by thiocholine (TCh) generated from the hydrolysis of acetylthiocholine iodide (ATCh) in the catalysis of AChE. On this basis, a fluorescence "turn-on" assay was developed for monitoring AChE activity with a detection limit of 0.03 U/L and a detection range of 0.25-50 U/L. This method demonstrates great potential for real-time detection of AChE activity in biological samples and screening of AChE inhibitors obtained from herbal extracts as anti-AD agents. Additionally, Cu3I (SR)2/MnO2 NS sensing system also exhibited a color change from brown to colorless as the increasing AChE activity, which allowed the colorimetric and smartphone detection of AChE activity.}, }
@article {pmid39708240, year = {2024}, author = {Zidan, EF and El-Mezayen, NS and Elrewini, SH and Afify, EA and Ali, MA}, title = {Memantine/Rosuvastatin Therapy Abrogates Cognitive and Hippocampal Injury in an Experimental Model of Alzheimer's Disease in Rats: Role of TGF-β1/Smad Signaling Pathway and Amyloid-β Clearance.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {20}, number = {1}, pages = {4}, pmid = {39708240}, issn = {1557-1904}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy ; Rats ; *Rosuvastatin Calcium/pharmacology/therapeutic use ; *Hippocampus/drug effects/metabolism ; *Signal Transduction/drug effects ; Male ; *Memantine/pharmacology/therapeutic use ; *Transforming Growth Factor beta1/metabolism ; *Amyloid beta-Peptides/metabolism ; *Rats, Wistar ; Smad Proteins/metabolism ; Disease Models, Animal ; Maze Learning/drug effects ; Cognitive Dysfunction/drug therapy/metabolism ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder of complex pathogenesis and multiple interacting signaling pathways where amyloidal-β protein (Aβ) clearance plays a crucial role in cognitive decline. Herein, the current study investigated the possible modulatory effects of memantine/ rosuvastatin therapy on TGF-β1/p-Smad/p21 signaling pathway and their correlation to the blood brain barrier transporters involved in Aβ-clearance and microRNAs as a novel molecular mechanism in AD treatment. AD was induced by a single intracerebroventricular streptozotocin injection (ICV-STZ, 3 mg/kg) in rats and drug therapy was continued for 28 days after AD induction. Efficacy was monitored by applying a battery of behavioral assessments, as well as biochemical, histopathological, molecular and gene expression techniques. The upregulated TGF-β1-signaling in the untreated rats was found to be highly correlated to transporters and microRNAs governing Aβ-efflux; ABCA1/miRNA-26 and LRP1/miRNA-205 expressions, rather than RAGE/miRNA-185 controlling Aβ-influx; an effect that was opposed by the tested drugs and was found to be correlated with the abolished TGF-β1-signaling as well. Combined memantine/rosuvastatin therapy ameliorated the STZ evoked decreases in escape latency and number of crossovers in the Morris water maze test, % spontaneous alternation in the Y-maze test, and discrimination and recognition indices in the object recognition test. The evoked behavioral responses were directly related to the β-amyloid accumulation and the alteration in its clearance. Additionally, drug treatment increased brain glutathione and decreased malondialdehyde levels. These findings were histopathologically confirmed by a marked reduction of gliosis and restoration of neuronal integrity in the CA1 region of the hippocampus of the AD rats. These findings implicated that the memantine/rosuvastatin combination could offer a new therapeutic potential for AD management by abrogating the TGF-β1/p-Smad2/p21 pathway and regulating Aβ-clearance.}, }
@article {pmid39708177, year = {2024}, author = {Zilioli, A and Rosenberg, A and Mohanty, R and Matton, A and Granberg, T and Hagman, G and Lötjönen, J and Kivipelto, M and Westman, E}, title = {Brain MRI volumetry and atrophy rating scales as predictors of amyloid status and eligibility for anti-amyloid treatment in a real-world memory clinic setting.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {84}, pmid = {39708177}, issn = {1432-1459}, mesh = {Humans ; Male ; Female ; Aged ; *Magnetic Resonance Imaging ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Atrophy/drug therapy ; *Alzheimer Disease/drug therapy/diagnostic imaging ; *Brain/diagnostic imaging/drug effects/pathology ; Middle Aged ; Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology/administration & dosage ; Neuropsychological Tests ; Aged, 80 and over ; Apolipoprotein E4/genetics ; Peptide Fragments/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; }, abstract = {Predicting amyloid status is crucial in light of upcoming disease-modifying therapies and the need to identify treatment-eligible patients with Alzheimer's disease. In our study, we aimed to predict CSF-amyloid status and eligibility for anti-amyloid treatment in a memory clinic by (I) comparing the performance of visual/automated rating scales and MRI volumetric analysis and (II) combining MRI volumetric data with neuropsychological tests and APOE4 status. Two hundred ninety patients underwent a comprehensive assessment. The cNeuro cMRI software (Combinostics Oy) provided automated computed rating scales and volumetric analysis. Amyloid status was determined using data-driven CSF biomarker cutoffs (Aβ42/Aβ40 ratio), and eligibility for anti-Aβ treatment was assessed according to recent recommendations published after the FDA approval of the anti-Aβ drug aducanumab. The automated rating scales and volumetric analysis demonstrated higher performance compared to visual assessment in predicting Aβ status, especially for parietal-GCA (AUC = 0.70), MTA (AUC = 0.66) scores, hippocampal (AUC = 0.68), and angular gyrus (AUC = 0.69) volumes, despite low global accuracy. When we combined hippocampal and angular gyrus volumes with RAVLT immediate recall and APOE4 status, we achieved the highest accuracy (AUC = 0.82), which remained high even in predicting anti-Aβ treatment eligibility (AUC = 0.81). Our study suggests that automated analysis of atrophy rating scales and brain volumetry outperforms operator-dependent visual rating scales. When combined with neuropsychological and genetic information, this computerized approach may play a crucial role not only in a research context but also in a real-world memory clinic. This integration results in a high level of accuracy for predicting amyloid-CSF status and anti-Aβ treatment eligibility.}, }
@article {pmid39705668, year = {2024}, author = {Khandia, R and Gurjar, P and Priyanka, and Romashchenko, V and Al-Hussain, SA and Zaki, MEA}, title = {Recent advances in stem cell therapy: efficacy, ethics, safety concerns, and future directions focusing on neurodegenerative disorders - a review.}, journal = {International journal of surgery (London, England)}, volume = {110}, number = {10}, pages = {6367-6381}, pmid = {39705668}, issn = {1743-9159}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; }, abstract = {Neurodegeneration refers to the gradual loss of neurons and extensive changes in glial cells like tau inclusions in astrocytes and oligodendrocytes, α-synuclein inclusions in oligodendrocytes and SOD1 aggregates in astrocytes along with deterioration in the motor, cognition, learning, and behavior. Common neurodegenerative disorders are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxia (SCA), and supranuclear palsy. There is a lack of effective treatment for neurodegenerative diseases, and scientists are putting their efforts into developing therapies against them. Stem cell therapy has emerged as a hope for neurodegenerative disorders since it is not only the damaged neurons that might be replaced, but other neuromodulators and neuroprotectors are secreted. Stem cell terminal differentiation before implantation ensures the implantation of correct cells and molecular markers like carbonic anhydrase II, CNPase (2',3'-cyclic nucleotide 3'-phosphohydrolase), myelin basic protein (MBP), and myelin oligodendrocyte glycoprotein (MOG) elucidate the differentiation. Secretion of various growth factors like epidermal growth factor (EGF), keratinocyte growth factor (KGF), vascular endothelial growth factor-α (VEGF-α), transforming growth factor (TGF), and macrophage inflammatory protein (MIP) supports cell survival, cell proliferation, blood vessel formation, axon regeneration, and neuroglial functional connection formation at the site of degeneration. Adverse effects of stem cell therapy, like teratogenicity and differentiation in different cells other than the desired one under the influence of microenvironment, are a few key concerns. Post-transplantation improved synaptic plasticity, apoptosis inhibition, and reduction in tau-phosphorylation and amyloid beta (Aβ) production has been observed in Alzheimer's patients. A large number of experimental, preclinical, and clinical studies have been conducted, and encouraging results have been obtained. The present review exhaustively discusses various kinds of stem cells, their usage in treating neurodegenerative disorders, limitations and challenges, and ethical issues related to stem cell therapy.}, }
@article {pmid39705156, year = {2024}, author = {Silva, AG and Rostirola, JVC and Speri, FD and Pina, JG and Kitahara, MV and Longato, GB and Sciani, JM}, title = {Tubastrine, an antioxidant molecule from Tubastraea tagusensis sun coral, in the reversion of oxidative stress and neuron's death induced by Aβ42.}, journal = {Journal of cellular and molecular medicine}, volume = {28}, number = {24}, pages = {e70165}, pmid = {39705156}, issn = {1582-4934}, support = {2019/19929-6//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; }, mesh = {*Amyloid beta-Peptides/metabolism ; Animals ; *Oxidative Stress/drug effects ; *Neurons/drug effects/metabolism ; *Antioxidants/pharmacology ; Humans ; *Anthozoa/chemistry ; *Peptide Fragments/pharmacology ; *Reactive Oxygen Species/metabolism ; *Cell Death/drug effects ; Cell Line, Tumor ; Alzheimer Disease/metabolism/drug therapy/pathology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving mitochondrial dysfunction and consequent production of reactive oxygen species (ROS), generated after amyloid peptide (Aβ42) accumulation. In this study, we isolated a new antioxidant molecule from the sun coral Tubastraea tagusensis and analysed it in cells exposed to oligomeric amyloid-beta peptide 1-42 (oAβ42). The coral was collected and immersed in methanol for the release of compounds, which were submitted to antioxidant DPPH and FRAP activity-guided fractionation using solid-phase extraction and HPLC. An active pure molecule was analysed by mass spectrometry and tested in SH-SY5Y differentiated neurons previously exposed to 5 μM oAβ42. The isolated active molecule was identified as tubastrine, which could significantly inhibit the cell death caused by the amyloid peptide. Moreover, oAβ42 increased the percentage of ROS in neurons-like from 40% to 65%, and the treatment with tubastrine reduced it to 50%. The antioxidant power of neurons-like after oAβ42 decreased significantly, while the compound reversed it, reaching similar values to the untreated cells. Therefore, tubastrine can reverse an important pathophysiological mechanism of AD, oxidative stress, by increasing neuronal antioxidant power and reducing ROS levels, able to prevent neuron-like cell death caused by oAβ42.}, }
@article {pmid39704877, year = {2024}, author = {Salari, A and Roghani, M and Khalili, M}, title = {HMG-CoA reductase inhibitor simvastatin ameliorates trimethyltin neurotoxicity and cognitive impairment through reversal of Alzheimer's-associated markers.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {74}, pmid = {39704877}, issn = {1573-7365}, support = {503338//Shahed University/ ; }, mesh = {Animals ; *Simvastatin/pharmacology/therapeutic use ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology/therapeutic use ; Male ; *Alzheimer Disease/drug therapy/metabolism ; *Trimethyltin Compounds/toxicity ; Rats ; *Cognitive Dysfunction/drug therapy/chemically induced/prevention & control ; Hippocampus/drug effects/metabolism ; Maze Learning/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Rats, Wistar ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder in elderly. The neurotoxicant trimethyltin (TMT) induces neurodegenerative changes, as observed in AD. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin (SV) has shown protective and promising therapeutic effects in neurological disorders such as AD and Parkinson's disease. The present study aimed to assess neuroprotective effect of simvastatin (SV) against trimethyltin (TMT) memory decline and hippocampal neurodegeneration. For inducing AD-like phenotype, rats were i.p. injected with TMT at 8 mg/kg and were treated with simvastatin daily for 3 weeks at 10 or 30 mg/kg. Our analysis of data indicated that simvastatin-treated TMT group has lower learning and memory deficits in behavioral tasks comprising Barnes maze, Y maze, and novel object discrimination (NOD). In addition, hippocampal inflammatory, oxidative, and apoptotic factors were attenuated besides reduction of acetylcholinesterase (AChE) activity and Alzheimer's pathology factors including presenilin-1 and hyperphorphorylated Tau (p-Tau) upon simvastatin. Moreover, simvastatin treatment of TMT group inverted hippocampal changes of Wnt, β-catenin, ERK, and Akt, ameliorated astrocytic and microglial reactivity, and also prevented injury of CA1 neurons. This study unraveled that simvastatin is capable to prevent TMT-induced Alzheimer's-like phenotype in association with Wnt/β-catenin/ERK/Akt as well as restraining hippocampal neurodegeneration.}, }
@article {pmid39704652, year = {2024}, author = {Shir, D and Shiner, T and Bregman, N}, title = {Anti-amyloid treatments for Alzheimer's disease: A study on physicians' perspectives.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {102}, number = {3}, pages = {627-632}, doi = {10.1177/13872877241289788}, pmid = {39704652}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/therapy/drug therapy ; *Physicians ; Male ; Female ; Israel ; Attitude of Health Personnel ; Neurologists ; Middle Aged ; }, abstract = {Advances in amyloid targeting therapies (ATT) for Alzheimer's disease have introduced new options, necessitating an understanding of physicians' perspectives as these therapies move from trials to practice. A survey of Israeli specialists found that 84% were familiar with new ATT, but 60% raised doubts about their ability to significantly impact disease progression. Neurologists were more likely to recommend these treatments, but concerns included treatment costs and limited real-world experience. The decision to refer patients was influenced by patient age, financial status, and diagnostic test availability. Strategies to enhance physician education and improve patient access to ATT are suggested.}, }
@article {pmid39704363, year = {2024}, author = {Mei, X and Zou, CJ and Zheng, CY and Hu, J and Zhou, DS}, title = {Effect of bright-light therapy on depression and anxiety of a patient with Alzheimer's disease combined with sleep disorder: A case report.}, journal = {World journal of psychiatry}, volume = {14}, number = {12}, pages = {1982-1987}, pmid = {39704363}, issn = {2220-3206}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a common type of dementia due to neuronal impairment. In addition, psychobehavioral symptoms including severe sleep disorders, depression and anxiety can occur in most patients with AD.
CASE SUMMARY: We report a case of a 68-year-old woman with a 2-year history of AD. She initially presented with memory loss, progressively more severe, leading to a depressive and anxious status. The clinical symptoms also included severe sleep disturbances. Considering the age and health state of the patient, a non-pharmacological treatment of bright light therapy was used to improve her sleep quality. The treatment was provided for 30 minutes twice a day, during 8:30 am to 9:00 am and 16:30 pm to 17:00 pm. After 4 weeks of therapy, the sleep quality notably improved, with a marked decrease in daytime sleep, increase in nighttime sleep, and disappearance of nocturnal activity. The depression and anxiety were also suppressed significantly.
CONCLUSION: This case report suggested that bright light therapy can have a positive effect on sleep quality in elderly patients with AD and can be used as an effective and safe non-pharmacological treatment.}, }
@article {pmid39703926, year = {2024}, author = {Paciaroni, L and Mastrosanti, E and Biscetti, L and Paolini, S and Mauri, S and Fabbietti, P and Riccardi, GR and Rocchi, MBL and Pelliccioni, G}, title = {Action observation treatment may improve daily living activities and verb recovery in Parkinson's disease-dementia: findings from a preliminary randomized controlled trial.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1488881}, pmid = {39703926}, issn = {1663-4365}, abstract = {BACKGROUND AND OBJECTIVES: Action observation treatment (AOT) is a novel rehabilitation approach aimed to the recovery of both motor and linguistic deficits in subjects with brain lesions. The aim of the present randomized controlled study was to assess the benefits of AOT treatment in the activities of daily living (ADLs) and in the linguistic abilities of the patients with Parkinson's disease dementia (PDD) at mild-moderate stage (Hoehn & Yahr's stage scale: 2-3).
METHODS: Twenty patients were enrolled and randomly assigned to an experimental group (submitted to AOT) or to a control group. The experimental group (AOT-group) underwent the vision of a video containing 6 complex ADLs, while the control group (C-group) was subjected to a video-clip regarding semantic information of a geographical-naturalistic type without motor content. The treatment duration was 4 weeks. All patients underwent assessment before and after the treatment by the following tools: Unified Parkinson's Disease Rating Scale Part III (UPDRS-Part III), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL), Direct Assessment of Functional Status (DAFS) and subtest Verb Naming of Analysis of Aphasic Deficit Battery (BADA). Paired samples t test was performed to compare all the variables of interest in the time, dividing by groups. p-value<0.05 was considered significant in all analyses.
RESULTS: AOT-group showed an improvement from baseline to the end of study in ADCS-ADL (p = 0.001), BADA (p = 0.011) and DAFS (p = 0.005), while C-group did not change significantly in the time.
CONCLUSION: These preliminary results suggest the potential efficacy of AOT in rehabilitation of ADLs and verb retrieval in people with PD. Further studies will be necessary to verify these findings.}, }
@article {pmid39703457, year = {2024}, author = {Eratne, D and Collins, S and Nestor, PJ and Pond, D and Velakoulis, D and Yates, M and Masters, CL}, title = {Using cerebrospinal fluid biomarkers to diagnose Alzheimer's disease: an Australian perspective.}, journal = {Frontiers in psychiatry}, volume = {15}, number = {}, pages = {1488494}, pmid = {39703457}, issn = {1664-0640}, abstract = {Cerebrospinal fluid (CSF) biomarkers are currently the only clinically validated biofluid diagnostic test for Alzheimer's Disease (AD) available in Australia. Testing of CSF biomarkers via lumbar puncture (LP), including quantification of amyloid-β peptide, total tau protein, and phosphorylated tau, can give insight into underlying pathophysiological changes and provide greater certainty in confirming or excluding the presence of Alzheimer's disease changes compared to standard clinical and radiological assessments. Despite CSF analysis being a safe and cost-effective diagnostic method, the use of CSF biomarkers in the evaluation of potential AD remains limited in Australian clinical practice due to a variety of factors, including regional access challenges, concerns over the perceived invasiveness of LP and a lack of confidence among clinicians in interpreting the results. The advent of disease-modifying therapies as a potential new treatment strategy to reduce the rate of progression in people with AD will drive the demand for early diagnosis of AD. This perspective argues for broader adoption of CSF biomarker testing by providing evidence-based, clinically informed expert guidance on when and why to consider CSF biomarker testing.}, }
@article {pmid39703418, year = {2025}, author = {Qin, G and Song, R and Sun, J and Chen, B and Liu, Z and Han, L and Sun, B and Li, C}, title = {Investigating the therapeutic effects of Shenzhiling oral liquid on Alzheimer's disease: a network pharmacology and experimental approach.}, journal = {3 Biotech}, volume = {15}, number = {1}, pages = {14}, pmid = {39703418}, issn = {2190-572X}, abstract = {There is currently no effective treatment for Alzheimer's disease (AD). This research explored Shenzhiling Oral Liquid (SZLD) against AD by pinpointing crucial elements and understanding its molecular mechanisms through network pharmacology and in vitro experiment. First, we used network pharmacology to screen the main targets and mechanisms of SZLD to improve AD. Then we conducted experiments with Aβ42-induced SH-SY5Y cells to assess SZLD's impact, focusing particularly on apoptotic pathways, thereby uncovering its mechanism of action in AD. Through our analysis, we discovered a notable link between SZLD's effect on AD and apoptosis processes. Specifically, the critical proteins Casapse3 and BCL-2 showed strong correlations in this context. Through systematic data analysis and experimental verification, we unveiled the healing advantages and the foundational molecular mechanisms of SZLD in AD. These findings underscore the promising and compelling potential of targeting the PI3K/Akt signaling pathway and apoptosis with SZLD as a therapeutic strategy to ameliorate AD.}, }
@article {pmid39703357, year = {2024}, author = {An, X and He, J and Bi, B and Wu, G and Xu, J and Yu, W and Ren, Z}, title = {The application of artificial intelligence in diagnosis of Alzheimer's disease: a bibliometric analysis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1510729}, pmid = {39703357}, issn = {1664-2295}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that severely impacts cognitive function, posing significant physical and psychological burdens on patients and substantial economic challenges to families and society, particularly in aging populations where its prevalence is rising. Current diagnostic and therapeutic strategies, including pharmacological treatments and non-pharmacological interventions, exhibit considerable limitations in early diagnosis, etiological treatment, and disease management. This study aims to investigate the application of artificial intelligence (AI) in the early diagnosis and progression monitoring of AD through a bibliometric analysis of relevant literature. A systematic search in the Web of Science Core Collection identified 530 publications related to AI and AD, consisting of 361 original research articles and 169 review articles, with a notable increase in annual publication rates, particularly between 2019 and 2024. The United States and China emerged as leading contributors, emphasizing the importance of international collaboration. Institutional analysis revealed that Harvard University and Indiana University System are at the forefront, highlighting the role of academic institutions in fostering interdisciplinary research. Furthermore, the Journal of Alzheimer's Disease was identified as the most influential publication outlet. Key highly cited papers provided essential theoretical foundations for ongoing research. This study underscores the growing relevance of AI in AD research and suggests promising avenues for future investigations, particularly in enhancing diagnostic accuracy and therapeutic strategies through advanced data analytics and machine learning techniques.}, }
@article {pmid39703326, year = {2024}, author = {Aljuhani, M and Ashraf, A and Edison, P}, title = {Evaluating clinical meaningfulness of anti-β-amyloid therapies amidst amyloid-related imaging abnormalities concern in Alzheimer's disease.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae435}, pmid = {39703326}, issn = {2632-1297}, abstract = {Alzheimer's disease is the most prevalent form of dementia in the elderly, which is clinically characterized by a gradual and progressive deterioration of cognitive functions. The central and early role of β-amyloid in the pathogenesis of Alzheimer's disease is supported by a plethora of studies including genetic analyses, biomarker research and genome-wide association studies in both familial (early-onset) and sporadic (late-onset) forms of Alzheimer's. Monoclonal antibodies directed against β-amyloid demonstrate slowing of the clinical deterioration of patients with early Alzheimer's disease. Aducanumab, lecanemab and donanemab clinical trials showed slowing of Alzheimer's disease progression on composite scores by 25-40% based on the measure used. Anti-β-amyloid antibodies can cause side effects of bleeding and swelling in the brain, called amyloid-related imaging abnormalities. Amyloid-related imaging abnormalities typically occur early in treatment and are often asymptomatic, and though in rare cases, they can lead to serious or life-threatening events. The aim of this review is to evaluate the clinical meaningfulness of anti-β-amyloid therapies amidst amyloid-related imaging abnormalities concern in Alzheimer's disease.}, }
@article {pmid39703103, year = {2025}, author = {Pahal, S and Pahal, V and Chaudhary, A}, title = {From data to discovery: Neuroinformatics in understanding Alzheimer's disease.}, journal = {Journal of biosciences}, volume = {50}, number = {}, pages = {}, pmid = {39703103}, issn = {0973-7138}, mesh = {*Alzheimer Disease/genetics/pathology/diagnostic imaging ; Humans ; *Computational Biology/methods ; Neuroimaging/methods ; Biomarkers/metabolism ; Brain/diagnostic imaging/pathology/physiopathology ; Precision Medicine ; Databases, Factual ; }, abstract = {Neuroinformatics, an interdisciplinary field integrating neuroscience and informatics, plays a crucial role in understanding the complexities of the brain and neurological diseases such as Alzheimer's disease (AD). This review explores the applications, databases, and tools used in neuroinformatics, focusing on their role in AD research. Neuroinformatics facilitates data integration, analysis, and modeling, enabling researchers to unravel the underlying mechanisms of AD pathology. Various databases and tools provide access to neuroimaging, and genetic and clinical data, facilitating collaborative research and the development of diagnostic and therapeutic strategies. Neuroinformatics holds promise in advancing our understanding and treatment of AD, offering insights into disease progression, biomarker identification, and personalized medicine approaches.}, }
@article {pmid39703045, year = {2025}, author = {Chipofya, E and Docrat, TF and Marnewick, JL}, title = {The Neuroprotective Effect of Rooibos Herbal Tea Against Alzheimer's Disease: A Review.}, journal = {Molecular nutrition & food research}, volume = {69}, number = {1}, pages = {e202400670}, pmid = {39703045}, issn = {1613-4133}, support = {//South African Rooibos Council/ ; //Cape Peninsula University of Technology/ ; }, mesh = {*Alzheimer Disease/prevention & control/drug therapy ; Humans ; *Neuroprotective Agents/pharmacology ; *Aspalathus/chemistry ; *Teas, Herbal/analysis ; *Oxidative Stress/drug effects ; Animals ; Antioxidants/pharmacology ; Polyphenols/pharmacology ; Flavonoids/pharmacology ; Plant Extracts/pharmacology ; tau Proteins/metabolism ; }, abstract = {The world is experiencing a demographic shift toward an increasing proportion of elderly persons. Alzheimer's disease (AD) and other neurological disorders are far more likely to develop as people age. AD is a gradual, irreversible, and degenerative brain disorder that progressively deteriorates memory and cognitive function, eventually leading to death. Treatment for AD is the most significant unmet clinical need in neurology. There are no effective treatment options to prevent or reverse the degenerative process. The current medical management focuses primarily on temporarily easing symptoms, with little or no overall improvement. Although genetic predisposition and lifestyle factors influence the risk of neurodegenerative disorders, recent research suggests that dietary polyphenols with solid antioxidant capacities play crucial roles in determining brain health and aging. Aspalathus linearis is used to produce Rooibos, a popular South African herbal tea, which may modulate neurodegenerative mechanisms such as oxidative stress, tau protein, amyloid plaques, inflammation, and metals, all of which have been associated with AD. We reviewed the literature to evaluate the potential neuroprotective effects of Rooibos and its major flavonoids and to understand the underlying molecular mechanisms.}, }
@article {pmid39702891, year = {2024}, author = {Alosaimi, ME and Almalki, AH and Abduljabbar, MH and Alnemari, RM and Alaqel, SI and Serag, A}, title = {Functionalized Graphene Quantum Dots as an Eco-Friendly Fluorescent Probe for Galantamine Analysis: Greenness Evaluation With Application to Pharmacokinetics Monitoring.}, journal = {Luminescence : the journal of biological and chemical luminescence}, volume = {39}, number = {12}, pages = {e70060}, doi = {10.1002/bio.70060}, pmid = {39702891}, issn = {1522-7243}, support = {PNURSP2024R466//Princess Nourah bint Abdulrahman University/ ; NBU-FFR-2024-1606-03//Deanship of Scientific Research at Northern Border University, Arar, KSA/ ; }, mesh = {*Galantamine/pharmacokinetics/chemistry/blood/analysis ; *Quantum Dots/chemistry ; *Graphite/chemistry ; *Fluorescent Dyes/chemistry ; *Spectrometry, Fluorescence ; Cholinesterase Inhibitors/pharmacokinetics/chemistry/analysis/blood ; Limit of Detection ; Green Chemistry Technology ; Humans ; }, abstract = {In this study, the use of functionalized graphene quantum dots (GQDs) as a fluorescent probe has been investigated for the quantitative determination of galantamine, a choline esterase inhibitor used for the treatment of Alzheimer's disease. The GQDs exhibit a significant quenching in their fluorescence intensity upon interaction with galantamine allowing for sensitive and selective detection of the drug. This quenching process follows a dynamic pattern with a linear relationship between fluorescence intensity and the concentration of galantamine. Several factors affecting the quenching process were investigated and optimized, including the concentration of GQDs, the pH of the solution, and the incubation time. The proposed probe exhibited excellent analytical performance with a linear range of 10-500 ng/mL, a limit of detection of 15 ng/mL, accuracy of 100.78 ± 0.698%, and intraday and interday precision of 0.742 and 1.369%, respectively. Furthermore, the GQDs-based sensor exhibited good selectivity towards galantamine in the presence of potentially interfering substances. Another advantage of the GQDs-based sensor is its greenness evaluation, as it offers a more environmentally friendly alternative compared to traditional methods. In addition, the GQDs-based sensor was successfully applied to analyze galantamine in pharmaceutical samples and in vivo samples, demonstrating its potential for pharmacokinetics monitoring.}, }
@article {pmid39702132, year = {2024}, author = {Dang, L and Wei, S and Zhao, Y and Zhou, R and Shang, S and Gao, F and Wang, J and Wang, J and Qu, Q}, title = {Effects of Probucol on plasma amyloid-β transport in patients with hyperlipidemia: a 12-week randomized, double-blind, placebo-controlled trial.}, journal = {Lipids in health and disease}, volume = {23}, number = {1}, pages = {410}, pmid = {39702132}, issn = {1476-511X}, support = {No. xzy022020044//Cardiovascular Alliance for Dyslipidemia and Arteriosclerosis and the Fundamental Research Funds for the Central Universities of the Xi'an Jiaotong University/ ; No. xzy022020044//Cardiovascular Alliance for Dyslipidemia and Arteriosclerosis and the Fundamental Research Funds for the Central Universities of the Xi'an Jiaotong University/ ; No. xzy022020044//Cardiovascular Alliance for Dyslipidemia and Arteriosclerosis and the Fundamental Research Funds for the Central Universities of the Xi'an Jiaotong University/ ; No. xzy022020044//Cardiovascular Alliance for Dyslipidemia and Arteriosclerosis and the Fundamental Research Funds for the Central Universities of the Xi'an Jiaotong University/ ; No. xzy022020044//Cardiovascular Alliance for Dyslipidemia and Arteriosclerosis and the Fundamental Research Funds for the Central Universities of the Xi'an Jiaotong University/ ; No. xzy022020044//Cardiovascular Alliance for Dyslipidemia and Arteriosclerosis and the Fundamental Research Funds for the Central Universities of the Xi'an Jiaotong University/ ; No. xzy022020044//Cardiovascular Alliance for Dyslipidemia and Arteriosclerosis and the Fundamental Research Funds for the Central Universities of the Xi'an Jiaotong University/ ; No. xzy022020044//Cardiovascular Alliance for Dyslipidemia and Arteriosclerosis and the Fundamental Research Funds for the Central Universities of the Xi'an Jiaotong University/ ; }, mesh = {Humans ; *Probucol/therapeutic use/pharmacology ; Female ; *Amyloid beta-Peptides/blood/metabolism ; Male ; Middle Aged ; Aged ; *Hyperlipidemias/drug therapy/blood ; Double-Blind Method ; Receptor for Advanced Glycation End Products/blood/metabolism ; Aged, 80 and over ; Alzheimer Disease/drug therapy/blood ; Antioxidants/therapeutic use/pharmacology ; }, abstract = {BACKGROUND: Although dyslipidemia has been acknowledged as a risk factor for Alzheimer's disease (AD), the effects of lipid-lowering drugs on AD have not been determined. The primary pathophysiological hallmark of AD is the deposition of amyloid-β (Aβ) plaques in the brain. Plasma Aβ levels are influenced by the transport of Aβ from the central nervous system to the peripheral blood. This study investigates the effects of Probucol, a lipid-lowering and antioxidant drug, on plasma Aβ transport.
METHODS: A total of 120 hyperlipidemic patients with normal cognition were randomly assigned (1:1 ratio) to receive either Probucol (1000 mg daily for 12 weeks) or a placebo. Plasma Aβ, soluble receptor of advanced glycation end products (sRAGE), and fasting lipid profiles were measured at baseline and every 6 weeks.
RESULTS: A total of 108 participants completed the study, with 55 in the Probucol group. The cohort consisted of 58 (53.7%) women, with a mean age of 58.4 ± 8.0 (range, 45-80) years. After 12 weeks of treatment, the changes in plasma Aβ42 and sRAGE levels significantly differed between the Probucol and placebo groups (ΔAβ42: β = 6.827, P = 0.030; ΔsRAGE: β = 98.668, P = 0.004). Furthermore, ΔsRAGE was positively correlated with the change in Aβ42 (β = 0.018, P = 0.048). When adjusted for ΔsRAGE, the effect of Probucol on plasma Aβ42 levels was attenuated (β = 5.065, P = 0.116). In the Probucol group only, ΔsRAGE was significantly correlated with oxidized low-density lipoproteins (β = 4.27, P = 0.011), total cholesterol (β = 67.50, P = 0.046), and low-density lipoproteins (β = - 91.01, P = 0.011).
CONCLUSIONS: Daily oral administration of Probucol (1000 mg) for 12 weeks significantly increased plasma Aβ42 levels, likely through modulation of sRAGE. This effect may be attributed to the antioxidant and lipid-lowering properties of Probucol. These findings suggest that Probucol could potentially serve as a protective agent against the pathological processes of AD.
TRIAL REGISTRATION: This study was registered on the Chinese Clinical Trial Registry platform in June 2019 (Trial registration number: ChiCTR-1900023542).}, }
@article {pmid39701548, year = {2025}, author = {Guareschi, F and Fonseca, C and Silva, S and Pescina, S and Nicoli, S and Buttini, F and Sonvico, F and Fortuna, A}, title = {Therapeutic effect of cyclosporine A-loading TPGS micelles on a mouse model of LPS-induced neuroinflammation.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {205}, number = {}, pages = {106994}, doi = {10.1016/j.ejps.2024.106994}, pmid = {39701548}, issn = {1879-0720}, mesh = {Animals ; *Micelles ; *Lipopolysaccharides/toxicity ; *Neuroinflammatory Diseases/drug therapy/chemically induced ; Male ; *Vitamin E/chemistry/administration & dosage/pharmacology ; *Cyclosporine/administration & dosage/pharmacology ; Mice ; *Disease Models, Animal ; *Administration, Intranasal ; Tissue Distribution ; Neuroprotective Agents/administration & dosage/pharmacology/pharmacokinetics ; Anti-Inflammatory Agents/pharmacology/administration & dosage/chemistry/pharmacokinetics ; Drug Carriers/chemistry ; }, abstract = {Neuroinflammation is an undoubted hallmark of neurodegenerative processes characterized by memory impairment, loss of coordination and muscle strength in diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis as well as depressive disorders. Cyclosporine A (CSA) has already been identified as a promising neuroprotective peptide, due to its well-known anti-inflammatory properties. Herein, CSA was encapsulated into α-tocopherol polyethylene glycol 1000 succinate (TPGS) micelles and intranasally administered to a lipopolysaccharide (LPS) induced mouse model of neuroinflammation. After the treatment, mice were subjected to behavioral tests to assess cognitive and motor skills, while the biodistribution of CSA in plasma and olfactory bulb was studied by a new HPLC method validated for precision and accuracy. The results highlighted that in comparison to the classic oral CSA suspension, the intranasal (IN) administration showed significatively better safety and efficiency profiles. Notably, IN administration of CSA micelles showed relevant antidepressive effects and a certain ability to revert LPS-induced motor impairment. This work pointed out that the innovative and noninvasive IN administration of TPGS micelles could represent a safe and effective alternative to the classic oral route to deliver CSA at the Central Nervous System level, where its beneficial activity against neuroinflammation can be exploited.}, }
@article {pmid39699743, year = {2025}, author = {Zhang, H and Tahami Monfared, AA and Zhang, Q and Honig, LS}, title = {Incidence and Prevalence of Alzheimer's Disease in Medicare Beneficiaries.}, journal = {Neurology and therapy}, volume = {14}, number = {1}, pages = {319-333}, pmid = {39699743}, issn = {2193-8253}, abstract = {INTRODUCTION: The availability of anti-amyloid therapy for mild cognitive impairment (MCI) due to Alzheimer's disease and mild Alzheimer's dementia (AD) has underscored the need for realistic estimates of the population with AD/MCI within the healthcare system to assure adequate preparedness. We hypothesize that administrative databases can provide real-world epidemiologic estimates reflecting the population with diagnosed (known) MCI and AD. This study was conducted to estimate diagnostic incidence and prevalence of AD and all-cause MCI among the Medicare fee-for-service (FFS) and Medicare Advantage (MA) beneficiaries in the United States.
METHODS: This was a retrospective analysis of Medicare beneficiaries (aged 65 and older) with identified diagnoses of AD/MCI based on ≥ 2 diagnostic codes ≥ 30 days apart. Incidence/prevalence estimates were reported per 10,000 person-years.
RESULTS: In FFS, AD incidence (2008-2018) decreased (138 to 104); MCI incidence increased (8 to 47), but the sum (MCI + AD) was relatively stable (146 to 151). Prevalence (2008-2017) increased for AD (318 to 354), and MCI (13 to 99). In MA (2016) epidemiological estimates were consistent with FFS. In 2017, older age, female sex and the Northeastern region were consistently associated with higher AD/MCI prevalence among FFS beneficiaries.
CONCLUSION: In FFS, AD/MCI diagnostic prevalence increased over 10 years, especially for MCI; prevalence estimates in MA (2016) were comparable. Diagnostic prevalence in 2016 (FFS + MA) was 3.4% for AD and 0.85% for MCI. Our findings address the reality of Alzheimer's disease in clinical practice in the United States that is confronted by healthcare professionals, payors, healthcare decision-makers, patients, and caregivers, and may offer a realistic gauge for patient triage for treatment, healthcare resource allocation, and health-systems' operational prioritization. With the availability of anti-amyloid treatments, we anticipate that the population with diagnosed MCI/AD within the Medicare database may rise over time; therefore, periodic updates of incidence/prevalence estimates may provide support for timely healthcare decision-making.}, }
@article {pmid39698778, year = {2024}, author = {Daly, T and Olluri, A and Kurkinen, M}, title = {Anti-amyloid treatments in Alzheimer's disease: elegance, evidence and ethics.}, journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University}, volume = {33}, number = {12}, pages = {1303-1309}, doi = {10.17219/acem/198674}, pmid = {39698778}, issn = {1899-5276}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy/pathology ; *Amyloid beta-Peptides/analysis/antagonists & inhibitors/metabolism ; Positron-Emission Tomography ; }, abstract = {The so-called "amyloid cascade hypothesis" provides an elegant explanation of Alzheimer's disease (AD), has motivated the amyloid-lowering therapeutic strategy, and led to the elaboration of a rich experimental and conceptual toolkit for the field to progress. But it might be incorrect. The scientific evidence base supporting the efficacy and safety of current anti-amyloid antibody treatments in AD is weak. Nevertheless, we argue that there is a bias towards the amyloid-lowering therapeutic strategy amongst key opinion leaders in the research and advocacy communities. To demonstrate this, we first focus on the AD lexicon: while any accrual of amyloid on a brain PET scan can now permit diagnosis/definition of AD, lowering positron emission tomography (PET) amyloid is considered disease modification, and treatment-induced side-effects are hidden behind neutral-sounding acronyms: ARIA (amyloid-β (Aβ)-related imaging abnormalities: brain bleeding and swelling) and ARPA (amyloid-β (Aβ) removal-related pseudo-atrophy: brain shrinkage). Second, we underline that drugmakers did not test anti-amyloid antibodies against the best proven interventions and did not adequately inform trial participants of risks, thus violating research ethics of the Declaration of Helsinki on 2 counts. In conclusion, we are critical of over-reliance on the idea that PET amyloid-lowering treatments for AD are a therapeutic revolution as claimed, and consider that optimism does not excuse a lack of scientific, regulatory, and ethical integrity. We argue for rigorous, properly controlled (e.g. donepezil) anti-amyloid trials demonstrating cognitive and functional benefit before accepting amyloid-lowering drugs as the new standard of care for AD patients.}, }
@article {pmid39698776, year = {2024}, author = {Haśko, A and Potocka, N and Skrzypa, M and Bartosik-Psujek, H and Zawlik, I}, title = {Prospective use of miRNAs as biomarkers in the diagnosis of Alzheimer's disease.}, journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University}, volume = {}, number = {}, pages = {}, doi = {10.17219/acem/190273}, pmid = {39698776}, issn = {1899-5276}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia in the aging population. Pathogenic processes related to the accumulation of amyloid plaques (Aβ) and intracellular neurofibrillary tangles (NFTs) begin during the asymptomatic stage long before the onset of deterioration in cognitive functions and neurodegeneration, which makes rapid diagnosis and treatment difficult. Although biochemical diagnostic markers isolated from the body fluids of AD patients are currently used, scientists are engaged in research into molecular biomarkers that will significantly accelerate the diagnosis long before the first clinical symptoms appear. The research presented here focused on microRNAs (miRNAs), small, non-coding RNA molecules that are involved in the regulation of the post-transcriptional expression of many genes. A review of the literature revealed that miRNAs play an important role in regulating the expression of genes involved in the pathophysiological mechanisms of AD. Changes in the levels of miRNAs in a patient's body fluids can be used for rapid diagnosis. Original scientific articles published between 2014 and 2023 describing clinical and experimental studies on the role and expression levels of various miRNAs were selected from scientific databases such as PubMed, NCBI, Science Direct, and Google Scholar. The selected miRNAs were divided into 2 groups based on their expression level in AD: those with increased expression and those with decreased expression. A review of the latest scientific reports confirms that miRNAs may be a promising source of non-invasive and widely available biomarkers. Additionally, their modulation may prove to be an effective therapeutic strategy in AD.}, }
@article {pmid39698413, year = {2024}, author = {Zhang, X and Che, X and Zhang, S and Wang, R and Li, M and Jin, Y and Wang, T and Song, Y}, title = {Mesenchymal stem cell-derived extracellular vesicles for human diseases.}, journal = {Extracellular vesicles and circulating nucleic acids}, volume = {5}, number = {1}, pages = {64-82}, pmid = {39698413}, issn = {2767-6641}, abstract = {Stem cell therapy is a novel approach for treating various severe and intractable diseases, including autoimmune disorders, organ transplants, tumors, and neurodegenerative diseases. Nevertheless, the extensive utilization of stem cells is constrained by potential tumorigenicity, challenges in precise differentiation, rejection concerns, and ethical considerations. Extracellular vesicles possess the ability to carry diverse bioactive factors from stem cells and deliver them to specific target cells or tissues. Moreover, they offer the advantage of low immunogenicity. Consequently, they have the potential to facilitate the therapeutic potential of stem cells, mitigating the risks associated with direct stem cell application. Therefore, the use of stem cell extracellular vesicles in clinical diseases has received increasing attention. This review summarizes advances in the use of extracellular vesicles from mesenchymal stem cells (MSC). MSC extracellular vesicles are used in the treatment of inflammatory diseases such as rheumatoid arthritis, liver injury, COVID-19, and allergies; in the repair of tissue damage in heart disease, kidney injury, and osteoarthritic diseases; as a carrier in the treatment of tumors; and as a regenerative agent in neurodegenerative disorders such as Alzheimer's and Parkinson's.}, }
@article {pmid39698294, year = {2024}, author = {Freyssin, A and Carles, A and Moha, B and Rubinstenn, G and Maurice, T}, title = {Long-Term Treatment with Fluoroethylnormemantine (FENM) Alleviated Memory Deficits, Amyloid Pathology, and Microglial Reaction in APP/PS1 Mice.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {12}, pages = {4069-4082}, pmid = {39698294}, issn = {2575-9108}, abstract = {Fluoroethylnormemantine (FENM, RST-01) shows different pharmacological properties from Memantine. The drug is neuroprotective in pharmacological and transgenic mouse models of Alzheimer's disease (AD), particularly limiting the neuroinflammatory response to amyloid-β (Aβ) accumulation. In order to define early therapeutic intervention aimed at preventing AD and targeting the early activation of proinflammatory pathways, we examined the impact of chronic FENM treatment starting presymptomatically in APPswe/PSEN1[∂E9] (APP/PS1) mice. APP/PS1 (32 males and 36 females) and wild-type (WT, 23 males and 36 females) mice received FENM (0, 1, and 5 mg/kg/day) in the drinking bottle between 3 and 12 months of age. They were tested once a month for spontaneous alternation and, at the end of the treatment, for object recognition, water-maze learning, and passive avoidance. Amyloid plaques, astrocytes, and microglia were assessed by immunofluorescence, and guanidine-soluble and insoluble Aβ1-40/42 levels were determined in the hippocampal formation. Spontaneous alternation performances regularly decreased in APP/PS1, but not in WT mice. The FENM treatments (1 and 5 mg/kg) prevented the deficit. At 12 months of age, APP/PS1 treated with 1 mg/kg FENM showed significant improvements in all behavioral procedures tested. The astroglial reaction was not significantly attenuated by FENM in the stratum radiatum, stratum moleculare, and polymorph layer of the dentate gyrus. The microglial reaction was significantly decreased in the two latter areas. In the polymorph layer, a significant effect on amyloid plaques was measured. Global analyses of amyloid load showed attenuations of soluble and insoluble Aβ1-40 levels and a significant decrease in the level of insoluble Aβ1-42. Moreover, significant negative correlations were observed for FENM impacts on amyloid load or microglial activation and the alternation score. FENM confirmed, under a chronic presymptomatic treatment, its neuroprotective efficacy in AD. Our data particularly suggested that an impact on Aβ and microglia could be related to the preservation of cognitive functions.}, }
@article {pmid39697158, year = {2025}, author = {Elhage, A and Cohen, S and Cummings, J and van der Flier, WM and Aisen, P and Cho, M and Bell, J and Hampel, H}, title = {Defining benefit: Clinically and biologically meaningful outcomes in the next-generation Alzheimer's disease clinical care pathway.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14425}, pmid = {39697158}, issn = {1552-5279}, support = {R35 AG071476/AG/NIA NIH HHS/United States ; NIA R25 AG083721-01//National Institute on Aging (NIA)/ ; P20 GM109025/GM/NIGMS NIH HHS/United States ; //Ted and Maria Quirk Endowment/ ; R25 AG083721/AG/NIA NIH HHS/United States ; //Alzheimer's Disease Drug Discovery Foundation/ ; //Joy Chambers-Grundy Endowment/ ; P20GM109025/GM/NIGMS NIH HHS/United States ; R35AG71476//National Institute on Aging (NIA)/ ; //Eisai Inc./ ; }, mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; *Biomarkers ; Precision Medicine ; Outcome Assessment, Health Care ; Clinical Trials as Topic ; }, abstract = {To understand the potential benefits of emerging Alzheimer's disease (AD) therapies within and beyond clinical trial settings, there is a need to advance current outcome measurements into meaningful information relevant to all stakeholders. The relationship between the impact on disease biology and clinically measurable outcomes in cognition, function, and behavior must be considered when defining the meaningful benefit of early AD therapies. In this review, we discuss: (1) the lack of consideration for biomarkers in the current concept of meaningfulness in AD; (2) the lack of gold standards for determining minimal biologically and clinically important differences (MBCIDs) in AD trials; (3) how the treatment benefits of disease-modifying treatments are cumulative and increase over time; and (4) the different concepts of meaningfulness among key stakeholders. This review utilizes the future clinical biological framework of AD and aims to further integrate and expand the parameters of meaningful benefits toward a precision medicine framework. HIGHLIGHTS: Definition of meaningful benefit from Alzheimer's disease (AD) treatment varies across disease stage and stakeholder perspectives. Observable and meaningful outcomes must consider the clinical-biological nature of AD. Statistically significant effects or outcomes do not always equate to clinically meaningfulness. Assessment tools must reflect stage-specific subtle changes following treatment. Real-world evidence will support consensus, definition, and interpretation of clinical meaningfulness.}, }
@article {pmid39696463, year = {2024}, author = {Hansen, CE and Hollaus, D and Kamermans, A and de Vries, HE}, title = {Tension at the gate: sensing mechanical forces at the blood-brain barrier in health and disease.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {325}, pmid = {39696463}, issn = {1742-2094}, support = {No. 813294//European Union´s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement/ ; }, mesh = {Humans ; *Blood-Brain Barrier/metabolism ; Animals ; Endothelial Cells/metabolism ; }, abstract = {Microvascular brain endothelial cells tightly limit the entry of blood components and peripheral cells into the brain by forming the blood-brain barrier (BBB). The BBB is regulated by a cascade of mechanical and chemical signals including shear stress and elasticity of the adjacent endothelial basement membrane (BM). During physiological aging, but especially in neurological diseases including multiple sclerosis (MS), stroke, small vessel disease, and Alzheimer's disease (AD), the BBB is exposed to inflammation, rigidity changes of the BM, and disturbed cerebral blood flow (CBF). These altered forces lead to increased vascular permeability, reduced endothelial reactivity to vasoactive mediators, and promote leukocyte transmigration. Whereas the molecular players involved in leukocyte infiltration have been described in detail, the importance of mechanical signalling throughout this process has only recently been recognized. Here, we review relevant features of mechanical forces acting on the BBB under healthy and pathological conditions, as well as the endothelial mechanosensory elements detecting and responding to altered forces. We demonstrate the underlying complexity by focussing on the family of transient receptor potential (TRP) ion channels. A better understanding of these processes will provide insights into the pathogenesis of several neurological disorders and new potential leads for treatment.}, }
@article {pmid39696300, year = {2024}, author = {Schwartz, SS and Herman, ME and Tun, MTH and Barone, E and Butterfield, DA}, title = {The double life of glucose metabolism: brain health, glycemic homeostasis, and your patients with type 2 diabetes.}, journal = {BMC medicine}, volume = {22}, number = {1}, pages = {582}, pmid = {39696300}, issn = {1741-7015}, mesh = {Humans ; Blood Glucose/drug effects/metabolism ; *Brain/metabolism ; *Diabetes Mellitus, Type 2/metabolism/drug therapy ; Glucose/metabolism ; *Homeostasis/drug effects/physiology ; Hypoglycemic Agents/pharmacology/therapeutic use ; }, abstract = {The maintenance of cognitive function is essential for quality of life and health outcomes in later years. Cognitive impairment, however, remains an undervalued long-term complication of type 2 diabetes by patients and providers alike. The burden of sustained hyperglycemia includes not only cognitive deficits but also the onset and progression of dementia-related conditions, including Alzheimer's disease (AD). Recent research has shown that the brain maintains an independent glucose "microsystem"-evolved to ensure the availability of fuel for brain neurons without interruption by transient hypoglycemia. When this milieu is perturbed, brain hyperglycemia, brain glucotoxicity, and brain insulin resistance can ensue and interfere with insulin signaling, a key pathway to cognitive function and neuronal integrity. This newly understood brain homeostatic system operates semi-autonomously from the systemic glucoregulatory apparatus. Large-scale clinical studies have shown that systemic dysglycemia is also strongly associated with poorer cognitive outcomes, which can be mitigated through appropriate clinical management of plasma glucose levels. Moreover, these studies demonstrated that glucose-lowering agents are not equally effective at preventing cognitive dysfunction. Glucagon-like peptide-1 (GLP-1) receptor analogs and sodium glucose cotransporter 2 inhibitors (SGLT2is) appear to afford the greatest protection; metformin and dipeptidyl peptidase 4 inhibitors (DPP-4is) also significantly improved cognitive outcomes. Sulfonylureas (SUs) and exogenous insulin, on the other hand, do not provide the same protection and may actually worsen cognitive outcomes. In the creation of a treatment plan, comorbid cognitive conditions should be considered. These efficacious treatments create a new gold standard of managing hyperglycemia-one which is consistent with the "complication-centric prescribing" mandates issued in type 2 diabetes treatment guidelines. The increasing longevity enjoyed by our populace places the onus on clinical care to play the "long game" in using targeted treatments for glucose control in patients with, or at risk for, cognitive decline to maintain cognitive wellness later in life. This article reviews critical emerging data for scientists and trialists and translates new enhancements in patient care for practitioners.}, }
@article {pmid39695988, year = {2024}, author = {Siripaopradit, Y and Chatsirisakul, O and Ariyapaisalkul, T and Sereemaspun, A}, title = {Exploring the gut-brain axis in alzheimer's disease treatment via probiotics: evidence from animal studies-a systematic review and meta-analysis.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {481}, pmid = {39695988}, issn = {1471-2377}, mesh = {Animals ; *Alzheimer Disease/therapy/microbiology/metabolism ; Brain/metabolism ; *Brain-Gut Axis/physiology ; Disease Models, Animal ; *Dysbiosis/metabolism/microbiology/therapy ; *Gastrointestinal Microbiome/physiology ; *Probiotics/administration & dosage ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder in the elderly, causing cognitive impairment. Its pathogenesis is characterized by amyloid beta deposition, neurofibrillary tangles, and neuroinflammation. Recent research has identified the link between gut dysbiosis, an imbalance of intestinal microorganisms, to this pathogenesis via the gut-brain axis. This study aims to review the probiotics' therapeutic effect, targeting the gut-brain axis, for AD treatment in animals.
METHODS: The method utilized in this study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Three reviewers searched articles through PubMed, Scopus, and Embase using advanced search strategy. Articles published between 2010 and 2023 that met the criteria were included.
RESULTS: Of 2,273 articles, 21 animal studies measuring the effects of probiotics genera Lactobacillus and/or Bifidobacterium on AD via at least one of these four outcomes: AD pathology, cognitive function, neuroinflammation, and gut microbiota composition. The results demonstrated that probiotics could repair gut dysbiosis by decreasing pro-inflammatory bacteria and increasing anti-inflammatory bacteria. Repaired dysbiosis was found to be associated with less neuroinflammation as significant reductions in neuroinflammatory markers related to the pathogenesis of AD such as TNF-α (SMD = -2.08, P = 0.005), IL-6 (SMD = -2.98, P < 0.0005), and IL-1β (SMD = -2.49, P = 0.003) were observed. Reduced amyloid beta deposition (SMD = -1.17, P = 0.009) was reported, but reduction in tau hyperphosphorylation was found to be insignificant. For cognitive function, positive results were demonstrated for all three aspects of cognitive function including long-term memory (SMD = 2.55, P < 0.00001), short-term memory (SMD = 1.32, P = 0.003), and spatial recognition (SMD = -1.13, P < 0.00001).
CONCLUSIONS: Particular formulas of probiotics showed potential effectiveness in AD therapies with demonstrated association with the gut-brain axis. Future studies are required to investigate strain-specific results and optimal dosages and regimens.}, }
@article {pmid39695324, year = {2025}, author = {Zhang, X and Wu, M and Cheng, L and Cao, W and Liu, Z and Yang, SB and Kim, MS}, title = {Fast-spiking parvalbumin-positive interneurons: new perspectives of treatment and future challenges in dementia.}, journal = {Molecular psychiatry}, volume = {30}, number = {2}, pages = {693-704}, pmid = {39695324}, issn = {1476-5578}, mesh = {Humans ; *Interneurons/metabolism ; *Parvalbumins/metabolism ; *Dementia/metabolism ; Animals ; *Alzheimer Disease/metabolism ; Brain/metabolism ; Dementia, Vascular/metabolism ; Cognitive Dysfunction/metabolism ; Lewy Body Disease/metabolism ; }, abstract = {Central nervous system parvalbumin-positive interneurons (PV-INs) are crucial and highly vulnerable to various stressors. They also play a significant role in the pathological processes of many neuropsychiatric diseases, especially those associated with cognitive impairment, such as Alzheimer's disease (AD), vascular dementia (VD), Lewy body dementia, and schizophrenia. Although accumulating evidence suggests that the loss of PV-INs is associated with memory impairment in dementia, the precise molecular mechanisms remain elusive. In this review, we delve into the current evidence regarding the physiological properties of PV-INs and summarize the latest insights into how their loss contributes to cognitive decline in dementia, particularly focusing on AD and VD. Additionally, we discuss the influence of PV-INs on brain development, the variations in their characteristics across different types of dementia, and how their loss affects the etiology and progression of cognitive impairments. Ultimately, our goal is to provide a comprehensive overview of PV-INs and to consider their potential as novel therapeutic targets in dementia treatment.}, }
@article {pmid39694350, year = {2025}, author = {Alrouji, M and Furkan, M and Alnuaimi, GRH and Yasmin, S and Alhumaydhi, FA and Khan, RH and Shahwan, M and Anwar, S and Islam, A and Shamsi, A}, title = {Employing spectroscopic, calorimetric and structural bioinformatics approaches to decipher the binding mechanism of mangiferin with human transferrin.}, journal = {International journal of biological macromolecules}, volume = {289}, number = {}, pages = {138829}, doi = {10.1016/j.ijbiomac.2024.138829}, pmid = {39694350}, issn = {1879-0003}, mesh = {*Xanthones/chemistry/pharmacology/metabolism ; Humans ; *Transferrin/metabolism/chemistry ; *Protein Binding ; *Molecular Docking Simulation ; *Calorimetry ; *Molecular Dynamics Simulation ; Binding Sites ; Thermodynamics ; Computational Biology/methods ; }, abstract = {In recent times, neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD) and others, represent a major global health challenge with increasing prevalence and significant socio-economic impact. These diseases, characterized by progressive neuronal loss, currently lack effective therapies. Phytochemicals offer promising therapeutic potential due to their diverse bioactive properties. Mangiferin, a glucosylxanthone found in mangoes and other plants, has shown significant therapeutic potential in NDs. Human transferrin (Tf), an iron-binding protein crucial for iron homeostasis, is implicated in ND pathogenesis. This study delineates the interaction between Mangiferin and Tf. Molecular docking revealed Mangiferin predominantly interacts with Tf's binding site, engaging critical residues. Molecular dynamics simulations over 200 ns demonstrated the stability of the Tf-Mangiferin complex without major deviations. Fluorescence binding assays confirmed the strong binding affinity of Mangiferin to Tf. Additionally, Isothermal titration calorimetry (ITC) validated the spontaneous binding of Mangiferin with Tf, providing detailed thermodynamic parameters. The findings highlight the therapeutic potential of Mangiferin in NDs treatment through its interaction with Tf, offering insights into novel mechanisms of action and pathways for disease modification.}, }
@article {pmid39694170, year = {2025}, author = {Xie, Y and Yang, M and Wang, H and Chen, Y and Shi, X and Tang, H and Sun, Q}, title = {Potential molecular mechanisms of tobacco smoke exposure in Alzheimer's disease.}, journal = {Brain research}, volume = {1848}, number = {}, pages = {149394}, doi = {10.1016/j.brainres.2024.149394}, pmid = {39694170}, issn = {1872-6240}, mesh = {*Alzheimer Disease/metabolism/genetics ; Humans ; *Protein Interaction Maps ; Molecular Docking Simulation ; Gene Ontology ; Signal Transduction/drug effects ; Smoking/genetics/metabolism/adverse effects ; Gene Regulatory Networks/drug effects ; Tobacco Smoke Pollution/adverse effects ; Nicotine/pharmacology ; }, abstract = {BACKGROUND: Smoking is detrimental to health, with tobacco use being a critical factor in the development of various neurodegenerative diseases, including Alzheimer's disease (AD), which progressively impairs brain function and poses a significant threat to public health. This study aims to examine the potential genetic alterations induced by smoking that are associated with AD and to investigate the underlying regulatory mechanisms. The research will provide theoretical foundations for targeted prevention and treatment strategies for AD.
METHODS: This study analyzed datasets from the Gene Expression Omnibus (GEO) and the Comparative Toxicogenomics Database (CTD) to identify genes affected by tobacco smoke exposure and those altered in patients with AD relative to normal controls. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses using OmicShare tools to screen for key pathways. Key genes were identified by constructing protein-protein interaction networks (PPI) in the STRING database with the aid of CytoHubba. Additionally, the binding activity of the proteins encoded by these key genes to nicotine, the main component of tobacco, was analyzed using molecular docking techniques. Finally, the analytical results were verified using Quantitative Real-Time Polymerase Chain Reaction.
RESULTS: The CTD identified 12,164 CE-related genes affected by tobacco smoke exposure. A comparison of these datasets yielded 94 common genes that were both influenced by tobacco and differentially expressed across all brain regions. The GO and KEGG pathway enrichment analyses showed that these common differentially expressed genes (DEGs) were predominantly enriched in the Wnt/β-catenin and PI3K-AKT signaling pathways. The DEGs' PPI network, constructed using the STRING database, highlighted key genes such as HSP90AB1, SOS2, MAGI1, and YWHAZ. Molecular docking studies demonstrated that nicotine binds effectively to the protein structures of these key genes, primarily through amino acid residues such as Ser and Glu. Experimental validation showed that HSP90AB1 and YWHAZ exhibited notable expression discrepancies under varying concentrations of cigarette smoke extract (CSE) treatments, particularly demonstrating a pronounced down-regulation trend at elevated concentrations.
CONCLUSION: The study indicates that tobacco may impact the function of transmembrane transporter proteins and contribute to the development of AD by affecting key genes such as HSP90AB1 and YWHAZ, as well as signaling pathways like PI3K-AKT.}, }
@article {pmid39693925, year = {2025}, author = {Xia, N and Huang, Y and He, C and Li, Y and Yang, S and Liu, L}, title = {Multifunctional porphyrin-substituted phenylalanine-phenylalanine nanoparticles for diagnostic and therapeutic applications in Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {154}, number = {}, pages = {108065}, doi = {10.1016/j.bioorg.2024.108065}, pmid = {39693925}, issn = {1090-2120}, mesh = {*Alzheimer Disease/drug therapy/diagnosis ; *Phenylalanine/chemistry/pharmacology ; *Nanoparticles/chemistry ; *Porphyrins/chemistry/pharmacology ; *Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Humans ; Reactive Oxygen Species/metabolism/analysis ; Molecular Structure ; Copper/chemistry ; Dose-Response Relationship, Drug ; }, abstract = {β-Amyloid (Aβ) peptides are believed as the diagnostic biomarkers and therapeutic targets of Alzheimer's disease (AD). Their complexes with copper ions can catalyze the generation of reactive oxygen species (ROS) to further promote neuronal death. Herein, we suggested that porphyrin-substituted phenylalanine-phenylalanine nanoparticles (TPP-FF NPs) could inhibit the aggregation of Aβ monomers, disassemble the fibrillar Aβ aggregates under light illumination, and depressing the Cu[2+]-induced generation of ROS. Meanwhile, the TPP-FF NPs could be used as the nanocarriers and quenchers of fluorescently-labeled probes for the detection of Aβ oligomer (AβO). Inhibition of Aβ assembly and dissolution of Aβ aggregates were monitored by Thioflavin T (ThT)-based fluorescent assay and characterized by atomic force microscopy. The Aβ/Cu[2+]-induced generation of ROS was limited by TPP-FF NPs. The fluorescein-labeled probe aptamers attached on the surface of TPP-FF NPs emitted low fluorescence. The interaction between AβO and aptamers induced the release of the probes from the surface of TPP-FF NPs, driving the fluorophore far away from the quenchers and turning on the fluorescence. The signal-on strategy can be used for the detection of AβO with a low detection limit. This work should be evaluable for the development of multifunctional candidates for the diagnosis and treatment of AD.}, }
@article {pmid39693689, year = {2025}, author = {Irum, I and Khan, F and Sufyan, M and Benish Ali, SH and Rehman, S}, title = {Developing multifaceted drug synergistic therapeutic strategy against neurological disorders.}, journal = {Computers in biology and medicine}, volume = {185}, number = {}, pages = {109495}, doi = {10.1016/j.compbiomed.2024.109495}, pmid = {39693689}, issn = {1879-0534}, mesh = {*Drug Synergism ; *Cholinesterase Inhibitors/chemistry/therapeutic use ; Humans ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism/chemistry ; Antioxidants/chemistry ; Molecular Dynamics Simulation ; Phytochemicals/chemistry/pharmacokinetics/therapeutic use ; Nervous System Diseases/drug therapy ; Donepezil/chemistry/therapeutic use ; Quercetin/chemistry ; }, abstract = {Drug synergism can alter the ultimate biological effects and bioavailability of phytoconstituents. Acetylcholinesterase (AChE) inhibitors as symptomatic drugs are potent therapeutic regimen for neurodegenerative diseases. In this context, this study characterized the synergistic antioxidant, anti-inflammatory and anti-AChE effects of the selected phytochemicals including standard drugs followed by enzyme kinetics, structure-based ligands screening and molecular dynamics simulation study. The synergistic interactions were evaluated through Isoradiation and Synergy finder 3.0 methods. The combinations of Quercetin (QCT), Folic acid (FA), and Swertiamarin (SWT) with specific reference drugs were studied. The combinations of SWT + GA (Gallic acid) and FA + GA at 1:1 (γ:0.10 & 0.08, respectively) showed the significant synergistic antioxidant effect via ABTS assay. Further, in combination, QCT + SWT showed the maximum synergistic effect (γ: 0.02-0.13) in anti-inflammatory assay. Moreover, the combinations QCT, FA, and SWT with reference drug, Donepezil (DP), illustrated potent synergistic activity as anti-AChE in 1:1 proportion (γ: 0.18). The interaction pattern of phytochemicals significantly exhibited synergism (γ < 1) depicting their optimum activity in combinations compared to individual components. Enzyme kinetics evaluation showed the competitive binding of SWT with AChE as of donepezil. All the parameters of ADMET study proposed the QCT and SWT as acceptable oral drug molecules. Computational docking study revealed that QCT and SWT with lowest RMSD (1.096, 2.104) and lowest docking score (-9.831, -7.435 kcal/mol) showed maximum binding efficacy. Furthermore, molecular simulation study depicted the stability of protein-ligand complexes. These findings provide novel insight in the development of dietary treatment based on their synergistic effects for neurological disorders as optimum alternative therapeutic agents.}, }
@article {pmid39691835, year = {2024}, author = {Lin, J and Liu, X and Lin, X and Liu, N and Pei, H and Zhao, Y and Yu, G and Wang, W and Chen, C and Hou, T and Li, X and Lin, X and Li, H}, title = {Effectiveness and Safety of Shenxiong Huanglian Detoxification Granule Combined with Donepezil for the Treatment of Alzheimer's Disease: Study Protocol for a Multicenter, Pragmatic, Randomized Controlled Clinical Trial.}, journal = {International journal of general medicine}, volume = {17}, number = {}, pages = {6153-6164}, pmid = {39691835}, issn = {1178-7074}, abstract = {BACKGROUND: Alzheimer's disease is a degenerative condition that causes patients to experience progressive memory decline and a significant decline in overall cognitive ability at any given moment. The increase in the elderly population has resulted in a notable surge in the prevalence of Alzheimer's disease, as has the global impact of the disease. Significant clinical efficacy of traditional Chinese medicine in combination with Western medicine for the treatment of Alzheimer's disease has been demonstrated in previous studies. The main purpose of this trial is to assess the effectiveness and safety of Shenxiong Huanglian Detoxification Granule combined with donepezil in individuals diagnosed with mild-to-moderate Alzheimer's disease.
METHODS: This is a multicenter, pragmatic, randomized controlled trial. A total of 386 eligible individuals with mild to moderate Alzheimer's disease will receive random assignment and equal access to the test or control group. The effectiveness and safety of Shenxiong Huanglian Detoxification Granule in combination with donepezil will be observed. The primary outcome is the alteration in scores acquired from the Alzheimer's Disease Assessment Scale-Cognitive Subscale. Secondary outcomes include the assessments of the Traditional Chinese Medicine Syndrome score scale, Mini-Mental State Examination, Clinical Dementia Rating, and Activity of Daily Living scale. We will also analyze blood biomarkers of Alzheimer's disease, inflammatory indicators, oxidative stress indicators, and hemorheology indicators. In addition, safety assessments will be conducted at baseline, after 12 weeks, and after 24 weeks of treatment.
DISCUSSION: These findings will offer reliable clinical evidence regarding the effectiveness and safety of Shenxiong Huanglian Detoxification Granule in combination with donepezil for treating patients with mild-to-moderate Alzheimer's disease. Additionally, this study will support the integration of traditional Chinese and Western medicine into mainstream treatment for Alzheimer's disease, promoting a multitarget strategy.
TRIAL REGISTRATION: Chinese Clinical Trial Registry, Registration Number: ChiCTR2300072768. Registered on 25 June 2023. https://www.chictr.org.cn/showproj.html?proj=195457.}, }
@article {pmid39691162, year = {2024}, author = {Jun, P and Chengye, H and Hui, W}, title = {Bibliometric analysis of rehabilitation in Alzheimer's disease (2000-2023): trends, hotspots and prospects.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1457982}, pmid = {39691162}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disease that leads to insidious deterioration of brain functions and is considered the sixth leading cause of death in the world. Multiple studies have shown that rehabilitation therapy is becoming an important field of AD research in recent years.
OBJECTIVE: We opted for bibliometric analysis to comprehensively summarize the advancements in the study of AD rehabilitation treatment, aiming to provide researchers with current trends and future research directions.
METHODS: All articles and reviews pertaining to rehabilitation treatment in Alzheimer's disease from 2000 to 2023 were downloaded through Web of Science Core Collection. The results were subjected to bibliometric analysis using Microsoft Excel (2019 version), CiteSpace (6.3 R1 Advanced) and VOSviewer 1.6.20.
RESULTS: Overall, 1,284 publications were included. The number of publications was increasing yearly. The United States has published the most publications. University of Toronto has published the most papers of all institutions. NEUROPSYCHOLOGICAL REHABILITATION and ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION were the journals with the most studies and the most commonly cited, respectively. Clare L is the author with the highest productivity and co-citation. After analysis, the most common keywords are mild cognitive impairment, cognitive, impairment memory and executive function indicates that cognitive impairment is the main focus of research. Transcranial magnetic stimulation, cognitive rehabilitation, and physical activity/exercise are the hotspots of research at the present stage and are likely to continue.
CONCLUSION: Distinguishing non pharmacological treatments at different stages of development is a research hotspot in AD rehabilitation; Sports intervention, brain functional imaging techniques represented by brain functional connectivity, virtual reality, and quality of life are research directions that need attention.}, }
@article {pmid39691161, year = {2024}, author = {Wang, H and Shi, C and Jiang, L and Liu, X and Tang, R and Tang, M}, title = {Neuroimaging techniques, gene therapy, and gut microbiota: frontier advances and integrated applications in Alzheimer's Disease research.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1485657}, pmid = {39691161}, issn = {1663-4365}, abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder marked by cognitive decline, for which effective treatments remain elusive due to complex pathogenesis. Recent advances in neuroimaging, gene therapy, and gut microbiota research offer new insights and potential intervention strategies. Neuroimaging enables early detection and staging of AD through visualization of biomarkers, aiding diagnosis and tracking of disease progression. Gene therapy presents a promising approach for modifying AD-related genetic expressions, targeting amyloid and tau pathology, and potentially repairing neuronal damage. Furthermore, emerging evidence suggests that the gut microbiota influences AD pathology through the gut-brain axis, impacting inflammation, immune response, and amyloid metabolism. However, each of these technologies faces significant challenges, including concerns about safety, efficacy, and ethical considerations. This article reviews the applications, advantages, and limitations of neuroimaging, gene therapy, and gut microbiota research in AD, with a particular focus on their combined potential for early diagnosis, mechanistic insights, and therapeutic interventions. We propose an integrated approach that leverages these tools to provide a multi-dimensional framework for advancing AD diagnosis, treatment, and prevention.}, }
@article {pmid39691160, year = {2024}, author = {Zhang, L and Gong, YM and Wang, SW and Shi, PL and Li, MZ and Wen, X and Wang, DX and Zheng, YB and Han, Y}, title = {Associations of posttraumatic stress disorder symptoms with amyloid burden in cognitively normal older adults.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1422862}, pmid = {39691160}, issn = {1663-4365}, abstract = {BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with the development of dementia. However, the link between PTSD and preclinical Alzheimer's disease pathology (amyloid β [Aβ]) remains controversial. Moreover, the correlation between the severity of PTSD with Aβ levels remains unknown.
METHODS: This cross-sectional study sought to investigate the associations of PTSD symptoms with global and regional brain Aβ burden. To this end, data were obtained from participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study. In addition, we explored the association between the severity of PTSD symptoms and Aβ levels.
RESULTS: A total of 4,228 participants aged 65 to 85 years were included in the final analysis. The results showed that PTSD symptoms were significantly associated with higher global Aβ levels (1.15 ± 0.20 vs. 1.09 ± 0.19; β = 0.056; p < 0.001), after adjusting for covariates. The association between PTSD symptoms and Aβ levels was not affected by sex, age, ApoE genotype, or psychiatric diseases. Similarly, PTSD symptoms were significantly associated with Aβ levels in all subregions, including the anterior cingulate, posterior cingulate, parietal cortex, precuneus, temporal cortex, and frontal cortex. In addition, the group with severe PTSD symptoms (1.22 ± 0.24) exhibited higher global Aβ levels than the groups with moderate (1.14 ± 0.19) or mild (1.12 ± 0.20) symptoms or the control (1.08 ± 0.18), with p < 0.001.
CONCLUSION: The findings imply a close relationship between PTSD and brain Aβ levels, irrespective of sex, age, ApoE genotype, or psychiatric diseases. More well-designed studies are needed to further explore the relationship and mechanism underlying the association between PTSD and Aβ burden.}, }
@article {pmid39690983, year = {2024}, author = {Asthana, A and Tripathi, S and Agarwal, R}, title = {Role of Nonsteroidal Anti-Inflammatory Drugs as a Protective Factor in Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Neurology India}, volume = {72}, number = {6}, pages = {1144-1151}, doi = {10.4103/ni.ni_1073_22}, pmid = {39690983}, issn = {1998-4022}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Protective Factors ; Randomized Controlled Trials as Topic ; }, abstract = {Alzheimer's disease (AD) is a major neurodegenerative disease, affecting more than two-third cases of dementia in the world. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used anti-inflammatory analgesic agents, representing 7.7% of worldwide prescriptions, of which 90% are in patients over 65 years old. Based on mixed findings by different randomized clinical trials (RCTs), a systematic review and meta-analysis were conducted to develop a better understanding of the protective role of NSAIDs in AD. Database search was Pubmed, WebScience, and Embase. RCTs investigating the effect of NSAIDs on AD or test scores assessing cognitive function in people without AD at baseline were included. Two indicators were the Mini-Mental State Examination (MMSE) Score and Hazard Ratio. 09 studies were included in the present Meta-analysis. For the MMSE score difference, the pooled effect size was - 0.06 (-0.22, 0.10) which was not statistically significant (P value = 0.47). For the MMSE score, the pooled effect size was - 0.0036(-0.0320, 0.0248), which was also not statistically significant (P value = 0.87). For Hazard Ratio (HR), the pooled HR calculated using the random effect model was 1.20 (95% CI: 0.95, 1.51), which was not statistically significant (P value = 0.15). Present meta-analysis shows that NSAIDs, in general, are not effective in the treatment of AD. They also have no protective effect against the development of AD on their sustained use.}, }
@article {pmid39690860, year = {2024}, author = {Bui, VT and Wu, KW and Chen, CC and Nguyen, AT and Huang, WJ and Lee, LY and Chen, WP and Huang, CY and Shiao, YJ}, title = {Exploring the Synergistic Effects of Erinacines on Microglial Regulation and Alzheimer's Pathology Under Metabolic Stress.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {12}, pages = {e70137}, pmid = {39690860}, issn = {1755-5949}, support = {MOST109-2622-B-010-004-CC1;MOST111-2320-B-077-003//National Science and Technology Council/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Microglia/drug effects/metabolism ; *Mice, Transgenic ; Mice ; Rats ; Stress, Physiological/drug effects ; Neuroprotective Agents/pharmacology ; Mice, Inbred C57BL ; Cells, Cultured ; Drug Synergism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Disease Models, Animal ; Rats, Sprague-Dawley ; Male ; Diterpenes ; }, abstract = {BACKGROUND: Hericium erinaceus mycelium and its constituents, erinacines A and S, have shown neuroprotective effects in APP/PS1 transgenic mice; however, the precise mechanisms by which they modulate microglial phenotypes remain unclear. Our study is the first to explore the effect of erinacines on microglia morphology and the underlying mechanisms using a novel primary mixed glia cell model and advanced bioinformatic tools. Furthermore, we emphasize the clinical relevance by evaluating erinacines in a metabolically stressed APP/PS1 mouse model, which more accurately reflects the complexities of human Alzheimer's disease (AD), where metabolic syndrome is a common comorbidity.
METHODS: Rat primary mixed glial cultures were used to simulate the spectrum of microglial phenotypes, particularly the transition from immature to mature states. Microarray sequencing, along with Connectivity Map, ConsensusPathDB, and Gene Set Enrichment Analysis, identified pathways influenced by erinacines. The therapeutic efficacy was further evaluated in metabolically stressed APP/PS1 mice.
RESULTS: Erinacines significantly promoted the development of a ramified, neuroprotective microglial phenotype. Bioinformatics revealed potential modulation of microglia via histone deacetylase inhibition, actin filament dynamics, and synaptic structure modification-pathways not previously linked to erinacines in AD. Importantly, erinacines significantly lower fasting blood glucose and insulin levels while reducing amyloid-beta plaque burden, suppressing hyperactivated glial responses, and enhancing neurogenesis in the metabolically stressed APP/PS1 mice.
CONCLUSION: Our findings demonstrate the dual action of erinacines in modulating microglia morphology and phenotype while providing neuroprotection in a model that closely mimic the complexities of human Alzheimer's disease. Additionally, this study provides the foundation for understanding the potential mechanisms of action of erinacines, highlighting their promise as a novel treatment approach for Alzheimer's, particularly in cases complicated by metabolic dysfunction.}, }
@article {pmid39690817, year = {2025}, author = {Xu, Y and Liu, S and Zhou, Z and Qin, H and Zhang, Y and Zhang, G and Ma, H and Han, X and Liu, H and Liu, Z}, title = {Integrated multi-omics analysis revealed the molecular networks and potential targets of cellular senescence in Alzheimer's disease.}, journal = {Human molecular genetics}, volume = {34}, number = {5}, pages = {381-391}, doi = {10.1093/hmg/ddae189}, pmid = {39690817}, issn = {1460-2083}, support = {221100310100//Science and Technology Department of Henan/ ; }, mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; Humans ; *Quantitative Trait Loci ; *DNA Methylation/genetics ; *Genome-Wide Association Study ; *Cellular Senescence/genetics ; *Genetic Predisposition to Disease ; Gene Regulatory Networks ; Male ; Female ; Transcriptome/genetics ; Brain/metabolism/pathology ; Mendelian Randomization Analysis ; Aged ; Gene Expression Profiling ; Polymorphism, Single Nucleotide ; Multiomics ; }, abstract = {Cellular senescence (CS) is a hallmark of Alzheimer's disease (AD). However, the mechanisms through which CS contributes to AD pathogenesis remain poorly understood. We found that CS level in AD was higher compared with the healthy control group. Transcriptome-based differential expression analysis identified 113 CS-related genes in blood and 410 in brain tissue as potential candidate genes involved in AD. To further explore the causal role of these genes, an integrative mendelian randomization analysis was conducted, combining AD genome-wide association study summary statistics with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) data from blood samples, which identified five putative AD-causal genes (CENPW, EXOSC9, HSPB11, SLC44A2, and SLFN12) and 18 corresponding DNA methylation probes. Additionally, integrative analysis between eQTLs and mQTLs from blood uncovered two genes and 12 corresponding regulatory elements involved in AD. Furthermore, two genes (CDKN2B and ITGAV) were prioritized as putative causal genes in brain tissue and were validated through in vitro experiments. The multi-omics integration study revealed the potential role and underlying biological mechanisms of CS driven by genetic predisposition in AD. This study contributed to fundamental understanding of CS in AD pathogenesis and facilitated the identification of potential therapeutic targets for AD prevention and treatment.}, }
@article {pmid39689941, year = {2025}, author = {Wang, J and Subramanian, A and Cockburn, N and Xiao, J and Nirantharakumar, K and Haroon, S}, title = {Obstructive sleep apnoea syndrome and future risk of dementia among individuals managed in UK general practice.}, journal = {Thorax}, volume = {80}, number = {3}, pages = {167-174}, doi = {10.1136/thorax-2024-221810}, pmid = {39689941}, issn = {1468-3296}, mesh = {Humans ; *Sleep Apnea, Obstructive/epidemiology/therapy/complications ; Male ; Female ; United Kingdom/epidemiology ; *Dementia/epidemiology ; Middle Aged ; Aged ; Risk Factors ; *General Practice ; Incidence ; Adult ; Risk Assessment/methods ; Proportional Hazards Models ; }, abstract = {BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) has been recognised as a potential risk factor for cognitive decline, yet its precise relationship with dementia remains uncertain. This study aimed to determine the risk of dementia among individuals with and without OSAS.
METHODS: Data derived from 2.3 million adults (aged ≥18 years) were extracted from the Clinical Practice Research Datalink (2000-2022), a nationally representative primary care electronic health records database in the UK. 193 600 individuals with OSAS were propensity score-matched to 536 701 individuals without OSAS. Cox proportional hazard regression models were applied to quantify the risk of developing all-cause dementia, vascular dementia and Alzheimer's disease between individuals with and without OSAS.
RESULTS: With a median follow-up of 4.0 (IQR 1.8-7.5) years, 2802 and 6211 individuals developed all-cause dementia in those with and without OSAS, corresponding to crude incidence rates of 2.47 and 2.34 per 1000 person-years, respectively. The presence of OSAS was associated with higher risks of all-cause dementia (adjusted HR (aHR) 1.12, 95% CI 1.07 to 1.17), vascular dementia (1.29, 95% CI 1.19 to 1.41) and unchanged risk of Alzheimer's disease (1.07, 95% CI 0.99 to 1.16). Individuals with OSAS who had received continuous positive airway pressure (CPAP) treatment exhibited a similar risk of all-cause dementia as their matched counterparts (0.99, 95% CI 0.74 to 1.32).
CONCLUSION: OSAS is associated with higher risks of all-cause dementia and some of its subtypes. Further investigation is needed to investigate the clinical benefits of screening for cognitive impairment in people with OSAS and to further evaluate the impact of CPAP on cognitive decline and dementia risk.}, }
@article {pmid39689736, year = {2025}, author = {Rasheed, N and Hussain, HK and Rehman, Z and Sabir, A and Ashraf, W and Ahmad, T and Alqahtani, F and Imran, I}, title = {Co-administration of coenzyme Q10 and curcumin mitigates cognitive deficits and exerts neuroprotective effects in aluminum chloride-induced Alzheimer's disease in aged mice.}, journal = {Experimental gerontology}, volume = {199}, number = {}, pages = {112659}, doi = {10.1016/j.exger.2024.112659}, pmid = {39689736}, issn = {1873-6815}, mesh = {Animals ; *Curcumin/pharmacology ; *Aluminum Chloride ; *Ubiquinone/analogs & derivatives/pharmacology ; *Neuroprotective Agents/pharmacology ; Male ; Mice ; *Alzheimer Disease/drug therapy/chemically induced ; *Cognitive Dysfunction/drug therapy/chemically induced ; *Mice, Inbred BALB C ; Acetylcholinesterase/metabolism ; Antioxidants/pharmacology ; Oxidative Stress/drug effects ; Drug Therapy, Combination ; Maze Learning/drug effects ; Disease Models, Animal ; }, abstract = {Aluminum chloride (AlCl3), a known neurotoxic and Alzheimerogenic metal disrupts redox homeostasis which plays a pivotal role in pathophysiology of neurodegenerative disorders, particularly cognitive decline. The current study was designed to unveil the long-term neuroprotective outcomes and efficacy of CoQ10 and curcumin low dose (100 mg/kg each) combination in 18-months old geriatric male Balb/c mice subjected to AlCl3-prompted memory derangements (200 mg/kg in water bottles) for 28 days. The neuroprotective properties driven by antioxidant mechanisms were assessed via observing cellular pathology in key-memory related brain regions including the cornuammonis (CA3 and DG) and cortex 2/3 layer. Our outcomes revealed that AlCl3 exposure significantly reduced spatial learning and memory. In contrast, CoQ10 and curcumin combinatorial regime markedly mitigated cognitive deficits Vs. individual high-dose in AlCl3-treated animals as demonstrated by their improved performance in neurobehavioral tests such as the Y-maze, novel object recognition, passive avoidance and Morris-water maze test. Additionally, CoQ10 and curcumin co-administration restored redox balance by significantly reducing the levels of oxidative stressor (MDA) and increasing the anti-oxidant capacity (SOD,GPx). AchE is an enzyme involved in acetylcholine breakdown which negatively impacts acetylcholine levels and memory function. AlCl3 exposure elevated AchE levels in mice brains vs. treatment. This neurochemical alteration was notably reversed in the dual-treatment group. Furthermore, CoQ10 and curcumin ameliorated AlCl3-induced neurotoxicity by preserving neuronal cytoarchitecture in both cortical and hippocampal regions. In conclusion, CoQ10 and curcumin combination might attenuate memory loss induced by AlCl3-intoxication via restoring aberrant AchE activity, enhanced anti-oxidant defenses and salvaging the deleterious neuronal damage.}, }
@article {pmid39689527, year = {2025}, author = {Bernardo, AM and Marcotte, M and Wong, K and Sharmin, D and Pandey, KP and Cook, JM and Sibille, EL and Prevot, TD}, title = {Procognitive and neurotrophic benefits of α5-GABA-A receptor positive allosteric modulation in a β-amyloid deposition mouse model of Alzheimer's disease pathology.}, journal = {Neurobiology of aging}, volume = {147}, number = {}, pages = {49-59}, doi = {10.1016/j.neurobiolaging.2024.12.001}, pmid = {39689527}, issn = {1558-1497}, mesh = {Animals ; *Alzheimer Disease/metabolism/psychology/pathology/drug therapy ; *Disease Models, Animal ; *Amyloid beta-Peptides/metabolism ; Female ; Male ; *Receptors, GABA-A/metabolism ; Allosteric Regulation ; Mice, Transgenic ; Cognition/drug effects ; Somatostatin/metabolism ; Dendritic Spines/metabolism/pathology ; Memory, Short-Term/drug effects ; }, abstract = {Reduced somatostatin (SST) and SST-expressing GABAergic neurons are well-replicated findings in Alzheimer's disease (AD) and are associated with cognitive deficits. SST cells inhibit pyramidal cell dendrites through α5-GABA-A receptors (α5-GABAA-R). α5-GABAAR positive allosteric modulation (α5-PAM) has procognitive and neurotrophic effects in stress and aging models. We tested whether α5-PAM (GL-II-73) could prevent cognitive deficits and neuronal spine loss in early stages, and reverse them in late stages of β-amyloid deposition in the 5xFAD model (N = 48/study; 50 % female). Acute administration of GL-II-73 prevented spatial working memory deficits in 5xFAD mice at 2 months of age, while chronic administration reversed the deficits at 5 months of age. Chronic GL-II-73 treatment prevented 5xFAD-induced loss of spine density, spine count and dendritic length at both time points, despite β-amyloid accumulation. These results demonstrate procognitive and neurotrophic effects of GL-II-73 in early and late stages of Alzheimer-related β-amyloid deposition. This suggests α5-PAM as a novel β-amyloid-independent symptomatic therapeutic approach.}, }
@article {pmid39689408, year = {2025}, author = {Cámara-Calmaestra, R and Martínez-Amat, A and Aibar-Almazán, A and Hita-Contreras, F and de Miguel-Hernando, N and Rodríguez-Almagro, D and Jiménez-García, JD and Achalandabaso-Ochoa, A}, title = {Resistance exercise to reduce risk of falls in people with Alzheimer's disease: a randomised clinical trial.}, journal = {Physiotherapy}, volume = {126}, number = {}, pages = {101440}, doi = {10.1016/j.physio.2024.101440}, pmid = {39689408}, issn = {1873-1465}, mesh = {Humans ; *Accidental Falls/prevention & control ; *Resistance Training/methods ; *Alzheimer Disease/rehabilitation ; Male ; Female ; Aged ; Single-Blind Method ; *Activities of Daily Living ; *Muscle Strength/physiology ; *Fear ; Aged, 80 and over ; Spain ; Postural Balance ; }, abstract = {OBJECTIVES: To evaluate the impact of resistance exercise on the risk of falls, fear of falling, muscle strength, neuropsychiatric symptoms and ability to perform activities of daily living in people with Alzheimer's disease (AD).
DESIGN: Single-blinded randomised controlled trial.
SETTING: Five aged care centres specialising in AD, located in Andalucía, Spain.
PARTICIPANTS: Sixty people diagnosed with AD were assigned at random to either the intervention group (n = 30) or the control group (n = 30).
INTERVENTIONS: The intervention group completed three weekly resistance exercise sessions for 12 weeks, in addition to cognitive training, until completion of the study. The control group undertook cognitive training alone.
MAIN OUTCOME MEASURE: Main outcome measure: risk of falls (Short Physical Performance Battery).
SECONDARY OUTCOMES: muscle strength (hand dynamometry), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire), fear of falling (Activities-Specific Balance Confidence Scale) and ability to perform activities of daily living (Lawton Instrumental Activities of Daily Living Scale).
RESULTS: The analysis demonstrated differences in favour of the intervention group, in both the short and medium term, for risk of falls [post-treatment: mean difference (MD) 1.5, 95% CI of the difference 0.9 to 2.0; 3-month follow up: MD 1.1, 95% CI of the difference 0.6 to 1.6]; fear of falling (post-treatment: MD 1.5, 95% CI of the difference 4.0 to 7.7; 3-month follow up: MD 6.3, 95% CI of the difference 4.3 to 8.2); activities of daily living (post-treatment: MD 0.2, 95% CI of the difference -0.01 to 0.4; 3-month follow up: MD 0.3, 95% CI of the difference 0.01 to 0.5); neuropsychiatric symptoms (post-treatment: MD -2.2, 95% CI of the difference -3.3 to -1.0; 3-month follow up: MD -2.4, 95% CI of the difference -3.7 to -1.2); and dynamometry (post-treatment: MD 3.1, 95% CI of the difference 2.5 to 3.7; 3-month follow up: MD 2.6, 95% CI of the difference 1.9 to 3.3).
CONCLUSION: Resistance exercise effectively reduces the risk of falls, fear of falling and neuropsychiatric symptoms, and improves muscle strength in people with AD in both the short and medium term. CONTRIBUTION OF THE PAPER.}, }
@article {pmid39689077, year = {2024}, author = {Musa, MS and Islam, MT and Billah, W and Hossain, MS and Rahat, MSS and Bayil, I and Munni, YA and Ganguli, S}, title = {Structure-based virtual screening of Trachyspermum ammi metabolites targeting acetylcholinesterase for Alzheimer's disease treatment.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0311401}, pmid = {39689077}, issn = {1932-6203}, mesh = {*Alzheimer Disease/drug therapy ; *Acetylcholinesterase/metabolism/chemistry ; Humans ; *Cholinesterase Inhibitors/chemistry/pharmacology ; *Molecular Docking Simulation ; Molecular Dynamics Simulation ; Apiaceae/chemistry ; Plant Extracts/chemistry/pharmacology ; Drug Evaluation, Preclinical ; }, abstract = {In recent decades, Alzheimer's disease (AD) has garnered significant attention due to its rapid global prevalence. The cholinergic hypothesis posits that the degradation of acetylcholine by acetylcholinesterase (AChE) contributes to AD development. Despite existing anti-AChE drugs, their adverse side effects necessitate new agents. This study analyzed 150 bioactive phytochemicals from Trachyspermum ammi using structure-based drug design and various in-silico tools to identify potent anti-AChE compounds. Compounds were screened for drug-likeness (QEDw ≥50%) and bioavailability (≥55%) and underwent toxicity profiling via the ProTox-II server. Selected compounds were prepared for molecular docking with the human AChE protein as the receptor. Viridifloral, 2-Methyl-3-glucosyloxy-5-isopropyl phenol, Alpha-Curcumene, and Sterol emerged as top candidates with high AChE affinity. These results were validated by molecular dynamics simulations, confirming stable interactions. The hit compounds were further evaluated for drug-likeness using Lipinski's rule and ADMET properties, confirming favorable pharmacokinetic profiles. DFT optimization analyzed frontier molecular orbitals and electrostatic potential, demonstrating favorable chemical reactivity and stability. This study suggests that these identified compounds could be novel nature-derived AChE inhibitors, potentially contributing to AD treatment. However, further in-vitro and in-vivo studies are necessary to confirm their efficacy in biological systems. Future research will focus on developing these compounds into safe and effective drugs to combat Alzheimer's disease.}, }
@article {pmid39688618, year = {2024}, author = {Kadamangudi, S and Marcatti, M and Zhang, WR and Fracassi, A and Kayed, R and Limon, A and Taglialatela, G}, title = {Amyloid-β oligomers increase the binding and internalization of tau oligomers in human synapses.}, journal = {Acta neuropathologica}, volume = {149}, number = {1}, pages = {2}, pmid = {39688618}, issn = {1432-0533}, support = {F30AG085974/NH/NIH HHS/United States ; R01AG072883/NH/NIH HHS/United States ; R01 AG073133/AG/NIA NIH HHS/United States ; F30 AG085974/AG/NIA NIH HHS/United States ; Kempner Fellowship//University of Texas Medical Branch/ ; R21 AG089708/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; *Synapses/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; Aged ; Aged, 80 and over ; Male ; Female ; *Synaptosomes/metabolism ; Tauopathies/metabolism/pathology ; Brain/metabolism/pathology ; Protein Binding/physiology ; Middle Aged ; }, abstract = {In Alzheimer's disease (AD), the propagation and spreading of CNS tau pathology closely correlates with cognitive decline, positioning tau as an attractive therapeutic target. Amyloid beta (Aβ) has been strongly implicated in driving tau spread, whereas primary tauopathies such as primary age-related tauopathy (PART)-which lack Aβ pathology-exhibit limited tau spread and minimal-to-no cognitive decline. Emerging evidence converges on a trans-synaptic mechanism of tau spread, facilitated by the transfer of misfolded tau aggregates (e.g. soluble oligomers). However, it is unclear whether Aβ oligomers modulate the binding and internalization of tau oligomers in human synapses. Our translationally focused paradigms utilize post-mortem brain specimens from Control, PART, and AD patients. Synaptosomes isolated from the temporal cortex of all three groups were incubated with preformed recombinant tauO (rtauO), ± preformed recombinant AβO (rAβO), and oligomer binding/internalization was quantified via flow cytometry following proteinase K (PK) digestion of surface-bound oligomers. TauO-synapse interactions were visualized using EM immunogold. Brain-derived tau oligomers (BDTO) from AD and PART PBS-soluble hippocampal fractions were co-immunoprecipitated and analyzed via mass spectrometry to compare synaptic tauO interactomes in primary and secondary tauopathies, thereby inferring the role of Aβ. AD synaptosomes, enriched in endogenous Aβ pathology, exhibited increased rtauO internalization compared to PART synaptosomes. This observation was mirrored in Control synaptosomes, where recombinant rAβO significantly increased rtauO binding and internalization. PK pre-treatment abolished this effect, implicating synaptic membrane proteins in AβO-mediated tauO internalization. While both PART and AD BDTO were broadly enriched in synaptic proteins, AD BDTO exhibited differential enrichment of endocytic proteins across pre- and post-synaptic compartments, whereas PART BDTO showed no significant synaptic enrichment. This study demonstrates that Aβ oligomers enhance tau oligomer binding and drive its internalization through synaptic membrane proteins. These findings offer novel mechanistic insights underlying pathological tau spreading directly within human synapses and emphasize the therapeutic potential of targeting Aβ-tau interactions.}, }
@article {pmid39688607, year = {2024}, author = {Liapis, CC}, title = {["Pseudoneurotransmission" and gut microbiome - brain communication in neuropsychiatric disorders].}, journal = {Psychiatrike = Psychiatriki}, volume = {}, number = {}, pages = {}, doi = {10.22365/jpsych.2024.024}, pmid = {39688607}, issn = {1105-2333}, abstract = {The gut microbiome, which comprises symbiotic bacteria colonizing the human digestive tract, undergoes dynamic changes during the lifespan, as evidenced by the fact that the number of species and the diversity of their composition decrease significantly with age. The aim of this review is to illuminate bilateral neuroimmunological pathways that determine the role of gut microbiome dysbiosis, not only as a cause but also as a byproduct of many neurodegenerative diseases of the CNS, such as Alzheimer's disease (AD) and Parkinson's disease (PD), but also in the frame of several behavioral and psychiatric pathological conditions such as depressive and anxiety disorders, schizophrenia, and autism spectrum disorder (ASD). Dysbiosis, in particular, reveals a model of "deceptive" mimicry of host molecules that might cause abnormal folding ("misfolding") and pathological aggregation of Aβ-peptide, leading to its dispersion through the gut-brain axis, precipitating microglia cell activation. By controlling myelination at the prefrontal cortex (PFC), a crucial area for multifaceted cognitive behavior, forecasting, and decision-making, the gut/microbiome-brain axis influences mood and social behavior, since major depressive disorder is correlated to white matter disturbance in the PFC, due to disregulations in the expression of myelin-related mRNA in this area. The gut microbiome is altered in psychosis compared to healthy controls, while medication with antipsychotics may result in reduced microbial community diversity. The vagus nerve, as a key element of the parasympathetic nervous system, regulating immune responses, may "detect" gut microbiome metabolites and transfer this intestinal information to the CNS, through its afferents, as in a "pseudo-neurotransmission" process. Scientific interest towards microbiome-based therapies increases as psychobiotics (which are strains of probiotics/prebiotics with specific properties to influence the gut-brain axis) appear to be able to exercise a beneficial effect in many CNS disorders. Lifestyle modifications, such as dietary interventions via psychobiotics intake that might enhance the gut microbiome's ability to produce beneficial metabolites that exert therapeutic effects on intestinal permeability, cognitive function, and immunity, may reveal new research pathways and therapeutic directions leading to a radical change of the "epistemology paradigm" as far as prevention and treatment of major neuro-psychiatric disorders is concerned.}, }
@article {pmid39688557, year = {2024}, author = {Komai, M and Takasugi, N}, title = {Potential treatment of Alzheimer's disease astrocyte pathology based on nuclear lipid regulation.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01125}, pmid = {39688557}, issn = {1673-5374}, }
@article {pmid39686962, year = {2024}, author = {Nakagawa, K and Iida, T and Kobayashi, M and Shimma, S}, title = {Combination of Probe Electrospray Ionization Mass Spectrometry and Mass Spectrometry Imaging to Analyze Plant Alkaloids in Narcissus tazetta.}, journal = {Mass spectrometry (Tokyo, Japan)}, volume = {13}, number = {1}, pages = {A0163}, pmid = {39686962}, issn = {2187-137X}, abstract = {Plant alkaloids are used in a variety of medicines, such as anti-cancer drugs and analgesics. Among these plant alkaloids, galanthamine is an Amaryllidaceae type alkaloid with acetylcholinesterase inhibition activity used in the treatment of neurological diseases such as Alzheimer's disease. Although the chemical synthesis of galanthamine has been successfully achieved, Narcissus tazetta is the main source of its production. Research shows that the galanthamine content varies not only with the type of daffodil but also with the stage of development and the part of the plant. Pharmaceutical companies seek plant species with higher galanthamine content to increase pharmaceutical availability. In this study, we were able to rapidly confirm the presence of alkaloids, such as galanthamine, lycorine, and tazettine in the N. tazetta sample using the probe electrospray ionization coupled with quadrupole time-of-flight type mass spectrometry. After confirmation of the components, we then visualized the distribution of the alkaloids by mass spectrometry imaging using the atmospheric pressure matrix-assisted laser desorption/ionization mass spectrometer. In our method, we can provide qualitative data and visualized data immediately.}, }
@article {pmid39686920, year = {2025}, author = {Sodagari, S and Sodagari, N}, title = {Examining vaccination-related adverse events in frequent neurodegenerative diseases.}, journal = {Brain, behavior, & immunity - health}, volume = {43}, number = {}, pages = {100902}, pmid = {39686920}, issn = {2666-3546}, abstract = {This study investigates adverse events following vaccination in patients with four neurodegenerative diseases: Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Multiple Sclerosis (MS), and Parkinson's disease. We applied advanced data processing techniques to analyze symptom patterns and severity scores across these disease groups. Patients were identified through filtering, and symptom clusters were extracted to group similar symptoms into distinct clusters, and severity scores were computed based on hospitalization and death reports. A chi-squared test was performed to assess the statistical significance of adverse event distributions among the diseases for different vaccines. The results reveal that ALS patients exhibit severe respiratory symptoms post-vaccination, while Alzheimer's patients report significant respiratory and gastrointestinal issues. MS patients commonly experience general symptoms such as fatigue, while Parkinson's patients face exacerbated motor symptoms. Notably, our analysis showed no significant difference in adverse event reporting rates between COVID-19 and pneumococcal vaccines across these disease groups. This research provides new insights into disease-specific responses to vaccines, emphasizing the importance of personalized monitoring and treatment strategies to mitigate risks and improve clinical outcomes in these vulnerable populations.}, }
@article {pmid39686878, year = {2025}, author = {Makhaeva, GF and Grishchenko, MV and Kovaleva, NV and Boltneva, NP and Rudakova, EV and Astakhova, TY and Timokhina, EN and Pronkin, PG and Lushchekina, SV and Khudina, OG and Zhilina, EF and Shchegolkov, EV and Lapshina, MA and Dubrovskaya, ES and Radchenko, EV and Palyulin, VA and Burgart, YV and Saloutin, VI and Charushin, VN and Richardson, RJ}, title = {Conjugates of amiridine and salicylic derivatives as promising multifunctional CNS agents for potential treatment of Alzheimer's disease.}, journal = {Archiv der Pharmazie}, volume = {358}, number = {1}, pages = {e2400819}, pmid = {39686878}, issn = {1521-4184}, support = {Project No. 24-63-00016//Russian Science Foundation/ ; }, mesh = {*Alzheimer Disease/drug therapy ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Butyrylcholinesterase/metabolism ; *Acetylcholinesterase/metabolism ; Humans ; Structure-Activity Relationship ; Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Blood-Brain Barrier/metabolism ; Molecular Structure ; Dose-Response Relationship, Drug ; Molecular Docking Simulation ; Peptide Fragments/pharmacology ; Antioxidants/pharmacology/chemical synthesis/chemistry ; Aminoquinolines ; }, abstract = {New conjugates of amiridine and salicylic derivatives (salicylamide, salicylimine, and salicylamine) with different lengths of alkylene spacers were designed, synthesized, and evaluated as potential multifunctional central nervous system therapeutic agents for Alzheimer's disease (AD). Conjugates demonstrated high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition (IC50: AChE, 0.265-4.24 μM; BChE, 0.01-0.64 μM) but poor activity against off-target carboxylesterase (CES). Specifically, conjugates with a (CH2)8 spacer showed the highest AChE and BChE inhibition: 3-16 times more effective than amiridine. Salicylamides 7b and 7c had the maximum BChE/AChE selectivity ratios: 193 and 138, respectively. Conjugates were mixed-type reversible inhibitors of both cholinesterases and displaced propidium from the AChE peripheral anionic site (PAS) at the level of donepezil. All conjugates inhibited Aβ42 self-aggregation in the thioflavin test; inhibition increased with spacer elongation, being greatest for (CH2)8. The results agreed with molecular docking to AChE, BChE, and Aβ42. Conjugates exhibited high 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)[•+]-scavenging activity comparable to the standard antioxidant Trolox, and they showed the ability to bind Cu[2+], Fe[2+], and Zn[2+]. Conjugates had favorable predicted intestinal absorption and blood-brain barrier permeability. Altogether, the results indicate that the new conjugates possess potential for further development as multifunctional anti-AD drug candidates.}, }
@article {pmid39686620, year = {2025}, author = {Boada, M and Neve, A and Das, B and Wojtowicz, J and Huang, Z and Bullain, S and Watkin, M and Lott, D and Bittner, T and Delmar, P and Klein, G and Hofmann, C and Kerchner, GA and Smith, J and Baudler, M and Fontoura, P and Doody, RS}, title = {Long-term safety of gantenerumab in participants with Alzheimer's disease: A phase III, open-label extension study (SCarlet RoAD).}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {2}, pages = {528-541}, doi = {10.1177/13872877241303644}, pmid = {39686620}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects/administration & dosage ; Female ; Aged ; Double-Blind Method ; Middle Aged ; Treatment Outcome ; Aged, 80 and over ; Amyloid beta-Peptides ; }, abstract = {BACKGROUND: Gantenerumab is a fully human anti-amyloid-β (Aβ) immunoglobulin G1 monoclonal antibody for subcutaneous (SC) administration. The efficacy and safety of low-dose (105 mg or 225 mg) gantenerumab were investigated in SCarlet RoAD (SR; NCT01224106), a Phase III, double-blind (DB), placebo-controlled study in participants with prodromal Alzheimer's disease. Following a pre-planned futility analysis, SR was converted into an open-label extension (OLE) study.
OBJECTIVE: To assess the long-term safety and tolerability of SC gantenerumab at doses of up to 1200 mg every 4 weeks (Q4W) in OLE participants who previously received placebo or gantenerumab in the DB part of SR.
METHODS: Participants of the DB part of SR, who met the eligibility criteria for the OLE, were offered the opportunity to receive gantenerumab up-titrated to 1200 mg Q4W according to prespecified titration regimens. Safety and tolerability were assessed using magnetic resonance imaging (MRI), physical and neurologic examinations, and adverse event monitoring.
RESULTS: Overall, 154 participants were rolled over from the DB part of SR and received at least one dose of gantenerumab in the SR OLE. The median duration of treatment was 2.9 years (152.9 weeks). Forty-seven (30.5%) participants had an amyloid-related imaging abnormalities - edema (ARIA-E) MRI finding, and 51 (33.1%) had an ARIA - hemorrhage MRI finding. Most ARIA-E findings were asymptomatic and manageable by MRI monitoring and dose intervention. There were no unexpected safety findings.
CONCLUSIONS: SC gantenerumab at doses of up to 1200 mg Q4W was well tolerated with no unexpected safety findings in participants with prodromal Alzheimer's disease.Trial registration: ClinicalTrials.gov ID NCT01224106.}, }
@article {pmid39686618, year = {2025}, author = {García-Lluch, G and Marseglia, A and Royo, LM and Albiach, JP and Garcia-Zamora, M and Baquero, M and Peña-Bautista, C and Álvarez, L and Westman, E and Cháfer-Pericás, C}, title = {Associations between antidiabetic medications and cerebrospinal fluid biomarkers of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {3}, pages = {758-774}, doi = {10.1177/13872877241304995}, pmid = {39686618}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/drug therapy ; Male ; Female ; Aged ; *Biomarkers/cerebrospinal fluid ; Cross-Sectional Studies ; *Hypoglycemic Agents/therapeutic use ; *Amyloid beta-Peptides/cerebrospinal fluid ; *tau Proteins/cerebrospinal fluid ; Middle Aged ; *Diabetes Mellitus, Type 2/cerebrospinal fluid/drug therapy ; Aged, 80 and over ; Peptide Fragments/cerebrospinal fluid ; Metformin/therapeutic use ; Insulin/cerebrospinal fluid ; }, abstract = {BACKGROUND: It has been hypothesized that insulin resistance is pivotal in mediating amyloid and tau dysregulations in Alzheimer's disease (AD).
OBJECTIVE: To investigate the impact of different antidiabetic agents, their daily dosage intake, and treatment duration on cerebrospinal fluid (CSF) AD biomarkers among patients with type 2 diabetes.
METHODS: This cross-sectional study selected patients between 50 and 80 years with diabetes and CSF AD biomarkers screened between 2017 and 2023 in the VALCODIS Cohort. CSF biomarkers were total tau (t-tau), phosphorylated tau 181 (p-tau), and amyloid-β 42 (Aβ42). Analytical variables were obtained. Antidiabetic prescriptions were recorded in defined daily doses (DDD), according to the ATC/DDD 2021 system, and years of drug exposure duration before lumbar puncture. Logistic regressions were performed to establish the correlations between drug usage and AD biomarker alteration.
RESULTS: Among patients with diabetes, Insulin consumption was associated with lower odds of abnormal Aβ42 levels (OR 0.36 [95% CI 0.15, 0.76]) and tau pathology (OR 0.49 [95% CI 0.24-0.98]). Metformin was related to lower odds of pathological p-tau when diabetes was uncontrolled, acting on t-tau and t-tau/Aβ42 ratio when it was concomitant with insulin, and patients had controlled diabetes. Lower odds of pathological levels of tau were observed when additional oral antidiabetic drugs were added among metformin users. iSGLT2 was associated with tau pathology.
CONCLUSIONS: The impact of antidiabetics on AD-related pathological biomarkers may depend on diabetes management.}, }
@article {pmid39686614, year = {2025}, author = {Sible, IJ and Nation, DA}, title = {Comparison of visit-to-visit blood pressure variability and time in target range in predicting risk for cognitive outcomes in the SPRINT trial.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {2}, pages = {396-405}, pmid = {39686614}, issn = {1875-8908}, support = {R01 AG064228/AG/NIA NIH HHS/United States ; R01 AG060049/AG/NIA NIH HHS/United States ; R01 AG082073/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P01 AG052350/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Aged ; *Blood Pressure/physiology ; *Cognitive Dysfunction ; Risk Factors ; Antihypertensive Agents/therapeutic use ; Dementia/epidemiology ; Hypertension/drug therapy ; Blood Pressure Determination/methods ; Middle Aged ; Aged, 80 and over ; }, abstract = {BACKGROUND: Blood pressure (BP) variability (BPV) and time in target range (TTR) are emerging vascular risk factors for dementia, independent of traditionally targeted mean BP.
OBJECTIVE: Determine whether BPV or TTR is most strongly associated with cognitive risk.
METHODS: In this post hoc analysis of the SPRINT trial, 8034 participants underwent repeated BP measurement and cognitive testing at baseline and follow-up. Visit-to-visit BPV was calculated as average real variability. TTR was the percent of time in desired treatment arm target range (standard: 120-140 mmHg systolic BP; intensive: 110-130 mmHg systolic BP). Adjudicated clinical outcomes were no cognitive impairment, mild cognitive impairment (MCI), and probable dementia. We investigated a direct comparison of BPV and TTR in predicting cognitive risk, stratified by BP treatment group.
RESULTS: Elevated BPV was associated with increased risk for MCI (adjusted HR: 1.21 [95% CI 1.10, 1.33], p < 0.001) and MCI/dementia (HR: 1.17 [95% CI 1.07, 1.27], p < 0.001) in the standard group, and dementia (HR: 1.17 [95% CI 1.01, 1.36], p = 0.039) in the intensive group. Higher TTR was related to lower dementia risk (HR: 0.72 [95% CI 0.60, 0.86], p < 0.001) in the intensive group only.
CONCLUSIONS: Visit-to-visit BPV outperformed TTR in predicting risk for MCI and MCI/dementia. TTR was more strongly associated with dementia risk under intensive treatment. Findings were independent of mean BP in a cohort with rigorously controlled BP and suggest newer aspects of BP control may be harnessed to further reduce cognitive risk.
CLINICAL TRIAL INFORMATION: ClinicalTrials.gov; NCT01206062.}, }
@article {pmid39686595, year = {2024}, author = {Lauber, MV and Bellitti, M and Kapadia, K and Jasodanand, VH and Au, R and Kolachalama, VB}, title = {Global amyloid burden enhances network efficiency of tau propagation in the brain.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877241294084}, doi = {10.1177/13872877241294084}, pmid = {39686595}, issn = {1875-8908}, abstract = {BACKGROUND: Amyloid-β (Aβ) and hyperphosphorylated tau are crucial biomarkers in Alzheimer's disease (AD) pathogenesis, interacting synergistically to accelerate disease progression. While Aβ initiates cascades leading to tau hyperphosphorylation and neurofibrillary tangles, PET imaging studies suggest a sequential progression from amyloidosis to tauopathy, closely linked with neurocognitive symptoms.
OBJECTIVE: To analyze the complex interactions between Aβ and tau in AD using probabilistic graphical models, assessing how regional tau accumulation is influenced by Aβ burden.
METHODS: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Anti-Aβ Treatment in Asymptomatic Alzheimer's (A4) study were utilized, involving participants across various cognitive stages and employing both Florbetapir and Flortaucipir as tracers. Tau standardized uptake value ratio values were harmonized across studies, and participants were stratified into quantile groups based on Aβ levels. A LASSO regularized Gaussian graphical model analyzed partial correlations among brain regions to discern patterns of tau accumulation across different Aβ levels.
RESULTS: Statistical analyses revealed significant differences in tau structure among low, medium, and high Aβ groups in both ADNI and A4 cohorts, with graph metrics, such as small-world coefficient, indicating increased tau efficiency as Aβ burden increased.
CONCLUSIONS: Our findings indicate that tau accumulates more efficiently with increasing Aβ burden, highlighting an interplay that could inform development of dual-targeting therapies in AD. This study underscores the importance of Aβ and tau interactions in AD progression and supports the hypothesis that targeting both pathologies could be crucial for therapeutic interventions.}, }
@article {pmid39684920, year = {2024}, author = {Lee, WJ and Cho, KJ and Kim, GW}, title = {Mitigation of Atherosclerotic Vascular Damage and Cognitive Improvement Through Mesenchymal Stem Cells in an Alzheimer's Disease Mouse Model.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684920}, issn = {1422-0067}, support = {2021R1F1A1051450//National Research Foundation of Korea (NRF)/ ; }, mesh = {Animals ; *Alzheimer Disease/therapy/metabolism/pathology ; *Disease Models, Animal ; Mice ; *Mesenchymal Stem Cells/metabolism/cytology ; *Mesenchymal Stem Cell Transplantation/methods ; *Atherosclerosis/therapy/pathology/metabolism ; *Cognition ; Male ; Diet, High-Fat/adverse effects ; Mice, Transgenic ; Maze Learning ; Cognitive Dysfunction/therapy/etiology ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other cognitive disturbances. Patients with AD can be vulnerable to vascular damage, and damaged vessels can lead to cognitive impairment. Mesenchymal stem cell (MSC) treatment has shown potential in ameliorating AD pathogenesis, but its effect on vascular function remains unclear. This study aimed to improve cognitive function by alleviating atherosclerosis-induced vessel damage using MSCs in mice with a genetic AD background. In this study, a 5xFAD mouse model of AD was used, and atherosclerotic vessel damage was induced by high-fat diets (HFDs). MSCs were injected into the tail vein along with mannitol in 5xFAD mice on an HFD. MSCs were detected in the brain, and vascular damage was improved following MSC treatment. Behavioral tests showed that MSCs enhanced cognitive function, as measured by the Y-maze and passive avoidance tests. Additionally, muscle strength measured by the rotarod test was also increased by MSCs in AD mice with vessel damage induced by HFDs. Overall, our results suggest that stem cells can alleviate vascular damage caused by metabolic diseases, including HFDs, and vascular disease in individuals carrying the AD gene. Consequently, this alleviates cognitive decline related to vascular dementia symptoms.}, }
@article {pmid39684900, year = {2024}, author = {Vo, DK and Trinh, KTL}, title = {Emerging Biomarkers in Metabolomics: Advancements in Precision Health and Disease Diagnosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684900}, issn = {1422-0067}, mesh = {Humans ; *Metabolomics/methods ; *Precision Medicine/methods ; *Biomarkers/metabolism ; Neoplasms/metabolism/diagnosis ; Cardiovascular Diseases/metabolism/diagnosis ; Neurodegenerative Diseases/metabolism/diagnosis ; Metabolome ; Gastrointestinal Microbiome ; }, abstract = {Metabolomics has come to the fore as an efficient tool in the search for biomarkers that are critical for precision health approaches and improved diagnostics. This review will outline recent advances in biomarker discovery based on metabolomics, focusing on metabolomics biomarkers reported in cancer, neurodegenerative disorders, cardiovascular diseases, and metabolic health. In cancer, metabolomics provides evidence for unique oncometabolites that are important for early disease detection and monitoring of treatment responses. Metabolite profiling for conditions such as neurodegenerative and mental health disorders can offer early diagnosis and mechanisms into the disease especially in Alzheimer's and Parkinson's diseases. In addition to these, lipid biomarkers and other metabolites relating to cardiovascular and metabolic disorders are promising for patient stratification and personalized treatment. The gut microbiome and environmental exposure also feature among the influential factors in biomarker discovery because they sculpt individual metabolic profiles, impacting overall health. Further, we discuss technological advances in metabolomics, current clinical applications, and the challenges faced by metabolomics biomarker validation toward precision medicine. Finally, this review discusses future opportunities regarding the integration of metabolomics into routine healthcare to enable preventive and personalized approaches.}, }
@article {pmid39684747, year = {2024}, author = {Morante-Carriel, J and Nájera, H and Samper-Herrero, A and Živković, S and Martínez-Esteso, MJ and Martínez-Márquez, A and Sellés-Marchart, S and Obrebska, A and Bru-Martínez, R}, title = {Therapeutic Potential of Prenylated Flavonoids of the Fabaceae Family in Medicinal Chemistry: An Updated Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684747}, issn = {1422-0067}, support = {University of Aicante//University of Alicante/ ; }, mesh = {*Flavonoids/chemistry/pharmacology/therapeutic use ; Humans ; *Prenylation ; *Fabaceae/chemistry ; Chemistry, Pharmaceutical/methods ; Animals ; Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use ; Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; }, abstract = {Much attention has been paid to the potential biological activities of prenylated flavonoids (PFs) in various plant families over the last decade. They have enormous potential for biological activities, such as anti-cancer, anti-diabetic, antimicrobial, anti-inflammatory, anti-Alzheimer's, and neuroprotective activities. Medicinal chemists have recently shown a strong interest in PFs, as they are critical to the development of new medicines. PFs have been rapidly prepared by isolation and semi- or full synthesis, demonstrating their significant utility in medicinal chemistry research. This study encompasses the research progress on PFs in the last decade, including their pharmacological activities in the Fabaceae family. This information demonstrates the bioactive potential of PF compounds and their role in the control and treatment of various human health problems.}, }
@article {pmid39684512, year = {2024}, author = {Żołek, T and Purgatorio, R and Kłopotowski, Ł and Catto, M and Ostrowska, K}, title = {Coumarin Derivative Hybrids: Novel Dual Inhibitors Targeting Acetylcholinesterase and Monoamine Oxidases for Alzheimer's Therapy.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684512}, issn = {1422-0067}, mesh = {*Coumarins/chemistry/pharmacology ; *Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology/therapeutic use ; *Monoamine Oxidase/metabolism/chemistry ; Humans ; *Molecular Docking Simulation ; *Acetylcholinesterase/metabolism/chemistry ; Molecular Dynamics Simulation ; Structure-Activity Relationship ; Protein Binding ; }, abstract = {Multi-target-directed ligands (MTDLs) represent a promising frontier in tackling the complexity of multifactorial pathologies like Alzheimer's disease (AD). The synergistic inhibition of MAO-B, MAO-A, and AChE is believed to enhance treatment efficacy. A novel coumarin-based molecule substituted with O-phenylpiperazine via three- and four-carbon linkers at the 5- and 7-positions, has been identified as an effective MTDL against AD. Employing a medicinal chemistry approach, combined with molecular docking, molecular dynamic simulation, and ΔGbind estimation, two series of derivatives emerged as potent MTDLs: 8-acetyl-7-hydroxy-4-methylcoumarin (IC50: 1.52-4.95 μM for hAChE, 6.97-7.65 μM for hMAO-A) and 4,7-dimethyl-5-hydroxycoumarin (IC50: 1.88-4.76 μM for hMAO-B). They displayed binding free energy (ΔGbind) of -76.32 kcal/mol (11) and -70.12 kcal/mol (12) against AChE and -66.27 kcal/mol (11) and -62.89 kcal/mol (12) against MAO-A. It is noteworthy that compounds 11 and 12 demonstrated efficient binding to both AChE and MAO-A, while compounds 3 and 10 significantly reduced MAO-B and AChE aggregation in vitro. These findings provide structural templates for the development of dual MAO and AChE inhibitors for the treatment of neurodegenerative diseases.}, }
@article {pmid39684486, year = {2024}, author = {Lazarova, M and Stefanova, M and Tsvetanova, E and Georgieva, A and Tasheva, K and Radeva, L and Yoncheva, K}, title = {Resveratrol-Loaded Pluronic Micelles Ameliorate Scopolamine-Induced Cognitive Dysfunction Targeting Acetylcholinesterase Activity and Programmed Cell Death.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684486}, issn = {1422-0067}, support = {KP-06-N 73/10//Bulgarian Science Fund/ ; }, mesh = {Animals ; *Resveratrol/pharmacology/administration & dosage ; *Micelles ; *Acetylcholinesterase/metabolism ; *Scopolamine ; Male ; Rats ; *Cognitive Dysfunction/drug therapy/chemically induced/metabolism ; *Rats, Wistar ; *Apoptosis/drug effects ; *Poloxamer/chemistry ; *Hippocampus/drug effects/metabolism ; Maze Learning/drug effects ; Disease Models, Animal ; }, abstract = {Numerous experimental studies suggest the potential for resveratrol (RVT) to be useful in the Alzheimer's disease treatment, but its low bioavailability limits its application. This study aimed to assess the potential of resveratrol-loaded micelles as a neuronal delivery platform to protect rats from scopolamine-induced memory impairment. Resveratrol was incorporated into Pluronic micelles, and the effects of micellar (mRVT) and pure resveratrol (RVT) were compared in the model of scopolamine-induced dementia in male Wistar rats. Memory performance was assessed by a T maze test. The effect of the treatment on specific neurotransmitter levels and protein expression in the cortex and the hippocampus were evaluated biochemically. Our results revealed that the polymeric micelles were in nanoscale (approximately 33 nm) and reached 79% encapsulation efficiency. The treatment with mRVT demonstrated better spatial memory protective effect. The biochemical assays showed that mRVT in a dose of 10 mg/kg enhanced the effects of the pure drug in regard to noradrenalin neurotransmission and acetylcholinesterase inhibitory activity in the hippocampus. Furthermore, micellar resveratrol increased the cAMP-response element-binding protein expression in the cortex and hippocampus of rats as well as the Bcl2/BAX ratio, which indicated an anti-apoptotic effect in the experimental dementia model. In conclusion, our results indicated the potential of a micellar system loaded with resveratrol for neurodegenerative diseases treatment.}, }
@article {pmid39684482, year = {2024}, author = {Iwaya, N and Sakudo, A and Kanda, T and Furusaki, K and Onishi, R and Onodera, T and Yoshikawa, Y}, title = {Degradation and/or Dissociation of Neurodegenerative Disease-Related Factor Amyloid-β by a Suspension Containing Calcium Hydrogen Carbonate Mesoscopic Crystals.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684482}, issn = {1422-0067}, support = {37//Wesco (Japan)/ ; 20K03919//Japan Society for the Promotion of Science/ ; 24K07444//Japan Society for the Promotion of Science/ ; }, mesh = {*Amyloid beta-Peptides/metabolism/chemistry ; Humans ; Protein Aggregates ; Peptide Fragments/chemistry/metabolism ; Alzheimer Disease/metabolism ; Neurodegenerative Diseases/metabolism ; Proteolysis ; }, abstract = {Amyloid-β (Aβ) aggregates accumulate in the brains of individuals with Alzheimer's disease and are thought to potentially act as prions, promoting further aggregation. Consequently, the biochemistry of Aβ has emerged as a promising target for Alzheimer's disease. CAC-717, a suspension of calcium bicarbonate mesoscopic structures derived from natural sources, has been shown to inactivate various pathogens, including prions. This study examined the effects of CAC-717 on both the formation and degradation/dissociation of Aβ aggregates using thioflavin T fluorescence and enzyme-linked immunosorbent assays. Aggregates of Aβ(1-42) peptide were generated by incubation at 37 °C for 24 h, and the effect of introducing CAC-717 on the aggregates was evaluated after further incubation at 25 °C for 30 min. Moreover, CAC-717 was also tested for its ability to inhibit the initial aggregation of Aβ. The results showed that CAC-717 significantly degraded and/or dissociated Aβ aggregates in a concentration-dependent manner. Specifically, CAC-717 treatment for 5 min disrupted Aβ aggregates to give Aβ monomer and oligomer concentrations as high as 130 nM compared to ~10 nM for the water control. In addition, CAC-717 degraded and/or dissociated aggregates within 10 s at 37 °C, and pre-treatment with CAC-717 significantly inhibited aggregation. These results suggest that CAC-717 not only degrades and/or dissociates Aβ aggregates but also inhibits their formation, highlighting its potential as a disinfectant for Alzheimer's disease.}, }
@article {pmid39684447, year = {2024}, author = {Bukowska, B}, title = {Current and Potential Use of Biologically Active Compounds Derived from Cannabis sativa L. in the Treatment of Selected Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684447}, issn = {1422-0067}, support = {B2011000000191.01//University of Lodz/ ; }, mesh = {Humans ; *Cannabis/chemistry ; Cannabinoids/therapeutic use/pharmacology ; Neoplasms/drug therapy ; Animals ; Plant Extracts/pharmacology/therapeutic use/chemistry ; COVID-19 Drug Treatment ; COVID-19/virology ; Cannabidiol/therapeutic use/pharmacology ; SARS-CoV-2/drug effects ; }, abstract = {Cannabis sativa L. contains numerous compounds with antioxidant and anti-inflammatory properties, including the flavonoids and the cannabinoids, particularly Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabinoids have an effect on the endocannabinoid system (ECS), a cellular communication network, and are, hence, widely studied for medical applications. Epidiolex[®], a 99% pure oral CBD extract, has been approved by the FDA for the treatment of epilepsy. Nabiximols (Sativex) is an oromucosal spray containing equal volume of THC and CBD, and it is commonly used as an add-on treatment for unresponsive spasticity in multiple sclerosis (MS) patients. Several in vitro and in vivo studies have also shown that cannabinoids can be used to treat various types of cancer, such as melanoma and brain glioblastoma; the first positive clinical trials on the anticancer effect of a THC:CBD blend with temozolomide (TMZ) in the treatment of highly invasive brain cancer are very promising. The cannabinoids exert their anticancer properties in in vitro investigations by the induction of cell death, mainly by apoptosis and cytotoxic autophagy, and the inhibition of cell proliferation. In several studies, cannabinoids have been found to induce tumor regression and inhibit angiogenic mechanisms in vitro and in vivo, as well as in two low-numbered epidemiological studies. They also exhibit antiviral effects by inhibiting ACE2 transcription, blocking viral replication and fusion, and acting as anti-inflammatory agents; indeed, prior CBD consumption (a study of 93,565 persons in Chicago) has also been associated with a much lower incidence of SARS-CoV-2 infections. It is postulated that cannabis extracts can be used in the treatment of many other diseases such as systemic lupus erythematosus, type 1 diabetes, or various types of neurological disorders, e.g., Alzheimer's disease. The aim of this review is to outline the current state of knowledge regarding currently used medicinal preparations derived from C. sativa L. in the treatment of selected cancer and viral diseases, and to present the latest research on the potential applications of its secondary metabolites.}, }
@article {pmid39684324, year = {2024}, author = {Toader, C and Tataru, CP and Munteanu, O and Serban, M and Covache-Busuioc, RA and Ciurea, AV and Enyedi, M}, title = {Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer's, Parkinson's, and ALS.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684324}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/genetics ; *Parkinson Disease/therapy/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; Animals ; Neurodegenerative Diseases/therapy/metabolism/genetics ; Drug Delivery Systems ; Gene Editing ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions. This review synthesizes the latest insights into the underlying molecular dynamics of neurodegeneration, revealing how intertwined pathways drive the course of these diseases. With an eye on the most promising advances, we explore innovative therapies emerging from cutting-edge research: nanotechnology-based drug delivery systems capable of navigating the blood-brain barrier, gene-editing tools like CRISPR designed to correct harmful genetic variants, and stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored therapies that align with individual genetic profiles, while molecular diagnostics and biomarkers are ushering in an era of early, precise disease detection. Furthermore, novel perspectives on the gut-brain axis are sparking interest as mounting evidence suggests that microbiome modulation may play a role in reducing neuroinflammatory responses linked to neurodegenerative progression. Taken together, these advances signal a shift toward a comprehensive, personalized approach that could transform neurodegenerative care. By integrating molecular insights and innovative therapeutic techniques, this review offers a forward-looking perspective on a future where treatments aim not just to manage symptoms but to fundamentally alter disease progression, presenting renewed hope for improved patient outcomes.}, }
@article {pmid39684197, year = {2024}, author = {García-González, N and Gonçalves-Sánchez, J and Gómez-Nieto, R and Gonçalves-Estella, JM and López, DE}, title = {Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684197}, issn = {1422-0067}, mesh = {Humans ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics ; Animals ; Amyotrophic Lateral Sclerosis/therapy/genetics ; }, abstract = {This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson's disease (n = 12), spinal muscular atrophy (n = 8), Huntington's disease (n = 3), Alzheimer's disease (n = 3), and amyotrophic lateral sclerosis (n = 6). For each condition, we assessed the therapeutic approach, curative or disease-modifying potential, delivery methods, advantages, drawbacks, and side effects. Results indicate that gene therapies targeting specific genes are particularly effective in monogenic disorders, with promising clinical outcomes expected in the near future. In contrast, in polygenic diseases, therapies primarily aim to promote cell survival. A major challenge remains: the translation of animal model success to human clinical application. Additionally, while intracerebral delivery methods enhance therapeutic efficacy, they are highly invasive. Despite these hurdles, gene therapy represents a promising frontier in the treatment of neurodegenerative diseases, underscoring the need for continued research to refine and personalize treatments for each condition.}, }
@article {pmid39683904, year = {2024}, author = {Puranik, N and Song, M}, title = {Glutamate: Molecular Mechanisms and Signaling Pathway in Alzheimer's Disease, a Potential Therapeutic Target.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {23}, pages = {}, pmid = {39683904}, issn = {1420-3049}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Signal Transduction/drug effects ; *Glutamic Acid/metabolism ; *Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; Cholinesterase Inhibitors/therapeutic use/pharmacology ; Animals ; Molecular Targeted Therapy ; }, abstract = {Gamma-glutamate is an important excitatory neurotransmitter in the central nervous system (CNS), which plays an important role in transmitting synapses, plasticity, and other brain activities. Nevertheless, alterations in the glutamatergic signaling pathway are now accepted as a central element in Alzheimer's disease (AD) pathophysiology. One of the most prevalent types of dementia in older adults is AD, a progressive neurodegenerative illness brought on by a persistent decline in cognitive function. Since AD has been shown to be multifactorial, a variety of pharmaceutical targets may be used to treat the condition. N-methyl-D-aspartic acid receptor (NMDAR) antagonists and acetylcholinesterase inhibitors (AChEIs) are two drug classes that the Food and Drug Administration has authorized for the treatment of AD. The AChEIs approved to treat AD are galantamine, donepezil, and rivastigmine. However, memantine is the only non-competitive NMDAR antagonist that has been authorized for the treatment of AD. This review aims to outline the involvement of glutamate (GLU) at the molecular level and the signaling pathways that are associated with AD to demonstrate the drug target therapeutic potential of glutamate and its receptor. We will also consider the opinion of the leading authorities working in this area, the drawback of the existing therapeutic strategies, and the direction for the further investigation.}, }
@article {pmid39683869, year = {2024}, author = {Petkova-Kirova, P and Anastassova, N and Minchev, B and Uzunova, D and Grigorova, V and Tsvetanova, E and Georgieva, A and Alexandrova, A and Stefanova, M and Yancheva, D and Kalfin, R and Tancheva, L}, title = {Behavioral and Biochemical Effects of an Arylhydrazone Derivative of 5-Methoxyindole-2-Carboxylic Acid in a Scopolamine-Induced Model of Alzheimer's Type Dementia in Rats.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {23}, pages = {}, pmid = {39683869}, issn = {1420-3049}, support = {project No BG-RRP-2.004-0002, "BiOrgaMCT"//European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria/ ; Young scientists project grant number KP06-M59/2//National Science Fund of Bulgaria/ ; }, mesh = {Animals ; *Scopolamine/adverse effects ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Rats ; *Disease Models, Animal ; Male ; *Oxidative Stress/drug effects ; *Hydrazones/pharmacology/chemistry ; *Indoles/pharmacology/chemistry ; Neuroprotective Agents/pharmacology/chemistry ; Maze Learning/drug effects ; Antioxidants/pharmacology ; Behavior, Animal/drug effects ; Hippocampus/drug effects/metabolism ; Memory/drug effects ; Rats, Wistar ; Lipid Peroxidation/drug effects ; Acetylcholinesterase/metabolism ; }, abstract = {Alzheimer's disease (AD) has long proven to be a complex neurodegenerative disorder, with cholinergic dysfunction, oxidative stress, and neuroinflammation being just a few of its pathological features. The complexity of the disease requires a multitargeted treatment covering its many aspects. In the present investigation, an arylhydrazone derivative of 5-methoxyindole-2-carboxylic acid (5MeO), with in vitro strong antioxidant, neuroprotective and monoamine oxidase B-inhibiting effects, was studied in a scopolamine-induced Alzheimer-type dementia in rats. Using behavioral and biochemical methods, we evaluated the effects of 5MeO on learning and memory, and elucidated the mechanisms of these effects. Our experiments demonstrated that 5MeO had a beneficial effect on different types of memory as assessed by the step-through and the Barnes maze tasks. It efficiently restored the decreased by scopolamine brain-derived neurotrophic factor and acetylcholine levels and normalized the increased by scopolamine acetylcholine esterase activity in hippocampus. Most effective 5MeO was in counteracting the induced by scopolamine oxidative stress by decreasing the increased by scopolamine levels of lipid peroxidation and by increasing the reduced by scopolamine catalase activity. Blood biochemical analyses demonstrated a favorable safety profile of 5MeO, prompting further pharmacological studies suggesting 5MeO as a safe and efficient candidate in a multitargeted treatment of AD.}, }
@article {pmid39683859, year = {2024}, author = {Guo, F and Qin, X and Mao, J and Xu, Y and Xie, J}, title = {Potential Protective Effects of Pungent Flavor Components in Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {23}, pages = {}, pmid = {39683859}, issn = {1420-3049}, support = {32072344//National Natural Science Foundation of China/ ; 82101506//National Natural Science Foundation of China/ ; 32272455//National Natural Science Foundation of China/ ; 2023000CC0140//the Scientific project of Beijing Life Science Academy/ ; 2023M733887//China Postdoctoral Science Foundation/ ; 110202102001//the Scientific and Technological Project of CNTC/ ; }, mesh = {Animals ; Humans ; Alkaloids/pharmacology/therapeutic use ; Benzodioxoles/pharmacology/therapeutic use ; Cannabinoids/therapeutic use/pharmacology ; Capsaicin/therapeutic use/pharmacology ; Curcumin/therapeutic use/pharmacology ; Disulfides/therapeutic use/pharmacology ; Flavoring Agents/pharmacology ; *Neurodegenerative Diseases/drug therapy/prevention & control ; *Neuroprotective Agents/therapeutic use/pharmacology ; Nicotine ; Piperidines/therapeutic use/pharmacology ; *Plant Extracts/pharmacology/therapeutic use/chemistry ; Polyunsaturated Alkamides/pharmacology ; Signal Transduction/drug effects ; Sulfinic Acids/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) have become a major global health burden, but the detailed pathogeneses of neurodegenerative diseases are still unknown, and current treatments are mainly aimed at controlling symptoms; there are no curative treatments for neurodegenerative diseases or treatments for the progressive cognitive, behavioral, and functional impairments that they cause. Studies have shown that some plant extracts with pungent flavor components have a certain neuroprotective effect in neurodegenerative diseases, and their mechanisms mainly involve inhibiting neuronal apoptosis, promoting neuronal regeneration, reducing mitochondrial degeneration, and reducing the production of oxides such as reactive oxygen species in cells, which are of great significance for exploring the treatment of neurodegenerative diseases. In this review, we searched the PubMed database for relevant literature collected in the past 15 years. Finally, we summarized the protective effects of pungent flavor components such as capsaicin, piperine, curcumin, cannabinoids, allicin, and nicotine on the nervous system, focusing on the molecular mechanisms and signaling pathways that they activate. In addition, we also compiled and summarized the laboratory experiments, preclinical experiments, and effects of various pungent flavor components in neurodegenerative diseases. The goal is to further explore their potential as effective drugs for the treatment of neurodegenerative diseases and provide new ideas for further research on the specific protective mechanisms of these substances for the treatment of neurodegenerative diseases and the targets of drug action in the future.}, }
@article {pmid39683603, year = {2024}, author = {Mohammadnezhad, P and Valdés, A and Cifuentes, A}, title = {Optimization and Chemical Characterization of Extracts Obtained from Ferula persica var. latisecta Aerial Parts and Roots and Their Neuroprotective Evaluation.}, journal = {Nutrients}, volume = {16}, number = {23}, pages = {}, pmid = {39683603}, issn = {2072-6643}, support = {PID2020-113050RB-I00//Ministry of Science and Innovation of Spain/ ; }, mesh = {*Ferula/chemistry ; *Plant Roots/chemistry ; *Plant Extracts/pharmacology/chemistry ; *Neuroprotective Agents/pharmacology/chemistry/isolation & purification ; *Plant Components, Aerial/chemistry ; *Cholinesterase Inhibitors/pharmacology/isolation & purification ; Acetylcholinesterase/metabolism ; Antioxidants/pharmacology ; Solvents/chemistry ; Butyrylcholinesterase/metabolism ; Phenols/pharmacology/analysis ; Molecular Docking Simulation ; }, abstract = {BACKGROUND/OBJECTIVES: The genus Ferula has been traditionally used for the treatment of various illnesses, but the potential of Ferula persica var. latisecta against different Alzheimer's disease (AD) hallmarks has never been achieved.
METHODS: In this work, a pressurized liquid extraction (PLE) method was optimized to extract F. persica L. aerial parts and roots. Four different solvents (water, ethanol, ethyl acetate (EtAc), and cyclopentyl methyl ether (CPME)) were first tested, and the extraction yield, total phenolic content, reactive oxygen species scavenging capacity, and acetylcholinesterase (AChE) inhibition activity were evaluated.
RESULTS: The results indicated that EtAc and CPME were the best solvents to be used, with the results obtained from the aerial parts being better than those obtained from the root samples. Thereafter, the PLE method was further optimized by combining these solvents in different percentages (100% EtAc, 100% CPME, and 50:50% (v/v) EtAc:CPME) and temperatures (50, 115, and 180 °C). Response surface methodology was then applied to analyze the data, and two optimum extraction conditions were obtained: EtAc:CPME (79:21%) at 180 °C for the aerial parts and 100% CPME at 180 °C for the roots. At these conditions, the total flavonoid content (TFC) and the inhibitory capacities against butyrylcholinesterase (BChE) and lipoxygenase (LOX) enzymes were also evaluated, indicating that the aerial part extracts had higher TFC and LOX inhibitory capacity than the root extracts but lower activity against BChE. The comprehensive LC/GC-MS chemical characterization allowed for the tentative identification of 222 compounds belonging to 66 chemical subclasses, the abundancies of which widely varied depending on the matrix and the extraction conditions used.
CONCLUSIONS: The results obtained together with the application of advanced statistical analysis and molecular docking simulations suggested several sesquiterpenoids, such as selina-3,7(11)-diene, guaiol acetate, α-cyperone, and farnesyl acetate, as the molecules responsible of the in vitro results observed, with good neuroprotective potential against AD.}, }
@article {pmid39683594, year = {2024}, author = {Minuti, A and Mazzon, E and Iori, R and Chiricosta, L and Artimagnella, O}, title = {Bioactivated Glucoraphanin Improves Cell Survival, Upregulating Phospho-AKT, and Modulates Genes Involved in DNA Repair in an In Vitro Alzheimer's Disease Model: A Network-Transcriptomic Analysis.}, journal = {Nutrients}, volume = {16}, number = {23}, pages = {}, pmid = {39683594}, issn = {2072-6643}, support = {Current Research Funds 2024//Ministero della Salute/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Sulfoxides/pharmacology ; *Cell Survival/drug effects ; *DNA Repair/drug effects ; *Proto-Oncogene Proteins c-akt/metabolism ; *Oximes/pharmacology ; *Glucosinolates/pharmacology ; *Amyloid beta-Peptides/metabolism ; Imidoesters/pharmacology ; Up-Regulation/drug effects ; Cell Line, Tumor ; Isothiocyanates/pharmacology ; Gene Expression Profiling ; Neuroprotective Agents/pharmacology ; Neurons/drug effects/metabolism ; Phosphorylation ; Transcriptome/drug effects ; }, abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, for which a definitive cure is still missing. Recently, natural compounds have been investigated for their possible neuroprotective role, including the bioactivated product of glucoraphanin (GRA), the sulforaphane (SFN), which is highly rich in cruciferous vegetables. It is known that SFN alleviates neuronal dysfunction, apoptosis, and oxidative stress in the brain. In the light of this evidence, the aim of this study was to investigate the molecular effects of SFN pre-treatment in differentiated SH-SY5Y neurons exposed to β-amyloid (Aβ).
METHODS: To this end, we first evaluated first cell viability via the Thiazolyl Blue Tetrazolium Bromide (MTT) assay, and then we analyzed the transcriptomic profiles by next-generation sequencing (NGS). Finally, we used a network analysis in order to understand which biological processes are affected, validating them by Western blot assay.
RESULTS: SFN pre-treatment counteracted Aβ-induced loss of cell viability. The network-transcriptomic analysis revealed that SFN upregulates genes associated with DNA repair, such as ABRAXAS1, BRCA1, BRCA2, CDKN1A, FANCA, FANCD2, FANCE, NBN, and XPC. Finally, SFN also increased the phosphorylation of AKT, which is associated with DNA repair and cell survival.
CONCLUSIONS: These data suggest that SFN is a natural compound that could be suitable in the prevention of AD, thanks to its neuroprotective role in increasing cell survival, potentially restoring DNA damage induced by Aβ exposure.}, }
@article {pmid39683582, year = {2024}, author = {Medina-Vera, D and López-Gambero, AJ and Verheul-Campos, J and Navarro, JA and Morelli, L and Galeano, P and Suárez, J and Sanjuan, C and Pacheco-Sánchez, B and Rivera, P and Pavon-Morón, FJ and Rosell-Valle, C and Fonseca, FR}, title = {Therapeutic Efficacy of the Inositol D-Pinitol as a Multi-Faceted Disease Modifier in the 5×FAD Humanized Mouse Model of Alzheimer's Amyloidosis.}, journal = {Nutrients}, volume = {16}, number = {23}, pages = {}, pmid = {39683582}, issn = {2072-6643}, support = {"DTS22/00021" and "PI22/00427"//Instituto de Salud Carlos III/ ; RTC2019-007329-1//Ministerio de Ciencia, Innovación y Universidades/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Disease Models, Animal ; *Inositol/pharmacology/analogs & derivatives ; Mice ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Humans ; tau Proteins/metabolism ; Amyloidosis/drug therapy ; Cognition/drug effects ; Gastrointestinal Microbiome/drug effects ; Hippocampus/drug effects/metabolism ; Phosphorylation/drug effects ; Male ; Insulin Resistance ; }, abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD), a leading cause of dementia, lacks effective long-term treatments. Current therapies offer temporary relief or fail to halt its progression and are often inaccessible due to cost. AD involves multiple pathological processes, including amyloid beta (Aβ) deposition, insulin resistance, tau protein hyperphosphorylation, and systemic inflammation accelerated by gut microbiota dysbiosis originating from a leaky gut. Given this context, exploring alternative therapeutic interventions capable of addressing the multifaceted components of AD etiology is essential.
METHODS: This study suggests D-Pinitol (DPIN) as a potential treatment modifier for AD. DPIN, derived from carob pods, demonstrates insulin-sensitizing, tau hyperphosphorylation inhibition, and antioxidant properties. To test this hypothesis, we studied whether chronic oral administration of DPIN (200 mg/kg/day) could reverse the AD-like disease progression in the 5×FAD mice.
RESULTS: Results showed that treatment of 5×FAD mice with DPIN improved cognition, reduced hippocampal Aβ and hyperphosphorylated tau levels, increased insulin-degrading enzyme (IDE) expression, enhanced pro-cognitive hormone circulation (such as ghrelin and leptin), and normalized the PI3K/Akt insulin pathway. This enhancement may be mediated through the modulation of cyclin-dependent kinase 5 (CDK5). DPIN also protected the gut barrier and microbiota, reducing the pro-inflammatory impact of the leaky gut observed in 5×FAD mice. DPIN reduced bacterial lipopolysaccharide (LPS) and LPS-associated inflammation, as well as restored intestinal proteins such as Claudin-3. This effect was associated with a modulation of gut microbiota towards a more balanced bacterial composition.
CONCLUSIONS: These findings underscore DPIN's promise in mitigating cognitive decline in the early AD stages, positioning it as a potential disease modifier.}, }
@article {pmid39683391, year = {2024}, author = {Nie, RZ and Luo, HM and Liu, YP and Wang, SS and Hou, YJ and Chen, C and Wang, H and Lv, HL and Tao, XY and Jing, ZH and Zhang, HK and Li, PF}, title = {Food Functional Factors in Alzheimer's Disease Intervention: Current Research Progress.}, journal = {Nutrients}, volume = {16}, number = {23}, pages = {}, pmid = {39683391}, issn = {2072-6643}, support = {No. 24A550019//Key Scientific Research Projects of Colleges and Universities in Henan Province/ ; 242102110106//Key Scientific and Technological Project of Henan Province/ ; 2022BSJJZK06//Doctoral Scientific Research Foundation of Zhengzhou University of Light Industry/ ; 2024XNQNPY15//Youth Cultivation Fund Project of Zhengzhou University of Light Industry/ ; }, mesh = {Animals ; Humans ; *Alzheimer Disease/diet therapy/prevention & control ; Antioxidants ; Cognition/drug effects ; Dietary Supplements ; Fatty Acids, Unsaturated/administration & dosage ; *Functional Food ; *Melatonin/administration & dosage ; Neuroprotective Agents/administration & dosage ; Oxidative Stress/drug effects ; *Polyphenols/administration & dosage ; Polysaccharides/administration & dosage ; }, abstract = {Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease. With the escalating aging of the global population, the societal burden of this disease is increasing. Although drugs are available for the treatment of AD, their efficacy is limited and there remains no effective cure. Therefore, the identification of safe and effective prevention and treatment strategies is urgently needed. Functional factors in foods encompass a variety of natural and safe bioactive substances that show potential in the prevention and treatment of AD. However, current research focused on the use of these functional factors for the prevention and treatment of AD is in its initial stages, and a complete theoretical and application system remains to be determined. An increasing number of recent studies have found that functional factors such as polyphenols, polysaccharides, unsaturated fatty acids, melatonin, and caffeine have positive effects in delaying the progression of AD and improving cognitive function. For example, polyphenols exhibit antioxidant, anti-inflammatory, and neuroprotective effects, and polysaccharides promote neuronal growth and inhibit inflammation and oxidative stress. Additionally, unsaturated fatty acids inhibit Aβ production and Tau protein phosphorylation and reduce neuroinflammation, and melatonin has been shown to protect nerve cells and improve cognitive function by regulating mitochondrial homeostasis and autophagy. Caffeine has also been shown to inhibit inflammation and reduce neuronal damage. Future research should further explore the mechanisms of action of these functional factors and develop relevant functional foods or nutritional supplements to provide new strategies and support for the prevention and treatment of AD.}, }
@article {pmid39683070, year = {2024}, author = {Rodrigues, T and Lima, A and Wortham, T and Arruda, F and Janeiro, A and Baptista, J and Lima, E}, title = {Essential Oil Composition and Anti-Cholinesterase Properties of Cryptomeria japonica Foliage Harvested in São Miguel Island (Azores) in Two Different Seasons.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {23}, pages = {}, pmid = {39683070}, issn = {2223-7747}, support = {M1.1.C/PROJ.EXPLORATÓRIOS/003/2022 - PotBioCJap//Direção Regional da Ciência e Tecnologia (DRCT)/ ; }, abstract = {The Azorean Cryptomeria japonica forest operations and wood industry generate considerable foliage biomass residues that are used for local essential oil (EO) production. However, research on seasonal variation of C. japonica EO remains scarce. In this study, the EOs from fresh Azorean C. japonica foliage (Az-CJF) collected in autumn (Aut) and spring (Spr) were obtained via hydrodistillation and investigated for their physical properties, yield, chemical composition, and bioactivities. Both EOs presented a strong odor, a yellowish color, a density around 0.9 g·mL[-1], and similar yields (approximately 1% v/w, dry matter). Nevertheless, the GC-MS analyses showed a decrease in monoterpene hydrocarbons (MH) and an increase in oxygenated sesquiterpenes (OS) contents in Spr-EO compared with Aut-EO (16% vs. 35% for MH and 45% vs. 31% for OS, respectively). In addition, the predominant components were kaur-16-ene (23%) for Spr-EO and phyllocladene (19%) for Aut-EO, revealing that both EOs were rich in diterpene hydrocarbons (29% vs. 26%). Concerning its toxicity against brine shrimp, a low mortality (0-38%) was observed at a concentration range of 100-180 μg·mL[-1]. Regarding the anti-cholinesterase properties, both EOs were inactive against acetylcholinesterase but showed anti-butyrylcholinesterase activity superior to (-)-α-pinene, a major compound of Az-CJF EO (IC50 values: 84, 148, and 648 μg·mL[-1] for Spr-EO, Aut-EO, and α-pinene, respectively). Overall, the results indicate the potential benefit of both seasonal EOs in Alzheimer's disease treatment. In conclusion, this study demonstrated that season strongly influences the Az-CJF EO quantitative composition and thus its bioactivity, aiding in the selection of the most high-quality raw materials for use in Azorean C. japonica EO aromatherapy industry.}, }
@article {pmid39682936, year = {2024}, author = {González-Manzano, S and Ayuda-Durán, B and Martín-Sanz, R and Garzón-García, L and Santos-Buelga, C and González-Paramás, AM}, title = {Exploring the Neuroprotective Effects of Grape Seed Procyanidins on Amyloid-β-Induced Toxicity in Caenorhabditis elegans.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {23}, pages = {}, pmid = {39682936}, issn = {2304-8158}, support = {PID2019-106167RB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; Project SA106P24//Consejería de Educación de la Junta de Castilla y León/ ; }, abstract = {Alzheimer's disease (AD), a major neurodegenerative disorder, is characterized by the progressive accumulation of amyloid-β (Aβ) plaques, leading to cognitive decline. Despite the existing treatments, their limited efficacy highlights the urgent need for novel therapeutic strategies. The present study investigates the neuroprotective effects of a grape seed polyphenol extract (GSPE) on transgenic Caenorhabditis elegans models specifically expressing human Aβ proteins. The obtained results show that GSPE not only significantly attenuates Aβ-induced paralysis but also extends the lifespan and improves sensory responses in these models, suggesting improved neural function and overall health. Additionally, GSPE treatment reduces proteasomal activity, which could lead to a reduction in the accumulation of misfolded proteins. It also modulates the expression of key genes involved in autophagy and proteostasis, thereby enhancing cellular mechanisms to manage protein aggregation and combat oxidative stress. On the whole, these findings support the potential of grape seed procyanidins (the main components in the extract) to be used as an effective dietary approach to mitigate Alzheimer's disease pathology through the modulation of critical neuroprotective pathways.}, }
@article {pmid39682726, year = {2024}, author = {Sundstrom, J and Vanderleeden, E and Barton, NJ and Redick, SD and Dawes, P and Murray, LF and Olson, MN and Tran, K and Chigas, SM and Orszulak, AR and Church, GM and Readhead, B and Oh, HS and Harlan, DM and Knipe, DM and Wang, JP and Chan, Y and Lim, ET}, title = {Herpes Simplex Virus 1 Infection of Human Brain Organoids and Pancreatic Stem Cell-Islets Drives Organoid-Specific Transcripts Associated with Alzheimer's Disease and Autoimmune Diseases.}, journal = {Cells}, volume = {13}, number = {23}, pages = {}, pmid = {39682726}, issn = {2073-4409}, support = {U01AG061835/NH/NIH HHS/United States ; COE-2020-967-M-N/JDRF/Breakthrough T1D/United States ; U01 AG061835/AG/NIA NIH HHS/United States ; U01AG088673/NH/NIH HHS/United States ; P01AI09681/NH/NIH HHS/United States ; P01 AI098681/AI/NIAID NIH HHS/United States ; U01 AG088673/AG/NIA NIH HHS/United States ; R01AG083881/NH/NIH HHS/United States ; R01 AG083881/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Organoids/virology/metabolism ; *Alzheimer Disease/genetics/virology/pathology ; *Herpesvirus 1, Human/genetics/physiology ; *Brain/virology/pathology/metabolism ; Herpes Simplex/genetics/virology ; Islets of Langerhans/virology/metabolism/pathology ; Autoimmune Diseases/genetics/virology ; Stem Cells/virology/metabolism ; Transcriptome/genetics ; Diabetes Mellitus, Type 1/virology/genetics/pathology ; }, abstract = {Viral infections leading to inflammation have been implicated in several common diseases, such as Alzheimer's disease (AD) and type 1 diabetes (T1D). Of note, herpes simplex virus 1 (HSV-1) has been reported to be associated with AD. We sought to identify the transcriptomic changes due to HSV-1 infection and anti-viral drug (acyclovir, ACV) treatment of HSV-1 infection in dissociated cells from human cerebral organoids (dcOrgs) versus stem cell-derived pancreatic islets (sc-islets) to gain potential biological insights into the relevance of HSV-1-induced inflammation in AD and T1D. We observed that differentially expressed genes (DEGs) in HSV-1-infected sc-islets were enriched for genes associated with several autoimmune diseases, most significantly, T1D, but also rheumatoid arthritis, psoriasis, Crohn's disease, and multiple sclerosis, whereas DEGs in HSV-1-infected dcOrgs were exclusively enriched for genes associated with AD. The ACV treatment of sc-islets was not as effective in rescuing transcript perturbations of autoimmune disease-associated genes. Finally, we identified gene ontology categories that were enriched for DEGs that were in common across, or unique to, viral treatment of dcOrgs and sc-islets, such as categories involved in the transferase complex, mitochondrial, and autophagy function. In addition, we compared transcriptomic signatures from HSV-1-infected sc-islets with sc-islets that were infected with the coxsackie B virus (CVB) that had been associated with T1D pathogenesis. Collectively, this study provides tissue-specific insights into the molecular effects of inflammation in AD and T1D.}, }
@article {pmid39682713, year = {2024}, author = {Aljuhani, M and Ashraf, A and Edison, P}, title = {Use of Artificial Intelligence in Imaging Dementia.}, journal = {Cells}, volume = {13}, number = {23}, pages = {}, pmid = {39682713}, issn = {2073-4409}, support = {PSAU/2024/R/1445//Prince Sattam bin Abdulaziz University/ ; }, mesh = {Humans ; Alzheimer Disease/diagnostic imaging ; *Artificial Intelligence ; Deep Learning ; *Dementia/diagnostic imaging ; *Neuroimaging/methods ; }, abstract = {Alzheimer's disease is the most common cause of dementia in the elderly population (aged 65 years and over), followed by vascular dementia, Lewy body dementia, and rare types of neurodegenerative diseases, including frontotemporal dementia. There is an unmet need to improve diagnosis and prognosis for patients with dementia, as cycles of misdiagnosis and diagnostic delays are challenging scenarios in neurodegenerative diseases. Neuroimaging is routinely used in clinical practice to support the diagnosis of neurodegenerative diseases. Clinical neuroimaging is amenable to errors owing to varying human judgement as the imaging data are complex and multidimensional. Artificial intelligence algorithms (machine learning and deep learning) enable automation of neuroimaging interpretation and may reduce potential bias and ameliorate clinical decision-making. Graph convolutional network-based frameworks implicitly provide multimodal sparse interpretability to support the detection of Alzheimer's disease and its prodromal stage, mild cognitive impairment. In patients with amyloid-related imaging abnormalities, radiologists had significantly better detection performances with both ARIA-E (sensitivity higher in the assisted/deep learning method [87%] compared to unassisted [71%]) and for ARIA-H signs (sensitivity was higher in assisted [79%] compared to unassisted [69%]). A convolutional neural network method was developed, and external validation predicted final clinical diagnoses of Alzheimer's disease, dementia with Lewy bodies, mild cognitive impairment due to Alzheimer's disease, or cognitively normal with FDG-PET. The translation of artificial intelligence to clinical practice is plagued with technical, disease-related, and institutional challenges. The implementation of artificial intelligence methods in clinical practice has the potential to transform the diagnostic and treatment landscape and improve patient health and outcomes.}, }
@article {pmid39682689, year = {2024}, author = {Clemente-Suárez, VJ and Rubio-Zarapuz, A and Belinchón-deMiguel, P and Beltrán-Velasco, AI and Martín-Rodríguez, A and Tornero-Aguilera, JF}, title = {Impact of Physical Activity on Cellular Metabolism Across Both Neurodegenerative and General Neurological Conditions: A Narrative Review.}, journal = {Cells}, volume = {13}, number = {23}, pages = {}, pmid = {39682689}, issn = {2073-4409}, mesh = {Humans ; *Exercise/physiology ; *Neurodegenerative Diseases/metabolism/therapy ; *Mitochondria/metabolism ; Animals ; Oxidative Stress ; Energy Metabolism ; }, abstract = {BACKGROUND: Regular physical activity plays a crucial role in modulating cellular metabolism and mitigating the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Multiple Sclerosis.
OBJECTIVE: The objective of this review is to evaluate the molecular mechanisms by which exercise influences cellular metabolism, with a focus on its potential as a therapeutic intervention for neurological disorders.
METHODS: A comprehensive literature review was conducted using peer-reviewed scientific articles, with a focus on the period between 2015 and 2024, to analyze the effects of exercise on mitochondrial function, oxidative stress, and metabolic health.
RESULTS: The findings indicate that exercise promotes mitochondrial biogenesis, enhances oxidative phosphorylation, and reduces reactive oxygen species, contributing to improved energy production and cellular resilience. These metabolic adaptations are associated with delayed disease progression and reduced symptoms in patients with neurodegenerative conditions. Additionally, integrating exercise with nutritional strategies may further enhance therapeutic outcomes by addressing metabolic disturbances comprehensively.
CONCLUSIONS: This review concludes that personalized exercise protocols should be developed to optimize metabolic benefits for patients with neurological diseases, while future research should focus on biomarker development for individualized treatment approaches. These findings highlight the importance of non-pharmacological interventions in managing neurodegenerative diseases.}, }
@article {pmid39681722, year = {2025}, author = {Weiner, HL}, title = {Immune mechanisms and shared immune targets in neurodegenerative diseases.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {2}, pages = {67-85}, pmid = {39681722}, issn = {1759-4766}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/therapy ; Microglia/immunology ; Animals ; Immunotherapy/methods/trends ; Alzheimer Disease/immunology/therapy ; }, abstract = {The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.}, }
@article {pmid39681699, year = {2025}, author = {Wei, Y and Bai, Q and Ning, X and Bai, X and Lv, J and Li, M}, title = {Covalent organic framework derived single-atom copper nanozymes for the detection of amyloid-β peptide and study of amyloidogenesis.}, journal = {Analytical and bioanalytical chemistry}, volume = {417}, number = {6}, pages = {1081-1092}, pmid = {39681699}, issn = {1618-2650}, support = {226Z2601G//the Central Guidance on Local Science and Technology Development Fund of Hebei Province/ ; QNBJ19004//the Youth Top-notch Talents Supporting Plan of Hebei Province/ ; }, mesh = {*Amyloid beta-Peptides/analysis/chemistry ; *Copper/chemistry ; *Metal-Organic Frameworks/chemistry ; *Limit of Detection ; Animals ; *Alzheimer Disease/diagnosis ; Rats ; Colorimetry/methods ; Nanospheres/chemistry ; Humans ; Carbon/chemistry ; Catalysis ; }, abstract = {Sensitive and accurate detection of the amyloid-β (Aβ) monomer is of fundamental significance for early diagnosis of Alzheimer's disease (AD). Herein, inspired by the specific Cu-Aβ monomer coordination, a cutting-edge colorimetric assay based on single-atom Cu anchored N-doped carbon nanospheres (Cu-NCNSs) was developed for Aβ monomer detection and an amyloidogenesis study. By directly pyrolyzing Cu[2+]-incorporated covalent organic frameworks (COFs), the resulting Cu-NCNSs with a high loading of Cu (8.04 wt %) exhibited outstanding peroxidase-like activity. The strong binding affinity of Aβ monomer to Cu-NCNSs effectively inhibited their catalytic activity, providing the basis for the colorimetric assay. The Cu-NCNSs-based sensor showed a detection limit of 1.182 nM for Aβ monomer, surpassing traditional techniques in terms of efficiency, accuracy and simplicity. Moreover, the system was successfully utilized for Aβ monomer detection in rat cerebrospinal fluid (CSF). Notably, the distinct inhibitory effects of monomeric and aggregated Aβ species on the catalytic activity of Cu-NCNSs were allowed for monitoring of the dynamic aggregation process of Aβ. Compared to thioflavin T (ThT), the most widely used amyloid dye, the detection system exhibited greater sensitivity towards toxic Aβ oligomers, which was crucial for early AD diagnosis and treatment. Our work not only sheds light on the rational design of highly active single-atom nanozymes from COFs but also expands the potential applications of nanozymes in early disease diagnosis.}, }
@article {pmid39681202, year = {2025}, author = {Zhao, W and Yang, R and Meng, X and Xu, SQ and Li, MM and Hao, ZC and Wang, SY and Jiang, YK and Naseem, A and Chen, QS and Zhang, LL and Kuang, HX and Yang, BY and Liu, Y}, title = {Panax quinquefolium saponins protects neuronal activity by promoting mitophagy in both in vitro and in vivo models of Alzheimer's disease.}, journal = {Journal of ethnopharmacology}, volume = {340}, number = {}, pages = {119250}, doi = {10.1016/j.jep.2024.119250}, pmid = {39681202}, issn = {1872-7573}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Mitophagy/drug effects ; Mice ; *Neurons/drug effects/metabolism ; Male ; *Saponins/pharmacology/isolation & purification ; *Disease Models, Animal ; *Neuroprotective Agents/pharmacology/isolation & purification ; Cell Line ; Cell Survival/drug effects ; }, abstract = {In the realm of traditional Chinese medicine, Panax quinquefolius L. has garnered significant attention for its potential to treat various ailments associated with deficiencies, including qi, blood, and kidneys. As its primary bioactive constituent, Panax quinquefolius saponins (PQS) have the potential therapeutic role of Alzheimer's disease (AD) treatment, but with unclear mechanisms of action. Meanwhile, AD is considered as a common dementia disease with kidney insufficiency and deficiency by traditional medicine, and often accompanied by autophagy in modern medical research.
AIM OF THE STUDY: This study aimed to investigate the therapeutic effects of PQS on AD through the regulation of mitophagy.
MATERIALS AND METHODS: The chemical constituents of PQS were characterized using the UPLC-QTOF-MS technique. After that, the HT22 cell line was used to establish the D-galactose-induced cell model, and the SAMP8 mice model of AD was also employed. Cell viability was assessed using the CCK-8 assay, ROS detection, JC-1 staining, Mito-tracker Red and LC3 staining, and Mito-tracker Green and Lyso-tracker Red staining were used to assess levels of mitophagy. The Morris Water Maze (MWM) was used for the experimental evaluation of learning and memory abilities in mice. Subsequently, the mechanism was studied by pathological staining and western blotting.
RESULTS: Fifty-eight triterpenoid saponins were identified from PQS, and PQS alleviated D-galactose-induced HT22 cell death and increased intracellular levels of mitochondrial autophagy-related factors. In vivo, PQS significantly improved cognitive deficits and mitigated AD-like pathological features by activating the mitophagy mechanism. Furthermore, PQS may promote Pink1/Parkin-mediated mitophagy by activating the AMPK/mTOR/ULK1/DRP1 and SIRT1/PGC-1α pathways.
CONCLUSION: In conclusion, PQS have demonstrated the potential to mitigate mitochondrial dysfunction and enhance cognitive function in AD through the activation of mitophagy. This promising strategy holds great promise for the treatment of AD.}, }
@article {pmid39679875, year = {2025}, author = {Ghosh, P and Mukhopadhyay, S and Kandasamy, T and Mondal, S and Ghosh, SS and Iyer, PK}, title = {Multifunctional hydroxyquinoline-derived turn-on fluorescent probe for Alzheimer's disease detection and therapy.}, journal = {Journal of materials chemistry. B}, volume = {13}, number = {4}, pages = {1412-1423}, doi = {10.1039/d4tb01740d}, pmid = {39679875}, issn = {2050-7518}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Fluorescent Dyes/chemistry/chemical synthesis/pharmacology ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Hydroxyquinolines/chemistry/pharmacology ; Neuroprotective Agents/chemistry/pharmacology/chemical synthesis ; Reactive Oxygen Species/metabolism ; Molecular Docking Simulation ; Oxyquinoline/chemistry/pharmacology ; Animals ; Molecular Structure ; Apoptosis/drug effects ; }, abstract = {Understanding molecular motifs that can interfere with amyloid fibrillation through non-covalent interactions is essential for addressing abnormal protein aggregation and associated human diseases. The pursuit of efficient diagnostic and treatment approaches for Alzheimer's disease (AD) has resulted in the development of M8HQ, a multifaceted small molecule turn-on probe derived from 8-hydroxyquinoline with versatile capabilities. M8HQ shows a strong affinity for amyloid beta (Aβ) fibrils, and its ability to target lysosomes enhances therapeutic precision by localizing within these organelles. This localization is essential for restoring cellular balance and maintaining LAMP1 expression, both of which are crucial for addressing AD. It also displays the ability to disaggregate Aβ fibrils and inhibit their formation, thus addressing therapeutic processes in AD progression. M8HQ further blocks reactive oxygen species (ROS)-mediated apoptosis, providing neuroprotective effects. Additionally, it chelates metal ions like Cu(II) and Fe(III), mitigating metal-induced aggregation and oxidative stress. Molecular docking and simulation studies have elucidated the interactions between M8HQ and Aβ, confirming its binding efficacy and stability. These combined properties highlight M8HQ's potential as a comprehensive diagnostic and therapeutic tool for AD.}, }
@article {pmid39679465, year = {2024}, author = {Wang, M and Ma, Y and Zeng, B and Yang, W and Huang, C and Tang, B}, title = {Influence of the Gut Microbiota, Metabolism and Environment on Neuropsychiatric Disorders.}, journal = {Current reviews in clinical and experimental pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/0127724328335219241202142003}, pmid = {39679465}, issn = {2772-4336}, abstract = {The two-way communication between intestinal microbiota and the central nervous system (the microbiota-gut-brain axis) is involved in the regulation of brain function, neurodevelopment, and aging. The microbiota-gut-brain axis dysfunction may be a predisposition factor for Parkinson's disease (PD), Alzheimer's disease (AD), Autism spectrum disorder (ASD), and other neurological diseases. However, it is not clear whether gut microbiota dysfunction contributes to neuropsychiatric disorders. Changes in the gut microbiota may modulate or modify the effects of environmental factors on neuropsychiatric disorders. Factors that impact neuropsychiatric disorders also influence the gut microbiota, including diet patterns, exercise, stress and functional gastrointestinal disorders. These factors change microbiome composition and function, along with the metabolism and immune responses that cause neuropsychiatric disorders. In this review, we summarized epidemiological and laboratory evidence for the influence of the gut microbiota, metabolism and environmental factors on neuropsychiatric disorders incidence and outcomes. Furthermore, the role of gut microbiota in the two-way interaction between the gut and the brain was also reviewed, including the vagus nerve, microbial metabolism, and immuno-inflammatory responses. We also considered the therapeutic strategies that target gut microbiota in the treatment of neuropsychiatric disorders, including prebiotics, probiotics, Fecal microbiota transplant (FMT), and antibiotics. Based on these data, possible strategies for microbiota-targeted intervention could improve people's lives and prevent neuropsychiatric disorders in the future.}, }
@article {pmid39679258, year = {2024}, author = {Tascedda, S and Sarti, P and Rivi, V and Guerrera, CS and Platania, GA and Santagati, M and Caraci, F and Blom, JMC}, title = {Advanced AI techniques for classifying Alzheimer's disease and mild cognitive impairment.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1488050}, pmid = {39679258}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease and mild cognitive impairment are often difficult to differentiate due to their progressive nature and overlapping symptoms. The lack of reliable biomarkers further complicates early diagnosis. As the global population ages, the incidence of cognitive disorders increases, making the need for accurate diagnosis critical. Timely and precise diagnosis is essential for the effective treatment and intervention of these conditions. However, existing diagnostic methods frequently lead to a significant rate of misdiagnosis. This issue underscores the necessity for improved diagnostic techniques to better identify cognitive disorders in the aging population.
METHODS: We used Graph Neural Networks, Multi-Layer Perceptrons, and Graph Attention Networks. GNNs map patient data into a graph structure, with nodes representing patients and edges shared clinical features, capturing key relationships. MLPs and GATs are used to analyse discrete data points for tasks such as classification and regression. Each model was evaluated on accuracy, precision, and recall.
RESULTS: The AI models provide an objective basis for comparing patient data with reference populations. This approach enhances the ability to accurately distinguish between AD and MCI, offering more precise risk stratification and aiding in the development of personalized treatment strategies.
CONCLUSION: The incorporation of AI methodologies such as GNNs and MLPs into clinical settings holds promise for enhancing the diagnosis and management of Alzheimer's disease and mild cognitive impairment. By deploying these advanced computational techniques, clinicians could see a reduction in diagnostic errors, facilitating earlier, more precise interventions, and likely to lead to significantly improved outcomes for patients.}, }
@article {pmid39678681, year = {2024}, author = {Zhu, F and Yin, S and Wang, Y and Zhong, Y and Ji, Q and Wu, J}, title = {Effects of Probiotics on Neurodegenerative Disease-Related Symptoms and Systemic Inflammation: A Systematic Review.}, journal = {International journal of general medicine}, volume = {17}, number = {}, pages = {5941-5958}, pmid = {39678681}, issn = {1178-7074}, abstract = {In recent years, probiotics, as a class of biologically active microorganisms, have increasingly attracted attention for their potential in treating neurodegenerative diseases (NDDs). To comprehensively assess the effects of probiotics on clinical symptoms and systemic inflammation regulation in various NDDs, this systematic review conducted a detailed search of the Cochrane Library, Embase, PubMed, and Web of Science databases, ultimately including 22 eligible randomized controlled trials (RCTs), with 4 RCTs for Alzheimer's Disease (AD), 10 RCTs for Parkinson's Disease (PD), 2 RCTs for Multiple Sclerosis (MS), and 2 RCTs for Mild Cognitive Impairment (MCI), and intervention durations ranging from 4 to 16 weeks. The comprehensive analysis indicates that probiotics help improve clinical symptoms related to NDDs, including gastrointestinal function, cognitive function, quality of life, and mental health. Additionally, probiotics generally have a positive effect on reducing systemic inflammation and enhancing antioxidant capacity in patients. In conclusion, existing evidence supports the promising potential of probiotics in treating NDDs. However, further large-scale, high-quality studies are needed to explore specific differences in efficacy among various probiotic strains, dosages, and modes of administration. Moreover, considering that lifestyle and dietary habits may modulate the effects of probiotics, these external factors should also be included in research considerations to gain a more comprehensive understanding of the mechanisms and application strategies of probiotics in NDDs treatment.}, }
@article {pmid39677973, year = {2024}, author = {Hu, Y and Xiong, R and Pan, S and Huang, K}, title = {A narrative review of vagus nerve stimulation in stroke.}, journal = {Journal of central nervous system disease}, volume = {16}, number = {}, pages = {11795735241303069}, pmid = {39677973}, issn = {1179-5735}, abstract = {Stroke is a significant health concern impacting society and the health care system. Reperfusion therapy for acute ischemic stroke and standard rehabilitative therapies may not always be effective at improving post-stroke neurological function, and developing alternative strategies is particularly important. Vagus nerve stimulation (VNS) is a treatment option currently approved by the Food and Drug Administration (FDA) for intractable epilepsy, refractory depression, primary headache disorders, obesity, and moderate to severe upper-limb motor dysfunction in chronic ischemic stroke patients. Moreover, VNS has demonstrated potential efficacy in various conditions, including autoimmune diseases, disorders of consciousness, Alzheimer's disease, Parkinson's disease, traumatic brain injury, stroke, and other diseases. Although the popularity and application of VNS continue to increase rapidly, the field generally lacks a consensus on the optimal stimulation parameters. The stimulation parameters for VNS are directly related to the clinical outcome, and determining the optimal stimulation conditions for VNS has become an essential concern in its clinical application. This review summarizes the current evidence on VNS for stroke in preclinical models and clinical trials in humans, paying attention to the current types and stimulation parameters of VNS, highlighting the mechanistic pathways involved in the beneficial effects of VNS, critically evaluating clinical implementation challenges and proposing some suggestions for its future research directions. Achieving safe and effective clinical transformation of VNS requires further animal and clinical studies to determine the optimal stimulation parameters and therapeutic mechanisms.}, }
@article {pmid39676969, year = {2024}, author = {Noori, M and Khalili Ghomi, M and Dastyafteh, N and Oliyaei, N and Hamedifar, H and Javanshir, S and Tanideh, N and Sattarinezhad, E and Sattari, F and Haghani, M and Rahmani, H and Larijani, B and Mahdavi, M and Hajimiri, MH and Iraji, A}, title = {Isoindolinedione-Benzamide Pyridinium Derivatives for Targeting Alzheimer's Disease.}, journal = {ACS omega}, volume = {9}, number = {49}, pages = {48032-48043}, pmid = {39676969}, issn = {2470-1343}, abstract = {An Isoindolinedione-benzamide pyridinium derivatives were designed through a structure-based strategy and synthesized as novel multifunctional anti-Alzheimer agents. The inhibitory activities of all 17 derivatives against acetylcholinesterase and butyrylcholinesterase were evaluated. Results exhibited that compound 7j displayed promising AChE inhibitory activity with an IC50 value of 0.26 ± 0.07 μM, and compound 7c exhibited an IC50 value of 0.08 ± 0.01 μM against BChE with 132-fold better inhibitory activity in comparison with positive control. Next, the enzyme kinetics studies and detailed binding mode via molecular docking were performed for the most potent compounds. Additionally, molecular dynamics simulations were accomplished to further investigate the potent compound's interaction, orientation, and conformation over the related enzymes. The neurotoxicity of the most potent derivative was executed against SH-SY5Y, and the mRNA levels of GSK-3α and GSK-3β after treatment with 7c on SH-SY5Y were evaluated. Results exhibited the mRNA levels of GSK-3β were decreased compared to the control group. All these results indicate that 7c is a good starting point for developing a multifunctional anti-Alzheimer compound.}, }
@article {pmid39676433, year = {2025}, author = {Quan, Z and Wang, S and Xie, H and Zhang, J and Duan, R and Li, M and Zhang, J}, title = {ROS Regulation in CNS Disorder Therapy: Unveiling the Dual Roles of Nanomedicine.}, journal = {Small (Weinheim an der Bergstrasse, Germany)}, volume = {21}, number = {5}, pages = {e2410031}, doi = {10.1002/smll.202410031}, pmid = {39676433}, issn = {1613-6829}, support = {32371442//National Natural Science Foundation of China/ ; 2022CX01029//Beijing Institute of Technology Science and Technology Innovation Plan Project/ ; }, mesh = {Humans ; *Nanomedicine/methods ; *Reactive Oxygen Species/metabolism ; Animals ; Blood-Brain Barrier/metabolism ; Central Nervous System Diseases/drug therapy/metabolism/therapy ; Photochemotherapy/methods ; }, abstract = {The treatment of brain diseases has always been the focus of attention. Due to the presence of the blood-brain barrier (BBB), most small molecule drugs are difficult to reach the brain, leading to undesirable therapeutic outcomes. Recently, nanomedicines that can cross the BBB and precisely target lesion sites have emerged as thrilling tools to enhance the early diagnosis and treat various intractable brain disorders. Extensive research has shown that reactive oxygen species (ROS) play a crucial role in the occurrence and progression of brain diseases, including brain tumors and neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, stroke, or traumatic brain injury, making ROS a potential therapeutic target. In this review, on the structure and function of BBB as well as the mechanisms are first elaborated through which nanomedicine traverses it. Then, recent studies on ROS production are summarized through photodynamic therapy (PDT), chemodynamic therapy (CDT), and sonodynamic therapy (SDT) for treating brain tumors, and ROS depletion for treating NDDs. This provides valuable guidance for the future design of ROS-targeted nanomedicines for brain disease treatment. The ongoing challenges and future perspectives in developing nanomedicine-based ROS management for brain diseases are also discussed and outlined.}, }
@article {pmid39676329, year = {2025}, author = {Ronchetti, S and Labombarda, F and Del Core, J and Roig, P and De Nicola, AF and Pietranera, L}, title = {The phytoestrogen genistein improves hippocampal neurogenesis and cognitive impairment and decreases neuroinflammation in an animal model of metabolic syndrome.}, journal = {Journal of neuroendocrinology}, volume = {37}, number = {2}, pages = {e13480}, doi = {10.1111/jne.13480}, pmid = {39676329}, issn = {1365-2826}, support = {348//Ministerio de Ciencia, Tecnología e Innovación/ ; 334//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; 20020100100089BA//Universidad de Buenos Aires/ ; //Williams, Brown and Cherny Foundations/ ; }, mesh = {Animals ; *Metabolic Syndrome/drug therapy/metabolism ; *Cognitive Dysfunction/drug therapy ; *Hippocampus/drug effects/metabolism/pathology ; *Neurogenesis/drug effects ; *Genistein/pharmacology/therapeutic use ; *Neuroinflammatory Diseases/drug therapy ; *Phytoestrogens/pharmacology/therapeutic use ; *Rats, Inbred SHR ; *Disease Models, Animal ; Rats ; *Doublecortin Protein ; Male ; Diet, High-Fat/adverse effects ; }, abstract = {Metabolic syndrome (MS) is the medical term for the combination of at least three of the following factors: obesity, hyperlipidemia, hyperglycemia, insulin resistance, and hypertension. The spontaneously hypertensive rat (SHR) is an accepted animal model for the study of human MS that reveals all the features of the syndrome when fed high-fat, high-carbohydrate diets. The intake of high-fat diets in rats has been shown to produce brain neuropathology. In humans, MS increases the risk of cognitive impairment, dementia, and Alzheimer's disease. Genistein (GEN) is a phytoestrogen found in soy that lacks feminizing and carcinogenic effects and was found to have neuroprotective and anti-inflammatory effects in many pathological conditions. Considering that multiple data support that natural phytoestrogens may be therapeutic options for CNS maladies, we aim to elucidate if these properties also apply to a rat model of MS. Thus, GEN effects on neuroinflammation, neurogenesis, and cognition were evaluated in SHR eating a fat/carbohydrate-enriched diet. To characterize the neuropathology and cognitive dysfunction of MS we fed SHR with a high-fat diet (4520 kcal/kg) along with a 20% sucrose solution to drink. MS rats displayed a significant increase in body weight, BMI and obesity indexes along with an increased in fasting glucose levels, glucose intolerance, high blood pressure, and high blood triglyceride levels. MS rats were injected with GEN during 2 weeks a dose of 10 mg/kg. We found that MS rats showed a decreased number of DCX+ neural progenitors in the dentate gyrus and treatment with GEN increased this parameter. Expression of GFAP was increased in the DG and CA1 areas of the hippocampus and treatment decreased astrogliosis in all of them. We measured the expression of IBA1+ microglia in the same regions and classified microglia according to their morphology: we found that MS rats presented an increased proportion of the hypertrophied phenotype and GEN produced a shift in microglial phenotypes toward a ramified type. Furthermore, colocalization of IBA1 with the proinflammatory marker TNFα showed increased proportion of proinflammatory microglia in MS and a reduction with GEN treatment. On the other hand, colocalization with the anti-inflammatory marker Arg1 showed that MS has decreased proportion of anti-inflammatory microglia and GEN treatment increased this parameter. Cognitive dysfunction was evaluated in rats with MS using a battery of behavioral tests that assessed hippocampus-dependent spatial and working memory, such as the novel object recognition test (NOR), the novel object location test (NOL), and the free-movement pattern Y-maze (FMP-YMAZE) and the d-YMAZE. In all of them, MS performed poorly and GEN was able to improve cognitive impairments. These results indicate that GEN was able to exert neuroprotective actions increasing neurogenesis and improving cognitive impairments while decreasing astrogliosis, microgliosis, and neuroinflammatory environment in MS rats. Together, these results open an interesting possibility for proposing this phytoestrogen as a neuroprotective therapy for MS.}, }
@article {pmid39676256, year = {2024}, author = {Zhang, Y and Song, D and Han, X and Liu, H and Wang, Y and Wang, X and Dou, C}, title = {Unlocking the potential of melanotransferrin (CD228): implications for targeted drug development and novel therapeutic avenues.}, journal = {Expert opinion on therapeutic targets}, volume = {28}, number = {12}, pages = {1117-1129}, doi = {10.1080/14728222.2024.2441705}, pmid = {39676256}, issn = {1744-7631}, mesh = {Humans ; *Neoplasms/drug therapy ; *Drug Development ; Animals ; *Molecular Targeted Therapy ; *Drug Delivery Systems ; *Antineoplastic Agents/pharmacology/administration & dosage ; Blood-Brain Barrier/metabolism ; Membrane Glycoproteins ; }, abstract = {INTRODUCTION: Melanotransferrin (CD228), a cell membrane-anchored protein, has emerged as a significant cancer antigen due to its high expression in various solid tumors. This review synthesizes the current understanding and therapeutic potential of CD228.
AREAS COVERED: We conducted a literature search using PubMed, Web of Science, and ClinicalTrials.gov with the keywords 'melanotransferrin' and 'CD228.' Our comprehensive review examines CD228 and its isoforms, membrane-bound CD228 (mMFI2) and soluble CD228 (sMFI2), their roles in tumorigenesis, angiogenesis, endothelial cell migration, plasminogen activation, and transendothelial transport across the BBB, as well as the current state of drug development efforts targeting CD228.
EXPERT OPINION: Targeting CD228 represents a promising therapeutic strategy in oncology, with mMFI2 as a potential target for solid tumors and sMFI2 valuable for disease diagnosis in malignant tumors, Alzheimer's disease, and arthritis, and facilitating macromolecular drug delivery across the blood-brain barrier (BBB). Despite its potential to transform the treatment landscape for numerous solid cancers, further research into the precise mechanisms and clinical translation of CD228-directed treatments is needed to maximize its therapeutic utility.}, }
@article {pmid39676234, year = {2024}, author = {Ekundayo, BE and Adewale, OB and Obafemi, BA and Ntwasa, MM and Lebelo, SL and Obafemi, TO}, title = {Synergistic Effect of Donepezil and Neurotropic B Vitamins on Dysregulated Antioxidant, Inflammation and Neurotransmitter Status in Aluminium Chloride-Induced Neurotoxicity in Rats.}, journal = {Cell biochemistry and function}, volume = {42}, number = {8}, pages = {e70028}, doi = {10.1002/cbf.70028}, pmid = {39676234}, issn = {1099-0844}, support = {//The authors received no specific funding for this work./ ; }, mesh = {Animals ; *Donepezil/pharmacology ; *Aluminum Chloride ; Rats ; *Antioxidants/pharmacology ; Male ; Rats, Wistar ; Drug Synergism ; Inflammation/metabolism/drug therapy/chemically induced/pathology ; Vitamin B 6/pharmacology ; Neurotransmitter Agents/metabolism ; Vitamin B 12/pharmacology ; Oxidative Stress/drug effects ; Aluminum Compounds ; Thiamine/pharmacology ; Vitamin B Complex/pharmacology ; Malondialdehyde/metabolism ; }, abstract = {Combination therapy offers a promising advantage because they target multiple pathways involved in the pathogenesis and progression of Alzheimer's disease. This study aimed to investigate the synergistic effect of donepezil and each of vitamin B12, vitamin B6 and vitamin B1 on aluminium chloride (AlCl3)-induced neurotoxicity in rats. Fifty-four rats were divided into nine groups of six. Group I received distilled water, group II-AlCl3 (100 mg/kg), group III- AlCl3 (100 mg/kg) + Donepezil (10 mg/kg), group IV-AlCl3(100 mg/kg) + Donepezil (10 mg/kg) + Vitamin B12 (5 mg/kg), group V-AlCl3 (100 mg/kg) + Donepezil (10 mg/kg) + Vitamin B6 (5 mg/kg), group VI-AlCl3 (100 mg/kg) + Donepezil (10 mg/kg) + Vitamin B1 (5 mg/kg), group VII-AlCl3 (100 mg/kg) + Vitamin B12 (5 mg/kg), group VIII-AlCl3 (100 mg/kg) + Vitamin B6 (5 mg/kg), group IX-AlCl3 (100 mg/kg) + Vitamin B1 (5 mg/kg). Treatment lasted for 40 days. Biochemical analyses of the brain revealed that chronic administration of AlCl3 significantly increased the level of inflammatory cytokines, caspase 9, malondialdehyde, nitric oxide and acetylcholinesterase (AChE) activity, while causing a significant decrease in superoxide dismutase (SOD) activity, Nrf2, reduced glutathione, dopamine and norepinephrine. Results also showed that AlCl3 caused cognitive impairment as indicated by a reduction in the percentage alternation index and hypo-activity towards novel object in animals treated with AlCl3 only. Moreover, results from biochemical evaluations indicated that treatment with donepezil, B vitamins and combination of donepezil and B vitamins attenuated the deficits in dopamine, norepinephrine, Nrf2, SOD and reduced glutathione, while also reducing the elevated levels of malondialdehyde, nitric oxide, AChE, caspase 9 and inflammatory markers. These observations were corroborated by result of histopathological evaluation. The combination of donepezil and vitamin B12, B6 and B1 proved to be more effective than donepezil monotherapy. Donepezil conferred significant protection against AlCl3-induced neurotoxicity, however, the combination of donepezil and vitamin B12, vitamin B6 and Vitamin B1 significantly performed better in neuroprotective indices than donepezil monotherapy. The combination of donepezil and vitamin B1 was better amongst the three combination therapies in this study.}, }
@article {pmid39675515, year = {2025}, author = {Liu, C and Chen, X and Yang, S and Wang, X and Sun, P and Wang, J and Zhu, G}, title = {Insight into cerebral microvessel endothelial regulation of cognitive impairment: A systematic review of the causes and consequences.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115116}, doi = {10.1016/j.expneurol.2024.115116}, pmid = {39675515}, issn = {1090-2430}, mesh = {Humans ; *Cognitive Dysfunction/physiopathology/etiology/pathology/metabolism ; Animals ; *Blood-Brain Barrier/pathology/physiopathology ; Microvessels/pathology ; Endothelial Cells/metabolism/pathology ; Endothelium, Vascular/pathology/physiopathology ; }, abstract = {Research on cognitive impairment (CI) has increasingly focused on the central nervous system, identifying numerous neuronal targets and circuits of relevance for CI pathogenesis and treatment. Brain microvascular endothelial cells (BMECs) form a barrier between the peripheral and central nervous systems, constituting the primary component of the blood-brain barrier (BBB) and playing a vital role in maintaining neural homeostasis. Stemming from the recognition of the close link between vascular dysfunction and CI, in recent years intense research has been devoted to characterize the pathological changes and molecular mechanisms underlying BMEC dysfunction both during normal aging and in disorders of cognition such as Alzheimer's disease and vascular dementia. In this review, keywords such as "dementia", "cognitive impairment", and "endothelium" were used to search PubMed and Web of Science. Based on the literature thus retrieved, we first review some common triggers of CI, i.e., amyloid beta and tau deposition, chronic cerebral hypoperfusion, hyperglycemia, viral infections, and neuroinflammation, and describe the specific mechanisms responsible for endothelial damage. Second, we review molecular aspects of endothelial damage leading to BBB disruption, neuronal injury, and myelin degeneration, which are crucial events underlying CI. Finally, we summarize the potential targets of endothelial damage in the development of cognitive dysfunction associated with Alzheimer's disease, vascular dementia, type 2 diabetes mellitus, and physiological aging. A thorough understanding of the induction mechanism and potential outcomes of microvascular endothelial damage is of great significance for the study of CI, to guide both diagnostic and therapeutic approaches for its prevention and treatment.}, }
@article {pmid39675388, year = {2025}, author = {Möller, JEL and Schmitt, FW and Günther, D and Stöver, A and Bouter, Y}, title = {The synthetic cannabinoid WIN 55,212-2 attenuates cognitive and motor deficits and reduces amyloid load in 5XFAD Alzheimer mice.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {247}, number = {}, pages = {173944}, doi = {10.1016/j.pbb.2024.173944}, pmid = {39675388}, issn = {1873-5177}, mesh = {Animals ; *Benzoxazines/pharmacology ; *Naphthalenes/pharmacology ; *Morpholines/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Male ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Cannabinoids/pharmacology/administration & dosage ; Disease Models, Animal ; Motor Activity/drug effects ; Maze Learning/drug effects ; Cognition/drug effects ; Cognition Disorders/drug therapy ; Anxiety/drug therapy ; Plaque, Amyloid/drug therapy/pathology ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive decline, with pathological features including amyloid β (Aβ) plaques and inflammation. Despite recent approvals of anti-amyloid antibodies, there remains a need for disease-modifying and easily accessible therapies. The endocannabinoid system presents a promising target for AD treatment, as it regulates various processes implicated in AD pathogenesis.
AIMS: This study assesses the effects of the synthetic cannabinoid WIN 55,212-2 on AD pathology and behavior deficits in aged 5XFAD mice, a well-established AD model.
METHODS: Male 9-month-old 5XFAD mice received either 0.2 mg/kg WIN 55,212-2 or a vehicle solution for 42 days. Memory, anxiety, and motor tests were conducted at 10 months to identify potential changes in behavior and cognition following WIN 55,212-2 treatment. Additionally, the effects of prolonged WIN 55,212-2 treatment on Aβ pathology and neuroinflammation in the brain were quantified immunohistochemically.
RESULTS: Therapeutic WIN 55,212-2 treatment improved the motor performance of 5XFAD mice on the rotarod and rescued memory deficits in the water maze. However, WIN 55,212-2 treatment did not significantly affect anxiety-like behavior in 5XFAD mice. Additionally, prolonged treatment with WIN 55,212-2 reduced Aβ plaque pathology and astrogliosis in the cortex and hippocampus.
CONCLUSIONS: This study highlights the therapeutic potential of WIN 55,212-2 in AD by ameliorating cognitive and motor deficits and reducing neuropathology. These findings support a cannabinoid-based therapy as a promising strategy for AD treatment, with WIN 55,212-2 emerging as a potential candidate.}, }
@article {pmid39675097, year = {2025}, author = {Wang, H and Wu, Y and Liu, A and Li, S and Zhu, P and Zuo, J and Kuang, Y and Li, J and Jiang, X}, title = {Design, synthesis and biological evaluation of novel pyrazolinone derivatives as multifunctional ligands for the treatment of Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {154}, number = {}, pages = {108052}, doi = {10.1016/j.bioorg.2024.108052}, pmid = {39675097}, issn = {1090-2120}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Drug Design ; *Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; *Acetylcholinesterase/metabolism ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Structure-Activity Relationship ; *Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Ligands ; Molecular Structure ; *Pyrazolones/pharmacology/chemistry/chemical synthesis ; Animals ; Dose-Response Relationship, Drug ; Antioxidants/pharmacology/chemical synthesis/chemistry ; Molecular Docking Simulation ; Cell Line, Tumor ; Mice ; Male ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the depletion of cholinergic neurons and the accumulation of amyloid β (Aβ) plaques. The complexity and multifaceted nature of AD necessitate further exploration of multi-target drugs for its treatment. In this study, a series of novel pyrazolinone-based compounds were designed, synthesized, and evaluated as acetylcholinesterase (AChE) inhibitors and antioxidants. The lead compounds ET11 and ET21 showed strong inhibitory activity against human AChE, with IC50 values of 6.34 and 1.81 nM, respectively. In vitro DPPH and ORACFL assays confirmed the compounds' strong antioxidant capabilities. ET11 exhibited excellent neuroprotective activity in the tBHP-induced SH-SY5Y cell damage model. Benefiting from the pyridopyrazolone moiety, ET11 showed significant Cu[2+] chelating ability and effectively inhibited Cu[2+]-induced Aβ aggregation. In vivo behavioral studies and histopathology analysis preliminarily confirmed the compound's cognitive improvement and neuroprotective effects. Overall, these findings suggested that compound ET11 is expected to play a synergistic role in the treatment of AD, potentially slowing disease progression.}, }
@article {pmid39674916, year = {2024}, author = {Dixit, D and Zhao, Y and Bardhi, O and Daneshmand, A and Phillips, J and Bala, T and Rosenthal, M and Mohr, A and Kandiah, P and Kamel, AY}, title = {Carnitine supplementation in progressive supranuclear palsy.}, journal = {Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1002/ncp.11262}, pmid = {39674916}, issn = {1941-2452}, abstract = {Mitochondrial dysfunction has been implicated in the pathogenesis of several neurodegenerative disorders, including progressive supranuclear palsy (PSP). PSP is a Parkinsonian syndrome characterized by a rapidly progressive state that manifests itself as tremors, bradykinesia, and supranuclear gaze palsy. Carnitine plays an essential role in mitochondrial function by transporting fatty acids across the mitochondrial membrane to be used in energy production. Mitochondrial dysfunction can bring about rapid neuronal depolarization and a calcium-mediated cellular apoptosis owing to a loss of oxidative metabolism, likely contributing to the PSP disease process. A White man aged 65 years with PSP presented with small bowel obstruction and severe malnutrition as a result of prior gastrointestinal surgeries for which a gastrostomy tube was placed. During his hospitalization, the patient was found to be deficient in both free and total carnitine. He was treated with levocarnitine supplementation and exhibited marked improvement in tremors, fatigue, and physical therapy activities. Posthospitalization follow-up showed sustained improvement in symptoms with continued levocarnitine supplementation. Treatment of PSP remains largely supportive in nature. No studies have investigated the role of carnitine supplementation in PSP. To our knowledge, this is the first case report to identify improvement in PSP symptoms after carnitine repletion and supportive care. Numerous animal studies have reported on carnitine supplementation in the context of mitochondrial dysfunction associated with neurodegenerative diseases, such as Parkinson disease and Alzheimer disease. Further investigation is necessary to elucidate the precise role of carnitine and other nutrition supplements in the pathophysiology of PSP.}, }
@article {pmid39673864, year = {2025}, author = {Elkotamy, MS and Elgohary, MK and Alkabbani, MA and Hefina, MM and Tawfik, HO and Fares, M and Eldehna, WM and Abdel-Aziz, HA}, title = {Design, synthesis, and evaluation of novel benzofuran and pyrazole-based derivatives as dual AChE/BuChE inhibitors with antioxidant properties for Alzheimer's disease management.}, journal = {European journal of medicinal chemistry}, volume = {283}, number = {}, pages = {117158}, doi = {10.1016/j.ejmech.2024.117158}, pmid = {39673864}, issn = {1768-3254}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Benzofurans/pharmacology/chemical synthesis/chemistry ; *Acetylcholinesterase/metabolism ; *Drug Design ; *Antioxidants/pharmacology/chemical synthesis/chemistry ; *Pyrazoles/pharmacology/chemistry/chemical synthesis ; *Alzheimer Disease/drug therapy ; *Butyrylcholinesterase/metabolism ; Structure-Activity Relationship ; Humans ; Animals ; Molecular Structure ; Molecular Docking Simulation ; Dose-Response Relationship, Drug ; Rats ; Male ; }, abstract = {As a complicated neurodegenerative disorder with several clinical hallmarks, Alzheimer's disease (AD) requires multi-target treatment medicines to address multiple elements of disease progression. In this study, we reported two novel series of compounds: benzofuran-based donepezil analogs (9a-i) and their pyrazole-based counterparts (11a-i) as potential dual inhibitors of AChE and BuChE with additional antioxidant properties, aiming to address multiple pathological aspects of AD simultaneously. The design strategy employed bioisosteric replacement, substituting donepezil's indanone motif with a benzofuran ring in series (9a-i) to maintain crucial hydrogen bonding interactions with the Phe295 residue in the enzyme's active site. Subsequently, the benzofuran ring underwent cleavage, yielding pyrazole-tethered hydroxyphenyl derivatives (11a-i). The biological evaluation revealed that benzofuran-based derivative 9g exhibited exceptional efficacy against both AChE and BuChE, with IC50 values of 0.39 and 0.51 μg/ml, respectively, although it lacked antioxidant activity. Compound 11f demonstrated dual inhibition of AChE (IC50 = 1.24 μg/ml) and BuChE (IC50 = 1.85 μg/ml) while also displaying strong DPPH free radical scavenging activity (IC50 = 3.15 μg/ml). In vivo toxicity studies on compound 11f revealed a favorable safety profile, with no signs of toxicity or adverse events in acute oral toxicity tests in male Wistar rats. Chronic administration of 11f resulted in negligible differences in blood profiles, hepatic enzymes, urea, creatinine, and albumin levels compared to the control group. Histopathological examination of hepatic and kidney tissues from treated rats showed normal histology without damage. In silico molecular docking analysis was performed to rationalize the design approaches and support the experimental findings. This study provides valuable insights into the development of multi-target compounds for potential Alzheimer's disease treatment.}, }
@article {pmid39657256, year = {2024}, author = {Xi, D and Zhang, M and Shang, M and Du, L and Han, J and , }, title = {Modeling multi-stage disease progression and identifying genetic risk factors via a novel collaborative learning method.}, journal = {Bioinformatics (Oxford, England)}, volume = {41}, number = {1}, pages = {}, pmid = {39657256}, issn = {1367-4811}, support = {61936007//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/genetics/diagnostic imaging ; Humans ; *Disease Progression ; *Genome-Wide Association Study/methods ; Risk Factors ; Algorithms ; Neuroimaging/methods ; Genetic Predisposition to Disease ; Machine Learning ; }, abstract = {MOTIVATION: Alzheimer's disease (AD) typically progresses gradually for ages rather than suddenly. Thus, staging AD progression in different phases could aid in accurate diagnosis and treatment. In addition, identifying genetic variations that influence AD is critical to understanding the pathogenesis. However, staging the disease progression and identifying genetic variations is usually handled separately.
RESULTS: To address this limitation, we propose a novel sparse multi-stage multi-task mixed-effects collaborative longitudinal regression method (MSColoR). Our method jointly models long disease progression as a multi-stage procedure and identifies genetic risk factors underpinning this complex trajectory. Specifically, MSColoR models multi-stage disease progression using longitudinal neuroimaging-derived phenotypes and associates the fitted disease trajectories with genetic variations at each stage. Furthermore, we collaboratively leverage summary statistics from large genome-wide association studies to improve the powers. Finally, an efficient optimization algorithm is introduced to solve MSColoR. We evaluate our method using both synthetic and real longitudinal neuroimaging and genetic data. Both results demonstrate that MSColoR can reduce modeling errors while identifying more accurate and significant genetic variations compared to other longitudinal methods. Consequently, MSColoR holds great potential as a computational technique for longitudinal brain imaging genetics and AD studies.
The code is publicly available at https://github.com/dulei323/MSColoR.}, }
@article {pmid39673650, year = {2024}, author = {Smail, SW}, title = {Targeting Neuroinflammation and Apoptosis: Cardamonin's Cognitive Benefits in Alzheimer's 5XFAD Mice.}, journal = {Neurochemical research}, volume = {50}, number = {1}, pages = {57}, pmid = {39673650}, issn = {1573-6903}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Mice, Transgenic ; *Apoptosis/drug effects ; Female ; *Chalcones/pharmacology/therapeutic use ; *Neuroprotective Agents/therapeutic use/pharmacology ; Mice ; Neuroinflammatory Diseases/drug therapy ; Cognition/drug effects ; Amyloid beta-Peptides/metabolism ; Maze Learning/drug effects ; Nootropic Agents/pharmacology/therapeutic use ; }, abstract = {This study aimed to evaluate the cognitive-enhancing and neuroprotective effects of cardamonin in the 5XFAD transgenic mouse model of Alzheimer's disease (AD). We treated six-month-old female 5XFAD mice with cardamonin at 5 mg/kg, 10 mg/kg, and 20 mg/kg. Cognitive function was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests. ELISA, western blot, and PCR analyses evaluated amyloid-beta (Aβ) levels, neuroinflammation markers, and apoptosis-related factor expression. All animals survived without toxicity. Cardamonin treatment significantly improved spatial learning and memory retention in MWM and NOR tests, with the 20 mg/kg dose showing the most pronounced effects. Additionally, cardamonin reduced soluble and insoluble Aβ levels in the frontal cortex and hippocampus. The treatment also significantly decreased neuroinflammatory markers, with IL-1β, IL-6, and TNF-α levels dropping substantially at higher doses. Cardamom treatment also normalizes cleaved caspase 3, GFAP, Iba-1, PSD-95, and synaptophysin, which aids in restoring synaptic integrity. Furthermore, cardamonin led to a marked reduction in apoptosis-related gene expression, indicating its potential to mitigate neurodegeneration. Cardamonin demonstrates significant cognitive-enhancing and neuroprotective properties in the 5XFAD mouse model, suggesting its potential as a therapeutic agent for AD. These findings support further investigation into cardamonin's mechanisms and applicability in treating neurodegenerative disorders.}, }
@article {pmid39672489, year = {2025}, author = {De Sousa, RAL and Mendes, BF}, title = {T-regulatory cells and extracellular vesicles in Alzheimer's disease: New therapeutic concepts and hypotheses.}, journal = {Brain research}, volume = {1850}, number = {}, pages = {149393}, doi = {10.1016/j.brainres.2024.149393}, pmid = {39672489}, issn = {1872-6240}, mesh = {*Alzheimer Disease/therapy/metabolism ; Humans ; *Extracellular Vesicles/metabolism ; *T-Lymphocytes, Regulatory/immunology ; Animals ; }, abstract = {Cell-based treatment has experienced exponential expansion in recent years in terms of clinical application and market share among pharmaceutical companies. When malignant cells in a healthy individual produce antigenic peptides derived from mutant or improperly synthesized proteins, the immune system attacks and kills the transforming cells. This process is carried out continuously by immune cells scanning the body for altered cells that could cause some harm. T-regulatory cells (Tregs), which preserve immunological tolerance and can exert neuroprotective benefits in numerous disorders, including animal models of Alzheimer's disease (AD), have demonstrated considerable therapeutic potential. Evidence also suggests that not only Tregs, but extracellular vesicles (EVs) are involved in a wide range of diseases, such as cellular homoeostasis, infection propagation, cancer development and heart disease, and have become a promisor cell-based therapeutic field too. Nevertheless, despite significant recent clinical and commercial breakthroughs, cell-based medicines still confront numerous challenges that hinder their general translation and commercialization. These challenges include, but are not limited to, choosing the best cell source, and creating a product that is safe, adequately viable, and fits the needs of individual patients and diseases. Here, we summarize what we know about Tregs and EVs and their potential therapeutic usage in AD.}, }
@article {pmid39672482, year = {2025}, author = {Manfredi, JN and Gupta, SK and Vyavahare, S and Deak, F and Lu, X and Buddha, L and Wankhade, U and Lohakare, J and Isales, C and Fulzele, S}, title = {Gut microbiota dysbiosis in Alzheimer's disease (AD): Insights from human clinical studies and the mouse AD models.}, journal = {Physiology & behavior}, volume = {290}, number = {}, pages = {114778}, doi = {10.1016/j.physbeh.2024.114778}, pmid = {39672482}, issn = {1873-507X}, support = {R01 AG062655/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/microbiology/pathology ; *Gastrointestinal Microbiome/physiology ; Animals ; Humans ; *Dysbiosis/microbiology ; *Disease Models, Animal ; Mice ; }, abstract = {Alzheimer's Disease (AD) is a debilitating neurocognitive disorder with an unclear underlying mechanism. Recent studies have implicated gut microbiota dysbiosis with the onset and progression of AD. The connection between gut microbiota and AD can significantly affect the prevention and treatment of AD patients. This systematic review summarizes primary outcomes of human and mouse AD models concerning gut microbiota alterations. A systematic literature search in February through March 2023 was conducted on PubMed, Embase, and Web of Science. We identified 711 as potential manuscripts of which 672 were excluded because of irrelevance to the identified search criteria. Primary outcomes include microbiota compositions of control and AD models in humans and mice. In total, 39 studies were included (19 mouse and 20 human studies), published between 2017 and 2023. We included studies involving well-established mice models of AD (5xFAD, 3xTg-AD, APP/PS1, Tg2576, and APPPS2) which harbor mutations and genes that drive the formation of Aß plaques. All human studies were included on those with AD or mild cognitive impairment. Among alterations in gut microbiota, most studies found a decreased abundance of the phyla Firmicutes and Bifidobacteria, a genus of the phylum Actinomycetota. An increased abundance of the phyla Bacteroidetes and Proteobacteria were identified in animal and human studies. Studies indicated that gut microbiota alter the pathogenesis of AD through its impact on neuroinflammation and permeability of the gastrointestinal tract. The ensuing increase in blood-brain barrier permeability may accelerate Aβ penetrance and formation of neuritic plaques that align with the amyloid hypothesis of AD pathogenesis. Further studies should assess the relationship between gut microbiota and AD progression and therapy preserving beneficial gut microbiota.}, }
@article {pmid39672227, year = {2025}, author = {Franklin, Z and Hull, C and Delibegovic, M and Platt, B}, title = {Pharmacological PTP1B inhibition rescues motor learning, neuroinflammation, and hyperglycaemia in a mouse model of Alzheimer's disease.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115115}, doi = {10.1016/j.expneurol.2024.115115}, pmid = {39672227}, issn = {1090-2430}, mesh = {Animals ; *Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors/metabolism ; Mice ; *Alzheimer Disease/drug therapy/metabolism ; Male ; *Hyperglycemia/drug therapy/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; *Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; Cholestanes/pharmacology/therapeutic use ; Humans ; Aspartic Acid Endopeptidases/metabolism/antagonists & inhibitors ; Enzyme Inhibitors/pharmacology/therapeutic use ; Spermine/analogs & derivatives ; }, abstract = {BACKGROUND: Patients with Alzheimer's Disease (AD) frequently suffer from comorbidities such as type 2 diabetes mellitus (T2DM), accompanied by shared common pathologies such as increased inflammation and impaired glucose homeostasis. Beta-secretase 1 (BACE1), the rate limiting enzyme in AD associated beta-amyloid (Aβ) production, is also implicated in metabolic dysfunction and can increase central and peripheral protein levels of protein tyrosine phosphatase 1B (PTP1B). PTP1B is a validated target in diabetes and obesity, and is a neuroinflammatory regulator involved in degenerative processes. This study investigated the effects of the PTP1B inhibitor, trodusquemine (MSI-1436) on the cognitive and metabolic phenotypes of the neuronal human BACE1 knock-in (PLB4) mouse, a co-morbidity model of AD and T2DM, and their wild-type (PLBWT) controls.
METHODS: Five-month-old male PLB4 and PLBWT mice received PTP1B inhibitor treatment (1 mg/kg intraperitoneal injection; 5 weeks). Activity and spatial habituation (Phenotyper), motor learning (RotaRod), glucose tolerance, and brain and liver molecular analyses were analysed following treatment.
RESULTS: Inhibition of PTP1B improved motor learning alongside glucose tolerance in PLB4 mice, without affecting body weight/adiposity. MSI-1436 treatment led to lower protein levels of amyloid precursor protein (APP), reduced astrogliosis and restoration of the endoplasmic chaperone immunoglobulin heavy chain binding protein (BIP) in the brain, alongside decreased insulin receptor substrate-1 (IRS1) and dipeptidyl peptidase-4 (DPP4) proteins in the liver.
CONCLUSION: We provide evidence that neuronal BACE1 contributes to neuroinflammation and hyperglycaemia in PLB4 mice, and this can be partially rescued by PTP1B inhibition. Targeting PTP1B may therefore offer an attractive therapeutic approach to ameliorate co-morbidity associated pathologies in AD and T2DM.}, }
@article {pmid39672208, year = {2025}, author = {Liu, Y and Wu, L and Peng, W and Mao, X}, title = {Glial polarization in neurological diseases: Molecular mechanisms and therapeutic opportunities.}, journal = {Ageing research reviews}, volume = {104}, number = {}, pages = {102638}, doi = {10.1016/j.arr.2024.102638}, pmid = {39672208}, issn = {1872-9649}, mesh = {Humans ; Animals ; *Nervous System Diseases/therapy ; *Neuroglia/metabolism/physiology ; Cell Polarity/physiology ; Astrocytes/metabolism/physiology ; }, abstract = {Glial cell polarization plays a pivotal role in various neurological disorders. In response to distinct stimuli, glial cells undergo polarization to either mitigate neurotoxicity or facilitate neural repair following injury, underscoring the importance of glial phenotypic polarization in modulating central nervous system function. This review presents an overview of glial cell polarization, focusing on astrocytes and microglia. It explores the involvement of glial polarization in neurological diseases such as Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis and meningoencephalitis. Specifically, it emphasizes the role of glial cell polarization in disease pathogenesis through mechanisms including neuroinflammation, neurodegeneration, calcium signaling dysregulation, synaptic dysfunction and immune response. Additionally, it summarizes various therapeutic strategies including pharmacological treatments, dietary supplements and cell-based therapies, aimed at modulating glial cell polarization to ameliorate brain dysfunction. Future research focused on the spatio-temporal manipulation of glial polarization holds promise for advancing precision diagnosis and treatment of neurological diseases.}, }
@article {pmid39672098, year = {2024}, author = {Asfour, AAR and Evren, AE and Sağlık Özkan, BN and Yurttaş, L}, title = {Investigating the potential of novel thiazole derivatives in treating Alzheimer's and Parkinson's diseases.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/07391102.2024.2437521}, pmid = {39672098}, issn = {1538-0254}, abstract = {The study aimed to investigate 12 novel thiazole compounds in the treatment of neurodegenerative disorders. The compounds produced were evaluated for their inhibitory efficacy against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases (MAOs). Among the compounds, 5d, 5e, and 5j showed the highest AChE inhibitory activity. The IC50 values for compounds are 0.223 ± 0.010 µM, 0.092 ± 0.003 µM, and 0.054 ± 0.002 µM, respectively. In addition, molecular docking analyses and molecular dynamic simulation were used to examine the interactions of these compounds with protein sites. The results suggest that thiazole-ring compounds could serve as a promising basis for the development of drugs aimed at treating neurodegenerative diseases (NDD), caused by Parkinson's and Alzheimer's diseases.}, }
@article {pmid39672085, year = {2025}, author = {Vilarinho, AC and Ferreira, RG}, title = {The Burden of Alzheimer's Disease and Its Costs to a Healthcare System in a Large Population in Brazil.}, journal = {Value in health regional issues}, volume = {45}, number = {}, pages = {101064}, doi = {10.1016/j.vhri.2024.101064}, pmid = {39672085}, issn = {2212-1102}, mesh = {Humans ; *Alzheimer Disease/economics/epidemiology ; Brazil/epidemiology ; *Health Care Costs/statistics & numerical data/trends ; *Cost of Illness ; Aged ; Male ; Female ; Life Expectancy/trends ; Aged, 80 and over ; Disability-Adjusted Life Years ; Middle Aged ; Risk Factors ; Hospitalization/economics/statistics & numerical data ; Delivery of Health Care/economics/statistics & numerical data ; }, abstract = {OBJECTIVES: In Brazil, cases of Alzheimer's disease (AD) are particularly prevalent in the southeastern region, including Minas Gerais, the largest state in the area. This study aimed to estimate the disease burden and healthcare costs from 2018 to 2022.
METHODS: Data on life expectancy, human development index, population size, and gross domestic product per capita were extracted to calculate disability-adjusted life-years (DALYs). Hospital admission data for AD were obtained from the Brazilian Unified Health System Department of Informatics (DATASUS) database, including the number of cases, deaths, age-specific data, and treatment costs. These variables, along with health, social, and environmental data, were processed to create risk factor layers, and the mean cost per DALY was calculated. Generalized estimating equation models were used to analyze the relationship between DALYs and various predictors, controlling for spatial autocorrelation. Maps were created to visualize the distribution of DALYs and cost per DALY.
RESULTS: There were 323 221 deaths from AD in Brazil, with cities averaging 3.61 deaths (range 1-73) and 5.43 hospitalizations (range 1-91) annually. The mean cost per city over these years was $9935.87 (range $44.22 to $787 307.93). In Minas Gerais, significant predictors of the estimated burden of AD include the percentage of the population aged 65 years and older, the human development index, and the prevalence of cardiovascular diseases. DALYs were higher than observed, indicating potential underreporting and insufficient resource allocation for AD treatment and prevention.
CONCLUSIONS: These results emphasize the need for region-specific policies and strategies to address the AD burden effectively. Policy makers should use this information to improve planning and allocate resources appropriately for treatment and prevention.}, }
@article {pmid39671964, year = {2025}, author = {Fu, YX and Liu, SY and Guo, WY and Mei, LC and Dai, YJ and Peng, XJ and Yin, J and Wang, DW and Yang, GF}, title = {Fluorescence imaging opens a new window for the diagnosis of early-stage Alzheimer's disease.}, journal = {Biosensors & bioelectronics}, volume = {271}, number = {}, pages = {117051}, doi = {10.1016/j.bios.2024.117051}, pmid = {39671964}, issn = {1873-4235}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis/metabolism ; Animals ; *Butyrylcholinesterase/metabolism/analysis ; Mice ; Humans ; *Fluorescent Dyes/chemistry ; *Optical Imaging/methods ; *Biosensing Techniques/methods ; Early Diagnosis ; Disease Models, Animal ; Brain/diagnostic imaging/pathology ; tau Proteins/metabolism/analysis ; }, abstract = {As the global population ages, the incidence and prevalence of Alzheimer's disease (AD) continues to rise, posing a serious threat to human health. Butyrylcholinesterase (BChE), which is overexpressed in the brains of patients with AD, is a potential drug target and biomarker. However, the molecular mechanism underlying BChE's role in the AD process remains unclear. Therefore, the development of tools for BChE detection can aid in the diagnosis of AD and deepen our understanding of BChE's contribution to disease progression. Motivated by a bioinspired strategy based on the natural substrate of BChE, we designed a BChE fluorescent probe (HCYO) with a novel recognition group for BChE detection to assist in the early diagnosis of AD. This probe can selectively detect endogenous BChE with an excellent detection limit of 28.9 ng/mL. Using HCYO, we successfully imaged four-week-old mice with an ultraearly AD model, the early diagnosis of the disease. Furthermore, using this HCYO probe, we confirmed that BChE influences the inflammation-induced upregulation the levels of phosphorylated tau and Trigger Receptor Expressed on Myeloid Cells 2, impacting AD progression. These findings provide a crucial theoretical basis for the development of BChE inhibitors for AD treatment.}, }
@article {pmid39671543, year = {2025}, author = {Grill, JD and Tam, S and Thai, G and Vides, B and Pierce, AL and Green, K and Gillen, DL and Teng, E and Kremen, S and Beigi, M and Rissman, RA and Léger, GC and Balasubramanian, A and Revta, C and Morrison, R and Jennings, R and Pa, J and Zhang, J and Jin, S and Messer, K and Feldman, HH}, title = {Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Nicotinamide in Early Alzheimer Disease.}, journal = {Neurology}, volume = {104}, number = {1}, pages = {e210152}, pmid = {39671543}, issn = {1526-632X}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease/drug therapy/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Double-Blind Method ; *Niacinamide/therapeutic use/adverse effects/administration & dosage ; Phosphorylation ; Proof of Concept Study ; *tau Proteins/cerebrospinal fluid ; Treatment Outcome ; Vitamin B Complex/administration & dosage/pharmacology ; }, abstract = {BACKGROUND AND OBJECTIVES: Nicotinamide is a coenzyme involved in cellular oxidation-reduction reactions that can inhibit Class III histone deacetylases (HDACs) or sirtuins. HDAC inhibition can affect numerous therapeutic pathways, including tau phosphorylation. We tested the hypothesis that nicotinamide treatment could reduce tau phosphorylation in early Alzheimer disease (AD).
METHODS: We performed a randomized, placebo-controlled, phase 2a proof-of-concept trial to evaluate the safety and tolerability of 48 weeks of treatment with 1,500 mg of nicotinamide twice a day. The primary outcome was level of tau phosphorylated at threonine 231 (p-tau231) in CSF. Prespecified secondary outcomes were levels of p-tau181, total tau, amyloid β40 (Aβ40), and Aβ42 in CSF and the clinical measures Alzheimer's Disease Assessment Scale (ADAS-cog13), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale-Mild Cognitive Impairment (ADCS-ADL-MCI), and Clinical Dementia Rating Summary of Boxes (CDR-SB). Participants were recruited at 2 academic clinical centers. Enrollment criteria included diagnosis of mild cognitive impairment or mild dementia with CSF biomarker confirmation of AD. The Holm-Bonferroni procedure was used to control type I error within biomarker and clinical domains.
RESULTS: Of 47 participants enrolled (mean age = 73.8 years; 43% female), 1 dropped out before treatment initiation and 6 before completion, including 2 in the nicotinamide and 4 in the placebo arm. Adverse events (AEs) were balanced by arm, with few attributed to treatment. Common AEs included infections and nervous system disorders. There was no statistically significant benefit of nicotinamide on the primary outcome of week 48 change from baseline in CSF p-tau231 (analysis of covariance; estimated mean difference in change between arms = -2.06, SE = 4.03; p = 0.61), with observed mean decline in CSF p-tau231 greater in the nicotinamide arm (-4.7 ± 14.5) than in the placebo arm (-2.3 ± 10.6). No significant effects of treatment were observed on secondary biomarker outcomes (CSF p-tau181, Aβ40, Aβ42, and total tau) in similar models (all p values >0.05), with observed mean changes in CSF p-tau181 (0.4 ± 29.8 vs 10.4 ± 41.8) and total tau (8.4 ± 228.6 vs 60.5 ± 237.5) favoring nicotinamide compared with placebo. At week 48, nicotinamide-treated participants experienced less decline on CDR-SB (mixed-effect model with repeated measures; estimate = -1.42, SE = 0.65; p = 0.03 unadjusted for multiple comparisons), without significant differences in cognitive (ADAS-cog; estimate = -1.93, SE = 1.93; p = 0.32) or functional (ADCS-ADL-MCI; estimate = -3.10, SE = 1.86; p = 0.10) outcomes.
DISCUSSION: Nicotinamide was safe but did not alter AD biomarkers.
CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with MCI or mild dementia with positive CSF AD biomarkers, 48 weeks of nicotinamide, 3,000 mg daily, is no better than placebo in reducing CSF p-tau231.
ClinicalTrials.gov: NCT03061474.}, }
@article {pmid39671432, year = {2024}, author = {Saeed, A and Waris, A and Fuwad, A and Iqbal, J and Khan, J and AlQahtani, D and Gilani, O and Shah, UH and , }, title = {Random survival forest model for early prediction of Alzheimer's disease conversion in early and late Mild cognitive impairment stages.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0314725}, pmid = {39671432}, issn = {1932-6203}, mesh = {*Alzheimer Disease/diagnosis ; Humans ; *Cognitive Dysfunction/diagnosis ; *Disease Progression ; Female ; Aged ; Male ; *Machine Learning ; Biomarkers ; Aged, 80 and over ; Proportional Hazards Models ; Early Diagnosis ; Neuroimaging/methods ; }, abstract = {With a clinical trial failure rate of 99.6% for Alzheimer's Disease (AD), early diagnosis is critical. Machine learning (ML) models have shown promising results in early AD prediction, with survival ML models outperforming typical classifiers by providing probabilities of disease progression over time. This study utilized various ML survival models to predict the time-to-conversion to AD for early (eMCI) and late (lMCI) Mild Cognitive Impairment stages, considering their different progression rates. ADNI data, consisting of 291 eMCI and 546 lMCI cases, was preprocessed to handle missing values and data imbalance. The models used included Random Survival Forest (RSF), Extra Survival Trees (XST), Gradient Boosting (GB), Survival Tree (ST), Cox-net, and Cox Proportional Hazard (CoxPH). We evaluated cognitive, cerebrospinal fluid (CSF) biomarkers, and neuroimaging modalities, both individually and combined, to identify the most influential features. Our results indicate that RSF outperformed traditional CoxPH and other ML models. For eMCI, RSF trained on multimodal data achieved a C-Index of 0.90 and an IBS of 0.10. For lMCI, the C-Index was 0.82 and the IBS was 0.16. Cognitive tests showed a statistically significant improvement over other modalities, underscoring their reliability in early prediction. Furthermore, RSF-generated individual survival curves from baseline data facilitate clinical decision-making, aiding clinicians in developing personalized treatment plans and implementing preventive measures to slow or prevent AD progression in prodromal stages.}, }
@article {pmid39671047, year = {2025}, author = {Hanazawa, R and Sato, H and Hirakawa, A and , }, title = {Mixture Disease Progression Model to Predict and Cluster the Long-Term Trajectory of Cognitive Decline in Alzheimer's Disease.}, journal = {Therapeutic innovation & regulatory science}, volume = {59}, number = {2}, pages = {264-277}, pmid = {39671047}, issn = {2168-4804}, mesh = {*Alzheimer Disease ; Humans ; *Disease Progression ; *Cognitive Dysfunction ; Aged ; Female ; Male ; Aged, 80 and over ; Cluster Analysis ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease for which many clinical trials failed to detect treatment effects, possibly due to the heterogeneity of disease progression among the patients. Predicting and clustering a long-term trajectory of cognitive decline from the short-term cognition data of individual patients would help develop therapeutic interventions for AD.
METHODS: This study developed mixture disease progression model to predict and cluster the long-term trajectory of cognitive decline in the population. We predicted the 30-year long-term trajectories of the three cognitive scales and categorized the individuals into rapid and slow cognitive decliners by applying the method, which was based on the two-component normal mixture nonlinear mixed-effects model, to the short-term follow-up data of the Mini-Mental State Examination, the 13-item Alzheimer's Disease Assessment Scale-Cognitive, and the Clinical Dementia Rating Scale-sum of boxes collected in patients with mild cognitive impairment and AD in the Alzheimer's Disease Neuroimaging Initiative.
RESULTS: For each cognitive scale, the models identified two distinct subpopulations, including a population of comprising approximately 10-20% of individuals experiencing rapid cognitive decline, wherein the posterior means of the differences in cognitive decline speed between the two groups ranged from 2 to 3 years. We also identified baseline background factors associated with rapid decliners for three cognitive scales.
CONCLUSION: Identifying the risk factors associated with rapid decline of cognition by the proposed method aids in planning eligibility criteria and allocation strategy for accounting for the varying disease progression speeds among the patients enrolled in clinical trials for AD.}, }
@article {pmid39670820, year = {2025}, author = {Lagiakos, HR and Zou, Y and Igawa, H and Therrien, E and Lawrenz, M and Kato, M and Svensson, M and Gray, F and Jensen, K and Dahlgren, MK and Pelletier, RD and Dingley, K and Bell, JA and Liu, Z and Jiang, Y and Zhou, H and Skene, RJ and Nie, Z}, title = {In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {3}, pages = {2720-2741}, doi = {10.1021/acs.jmedchem.4c02074}, pmid = {39670820}, issn = {1520-4804}, mesh = {Animals ; *Neurodegenerative Diseases/drug therapy ; Humans ; Mice ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use/chemical synthesis ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis ; MAP Kinase Kinase Kinases/antagonists & inhibitors/metabolism ; Neurons/drug effects/pathology/metabolism ; Drug Discovery ; Computer Simulation ; Structure-Activity Relationship ; Rats ; }, abstract = {Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.}, }
@article {pmid39669488, year = {2024}, author = {Zhang, J and Li, Q and Yan, B and Wang, Q and Zhou, Y}, title = {Integrated network pharmacology and brain metabolomics to analyze the mechanism of Dihuang Yinzi intervention in Alzheimer's disease.}, journal = {Heliyon}, volume = {10}, number = {5}, pages = {e26643}, pmid = {39669488}, issn = {2405-8440}, abstract = {Alzheimer's disease (AD) is an incurable neurodegenerative disease that has become one of the most important diseases threatening global public health security. Dihuang Yinzi (DHYZ) is a traditional Chinese medicine that has been widely used for the treatment of AD and has significant therapeutic effects, but its specific mechanism of action is still unclear.The aim of the study is to investigate the specific mechanism of DHYZ in treating AD based on brain metabolomics and network pharmacology.
MATERIALS AND METHODS: In this study, the classic APPswe/PS1E9 (APP/PS1) mice were selected as the AD animal model, and the mechanism of DHYZ was studied. The learning and memory ability of mice was detected by Y-maze test, and the ultrastructure of neural cells in the brain of the mice was observed by transmission electron microscope (TEM). Then, the mechanism of DHYZ intervention in AD was analyzed by constructing network pharmacology, and combined with brain metabolomics based on ultra performance liquid chromatography-mass spectrometry (UPLC-MS) to detect differential metabolic markers and their metabolic pathways. In addition, a joint analysis of differential metabolites and potential targets for DHYZ treatment of AD is conducted to deeply explore the relationship between key targets, differential metabolites, and metabolic pathways.
RESULTS: After 30 days of DHYZ treatment, the spatial work and reference memory ability of APP/PS1 mice were significantly improved, the structure of mitochondria and synapses in the neurons of the brain were basically normal. 202 potential targets for DHYZ treatment of AD were screened through network pharmacology, and after enrichment analysis, these targets showed correlation with redox reactions, mitochondrial and synaptic functional pathways. And 7 differential metabolites were identified in brain metabolomics are Nicotinic acid, N-Formyl-L-glutamic acid, 5-(2-Hydroxyethyl)-4-methylthiazole, D-Gulono-1,4-lactone, Norepinephrine, 3-Methylotrophicacid, Palmitic acid. These differential metabolites mainly involve nicotinite and nicotinamide metabolism, pertussis, cAMP signaling pathway, cysteine and methionine metabolism. Notablely, through matching analysis of targets and metabolites, a total of 20 genes were found to match Nicotinic acid, 51 genes were found to match norepinephrine, and 14 genes intersected with the two metabolites, enrichment analysis of the intersected genes showed that neuroactive light receptor interaction, serotonergic synapse, and cAMP signaling were significantly affected, which is consistent with previous network pharmacology results.
CONCLUSION: This study identified the main chemical ingredients of DHYZ intervention in AD may originated from Polygala tenuifolia Wild, Dendrobium nobile Line and Ophiogon japonicus (L.f) Ker-Gawl. Combined with Y Maze, TEM and brain metabolomics, revealed that DHYZ can improve the learning and memory abilities and brain pathological morphology of APP/PS1 mice by regulating nicotinic acid, 3-Methylthiopropionic acid, pertussis and their metabolic pathways, including nicotinate and nicotinamide metabolism, cAMP signaling pathway and cysteine and methionine metabolism. In short, this study provides a new research foundation and direction for the treatment of AD with traditional Chinese medicine.}, }
@article {pmid39668705, year = {2025}, author = {Fazio-Eynullayeva, E and Cunnington, M and Mystkowski, P and Lv, L and Aly, A and Yee, CW and Desai, R and Liu, CL and Duh, MS and Mattke, S}, title = {Real-world healthcare resource utilization of Alzheimer's disease in the early and advanced stages: a retrospective cohort study.}, journal = {Journal of medical economics}, volume = {28}, number = {1}, pages = {81-88}, doi = {10.1080/13696998.2024.2442240}, pmid = {39668705}, issn = {1941-837X}, mesh = {Humans ; *Alzheimer Disease ; Female ; Male ; Retrospective Studies ; Aged ; Aged, 80 and over ; *Insurance Claim Review ; *Patient Acceptance of Health Care/statistics & numerical data ; Severity of Illness Index ; Health Resources/statistics & numerical data/economics ; Mental Status and Dementia Tests ; }, abstract = {AIMS: To compare all-cause and Alzheimer's disease (AD)-related healthcare resource utilization (HCRU) by cognitive stage.
METHODS AND MATERIALS: This retrospective study analyzed insurance claims data linked to electronic health records (01/01/2015-12/31/2021). Patients with ≥1 cognitive assessment (Mini-Mental State Examination or Montreal Cognitive Assessment) and ≥1 medical or pharmacy claim for an AD diagnosis or AD medications were included. Inverse probability of treatment weighting (IPTW) was used to address potential confounding. All-cause and AD-related HCRU were summarized per patient per year (PPPY) and compared between early AD and advanced AD cohorts (defined according to cognitive scores) using generalized linear regression models; adjusted incidence rate ratios (IRRs), and 95% confidence intervals (CI) were reported.
RESULTS: A total of 193 patients were included (median age: 82 years; 63.2% female), 108 with early AD and 85 with advanced AD, with similar mean follow up. All-cause HCRU, on average, was similar between early AD and advanced AD cohorts (37.4 PPPY and 38.9 encounters PPPY, respectively). For AD-related HCRU, patients with early AD had fewer encounters PPPY, on average, than patients with advanced AD (1.26 and 3.88 encounters, respectively). Following IPTW adjustment, the advanced AD cohort had significantly higher overall AD-related HCRU (IRR: 3.64 [95% CI: 1.96-6.75], p < 0.001) and outpatient visits (IRR: 2.76 [95% CI: 1.68-4.54], p < 0.001) compared to the early AD cohort.
LIMITATIONS: The relatively small sample size of patients with linked claims and cognitive score data limited the ability to assess contribution of all encounter types to HCRU trends, as well as generalizability to the broader AD population.
CONCLUSIONS: Although all-cause HCRU was similar, patients with advanced AD incurred higher AD-related HCRU compared to patients living with early AD. Further research is needed to determine whether interventions earlier in disease progression can mitigate the AD-related healthcare burden for patients with advanced AD.}, }
@article {pmid39667582, year = {2025}, author = {Jain, S and Singh, R and Paliwal, T and Verma, K and Dwivedi, J and Paliwal, S and Sharma, S}, title = {Discovery of novel fatty acid amide hydrolase (FAAH) inhibitors as anti-alzheimer agents via in-silico-based drug design, virtual screening, molecular docking, molecular dynamics simulation, DFT, and non-clinical studies.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {247}, number = {}, pages = {173943}, doi = {10.1016/j.pbb.2024.173943}, pmid = {39667582}, issn = {1873-5177}, mesh = {*Amidohydrolases/antagonists & inhibitors ; Animals ; *Alzheimer Disease/drug therapy ; *Molecular Docking Simulation ; Mice ; *Molecular Dynamics Simulation ; Male ; *Enzyme Inhibitors/pharmacology/chemistry ; Drug Design ; Drug Evaluation, Preclinical ; Disease Models, Animal ; Humans ; Computer Simulation ; Drug Discovery ; Streptozocin ; }, abstract = {AIM: To identify some novel fatty acid hydrolase (FAAH) inhibitors that may contribute to the treatment of Alzheimer's disease (AD).
METHODS: In-silico pharmacophore modelling including ligand-based pharmacophore modelling, virtual screening, molecular docking, molecular dynamics modelling, density functional theory and in-silico pharmacokinetics and toxicological studies were employed for the retrieving of novel FAAH inhibitors. Further, these compounds were evaluated for FAAH inhibitory activity using an in vitro enzymatic assay, and later, an in vivo streptozotocin (STZ)-induced AD model was examined in mice.
RESULTS: Using an in-silico pharmacophore modelling process with molecular docking, molecular dynamic modelling, density functional theory and in-silico pharmacokinetics and toxicological analysis, three compounds (NCI1697, NCI1001and NCI1041) were retrieved. The in vitro FAAH activity assay kit (Fluorometric) was employed to examine the FAAH inhibitory activity of identified compounds. Further, in in-vivo studies, treatment with these compounds at 2.5 and 5 mg/kg doses orally for 10 days restored the STZ-induced memory deficits in mice, as evident in the radial arm and Morris's water maze assays. Also, these compounds ameliorated oxidative stress profiles and neuroinflammatory biomarkers in mice. Interestingly, STZ-induced disturbance in gene expressions related to AD pathophysiology including endocannabinoid signalling neuroinflammation and neuroimmune signalling were also restored after the treatment. Histopathological findings also confirmed the improvement in the organization of cells and reduction in vacuolation in mice hippocampal tissue in treated mice.
CONCLUSION: The in-silico, in vitro and in-vivo findings collectively indicated that these compounds have impressive FAAH inhibitory activity and may be developed as therapeutic agents in the management of AD.}, }
@article {pmid39667052, year = {2025}, author = {Shankar, G and Kumar, P and Rai, S and Ghosh, A and Varma, T and Wani, MA and Kumar, S and Mandloi, U and Singh, GK and Garg, P and Kulkarni, O and Srikrishna, S and Kumar, S and Modi, G}, title = {Discovery of novel hybrid tryptamine-rivastigmine molecules as potent AChE and BChE inhibitors exhibiting multifunctional properties for the management of Alzheimer's disease.}, journal = {European journal of medicinal chemistry}, volume = {283}, number = {}, pages = {117066}, doi = {10.1016/j.ejmech.2024.117066}, pmid = {39667052}, issn = {1768-3254}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Alzheimer Disease/drug therapy/metabolism ; *Rivastigmine/pharmacology/chemistry/chemical synthesis ; *Acetylcholinesterase/metabolism ; *Butyrylcholinesterase/metabolism ; Animals ; Humans ; Structure-Activity Relationship ; *Tryptamines/chemistry/pharmacology/chemical synthesis ; Molecular Docking Simulation ; Molecular Structure ; Drug Discovery ; Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Dose-Response Relationship, Drug ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Mice ; }, abstract = {Contemporary research evidence has corroborated a gradual loss of central cholinergic neurons in Alzheimer's Disease (AD). This progressive deterioration leads to cognitive dysfunction and impaired motor activity, culminating in the brain cell's death in the disease. The approved drugs for AD treatment can only offer relief from symptoms without addressing the underlying pathological hallmarks of the disease. To address the limitations associated with rivastigmine (RIV), a marketed drug for AD, a series of tryptamine derivatives was designed, synthesized, and evaluated in various in-vitro and in-vivo AD models. Enzyme inhibition studies identified compounds 6d and 6e as the lead molecules with potent inhibitors against AChE (6d, IC50: 0.99 ± 0.009 nM and 6e IC50: 7.97 ± 0.016 nM and BChE (6d, IC50: 27.79 ± 0.21 nM and 6e, IC50: 0.79 ± 0.005 nM), compared to the marketed drug Riv (AChE, IC50: 6630 ± 0.76 nM, BChE IC50 = 91 ± 0.40 nM). The molecular docking and dynamics studies corroborated the enzyme inhibition studies. The PAMPA assay strongly suggested the BBB crossing ability of the lead molecules. Further, 6d and 6e demonstrated the capability to counteract oxidative stress and Aβ1-42 in various in-vitro studies. Compound 6e exhibited remarkable radical scavenging activity in the DPPH assay (IC50: 22.91 ± 1.73 μM) compared to rivastigmine (% radical scavenging activity: 3.71 ± 0.09 at 200 μM). Interestingly, 6d and 6e exhibited promising activity in the AD Drosophila model by protecting eye phenotypes from degeneration induced by Aβ1-42 toxicity and reduced mitochondrial and cellular oxidative stress in this model. Furthermore, upon oral administration, 6d and 6e could reverse scopolamine-induced amnesia by improving spatial and cognitive memory in mice at 0.3 and 0.5 mg/kg compared to rivastigmine at 3 mg/kg and were found to have potent ex-vivo anti-ChEs properties, which are correlated with the observed pro-cognitive effects in the Morris Water Maze, likely mediated through the inhibition of both cholinesterases. The expression of various neuroprotection markers, such as BDNF and TRKB, was significantly overexpressed compared to the disease control group.}, }
@article {pmid39666629, year = {2024}, author = {Shim, SR and Kim, JY and Kwon, KY and Shin, J and Lee, Y and Lee, SM}, title = {Effects of rivastigmine on gait in patients with neurodegenerative disorders: A systematic review and meta-analysis.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0310900}, pmid = {39666629}, issn = {1932-6203}, mesh = {Humans ; *Accidental Falls/prevention & control/statistics & numerical data ; Alzheimer Disease/complications/drug therapy/physiopathology ; Cholinesterase Inhibitors/pharmacology/therapeutic use ; *Gait/drug effects/physiology ; *Neurodegenerative Diseases/complications/drug therapy/physiopathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Parkinson Disease/drug therapy/complications/physiopathology ; *Rivastigmine/pharmacology/therapeutic use ; }, abstract = {BACKGROUND & AIMS: Gait disturbances are commonly observed in patients with neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and higher-level gait disorders, which are associated with cholinergic deficits. We conducted a systematic review and meta-analysis to investigate the effects of rivastigmine on improvement in gait.
METHODS: A comprehensive literature search was conducted using Medical Subject Heading (MeSH) terms and text keywords related to gait and falls after rivastigmine treatment for neurodegenerative disorders. The intervention (rivastigmine), comparison (control or no treatment), and outcomes of improvement in gait speed and fall were assessed from database inception to April 2024. References and collected data were meticulously reviewed to ensure the integrity of the included studies. Standardized mean differences (SMDs) and Hedges'g, along with their 95% confidence intervals (Cls), were calculated for gait speed and number of falls.
RESULTS: A total of 222 articles were identified during the initial search across different electronic databases, 50 including PubMed (n = 23), Cochrane (n = 19), Embase (n = 139), Scopus (n = 38), and a manual search (n = 3). Finally, we conducted a systematic review and meta-analysis focusing on the final four studies, encompassing 286 participants. The pooled SMD for the overall gait speed without a comparison group was 0.761 (95% CI: -1.165 to 2.688), indicating no significant improvement in gait speed. For the overall number of falls between the rivastigmine treatment and control groups, the pooled SMD was -0.366 (95% CI: -0.650 to -0.083). A statistically significant reduction in the number of falls was observed in the rivastigmine group than in the control group.
CONCLUSION: Rivastigmine treatment in patients with neurodegenerative disorders tend to improve gait speed and significantly reduces fall incidence. Given the limited efficacy of current treatments for gait disturbances and falls, dual cholinesterase inhibitors like rivastigmine could be a promising therapeutic option.}, }
@article {pmid39666359, year = {2024}, author = {Baicker, K and Simon, K}, title = {Developing Evidence-Based Health Policy for Dementia Care.}, journal = {JAMA health forum}, volume = {5}, number = {12}, pages = {e245252}, doi = {10.1001/jamahealthforum.2024.5252}, pmid = {39666359}, issn = {2689-0186}, }
@article {pmid39665609, year = {2024}, author = {Feng, Y and Yu, X and Han, J}, title = {Quercetin Regulates the Polarization of Microglia through the NRF2/HO1 Pathway and Mitigates Alzheimer's Disease.}, journal = {Actas espanolas de psiquiatria}, volume = {52}, number = {6}, pages = {786-799}, pmid = {39665609}, issn = {1578-2735}, mesh = {*NF-E2-Related Factor 2/metabolism ; Animals ; *Alzheimer Disease/metabolism/drug therapy ; *Microglia/metabolism/drug effects ; Mice ; *Quercetin/pharmacology ; Male ; Heme Oxygenase-1/metabolism ; Antioxidants/pharmacology ; Signal Transduction/drug effects ; Disease Models, Animal ; Humans ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a burdening disease and is the main cause of dementia. Quercetin (Que), an antioxidant, plays potential roles in treating age-related disorders, including AD. This study aimed to validate the effects of Que on AD and explore the underlying mechanisms.
METHODS: Mice with no treatment, amyloid-β Aβ (1-42) treatment (for acquiring AD model), or Aβ (1-42) plus Que treatment were used. Cognitive function was determined using the open field test (OFT), objective recognition test, and Y-maze test. In brain tissues, mRNA levels of inflammation cytokines, the M1 microglia marker cluster of differentiation (CD)86, and the M2 microglia markers arginase 1 (Arg1) and CD206 were measured. Nuclear factor E2-related factor 2 (NRF2)/heme oxygenase-1 (HO1) pathway-related proteins were detected by western blot. Additionally, mechanisms were investigated using human microglia HMC3 cells treated with Aβ (1-42) and Aβ (1-42) plus Que. The NRF2/HO1 pathway in HMC3 cells was inhibited using the selective inhibitor ML385. Cell viability and death were assessed using the cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) release levels, respectively. Cell apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Levels of NRF2/HO1 pathway-related proteins, inflammation cytokines, and oxidative stress-related markers, including malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (reduced glutathione (GSH)/oxidized glutathione disulfide (GSSG)), were determined in HMC3 cells. Flow cytometry was used to determine M1 markers CD86 and CD80 and M2 markers CD206 and CD163.
RESULTS: Cognitive ability was impaired in AD model mice, and Que treatment reversed this impairment (p < 0.05). Levels of interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), and IL-6 were increased, while M2 markers were decreased in the AD model mouse brain. Que treatment reversed these changes (p < 0.001). The NRF2/HO1 pathway was slightly inhibited in AD mice brain, while further activated by Que (p < 0.05). Que reversed the Aβ (1-42)-impaired cell viability. Through greatly activating NRF2/HO1 pathway, Que suppressed Aβ (1-42)-induced cell death, decreased Aβ (1-42)-promoted IL-1β, TNF-α, IL-6, MDA, CD86 and CD80, increased Aβ (1-42)-suppressed SOD and GSH/GSSG, and greatly increased CD206 and CD163 (p < 0.01).
CONCLUSION: Quercetin, through the activation of the NRF2/HO1 pathway, promotes M2 polarization of microglia, suppresses Aβ (1-42)-induced inflammation and oxidative stress, protects microglia from Aβ (1-42)-induced damage, improves cognitive function in mice, and demonstrates therapeutic potential for AD.}, }
@article {pmid39665555, year = {2024}, author = {Eng, S and Aifuwa, E and Frishman, WH and Aronow, WS}, title = {Cardiovascular Effect of Drugs Used to Treat Alzheimer's Disease.}, journal = {Cardiology in review}, volume = {}, number = {}, pages = {}, doi = {10.1097/CRD.0000000000000831}, pmid = {39665555}, issn = {1538-4683}, abstract = {This review examines the cardiovascular effects of the mainstay drugs used to treat Alzheimer's disease (AD), namely cholinesterase inhibitors (ChEIs) and memantine. ChEIs represent the current first-line treatment for AD. Memantine is typically reserved for moderate to severe AD. Conventionally, ChEIs are thought to increase vagal tone, resulting in an increased risk of cardiac side effects such as bradycardia. However, emerging evidence suggests that ChEIs may offer a protective role on overall cardiovascular mortality in patients with dementia. Similarly, memantine, which is an N-methyl-D-aspartate receptor antagonist, has demonstrated cardioprotective properties in animal studies, raising the question of its clinical applications. Recently, aducanumab and lecanemab, antiamyloid-β monoclonal antibodies that aim to slow the progression of disease, have been Food and Drug Administration-approved for the treatment of AD. This review explores the current evidence regarding potential cardiovascular risks and protective effects of ChEIs and memantine in the treatment of AD, as well as the cardiovascular effects of aducanumab and lecanemab.}, }
@article {pmid39665445, year = {2025}, author = {Wang, W and Zhang, J and Li, C}, title = {Randomized controlled trial of Bushen Yinao pill combined with conventional therapy on intestinal flora and cognitive function in older patients with Alzheimer's disease.}, journal = {International journal of psychiatry in medicine}, volume = {60}, number = {3}, pages = {280-295}, doi = {10.1177/00912174241290962}, pmid = {39665445}, issn = {1541-3527}, mesh = {Humans ; *Alzheimer Disease/drug therapy/microbiology/blood ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/pharmacology/administration & dosage ; Male ; Female ; Aged ; Aged, 80 and over ; *Outcome Assessment, Health Care ; }, abstract = {ObjectiveThis study evaluated the effects of the Bushen Yinao pill, combined with standard therapy, on gut flora, inflammatory markers, and cognitive function in older patients with Alzheimer's disease (AD).MethodsA total of 136 AD patients treated at the department of neurology at a hospital in China from August 2022 to September 2023 were randomly assigned to two groups: 68 patients received standard treatment (control group, CTG), and 68 patients received the Bushen Yinao pill plus standard treatment (intervention group, ITG). Outcomes included Traditional Chinese Medicine (TCM) syndrome scores, gut microbiota composition, inflammatory markers, cognitive function, overall efficacy, and safety.ResultsAfter treatment, the intervention group (ITG) showed significant reductions in TCM syndrome scores compared to the control group (CTG) (P < 0.05). The ITG also showed significant increases in beneficial bacterial flora in the gut and decreases in harmful bacteria compared to the CTG (P < 0.05). Inflammatory markers (Aβ, IL-6, TNF-α) were reduced, and cognitive function improved significantly more in the ITG (P < 0.05). There were no significant differences in adverse reactions between the groups (P > 0.05).ConclusionThe Bushen Yinao pill, when combined with standard therapy, may help to regulate gut microbiota, reduce inflammatory markers, and enhance cognitive function in AD patients, while also showing a favorable safety profile. Further research is recommended to validate these findings in other populations.}, }
@article {pmid39665408, year = {2025}, author = {Muolokwu, CE and Gothwal, A and Kanekiyo, T and Singh, J}, title = {Synthesis and Characterization of Transferrin and Cell-Penetrating Peptide-Functionalized Liposomal Nanoparticles to Deliver Plasmid ApoE2 In Vitro and In Vivo in Mice.}, journal = {Molecular pharmaceutics}, volume = {22}, number = {1}, pages = {229-241}, pmid = {39665408}, issn = {1543-8392}, support = {R01 AG068034/AG/NIA NIH HHS/United States ; R01 AG083981/AG/NIA NIH HHS/United States ; RF1 AG068034/AG/NIA NIH HHS/United States ; S10 OD030309/OD/NIH HHS/United States ; }, mesh = {Animals ; *Liposomes/chemistry ; Mice ; *Transferrin/chemistry ; *Nanoparticles/chemistry ; *Apolipoprotein E2/genetics ; *Cell-Penetrating Peptides/chemistry/administration & dosage ; *Blood-Brain Barrier/metabolism ; *Plasmids/administration & dosage/genetics ; Alzheimer Disease/therapy/drug therapy ; Brain/metabolism ; Mice, Inbred C57BL ; Humans ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by the aggregation of amyloid-β plaques and neurofibrillary tangles in the brain, leading to synaptic dysfunction and neuronal degeneration. Recently, new treatment approaches involving drugs such as donanemab and lecanemab have been introduced for AD. However, these drug regimens have been associated with adverse effects, leading to the exploration of gene therapy as a potential treatment option. The apolipoprotein E (ApoE) isoforms (ApoE2, ApoE3, and ApoE4) play pivotal roles in AD pathology, with ApoE2 known for its protective effects against AD, making it a promising candidate for gene therapy interventions. However, delivering therapeutics across the blood-brain barrier (BBB) remains a crucial challenge in treating neurological disorders. Liposomes, lipid-based vesicles, are effective nanocarriers due to their ability to shield therapeutics from degradation, though they often lack specificity for brain delivery. To address this issue, liposomes were functionalized with cell-penetrating peptides such as penetratin (Pen), cingulin (Cgn), and a targeting ligand transferrin (Tf). This modification strategy aimed to enhance the delivery of therapeutic ApoE2 plasmids across the BBB to neurons, thereby increasing the level of ApoE2 protein expression. Experimental findings demonstrated that dual-functionalized liposomes (CgnTf and PenTf) exhibited higher cellular uptake, biodistribution, and transfection efficiency than single-functionalized (Pen, Cgn, or Tf) and nonfunctionalized liposomes. In vitro studies using primary neuronal cells, bEnd.3 cells, and primary astrocytes consistently supported these findings. Following a single dose treatment via tail vein administration in C57BL6/J mice, in vivo biodistribution results showed significantly higher biodistribution levels in the brain (∼12% ID/gram of tissue) for dual-functionalized liposomes. Notably, treatment with dual-functionalized liposomes resulted in a 2-fold increase in ApoE2 expression levels compared to baseline levels. These findings highlight the potential of dual-functionalized liposomes as an efficacious delivery system for ApoE2 gene therapy in AD, highlighting a promising strategy to address the disease's underlying mechanisms.}, }
@article {pmid39665306, year = {2024}, author = {Zhang, N and Nao, J and Dong, X}, title = {Efficacy and Safety of Natural Apigenin Treatment for Alzheimer's Disease: Focus on In vivo Research Advancements.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/1570159X23666241211095018}, pmid = {39665306}, issn = {1875-6190}, abstract = {BACKGROUND: Alzheimer's Disease (AD) is the most common dementia in clinics. Despite decades of progress in the study of the pathogenesis of AD, clinical treatment strategies for AD remain lacking. Apigenin, a natural flavonoid compound, is present in a variety of food and Chinese herbs and has been proposed to have a wide range of therapeutic effects on dementia.
OBJECTIVE: To clarify the relevant pharmacological mechanism and therapeutic effect of apigenin on animal models of AD.
METHODS: Computer-based searches of the PubMed, Cochrane Library, Embase, and Web of Science databases were used to identify preclinical literature on the use of apigenin for treating AD. All databases were searched from their respective inception dates until June 2023. The meta-analysis was performed with Review manager 5.4.1 and STATA 17.0.
RESULTS: Thirteen studies were eventually enrolled, which included 736 animals in total. Meta-analysis showed that apigenin had a positive effect on AD. Compared to controls, apigenin treatment reduced escape latency, increased the percentage of time spent in the target quadrant and the number of plateaus traversed; apigenin was effective in reducing nuclear factor kappa-B (NF-κB) p65 levels; apigenin effectively increased antioxidant molecules SOD and GSH-px and decreased oxidative index MDA; for ERK/CREB/BDNF pathway, apigenin effectively increased BDNF and pCREB molecules; additionally, apigenin effectively decreased caspase3 levels and the number of apoptotic cells in the hippocampus.
CONCLUSION: The results show some efficacy of apigenin in the treatment of AD models. However, further clinical studies are needed to confirm the clinical efficacy of apigenin.}, }
@article {pmid39664778, year = {2024}, author = {Llorente-Saguer, I and Oxtoby, NP}, title = {A data-driven framework for biomarker discovery applied to optimizing modern clinical and preclinical trials on Alzheimer's disease.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae438}, pmid = {39664778}, issn = {2632-1297}, support = {P30 AG062677/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; }, abstract = {PET is used to measure tau protein accumulation in Alzheimer's disease. Multiple biomarkers have been proposed to track disease progression, most notably the standardized uptake value ratio of PET tracer uptake in a target region of interest relative to a reference region, but literature suggests these region choices are nontrivial. This study presents and evaluates a novel framework, BioDisCVR, designed to facilitate the discovery of useful biomarkers, demonstrated on [[18]F]AV-1451 tau PET data in multiple cohorts. BioDisCVR enhances signal-to-noise by conducting a data-driven search through the space of possible combinations of regional tau PET signals into a ratio of two composite regions, driven by a user-defined fitness function. This study compares ratio-based biomarkers discovered by the framework with state-of-the-art standardized uptake value ratio biomarkers. Data used is tau PET regional measurements from 198 individuals from the Alzheimer's Disease Neuroimaging Initiative database, used for discovery, and 42 from the Mayo Clinic Alzheimer's Disease Research Center and Mayo Clinic Study of Aging (MCSA), used for external validation. Biomarkers are evaluated by calculating clinical trial sample size estimates for 80% power and 20% effect size. Secondary metrics are a measure of longitudinal consistency (standard deviation of linear mixed-effects model residuals), and separation between cognitive groups (t-statistic of the change over time due to being cognitively impaired). When applied to preclinical (secondary prevention with CU individuals) and clinical (treatment aimed at cognitively impaired individuals) trials on Alzheimer's disease, our data-driven framework BioDisCVR discovered ratio-based tau PET biomarkers vastly superior to previous work, both reducing measurement error and sample size estimates for hypothetical clinical trials. Our analysis suggests remarkable potential for patient benefit (reduced exposure to health risks associated with experimental drugs) and substantial cost savings, through accelerated trials and reduced sample sizes. Our study supports the leveraging of data-driven methods like BioDisCVR for clinical benefit, with the potential to positively impact drug development in Alzheimer's disease and beyond.}, }
@article {pmid39664445, year = {2024}, author = {Maleki, L and Mohammadian, F and Panahishokouh, M and Mohebbi, N}, title = {A randomized, double-blind, placebo-controlled clinical trial to evaluate pregabalin efficacy in the treatment of behavioral and psychological symptoms of dementia in patients with Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1460325}, pmid = {39664445}, issn = {1662-4548}, abstract = {BACKGROUND: Behavioral and Psychological Symptoms of Dementia (BPSD) are common during Alzheimer's disease and cause severe problems for patients and their caregivers.
OBJECTIVES: To assess the therapeutic efficacy of Pregabalin in comparison with a placebo in treating BPSD in patients with Alzheimer's disease (AD) visiting the memory and cognition clinic of Roozbeh Psychiatric Hospital in Tehran, Iran.
METHODS: A 12-week double-blind, randomized comparison of Pregabalin and placebo treatments was conducted in 53 patients with DSM-V diagnosis of dementia of Alzheimer's type. They were randomly assigned to receive Pregabalin (doses: 50 titrated up to 300 mg/day) or a placebo. Clinical response was evaluated using the Neuropsychiatric Inventory (NPI), and the Behavioral Pathology in AD Rating Scale (BEHAVE-AD) scores compared with baseline. Side effects were also recorded carefully.
RESULTS: Patients receiving Pregabalin had better outcomes in comparison with patients receiving a placebo regarding both NPI and BEHAVE-AD scores after 12 weeks (p-value = 0.009 for NPI and p-value = 0.003 for BEHAVE-AD). There was also a statistically significant decrease in the treatment group depression sub-score regarding NPI and BEHAVE-AD (respectively, p-value =0.000, 0.003). The caregiver burden sub-score of the NPI test was also lower in patients receiving pregabalin (p-value = 0.000). There was no statistically significant difference between the occurrence of adverse effects between the two groups (p-value = 1.00).
CONCLUSION: Pregabalin at a dose of 300 mg/day was well tolerated and associated with reductions in the severity and frequency of behavioral symptoms in patients with AD. Pregabalin could be considered a favorable choice for treating BPSD in adults with mild to moderate stages of Alzheimer 's-type dementia, considering its befitting safety profile.
CLINICAL TRIAL REGISTRATION: https://www.irct.ir/trial/52750, identifier IRCT20201201049553N1.}, }
@article {pmid39664391, year = {2024}, author = {Ge, A and Xiang, W and Li, Y and Zhao, D and Chen, J and Daga, P and Dai, CC and Yang, K and Yan, Y and Hao, M and Zhang, B and Xiao, W}, title = {Broadening horizons: the multifaceted role of ferroptosis in breast cancer.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1455741}, pmid = {39664391}, issn = {1664-3224}, mesh = {*Ferroptosis ; Humans ; *Breast Neoplasms/metabolism/pathology/drug therapy ; Female ; Animals ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Lipid Peroxidation ; Antineoplastic Agents/therapeutic use/pharmacology ; }, abstract = {Breast cancer poses a serious threat to women's health globally. Current radiotherapy and chemotherapy regimens can induce drug-resistance effects in cancer tissues, such as anti-apoptosis, anti-pyroptosis, and anti-necroptosis, leading to poor clinical outcomes in the treatment of breast cancer. Ferroptosis is a novel programmed cell death modality characterized by iron overload, excessive generation of reactive oxygen species, and membrane lipid peroxidation. The occurrence of ferroptosis results from the imbalance between intracellular peroxidation mechanisms (executive system) and antioxidant mechanisms (defensive system), specifically involving iron metabolism pathways, amino acid metabolism pathways, and lipid metabolism pathways. In recent years, it has been found that ferroptosis is associated with the progression of various diseases, including tumors, hypertension, diabetes, and Alzheimer's disease. Studies have confirmed that triggering ferroptosis in breast cancer cells can significantly inhibit cancer cell proliferation and invasion, and improve cancer cell sensitivity to radiotherapy and chemotherapy, making induction of ferroptosis a potential strategy for the treatment of breast cancer. This paper reviews the development of the concept of ferroptosis, the mechanisms of ferroptosis (including signaling pathways such as GSH-GPX4, FSP1-CoQ1, DHODH-CoQ10, and GCH1-BH4) in breast cancer disease, the latest research progress, and summarizes the research on ferroptosis in breast cancer disease within the framework of metabolism, reactive oxygen biology, and iron biology. The key regulatory factors and mechanisms of ferroptosis in breast cancer disease, as well as important concepts and significant open questions in the field of ferroptosis and related natural compounds, are introduced. It is hoped that future research will make further breakthroughs in the regulatory mechanisms of ferroptosis and the use of ferroptosis in treating breast cancer cells. Meanwhile, natural compounds may also become a new direction for potential drug development targeting ferroptosis in breast cancer treatment. This provides a theoretical basis and opens up a new pathway for research and the development of drugs for the prevention and treatment of breast cancer.}, }
@article {pmid39664082, year = {2024}, author = {An, C and Cai, H and Ren, Z and Fu, X and Quan, S and Jia, L}, title = {Biofluid biomarkers for Alzheimer's disease: past, present, and future.}, journal = {Medical review (2021)}, volume = {4}, number = {6}, pages = {467-491}, pmid = {39664082}, issn = {2749-9642}, abstract = {Alzheimer's disease (AD) is a gradually progressive neurodegenerative disease with tremendous social and economic burden. Therefore, early and accurate diagnosis is imperative for effective treatment or prevention of the disease. Cerebrospinal fluid and blood biomarkers emerge as favorable diagnostic tools due to their relative accessibility and potential for widespread clinical use. This review focuses on the AT(N) biomarker system, which includes biomarkers reflecting AD core pathologies, amyloid deposition, and pathological tau, as well as neurodegeneration. Novel biomarkers associated with inflammation/immunity, synaptic dysfunction, vascular pathology, and α-synucleinopathy, which might contribute to either the pathogenesis or the clinical progression of AD, have also been discussed. Other emerging candidates including non-coding RNAs, metabolites, and extracellular vesicle-based markers have also enriched the biofluid biomarker landscape for AD. Moreover, the review discusses the current challenges of biofluid biomarkers in AD diagnosis and offers insights into the prospective future development.}, }
@article {pmid39663578, year = {2024}, author = {Mohan, R and Arunachalam, R and Verma, N and Mali, S}, title = {ViTBayesianNet: An adaptive deep bayesian network-aided alzheimer disease detection framework with vision transformer-based residual densenet for feature extraction using MRI images.}, journal = {Network (Bristol, England)}, volume = {}, number = {}, pages = {1-41}, doi = {10.1080/0954898X.2024.2435491}, pmid = {39663578}, issn = {1361-6536}, abstract = {One of the most familiar types of disease is Alzheimer's disease (AD) and it mainly impacts people over the age limit of 60. AD causes irreversible brain damage in humans. It is difficult to recognize the various stages of AD, hence advanced deep learning methods are suggested for recognizing AD in its initial stages. In this experiment, an effective deep model-based AD detection approach is introduced to provide effective treatment to the patient. Initially, an essential MRI is collected from the benchmark resources. After that, the gathered MRIs are provided as input to the feature extraction phase. Also, the important features in the input image are extracted by Vision Transformer-based Residual DenseNet (ViT-ResDenseNet). Later, the retrieved features are applied to the Alzheimer's detection stage. In this phase, AD is detected using an Adaptive Deep Bayesian Network (Ada-DBN). Additionally, the attributes of Ada-DBN are optimized with the help of Enhanced Golf Optimization Algorithm (EGOA). So, the implemented Alzheimer's detection model accomplishes relatively higher reliability than existing techniques. The numerical results of the suggested framework obtained an accuracy value of 96.35 which is greater than the 91.08, 91.95, and 93.95 attained by the EfficientNet-B2, TF- CNN, and ViT-GRU, respectively.}, }
@article {pmid39662968, year = {2025}, author = {Leclercq, L and de Vries, R and Koppen, V and Verboven, P and Cuyckens, F and Wynant, I and Vermeulen, WAA and Naisbitt, D and Ford, M and Meng, X and Sakamoto, S and Fukushima, T and Snoeys, J}, title = {CYP3A4-Mediated Bioactivation of the β-Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor JNJ-54861911 Results in Redox-Neutral Addition of Glutathione via Catalysis by Glutathione S-Transferase α1, Identified as the Major Target Protein in Human Hepatocytes.}, journal = {Chemical research in toxicology}, volume = {38}, number = {1}, pages = {58-72}, doi = {10.1021/acs.chemrestox.4c00279}, pmid = {39662968}, issn = {1520-5010}, mesh = {Humans ; *Hepatocytes/drug effects/metabolism ; *Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; *Cytochrome P-450 CYP3A/metabolism ; *Glutathione/metabolism ; *Oxidation-Reduction ; *Glutathione Transferase/metabolism/antagonists & inhibitors ; Biocatalysis ; Thiazines/chemistry/pharmacology/metabolism ; Isoenzymes ; Aspartic Acid Endopeptidases ; }, abstract = {The β-amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor JNJ-54861911, a candidate for the treatment of Alzheimer's disease, was withdrawn from clinical trials due to drug-induced liver injury (DILI). This paper describes our investigation of the metabolism of JNJ-54861911 to understand the potential contribution to the observed DILI. In human hepatocytes, JNJ-54861911 is metabolized by CYP450 3A4 to a reactive intermediate (RI), which undergoes glutathione (GSH) addition at C6 of the 2-amino-4-methyl-1,3-thiazin-4-yl moiety via glutathione S-transferase α1 (GSTA1) catalysis. Despite the preponderant role of CYP3A4 as an enabler, the adduct has the same level of oxidation as that of JNJ-54861911. The exact mechanism of RI formation might involve a sulfoxide (with further reduction) or tautomeric forms of JNJ-54861911 bearing a reactive thiazinium cation activating both the C2 and C6 positions. The cell pellet from the human hepatocyte incubated with [14]C-JNJ-54861911 was analyzed via gel electrophoresis, resulting in the identification of a major protein adduct on GSTA1, a cross-link resulting from the addition of GSH and lysine 120 to JNJ-54861911, most likely on position C6 and on the nitrile, respectively. Ultimately, this major adduct might only account for 15-25% of the total covalent binding (CVB). Other important contributors to CVB might exist, like the bioactivation of the major diaminothiazine metabolite (DIAT). The level of covalent binding (CVB) burden (fraction of the dose resulting in CVB) is clearly below 1 mg/day, with a low daily dose of 25 mg. Despite this limited magnitude of CVB, it could still contribute to the liver enzyme elevations observed in approximately 20% of the patients and to the few cases of severe immune-mediated DILI. The latter could occur through a haptenization phenomenon and/or by inducing stress in hepatocytes. Such stress may activate an innate immune response, which, in turn, promotes the adaptive immune response.}, }
@article {pmid39662855, year = {2025}, author = {Yang, ZF and Jiang, XC and Gao, JQ}, title = {Present insights into the progress in gene therapy delivery systems for central nervous system diseases.}, journal = {International journal of pharmaceutics}, volume = {669}, number = {}, pages = {125069}, doi = {10.1016/j.ijpharm.2024.125069}, pmid = {39662855}, issn = {1873-3476}, mesh = {Humans ; *Genetic Therapy/methods ; *Central Nervous System Diseases/therapy ; Animals ; *Gene Transfer Techniques ; *Genetic Vectors/administration & dosage ; Dependovirus/genetics ; }, abstract = {Central nervous system (CNS) diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), spinal cord injury (SCI), and ischemic strokes and certain rare diseases, such as amyotrophic lateral sclerosis (ALS) and ataxia, present significant obstacles to treatment using conventional molecular pharmaceuticals. Gene therapy, with its ability to target previously "undruggable" proteins with high specificity and safety, is increasingly utilized in both preclinical and clinical research for CNS ailments. As our comprehension of the pathophysiology of these conditions deepens, gene therapy stands out as a versatile and promising strategy with the potential to both prevent and treat these diseases. Despite the remarkable progress in refining and enhancing the structural design of gene therapy agents, substantial obstacles persist in their effective and safe delivery within living systems. To surmount these obstacles, a diverse array of gene delivery systems has been devised and continuously improved. Notably, Adeno-Associated Virus (AAVs)-based viral gene vectors and lipid-based nanocarriers have each advanced the in vivo delivery of gene therapies to various extents. This review aims to concisely summarize the pathophysiological foundations of CNS diseases and to shed light on the latest advancements in gene delivery vector technologies. It discusses the primary categories of these vectors, their respective advantages and limitations, and their specialized uses in the context of gene therapy delivery.}, }
@article {pmid39662839, year = {2025}, author = {Zhou, XP and Sun, LB and Liu, WH and Zhu, WM and Li, LC and Song, XY and Xing, JP and Gao, SH}, title = {The complex relationship between gut microbiota and Alzheimer's disease: A systematic review.}, journal = {Ageing research reviews}, volume = {104}, number = {}, pages = {102637}, doi = {10.1016/j.arr.2024.102637}, pmid = {39662839}, issn = {1872-9649}, mesh = {*Alzheimer Disease/microbiology/therapy ; Humans ; *Gastrointestinal Microbiome/physiology ; *Brain-Gut Axis/physiology ; Animals ; Brain/physiopathology ; Medicine, Chinese Traditional/methods ; }, abstract = {Alzheimer's disease (AD) is a progressive, degenerative disorder of the central nervous system. Despite extensive research conducted on this disorder, its precise pathogenesis remains unclear. In recent years, the microbiota-gut-brain axis has attracted considerable attention within the field of AD. The gut microbiota communicates bidirectionally with the central nervous system through the gut-brain axis, and alterations in its structure and function can influence the progression of AD. Consequently, regulating the gut microbiota to mitigate the progression of AD has emerged as a novel therapeutic approach. Currently, numerous studies concentrate on the intrinsic relationship between the microbiota-gut-brain axis and AD. In this paper, we summarize the multifaceted role of the gut microbiota in AD and present detailed therapeutic strategies targeting the gut microbiota, including the treatment of AD with Traditional Chinese Medicine (TCM), which has garnered increasing attention in recent years. Finally, we discuss potential therapeutic strategies for modulating the gut microbiota to alleviate the progression of AD, the current challenges in this area of research, and provide an outlook on future research directions in this field.}, }
@article {pmid39662651, year = {2025}, author = {Keethedeth, N and Anantha Shenoi, R}, title = {Mitochondria-targeted nanotherapeutics: A new frontier in neurodegenerative disease treatment.}, journal = {Mitochondrion}, volume = {81}, number = {}, pages = {102000}, doi = {10.1016/j.mito.2024.102000}, pmid = {39662651}, issn = {1872-8278}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Mitochondria/drug effects/metabolism ; Drug Delivery Systems ; Nanoparticles/chemistry ; Animals ; }, abstract = {Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.}, }
@article {pmid39662542, year = {2025}, author = {Gong, M and Yu, W and Ma, J and Liu, JR and Sun, Q and Luo, X and Zhang, MZ}, title = {Visual screening of butyrylcholinesterase inhibitors by a cellulose membrane biosensor with amide-bonded immobilization of butyrylcholinesterase in a solid-phase enzyme-catalyzed reaction.}, journal = {International journal of biological macromolecules}, volume = {285}, number = {}, pages = {138598}, doi = {10.1016/j.ijbiomac.2024.138598}, pmid = {39662542}, issn = {1879-0003}, mesh = {*Butyrylcholinesterase/chemistry/metabolism ; *Cellulose/chemistry/analogs & derivatives ; *Biosensing Techniques/methods ; *Enzymes, Immobilized/chemistry/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology ; *Membranes, Artificial ; Amides/chemistry ; Humans ; Tacrine/chemistry ; }, abstract = {The rapid discovery of highly active butyrylcholinesterase (BChE) inhibitors is key to the treatment of the late stages of Alzheimer's disease. Herein, a colorimetric cellulose membrane (CM)-based biosensor was developed. The CM was employed as a carrier, which can be immobilized with the BChE and 5,5'-dithio-(2-nitrobenzoic acid) (DTNB) to prepare the biosensor for the solid-phase enzyme-catalyzed reaction. Specifically, the CM was oxidized to the oxidized cellulose membrane (OCM), which can further covalently bind the BChE to prepare the BChE-immobilized cellulose membrane (BCM). Then, the DTNB was adsorbed to the BCM to prepare the BDCM biosensor. The BDCM biosensor can visually detect S-butyrylthiocholine iodide at the yellow light signal with several characters, including sensitivity (LOD 1.56 μM), affinity (Km = 140.48 ± 5.42 μM), stability (over 1 month), via the BChE-catalyzed solid-phase reaction. Furthermore, the BDCM biosensor was applied to screen and determine the specific commercial BChE inhibitors tacrine and rivastigmine, with the IC50 values of 30.99 ± 12.20 nM and 2.02 ± 0.13 μM, respectively, from 13 different commercial inhibitors. This work provided a new method of visual BChE inhibitor screening and a useful strategy for the design of enzyme-based immobilization technology cellulose membrane biosensors.}, }
@article {pmid39661296, year = {2024}, author = {Natarajan, K and Chandrasekaran, R and Sundararaj, R and Joseph, J and Asaithambi, K}, title = {Neuroprotective Assessment of Nutraceutical (Betanin) in Neuroblastoma Cell Line SHSY-5Y: An in-Vitro and in-Silico Approach.}, journal = {Neurochemical research}, volume = {50}, number = {1}, pages = {54}, pmid = {39661296}, issn = {1573-6903}, mesh = {Humans ; *Neuroprotective Agents/pharmacology ; Cell Line, Tumor ; *Neuroblastoma/metabolism/pathology ; *Betacyanins/pharmacology ; *Reactive Oxygen Species/metabolism ; *Cell Survival/drug effects ; *Amyloid beta-Peptides/toxicity/metabolism ; Molecular Docking Simulation ; Dietary Supplements ; Autophagy/drug effects ; Computer Simulation ; }, abstract = {The cognitive dysfunction in the brain cause severe pathological consequences such as Alzheimer's disease (AD), Parkinson's disease. The current treatments are cost expensive and also cause negative side effects. Therefore it is inevitable to develop natural phyto-compounds as a drug like molecules to treat neurodegenerative diseases. In this context, we have assayed the neuroprotective effects of betanin, an indole derivative, in the neuroblastoma cell line SHSY-5Y cells. The neuroprotective effect was investigated in the β-amyloid (Aβ) - induced SHSY-5Y cells; betanin (25 µg) protected the SHSY-5Y cells from the toxic effects and maintained the cell viability. Moreover, the acridine orange and ethidum Bromide staining decipher that treatment of betanin in the Aβ-induced SHSY-5Y cells maintain the cell viablity sustainably. The Reactive Oxygen Species (ROS) assay infers that betanin quenches the generation of free radicals progressively in the Aβ-induced SHSY-5Y cells. In addition, the autophagy determination by flow cytometry revealed that betanin induces autophagy to remove the neurodegenerated cells. Further, we examined the docking and simulation patterns with the angiotensin-converting enzyme (ACE), TNF-α converting enzyme (TACE), glycogen synthase kinase 3 (GK3), and acetylcholinesterase enzymes (AChE) and amyloid precursor protein (APP). The insilico docking analysis denotes that betanin had a significant docking score with the target molecules. Thus, from the invitro and insilico studies, betanin strongly inhibit the toxic effects of Aβand protect the cells from degeneration.}, }
@article {pmid39661258, year = {2024}, author = {Kaur, D and Grewal, AK and Fouad, D and Kumar, A and Singh, V and Alexiou, A and Papadakis, M and Batiha, GE and Welson, NN and Singh, TG}, title = {Exploring the Neuroprotective Effects of Rufinamide in a Streptozotocin-Induced Dementia Model.}, journal = {Cellular and molecular neurobiology}, volume = {45}, number = {1}, pages = {4}, pmid = {39661258}, issn = {1573-6830}, support = {D753//Universität Witten/Herdecke/ ; }, mesh = {Animals ; *Streptozocin ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Male ; *Disease Models, Animal ; *Dementia/drug therapy ; *Oxidative Stress/drug effects ; *Triazoles/pharmacology/therapeutic use ; Cyclic AMP Response Element-Binding Protein/metabolism ; Brain/drug effects/metabolism/pathology ; Antioxidants/pharmacology ; }, abstract = {Due to the complex pathophysiology of AD (Alzheimer's Disease), there are currently no effective clinical treatments available, except for acetylcholinesterase inhibitors. However, CREB (cyclic AMP-responsive element binding protein) has been identified as the critical factor for the transcription in memory formation. Understanding the effect of potential drugs on the CREB pathway could lead to the development of new therapeutic molecules. Rufinamide has shown promise in improving memory in animal models, and these effects may be associated with modulation of the CREB pathway, however, this has not been previously reported. Thus, the present study aimed to determine the involvement of the CREB pathway in the cognitive improvement effects of rufinamide in STZ (streptozotocin) induced mouse model of dementia. Administration of STZ [3 mg/kg, i.c.v. (intracerebroventricular) bilaterally] significantly impaired cognitive performance in step-down passive avoidance and Morris water maze tests in animals, reduced brain endogenous antioxidant levels (GSH, superoxide dismutase, and catalase), and increased marker of brain oxidative stress [TBARS (thiobarbituric acid reactive substances)] and inflammation [IL-1β (Interleukin-1 beta), IL-6 (Interleukin-6), TNF-α (Tumor necrosis factor alpha) and NF-κB (Nuclear factor kappa B)], along with neurodegeneration. These effects were markedly reversed by rufinamide (50 and 100 mg/kg) when administered to STZ animals. However, the pre-treatment with the CREB inhibitor (666-15) in STZ and rufinamide-administered animals neutralized the beneficial influence of rufinamide. Our data suggest that rufinamide, acting via CREB signaling, reduced oxidative stress and inflammatory markers while elevating anti-oxidant levels. Our study has established that rufinamide may act through CREB signaling in an investigational AD model, which could be crucial for developing new treatments beneficial in progressive neurological disorders.}, }
@article {pmid39660534, year = {2024}, author = {Ji, YF and Wang, YJ and Chen, SH and Cheng, Y}, title = {Interleukin-4 promotes the clearance of amyloid-β by monocyte through enhancing the recognition and intracellular processing of amyloid-β.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {102}, number = {4}, pages = {1017-1026}, doi = {10.1177/13872877241295361}, pmid = {39660534}, issn = {1875-8908}, mesh = {*Monocytes/metabolism/drug effects ; *Amyloid beta-Peptides/metabolism ; Humans ; *Interleukin-4/metabolism/pharmacology ; Peptide Fragments/metabolism/pharmacology ; }, abstract = {BACKGROUND: Impaired clearance of amyloid-β protein (Aβ) in the peripheral system is a crucial event in the pathogenesis of sporadic Alzheimer's disease (AD). Dysfunctional monocytes with deficient clearance of Aβ and increased secretion of pro-inflammatory factors in the periphery are considered to contribute to AD development. Multiple studies suggest that IL-4 can inhibit the inflammatory response and enhance the expression and activity of cathepsin protease associated with intracellular clearance of Aβ by monocytes.
OBJECTIVE: To investigate the effects of interleukin-4 (IL-4) on Aβ clearance and inflammatory response of monocytes in vitro.
METHODS: In this study, flow cytometry, confocal microscopy and ELISA techniques were used for measurement of Aβ clearance and its related mechanisms of monocytes.
RESULTS: We found that the mean intracellular content and uptake ratios of Aβ42 in total monocytes, as well as in the CD14 [+ ]CD16[-] subset, were enhanced by IL-4, concomitant with the degradation of Aβ42 by monocytes. And IL-4 treatment also increased expression of scavenger receptor CD36 and Macrophage scavenger receptor 1 (MSR1) on monocytes. It was shown that IL-4 increased the Aβ immunoreactive area within lysosomal markers, including early endosome antigen 1 (EEA1), lysosome-associated membrane glycoprotein 1 and 2 (LAMP1 and 2) and Aβ degradative enzymes cathepsin B and S in monocytes, but reduced secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interferon-γ (IFN-γ) by monocytes.
CONCLUSIONS: Our study supports the role of IL-4 in regulating Aβ clearance and inflammatory response by monocytes, suggesting that IL-4 may have therapeutic potential for AD.}, }
@article {pmid39660440, year = {2025}, author = {Greenberg, SM and Aparicio, HJ and Furie, KL and Goyal, MS and Hinman, JD and Kozberg, M and Leonard, A and Fisher, MJ and , }, title = {Vascular Neurology Considerations for Antiamyloid Immunotherapy: A Science Advisory From the American Heart Association.}, journal = {Stroke}, volume = {56}, number = {1}, pages = {e30-e38}, doi = {10.1161/STR.0000000000000480}, pmid = {39660440}, issn = {1524-4628}, mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology/therapy ; *American Heart Association ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Cerebrovascular Disorders/therapy/immunology ; *Immunotherapy/methods ; Stroke/immunology ; United States ; }, abstract = {Antibodies directed at the amyloid-β peptide offer the prospect of disease-modifying therapy for early-stage Alzheimer disease but also carry the risk of brain edema or bleeding events, collectively designated amyloid-related imaging abnormalities. Introduction of the antiamyloid immunotherapies into practice is therefore likely to present a new set of questions for clinicians treating patients with cerebrovascular disease: Which manifestations of cerebrovascular disease should preclude, or permit, antibody treatment? Is it safe to prescribe amyloid immunotherapies to individuals who require antithrombotic treatment, or to administer thrombolysis to antibody-treated individuals with acute stroke? How should severe amyloid-related imaging abnormalities be managed? This science advisory summarizes the data and key considerations to guide these challenging decisions as the medical community collects further data and experience with these groundbreaking agents.}, }
@article {pmid39660432, year = {2025}, author = {Chib, S and Dutta, BJ and Chalotra, R and Abubakar, M and Kumar, P and Singh, TG and Singh, R}, title = {Role of Flavonoids in Mitigating the Pathological Complexities and Treatment Hurdles in Alzheimer's Disease.}, journal = {Phytotherapy research : PTR}, volume = {39}, number = {2}, pages = {747-775}, doi = {10.1002/ptr.8406}, pmid = {39660432}, issn = {1099-1573}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Flavonoids/pharmacology/therapeutic use ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; }, abstract = {With the passage of time, people step toward old age and become more prone to several diseases associated with the age. One such is Alzheimer's disease (AD) which results into neuronal damage and dementia with the progression of age. The existing therapeutics has been hindered by various enkindles like less eminent between remote populations, affordability issues and toxicity profiles. Moreover, lack of suitable therapeutic option further worsens the quality of life in older population. Developing an efficient therapeutic intervention to cure AD is still a challenge for medical fraternity. Recently, alternative approaches attain the attention of researchers to focus on plant-based therapy in mitigating AD. In this context, flavonoids gained centrality as a feasible treatment in modifying various neurological deficits. This review mainly focuses on the pathological facets and economic burden of AD. Furthermore, we have explored the possible mechanism of flavonoids with the preclinical and clinical aspects for curing AD. Flavonoids being potential therapeutic, target the pathogenic factors of AD such as oxidative stress, inflammation, metal toxicity, Aβ accumulation, modulate neurotransmission and insulin signaling. In this review, we emphasized on potential neuroprotective effects of flavonoids in AD pathology, with focus on both experimental and clinical findings. While preclinical studies suggest promising therapeutic benefits, clinical data remains limited and inconclusive. Thus, further high-quality clinical trials are necessary to validate the efficacy of flavonoids in AD. The study aim is to promote the plant-based therapies and encourage people to add flavonoids to regular diet to avail the beneficial effects in preventive therapy for AD.}, }
@article {pmid39659569, year = {2024}, author = {Peng, D and Liu, T and Lu, H and Zhang, L and Chen, H and Huang, Y and Hu, B and Zhang, Q}, title = {Intranasal delivery of engineered extracellular vesicles loaded with miR-206-3p antagomir ameliorates Alzheimer's disease phenotypes.}, journal = {Theranostics}, volume = {14}, number = {19}, pages = {7623-7644}, pmid = {39659569}, issn = {1838-7640}, mesh = {Animals ; *Alzheimer Disease/therapy/genetics ; *MicroRNAs/genetics/metabolism/administration & dosage ; *Extracellular Vesicles/metabolism ; *Administration, Intranasal ; Mice ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; *Mesenchymal Stem Cells/metabolism ; *Hippocampus/metabolism ; *Antagomirs/administration & dosage/pharmacology ; *Disease Models, Animal ; Male ; Phenotype ; Humans ; Neurogenesis/drug effects ; Mice, Inbred C57BL ; Amyloid beta-Peptides/metabolism ; }, abstract = {Rationale: The level of miR-206-3p in the plasma and temporal cortex is increased in Alzheimer's disease (AD) patients. miR-206-3p antagomir injected into hippocampus ameliorates cognitive deficits by enhancing the level of BDNF. However, the trauma caused by brain injection and susceptibility to degradation limit its application. Methods: To overcome these challenges, we constructed engineered extracellular vesicles derived from mesenchymal stem cell (MSC-EVs) loaded with miR-206-3p antagomir (MSC-EVs-anta) by electroporation technology, and explored the therapeutic effects of MSC-EVs-anta delivered by intranasal administration on AD mice. Transcriptome sequencing and LC-MS/MS proteomic analysis were employed to disclose the mechanism underlying the attenuation of AD phenotypes by MSC-EVs-anta. Results: MSC-EVs-anta had favorable neuroprotection by promoting neurite outgrowth in vitro. Following intranasal administration, MSC-EVs-anta improved learning and memory deficits, promoted hippocampal neurogenesis and synaptic plasticity, and alleviated Aβ deposition. Compared with MSC-EVs or miR-206-3p antagomir alone, MSC-EVs-anta showed superior therapeutic effects. Mechanistically, MSC-EVs-anta significantly upregulated brain-derived neurotrophic factor (BDNF) in AD mice, and activated the BDNF/TrkB signaling pathway. The data from two-omics analyses demonstrated that the differentially expressed proteins and genes significantly regulated by MSC-EVs-anta were primarily enriched in the pathways involved in neurogenesis and synapse. Conclusions: Our findings highlight the intranasal administration of MSC-EVs-anta as a promising strategy for the treatment of AD.}, }
@article {pmid39659516, year = {2024}, author = {Simfukwe, C and An, SSA and Youn, YC}, title = {Contribution of Scalp Regions to Machine Learning-Based Classification of Dementia Utilizing Resting-State qEEG Signals.}, journal = {Neuropsychiatric disease and treatment}, volume = {20}, number = {}, pages = {2375-2389}, pmid = {39659516}, issn = {1176-6328}, abstract = {PURPOSE: This study aims to investigate using eyes-open (EO) and eyes-closed (EC) resting-state EEG data to diagnose cognitive impairment using machine learning methods, enhancing timely intervention and cost-effectiveness in dementia research.
PARTICIPANTS AND METHODS: A total of 890 participants aged 40-90 were included in the study, comprising 269 healthy controls (HC), 356 individuals with mild cognitive impairment (MCI), and 265 with Alzheimer's disease (AD) from a cohort study. Resting-state EEG (rEEG) signals were recorded and transformed into relative power spectral density (PSD) data for analysis. The processed PSD data, representing 19 scalp regions, were then input into a Random Forest (RF) machine learning classifier to identify distinctive EEG patterns across the groups. Statistical comparisons between the groups were conducted using one-way ANOVA, applied to the relative PSD features extracted from the EEG data, to assess significant differences in EEG activity across the diagnostic categories.
RESULTS: The study found that rEEG-based categorization effectively differentiates between cognitively impaired individuals and healthy individuals. The EO rEEG achieved the highest performance metrics across various models. For HC vs MCI (combined hemisphere), the accuracy, sensitivity, specificity, and AUC were 92%, 99%, 83%, and 96%, respectively. For HC vs AD (parietal, temporal, occipital), these metrics were 95%, 96%, 94%, and 99%. The HC vs CASE (MCI + AD) (combined hemisphere) results were 90%, 99%, 73%, and 92%. The metrics for HC vs MCI vs AD (frontal, parietal, temporal) were 89%, 88%, 94%, and 96%.
CONCLUSION: The study demonstrates that EO rEEG can effectively distinguish between cognitive impairment and healthy states, leading to early diagnosis, cost-effective treatment, and better clinical outcomes for dementia patients. EO and EC rEEG models trained with relative PSD, particularly from parietal, temporal, occipital, and central scalp regions, can significantly assist clinicians in practice.}, }
@article {pmid39658957, year = {2024}, author = {Zhu, XC and Wang, YW and Zhou, HW}, title = {The mechanism and related research progress of GLP-1 receptor agonists in treating Alzheimer's disease.}, journal = {Yi chuan = Hereditas}, volume = {46}, number = {12}, pages = {1017-1027}, doi = {10.16288/j.yczz.24-178}, pmid = {39658957}, issn = {0253-9772}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Animals ; Diabetes Mellitus, Type 2/drug therapy ; *Glucagon-Like Peptide-1 Receptor Agonists ; }, abstract = {GLP-1 receptor agonists are primarily used clinically for the treatment of type 2 diabetes and have the potential for weight loss, while they are currently expanding their horizons in the treatment of hypertension, non-alcoholic liver disease, depression, and neurodegenerative diseases. In particular, in the treatment of Alzheimer's disease, a large number of animal models and a handful of clinical studies have demonstrated the potential efficacy of GLP-1 receptor agonists, making it highly probable that they will become a new entrant in the drug list for Alzheimer's disease. At present, the research on the mechanism of GLP-1 receptor agonist in the treatment of Alzheimer's disease is mainly based on in-depth analysis of the pathogenesis of Alzheimer's disease and exploration of the mechanism of its comorbidity with diabetes. This article mainly reviews the latest advances in the mechanism of GLP-1 receptor agonists in the treatment of Alzheimer's disease, introduces the latest achievements in animal studies and clinical studies, and aims to provide reference for the subsequent relevant basic research and clinical application.}, }
@article {pmid39657444, year = {2025}, author = {Zhou, J and Kim, YK and Li, C and Park, S}, title = {Natural compounds for Alzheimer's prevention and treatment: Integrating SELFormer-based computational screening with experimental validation.}, journal = {Computers in biology and medicine}, volume = {185}, number = {}, pages = {109523}, doi = {10.1016/j.compbiomed.2024.109523}, pmid = {39657444}, issn = {1879-0534}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *Molecular Docking Simulation ; Rats ; PC12 Cells ; Humans ; Quantitative Structure-Activity Relationship ; Deep Learning ; Biological Products/chemistry/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: This study aimed to develop and apply a novel computational pipeline combining SELFormer, a transformer architecture-based chemical language model, with advanced deep learning techniques to predict natural compounds (NCs) with potential in Alzheimer's disease (AD) treatment. The NCs were identified based on activity related to seven AD-specific genes, including acetylcholinesterase (AChE), amyloid precursor protein (APP), beta-secretase 1 (BACE1), and presenilin-1 (PSEN1).
METHODS: We implemented a computational pipeline using SELFormer and deep learning techniques, conducted optimal clustering and quantitative structure-activity relationship (QSAR) analyses, and performed a uniform manifold approximation and projection (UMAP) to categorize compounds based on bioactivity levels. Molecular docking analysis was carried out on selected compounds. To validate the computational predictions, we conducted in vitro studies using nerve growth factor (NGF)-differentiated PC12 cells. Finally, we mapped the relationships between food sources containing the identified compounds and their target proteins.
RESULTS: Optimal clustering analysis revealed five distinct groups of NCs, while QSAR analysis highlighted variations in molecular properties across clusters. The UMAP projection identified 17 highly active NCs (pIC50>7). Molecular docking analysis showed that cowanin, β-caryophyllene, and L-citronellol demonstrated decreased binding energy across target proteins. In vitro studies confirmed significant biological activities of these compounds, including increased cell viability, decreased AChE activity, reduced lipid peroxidation and tumor necrosis factor (TNF)-α mRNA expression, and increased brain-derived neurotrophic factor (BDNF) mRNA expression compared to the control. The study also identified natural sources of these compounds, such as anatidae, mangosteen, and celery, providing insights into potential dietary interventions.
CONCLUSION: This integrated computational and experimental approach offers a promising framework for identifying potential NCs for AD treatment. The results contribute to exploring effective therapeutic strategies against AD.}, }
@article {pmid39656222, year = {2024}, author = {Singh, B and Pandey, S and Rumman, M and Gupta, M and Mahdi, AA}, title = {Bacopaside-I ameliorates motor dysfunction and neurodegeneration in rat model of Parkinson's disease.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {39656222}, issn = {1432-1912}, abstract = {Chronic administration of Bacopa monnieri extract exerts neuroprotective potential in multiple animal models of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), depression, and other cognitive impairments. However, the underlying mechanism of action remained unclear. Rotenone model of PD holds a great potential for investigating PD pathology and motor and nonmotor symptoms. Herein, we evaluated the neuroprotective effect of Bacopaside-I (BS-I), a major triterpenoid saponin of Bacopa monnieri extract, against rotenone-induced in vivo model of PD and explored the possible molecular mechanism. Rats were exposed to rotenone (2 mg/kg body weight) for a period of 4 consecutive weeks to induce PD-like behavior. BS-I (5, 15, and 45 mg/kg) was administered orally. Behavioral data (rotarod, foot printing, and grip strength test) suggest that BS-I plays a significant role in attenuating the motor function deficit. Exposure to rotenone reduces the dopamine level and increases oxidative stress, while BS-I treatment reversed these changes. Furthermore, chronic administration of BS-I increased the expression levels of dopamine transporter (DAT) and vesicular monoamine transporter (VMAT) genes and the numbers of tyrosine hydroxylase (TH)-positive neurons as compared to rotenone-exposed animals. Our study established the neuroprotective role of BS-I in PD model and laid the foundation for further evaluation of BS-I-based drug in future studies.}, }
@article {pmid39655696, year = {2025}, author = {Di Iacovo, A and D'Agostino, C and Bhatt, M and Romanazzi, T and Giovannardi, S and Cinquetti, R and Roseti, C and Bossi, E}, title = {The kinase LRRK2 is required for the physiological function and expression of the glial glutamate transporter EAAT2 (SLC1A2).}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16265}, pmid = {39655696}, issn = {1471-4159}, support = {860954//H2020 Marie Skłodowska-Curie Actions/ ; }, mesh = {Animals ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics/metabolism/biosynthesis ; *Excitatory Amino Acid Transporter 2/metabolism/genetics/biosynthesis ; *Xenopus laevis ; Humans ; Oocytes/metabolism ; Female ; Neuroglia/metabolism ; }, abstract = {Neurotransmitter transporters (NTTs) control synaptic responses by modulating the concentration of neurotransmitters at the synaptic cleft. Glutamate is the most abundant excitatory neurotransmitter in the brain and needs to be finely tuned in time and space to maintain a healthy brain and precise neurotransmission. The glutamate transporter EAAT2 (SLC1A2) is primarily responsible for glutamate clearance. EAAT2 impairment has been associated with Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both monogenic and sporadic forms of PD, of which the common substitution Gly2019Ser is associated with a significant deficit in EAAT2 expression. The role of pathological mutants of the LRRK2 is intensively studied and reviewed. Here we have focused the attention on the physiological role of LRRK2 on EAAT2, comparing the activity of NTTs with or without the LRRK2 kinase. By heterologous expression in Xenopus laevis oocytes and two-electrode voltage clamp, the current amplitudes of the selected NTTs and kinetic parameters have been collected in the presence and absence of LRRK2. The results show that EAAT2 expression and function are impaired in the absence of the kinase and also under its pharmacological inhibition via MLi-2 treatment. LRRK2 stabilizes EAAT2 expression increasing the amount of transporter at the plasma membrane. Interestingly, the LRRK2 action is EAAT2-specific, as we observed no significant changes in the transport current amplitude and kinetic parameters obtained for the other excitatory and inhibitory NTTs studied. This study, for the first time, demonstrates the physiological importance of LRRK2 in EAAT2 function, highlighting the specificity of LRRK2-mediated modulation of EAAT2 and suggesting a potential role for the kinase as a checkpoint for preserving neurons from excitotoxicity. In brain conditions associated with impaired glutamate clearance, targeting LRRK2 for EAAT2 regulation may offer novel therapeutic opportunities.}, }
@article {pmid39655162, year = {2024}, author = {Li, H and Yao, Q and Huang, X and Yang, X and Yu, C}, title = {The role and mechanism of Aβ clearance dysfunction in the glymphatic system in Alzheimer's disease comorbidity.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1474439}, pmid = {39655162}, issn = {1664-2295}, abstract = {Alzheimer's disease (AD) is the leading type of dementia globally, characterized by a complex pathogenesis that involves various comorbidities. An imbalance in the production and clearance of amyloid β-protein (Aβ) peptides in the brain is a key pathological mechanism of AD, with the glymphatic system playing a crucial role in Aβ clearance. Comorbidities associated with AD, such as diabetes, depression, and hypertension, not only affect Aβ production but also impair the brain's lymphatic system. Abnormalities in the structure and function of this system further weaken Aβ clearance capabilities, and the presence of comorbidities may exacerbate this process. This paper aims to review the role and specific mechanisms of impaired Aβ clearance via the glymphatic system in the context of AD comorbidities, providing new insights for the prevention and treatment of AD. Overall, the damage to the glymphatic system primarily focuses on aquaporin-4 (AQP4) and perivascular spaces (PVS), suggesting that maintaining the health of the glymphatic system may help slow the progression of AD and its comorbidities. Additionally, given the ongoing controversies regarding the structure of the glymphatic system, this paper revisits this structure and discusses the principles and characteristics of current detection methods for the glymphatic system.}, }
@article {pmid39654857, year = {2024}, author = {Bojkiewicz, E and Toczylowski, K and Lewandowski, D and Martonik, D and Flisiak, R and Sulik, A}, title = {The Role of Chitinase 3-Like-1 (YKL-40) and Proinflammatory Biomarkers in the Pathogenesis of Pediatric Tick-Borne Encephalitis in a Polish Cohort.}, journal = {Journal of inflammation research}, volume = {17}, number = {}, pages = {10239-10254}, pmid = {39654857}, issn = {1178-7031}, abstract = {BACKGROUND: Chitinase 3-like-1 (CHI3L1), also known as YKL-40, is a potential biomarker for neuroinflammatory conditions. It is upregulated in Alzheimer's disease, multiple sclerosis, and traumatic brain injury. However, its involvement in pediatric tick-borne encephalitis (TBE) has not been addressed yet. This study aimed to evaluate CHI3L1 and its relationship with other inflammatory cytokines, blood-brain barrier (BBB) integrity, immune response, and disease severity in pediatric patients with TBE.
PATIENTS AND METHODS: A total of 22 pediatric TBE patients hospitalized in Bialystok, Poland were included in this study. Participants were categorized as having meningoencephalitis (n=6) or meningitis (n=16). The integrity of the brain-blood barrier (BBB) was assessed using the albumin quotient (albQ). Biomarker indices were calculated to account for variations in BBB permeability. The concentrations of CHI3L1, CCL2, chemerin, CXCL2, IFN-γ, IL-1-β, IL-4, IL-6, IL-13, and TNF-α in both serum and CSF, were measured using the Luminex Multiplex Assay od admission and two weeks later when symptoms resolved.
RESULTS: CSF and serum concentrations of CHI3L1 did not differ between the encephalitis and meningitis cases. After adjusting for BBB permeability, the CHI3L1 index was 2.4-fold lower in patients with encephalitis than in those with meningitis (P=0.008). There was a post-treatment reduction of CHI3L1, IL-6, and TNF-α CSF concentrations. We also found and improvement in BBB permeability in younger children but in older albQ remained abnormal. Correlation analysis revealed associations between CHI3L1 levels and pro-inflammatory markers, notably chemerin, IL-6, and TNF-α, across both clinical groups.
CONCLUSION: Our findings suggest that CHI3L1 CSF levels reflect the inflammatory activity in pediatric TBE and may help to differentiate between meningoencephalitis and meningitis. The observed interactions between CHI3L1 and other cytokines underscore its potential involvement in inflammatory response to the virus. The prolonged disruption in BBB integrity in older children might reflect age-dependent differences in the severity of TBE. These insights advance our understanding of TBE pathogenesis in children and support further investigation of CHI3L1 as a biomarker for TBE diagnosis and management.}, }
@article {pmid39654855, year = {2024}, author = {Fu, XX and Huang, ZH and Wang, SY and Qi, JW and Luo, ZJ and E, Y and Zhang, YD and Jiang, T}, title = {Knockdown of TREML2 Alleviates Neuropathological Hallmarks and Cognitive Deficiency in a Model of Sporadic Alzheimer's Disease.}, journal = {Journal of inflammation research}, volume = {17}, number = {}, pages = {10471-10478}, pmid = {39654855}, issn = {1178-7031}, abstract = {OBJECTIVE: Recently, we revealed that triggering receptor expressed on myeloid cells-like 2 (TREML2) modulated inflammation by regulating microglial polarization and NLRP3 inflammasome activation. However, the role of TREML2 in Alzheimer's disease (AD) pathogenesis remains poorly understood. In this study, we tried to observe the impact of TREML2 on neuropathological hallmarks (including amyloid-β (Aβ) pathology, hyperphosphorylated tau and neuroinflammation) and cognitive deficiency in senescence-accelerated mouse prone substrain 8 (SAMP8) mice, an animal model of sporadic AD.
METHODS: A lentiviral-based strategy was employed to manipulate TREML2 levels in the brain of SAMP8 mice. Enzyme-linked immunosorbent assay was used to detect the protein levels of inflammatory cytokines, Aβ42 and hyperphosphorylated tau. The mRNA levels of microglial polarization markers were assessed by qRT-PCR. Morris water maze test was performed to evaluate the spatial cognitive functions.
RESULTS: TREML2 overexpression elevated inflammatory cytokines levels, induced microglial M1-type polarization, and exacerbated Aβ and tau pathology in SAMP8 mice. Contrastingly, knocking down TREML2 mitigated inflammatory cytokines release, promoted microglial M2-type polarization, ameliorated Aβ and tau pathology, and rescued cognitive deficiency in SAMP8 mice.
CONCLUSION: This study offers the first in vivo evidence that TREML2 contributes to the pathogenesis of AD. Furthermore, this study also proves that inhibition of TREML2 signaling may represent a potential treatment strategy for this disease.}, }
@article {pmid39654807, year = {2024}, author = {Wu, J and Tang, J and Huang, D and Wang, Y and Zhou, E and Ru, Q and Xu, G and Chen, L and Wu, Y}, title = {Effects and mechanisms of APP and its cleavage product Aβ in the comorbidity of sarcopenia and Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1482947}, pmid = {39654807}, issn = {1663-4365}, abstract = {Sarcopenia and AD are both classic degenerative diseases, and there is growing epidemiological evidence of their comorbidity with aging; however, the mechanisms underlying the biology of their commonality have not yet been thoroughly investigated. APP is a membrane protein that is expressed in tissues and is expressed not only in the nervous system but also in the NMJ and muscle. Deposition of its proteolytic cleavage product, Aβ, has been described as a central component of AD pathogenesis. Recent studies have shown that excessive accumulation and aberrant expression of APP in muscle lead to pathological muscle lesions, but the pathogenic mechanism by which APP and its proteolytic cleavage products act in skeletal muscle is less well understood. By summarizing and analyzing the literature concerning the role, pathogenicity and pathological mechanisms of APP and its cleavage products in the nervous system and muscles, we aimed to explore the intrinsic pathological mechanisms of myocerebral comorbidities and to provide new perspectives and theoretical foundations for the prevention and treatment of AD and sarcopenia comorbidities.}, }
@article {pmid39654705, year = {2024}, author = {Zhu, W and Huang, L and Cheng, H and Li, N and Zhang, B and Dai, W and Wu, X and Zhang, D and Feng, W and Li, S and Xu, H}, title = {GABA and its receptors' mechanisms in the treatment of insomnia.}, journal = {Heliyon}, volume = {10}, number = {23}, pages = {e40665}, pmid = {39654705}, issn = {2405-8440}, abstract = {Insomnia has now become a major health problem of global concern, with about 1/3 of the population suffering from sleep problems, a proportion that is still rising year by year. Most of the therapeutic drugs for insomnia currently used in clinical practice are not developed in a targeted manner, but are discovered by chance, and have unavoidable side effects such as addiction. Finding a safer and more effective therapeutic drug has become an urgent need for current research. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. It can ameliorate Insomnia, Alzheimer's disease, Parkinson's disease, Epilepsy, and other neurological disorders. Various mechanisms have been reported for GABA to ameliorate insomnia, such as GABAA receptor modulation, GABAB receptor modulation, inhibition of neuroinflammatory responses, repair of oxidative damage, and inter-regulation of the circadian rhythm hormone melatonin. GABA is a potential therapeutic target in the prevention and treatment of insomnia. This paper reviews mechanisms of GABA and its receptors in insomnia diseases and the potential of GABA analogs application and discusses the research progress of GABA as a promising therapeutic drug for insomnia diseases. This will help the development of novel targeted GABA-like drugs and provide new ideas and methods for the clinical treatment of insomnia.}, }
@article {pmid39654167, year = {2024}, author = {Bai, L and Li, F}, title = {To explore the protective mechanism of promethazine against hippocampal neuron injury based on network pharmacology and experimental verification.}, journal = {Medicine}, volume = {103}, number = {49}, pages = {e40550}, pmid = {39654167}, issn = {1536-5964}, mesh = {Animals ; *Hippocampus/drug effects/metabolism ; *Promethazine/pharmacology ; Mice ; *Neurons/drug effects/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Reactive Oxygen Species/metabolism ; *Cell Survival/drug effects ; *Network Pharmacology ; Neuroprotective Agents/pharmacology ; Glutathione/metabolism ; Oxidative Stress/drug effects ; Glutamic Acid/metabolism ; Tumor Suppressor Protein p53/metabolism ; Glutathione Peroxidase/metabolism ; Male ; Amino Acid Transport System y+ ; }, abstract = {This study aims to investigate the effect of promethazine (PMZ) on hippocampal neuronal injury through network pharmacology and in vivo experiments. Network pharmacology: The intersection genes of PMZ and Alzheimer Disease (AD) were obtained, and the core genes of PMZ in AD were screened. The intersection genes were enriched by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. In the in vitro experiment, mouse hippocampal neurons (HT22) were divided into control, glutamate (GLU) model, and GLU + PMZ treatment groups. The control group was given a complete culture medium, the model group was given GLU for 24 hours, the treatment group was given PMZ pretreatment for 3 hours, and then GLU was administered for 24 hours. Cell viability was determined, cell morphology was observed by microscopy, reactive oxygen species levels and glutathione content were detected, and protein expression of P53, PTGS2, SLC7A11, and GPX4 was detected by western blotting. Network pharmacology: A total of 317 PMZ targets, 1934 AD genes, 125 intersection genes, and 18 core genes, including P53 and PTGS2. Gene Ontology enrichment analysis showed that the effect of PMZ on AD was mainly related to cell proliferation, inflammation, hypoxia, synaptic structure, plasma membrane, and oxidoreductase activity. Kyoto Encyclopedia of Genes and Genomes results showed neuroactive ligand-receptor interaction, cell senescence, cancer pathway, PI3K-AKT signal pathway, neurodegeneration, and HIF-1 signal pathway. In vitro experiments: PMZ improved the GLU-induced decrease in cell viability and morphological changes in hippocampal neurons. PMZ inhibited reactive oxygen species levels and increased glutathione content in injured hippocampal neurons. Up-regulated of P53, SLC7A11 and GPX4 expression, and inhibited expression of PTGS2. PMZ regulates the SLC7A11-GPX4 antioxidant system to protect hippocampal neurons from oxidative stress injury.}, }
@article {pmid39653966, year = {2024}, author = {Baghcheghi, Y and Razazpour, F and Mirzaee, F and Dalfardi, M and Pourfridoni, M and Hedayati-Moghadam, M}, title = {Exploring the molecular mechanisms of curcumin in modulating memory impairment in neurodegenerative disorders.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {45}, pmid = {39653966}, issn = {1573-4978}, mesh = {Animals ; Humans ; Alzheimer Disease/drug therapy/metabolism ; *Curcumin/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism ; Memory/drug effects ; *Memory Disorders/drug therapy/etiology/metabolism ; *Neurodegenerative Diseases/complications/drug therapy/metabolism ; Neuronal Plasticity/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; }, abstract = {INTRODUCTION: Memory impairment is a critical challenge in neurodegenerative disorders, particularly in Alzheimer's disease, Parkinson's disease, and age-related cognitive decline. This research explores the molecular mechanisms by which curcumin, a polyphenolic compound derived from Curcuma longa, exerts neuroprotective effects that may ameliorate cognitive deficits associated with these conditions.
RESULTS AND CONCLUSION: Evidence from both preclinical studies and emerging clinical trials indicates that curcumin enhances neuronal signaling and synaptic plasticity, primarily through the modulation of pathways such as NF-κB and PI3K/Akt. Specifically, curcumin has been shown to reduce neuroinflammation and oxidative stress, thereby promoting synaptic integrity and function. For instance, studies demonstrate that curcumin treatment increases the density of dendritic spines in the hippocampus, which correlates with improved spatial learning and memory performance in animal models. Despite promising findings, significant gaps remain in our understanding of curcumin's efficacy in humans. Most existing research is derived from animal studies, with limited large-scale clinical trials to substantiate its therapeutic potential. Furthermore, challenges such as curcumin's low bioavailability and inconsistencies in dosing complicate its clinical application. This review underscores the need for future research focused on enhancing curcumin's bioavailability, establishing optimal dosages, and conducting comprehensive human trials to validate its effectiveness. By addressing these issues, we aim to clarify curcumin's role as a potential therapeutic agent for memory impairment in neurodegenerative disorders, paving the way for innovative treatment strategies.}, }
@article {pmid39653749, year = {2024}, author = {Heneka, MT and van der Flier, WM and Jessen, F and Hoozemanns, J and Thal, DR and Boche, D and Brosseron, F and Teunissen, C and Zetterberg, H and Jacobs, AH and Edison, P and Ramirez, A and Cruchaga, C and Lambert, JC and Laza, AR and Sanchez-Mut, JV and Fischer, A and Castro-Gomez, S and Stein, TD and Kleineidam, L and Wagner, M and Neher, JJ and Cunningham, C and Singhrao, SK and Prinz, M and Glass, CK and Schlachetzki, JCM and Butovsky, O and Kleemann, K and De Jaeger, PL and Scheiblich, H and Brown, GC and Landreth, G and Moutinho, M and Grutzendler, J and Gomez-Nicola, D and McManus, RM and Andreasson, K and Ising, C and Karabag, D and Baker, DJ and Liddelow, SA and Verkhratsky, A and Tansey, M and Monsonego, A and Aigner, L and Dorothée, G and Nave, KA and Simons, M and Constantin, G and Rosenzweig, N and Pascual, A and Petzold, GC and Kipnis, J and Venegas, C and Colonna, M and Walter, J and Tenner, AJ and O'Banion, MK and Steinert, JR and Feinstein, DL and Sastre, M and Bhaskar, K and Hong, S and Schafer, DP and Golde, T and Ransohoff, RM and Morgan, D and Breitner, J and Mancuso, R and Riechers, SP}, title = {Neuroinflammation in Alzheimer disease.}, journal = {Nature reviews. Immunology}, volume = {}, number = {}, pages = {}, pmid = {39653749}, issn = {1474-1741}, support = {MR/P024572/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients.}, }
@article {pmid39653128, year = {2025}, author = {Liu, J and Zhang, Y and Zhang, M and Wang, Q and Pang, Y and Xie, J}, title = {6‴-Feruloylspinosin alleviates Aβ-induced toxicity by modulating relevant neurotransmitter and the AMPK/mTOR signaling pathway.}, journal = {Free radical biology & medicine}, volume = {227}, number = {}, pages = {434-445}, doi = {10.1016/j.freeradbiomed.2024.12.028}, pmid = {39653128}, issn = {1873-4596}, mesh = {*TOR Serine-Threonine Kinases/metabolism/genetics ; *Signal Transduction/drug effects ; Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *AMP-Activated Protein Kinases/metabolism ; Humans ; *Neurotransmitter Agents/metabolism/pharmacology ; *Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Autophagy/drug effects ; Rats ; Mitochondria/drug effects/metabolism ; Metabolomics/methods ; Tandem Mass Spectrometry ; }, abstract = {Alzheimer's disease (AD) is a gradually progressive neurodegenerative disease with a serious impact on patients' quality of life. However, single-targeted therapies are not currently effective, and there is a need to find pluripotent drugs with multiple properties. This study aimed to characterize the metabolism of neurotransmitters using a targeted metabolomics approach and to identify the major metabolic pathways mainly affected by 6‴-feruloylspinosin (6-FS). The mechanism of action of 6-FS in the treatment of AD was elucidated based on experimental validation. The metabolomics analysis revealed changes in 13 metabolic profiles by the LC-MS/MS, with significant changes in five amino acid-related neurotransmitters identified primarily. Based on the correlations, we found an effect of mTOR inhibition on the above neurotransmitter metabolism. Furthermore, pretreatment with 6-FS activated the AMPK/mTOR signaling pathway, promoting cellular autophagy, regulating oxidative stress homeostasis and inhibiting mitochondrial dysfunction. In short, these comprehensive analysis methods help clarify the preventive mechanism of 6-FS and potential targets in AD and provide the necessary support for developing natural products to prevent AD.}, }
@article {pmid39652363, year = {2025}, author = {İş, Ö and Min, Y and Wang, X and Oatman, SR and Abraham Daniel, A and Ertekin-Taner, N}, title = {Multi Layered Omics Approaches Reveal Glia Specific Alterations in Alzheimer's Disease: A Systematic Review and Future Prospects.}, journal = {Glia}, volume = {73}, number = {3}, pages = {539-573}, pmid = {39652363}, issn = {1098-1136}, support = {U19 AG074879/AG/NIA NIH HHS/United States ; ZEN-22-969810/ALZ/Alzheimer's Association/United States ; RF1 AG051504/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; R01 AG061796/AG/NIA NIH HHS/United States ; RF AG051504/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism/genetics/pathology ; Humans ; *Neuroglia/metabolism/pathology ; *Genomics/methods ; *Metabolomics/methods ; Proteomics/methods ; Animals ; Brain/metabolism/pathology ; Epigenomics ; }, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative dementia with multi-layered complexity in its molecular etiology. Multiple omics-based approaches, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and lipidomics are enabling researchers to dissect this molecular complexity, and to uncover a plethora of alterations yielding insights into the pathophysiology of this disease. These approaches reveal multi-omics alterations essentially in all cell types of the brain, including glia. In this systematic review, we screen the literature for human studies implementing any omics approach within the last 10 years, to discover AD-associated molecular perturbations in brain glial cells. The findings from over 200 AD-related studies are reviewed under four different glial cell categories: microglia, oligodendrocytes, astrocytes and brain vascular cells. Under each category, we summarize the shared and unique molecular alterations identified in glial cells through complementary omics approaches. We discuss the implications of these findings for the development, progression and ultimately treatment of this complex disease as well as directions for future omics studies in glia cells.}, }
@article {pmid39651698, year = {2025}, author = {Cai, J and Liu, Y and Fan, H}, title = {Review on pathogenesis and treatment of Alzheimer's disease.}, journal = {Developmental dynamics : an official publication of the American Association of Anatomists}, volume = {254}, number = {4}, pages = {296-309}, doi = {10.1002/dvdy.762}, pmid = {39651698}, issn = {1097-0177}, support = {2021YFC2600503//National Key Research and Development Program of China/ ; }, mesh = {*Alzheimer Disease/therapy/etiology/pathology/metabolism ; Humans ; Animals ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {The rising incidence of Alzheimer's disease (AD) and the associated economic impacts has prompted a global focus in the field. In recent years, there has been a growing understanding of the pathogenic mechanisms of AD, including the aggregation of β-amyloid, hyperphosphorylated tau, and neuroinflammation. These processes collectively lead to neurodegeneration and cognitive decline, which ultimately results in the loss of autonomy in patients. Currently, there are three main types of AD treatments: clinical tools, pharmacological treatment, and material interventions. This review provides a comprehensive analysis of the underlying etiology and pathogenesis of AD, as well as an overview of the current prevalence of AD treatments. We believe this article can help deepen our understanding of the AD mechanism, and facilitate the clinical translation of scientific research or therapies, to address this global problem of AD.}, }
@article {pmid39651604, year = {2024}, author = {Maboko, LM and Theron, A and Panayides, JL and Cordier, W and Fisher, D and Steenkamp, V}, title = {Evaluating Blood-Brain Barrier Permeability, Cytotoxicity, and Activity of Potential Acetylcholinesterase Inhibitors: In Vitro and In Silico Study.}, journal = {Pharmacology research & perspectives}, volume = {12}, number = {6}, pages = {e70043}, pmid = {39651604}, issn = {2052-1707}, support = {608664//University of Pretoria/ ; //Department of Science and Innovation, South Africa/ ; //Council for Scientific and Industrial Research, South Africa/ ; }, mesh = {*Blood-Brain Barrier/metabolism/drug effects ; *Cholinesterase Inhibitors/pharmacology/pharmacokinetics/toxicity ; Humans ; *Computer Simulation ; *Permeability/drug effects ; Animals ; *Acetylcholinesterase/metabolism ; Donepezil/pharmacology ; Cell Line, Tumor ; Mice ; Cell Survival/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Drug Synergism ; Cell Line ; Indans/pharmacology/pharmacokinetics ; }, abstract = {Acetylcholinesterase inhibitors (AChEIs) remain the first-line treatment for Alzheimer's disease. However, these drugs are largely symptomatic and often associated with adverse effects. This study aimed to evaluate novel pharmacophores for their in vitro AChEI activity, blood-brain barrier (BBB) permeability, and cytotoxic potential, hypothesizing that a combination of AChEIs could enhance symptom management while minimizing toxicity. A library of 1453 synthetic pharmacophores was assessed using in vitro and in silico methods to determine their feasibility as an inhibitor of the AChE enzyme. An in-house miniaturized Ellman's assay determined acellular AChEI activities, while pharmacokinetic properties were evaluated using the SwissADME web tool. The combinational effects of in silico BBB-permeable pharmacophores and donepezil were examined using a checkerboard AChEI assay. Cytotoxicity of active compounds and their synergistic combinations was assessed in SH-SY5Y neuroblastoma and bEnd.5 cells using the sulforhodamine B assay. Cellular AChEI activity of active in silico BBB-permeable predicted compounds was determined using an SH-SY5Y AChE-based assay. An in vitro BBB model was used to assess the effect of compounds on the integrity of the bEnd.5 monolayer. Out of the screened compounds, 12 demonstrated 60% AChEI activity at 5 μM, with compound A51 showing the lowest IC50 (0.20 μM). Five compounds were identified as BBB-permeable, with the donepezil-C53 combination at ¼IC50 exhibiting the strongest synergy (CI = 0.82). Compounds A136 and C129, either alone or with donepezil, showed cytotoxicity. Notably, compound C53, both alone and in combination with donepezil, demonstrated high AChEI activity and promising BBB permeability, warranting further investigation.}, }
@article {pmid39651126, year = {2024}, author = {Bhuiyan, P and Zhang, W and Chae, R and Kim, K and St Louis, L and Wang, Y and Liang, G and Wei, H}, title = {Intranasal dantrolene nanoparticles inhibit inflammatory pyroptosis in 5XFAD mice brains.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.25.625293}, pmid = {39651126}, issn = {2692-8205}, abstract = {BACKGROUND: This study investigates the effects of intranasal dantrolene nanoparticles on inflammation and programmed cell death by pyroptosis in 5XFAD Alzheimer's Disease (AD) mice.
METHODS: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal dantrolene nanoparticles (5 mg/kg), daily, Monday to Friday, for 12 weeks continuously, starting at 9 months of age. Blood and brain were harvested at 13 months of age, one month after completion of 12 weeks intranasal dantrolene nanoparticle treatment. Blood biomarkers function of liver (Alanine transaminase, ALT), kidney (Creatinine), and thyroid (TSH: Thyroid-stimulating hormone) were measured using ELISA. The changes of whole brain tissue proteins on Ca [2+] release channels on membrane of endoplasmic reticulum (type 2 ryanodine and type 1 InsP3 receptors, RyR-2 and InsP3R-1), lipid peroxidation byproduct malondialdehyde (MDA)-modified proteins, 4-HNE, pyroptosis regulatory proteins (NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, full length or N-terminal of Gasdermin D (GSDMD), cytotoxic (IL-1, IL-18, IL-6, TNF-a) and cytoprotective (IL-10) cytokines, astrogliosis (GFAP), microgliosis (IBA-1) and synapse proteins (PSD-95, Synapsin-1) were determined using immunoblotting. Body weights were monitored regularly.
RESULTS: Intranasal dantrolene nanoparticles significantly inhibited the increase of RyR-2 and InsP3R-1 proteins, MDA-modified proteins, 4-NHE, pyroptosis regulatory proteins (NLRP3, cleaved caspase-1, N-terminal GSDMD), cytotoxic cytokine (IL-1β, IL-18, IL-6, TNF-α), biomarkers for astrogliosis (GFAP) and microgliosis (IBA-1), and the decrease of cytoprotective cytokine (IL-10) and synaptic proteins (PSD-95, synpasin-1). Intranasal dantrolene nanoparticles for 12 weeks did not affect blood biomarkers for function of liver, kidney, and thyroid, not did it change body weight significantly.
CONCLUSION: Intranasal dantrolene nanoparticles significantly inhibit the increase of RyR-2 and InsP 3 R-1 Ca [2+] channel receptor proteins, ameliorate activation of the pyroptosis pathway and pathological inflammation, and the associated loss of synapse proteins. Intranasal dantrolene nanoparticles for three months did not affect liver, kidney and thyroid functions or cause other side effects.}, }
@article {pmid39650656, year = {2024}, author = {Wang, W and Lu, J and Pan, N and Zhang, H and Dai, J and Li, J and Chi, C and Zhang, L and Wang, L and Zhang, M}, title = {Identification of early Alzheimer's disease subclass and signature genes based on PANoptosis genes.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1462003}, pmid = {39650656}, issn = {1664-3224}, mesh = {Humans ; *Alzheimer Disease/genetics ; *Protein Interaction Maps ; *Gene Expression Profiling ; Necroptosis/genetics ; Transcriptome ; Gene Regulatory Networks ; Databases, Genetic ; Pyroptosis/genetics ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is one of the most prevalent forms of dementia globally and remains an incurable condition that often leads to death. PANoptosis represents an emerging paradigm in programmed cell death, integrating three critical processes: pyroptosis, apoptosis, and necroptosis. Studies have shown that apoptosis, necroptosis, and pyroptosis play important roles in AD development. Therefore, targeting PANoptosis genes might lead to novel therapeutic targets and clinically relevant therapeutic approaches. This study aims to identify different molecular subtypes of AD and potential drugs for treating AD based on PANoptosis.
METHODS: Differentially expressed PANoptosis genes associated with AD were identified via Gene Expression Omnibus (GEO) dataset GSE48350, GSE5281, and GSE122063. Least Absolute Shrinkage and Selection Operator (LASSO) regression was employed to construct a risk model linked to these PANoptosis genes. Consensus clustering analysis was conducted to define AD subtypes based on these genes. We further performed gene set variation analysis (GSVA), functional enrichment analysis, and immune cell infiltration analysis to investigate differences between the identified AD subtypes. Additionally, a protein-protein interaction (PPI) network was established to identify hub genes, and the DGIdb database was consulted to identify potential therapeutic compounds targeting these hub genes. Single-cell RNA sequencing analysis was utilized to assess differences in gene expression at the cellular level across subtypes.
RESULTS: A total of 24 differentially expressed PANoptosis genes (APANRGs) were identified in AD, leading to the classification of two distinct AD subgroups. The results indicate that these subgroups exhibit varying disease progression states, with the early subtype primarily linked to dysfunctional synaptic signaling. Furthermore, we identified hub genes from the differentially expressed genes (DEGs) between the two clusters and predicted 38 candidate drugs and compounds for early AD treatment based on these hub genes. Single-cell RNA sequencing analysis revealed that key genes associated with the early subtype are predominantly expressed in neuronal cells, while the differential genes for the metabolic subtype are primarily found in endothelial cells and astrocytes.
CONCLUSION: In summary, we identified two subtypes, including the AD early synaptic abnormality subtype as well as the immune-metabolic subtype. Additionally, ten hub genes, SLC17A7, SNAP25, GAD1, SLC17A6, SLC32A1, PVALB, SYP, GRIN2A, SLC12A5, and SYN2, were identified as marker genes for the early subtype. These findings may provide valuable insights for the early diagnosis of AD and contribute to the development of innovative therapeutic strategies.}, }
@article {pmid39650412, year = {2024}, author = {Narayanee Nimeshika, G and D, S}, title = {Enhancing Alzheimer's disease classification through split federated learning and GANs for imbalanced datasets.}, journal = {PeerJ. Computer science}, volume = {10}, number = {}, pages = {e2459}, pmid = {39650412}, issn = {2376-5992}, abstract = {In the rapidly evolving healthcare sector, using advanced technologies to improve medical classification systems has become crucial for enhancing patient care, diagnosis, and treatment planning. There are two main challenges faced in this domain (i) imbalanced distribution of medical data, leading to biased model performance and (ii) the need to preserve patient privacy and comply with data protection regulations. The primary goal of this project is to develop a medical classification model for Alzheimer's disease detection that can effectively learn from decentralized and imbalanced datasets without compromising on data privacy. The proposed system aims to address these challenges by employing an approach that combines split federated learning (SFL) with conditional generative adversarial networks (cGANs) to enhance medical classification models. SFL enables efficient set of distributed agents that collaboratively train learning models without sharing their data, thus improving data privacy and the integration of conditional GANs aims to improve the model's ability to generalize across imbalanced classes by generating realistic synthetic samples for minority classes. The proposed system provided an accuracy of approximately 83.54 percentage for the Alzheimer's disease classification dataset.}, }
@article {pmid39649663, year = {2024}, author = {Izadi, R and Bahramikia, S and Akbari, V}, title = {Green synthesis of nanoparticles using medicinal plants as an eco-friendly and therapeutic potential approach for neurodegenerative diseases: a comprehensive review.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1453499}, pmid = {39649663}, issn = {1662-4548}, abstract = {Central nervous system disorders impact over 1.5 billion individuals globally, with neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases being particularly prominent. These conditions, often associated with aging, present debilitating symptoms including memory loss and movement difficulties. The growing incidence of neurological disorders, alongside a scarcity of effective anti-amyloidogenic therapies, highlights an urgent need for innovative treatment methodologies. Nanoparticles (NPs), derived from medicinal plants and characterized by their favorable pharmacological properties and minimal side effects, offer a promising solution. Their inherent attributes allow for successful traversal of the blood-brain barrier (BBB), enabling targeted delivery to the brain and the modulation of specific molecular pathways involved in neurodegeneration. NPs are crucial in managing oxidative stress, apoptosis, and neuroinflammation in ND. This study reviews the efficacy of green-synthesized nanoparticles in conjunction with various medicinal plants for treating neurodegenerative diseases, advocating for further research to refine these formulations for enhanced clinical applicability and improved patient outcomes.}, }
@article {pmid39649166, year = {2024}, author = {Zhang, W and Lukacsovich, D and Young, JI and Gomez, L and Schmidt, MA and Martin, ER and Kunkle, BW and Chen, X and O'Shea, DM and Galvin, JE and Wang, L}, title = {DNA Methylation Signature of a Lifestyle-based Resilience Index for Cognitive Health.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39649166}, issn = {2693-5015}, support = {U01 AG046152/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; R01 AG071514/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; R01 NS101483/NS/NINDS NIH HHS/United States ; RF1 NS128145/NS/NINDS NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG062634/AG/NIA NIH HHS/United States ; R61 NS135587/NS/NINDS NIH HHS/United States ; R01 AG030146/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; R01 AG036836/AG/NIA NIH HHS/United States ; K12 TR004555/TR/NCATS NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, abstract = {Cognitive resilience (CR) contributes to the variability in risk for developing and progressing in Alzheimer's disease (AD) among individuals. Beyond genetics, recent studies highlight the critical role of lifestyle factors in enhancing CR and delaying cognitive decline. DNA methylation (DNAm), an epigenetic mechanism influenced by both genetic and environmental factors, including CR-related lifestyle factors, offers a promising pathway for understanding the biology of CR. We studied DNAm changes associated with the Resilience Index (RI), a composite measure of lifestyle factors, using blood samples from the Healthy Brain Initiative (HBI) cohort. After corrections for multiple comparisons, our analysis identified 19 CpGs and 24 differentially methylated regions significantly associated with the RI, adjusting for covariates age, sex, APOE ε4, and immune cell composition. The RI-associated methylation changes are significantly enriched in pathways related to lipid metabolism, synaptic plasticity, and neuroinflammation, and highlight the connection between cardiovascular health and cognitive function. By identifying RI-associated DNAm, our study provided an alternative approach to discovering future targets and treatment strategies for AD, complementary to the traditional approach of identifying disease-associated variants directly. Furthermore, we developed a Methylation-based Resilience Score (MRS) that successfully predicted future cognitive decline in an external dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), even after accounting for age, sex, APOE ε4, years of education, baseline diagnosis, and baseline MMSE score. Our findings are particularly relevant for a better understanding of epigenetic architecture underlying cognitive resilience. Importantly, the significant association between baseline MRS and future cognitive decline demonstrated that DNAm could be a predictive marker for AD, laying the foundation for future studies on personalized AD prevention.}, }
@article {pmid39649104, year = {2024}, author = {Liu, D and Guo, P and Wang, Y and Li, W}, title = {Regulation of adult neurogenesis: the crucial role of astrocytic mitochondria.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1516119}, pmid = {39649104}, issn = {1662-5099}, abstract = {Neurogenesis has emerged as a promising therapeutic approach for central nervous system disorders. The role of neuronal mitochondria in neurogenesis is well-studied, however, recent evidence underscores the critical role of astrocytic mitochondrial function in regulating neurogenesis and the underlying mechanisms remain incompletely understood. This review highlights the regulatory effects of astrocyte mitochondria on neurogenesis, focusing on metabolic support, calcium homeostasis, and the secretion of neurotrophic factors. The effect of astrocytic mitochondrial dysfunction in the pathophysiology and treatment strategies of Alzheimer's disease and depression is discussed. Greater attention is needed to investigate the mitochondrial autophagy, dynamics, biogenesis, and energy metabolism in neurogenesis. Targeting astrocyte mitochondria presents a potential therapeutic strategy for enhancing neural regeneration.}, }
@article {pmid39649074, year = {2024}, author = {Wu, CC and Lee, YK and Tsai, JK and Su, YT and Ho, YC and Chu, TH and Chen, KT and Chang, CL and Chen, JS}, title = {Cholinesterase Inhibitor Reveals Synergistic Potential for Neural Stem Cell-Based Therapy in the 5xFAD Mouse Model of Alzheimer's Disease.}, journal = {Biologics : targets & therapy}, volume = {18}, number = {}, pages = {363-375}, pmid = {39649074}, issn = {1177-5475}, abstract = {BACKGROUND AND OBJECTIVES: Stem cell therapy shows great promise for treating Alzheimer's disease (AD). Cholinesterase inhibitors (ChEIs) like donepezil are well-established for alleviating AD symptoms. This study aimed to determine if combining ChEI treatment with stem cell therapy could improve therapeutic outcomes.
METHODS: Neural stem cells (NSCs) were injected into the hippocampus of the 5xFAD AD mice using a stereotactic technique. Following this, donepezil or a placebo was administered for one month. We assessed behavioral improvements, survival and health of the grafts, and changes in synaptic density.
RESULTS: The AD mice demonstrated cognitive impairment in both the Morris water maze and novel object recognition tests. In groups receiving stem cell therapy, donepezil enhanced the survival and neuronal differentiation of grafted NSCs, promoting the establishment of synaptic connections with the host brain. The combined treatment with donepezil and NSC transplantation more effectively increased synaptic density and improved behavioral performance in AD mice compared to NSC transplantation alone.
CONCLUSION: Combining ChEIs with NSC transplantation produces synergistic effects in AD treatment. This approach highlights the potential of integrating these therapies to develop more effective strategies for managing Alzheimer's disease.}, }
@article {pmid39648189, year = {2025}, author = {Chauhan, P and Begum, MY and Narapureddy, BR and Gupta, S and Wadhwa, K and Singh, G and Kumawat, R and Sharma, N and Ballal, S and Jha, SK and Abomughaid, MM and B, D and Ojha, S and Jha, NK}, title = {Unveiling the Involvement of Herpes Simplex Virus-1 in Alzheimer's Disease: Possible Mechanisms and Therapeutic Implications.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {5850-5874}, pmid = {39648189}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/virology/therapy ; *Herpesvirus 1, Human/physiology ; Animals ; *Herpes Simplex/virology/complications ; Neurons/virology/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; }, abstract = {Viruses pose a significant challenge and threat to human health, as demonstrated by the current COVID-19 pandemic. Neurodegeneration, particularly in the case of Alzheimer's disease (AD), is significantly influenced by viral infections. AD is a neurodegenerative disease that affects people of all ages and poses a significant threat to millions of individuals worldwide. The precise mechanism behind its development is not yet fully understood; however, the emergence and advancement of AD can be hastened by various environmental factors, such as bacterial and viral infections. There has been a longstanding suspicion that the herpes simplex virus-1 (HSV-1) may have a role to play in the development or advancement of AD. Reactivation of HSV-1 could potentially lead to damage to neurons, either by direct means or indirectly by triggering inflammation. This article provides an overview of the connection between HSV-1 infections and immune cells (astrocytes, microglia, and oligodendrocytes) in the progression of AD. It summarizes recent scientific research on how HSV-1 affects neurons, which could potentially shed light on the clinical features and treatment options for AD. In addition, the paper has explored the impact of HSV-1 on neurons and its role in various aspects of AD, such as Aβ secretion, tau hyperphosphorylation, metabolic dysregulation, oxidative damage, apoptosis, and autophagy. It is believed that the immune response triggered by HSV-1 reactivation plays a role in the development of neurodegeneration in AD. Despite the lack of a cure for AD, researchers have made significant efforts to study the clinical and pathological aspects of the disease, identify biomarkers, and gain insight into its underlying causes. The goal is to achieve early diagnosis and develop treatments that can modify the progression of the disease. The current article discusses the most promising therapy for combating the viral impacts, which provides additional evidence for the frequent reactivations of latent HSV-1 in the AD brain. However, further research is still required to establish the molecular and cellular mechanisms underlying the development of AD through the reactivation of HSV-1. This could potentially lead to new insights in drug development aimed at preventing HSV-1 reactivation and the subsequent development and progression of AD.}, }
@article {pmid39648108, year = {2025}, author = {Aga, VM}, title = {Brexpiprazole for the Treatment of Agitation in Alzheimer's Disease Dementia: Clinical Uncertainties and the Path Forward.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {33}, number = {3}, pages = {322-329}, doi = {10.1016/j.jagp.2024.11.003}, pmid = {39648108}, issn = {1545-7214}, mesh = {Humans ; *Alzheimer Disease/drug therapy/complications ; *Psychomotor Agitation/drug therapy/etiology ; *Thiophenes/therapeutic use ; *Quinolones/therapeutic use ; Antipsychotic Agents/therapeutic use ; Aged ; }, abstract = {Brexpirazole was approved for the treatment of nonpsychotic agitation in Alzheimer's disease (AD) dementia by the United States Food and Drug Administration (FDA) in May 2023 after three phase 3 clinical trials found brexpiprazole 2 to 3 mg/day to be an effective and well-tolerated treatment for agitation in AD dementia, albeit with small effect sizes. It appeared to especially benefit dementia patients with severe agitation/aggression, but it took between 6 and 12 weeks across the three studies for the medication to separate from placebo. However, much remains unknown about its place in the psychopharmacological armamentarium for the treatment of AD dementia-related agitation, including the optimal duration of a brexpiprazole trial, bridging options during the time it takes for brexpiprazole to become effective, and whether it should be continued in the presence of or upon emergence of psychosis during treatment. This Research in Action article uses a case vignette to synthesize the findings of the brexpiprazole trials and apply them to clinical practice, highlight the current uncertainties associated with its use, and compare it with other psychopharmacological options for the treatment of agitation in AD dementia.}, }
@article {pmid39647916, year = {2025}, author = {Ma, LY and Liu, SF and Ma, ZQ and Guo, YG and Li, M and Gao, Y and Wen, YT and Niu, Y and Sui, HX and Li, BS and Li, Y and Lv, YL and Huang, Y and Zhai, JJ}, title = {Liraglutide improves cognition function in streptozotocin-induced diabetic rats by downregulating β-secretase and γ-secretase and alleviating oxidative stress in HT-22 cells.}, journal = {Endocrine journal}, volume = {72}, number = {3}, pages = {285-294}, pmid = {39647916}, issn = {1348-4540}, mesh = {Animals ; *Liraglutide/pharmacology/therapeutic use ; *Oxidative Stress/drug effects ; *Diabetes Mellitus, Experimental/drug therapy/metabolism ; *Amyloid Precursor Protein Secretases/metabolism ; Rats ; Male ; *Cognition/drug effects ; *Down-Regulation/drug effects ; Hippocampus/drug effects/metabolism ; Mice ; Hypoglycemic Agents/pharmacology/therapeutic use ; Cell Line ; Amyloid beta-Peptides ; Cell Survival/drug effects ; Rats, Sprague-Dawley ; }, abstract = {Diabetes has been regarded as an independent risk factor for Alzheimer's disease (AD). Liraglutide could improve cognition in AD mouse models, but its precise mechanism remains unclear. In this study, we used STZ-induced diabetic rats and HT-22 cells to investigate the effects of liraglutide. The MWM test, MTT assay, ELISA, western blot, and immunofluorescence were used in this research. Diabetic rats induced by STZ displayed a longer escape latency and entered the target zone less frequently (p < 0.05) in the MWM test. Intraperitoneal injection of liraglutide improved the cognition of diabetic rats (p < 0.05) and reduced Aβ42 expression in the hippocampus (p < 0.05). In vivo experiments showed that HT-22 cell viability decreased in the HG group, but liraglutide (100 nmol/L and 1 μmol/L) enhanced HT-22 cell viability (p < 0.05). Oxidative stress markers were upregulated in HT-22 cells in the HG group, while liraglutide treatment significantly reduced these markers (p < 0.05). Western blot and immunofluorescence analyses demonstrated increased levels of Aβ, BACE1, and γ-secretase in HT-22 cells in the HG group (p < 0.05), whereas these levels were reduced in the liraglutide treatment group (p < 0.05). These effects were reversed by the nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors (p < 0.05). These findings suggest that liraglutide improved the cognition of diabetic rats and might exert its protective effects by reducing oxidative stress, downregulating BACE1 and γ-secretase expression, and decreasing Aβ deposition via the NF-κB and ERK1/2 pathways.}, }
@article {pmid39647702, year = {2025}, author = {Shi, L and Wang, X and Si, H and Song, W}, title = {PDE4D inhibitors: Opening a new era of PET diagnostics for Alzheimer's disease.}, journal = {Neurochemistry international}, volume = {182}, number = {}, pages = {105903}, doi = {10.1016/j.neuint.2024.105903}, pmid = {39647702}, issn = {1872-9754}, mesh = {*Alzheimer Disease/diagnostic imaging/drug therapy/metabolism ; Humans ; *Positron-Emission Tomography/methods ; Animals ; *Phosphodiesterase 4 Inhibitors/therapeutic use/pharmacology ; *Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; Radiopharmaceuticals ; Brain/diagnostic imaging/metabolism/drug effects ; }, abstract = {As the incidence of Alzheimer's disease (AD) continues to rise, the need for an effective PET radiotracer to facilitate early diagnosis has become more pressing than ever before in modern medicine. Phosphodiesterase (PDE) is closely related to cognitive impairment and neuroinflammatory processes in AD. Current research progress shows that specific PDE4D inhibitors radioligands can bind specifically to the PDE4D enzyme in the brain, thereby showing pathology-related signal enhancement in AD animal models, indicating the potential of these ligands as effective radiotracers. At the same time, we need to pay attention to the important role computer aided drug design (CADD) plays in advancing AD drug design and PET imaging. Future research will verify the potential of these ligands in clinical applications through computer simulation techniques, providing patients with timely intervention and treatment, which is of great significance.}, }
@article {pmid39647472, year = {2024}, author = {Pozuelo Moyano, B and Zullo, L and Rouaud, O and Vandel, P and von Gunten, A and Allali, G}, title = {Anti-Amyloid Drugs for Alzheimer's Disease: Considering the Role of Depression.}, journal = {Neuro-degenerative diseases}, volume = {}, number = {}, pages = {1-14}, doi = {10.1159/000541783}, pmid = {39647472}, issn = {1660-2862}, }
@article {pmid39647419, year = {2025}, author = {Han, X and Zhang, Y and Zhang, L and Zhuang, Y and Wang, Y}, title = {Efficacy and molecular mechanisms of hesperidin in mitigating Alzheimer's disease: A systematic review.}, journal = {European journal of medicinal chemistry}, volume = {283}, number = {}, pages = {117144}, doi = {10.1016/j.ejmech.2024.117144}, pmid = {39647419}, issn = {1768-3254}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Hesperidin/pharmacology/chemistry/therapeutic use ; Humans ; *Neuroprotective Agents/pharmacology/chemistry ; Animals ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; }, abstract = {Hesperidin, a flavonoid glycoside, is a natural phenolic compound that has broad biological effects. Increasing evidence suggests that hesperidin inhibits the occurrence and development of neurodegenerative diseases, including Alzheimer's disease (AD). This article reviews the neuropharmacological mechanisms of hesperidin in the prevention and treatment of AD through in vitro and in vivo studies. A systematic review of preclinical studies was conducted using PubMed, Web of Science, Scopus, and Google Scholar (up to July 1, 2024). The neuroprotective potential of hesperidin was mediated through mechanisms such as inhibition of β-amyloid (Aβ) aggregation, enhancement of endogenous antioxidant defense functions, reduction of neuroinflammation and apoptosis, improvement of mitochondrial dysfunction, regulation of autophagy, and promotion of neurogenesis. Despite various preclinical studies on the role of hesperidin in AD, its exact effects on humans remain unclear. Few clinical trials have indicated that dietary supplements rich in hesperidin can improve cerebral blood flow, cognition, and memory performance. The neuroprotective effect of hesperidin may be exerted via regulating different molecular pathways, including the RAGE/NF-κB, Akt/Nrf2, and AMPK/BDNF/CREB pathways. However, further clinical trials are needed to confirm the neuroprotective effects of this natural flavonoid compound and to assess its safety.}, }
@article {pmid39644998, year = {2025}, author = {Hojjati, SH and Chen, K and Chiang, GC and Kuceyeski, A and Wang, XH and Razlighi, QR and Pahlajani, S and Glodzik, L and Tanzi, EB and Reinhardt, M and Butler, TA}, title = {Utilizing structural MRI and unsupervised clustering to differentiate schizophrenia and Alzheimer's disease in late-onset psychosis.}, journal = {Behavioural brain research}, volume = {480}, number = {}, pages = {115386}, doi = {10.1016/j.bbr.2024.115386}, pmid = {39644998}, issn = {1872-7549}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Schizophrenia/diagnostic imaging/pathology ; *Magnetic Resonance Imaging ; Male ; Female ; *Psychotic Disorders/diagnostic imaging/pathology ; Middle Aged ; Aged ; Cluster Analysis ; Diagnosis, Differential ; Brain/diagnostic imaging/pathology ; Age of Onset ; }, abstract = {Late-onset psychosis (LOP) represents a highly heterogeneous and understudied condition, with potential origins ranging from atypically late onset of schizophrenia (SCZ) to Alzheimer's Disease (AD). Despite the clinical necessity of differentiating these conditions to guide effective treatment, achieving an accurate diagnosis remains challenging. This study aimed to utilize data-driven analyses of structural magnetic resonance imaging (MRI) to distinguish between these diagnostic possibilities. Utilizing publicly available datasets of MRI scans from 699 healthy control (HC) participants and 469 patients diagnosed with SCZ or AD, our analysis focused on bilateral subcortical volumetric measures in the caudate, hippocampus, putamen, and amygdala. We first trained an unsupervised K-means clustering algorithm based on SCZ and AD patients and achieved a clustering accuracy of 81 % and an area under curvature (AUC) of 0.79 in distinguishing between these two groups. Subsequently, we calculated the Euclidean distance between the AD and SCZ cluster centroids for each of ten patients with unexplained onset of psychosis after age 45 from a clinical MRI registry. Six patients were classified as AD and four as SCZ. Our findings revealed that among LOP participants, those classified in the SCZ cluster exhibited significantly greater right putamen volumes compared to those in the AD cluster (p < 0.0025). There were also intriguing clinical differences. While we do not have diagnostic biomarker information to confirm these classifications, this study sheds light on the heterogeneity of psychoses in late life and illustrates the potential use of widely available structural MRI and data-driven methods to enhance diagnostic accuracy and treatment outcomes for LOP patients.}, }
@article {pmid39644533, year = {2025}, author = {Fruijtier, AD and van der Flier, WM and van Maurik, I and van der Schaar, J and Pijnenburg, YAL and Smets, EMA and Visser, LNC}, title = {The need for personalization when sharing results of amyloid imaging for Alzheimer's disease: Insights from a randomized experimental study.}, journal = {Patient education and counseling}, volume = {131}, number = {}, pages = {108587}, doi = {10.1016/j.pec.2024.108587}, pmid = {39644533}, issn = {1873-5134}, mesh = {Humans ; Female ; Male ; *Alzheimer Disease/diagnostic imaging/psychology ; Middle Aged ; Aged ; *Cognitive Dysfunction ; *Positron-Emission Tomography ; Communication ; Surveys and Questionnaires ; Adaptation, Psychological ; Physician-Patient Relations ; Mental Recall ; Health Literacy ; }, abstract = {OBJECTIVE: To study information needs after receiving abnormal amyloid-PET results, and how individual characteristics moderate effects of different communication strategies on information recall.
METHODS: In an online video-vignette experiment, seven vignettes each depicted a consultation of a physician sharing abnormal amyloid-PET results with a patient with Mild Cognitive Impairment(MCI), using different communication strategies. Healthy individuals (N = 1017; age 64 ± 8, 808(79 %) female), instructed to imagine themselves as the video-patient, viewed a randomly-assigned vignette and completed questionnaires to assess information needs and test moderation effects of gender, age, care-partner experience, health literacy, and coping.
RESULTS: Sixty-three percent of participants (645/1017) would have liked to receive more information, e.g., on prognosis, additional information sources, lifestyle advice, and/or treatment. Emotional support benefited information recall in women, but not men. Emotional support and visually presenting the PET-scan were less beneficial for individuals with a stronger avoidant coping style, compared to most other strategies.
CONCLUSION: Most people wanted more information on varying topics, and gender and coping style influenced how communication strategies impacted information recall. PRACTICE IMPLICATIONS The importance of personalized information provision was emphasized, both in terms of what information is provided and how physicians share information, by paying attention to individuals' needs and characteristics.}, }
@article {pmid39644364, year = {2024}, author = {Apiraksattayakul, S and Pingaew, R and Prachayasittikul, V and Ruankham, W and Tantimongcolwat, T and Prachayasittikul, V and Prachayasittikul, S and Phopin, K}, title = {Neuroprotective Potential of Aminonaphthoquinone Derivatives Against Amyloid Beta-Induced Neuronal Cell Death Through Modulation of SIRT1 and BACE1.}, journal = {Neurochemical research}, volume = {50}, number = {1}, pages = {50}, pmid = {39644364}, issn = {1573-6903}, mesh = {*Neuroprotective Agents/pharmacology ; *Sirtuin 1/metabolism ; *Amyloid beta-Peptides/toxicity/metabolism ; Humans ; *Amyloid Precursor Protein Secretases/metabolism ; *Naphthoquinones/pharmacology ; *Neurons/drug effects/metabolism ; Cell Line, Tumor ; *Molecular Docking Simulation ; *Aspartic Acid Endopeptidases/metabolism/antagonists & inhibitors ; *Cell Death/drug effects ; Cell Survival/drug effects/physiology ; Peptide Fragments/pharmacology ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; }, abstract = {Alzheimer's disease (AD) is characterized by the accumulation of tau protein tangles and amyloid-β (Aβ) plaques in the central nervous system (CNS), leading to progressive neurodegeneration. Hence, the discovery of disease-modifying agents capable of delaying the progression is essential for effective management. Aminonaphthoquinone (ANQ) is an attractive pharmacophore with various biological effects. This study explores the neuroprotective potentials of ANQ derivatives (1-18) using in vitro models of AD pathology (i.e., Aβ42-induced SH-SY5Y cells). Findings demonstrated that all compounds mitigated Aβ42-induced cellular damage by preserving cell viability and morphology. Among all, four compounds (10, 12, 16, and 18) showed potent antioxidant activities as well as abilities to minimize AD-related damages (i.e. decreasing intracellular reactive oxygen species (ROS) production, preserving mitochondrial membrane potential (MMP), protecting membrane damage, and modulating beta-secretase 1 (BACE1) activity) with comparable protective effects to the well-known neuroprotectant, resveratrol (RSV). A molecular docking study indicated these compounds could suitably bind to sirtuin 1 (SIRT1) protein with preferable affinity. Key amino acid residues and key functional groups essential for binding interactions were revealed. Target prediction identified a list of possible AD-related targets of these compounds offering insights into their mechanisms of action and suggesting their multifunctional potentials. Additionally, in silico predictions revealed that these candidates showed favorable drug-like properties. Overall, this study highlighted the therapeutic potential of ANQ derivatives in AD treatment, emphasizing the need for further experimental validation and comprehensive investigations to fully realize their therapeutic benefits.}, }
@article {pmid39644140, year = {2025}, author = {Sharma, A and Nayak, M and Thakur, S and Jadhav, HR and Bharate, SB}, title = {Structure-Based Virtual Screening and Biological Characterization of Novel BACE-1 and Amyloid-β Aggregation Inhibitors.}, journal = {ChemMedChem}, volume = {20}, number = {6}, pages = {e202400685}, doi = {10.1002/cmdc.202400685}, pmid = {39644140}, issn = {1860-7187}, support = {//IIIM/ ; }, mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; Humans ; *Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Structure-Activity Relationship ; Molecular Docking Simulation ; Protein Aggregates/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Small Molecule Libraries/chemistry/pharmacology/chemical synthesis ; Molecular Structure ; Drug Evaluation, Preclinical ; Molecular Dynamics Simulation ; Enzyme Inhibitors/chemistry/pharmacology/chemical synthesis ; Dose-Response Relationship, Drug ; Pyrazoles/chemistry/pharmacology/chemical synthesis ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder having limited treatment options. The beta-site APP cleaving enzyme 1 (BACE-1) is a key target for therapeutic intervention in Alzheimer's disease. To discover new scaffolds for BACE-1 inhibitors, a ChemBridge DIVERSet library of 20,000 small molecules was employed to structure-based virtual screening. The top 45 compounds, based on docking scores and binding affinities, were tested for BACE-1 inhibitory activity using a FRET assay. Four compounds, 18 (5353320), 20 (5262831), 29 (5784196) and 32 (5794006) demonstrated more than 35 % inhibitory activity at 10 μM. Notably, pyrazole-5-carbohydrazide 29 (5784196) exhibited BACE-1 inhibition with an IC50 value of 14.5 μM and a ki value of 0.25 μM. Additionally, it also inhibits the self-aggregation of β-amyloid, with IC50 value of 14.87 μM. Molecular modeling and dynamics simulations provided insights into its interaction pattern and stability of the enzyme-inhibitor complex. These findings suggest that virtual screening is an efficient and cost-effective method for identifying potential leads for AD.}, }
@article {pmid39642444, year = {2025}, author = {Andriambelo, B and Vachon, A and Dansereau, MA and Laurent, B and Plourde, M}, title = {Providing lysophosphatidylcholine-bound omega-3 fatty acids increased eicosapentaenoic acid, but not docosahexaenoic acid, in the cortex of mice with the apolipoprotein E3 or E4 allele.}, journal = {Prostaglandins, leukotrienes, and essential fatty acids}, volume = {204}, number = {}, pages = {102661}, doi = {10.1016/j.plefa.2024.102661}, pmid = {39642444}, issn = {1532-2823}, mesh = {Animals ; *Docosahexaenoic Acids/metabolism ; *Lysophosphatidylcholines/metabolism ; *Apolipoprotein E4/genetics/metabolism ; Mice ; *Eicosapentaenoic Acid/metabolism ; *Apolipoprotein E3/genetics/metabolism ; Fatty Acids, Omega-3/metabolism ; Alleles ; Male ; Frontal Lobe/metabolism ; Cerebral Cortex/metabolism ; Dietary Supplements ; }, abstract = {BACKGROUND: Several mechanisms have been proposed for the brain uptake of omega-3 fatty acids (n-3), including passive diffusion of the unesterified form and the use of Mfsd2a transporter for the lysophosphatidylcholine (LPC) form. We hypothesize that the accumulation of LPC n-3 in the brain is lower in mice carrying the apolipoprotein E ε4 allele (APOE4), a major genetic risk factor for developing sporadic Alzheimer's disease in humans.
OBJECTIVE: Determine whether two or four months of supplementation with LPC n-3 increases the levels of docosahexaenoic acids (DHA) and eicosapentaenoic acids (EPA) in the frontal cortex of APOE3 and APOE4 mice.
METHODS: APOE3 and APOE4 mice were administered LPC n-3 (9.6 mg DHA + 18.3 mg EPA) or sunflower oil (control) by oral gavage for two or four months (n = 5-8 per genotype, per treatment, and per treatment duration). At the end of the treatment period, frontal cortices were collected, and their FA profiles analyzed by gas chromatography with flame ionization detection.
RESULTS: After two months of gavage with LPC n-3, APOE3 mice showed increased levels of EPA in their cortex, but not DHA. In APOE4 mice, neither EPA nor DHA levels were significantly affected. After four months of LPC n-3, both APOE3 and APOE4 mice exhibited higher EPA levels, while changes in DHA levels were not statistically significant.
CONCLUSION: LPC n-3 supplementation increased EPA, but not DHA, levels in the frontal cortex of mice in a duration- and APOE genotype-dependent manner. Further research is needed to explore the implications for brain health.}, }
@article {pmid39641889, year = {2024}, author = {Gao, XM and Liu, H}, title = {Effect of Acupuncture Combined with Nerve Block on Cerebral Functional Area Blood Perfusion in Treatment of Alzheimer's Disease: A Case Report.}, journal = {Chinese journal of integrative medicine}, volume = {}, number = {}, pages = {}, pmid = {39641889}, issn = {1993-0402}, }
@article {pmid39641407, year = {2025}, author = {Cheon, J and Kwon, S and Kim, M}, title = {Exerkines mitigating Alzheimer's disease progression by regulating inflammation: Focusing on macrophage/microglial NLRP3 inflammasome pathway.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14432}, pmid = {39641407}, issn = {1552-5279}, support = {NRF-2021R1G1A1093620//National Research Foundation (NRF) of Korea/ ; }, mesh = {*Alzheimer Disease/pathology/metabolism ; Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Macrophages ; *Inflammasomes/metabolism ; *Inflammation/metabolism ; *Disease Progression ; *Microglia/metabolism ; Exercise/physiology ; Animals ; Signal Transduction ; }, abstract = {Recent research highlights the critical role of inflammation in accelerating amyloid beta and phosphorylated tubulin-associated protein tau cascade and Alzheimer's disease (AD) progression. Emerging evidence suggests that exercise influences AD by modulating inflammatory responses. We conducted a comprehensive search across multiple online databases. Our approach focused on previous and recent studies exploring the links among inflammation, AD, and the effects of exercise, specifically targeting research articles and books published in English. We pointed out that inflammation extends from the periphery to the central nervous system, facilitated by macrophage/microglial NLRP3 (nucleotide-binding domain, leucine rich-containing family, pyrin domain-containing protein 3) inflammasome signaling, which exacerbates classical AD mechanisms. Moreover, we provided further insights into the modulation of inflammasome signaling through exercise and exerkines, which may contribute to mitigating AD development. These insights deepen our understanding of AD mechanisms and offer the potential for identifying key therapeutic targets and biomarkers crucial for effective disease management and treatment. HIGHLIGHTS: Inflammation is potentially linked to the acceleration of classical Alzheimer's disease (AD) pathogenesis, including the pathways involving amyloid beta and phosphorylated tau, mediated by pro-inflammatory cytokines. Inflammation, initiated by the nucleotide-binding domain, leucine rich-containing family, pyrin domain-containing protein 3 (NLRP3) inflammasome signaling pathway within M1-type macrophages/microglia, may contribute to neuroinflammation and AD progression. Exercise has the potential to reduce inflammation and the development of AD by influencing NLRP3 inflammasome signaling via exerkines.}, }
@article {pmid39641322, year = {2025}, author = {Xu, J and Song, W and Xu, Z and Danziger, MM and Karavani, E and Zang, C and Chen, X and Li, Y and Paz, IMR and Gohel, D and Su, C and Zhou, Y and Hou, Y and Shimoni, Y and Pieper, AA and Hu, J and Wang, F and Rosen-Zvi, M and Leverenz, JB and Cummings, J and Cheng, F}, title = {Single-microglia transcriptomic transition network-based prediction and real-world patient data validation identifies ketorolac as a repurposable drug for Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14373}, pmid = {39641322}, issn = {1552-5279}, support = {RF1 AG048083/AG/NIA NIH HHS/United States ; RF1AG082211/AG/NIA NIH HHS/United States ; U24 AG21886//National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)/ ; RF1 NS133812/NS/NINDS NIH HHS/United States ; R56AG074001/AG/NIA NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; //Alzheimer's Disease Drug Discovery Foundation (ADDF)/ ; R56 AG057478/AG/NIA NIH HHS/United States ; R35AG071476/AG/NIA NIH HHS/United States ; //Keep Memory Alive (KMA)/ ; P30 AG072959/AG/NIA NIH HHS/United States ; R21 AG083003/AG/NIA NIH HHS/United States ; R01AG076448/AG/NIA NIH HHS/United States ; R01 AG082118/AG/NIA NIH HHS/United States ; R21AG083003/AG/NIA NIH HHS/United States ; P30AG072959//Cleveland Alzheimer's Disease Research Center (NIH/NIA)/ ; U01AG073323/AG/NIA NIH HHS/United States ; R56 AG074001/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01AG082118/AG/NIA NIH HHS/United States ; RF1NS133812/NS/NINDS NIH HHS/United States ; RF1AG048083-01//National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)/ ; U01 NS093334/NS/NINDS NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; U01NS093334/NS/NINDS NIH HHS/United States ; R01 AG076448/AG/NIA NIH HHS/United States ; P20GM109025/GM/NIGMS NIH HHS/United States ; P20 GM109025/GM/NIGMS NIH HHS/United States ; R01AG066707/AG/NIA NIH HHS/United States ; R01 AG053798/AG/NIA NIH HHS/United States ; R01AG084250/AG/NIA NIH HHS/United States ; ALZDISCOVERY-1051936//Alzheimer's Association award/ ; R01AG053798/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; *Transcriptome/drug effects ; *Microglia/drug effects/metabolism ; *Ketorolac/pharmacology ; Drug Repositioning ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; Brain/metabolism/drug effects ; }, abstract = {INTRODUCTION: High microglial heterogeneities hinder the development of microglia-targeted treatment for Alzheimer's disease (AD).
METHODS: We integrated 0.7 million single-nuclei RNA-sequencing transcriptomes from human brains using a variational autoencoder. We predicted AD-relevant microglial subtype-specific transition networks for disease-associated microglia (DAM), tau microglia, and neuroinflammation-like microglia (NIM). We prioritized drugs by specifically targeting microglia-specific transition networks and validated drugs using two independent real-world patient databases.
RESULTS: We identified putative AD molecular drivers (e.g., SYK, CTSB, and INPP5D) in transition networks of DAM and NIM. Via specifically targeting NIM, we identified that usage of ketorolac was associated with reduced AD incidence in both MarketScan (hazard ratio [HR] = 0.89) and INSIGHT (HR = 0.83) Clinical Research Network databases, mechanistically supported by ketorolac-treated transcriptomic data from AD patient induced pluripotent stem cell-derived microglia.
DISCUSSION: This study offers insights into the pathobiology of AD-relevant microglial subtypes and identifies ketorolac as a potential anti-inflammatory treatment for AD.
HIGHLIGHTS: An integrative analysis of ≈ 0.7 million single-nuclei RNA-sequencing transcriptomes from human brains identified Alzheimer's disease (AD)-relevant microglia subtypes. Network-based analysis identified putative molecular drivers (e.g., SYK, CTSB, INPP5D) of transition networks between disease-associated microglia (DAM) and neuroinflammation-like microglia (NIM). Via network-based prediction and population-based validation, we identified that usage of ketorolac (a US Food and Drug Administration-approved anti-inflammatory medicine) was associated with reduced AD incidence in two independent patient databases. Mechanistic observation showed that ketorolac treatment downregulated the Type-I interferon signaling in patient induced pluripotent stem cell-derived microglia, mechanistically supporting its protective effects in real-world patient databases.}, }
@article {pmid39640295, year = {2024}, author = {Ou, CM and Xue, WW and Liu, D and Ma, L and Xie, HT and Ning, K}, title = {Stem cell therapy in Alzheimer's disease: current status and perspectives.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1440334}, pmid = {39640295}, issn = {1662-4548}, abstract = {An incurable neurogenerative illness, Alzheimer's disease, is the cause of most global health, medical, and social disasters. The two main symptoms are cognitive impairment and neuronal loss. Current medications that target tau protein tangles and Aβ plaques are not very effective because they only slow the symptoms of AD and do not repair damaged cells. Stem cell-based treatments, however, present an alternative strategy in the treatment of AD. They have the capacity to divide into specialized adult cells, have self-renewal abilities, and multiplication. Stem cells can now be employed as a donor source for cell therapy due to developments in stem cell technology. This review covers preclinical and clinical updates on studies based on targeting the tau protein tangles and Aβ plaque, as well as four types of stem cells employed in AD treatment. The review also outlines the two basic pathologic aspects, tau protein tangles and Aβ plaques, of AD.}, }
@article {pmid39640288, year = {2024}, author = {Hooshmand, M and Asoodeh, A}, title = {Coadministration of Monophosphoryl Lipid and Curcumin Modulates Neuroprotective Effects in LPS Stimulated Rat Primary Microglial Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2024}, number = {}, pages = {9422312}, pmid = {39640288}, issn = {1942-0994}, mesh = {Animals ; *Curcumin/pharmacology ; *Microglia/drug effects/metabolism ; *Lipopolysaccharides/pharmacology ; Rats ; *Neuroprotective Agents/pharmacology ; Lipid A/analogs & derivatives/pharmacology ; Cell Survival/drug effects ; Nitric Oxide Synthase Type II/metabolism ; Cytokines/metabolism ; }, abstract = {Lipopolysaccharide (LPS)-induced activation of microglia triggers the release of neuroinflammatory molecules, contributing to the progression of neurodegenerative diseases. Targeting these neuroinflammatory molecules could serve as a potential therapeutic strategy. Given the evidence supporting the immune-boosting properties of curcumin (Curc) and the protective effects of monophosphoryl lipid A (MPL) in the central nervous system (CNS) related to Alzheimer's disease (AD), this study aimed to assess the anti-inflammatory effects of these compounds on primary rat microglial cells, which are crucial in the response to neuroinflammation. This in vitro study investigated the effects of Curc, MPL, and their coadministration (Curc + MPL) on inflammatory cytokine levels in activated microglial cells. Primary microglial cells were isolated from 1-day-old rats and treated with various concentrations of Curc, MPL, and Curc + MPL prior to LPS stimulation. Cell viability was assessed using the MTT assay, followed by the Griess assay to evaluate nitric oxide (NO) production. The levels of inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), as well as the gene expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), were analyzed via real-time PCR. Additionally, enzyme-linked immunosorbent assay (ELISA) was employed to quantify the protein levels of IL-1β, TNF-α, and IL-6. Our findings demonstrate that Curc and MPL possess antineuroinflammatory properties in LPS-stimulated microglial cells. Notably, the coadministration of Curc and MPL (Curc + MPL) significantly inhibited the production of pro-inflammatory cytokines IL-1β, TNF-α, and IL-6. Furthermore, Curc + MPL suppressed the expression of iNOS and COX-2. These results strongly suggest that Curc + MPL is a promising neuroprotective agent for the treatment of neurodegenerative disorders by mitigating neuroinflammatory responses.}, }
@article {pmid39638950, year = {2025}, author = {Dong, N and Ali-Khiavi, P and Ghavamikia, N and Pakmehr, S and Sotoudegan, F and Hjazi, A and Gargari, MK and Gargari, HK and Behnamrad, P and Rajabi, M and Elhami, A and Saffarfar, H and Nourizadeh, M}, title = {Nanomedicine in the treatment of Alzheimer's disease: bypassing the blood-brain barrier with cutting-edge nanotechnology.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {4}, pages = {1489-1507}, pmid = {39638950}, issn = {1590-3478}, support = {PSAU/2023/R/1445//Deanship of Scientific Research, Prince Sattam bin Abdulaziz University/ ; }, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Blood-Brain Barrier/drug effects/metabolism ; *Nanomedicine/methods ; Animals ; Drug Delivery Systems/methods ; }, abstract = {Alzheimer's disease (AD) remains a formidable challenge in the field of neurodegenerative disorders, necessitating innovative therapeutic strategies. Nanomedicine, leveraging nanomaterials, has emerged as a promising avenue for AD treatment, with a key emphasis on overcoming the blood-brain barrier (BBB) to enhance drug delivery efficiency. This review provides a comprehensive analysis of recent advancements in the application of nanomaterials for AD therapy, highlighting their unique properties and functions. The blood-brain barrier, a complex physiological barrier, poses a significant hurdle for traditional drug delivery to the brain. Nanomedicine addresses this challenge by utilizing various nanomaterials such as liposomes, polymeric nanoparticles, and metal nanoparticles. These nanocarriers enable improved drug bioavailability, sustained release, and targeted delivery to specific brain regions affected by AD pathology. The review discusses the diverse range of nanomaterials employed in AD treatment, exploring their capacity to encapsulate therapeutic agents, modulate drug release kinetics, and enhance drug stability. Additionally, the multifunctionality of nanomaterials allows for simultaneous imaging and therapy, facilitating early diagnosis and intervention. Key aspects covered include the interaction of nanomaterials with Aβ aggregates, the role of antioxidants in mitigating oxidative stress, and the potential of nanomedicine in alleviating neuroinflammation associated with AD. Furthermore, the safety, biocompatibility, and toxicity profiles of various nanomaterials are scrutinized to ensure their clinical applicability. In conclusion, this review underscores the pivotal role of nanomedicine and nanomaterials in revolutionizing AD treatment strategies. By specifically addressing BBB challenges, these innovative approaches offer new avenues for targeted drug delivery and improved therapeutic outcomes in the complex landscape of Alzheimer's disease.}, }
@article {pmid39638823, year = {2024}, author = {Rawat, K and Tewari, D and Bisht, A and Chandra, S and Tiruneh, YK and Hassan, HM and Al-Emam, A and Sindi, ER and Al-Dies, AM}, title = {Identification of AChE targeted therapeutic compounds for Alzheimer's disease: an in-silico study with DFT integration.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {30356}, pmid = {39638823}, issn = {2045-2322}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Cholinesterase Inhibitors/chemistry/therapeutic use/pharmacology ; *Acetylcholinesterase/chemistry/metabolism ; *Molecular Docking Simulation ; Humans ; *Molecular Dynamics Simulation ; Density Functional Theory ; Computer Simulation ; Protein Binding ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by cognitive deterioration and changes in behavior. Acetylcholinesterase (AChE), which hydrolyzes acetylcholine, is a key drug target for treating AD. This research aimed to identify new AChE inhibitors using the IMPPAT database. We used known drugs as a basis to search for similar chemicals in the IMPPAT database and created a library of 127 plant-based compounds. Initial screening of these compounds was performed using molecular docking, followed by an analysis of their drug-likeness and ADMET properties. Compounds with favorable properties underwent density functional theory (DFT) calculations to assess their electronic properties such as HOMO-LUMO gap, electron density, and molecular orbital distribution. These descriptors provided insights into each compound's reactivity, stability, and binding potential with AChE. Promising candidates were further evaluated through molecular dynamics (MD) simulations over 100 ns and MMPBSA analysis for the last 30 ns. Two compounds, Biflavanone (IMPHY013027) with a binding free energy of - 130.394 kcal/mol and Calomelanol J (IMPHY007737) with - 107.908 kcal/mol, demonstrated strong binding affinities compared to the reference molecule HOR, which has a binding free energy of - 105.132 kcal/mol. These compounds exhibited promising drug-ability profiles in both molecular docking and MD simulations, indicating their potential as novel AChE inhibitors for AD treatment. However, further experimental validation is necessary to verify their effectiveness and safety.}, }
@article {pmid39638097, year = {2025}, author = {Arroyo-Pacheco, N and Sarmiento-Blanco, S and Vergara-Cadavid, G and Castro-Leones, M and Contreras-Puentes, N}, title = {Monoclonal therapy with lecanemab in the treatment of mild Alzheimer's disease: A systematic review and meta-analysis.}, journal = {Ageing research reviews}, volume = {104}, number = {}, pages = {102620}, doi = {10.1016/j.arr.2024.102620}, pmid = {39638097}, issn = {1872-9649}, mesh = {Humans ; *Alzheimer Disease ; Antibodies, Monoclonal, Humanized/therapeutic use ; Cognitive Dysfunction ; }, abstract = {Alzheimer's disease, a progressive neurodegenerative pathology, is characterized by the accumulation of Amyloid-β plaques in the brain. Lecanemab (BAN2401), a humanized IgG1 monoclonal antibody, binds with high affinity to Amyloid-β protofibrils. It is the first monoclonal antibody for Alzheimer's disease to receive full FDA approval. This systematic review, conducted meticulously, examines the current use and safety of Lecanemab in treating Alzheimer's disease. We screened literature from databases such as PubMed Central, PubMed (MedLine), ScienceDirect, Scopus, Web of Science, and Wolters Kluwer for randomized controlled trials testing Lecanemab for cognitive decline in patients with mild cognitive impairment due to Alzheimer's disease. Outcomes measured included CDR-SB, ADCOMS, ADAS-Cog, and Amyloid burden on PET in centiloids. Likewise, reports were analyzed for adverse events associated with ARIA-A and ARIA-H. Five papers were included in the systematic review and three in the meta-analysis. The meta-analysis showed that Lecanemab slowed the progression of cognitive impairment as measured by CDR-SB, ADCOMS, and ADASCog, and significantly reduced Amyloid burden on PET in centiloids. However, Lecanemab was associated with an increased risk of ARIA-E and ARIA-H. Lecanemab has demonstrated efficacy in slowing cognitive impairment progression in Alzheimer's disease as measured by ADCOMS, ADAS-Cog, and CDR-SB. However, it is associated with an increased risk of ARIA-E and ARIA-H, particularly in ApoE4 carriers.}, }
@article {pmid39637486, year = {2025}, author = {Zhu, X and Xu, JB and Gao, F and Wan, LX}, title = {Advances in the structural modification of Alzheimer's disease drug - Huperzine A.}, journal = {Bioorganic chemistry}, volume = {154}, number = {}, pages = {108012}, doi = {10.1016/j.bioorg.2024.108012}, pmid = {39637486}, issn = {1090-2120}, mesh = {*Alzheimer Disease/drug therapy ; *Alkaloids/chemistry/pharmacology/chemical synthesis ; Humans ; *Sesquiterpenes/chemistry/pharmacology ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis/therapeutic use ; Structure-Activity Relationship ; Molecular Structure ; Acetylcholinesterase/metabolism/chemistry ; Animals ; Huperzia/chemistry ; }, abstract = {Huperzine A is an alkaloid featuring a bicyclo [3.3.1] nonane scaffold with an integrated piperidine ring, which was firstly isolated from Huperzia selago in 1960. As a reversible acetylcholinesterase inhibitor, it was clinically approved in China for treatment of Alzheimer's disease in 1996. Although huperzine A shows therapeutic potential, it is often associated with adverse events, such as dizziness, nausea, and digestive disorders. To enhance the efficacy and therapeutic index of huperzine A, many structural modification efforts have been undertaken. This review comprehensively summarizes the structural modification investigations on huperzine A conducted over the past three decades, and the structure-activity relationships are also discussed. The insights from this review are expected to inspire more effective modification strategies in the future.}, }
@article {pmid39637477, year = {2025}, author = {Abeysinghe, S and Tao, Y and Kyei-Baffour, P and Adrion, E}, title = {'Small benefits and a certain risk': Media representations of novel treatments for Alzheimer's disease.}, journal = {Social science & medicine (1982)}, volume = {365}, number = {}, pages = {117554}, doi = {10.1016/j.socscimed.2024.117554}, pmid = {39637477}, issn = {1873-5347}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; United States ; *Mass Media/statistics & numerical data ; United States Food and Drug Administration ; Risk Assessment/methods ; }, abstract = {The media is a key site for developing and communicating public understanding of Alzheimer's disease. Alzheimer's disease is a leading cause of dementia, and a condition that is prominent in public perceptions of ageing and cognitive decline. Novel disease-modifying treatments (DMTs) are the first innovation in Alzheimer's disease treatment for two decades, and have the potential to change how society thinks about Alzheimer's disease. This study investigates representation of risks and uncertainties of DMTs in articles published within the five highest circulation US newspapers between November 2020 and May 2024. This was a period of focused media attention on DMTs in the US, including reporting on Food and Drug Administration (FDA) review and approval processes and debates over public funding of these treatments through the Medicare program. The analysis finds that the media associated risks with the relative efficacy of the medications in comparison to the costs of these treatments. We further find that media representations highlight institutional challenges for the FDA in managing these uncertainties, within a situation characterized by expert contestation of the evidentiary basis for DMTs and patient hope for the promise that DMTs hold.}, }
@article {pmid39636462, year = {2024}, author = {Pashaei, S and Shabani, S and Mohammadi, S and Morozova-Roche, LA and Salari, N and Rahimi, Z and Khodarahmi, R}, title = {Differential Expression of Neurodegeneration-Related Genes in SH-SY5Y Neuroblastoma Cells Under the Influence of Cyclophilin A: Could the Enzyme be a Likely Trigger and Therapeutic Target for Alzheimer's Disease?.}, journal = {Neurochemical research}, volume = {50}, number = {1}, pages = {47}, pmid = {39636462}, issn = {1573-6903}, support = {4000930//Kermanshah University of Medical Sciences/ ; 4000930//Kermanshah University of Medical Sciences/ ; 4000930//Kermanshah University of Medical Sciences/ ; 4000930//Kermanshah University of Medical Sciences/ ; 4000930//Kermanshah University of Medical Sciences/ ; 4000930//Kermanshah University of Medical Sciences/ ; 4000930//Kermanshah University of Medical Sciences/ ; 4000758//Iran National Institute for Medical Research Development/ ; 4000758//Iran National Institute for Medical Research Development/ ; 4000758//Iran National Institute for Medical Research Development/ ; 4000758//Iran National Institute for Medical Research Development/ ; 4000758//Iran National Institute for Medical Research Development/ ; 4000758//Iran National Institute for Medical Research Development/ ; 4000758//Iran National Institute for Medical Research Development/ ; }, mesh = {*Cyclophilin A/metabolism/genetics ; Humans ; *Alzheimer Disease/metabolism/drug therapy ; Cell Line, Tumor ; *Neuroblastoma/metabolism ; }, abstract = {The function and mechanism of Cyclophilin A (CypA) in modulating gene expression associated with Alzheimer's disease (AD) remain unclear. This multifunctional protein is found to be elevated in the cerebrospinal fluid (CSF) of individuals at risk for AD. The cytotoxic effects of CypA, including both wild-type and the mutant R55A, were assessed using the MTT assay. Prior to this evaluation, the purified recombinant protein was validated through enzymatic activity assays and western blot analysis. Following treatment with CypA and transient transfection using the CypA construct, real-time PCR (qRT-PCR) and western blotting were conducted to analyze the expression of factors involved in various signaling pathways, with an emphasis on inflammation, cell death, and intercellular communication. The findings indicate that CypA has a significant impact on the gene expression of factors associated with inflammation and the progression of AD in SH-SY5Y cells. It can be concluded that CypA is capable of regulating gene expression in SH-SY5Y cells, either in a manner dependent on or independent of its enzymatic activity. Additionally, the influence of this multifunctional protein on gene expression is contingent upon the specific site of action, as well as the dosage and duration of exposure to the cells.}, }
@article {pmid39634577, year = {2025}, author = {Yuan, H and Yang, J and Qin, G and Sun, Y and Zhao, C and Wang, C and Ren, J and Qu, X}, title = {Regulation of STING G-quadruplex for rescuing cellular senescence and Aβ phagocytic capacity of microglia.}, journal = {Chemical science}, volume = {16}, number = {2}, pages = {693-699}, pmid = {39634577}, issn = {2041-6520}, abstract = {Alzheimer's disease (AD), the most common form of dementia, affects millions of people worldwide and its cause is very complicated. Besides the classical amyloid cascade hypothesis, oxidative stress, metal ion imbalance, cellular senescence and neuroinflammation are also considered crucial triggers of AD. Therefore, therapeutic strategies other than inhibiting Aβ deposition are very promising. As a crucial innate immune pathway, the abnormal activation of the cGAS-STING pathway in AD has attracted much attention and become a promising target for AD treatment. Here, we identify a highly conserved and stable G-quadruplex (G4) in the STING promoter region, and further verify its function in transcriptional inhibition of STING by using CRISPR technology to precisely target STING G4. Intriguingly, down-regulation of STING expression can alleviate cellular senescence and restore the Aβ phagocytic capacity of microglia. Our results highlight the compelling therapeutic potential of STING promoter G4 for regulation of the abnormal activation of the cGAS-STING pathway in AD. Different from the existing therapeutic strategies for AD, this work provides an alternative way of targeting the functional gene secondary structure, such as the STING promoter region, which may promote the design and synthesis of drug candidates for AD.}, }
@article {pmid39634029, year = {2024}, author = {Bang, S and Song, JK and Lee, KH}, title = {Hyperphosphorylated tau targeting human serum albumin Fusion protein as therapeutics for Alzheimer's diseases.}, journal = {IBRO neuroscience reports}, volume = {17}, number = {}, pages = {423-430}, pmid = {39634029}, issn = {2667-2421}, abstract = {INTRODUCTION: Neurofibrillary tangles (NFTs) are composed of hyperphosphorylated forms of microtubule-associated protein tau (Tau), which is responsible for neurodegeneration in Alzheimer's disease (AD). The hippocampal region has been a major focus of AD research because the deposits of phosphorylated tau protein in these regions are correlated with early memory deficits. Despite extensive studies, therapeutic strategies to reduce tau hyperphosphorylation and NFTs deposition remain unclear. AL04, a recently developed recombinant fusion protein comprising Cystatin C, human serum albumin, and a novel blood brain barrier (BBB) penetrating peptide, is currently under investigation. Previous studies have demonstrated its effectiveness in reducing amyloid beta plaques in AD mouse model.
METHODS: In this study, we investigated the effects of AL04 on lowering hyperphosphorylated tau and NFTs in JNPL3 mouse model harboring human tau-P301L mutation. 3-month-old female mice intraperitoneally received AL04 (5 mg/kg) or PBS treatment every other week for 24 weeks. We used confocal microscopy and western blot to visualize and analyze changes in hyperphosphorylated tau Ser202/Thr205 labeled with AT8 antibody in the brain.
RESULTS: We found that the AL04 treatment decreases hyperphosphorylated tau at PP2A-sensitive epitope Ser202/Thr205 in the hippocampus of the brain. In the brain lysates of AL04 treated mice, we observed the reduction of I2PP2A, inhibitor of PP2A, and the induction of autophagy receptor proteins such as SQSTM-1/p62 and OPTN.
CONCLUSION: Our data suggests that AL04 can be used as an AD prophylactic/therapeutic agent as it lowers the hyperphosphorylated tau by downregulating I2PP2A. We also propose that AL04 can induce the degradation of hyperphosphorylated tau aggregates through the upregulation of the autophagy pathway.}, }
@article {pmid39633610, year = {2024}, author = {Putri, IS and Shamsudin, NF and Abdullah, MA and Nurcholis, M and Imran, S and Yu, CX and Tham, CL and Mohd Aluwi, MFF and Leong, SW and Joko Raharjo, S and Ibrahim, Z and Islami, D and Huq, AM and Taher, M and Rullah, K}, title = {Theoretical investigation of selective inhibitory activity of chromone-based compounds against monoamine oxidase (MAO)-A and -B.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/07391102.2024.2436553}, pmid = {39633610}, issn = {1538-0254}, abstract = {Monoamine oxidase (MAO) is crucial for the breakdown of monoamine neurotransmitters, making it a promising target for treating neurodegenerative disorders, such as depression, Alzheimer's disease, and Parkinson's disease. In this study, we investigated the selective inhibitory activity of chromone-based compounds against MAO-A and MAO-B for neurodegenerative disease treatment. In literary sources, thirty chromone derivatives have been identified as potential ligands for MAO-A and MAO-B inhibitors. We utilized molecular docking to evaluate how the most active compound interacted with the targeted MAO-A and MAO-B. Compound 2 g, the most active for MAO-A, demonstrated a lower CDOCKER energy compared to the co-crystallized ligand. Meanwhile, compound 2f, the most active for MAO-B, showed a CDOCKER energy similar to the co-crystallized ligand and exhibited similar binding patterns. Furthermore, we constructed a quantitative structure-activity relationship (QSAR) model to predict the properties and estimate IC50 values for 30 chromone derivatives functioning as MAO-A and MAO-B inhibitors. The model predictions were validated against experimental measurements. Our 2D QSAR model demonstrated robustness, with a statistically significant non-cross-validated coefficient (r[2] < 0.9), cross-validated correlation coefficient (q[2] < 0.6), and predictive squared correlation coefficient (r[2]pred < 0.8). Additionally, MD simulations confirmed the stable binding of compounds 2 g and 2f with MAO-A and MAO-B, respectively, displaying substantial binding energy. The most effective pharmacophore model identified key features, such as hydrogen bond acceptors and hydrophobic interactions, that contribute significantly to inhibitory potency. This study offers valuable insight into the selection of compounds with improved selectivity for MAO inhibition.}, }
@article {pmid39631655, year = {2025}, author = {Zeng, HX and Qin, SJ and Andersson, J and Li, SP and Zeng, QG and Li, JH and Wu, QZ and Meng, WJ and Oudin, A and Kanninen, KM and Jalava, P and Dong, GH and Zeng, XW}, title = {The emerging roles of particulate matter-changed non-coding RNAs in the pathogenesis of Alzheimer's disease: A comprehensive in silico analysis and review.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {366}, number = {}, pages = {125440}, doi = {10.1016/j.envpol.2024.125440}, pmid = {39631655}, issn = {1873-6424}, mesh = {*Alzheimer Disease/genetics/metabolism ; *Particulate Matter ; Humans ; *RNA, Untranslated/genetics/metabolism ; Computer Simulation ; Air Pollutants ; MicroRNAs/genetics/metabolism ; }, abstract = {Research on epigenetic‒environmental interactions in the development of Alzheimer's disease (AD) has accelerated rapidly in recent decades. Numerous studies have demonstrated the contribution of ambient particulate matter (PM) to the onset of AD. Emerging evidence indicates that non-coding RNAs (ncRNAs), including long non-coding RNAs, circular RNAs, and microRNAs, play a role in the pathophysiology of AD. In this review, we provide an overview of PM-altered ncRNAs in the brain, with emphasis on their potential roles in the pathogenesis of AD. These results suggest that these PM-altered ncRNAs are involved in the regulation of amyloid-beta pathology, microtubule-associated protein Tau pathology, synaptic dysfunction, damage to the blood‒brain barrier, microglial dysfunction, dysmyelination, and neuronal loss. In addition, we utilized in silico analysis to explore the biological functions of PM-altered ncRNAs in the development of AD. This review summarizes the knowns and unknowns of PM-altered ncRNAs in AD pathogenesis and discusses the current dilemma regarding PM-altered ncRNAs as promising biomarkers of AD. Altogether, this is the first thorough review of the connection between PM exposure and ncRNAs in AD pathogenesis, which may offer novel insights into the prevention, diagnosis, and treatment of AD associated with ambient PM exposure.}, }
@article {pmid39630495, year = {2024}, author = {Ni, C and Song, Q and Chen, Q and Song, L and Commiskey, P and Stratton, L and Malin, B and Yin, Z}, title = {Sentiment Dynamics Among Informal Caregivers in Web-Based Alzheimer Communities: Systematic Analysis of Emotional Support and Interaction Patterns.}, journal = {JMIR aging}, volume = {7}, number = {}, pages = {e60050}, pmid = {39630495}, issn = {2561-7605}, mesh = {Humans ; *Caregivers/psychology ; *Alzheimer Disease/psychology ; *Social Media ; *Social Support ; Internet ; Emotions ; Male ; Female ; }, abstract = {BACKGROUND: Alzheimer disease and related dementias (ADRD) are a growing global health challenge. ADRD place significant physical, emotional, and financial burdens on informal caregivers and negatively affects their well-being. Web-based social media platforms have emerged as valuable sources of peer support for these caregivers. However, there has been limited investigation into how web-based peer support might influence their mental well-being.
OBJECTIVE: This study aims to examine the dynamics of sentiment scores, a major indicator of mental well-being, among informal ADRD caregivers, specifically how their sentiment changes as they participate in caregiving experience discussions within 2 ADRD web-based communities.
METHODS: We collected data from 2 large web-based ADRD caregiving communities, ALZConnected (from November 2011 to August 2022) and TalkingPoint (from March 2003 to November 2022). Using the Valence Aware Dictionary for Sentiment Reasoning and Linguistic Inquiry and Word Count, we calculated sentiment scores for each post and evaluated how the initial sentiment score of a topic initiator evolves within a discussion thread. Structured topic modeling and regression analysis were used to identify the primary topics consistently associated with sentiment changes within these threads. We investigated longitudinal sentiment trends to identify patterns of sentimental stability or enhancement due to prolonged engagement in web-based communities by plotting linear interpolation lines of the sentiment values of each individual user.
RESULTS: The ALZConnected dataset comprised 532,992 posts, consisting of 57,641 topic threads and 475,351 comments. The TalkingPoint dataset was composed of 846,344 posts, consisting of 81,068 topic threads and 765,276 comments. Our research revealed that topic initiators experienced a notable increase in sentiment as they engaged in subsequent discussions within their threads, with a significant uptick in positivity in the short term. This phenomenon is part of a broader trend of steadily rising positive sentiment among ADRD caregivers. Using structured topic modeling, we cataloged a diverse range of topics that included both emotional aspects, such as family emotions, and practical concerns, such as diagnosis and treatment and everyday care practices. We observed that sentiment scores were positively aligned with discussions about family and daily routines life (coefficient=3.53; P<.001), while topics related to illness (coefficient=-1.37; P<.001) and caregiving facilities (coefficient=-1.98; P<.001) tended to correlate with lower sentiment scores. This evidence highlights the significant impact that both the time of participation and the posting content have on the sentiment changes of caregivers.
CONCLUSIONS: This study identifies sentiment changes among informal ADRD caregivers through their interactions in 2 extensive web-based communities. These findings emphasize the importance of early emotional support within a topic thread and demonstrate a predominantly positive sentiment in these communities over time. These further highlight the value of web-based peer support and its potential to enhance the emotional well-being of informal ADRD caregivers.}, }
@article {pmid39630406, year = {2025}, author = {Dastan, M and Rajaei, Z and Sharifi, M and Salehi, H}, title = {Crocin Improves Cognitive Impairment in LPS-treated Rats through Anti-Apoptotic, Anti-Inflammatory, and Antioxidant Activities.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {5804-5815}, pmid = {39630406}, issn = {1559-1182}, support = {3400804//Isfahan University of Medical Sciences,/ ; }, mesh = {Animals ; *Carotenoids/pharmacology ; Male ; *Lipopolysaccharides ; *Rats, Wistar ; *Antioxidants/pharmacology/metabolism ; *Apoptosis/drug effects ; *Anti-Inflammatory Agents/pharmacology ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced/pathology ; Rats ; Hippocampus/metabolism/drug effects/pathology ; Oxidative Stress/drug effects ; Lipid Peroxidation/drug effects ; NF-kappa B/metabolism ; Maze Learning/drug effects ; }, abstract = {Brain inflammation and oxidative stress play critical roles in neuronal apoptosis and memory dysfunction in Alzheimer's disease. Crocin, a natural carotenoid in the stigma of saffron, possesses radical scavenging, anti-inflammatory, and anti-apoptotic properties. This study investigates the protective impact of crocin on neuronal apoptosis, oxidative stress, neuroinflammation, and memory deficits induced by lipopolysaccharide (LPS) in rats. Male Wistar rats received 100 mg/kg of crocin for 12 days, with LPS (1 mg/kg, ip) injected on days 8-12. Spatial learning and memory were evaluated in the Morris water maze two hours after LPS injection. Gene expression of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), caspase 3, and lipid peroxidation was assessed in hippocampal homogenates at the end of the behavioral test. Histopathological changes in the hippocampus and cerebral cortex were evaluated using H&E staining. The results indicated that LPS administration caused spatial learning and memory dysfunction (P = 0.001, P < 0.01) accompanied by upregulation of Nfkb, Tnfα, and Casp3 mRNA expression (P < 0.0001), increased TNF-α (P < 0.01) and lipid peroxidation level (P < 0.01), decreased total thiol concentration (P < 0.05), tissue damage and neuronal loss in the hippocampus (P < 0.0001). Furthermore, crocin treatment at a dosage of 100 mg/kg attenuated learning and memory impairments (P = 0.001, P < 0.01), downregulated Nfkb, Tnfα, and Casp3 mRNA expression (P < 0.0001), decreased TNF-α level (P < 0.01) and lipid peroxidation (P < 0.05) and increased total thiol level (P < 0.05) in the hippocampus. Crocin also ameliorated LPS-induced pathological changes and neuronal loss in the hippocampus (P < 0.001) and cerebral cortex (P < 0.01). In conclusion, the neuroprotective effects of crocin against LPS-induced histopathological and behavioral changes could be attributed to its anti-apoptotic, anti-inflammatory, and radical-scavenging activities in the rat brain.}, }
@article {pmid39630012, year = {2024}, author = {Verma, S and Kurdekar, A}, title = {Effectiveness of neuro-feedback on Alzheimer's rehabilitation: a bibliometric analysis.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {6}, pages = {257-266}, pmid = {39630012}, issn = {1758-2032}, mesh = {Humans ; *Alzheimer Disease/diagnosis/rehabilitation ; *Bibliometrics ; *Neurofeedback/methods ; }, abstract = {BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative disorder with limited treatment options. Neurofeedback, a technique that trains brainwaves, has shown promise in addressing cognitive impairments.
OBJECTIVES: To conduct a bibliometric analysis to explore the current research on neurofeedback as a treatment for AD.
METHODS: A systematic literature review was performed based on PRISMA guidelines on 142 papers. Different bibliometric parameters like the author's country, author names, keywords, journal names, and country of citations were analyzed, and a network visualization chart was generated to understand the correlation of Alzheimer-related search terms to neurofeedback.
RESULTS: Research is concentrated in Europe and North America, with a significant gap in Asian countries. A growing body of evidence supports the potential benefits of neurofeedback for AD. A strong correlation has been found between neurofeedback and AD-related terms. Clinical trials suggest positive outcomes for neurofeedback in improving cognitive impairments and working memory.
CONCLUSION: Neurofeedback shows promise as a potential treatment for AD. Further research and clinical studies are needed to explore the full potential of neurofeedback for enhancing the quality of life for individuals with AD.}, }
@article {pmid39629569, year = {2024}, author = {Vetrithangam, D and Arunadevi, B and Pegada, NK and Mehta, A and Kumar, P and Neha, and Parihar, P and Selvakumar, S}, title = {Towards Explainable Detection of Alzheimer's Disease: A Fusion of Deep Convolutional Neural Network and Enhanced Weighted Fuzzy C-Mean.}, journal = {Current medical imaging}, volume = {20}, number = {}, pages = {e15734056317205}, doi = {10.2174/0115734056317205241014060633}, pmid = {39629569}, issn = {1573-4056}, mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; *Fuzzy Logic ; *Neural Networks, Computer ; *Magnetic Resonance Imaging/methods ; *Algorithms ; Deep Learning ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, posing a significant challenge for individuals and society. Early detection and treatment are essential for effective disease management.
OBJECTIVE: The objective of this research is to develop a novel and interpretable deep learning model for rapid and accurate Alzheimer's disease detection, incorporating Explainable Artificial Intelligence (XAI) techniques. The model aims to ensure generalizability through cross-validation and data augmentation, while enhancing interpretability and transparency by using Explainable Artificial Intelligence methods such as Grad-CAM, SHAP, and LIME, alongside an Enhanced Fuzzy C-Means (FCM) algorithm to clarify feature categorization and improve understanding of the model's decision-making process.
METHODS: The proposed model employs a multi-stage approach. Initially, MRI scans are transformed into feature vectors suitable for input into a Deep Convolutional Neural Network (CNN). Subsequently, an Enhanced Fuzzy C-Mean (FCM) algorithm, incorporating spatial information, refines these features to improve clustering precision. The model integrates Explainable Artificial Intelligence techniques, including Grad-CAM, SHAP, and LIME, to elucidate critical features and regions influencing classification outcomes. The performance metrics such as Accuracy, Recall and Specificity are used for assessing the performance of the model.
RESULTS: The XAI-DEF Alzheimer's disease detection model consistently demonstrated exceptional performance across both the ADNI and OASIS datasets. On ADNI, the model achieved an accuracy of 99.39%, recall of 99.47%, and specificity of 99.3%. Similarly, on OASIS, the model attained an accuracy of 99.36%, recall of 99.53%, and specificity of 99.15%. These results underscore the model's effectiveness in accurately classifying Alzheimer's disease cases while minimizing false positives and negatives.
CONCLUSION: Through the development of this model, we contribute to the advancement of dependable diagnostic tools tailored for the detection and management of Alzheimer's disease. By prioritizing interpretability alongside accuracy, our approach provides valuable insights into the decisionmaking process of the model, ultimately improving patient outcomes and facilitating further research in neurodegenerative disorders.}, }
@article {pmid39629477, year = {2024}, author = {Schwabe, MR and Fleischer, AW and Kuehn, RK and Chaudhury, S and York, JM and Sem, DS and Donaldson, WA and LaDu, MJ and Frick, KM}, title = {The novel estrogen receptor beta agonist EGX358 and APOE genotype influence memory, vasomotor, and anxiety outcomes in an Alzheimer's mouse model.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1477045}, pmid = {39629477}, issn = {1663-4365}, abstract = {INTRODUCTION: Alzheimer's disease (AD) prevalence and severity are associated with increased age, female sex, and apolipoprotein E4 (APOE4) genotype. Although estrogen therapy (ET) effectively reduces symptoms of menopause including hot flashes and anxiety, and can reduce dementia risk, it is associated with increased risks of breast and uterine cancer due to estrogen receptor alpha (ERα)-mediated increases in cancer cell proliferation. Because ERβ activation reduces this cell proliferation, selective targeting of ERβ may provide a safer method of improving memory and reducing hot flashes in menopausal women, including those with AD. APOE genotype influences the response to ET, although it is unknown whether effects of ERβ activation vary by genotype.
METHODS: Here, we tested the ability of long-term oral treatment with a novel highly selective ERβ agonist, EGX358, to enhance object recognition and spatial recognition memory, reduce drug-induced hot flashes, and influence anxiety-like behaviors in female mice expressing 5 familial AD mutations (5xFAD-Tg) and human APOE3 (E3FAD) or APOE3 and APOE4 (E3/4FAD). Mice were ovariectomized at 5 months of age and were then treated orally with vehicle (DMSO) or EGX358 (10 mg/kg/day) via hydrogel for 8 weeks. Spatial and object recognition memory were tested in object placement (OP) and object recognition (OR) tasks, respectively, and anxiety-like behaviors were tested in the open field (OF) and elevated plus maze (EPM). Hot flash-like symptoms (change in tail skin temperature) were measured following injection of the neurokinin receptor agonist senktide (0.5 mg/kg).
RESULTS: EGX358 enhanced object recognition memory in E3FAD and E3/4FAD mice but did not affect spatial recognition memory. EGX358 also reduced senktide-induced tail temperature elevations in E3FAD, but not E3/4FAD, females. EGX358 did not influence anxiety-like behaviors or body weight.
DISCUSSION: These data indicate that highly selective ERβ agonism can facilitate object recognition memory in both APOE3 homozygotes and APOE3/4 heterozygotes, but only reduce the magnitude of a drug-induced hot flash in APOE3 homozygotes, suggesting that APOE4 genotype may blunt the beneficial effects of ET on hot flashes. Collectively, these data suggest a potentially beneficial effect of selective ERβ agonism for memory and hot flashes in females with AD-like pathology, but that APOE genotype plays an important role in responsiveness.}, }
@article {pmid39629139, year = {2024}, author = {Peng, L and Zhang, Z and Li, Q and Song, Z and Yan, C and Ling, H}, title = {Unveiling the multifaceted pathogenesis and therapeutic drugs of Alzheimer's disease: A comprehensive review.}, journal = {Heliyon}, volume = {10}, number = {20}, pages = {e39217}, pmid = {39629139}, issn = {2405-8440}, abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ) plaques and tau phosphorylation-induced neurofibrillary tangles. This review comprehensively summarizes AD pathogenesis and related factors, drawing on a wealth of authoritative reports and research findings. Specifically, we delve into the intricate mechanisms underlying AD pathology, including Aβ deposition, tau protein phosphorylation, cholinergic dysfunction, neuroinflammation, mitochondrial oxidative stress, ferroptosis, imbalance in the gut microbiota, and microRNA dysregulation. We also explored the effects of these factors on the brain, including synaptic damage and cognitive impairment. Moreover, our review highlights the associations between the pathogenesis of AD and inflammatory cytokines in the peripheral blood and cerebrospinal fluid, dysbiosis of the gut microbiota, and changes in microRNA expression. Overall, we provided a systematic and illustrative overview of the pathogenesis and therapeutic drugs for AD, offering help in the prevention and treatment of this condition.}, }
@article {pmid39628659, year = {2024}, author = {Ye, Q and Li, X and Gao, W and Gao, J and Zheng, L and Zhang, M and Yang, F and Li, H}, title = {Role of Rho-associated kinases and their inhibitor fasudil in neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1481983}, pmid = {39628659}, issn = {1662-4548}, abstract = {Neurodegenerative diseases (NDDs) are prevalent in the elderly. The pathogenesis of NDDs is complex, and currently, there is no cure available. With the increase in aging population, over 20 million people are affected by common NDDs alone (Alzheimer's disease and Parkinson's disease). Therefore, NDDs have profound negative impacts on patients, their families, and society, making them a major global health concern. Rho-associated kinases (ROCKs) belong to the serine/threonine protein kinases family, which modulate diverse cellular processes (e.g., apoptosis). ROCKs may elevate the risk of various NDDs (including Huntington's disease, Parkinson's disease, and Alzheimer's disease) by disrupting synaptic plasticity and promoting inflammatory responses. Therefore, ROCK inhibitors have been regarded as ideal therapies for NDDs in recent years. Fasudil, one of the classic ROCK inhibitor, is a potential drug for treating NDDs, as it repairs nerve damage and promotes axonal regeneration. Thus, the current review summarizes the relationship between ROCKs and NDDs and the mechanism by which fasudil inhibits ROCKs to provide new ideas for the treatment of NDDs.}, }
@article {pmid39628626, year = {2024}, author = {Ma, YN and Xia, Y and Karako, K and Song, P and Hu, X}, title = {Extrachromosomal DNA: Molecular perspectives in aging and neurodegenerative diseases.}, journal = {Intractable & rare diseases research}, volume = {13}, number = {4}, pages = {251-254}, pmid = {39628626}, issn = {2186-3644}, abstract = {Extrachromosomal DNA (ecDNA) refers to a class of circular, non-chromosomal DNA that has recently gained widespread attention due to its potential role in aging and neurodegenerative diseases. The generation of ecDNA is closely associated with processes such as double-strand breaks, micronuclei formation, and the breakage-fusion-bridge (BFB) cycle, all of which are integral to regulation of gene expression, genetic stability, and clonal evolution. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, the aberrant formation of ecDNA is closely linked to defects in DNA repair, alterations in synaptic plasticity, and neuronal dysfunction. The distinct distribution and functional roles of ecDNA in these conditions make it a potential diagnostic biomarker and therapeutic target. This review provides an overview of the mechanisms underlying ecDNA formation and its functions in the nervous system. Additionally, it explores the clinical potential of ecDNA in disease diagnosis, targeted therapy, and personalized medicine, offering new insights for future research and treatment strategies.}, }
@article {pmid39628325, year = {2024}, author = {Elawad, MA and Ayaz, M and Mosa, OF and Usman, A and Hamdoon, AAE and Almawash, S and Salim, LHM and Ahmed, A and Elkhalifa, MEM}, title = {Polyphenols and Their Biogenic Nano-Formulations Targeting BACE1 as Anti-Amyloid Therapies; Meeting the Challenges of Bioavailability, Safety, and Specificity for the Treatment of Alzheimer's Disease.}, journal = {Molecular nutrition & food research}, volume = {68}, number = {24}, pages = {e2400525}, doi = {10.1002/mnfr.202400525}, pmid = {39628325}, issn = {1613-4133}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Aspartic Acid Endopeptidases/metabolism/antagonists & inhibitors ; *Polyphenols/pharmacology/pharmacokinetics ; *Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; *Biological Availability ; *Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; Nanoparticles ; Amyloid beta-Protein Precursor/metabolism ; }, abstract = {Alzheimer's disease (AD), a progressiveneurodegenerative condition is marked by extensive damage in the brain and dementia. Among the pathological hallmarks of AD is beta-amyloid (Aβ). Production of toxic Aβ oligomers production and accumulation in the brain is among the characteristic features of the disease. The abnormal accumulation Aβ is initiated by the catalytic degradation of Amyloid Precursor Proteins (APP) by Beta Amyloid Cleaving Enzyme 1 (BACE1) to generate insoluble amyloid plaques. The abnormal proteins are mitochondrial poison which disrupt the energy production and liberate excessive free radicals causing neuronal damage and mutations. Consequently, targeting Aβ-associated pathways has become a focus in the pursuit of developing effective AD treatments. An obstacle faced by many medications used to treat neurodegenerative diseases (NDs) is the restricted permeability across the blood-brain barrier (BBB). Unfortunately, no anti-amyloid drug is clinically approved till now. Recent advancements in nanotechnology have provided a possible solution for delivering medications to specific targets. By integrating natural products with nano-medicinal approaches, it is possible to develop novel and highly efficient therapeutic strategies for the treatment of AD.}, }
@article {pmid39628105, year = {2025}, author = {Antony, D and Sheth, P and Swenson, A and Smoller, C and Maguire, K and Grossberg, G}, title = {Recent advances in Alzheimer's disease therapy: clinical trials and literature review of novel enzyme inhibitors targeting amyloid precursor protein.}, journal = {Expert opinion on pharmacotherapy}, volume = {26}, number = {1}, pages = {63-73}, doi = {10.1080/14656566.2024.2438317}, pmid = {39628105}, issn = {1744-7666}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; Animals ; *Enzyme Inhibitors/pharmacology/therapeutic use ; Drug Development ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Molecular Targeted Therapy ; }, abstract = {INTRODUCTION: Amyloid precursor protein (APP) plays a central role in the pathophysiology of Alzheimer's disease (AD). The accumulation of beta-amyloid protein is believed to be a crucial step in the development of AD. Therefore, understanding the complex biology of APP and its various cleavage products may be useful for developing effective therapeutic strategies for AD.
AREAS COVERED: The amyloidogenic pathway of APP processing involves proteolytic cleavage by two prominent secretases, γ-Secretase and β-secretase. In the late 2000s, multiple pharmaceutical drugs that inhibited γ-Secretase and β-Secretase were synthesized, some of which advanced to human clinical trials. Unfortunately, neither γ-Secretase nor β-secretase inhibitors have been approved by the FDA due to both lack of efficacy and concerns for serious side effects.
EXPERT OPINION: While targeting of Aβ accumulation through secretase inhibitors was halted due to severe side effects, γ-Secretase modulators (GSMs) have arisen as a potential alternative approach. First-generation GSMs could modulate γ-secretase activity without affecting Notch cleavage. However, to improve potency and brain penetration, second-generation GSMs were developed to reduce levels of the amylogenic form of Aβ, Aβ42, without affecting the NOTCH signaling pathway. Several of these drugs have progressed to clinical trials, although with mixed results. The development of GSM's continues to serve as a potentially safer approach to modulating Aβ production in AD treatment.}, }
@article {pmid39627617, year = {2024}, author = {Wiersema, AF and Rennenberg, A and Smith, G and Varderidou-Minasian, S and Pasterkamp, RJ}, title = {Shared and distinct changes in the molecular cargo of extracellular vesicles in different neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {479}, pmid = {39627617}, issn = {1420-9071}, support = {XS grant//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; GoALS//Stichting ALS Nederland/ ; TOTALS//Stichting ALS Nederland/ ; MUSALS//Stichting ALS Nederland/ ; ATAXALS//Stichting ALS Nederland/ ; MAXOMOD//E-rare3/ ; INTEGRALS//Rare-3/ ; TRIAGE//JPND/ ; }, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Biomarkers/analysis/metabolism ; *Cell Communication ; *Extracellular Vesicles/metabolism ; MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/diagnosis/metabolism/pathology ; Parkinson Disease/metabolism/pathology ; tau Proteins/metabolism ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) affect millions of people worldwide. Curative treatment for these neurodegenerative disorders is still lacking and therefore a further understanding of their cause and progression is urgently needed. Extracellular vesicles (EVs) are nanosized vesicles loaded with cargo, such as proteins and miRNAs, that are released by cells and play an important role in intercellular communication. Intercellular communication through EVs can contribute to the spread of pathological proteins, such as amyloid-beta and tau, or cause pathogenesis through other mechanisms. In addition, EVs may serve as potential biomarkers for diagnosis and for monitoring disease progression. In this review, we summarize and discuss recent advances in our understanding of the role of EVs in AD, ALS an PD with an emphasis on dysregulated cargo in each disease. We highlight shared dysregulated cargo between these diseases, discuss underlying pathways, and outline future implications for therapeutic strategies.}, }
@article {pmid39627450, year = {2024}, author = {Leal, CBQS and Zimmer, CGM and Sinatti, VVC and Soares, ES and Poppe, B and de Wiart, AC and Chua, XY and da Silva, RV and Magdesian, MH and Rafii, MS and Buée, L and Bottos, RM}, title = {Effects of the therapeutic correction of U1 snRNP complex on Alzheimer's disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {30085}, pmid = {39627450}, issn = {2045-2322}, mesh = {*Alzheimer Disease/metabolism/drug therapy ; Animals ; *Ribonucleoprotein, U1 Small Nuclear/metabolism ; Mice ; Humans ; *tau Proteins/metabolism ; Disease Models, Animal ; Neurons/metabolism ; Amyloid beta-Peptides/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Hippocampus/metabolism ; Male ; }, abstract = {The U1 snRNP complex recognizes pre-mRNA splicing sites in the early stages of spliceosome assembly and suppresses premature cleavage and polyadenylation. Its dysfunction may precede Alzheimer's disease (AD) hallmarks. Here we evaluated the effects of a synthetic single-stranded cDNA (APT20TTMG) that interacts with U1 snRNP, in iPSC-derived neurons from a donor diagnosed with AD and in the SAMP8 mouse model. APT20TTMG effectively binds to U1 snRNP, specifically decreasing TAU in AD neurons, without changing mitochondrial activity or glutamate. Treatment enhanced neuronal electrical activity, promoted an enrichment of differentially expressed genes related to key processes affected by AD. In SAMP8 mice, APT20TTMG reduced insoluble pTAU in the hippocampus, amyloid-beta and GFAP in the cortex, and U1-70 K in both brain regions, without cognitive changes. This study highlights the correction of the U1 snRNP complex as a new target for AD.}, }
@article {pmid39626378, year = {2024}, author = {Yang, H and Byun, MS and Ha, NY and Yang, J and Park, SY and Park, JE and Yi, D and Chang, YT and Jung, WS and Kim, JY and Kim, J and Lee, DY and Bae, H}, title = {A preclinical and phase I clinical study of ex vivo-expanded amyloid beta-specific human regulatory T cells in Alzheimer's disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {181}, number = {}, pages = {117721}, doi = {10.1016/j.biopha.2024.117721}, pmid = {39626378}, issn = {1950-6007}, mesh = {Aged ; Animals ; Female ; Humans ; Male ; Mice ; Middle Aged ; *Alzheimer Disease/drug therapy/immunology ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Mice, Transgenic ; *T-Lymphocytes, Regulatory/immunology ; }, abstract = {INTRODUCTION: Despite advancements in adoptive regulatory T cell (Treg) therapy, its application in Alzheimer's disease (AD) remains constrained by challenges in ex vivo Treg selection and expansion with antigen specificity. Our previous findings demonstrated the bystander suppressive immunomodulatory mechanism of ex vivo expanded amyloid β-specific mouse Tregs in AD models, prompting inquiry into the efficacy of ex vivo expanded human Tregs in AD.
METHODS: We developed an effective ex vivo expansion method for manufacturing amyloid β-specific human Tregs (Aβ-hTreg) and evaluated their safety and efficacy in 3xTg mouse models of AD and a phase 1 clinical trial with six AD patients. The phenotype of Aβ-hTreg was analyzed using single-cell transcriptomics. The clinical trial involved intravenous administration of Aβ-hTreg, with three patients receiving a low dose and three receiving a high dose. Exploratory assessments of effectiveness, including cognitive tasks and functional evaluations, were conducted ninety days post-treatment.
RESULTS: Behavioral spatial learning and memory impairment, neuroinflammatory and amyloid pathology were dramatically ameliorated by single intrathecal administration of ex vivo expanded Aβ-hTreg to 3xTg AD mice. Single cell transcriptomics analysis revealed alterations in five key genes within a cluster of Tregs under antigen-specific manufacturing conditions. In the clinical trial with six AD patients, dose-limiting toxicity was experienced by none of the participants within five days of receiving GMP-grade Aβ-hTreg (VT301), indicating its good tolerability. Although exploratory assessments of effectiveness did not reach statistically significant values among the groups, these findings offer valuable insights for AD treatment and management, guiding the planning of the next phase of clinical trials.
DISCUSSION: This study suggests that hTregs may modulate Alzheimer's disease pathology by suppressing neuroinflammation, while VT301 shows promise as a safe treatment option. However, further research is necessary to confirm its clinical efficacy and optimize treatment strategies.
TRIAL REGISTRATION: Title: A Study of Possibility of Using Regulatory T Cells (VT301) for Treatment of Alzheimer's Disease, ClinicalTrials.gov NCT05016427, Study approval date: Ministry of Food and Drug Safety of the Republic of Korea (MFDS) - August 31st, 2020, Institutional Review Board (IRB) of Seoul National University Hospital, Republic of Korea - September 29th, 2020, The date of first patient enrollment: December 7th, 2020. https://clinicaltrials.gov/study/NCT05016427.}, }
@article {pmid39625718, year = {2024}, author = {Yang, H and Tan, H and Wen, H and Xin, P and Liu, Y and Deng, Z and Xu, Y and Gao, F and Zhang, L and Ye, Z and Zhang, Z and Chen, Y and Wang, Y and Sun, J and Lam, JWY and Zhao, Z and Kwok, RTK and Qiu, Z and Tang, BZ}, title = {Recent Progress in Nanomedicine for the Diagnosis and Treatment of Alzheimer's Diseases.}, journal = {ACS nano}, volume = {18}, number = {50}, pages = {33792-33826}, doi = {10.1021/acsnano.4c11966}, pmid = {39625718}, issn = {1936-086X}, mesh = {*Alzheimer Disease/diagnosis/drug therapy/metabolism ; Humans ; *Nanomedicine/methods ; *Nanoparticles/chemistry ; *Blood-Brain Barrier/metabolism/drug effects ; Animals ; Drug Delivery Systems ; Drug Carriers/chemistry ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that causes memory loss and progressive and permanent deterioration of cognitive function. The most challenging issue in combating AD is its complicated pathogenesis, which includes the deposition of amyloid β (Aβ) plaques, intracellular hyperphosphorylated tau protein, neurofibrillary tangles (NFT), etc. Despite rapid advancements in mechanistic research and drug development for AD, the currently developed drugs only improve cognitive ability and temporarily relieve symptoms but cannot prevent the development of AD. Moreover, the blood-brain barrier (BBB) creates a huge barrier to drug delivery in the brain. Therefore, effective diagnostic tools and treatments are urgently needed. In recent years, nanomedicine has provided opportunities to overcome the challenges and limitations associated with traditional diagnostics or treatments. Various types of nanoparticles (NPs) play an essential role in nanomedicine for the diagnosis and treatment of AD, acting as drug carriers to improve targeting and bioavailability across/bypass the BBB or acting as drugs directly on AD lesions. This review categorizes different types of NPs and summarizes their applications in nanomedicine for the diagnosis and treatment of AD. It also discusses the challenges associated with clinical applications and explores the latest developments and prospects of nanomedicine for AD.}, }
@article {pmid39625499, year = {2024}, author = {Shao, N and Lu, Q and Ouyang, Z and Yang, P and Wei, T and Wang, J and Cai, B}, title = {Ganoderic acid a alleviates Aβ25-35-induced HT22 cell apoptosis through the ERK/MAPK pathway: a system pharmacology and in vitro experimental validation.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {51}, pmid = {39625499}, issn = {1573-7365}, support = {2023xscx096//the Postgraduate Quality Engineering Project in Anhui Province/ ; 2023AH050823//the Key Scientific Research Project of Anhui Provincial Department of Education/ ; 2023rcZD001//the Talent Support Programme in Anhui University of Traditional Chinese Medicine/ ; gxbjZD2022024//the Cultivation Programme for Excellent and Top Talents in Anhui Universities/ ; }, mesh = {*Amyloid beta-Peptides/toxicity ; *Apoptosis/drug effects ; *Peptide Fragments/toxicity ; *MAP Kinase Signaling System/drug effects ; *Lanosterol/analogs & derivatives/pharmacology ; Animals ; *Neuroprotective Agents/pharmacology ; *Network Pharmacology ; *Heptanoic Acids/pharmacology ; Mice ; Alzheimer Disease/drug therapy/metabolism ; Cell Line ; Molecular Docking Simulation ; Oxidative Stress/drug effects ; Triterpenes/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that occurs with aging. Ganoderma lucidum (Curtis.) P. Karst. (G. lucidum) is a traditional medicinal fungus believed to nourish the brain and anti-aging. Ganoderic acid A (GAA), a triterpenoid from G. lucidum, has demonstrated natural neuroprotective effects. This study aims to explore the therapeutic effect and molecular mechanism of GAA on AD. Systematic network pharmacology identified 95 targets, 8 biological functions, and multiple pathways. The results highlighted MAPK family members as core genes, with MAPK1 (ERK2) showing the highest binding affinity to GAA in molecular docking. In vitro experiments revealed that GAA dose-dependently increased the viability of Aβ25-35-injured HT22 cells and inhibited MAPK pathway-related protein expression. Similar to FR180204, 100 µM GAA significantly reversed ERK protein expression, oxidative stress markers, and mitochondrial damage in AD cell model. GAA also downregulated cleaved caspase-3 protein levels, apoptosis rates, Aβ and p-Tau expression by inhibiting the ERK signaling pathway. The therapeutic effect of GAA on AD was predicted and validated through network pharmacology and in vitro experiments. The ability of GAA to inhibit apoptosis via the ERK/MAPK signaling pathway positions it as a promising candidate for AD treatment.}, }
@article {pmid39625180, year = {2024}, author = {Wei, Y and Qiao, Z}, title = {Neurologic Music Therapy's Impact on Neurological Disorders.}, journal = {Journal of neuroscience research}, volume = {102}, number = {12}, pages = {e70000}, doi = {10.1002/jnr.70000}, pmid = {39625180}, issn = {1097-4547}, mesh = {*Music Therapy/methods ; Humans ; *Nervous System Diseases/therapy ; Brain/physiopathology/diagnostic imaging ; Neuronal Plasticity/physiology ; Parkinson Disease/therapy ; }, abstract = {Neurologic music therapy (NMT) represents a groundbreaking, interdisciplinary approach that combines the therapeutic properties of music with neuroscientific principles to treat a range of neurological and psychiatric conditions. This interdisciplinary approach, increasingly recognized in clinical and research settings, leverages advances in neuroimaging to explore how music affects the structure and activity of the brain. This review provides an in-depth exploration of the multifaceted effects of NMT on brain function, highlighting its role in promoting neuroplastic changes and enhancing cognitive, emotional and motor functions in diverse patient groups. This review consolidates current knowledge on NMT and provides insights into how music affects brain structure and function and the mechanisms of action. The article then discusses the application and research results of NMT in various diseases such as stroke, Alzheimer's disease and Parkinson's disease. Its potential in personalizing therapeutic interventions and its ability to improve treatment access and effectiveness in various settings are highlighted.}, }
@article {pmid39624645, year = {2024}, author = {Li, X and Wang, P and Qi, S and Zhou, J and Amalraj, J and Wang, J and Ding, Z}, title = {The clinical perspective of circular RNAs in neurodegenerative diseases: potential diagnostic tools and therapeutic targets.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1470641}, pmid = {39624645}, issn = {1662-5102}, abstract = {Neurodegenerative diseases (NDDs) mostly occur in older demographics. With the average lifespan increasing over time, NDDs are becoming one of the major adverse factors affecting human health and the quality of life. Currently, there are no specific diagnostic methods for NDDs and they are usually diagnosed based on nonspecific clinical symptoms and occasionally by biomarkers, such as β-amyloid (Aβ) for Alzheimer's disease (AD) and a-synuclein (α-syn) for Parkinson's disease, etc. However, it is usually too late for most treatment to startr when the aforementioned criteria become detectable. Circular RNAs (circRNAs) are a type of single-stranded, covalently closed, non-coding RNAs that lack a 5' cap structure and 3' terminal poly-A tail. According to recent research, circRNAs may play a crucial role for the onset and progression of some NDDs. These small RNAs may be potential diagnostic and prognostic markers and therapeutic targets for these diseases. This review will provide a comprehensive overview of the recent advancements of knowledge on the functions and the possible underlying mechanism of circRNAs in the pathogenesis and treatment of NDDs.}, }
@article {pmid39624588, year = {2025}, author = {Yu, Q and Shi, Y and Wu, Y and Liu, R and Zhang, H and Wu, L and Ding, M}, title = {Magnolol acts as a neurorestorative agent in an Aβ1‑42‑induced mouse model of Alzheimer's disease.}, journal = {Experimental and therapeutic medicine}, volume = {29}, number = {1}, pages = {12}, pmid = {39624588}, issn = {1792-1015}, abstract = {Magnolol may have the potential to alleviate the progression of Alzheimer's disease (AD). The present study was conducted to investigate the broader mechanism of action of magnolol in AD pathogenesis. C57BL/6 mice were randomly divided into five groups (n=6 mice/group): i) Control; ii) AD model; iii) 5 mg/kg magnolol + AD model; iv) 10 mg/kg magnolol + AD model; and v) 20 mg/kg magnolol + AD model. A total of 7 days after modeling, the treatment groups were administered different doses of magnolol (5, 10 and 20 mg/kg) by gavage every day, and a Morris water maze test was conducted after 2 months of treatment. The impacts of magnolol on amyloid β (Aβ) plaque deposition and neuroinflammation were assessed using Congo red and immunofluorescence staining. Immunofluorescence staining results were supplemented with western blotting and reverse transcription-quantitative PCR to ascertain the role of magnolol in other pivotal pathological mechanisms, including the formation of intracellular neurofibrillary tangles, compromised synaptic plasticity, and astrocyte and microglia activation. Administration of magnolol effectively mitigated cognitive impairment, reduced Aβ plaque deposition and inhibited neuroinflammation in Aβ1-42-induced mice. Moreover, hippocampal levels of tau, phosphorylated (p-)tau, glycogen synthase kinase 3β (GSK3β), p-GSK3β, synaptophysin, brain-derived neurotrophic factor, glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 revealed that magnolol also limited neurofibrillary tangle formation, repaired synaptic plasticity, and inhibited astrocyte and microglia activation. In conclusion, the present findings broaden the current understanding of the mechanisms explaining the neuroprotective effects of magnolol against AD progression. Notably, it may inhibit multiple manifestations of AD, including plaques and neuroinflammation, while also exhibiting the capacity to restore AD-related neurological damage.}, }
@article {pmid39624221, year = {2024}, author = {Anyanwu G, E and Nwachukwu I, J and Oria S, R and Obasi K, K and Ekwueme E, P and Nto J, N and Anyanwu N, C}, title = {Fisetin attenuates AlCl3-induced neurodegeneration by modulating oxidative stress and inflammatory cytokine release in adult albino wistar rats.}, journal = {Toxicology reports}, volume = {13}, number = {}, pages = {101812}, pmid = {39624221}, issn = {2214-7500}, abstract = {AIM: Natural flavonoids have powerful antioxidant and anti-inflammatory activities against neurodegenerative diseases. Fisetin is a powerful flavonoid that targets a variety of neurological disorders. Aluminum (Al) has been linked to several neurological conditions, such as Parkinsons disease, autism, and Alzheimer's disease (AD). This study was designed to assess the modulatory role of fisetin in reversing oxidative stress and neuroinflammation caused by Aluminum chloride (AlCl3) induced neurological conditions in rats.
METHODS: Adult male Wistar were randomly divided into eight groups of four animals per group. Group 1; the control group received phosphate-buffered saline, group 2 received 100 mg/kg/bodyweight of aluminum chloride, and group 3,4, and 5 received 25, 50, and 75 mg/kg/bodyweight of fisetin respectively for 21 days. Groups 6, 7, and 8 received 25, 50, and 75 mg/kg/bodyweight of fisetin for 14 days followed by 100 mg/kg/bodyweight of aluminum chloride for 7 days respectively. The administration was via the oral route. Following treatment, the rats were euthanized, and biochemical alterations were observed by measuring the serum levels of Glutathione S-Transferase (GST) and Malondialdehyde (MDA) for oxidative stress and Interleukin-6 (IL-6) for neuroinflammation. Furthermore, histopathological evaluations of the thalamus were carried out using routine Hematoxylin and Eosin (H&E) and Cresyl Fast Violet (CFV) techniques while expressions of Glial Fibrillary Acidic Protein (GFAP) for astrocytes, and Ionized Calcium Binding Adapter Molecule 1 (IBA1) for microglia, were examined by immunohistochemical methods.
RESULTS: The findings in the AlCl3 group indicated a rise in lipid peroxidation, decreased antioxidant activity, altered thalamic histomorphology, and increased expression of GFAP and IBA1 markers for astrocytes and microglia, respectively. These effects were mitigated in the Fisetin pretreated groups.
CONCLUSION: These results imply that fisetin can attenuate AlCl3-induced neurodegeneration possibly by mitigating oxidative stress and neuroinflammation.}, }
@article {pmid39623973, year = {2024}, author = {Levy, B and D'Ambrozio, G}, title = {Stepwise identification of prodromal dementia: Testing a practical model for primary care.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {102}, number = {4}, pages = {1239-1248}, doi = {10.1177/13872877241297410}, pmid = {39623973}, issn = {1875-8908}, mesh = {Humans ; *Primary Health Care ; Female ; *Prodromal Symptoms ; Male ; Aged ; *Dementia/diagnosis ; *Cognitive Dysfunction/diagnosis ; Mental Status and Dementia Tests ; Neuropsychological Tests ; Surveys and Questionnaires ; Aged, 80 and over ; }, abstract = {BACKGROUND: Prodromal dementia is largely underdiagnosed in primary care.
OBJECTIVE: To develop a clinical model for detecting prodromal dementia within the operative boundaries of primary care practice.
METHODS: The study employed the Functional Activities Questionnaire (FAQ) and Montreal Cognitive Assessment (MoCA) to evaluate a "functional-cognitive" step-down screening model, in which the MoCA is administered subsequent to reported symptoms on the FAQ. It classified participants from the Alzheimer's Disease Imaging Initiative to three diagnostic categories: (1) healthy cognition (n = 396), (2) mild cognitive impairment without conversion (n = 430), and (3) prodromal dementia assessed 24 months before diagnosis (n = 164).
RESULTS: Analyses indicated that the step-down model (Model 1) performed significantly better than an alternative model that applied the FAQ as a single measure (Model 2) and compared well with another model that administered both screening measures to all participants (Model 3). Gradient Boosting Trees classifications yielded the following estimations for Model 1/Model 2/ Model 3, respectively: Sensitivity = 0.87/0.77/0.89, Specificity = 0.68/0.47/0.70, PPV = 0.73/0.40/0.75, NVP = 0.84/0.81/0.87, F1 Score = 0.79/0.52/0.81, AUC = 0.78/0.67/0.79.
CONCLUSIONS: These analyses support the proposed model. The study offers algorithms for validated measures, which were developed from a well characterized clinical sample. Their accuracy will likely improve further with new data from diverse clinical settings. These results can serve primary care in a timely manner in light of the recent advances in pharmacological treatment of dementia and the expected increase in demand for screening.}, }
@article {pmid39623809, year = {2025}, author = {Salama, RM and Yehia, R and Elmongy, NF and Sallam, AA and Abd-Elgalil, MM and Schaalan, MF and Abdel-Mottaleb, MMA and Bazan, LS}, title = {Evaluation of betanin-loaded liposomal nanocarriers in AlCl3-induced Alzheimer's disease in rats: Impact on cognitive function, neurodegeneration, and TREM2/ADAM10 pathways.}, journal = {Archiv der Pharmazie}, volume = {358}, number = {1}, pages = {e2400641}, doi = {10.1002/ardp.202400641}, pmid = {39623809}, issn = {1521-4184}, support = {//None/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced ; Male ; *Aluminum Chloride ; *Rats, Wistar ; *Receptors, Immunologic/metabolism ; Rats ; *Liposomes/chemistry ; *Membrane Glycoproteins/metabolism ; *Cognition/drug effects ; ADAM10 Protein/metabolism ; Disease Models, Animal ; Nanoparticles/chemistry ; Drug Carriers/chemistry ; Maze Learning/drug effects ; Morris Water Maze Test/drug effects ; Neuroprotective Agents/pharmacology/chemistry/administration & dosage ; }, abstract = {Betanin (BET) has been studied for its therapeutic benefits in various diseases, but its low bioavailability and uncertain brain penetration limit its efficacy. Accordingly, this study aimed to explore BET-loaded liposomal nanocarriers (LPN) as a novel treatment for Alzheimer's disease (AD), focusing on the triggering receptor expressed on myeloid cells 2 (TREM2)/DNAX-activating protein of 12 kDa (DAP12) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways implicated in AD. In an AlCl3-induced AD rat model, 48 male Wistar rats were divided into four groups: control, AlCl3 (50 mg/kg, intraperitoneal), AlCl3+BET (100 mg/kg, per os), and AlCl3+BET LPN (25 mg/kg, intranasally), with treatments administered for 28 days. Morris water maze test and histopathological examination showed that BET LPN-treated rats had improved spatial and learning memory and less hippocampal and cortical degeneration compared with the AlCl3 and oral BET groups. Mechanistically, BET LPN treatment corrected AD biomarkers, increased miR-132 and ADAM10 expression, and reduced oxidative stress, inflammation, and apoptosis. Additionally, BET LPN treatment suppressed the expression of TREM2, DAP12, ERK1/2, and mitogen-activated protein kinase 1/2 (MEK1/2), showing greater improvement than oral BET. These findings suggest that BET LPN enhances cognitive function and neuroprotection in AD by modulating miR-132 and ADAM10 and inhibiting ERK1/2 and TREM2/DAP12 pathways, providing a more effective treatment compared with traditional oral BET administration.}, }
@article {pmid39623797, year = {2024}, author = {Ding, Q and Zhao, Y and Xi, E and Liu, K and Gao, N and Zhu, G}, title = {Constructing a Metal-Organic Frameworks-Based Long-Acting Sequential Release System for the Treatment of Alzheimer's Disease.}, journal = {Advanced healthcare materials}, volume = {}, number = {}, pages = {e2402425}, doi = {10.1002/adhm.202402425}, pmid = {39623797}, issn = {2192-2659}, support = {2022YFB3805902//National Key R&D Program of China/ ; 22131004//National Natural Science Foundation of China/ ; U21A20330//National Natural Science Foundation of China/ ; 21975039//National Natural Science Foundation of China/ ; 22077118//National Natural Science Foundation of China/ ; B18012//"111" project/ ; 2412023YQ001//Fundamental Research Funds for the Central Universities, Excellent Youth Team Program/ ; JLSWSRCZX2023-52//Finance Special Project on Medical and Health Talents of the Finance Department of Jilin Province/ ; 2020009//WBE Liver Fibrosis Foundation/ ; YDZJ202401202ZYTS//Jilin Province Science and Technology Development Plan Project/ ; }, abstract = {Due to the unclear pathogenesis of Alzheimer's disease (AD) and the lack of a completely cured medication, AD patients need to take medication in order and on time every day all one's life, which is difficult for severe memory impairment patients to strictly follow on time. Traditional AD drug carriers, such as sugar coating and capsules, rely on dissolution or fragmentation to achieve drug release, which lacks the interaction between drug molecules and carriers, thus they cannot achieve sufficient long-acting and sequential drug release. Herein, Mn-MOF-74, which ligand structure is similar to two antioxidants dihydroquercetin (DHQ) and resveratrol (Res) is chosen as the carrier. Due to the differences in adsorption energy between DHQ/MOF and Res/MOF, the release speed of DHQ is much faster than Res. Therefore, Mn-MOF-74 loaded with DHQ and Res (DR@MOF) showed sequential drug release and a long-term antioxidant effect for ≈72 h, with an efficacy time six times longer than that of vitamin E. In 5×FAD transgenic mice, DR@MOF exhibited excellent capacity in maintaining oxidative balance in the brain, ameliorating spatial learning and memory deficits, and showed the potential of an AD agent for long-acting and sequential treatment.}, }
@article {pmid39623428, year = {2024}, author = {Power, SK and Venkatesan, S and Qu, S and McLaurin, J and Lambe, EK}, title = {Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer's disease models.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {58}, pmid = {39623428}, issn = {2047-9158}, support = {PRJ153101//Institute of Neurosciences, Mental Health and Addiction/ ; MOP89825//Institute of Neurosciences, Mental Health and Addiction/ ; }, mesh = {*Alzheimer Disease/metabolism/genetics ; Animals ; *Prefrontal Cortex/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; Mice ; *Receptors, Nicotinic/metabolism/genetics ; Rats ; Signal Transduction/physiology ; Acetylcholine/metabolism ; Pyramidal Cells/metabolism ; Humans ; Rats, Transgenic ; Male ; }, abstract = {BACKGROUND: Cognitive reserve allows for resilience to neuropathology, potentially through active compensation. Here, we examine ex vivo electrophysiological evidence for active compensation in Alzheimer's disease (AD) focusing on the cholinergic innervation of layer 6 in prefrontal cortex. Cholinergic pathways are vulnerable to neuropathology in AD and its preclinical models, and their modulation of deep layer prefrontal cortex is essential for attention and executive function.
METHODS: We functionally interrogated cholinergic modulation of prefrontal layer 6 pyramidal neurons in two preclinical models: a compound transgenic AD mouse model that permits optogenetically-triggered release of endogenous acetylcholine and a transgenic AD rat model that closely recapitulates the human trajectory of AD. We then tested the impact of therapeutic interventions to further amplify the compensated responses and preserve the typical kinetic profile of cholinergic signaling.
RESULTS: In two AD models, we found potentially compensatory upregulation of functional cholinergic responses above non-transgenic controls after onset of pathology. To identify the locus of this enhanced cholinergic signal, we dissected key pre- and post-synaptic components with pharmacological strategies. We identified a significant and selective increase in post-synaptic nicotinic receptor signalling on prefrontal cortical neurons. To probe the additional impact of therapeutic intervention on the adapted circuit, we tested cholinergic and nicotinic-selective pro-cognitive treatments. Inhibition of acetylcholinesterase further enhanced endogenous cholinergic responses but greatly distorted their kinetics. Positive allosteric modulation of nicotinic receptors, by contrast, enhanced endogenous cholinergic responses and retained their rapid kinetics.
CONCLUSIONS: We demonstrate that functional nicotinic upregulation occurs within the prefrontal cortex in two AD models. Promisingly, this nicotinic signal can be further enhanced while preserving its rapid kinetic signature. Taken together, our work suggests that compensatory mechanisms are active within the prefrontal cortex that can be harnessed by nicotinic receptor positive allosteric modulation, highlighting a new direction for cognitive treatment in AD neuropathology.}, }
@article {pmid39622402, year = {2025}, author = {Zhen, M and Dang, M and Cao, Z and Xia, X and Peng, F and Wang, S and Liu, Y}, title = {Methylated cell-free DNA as a novel biomarker in Alzheimer's disease.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {566}, number = {}, pages = {120069}, doi = {10.1016/j.cca.2024.120069}, pmid = {39622402}, issn = {1873-3492}, mesh = {*Alzheimer Disease/diagnosis/blood/genetics ; Humans ; *Cell-Free Nucleic Acids/blood/genetics ; *Biomarkers/blood ; *DNA Methylation ; }, abstract = {Due to an aging population, Alzheimer's disease (AD), a neurodegenerative disorder, has affected more than 40 million people worldwide, a figure predicted to significantly increase in the coming decades. Despite much effort to understand AD pathogenesis, effective diagnosis and treatment remain a challenge. However, the development of liquid biopsy including the analysis of cell-free DNA (cfDNA) and methylation thereof has provided an alternative source of investigation to further explore the pathophysiology of AD. Herein, we discuss the research progress to date and highlight clinical applications of methylated cfDNA in AD.}, }
@article {pmid39621206, year = {2024}, author = {Yuan, Y and Zhao, G and Zhao, Y}, title = {Dysregulation of energy metabolism in Alzheimer's disease.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {2}, pmid = {39621206}, issn = {1432-1459}, support = {81600924//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Humans ; *Alzheimer Disease/metabolism/physiopathology ; *Brain/metabolism/physiopathology ; *Energy Metabolism/physiology ; Mitochondria/metabolism ; }, abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Its etiology and associated mechanisms are still unclear, which largely hinders the development of AD treatment strategies. Many studies have shown that dysregulation of energy metabolism in the brain of AD is closely related to disease development. Dysregulation of brain energy metabolism in AD brain is associated with reduced glucose uptake and utilization, altered insulin signaling pathways, and mitochondrial dysfunction. In this study, we summarized the relevant pathways and mechanisms regarding the dysregulation of energy metabolism in AD. In addition, we highlight the possible role of mitochondrial dysfunction as a central role in the AD process. A deeper understanding of the relationship between energy metabolism dysregulation and AD may provide new insights for understanding learning memory impairment in AD patients and in improving AD prevention and treatment.}, }
@article {pmid39620848, year = {2024}, author = {Ramanan, VK}, title = {Implementing New Dementia Care Models in Practice.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {30}, number = {6}, pages = {1863-1873}, pmid = {39620848}, issn = {1538-6899}, mesh = {Humans ; Alzheimer Disease/therapy/diagnosis ; *Dementia/therapy/diagnosis ; }, abstract = {Care for patients with Alzheimer disease and related neurodegenerative causes of dementia is in the midst of a transformation. Recent advancements in diagnostics and therapeutics reflect a rapidly evolving knowledge base and represent positive steps for patients and clinicians facing these progressive diseases; however, the complexities of emerging biomarkers and treatment options present challenges that will require systematic adaptations to routine care to facilitate effective incorporation of these options. This article reviews ongoing updates in the assessment and management of neurodegenerative causes of dementia, focusing on practical models for innovation that practices and health care systems can use to implement these new tools. In particular, sustainable adaptation in the field will benefit from a comprehensive approach implemented at local levels, including (1) education of clinicians and communities to refine perceptions about dementia care, (2) multifaceted stakeholder engagement to optimize infrastructure and workflows to the new era, and (3) investments in personnel to address existing and exacerbated gaps.}, }
@article {pmid39620846, year = {2024}, author = {Geldmacher, DS}, title = {Treatment of Alzheimer Disease.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {30}, number = {6}, pages = {1823-1844}, pmid = {39620846}, issn = {1538-6899}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Cholinesterase Inhibitors/therapeutic use/administration & dosage ; }, abstract = {OBJECTIVE: Symptom-oriented treatment has been the mainstay of Alzheimer disease (AD) pharmacotherapy for decades. This article reviews the evidence basis for symptomatic treatments for AD and the emerging data on amyloid-lowering therapies with possible disease-slowing effects.
LATEST DEVELOPMENT: Amyloid-lowering monoclonal antibody therapies entered clinical use in 2021. In July 2023, lecanemab became the first of these to gain full US Food and Drug Administration (FDA) approval and limited Medicare payment coverage. Donanemab gained similar approval status in July 2024. The approved agents remove amyloid plaque from the brain and appear to slow clinical disease progression but can produce significant adverse events known as amyloid-related imaging abnormalities with cerebral edema or effusion and with cerebral hemorrhages. Extensive safety monitoring is therefore required, including scheduled MRI scans. Also in 2023, brexpiprazole became the first agent specifically approved by the FDA for agitation associated with AD. Suvorexant, an orexin receptor antagonist, previously was approved for the treatment of insomnia in people with mild and moderate AD.
ESSENTIAL POINTS: There is robust evidence for the use of acetylcholinesterase inhibitors for patients with mild, moderate, and severe dementia due to AD, including outcomes beyond changes in cognitive screening test scores. More limited studies support the use of memantine in moderate and severe stages. These agents have a primary effect of delaying decline in cognition and function and postponing the emergence of adverse behaviors. Pharmacotherapy for behavioral and psychological symptoms is less predictable, and most clinical trials have had negative results. Anti-amyloid therapies provide the first FDA-approved option to alter AD pathology, but an understanding of overall utility and value to patients remains in its infancy.}, }
@article {pmid39620844, year = {2024}, author = {Quinn, JF and Gray, NE}, title = {Fluid Biomarkers in Dementia Diagnosis.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {30}, number = {6}, pages = {1790-1800}, pmid = {39620844}, issn = {1538-6899}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; alpha-Synuclein/cerebrospinal fluid/blood ; Alzheimer Disease/diagnosis/cerebrospinal fluid/blood ; *Biomarkers/cerebrospinal fluid/blood ; *Dementia/diagnosis/cerebrospinal fluid ; Lewy Body Disease/diagnosis/cerebrospinal fluid/blood ; }, abstract = {OBJECTIVE: This article familiarizes neurologists with the currently available CSF and plasma biomarkers for the diagnosis of dementia and diagnosis-dependent treatment decisions.
LATEST DEVELOPMENTS: For Alzheimer disease, the recent US Food and Drug Administration (FDA) approval of monoclonal antibody therapy has increased the urgency of confirming the pathologic diagnosis with biomarkers before initiating therapy. The new availability of disease-modifying therapies also highlights the need for biomarkers to monitor efficacy over time. Both of these needs have been partially addressed by the emergence of improved blood-based biomarkers for Alzheimer disease. Regarding other forms of dementia, the latest development is a CSF assay for aggregated α-synuclein, which permits the biomarker confirmation of synuclein pathology in Lewy body dementia.
ESSENTIAL POINTS: CSF biomarkers for the diagnosis of Alzheimer disease, Lewy body dementia, and Creutzfeldt-Jakob disease are well established. Blood-based biomarkers for dementia diagnosis are emerging and rapidly evolving. Sensitivity and specificity for diagnosis continue to improve, and they are being incorporated into diagnostic decisions. Fluid biomarkers for monitoring the efficacy of therapy are not yet established. Because serial CSF examinations are impractical, the validation of blood-based biomarkers of disease activity will be critical for addressing this unmet need.}, }
@article {pmid39620843, year = {2024}, author = {Risacher, SL}, title = {Neuroimaging in Dementia.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {30}, number = {6}, pages = {1761-1789}, pmid = {39620843}, issn = {1538-6899}, mesh = {Aged ; Female ; Humans ; Male ; Alzheimer Disease/diagnostic imaging/diagnosis ; *Dementia/diagnostic imaging/diagnosis ; Magnetic Resonance Imaging ; *Neuroimaging/methods ; Positron-Emission Tomography/methods ; }, abstract = {OBJECTIVE: This article captures the current literature regarding the use of neuroimaging measures to study neurodegenerative diseases, including early- and late-onset Alzheimer disease, vascular cognitive impairment, frontotemporal lobar degeneration disorders, dementia with Lewy bodies, and Parkinson disease dementia. In particular, the article highlights significant recent changes in novel therapeutics now available for the treatment of Alzheimer disease and in defining neurodegenerative disease using biological frameworks. Studies summarized include those using structural and functional MRI (fMRI) techniques, as well as metabolic and molecular emission tomography imaging (ie, positron emission tomography [PET] and single-photon emission computerized tomography [SPECT]).
LATEST DEVELOPMENTS: Neuroimaging measures are considered essential biomarkers for the detection and diagnosis of most neurodegenerative diseases. The recent approval of anti-amyloid antibody therapies has highlighted the importance of MRI and PET techniques in treatment eligibility and monitoring for associated side effects. Given the success of the initial biomarker-based classification system for Alzheimer disease (the amyloid, tau, neurodegeneration [A/T/N] framework), researchers in vascular cognitive impairment have created similar techniques for biomarker-based diagnosis. Further, the A/T/N framework for Alzheimer disease has been updated to include several pathologic targets for biomarker detection.
ESSENTIAL POINTS: Neurodegenerative diseases have a major health impact on millions of patients around the world. Neuroimaging biomarkers are rapidly becoming major diagnostic tools for the detection, monitoring, and treatment of neurodegenerative diseases. This article educates readers about the current literature surrounding the use of neuroimaging tools in neurodegenerative diseases along with recent important developments in the field.}, }
@article {pmid39620842, year = {2024}, author = {Marshall, GA}, title = {Neuropsychiatric Symptoms in Dementia.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {30}, number = {6}, pages = {1744-1760}, pmid = {39620842}, issn = {1538-6899}, mesh = {Humans ; *Dementia/drug therapy ; Mental Disorders/drug therapy/etiology/diagnosis ; }, abstract = {OBJECTIVE: This article discusses the prevalence, pathophysiology, assessment, and management of neuropsychiatric symptoms in patients with dementia.
LATEST DEVELOPMENTS: There is a growing body of evidence localizing neuropsychiatric symptoms in dementia to frontal circuits in the brain, as well as relating them to pathologic changes seen in different dementias. Although very few medications have been approved by the US Food and Drug Administration (FDA) for the treatment of neuropsychiatric symptoms in dementia, there are more clinical trials showing the benefit of antidepressants, stimulants, and antipsychotics. In line with that trend, in 2023, the FDA approved the use of brexpiprazole, an atypical antipsychotic, for the treatment of agitation in Alzheimer disease dementia.
ESSENTIAL POINTS: Neuropsychiatric symptoms are a core feature of all dementias and often emerge before cognitive symptoms manifest. They are highly clinically significant symptoms that disrupt the lives of patients and care partners and greatly influence the decision to place patients in long-term care facilities. The first line of treatment for neuropsychiatric symptoms in dementia is nonpharmacologic behavioral modification, but clinicians often must supplement this intervention with medications using an empiric approach.}, }
@article {pmid39620840, year = {2024}, author = {Silbert, LC}, title = {Vascular Cognitive Impairment.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {30}, number = {6}, pages = {1699-1725}, pmid = {39620840}, issn = {1538-6899}, mesh = {Aged ; Female ; Humans ; Male ; Cerebrovascular Disorders/complications/physiopathology/diagnosis/diagnostic imaging ; *Cognitive Dysfunction/physiopathology/etiology/diagnosis ; *Dementia, Vascular/physiopathology/diagnosis ; }, abstract = {OBJECTIVE: Vascular cognitive impairment is a major contributor to age-associated cognitive decline, both independently and as a contributor to mixed dementia syndromes. This article reviews the current understanding of how vascular dysfunction contributes to cognitive impairment and dementia risk in older individuals and includes updated diagnostic criteria and treatment recommendations.
LATEST DEVELOPMENTS: Clinical and research criteria have been evolving to more accurately determine the full prevalence of vascular cognitive impairment. The Boston Criteria version 2.0 for cerebral amyloid angiopathy now includes multiple punctate MRI T2 white matter hyperintensities and MR-visible perivascular spaces in addition to previously described T2* hemorrhagic signatures. MR-visible perivascular spaces are associated with both vascular cognitive impairment and Alzheimer disease, potentially linking cerebrovascular dysfunction to neurodegenerative disorders through its role in brain waste clearance. The American Heart Association's goal for cardiovascular health promotion, "Life's Essential 8," has been updated to include sleep health and acknowledges psychological well-being and social determinants of health as fundamental components necessary to achieve optimal cardiovascular health for all adults.
ESSENTIAL POINTS: Vascular cognitive impairment is a common and often underrecognized contributor to cognitive impairment in older individuals, with heterogeneous etiologies requiring individualized treatment strategies. Effective cerebrovascular disease risk factor modification starting in midlife is critical to reducing the risk of Alzheimer disease and related dementias, with the goal of preventing vascular brain injury and maintaining cognitive reserve in the presence of nonvascular age-related brain pathologies.}, }
@article {pmid39620434, year = {2024}, author = {Goyal, A and Kumari, A and Verma, A and Chaudhary, V and Agrawal, V and Yadav, HN}, title = {Silent Information Regulator 1/Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Axis: A Promising Target for Parkinson's and Alzheimer's Disease Therapies.}, journal = {Journal of biochemical and molecular toxicology}, volume = {38}, number = {12}, pages = {e70078}, doi = {10.1002/jbt.70078}, pmid = {39620434}, issn = {1099-0461}, support = {//The authors received no specific funding for this work./ ; }, mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; *Sirtuin 1/metabolism ; *Parkinson Disease/metabolism/drug therapy ; Animals ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; }, abstract = {One of the key challenges in medical research is developing safe medications to treat neurodegenerative disorders. Increased oxidative stress, mitochondrial dysfunction, and neuroinflammation are common features of Alzheimer's disease (AD) and Parkinson's disease (PD). Silent information regulator 1 (SIRT-1), part of the sirtuin family, plays a critical role in various physiological processes by binding to histones and nonhistone proteins. SIRT-1 primarily mitigates oxidative stress and regulates mitochondrial activity by maintaining the deacetylated form of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), ensuring stable PGC-1α levels. Research has shown reduced SIRT-1/PGC-1α expression in AD and PD models. Targeting this pathway presents a promising therapeutic approach for managing AD and PD, potentially leading to disease-modifying treatments and improved outcomes. This review highlights the findings of various studies suggesting that the SIRT-1/PGC-1α pathway promotes mitochondrial biogenesis, synaptic plasticity, and cognitive function, as well as exerts antioxidant, anti-inflammatory, and anti-apoptotic effects, offering a potential method for AD and PD treatment.}, }
@article {pmid39620329, year = {2024}, author = {Jia, D and He, T and Sun, L and Wang, Q and Yu, H}, title = {Molecular Signatures and Clinical Significance of Notch Signaling Pathway in Peripheral Blood of Patients with Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {21}, number = {7}, pages = {479-490}, doi = {10.2174/0115672050339307241108101528}, pmid = {39620329}, issn = {1875-5828}, mesh = {Humans ; *Alzheimer Disease/blood/genetics/diagnosis ; *Signal Transduction/physiology/genetics ; *Receptors, Notch/genetics ; Male ; Biomarkers/blood ; Female ; Aged ; Transcriptome ; Cohort Studies ; Gene Expression Profiling ; Computational Biology ; Clinical Relevance ; }, abstract = {INTRODUCTION: Alzheimer's Disease (AD) is the most common neurodegenerative disease, and timely and effective diagnosis is essential for the prevention and treatment of AD. Peripheral blood is readily available, inexpensive, and non-invasive, making it an ideal substrate for screening diagnostic biomarkers.
METHOD: The Notch signaling pathway is closely related to AD, so genes related to the Notch signaling pathway may be candidate diagnostic biomarkers for AD. Here, we have performed an integrated analysis of peripheral blood cells transcriptomics from two AD cohorts (GSE63060: Ctrl = 104, MCI = 80, AD = 145; GSE63061: Ctrl = 134, MCI = 109, AD = 139) to reveal the expression levels of 16 Notch signals involving 100 genes.
RESULT: The results have shown the changes in Notch signaling-related genes to be highly consistent in both AD cohorts. Bioinformatics analysis has found Differentially Expressed Genes (DEGs) related to Notch signaling to mainly play important roles in Alzheimer's disease, the Notch signaling pathway, and the C-type lectin receptor signaling pathway. Multiple machine learning analyses have revealed IKBKB, HDAC2, and PIK3R1 to exhibit good diagnostic value in both AD cohorts and that they may be ideal biomarkers for early diagnosis of AD.
CONCLUSION: This study has provided a comprehensive description of the molecular signatures of the Notch signaling pathway in AD peripheral blood and a potential diagnostic model for AD clinical screening.}, }
@article {pmid39618963, year = {2024}, author = {Dow, LF and Pathirage, R and Erickson, HE and Amani, E and Ronning, DR and Trippier, PC}, title = {Synthesis and biological characterization of a 17β hydroxysteroid dehydrogenase type 10 (17β-HSD10) inhibitor.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {39618963}, issn = {2632-8682}, support = {T32 AG076407/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is estimated to affect over 55 million people across the world. Small molecule treatment options are limited to symptom management with no impact on disease progression. The need for new protein targets and small molecule hit compounds is unmet and urgent. Hydroxysteroid 17-β dehydrogenase type 10 (17β-HSD10) is a mitochondrial enzyme known to bind amyloid beta, a hallmark of AD, and potentiate its toxicity to neurons. Identification of small molecules capable of interacting with 17β-HSD10 may drive drug discovery efforts for AD. The screening compound BCC0100281 (1), was previously identified as an inhibitor of 17β-HSD10. Herein we report the first synthetic access to the hit compound following a convergent pathway starting from simple heterocyclic building blocks. The compound was found to be toxic to 'neuron-like' cells, specifically those of neuroblastoma origin, providing a potential hit compound for cancer drug discovery, wherein the protein is known to be overexpressed. However, assay of synthetic intermediates identified novel scaffolds with effect to rescue amyloid beta-induced cytotoxicity, showcasing the power of organic synthesis and medicinal chemistry to optimize hit compounds.}, }
@article {pmid39618111, year = {2024}, author = {Lee, JJ and Keener, LC and Phan, TX and Reeder, JE and Wang, S and Considine, CM and Darby, RR}, title = {Distinct Patterns of Socioemotional Dysfunction Relate to Aggressive Versus Nonaggressive Rule-breaking Antisocial Behaviors in Behavioral Variant Frontotemporal Dementia.}, journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology}, volume = {37}, number = {4}, pages = {194-204}, pmid = {39618111}, issn = {1543-3641}, support = {K23 AG070320/AG/NIA NIH HHS/United States ; R01 AG081655/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/psychology ; Male ; Female ; Aged ; *Aggression/psychology ; Middle Aged ; *Alzheimer Disease/psychology/complications ; Social Behavior ; Empathy/physiology ; Emotions/physiology ; Neuropsychological Tests/statistics & numerical data ; }, abstract = {BACKGROUND: Antisocial behaviors occur in up to 91% of individuals with behavioral variant frontotemporal dementia (bvFTD). Prior work has shown that antisocial behaviors can be differentiated into aggressive and nonaggressive rule-breaking behavioral subtypes. Socioemotional dysfunction is common in bvFTD and unique compared to other types of dementia.
OBJECTIVE: To determine whether socioemotional dysfunction relates to general antisocial behaviors in individuals with bvFTD, or whether different types of socioemotional dysfunction relate to aggressive versus rule-breaking behaviors.
METHODS: Informants for 28 participants with bvFTD and 21 participants with Alzheimer disease (AD) completed the Social Behavior Questionnaire (SBQ) and the Interpersonal Reactivity Index (IRI). The SBQ measures the presence and severity of 26 antisocial behaviors, including subscales for aggressive behaviors (SBQ-AGG) and nonaggressive rule-breaking behaviors (SBQ-RB). The IRI measures cognitive and emotional empathy capabilities, including subscales for Empathic Concern (IRI-EC) and Perspective-taking (IRI-PT).
RESULTS: As expected, participants with bvFTD had higher scores on the SBQ in total than participants with AD, as well as on the SBQ-AGG and SBQ-RB separately. Participants with bvFTD had lower scores on the IRI-EC and IRI-PT than participants with AD (P < 0.0001 for all measures). Lower scores on the IRI-PT correlated with higher scores on the SBQ-AGG-but not with higher scores on the SBQ-RB-across the combined group of participants (P = 0.007), and within participants in the bvFTD group (P = 0.01) specifically, after controlling for covariates of age, sex, dementia severity, and IRI-EC scores. Lower scores on the IRI-EC correlated with higher scores on the SBQ-AGG-but not with higher scores on the SBQ-RB-across the combined group of participants (P = 0.02) after controlling for covariates of age, sex, dementia severity, and IRI-PT scores.
CONCLUSION: Our results suggest that socioemotional dysfunction relates to antisocial behaviors in individuals with bvFTD, but that the mechanisms leading to aggressive and rule-breaking behaviors are differentiable, providing meaningful implications for distinct approaches to treatment and prevention.}, }
@article {pmid39617303, year = {2025}, author = {Lin, G and Yie, SLJ and Guo, S and Li, X and Xu, L}, title = {Clinical evidence of acupuncture for amnestic mild cognitive impairment: A systematic review and meta-analysis of randomized controlled trials.}, journal = {Complementary therapies in medicine}, volume = {88}, number = {}, pages = {103114}, doi = {10.1016/j.ctim.2024.103114}, pmid = {39617303}, issn = {1873-6963}, mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods ; *Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: People with amnestic mild cognitive impairment (aMCI) carry a substantial risk of developing dementia compared to non-amnestic MCI (naMCI). Several previous studies proved the remarkable effectiveness of acupuncture for MCI, but they didn't distinguish between aMCI and naMCI. We conducted this meta-analysis to systematically assess the evidence of the efficacy of acupuncture in this unique population with aMCI.
METHODS: We comprehensively searched nine databases on January 09, 2024, to identify relevant articles estimating the effects of acupuncture for aMCI, and then assessed the risk of bias of the included trials utilizing the RoB 2.0 tool which included the domain of randomization process, deviation from intended interventions, missing outcome data, measurement of the outcome, selection of the reported outcome, and overall bias. The results of this meta-analysis were exhibited with forest plots. Sensitivity analyses were conducted to determine the robustness of the pooled results, and publication bias was estimated by Egger's and Begg's tests. Besides, we also performed subgroup analysis to determine whether there was a difference in therapeutic effects between four weeks and eight weeks of treatment duration. The certainty of the evidence was graded using GRADEpro GDT.
RESULTS: A total of 15 randomized controlled trials (RCTs) involving 908 people with aMCI were included in this study. According to the meta-analysis, acupuncture treatment provided a remarkable improvement in cognitive function as assessed by Mini-Mental State Examination (MD = 1.09, 95 %CI [0.86, 1.31], p < 0.00001), Montreal Cognitive Assessment (MD = 0.93, 95 %CI [0.80, 1.07], p < 0.00001), Alzheimer's Disease Assessment Scale-Cognitive (MD = 1.00, 95 %CI [-1.23, -0.77], p < 0.00001), and P300 latency (MD = -15.40, 95 %CI [-23.68, -7.12], p = 0.0003). Subgroup analysis showed evidence that the efficacy of four weeks of acupuncture treatment was consistent with that of eight weeks. Sensitivity analyses, Egger's and Begg's tests suggested the pooled results were robust and reliable. The overall quality of the evidence, as appraised by the GRADE criteria, was very low or low for all outcomes.
CONCLUSIONS: The evidence from 15 RCTs demonstrated that acupuncture interventions are effective in ameliorating cognitive function in people with aMCI. There is a need for larger-scale multicenter RCTs using standardised training protocols and more rigorous designs to confirm the conclusions further.
REGISTRATION: This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO). The registration number is CRD42023460470.}, }
@article {pmid39617173, year = {2025}, author = {Silva, RO and Haddad, M and Counil, H and Zaouter, C and Patten, SA and Fulop, T and Ramassamy, C}, title = {Exploring the potential of plasma and adipose mesenchymal stem cell-derived extracellular vesicles as novel platforms for neuroinflammation therapy.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {377}, number = {}, pages = {880-898}, doi = {10.1016/j.jconrel.2024.11.060}, pmid = {39617173}, issn = {1873-4995}, mesh = {*Extracellular Vesicles/metabolism ; Animals ; *Mesenchymal Stem Cells/metabolism ; Humans ; *Zebrafish ; *Neuroinflammatory Diseases ; *Blood-Brain Barrier/metabolism/drug effects ; *Adipose Tissue/cytology ; *Donepezil/administration & dosage ; Cholinesterase Inhibitors/administration & dosage ; Drug Delivery Systems ; Reactive Oxygen Species/metabolism ; Anti-Inflammatory Agents/administration & dosage ; Neuroprotective Agents/administration & dosage ; Brain/metabolism ; }, abstract = {Persistent reactive oxygen species (ROS) and neuroinflammation contribute to the onset and progression of neurodegenerative diseases, underscoring the need for targeted therapeutic strategies to mitigate these effects. Extracellular vesicles (EVs) show promise in drug delivery due to their biocompatibility, ability to cross biological barriers, and specific interactions with cell and tissue receptors. In this study, we demonstrated that human plasma-derived EVs (pEVs) exhibit higher brain-targeting specificity, while adipose-derived mesenchymal stem cells EVs (ADMSC-EVs) offer regenerative and immunomodulatory properties. We further investigated the potential of these EVs as therapeutic carriers for brain-targeted drug delivery, using Donepezil (DNZ) as the model drug. DNZ, a cholinesterase inhibitor commonly used for Alzheimer's disease (AD), also has neuroprotective and anti-inflammatory properties. The size of EVs used ranged from 50 to 300 nm with a surface charge below -30 mV. Both formulations showed rapid cellular internalization, without toxicity, and the ability to cross the blood-brain barrier (BBB) in a zebrafish model. The have analyzed the anti-inflammatory and antioxidant actions of pEVs-DNZ and ADMSC-EVs-DNZ in the presence of lipopolysaccharide (LPS). ADMSC-EVs significantly reduced the inflammatory mediators released by HMC3 microglial cells while treatment with pEVs-DNZ and ADMSC-EVs-DNZ lowered both phagocytic activity and ROS levels in these cells. In vivo experiments using zebrafish larvae revealed that both EV formulations reduced microglial proliferation and exhibited antioxidant effects. Overall, this study highlights the potential of EVs loaded with DNZ as a novel approach for treating neuroinflammation underlying various neurodegenerative diseases.}, }
@article {pmid39616884, year = {2024}, author = {Dustin, CM and Shiva, SS and Vazquez, A and Saeed, A and Pascoal, T and Cifuentes-Pagano, E and Pagano, PJ}, title = {NOX2 in Alzheimer's and Parkinson's disease.}, journal = {Redox biology}, volume = {78}, number = {}, pages = {103433}, pmid = {39616884}, issn = {2213-2317}, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/etiology ; *NADPH Oxidase 2/metabolism/genetics ; *Parkinson Disease/metabolism/pathology ; *Reactive Oxygen Species/metabolism ; Animals ; Signal Transduction ; Microglia/metabolism/pathology ; Brain/metabolism/pathology ; Neurons/metabolism/pathology ; }, abstract = {Alzheimer's Disease (AD), and related dementias, represent a growing concern for the worldwide population given the increased numbers of people of advanced age. Marked by significant degradation of neurological tissues and critical processes, in addition to more specific factors such as the presence of amyloid plaques and neurofibrillary tangles in AD, robust discussion is ongoing regarding the precise mechanisms by which these diseases arise. One of the major interests in recent years has been the contribution of reactive oxygen species (ROS) and, particularly, the contribution of the ROS-generating NADPH Oxidase proteins. NADPH Oxidase 2 (NOX2), the prototypical member of the family, represents a particularly interesting target for study given its close association with vascular and inflammatory processes in all tissues, including the brain, and the association of these processes with AD development and progression. In this review, we discuss the most relevant and recent work regarding the contribution of NOX2 to AD progression in neuronal, microglial, and cerebrovascular signaling. Furthermore, we will discuss the most promising NOX2-targeted therapeutics for potential AD management and treatment.}, }
@article {pmid39614969, year = {2025}, author = {Yamaguchi, T and Sasaki, H and Yatsu, G and Koyama, K and Kinoshita, K}, title = {Meroterpenoids with BACE1-inhibitory activity from the fruiting bodies of Suillus bovinus and Boletinus cavipes.}, journal = {Journal of natural medicines}, volume = {79}, number = {1}, pages = {233-241}, pmid = {39614969}, issn = {1861-0293}, support = {17K08351//Japan Society for the Promotion of Science/ ; 24K09868//Japan Society for the Promotion of Science/ ; }, mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; *Terpenes/chemistry/pharmacology/isolation & purification ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; *Fruiting Bodies, Fungal/chemistry ; Structure-Activity Relationship ; Agaricales/chemistry ; Molecular Structure ; Humans ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Alzheimer disease (AD) is the most common type of dementia and accounts for the largest proportion of dementia cases. The amyloid cascade hypothesis is known for the pathogenesis of AD, in which excessive accumulation of amyloid-β (Aβ) leads to the formation of senile plaques and ultimately to AD. Inhibition of β-secretase (BACE1) may contribute to the treatment of AD by suppressing Aβ production. In this study, we isolated and characterized the activity of new and known BACE1-inhibiting compounds from two mushrooms of the Boletales order, Suillus bovinus and Boletinus cavipes, using a BACE1-inhibitory activity-guided separation approach. Three compounds (1-3) were isolated from Suillus bovinus CHCl3 extract and three compounds (4-6) were isolated from Boletinus cavipes CHCl3 extract. Compound 1 was a new compound. The structures were elucidated using MS, IR, and NMR. Compounds 1-6 showed BACE1-inhibitory activity (IC50; 21.2, 17.8, 1.0, 1.6, 23.7, and 22.8 μM, respectively). To examine the structure-activity relationship, we also evaluated the activity of geranylgerniol, farnesol, 2,5-dihydroxy-1,4-benzoquinone and mesaconic acid. These compounds showed no activity, and these results indicate that chain terpenes alone do not show BACE1-inhibitory activity, but only when mesaconic acid or a quinone with a hydroxyl group is bound. In addition, the mode of inhibition of 2 and 3 were competitive and 4 was uncompetitive inhibition, respectively, as determined by analysis of Lineweaver-Burk and Dixon plots.}, }
@article {pmid39614747, year = {2025}, author = {Shaw, LM and Korecka, M and Lee, EB and Cousins, KAQ and Vanderstichele, H and Schindler, SE and Tosun, D and DeMarco, ML and Brylska, M and Wan, Y and Burnham, S and Sciulli, A and Vulaj, A and Tropea, TF and Chen-Plotkin, A and Wolk, DA and , }, title = {ADNI Biomarker Core: A review of progress since 2004 and future challenges.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14264}, pmid = {39614747}, issn = {1552-5279}, support = {//the Foundation for the National Institutes of Healt/ ; U01 AG024904/AG/NIA NIH HHS/United States ; U01 AG024904/NH/NIH HHS/United States ; //Alzheimer's Disease Neuroimaging Initiative (ADNI)/ ; /EB/NIBIB NIH HHS/United States ; W81XWH-12-2-0012//DOD ADNI/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid/blood ; Neuroimaging ; Biological Specimen Banks ; Disease Progression ; Mass Spectrometry ; }, abstract = {BACKGROUND: We describe the Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core major activities from October 2004 to March 2024, including biobanking ADNI cerebrospinal fluid (CSF), plasma, and serum biofluid samples, biofluid analyses for Alzheimer's disease (AD) biomarkers in the Biomarker Core and various non-ADNI laboratories, and continuous assessments of pre-analytics.
RESULTS: Validated immunoassay and mass spectrometry-based assays were performed in CSF with a shift to plasma, a more accessible biofluid, as qualified assays became available. Performance comparisons across different CSF and plasma AD biomarker measurement platforms have enriched substantially the ADNI participant database enabling method performance determinations for AD pathology detection and longitudinal assessments of disease progression.
DISCUSSION: Close collaboration with academic and industrial partners in the validation and implementation of AD biomarkers for early detection of disease pathology in treatment trials and ultimately in clinical practice is a key factor for the success of the work done in the Biomarker Core.
HIGHLIGHTS: Describe ADNI Biomarker Core biobanking and sample distribution from 2007 to 2024. Discuss validated mass spectrometry and immunoassay methods for ADNI biofluid analyses. Review collaborations with academic and industrial partners to detect AD and progression. Discuss major challenges, and progress to date, for co-pathology detection. Implementation in the ATN scheme: co-pathology and modeling disease progression.}, }
@article {pmid39614308, year = {2024}, author = {Banna, HU and Slayo, M and Armitage, JA and Del Rosal, B and Vocale, L and Spencer, SJ}, title = {Imaging the eye as a window to brain health: frontier approaches and future directions.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {309}, pmid = {39614308}, issn = {1742-2094}, support = {DP230101331//ARC/ ; DP230101331//ARC/ ; JPND2021-650-233//JPND/ ; 2019196//NHMRC/ ; }, mesh = {Humans ; Animals ; *Brain/diagnostic imaging/pathology ; Retina/diagnostic imaging/pathology ; Brain Diseases/pathology/diagnostic imaging/diagnosis ; Optical Imaging/methods/trends ; }, abstract = {Recent years have seen significant advances in diagnostic testing of central nervous system (CNS) function and disease. However, there remain challenges in developing a comprehensive suite of non- or minimally invasive assays of neural health and disease progression. Due to the direct connection with the CNS, structural changes in the neural retina, retinal vasculature and morphological changes in retinal immune cells can occur in parallel with disease conditions in the brain. The retina can also, uniquely, be assessed directly and non-invasively. For these reasons, the retina may prove to be an important "window" for revealing and understanding brain disease. In this review, we discuss the gross anatomy of the eye, focusing on the sensory and non-sensory cells of the retina, especially microglia, that lend themselves to diagnosing brain disease by imaging the retina. We include a history of ocular imaging to describe the different imaging approaches undertaken in the past and outline current and emerging technologies including retinal autofluorescence imaging, Raman spectroscopy, and artificial intelligence image analysis. These new technologies show promising potential for retinal imaging to be used as a tool for the diagnosis of brain disorders such as Alzheimer's disease and others and the assessment of treatment success.}, }
@article {pmid39613776, year = {2024}, author = {Hansen, LS and Carstensen, MH and Henney, MA and Nguyen, NM and Thorning-Schmidt, MW and Broeng, J and Petersen, PM and Andersen, TS}, title = {Light-based gamma entrainment with novel invisible spectral flicker stimuli.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {29747}, pmid = {39613776}, issn = {2045-2322}, support = {501100005192//Danmarks Tekniske Universitet (Technical University of Denmark)/ ; 1044-00177A//Innovationsfonden (Innovation Fund Denmark)/ ; }, mesh = {Humans ; Male ; Female ; *Evoked Potentials, Visual/physiology ; *Photic Stimulation/methods ; Adult ; Light ; Alzheimer Disease/physiopathology ; Young Adult ; Electroencephalography ; Gamma Rhythm/physiology ; }, abstract = {Light-based gamma entrainment using sensory stimuli (GENUS) shows considerable potential for the treatment of Alzheimer's disease (AD) in both animal and human models. While the clinical efficacy of GENUS for AD is paramount, its effectiveness will eventually also rely on the barrier to treatment adherence imposed by the discomfort of gazing at luminance flickering (LF) light. Currently, there have been few attempts to improve the comfort of GENUS. Here we investigate if Invisible spectral flicker (ISF), a novel type of light-based 40 Hz GENUS for which the flicker is almost imperceptible, can be used as a more comfortable option. We found that whereas ISF, LF, and chromatic flicker (CF) all produce a 40 Hz steady-state visually evoked potential (SSVEP), ISF scores significantly better on measures of comfort and perceived flicker. We also demonstrate that, while there is a trend towards a lower SSVEP response, reducing the stimulation brightness has no significant effect on the 40 Hz SSVEP or perceived flicker, though it significantly improves comfort. Finally, there is a slight decrease in the 40 Hz SSVEP response when stimulating with ISF from increasingly peripheral angles. This may ease the discomfort of GENUS treatment by freeing patients from gazing directly at the light.}, }
@article {pmid39611008, year = {2024}, author = {Lavanya, M and Namasivayam, SKR and Priyanka, S and Abiraamavalli, T}, title = {Microencapsulation and nanoencapsulation of bacterial probiotics: new frontiers in Alzheimer's disease treatment.}, journal = {3 Biotech}, volume = {14}, number = {12}, pages = {313}, pmid = {39611008}, issn = {2190-572X}, abstract = {Alzheimer's disease, a progressive neurodegenerative disorder marked by cognitive decline, affects millions worldwide. The presence of amyloid plaques and neurofibrillary tangles in the brain is the key pathological feature, leading to neuronal dysfunction and cell death. Current treatment options include pharmacological approaches such as cholinesterase inhibitors, as well as non-pharmacological strategies like cognitive training and lifestyle modifications. Recently, the potential role of probiotics, particularly strains, such as Lactobacillus and Bifidobacterium, in managing neurodegenerative diseases through the gut-brain axis has garnered significant attention. Probiotics can modulate inflammation, produce neurotransmitters, and support neuronal health, potentially slowing disease progression and alleviating symptoms, such as stress and anxiety. Optimizing the pharmacotherapeutic effects of probiotics is critical and involves advanced formulation techniques, such as microencapsulation and nanoencapsulation. Microencapsulation employs natural or synthetic polymers to protect probiotic cells, enhancing their viability and stability against environmental stressors. Methods like extrusion, emulsion, and spray-drying are used to create microcapsules suited for various applications. Nanoencapsulation, on the other hand, operates at the nanoscale, utilizing polymeric or lipid-based nanoparticles to improve the bioavailability and shelf life of probiotics. Techniques, such as nanoprecipitation and emulsification, are employed to ensure stable nanocapsule formation, thereby augmenting the therapeutic potential of probiotics as nutraceutical agents. This study delves into the essential formulation aspects of microencapsulation and nanoencapsulation for beneficial probiotic strains, aimed at managing Alzheimer's disease by optimizing the gut-brain axis. The insights gained from these advanced techniques promise to enhance probiotic delivery efficacy, potentially leading to improved health outcomes for patients suffering from neurodegenerative disorders.}, }
@article {pmid39610298, year = {2024}, author = {Juday, TR and Holub, A and Mattke, S and Betts, KA and Kitchen, SA and Liu, H and Batrla, R and Frech, FH and Khachaturian, AS}, title = {Real-world diagnostic, referral, and treatment patterns in early Alzheimer's disease among community-based practices in the United States.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {102}, number = {4}, pages = {1172-1182}, doi = {10.1177/13872877241297128}, pmid = {39610298}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/epidemiology ; Male ; Female ; Aged ; *Referral and Consultation/statistics & numerical data ; United States ; *Cognitive Dysfunction/diagnosis/therapy ; Aged, 80 and over ; Neuropsychological Tests ; Middle Aged ; Practice Patterns, Physicians'/statistics & numerical data ; Physicians, Primary Care ; Neurologists ; }, abstract = {BACKGROUND: Over 90% of individuals with mild cognitive impairment (MCI) may not receive a timely diagnosis. Understanding community-based practice patterns, where most individuals are seen, is critical to improving patient care.
OBJECTIVE: To understand how patients with MCI and mild dementia due to Alzheimer's disease (AD) are diagnosed and managed in community-based settings, including the use of clinical and cognitive assessments, referrals to dementia-related specialties, and receipt of treatment.
METHODS: This observational study recruited community-based primary care physicians (PCPs) (N = 177) and neurologists (N = 147) in August-September 2023, through a verified physician panel with broad geographic representation across the US. Physicians abstracted medical chart data from patients diagnosed with MCI or mild AD within the previous two years. Data collected included use of neurocognitive assessments, biomarker and structural imagine tests, referrals, and treatments. Descriptive statistics were used.
RESULTS: Medical records for 817 MCI and 467 mild AD patients were abstracted. The mean age was 70.2 years, 56.4% were female, and 67.2% were White. Symptoms were commonly reported by a family member (67.2%). Nearly 1 in 6 patients did not receive any neurocognitive assessments (16.1%), and nearly 1 in 4 did not receive a structural imaging or AD-specific biomarker test (23.7%). AD-specific biomarker tests were more common among patients aged ≥65 (87.1% versus 75.3%; p < 0.05). Less than 1 in 4 patients were referred for cognitive/behavioral concerns.
CONCLUSIONS: As the diagnostic and treatment landscape changes, education on symptom recognition, and physician training on new technologies may facilitate timely diagnoses and improve patient outcomes.}, }
@article {pmid39610292, year = {2025}, author = {Lam, A and D'Rozario, AL and Kong, S and Ireland, C and Mowszowski, L and LaMonica, HM and Phillips, CL and Hoyos, CM and Grunstein, RR and Naismith, SL}, title = {Screening for obstructive sleep apnea in the memory clinic: A comparison of questionnaires, pulse oximetry, and polysomnography.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {1}, pages = {218-229}, doi = {10.1177/13872877241299458}, pmid = {39610292}, issn = {1875-8908}, mesh = {Humans ; *Sleep Apnea, Obstructive/diagnosis ; *Oximetry/methods ; Male ; Female ; *Polysomnography/methods ; Aged ; Surveys and Questionnaires ; Middle Aged ; Reproducibility of Results ; Mass Screening/methods ; Sensitivity and Specificity ; Cognitive Dysfunction/diagnosis ; }, abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is highly prevalent among older adults and has been associated with cognitive decline and dementia risk. The suitability of screening tools for detecting OSA in memory clinic settings is unclear.
OBJECTIVE: To evaluate the utility and validity of the STOP-Bang questionnaire (SBQ) and pulse oximeter as a screening tool, compared to gold-standard polysomnography (PSG) in older adults attending a memory clinic.
METHODS: Participants aged over 50 with new onset cognitive/mood concerns attended a memory clinic, then completed the SBQ, oximetry, and PSG. The SBQ and oximetry's accuracy in detecting moderate-severe and severe OSA was evaluated using receiver operating curves. Intraclass correlation and Bland-Altman plots compared the oximeter's adjusted oxygen desaturation index (ODI-Ox) and PSG's apnea-hypopnea index (AHI-PSG).
RESULTS: Of 194 participants (mean age = 65.6, 64 males) who completed PSG, 184 completed the SBQ, and 138 completed oximetry. SBQ demonstrated limited performance for moderate-severe OSA (sensitivity = 52%, specificity = 62%, AUC = 0.600) and severe OSA (sensitivity = 18%, specificity = 87%, AUC = 0.577). Oximetry was satisfactory for moderate-severe OSA (sensitivity = 67%, specificity = 73%, AUC = 0.769) and severe OSA (sensitivity = 50%, specificity = 88%, AUC = 0.730). The diagnostic performance was improved with new cut-offs at ODI-Ox ≥ 11 for AHI-PSG ≥ 15 and ODI-Ox ≥ 20 for AHI-PSG ≥ 30. Bland-Altman plots and intraclass correlation indicated acceptable agreement for oximetry.
CONCLUSIONS: The findings suggest that while the SBQ may be unsuitable to detect moderate or severe OSA for older adults with cognitive impairment, oximetry may be a viable screening tool. Given OSA treatment can optimize sleep and may slow cognitive decline, routine screening for OSA should be part of memory clinic assessments.}, }
@article {pmid39610284, year = {2025}, author = {Malik, R and Beaton, D and Ahmed, J and Nho, K and Saykin, AJ and Wang, J and Hegele, RA and Finger, E and , }, title = {A DAT1 gene and APOE ε4 interaction is associated with apathy and structural brain changes in mild cognitive impairment and Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {1}, pages = {230-242}, doi = {10.1177/13872877241299785}, pmid = {39610284}, issn = {1875-8908}, support = {T32 AG071444/AG/NIA NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; R01 LM013463/LM/NLM NIH HHS/United States ; U01 AG072177/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Cognitive Dysfunction/genetics/pathology/diagnostic imaging ; Male ; *Alzheimer Disease/genetics/pathology ; Female ; *Apathy ; Aged ; *Apolipoprotein E4/genetics ; *Brain/pathology/diagnostic imaging ; *Dopamine Plasma Membrane Transport Proteins/genetics ; *Polymorphism, Single Nucleotide ; Magnetic Resonance Imaging ; Aged, 80 and over ; Atrophy/pathology ; }, abstract = {BACKGROUND: Apathy in patients with Alzheimer's disease (AD) is associated with significant morbidity and is often one of the first neuropsychiatric symptoms to present in mild cognitive impairment (MCI). Apathy is associated with accelerated cognitive decline and atrophy in fronto-striatal regions of the brain. Previous work has shown a link between apathy and the APOE gene in the context of AD, as the APOE ε4 allele is already known to be associated with the onset of AD. However, other genetic associations with apathy are largely unexplored.
OBJECTIVE: To examine whether interactions between genetic variants related to neurotransmitter systems and regional brain atrophy are associated with apathy in patients with MCI and AD.
METHODS: In a sample of individuals with AD (n = 266), MCI (n = 518), and cognitively normal controls (n = 378), a partial least squares correspondence analysis modeled interactions between single nucleotide polymorphisms, structural whole-brain imaging variables, and apathy.
RESULTS: An interaction was found between apathy, the possession of an APOE ε4 allele combined with minor homozygosity for the DAT1 (dopamine transporter 1) gene, and regional brain atrophy. This interaction was closely linked to the MCI and AD groups.
CONCLUSIONS: The results point to an association of a dopaminergic genetic marker and apathy in the AD continuum and may inform future design of clinical trials of apathy, as well as new treatment targets.}, }
@article {pmid39610283, year = {2025}, author = {Engel, MG and Narayan, S and Cui, MH and Branch, CA and Zhang, X and Gandy, SE and Ehrlich, M and Huffman, DM}, title = {Intranasal long R3 insulin-like growth factor-1 treatment promotes amyloid plaque remodeling in cerebral cortex but fails to preserve cognitive function in male 5XFAD mice.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {1}, pages = {113-126}, doi = {10.1177/13872877241299056}, pmid = {39610283}, issn = {1875-8908}, mesh = {Animals ; Male ; *Insulin-Like Growth Factor I/metabolism ; *Administration, Intranasal ; *Mice, Transgenic ; *Cerebral Cortex/drug effects/pathology/metabolism ; *Plaque, Amyloid/pathology/drug therapy ; Mice ; *Disease Models, Animal ; Alzheimer Disease/drug therapy/pathology/metabolism ; Presenilin-1/genetics ; Humans ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Mice, Inbred C57BL ; Maze Learning/drug effects ; Cognition/drug effects ; Insulin-Like Peptides ; }, abstract = {BACKGROUND: Insulin-like growth factor-1 (IGF-1) promotes neurogenesis, cell survival, and glial function, making it a promising candidate therapy in Alzheimer's disease (AD).
OBJECTIVE: Long arginine 3-IGF-1 (LR3-IGF-1) is a potent IGF-1 analogue. We sought to determine whether intranasal (IN) LR3 treatment would delay cognitive decline and pathology in 5XFAD mice.
METHODS: Wildtype and 5XFAD male mice were treated for 7 months (3-10 months of age), with IN LR3-IGF-1 or IN Vehicle (Veh) (n = 19-27 mice/group). Behavior, memory, and brain imaging were assessed at 8-9 months of age and tissues collected at 10 months. A comprehensive amyloid-β (Aβ) profile and other pathologic features were conducted and supportive in vitro stimulation studies in BV-2 microglial cells were also performed.
RESULTS: In male 5XFAD mice, IN LR3-IGF-1 treatment improved body composition, but did not significantly alter cognitive symptoms, as assessed by multiple assays. In cortex, LR3 treatment improved some facets of pathology, including a reduction in filamentous plaques, and increase in inert plaques, corresponding with a reduction in low molecular weight Aβ oligomers. In vitro, uptake of Aβ1-42 peptide by BV2 cells was enhanced by LR3-IGF-1, which was also found to promote gene pathways implicated in actin remodeling and endocytosis.
CONCLUSIONS: LR3 promotes favorable effects on Aβ plaque remodeling in cortex of male 5XFAD mice but fails to preserve aspects of behavior or memory. While these data do not support LR3 as a monotherapy per se, they do warrant further investigation into its potential for combinatorial formulations aimed at targeting the complexity of AD.}, }
@article {pmid39610096, year = {2025}, author = {Pierzynowska, K and Karaszewski, B and Węgrzyn, G}, title = {Genistein: a possible solution for the treatment of Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {20}, number = {10}, pages = {2903-2905}, pmid = {39610096}, issn = {1673-5374}, }
@article {pmid39609333, year = {2025}, author = {Bhardwaj, V and Kumari, S and Dhapola, R and Sharma, P and Beura, SK and Singh, SK and Vellingiri, B and HariKrishnaReddy, D}, title = {Shedding light on microglial dysregulation in Alzheimer's disease: exploring molecular mechanisms and therapeutic avenues.}, journal = {Inflammopharmacology}, volume = {33}, number = {2}, pages = {679-702}, pmid = {39609333}, issn = {1568-5608}, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Microglia/metabolism ; Animals ; Inflammation/metabolism/drug therapy/pathology ; Cytokines/metabolism ; Amyloid beta-Peptides/metabolism ; Neuroinflammatory Diseases/drug therapy/metabolism ; Signal Transduction ; }, abstract = {Alzheimer's disease (AD) stands out as the foremost prevalent neurodegenerative disorder, characterized by a complex etiology. Various mechanisms have been proposed to elucidate its onset, encompassing amyloid-beta (Aβ) toxicity, tau hyperphosphorylation, oxidative stress and reactive gliosis. The hallmark of AD comprises Aβ and tau aggregation. These misfolded protein aggregates trigger the activation of glial cells, primarily microglia. Microglial cells serve as a major source of inflammatory mediators and their cytotoxic activation has been implicated in various aspects of AD pathology. Activated microglia can adopt M1 or M2 phenotypes, where M1 promotes inflammation by increasing pro-inflammatory cytokines and M2 suppresses inflammation by boosting anti-inflammatory factors. Overexpressed pro-inflammatory cytokines include interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in adjacent brain regions. Furthermore, microglial signaling pathways dysregulated in AD are myeloid differentiation primary-response protein 88 (Myd 88), colony-stimulating factor-1 receptor (CSF1R) and dedicator of cytokinesis 2 (DOCK2), which alter the physiology. Despite numerous findings, the causative role of microglia-mediated neuroinflammation in AD remains elusive. This review concisely explores cellular and molecular mechanisms of activated microglia and their correlation with AD pathogenesis. Additionally, it highlights promising therapeutics targeting microglia modulation, currently undergoing preclinical and clinical studies, for developing effective treatment for AD.}, }
@article {pmid39608999, year = {2024}, author = {Climacosa, FMM and Anlacan, VMM and Gordovez, FJA and Reyes, JCB and Tabios, IKB and Manalo, RVM and Cruz, JMC and Asis, JLB and Razal, RB and Abaca, MJM and Dacasin, AB and Espiritu, APN and Gapaz, NCLL and Lee Yu, MHL}, title = {Monitoring drug Efficacy through Multi-Omics Research initiative in Alzheimer's Disease (MEMORI-AD): A protocol for a multisite exploratory prospective cohort study on the drug response-related clinical, genetic, microbial and metabolomic signatures in Filipino patients with Alzheimer's disease.}, journal = {BMJ open}, volume = {14}, number = {11}, pages = {e078660}, pmid = {39608999}, issn = {2044-6055}, mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; Philippines ; Prospective Studies ; Aged ; Cholinesterase Inhibitors/therapeutic use ; Rivastigmine/therapeutic use ; Donepezil/therapeutic use ; Cross-Sectional Studies ; Memantine/therapeutic use ; Male ; Female ; Metabolomics ; Gastrointestinal Microbiome/drug effects ; Multiomics ; }, abstract = {INTRODUCTION: Dementia is one of the leading causes of disability among older people aged 60 years and above, with majority eventually being diagnosed with Alzheimer's disease (AD). Pharmacological agents approved for dementia include acetylcholinesterase enzyme (AChE) inhibitors like rivastigmine, donepezil and galantamine and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, prescribed as monotherapy or in combination with each other, depending on the severity of disease. There is currently no available study demonstrating the clinical response to these drugs for AD in the Filipino population. Hence, this protocol aims to characterise the clinical, genetic, microbial and metabolic factors associated with drug responses to donepezil, rivastigmine and/or memantine for AD in a cohort of Filipinos with late-onset AD.
METHODS AND ANALYSIS: This protocol involves a multisite descriptive study that will use two study designs: (1) a descriptive, cross-sectional study to characterise the clinical profile of Filipino dementia patients with AD and (2) an exploratory prospective cohort study to investigate drug response-related genetic, gut microbiome and metabolome signatures of a subset of the recruited AD patients. At least 153 patients with mild or moderate AD aged 65 years old and above will be recruited regardless of their treatment status. A subset of these patients (n=60) who meet inclusion and exclusion criteria will be included further in the exploratory cohort study. These patients will be grouped according to their baseline medications and will be observed for treatment response in 6 months. The cognitive, functional and behavioural domains of patients and levels of functioning will be measured using different assessment tools. Drug responses of Filipino patients will then be investigated employing multi-omics technology to characterise genetic variations via whole exome sequencing, gut microbiome profile via shotgun metagenomic sequencing and metabolome profile via liquid chromatography with mass spectrometry.
ETHICS AND DISSEMINATION: The study has received ethical clearance from the Department of Health Single Joint Research Ethics Board (SJREB-2022-15). Results of psychometric scales will be made available to enrolled patients. The study results will be presented at national/international conferences and published in international peer-reviewed scientific journals, and summaries of the results will be provided to the study funders and institutional review boards of the three tertiary referral hospitals.
TRIAL REGISTRATION NUMBER: Philippine Health Research Registry ID PHRR230220-0054116; ClinicalTrials.gov ID NCT05801380.}, }
@article {pmid39608234, year = {2025}, author = {Hu, T and Li, M and Zhang, X and Gao, Y and Gao, H and Liu, L and Zuo, A and Wang, Y and Guo, J and Zheng, Y}, title = {Combination of mass spectrometry analysis and bioinformatic analysis for characterizing anti-inflammation active components from Boschniakia rossica and the targets.}, journal = {Journal of chromatography. A}, volume = {1739}, number = {}, pages = {465544}, doi = {10.1016/j.chroma.2024.465544}, pmid = {39608234}, issn = {1873-3778}, mesh = {Animals ; Rats ; *Alzheimer Disease/drug therapy ; *Computational Biology ; *Anti-Inflammatory Agents/pharmacology/chemistry ; Male ; Rats, Sprague-Dawley ; Molecular Docking Simulation ; Mass Spectrometry/methods ; Plant Extracts/pharmacology/chemistry ; Signal Transduction/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Hippocampus/drug effects/chemistry ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Chromatography, High Pressure Liquid/methods ; }, abstract = {Alzheimer's disease (AD), a demonstrativeness disease with insidious onset, has become an important public health problem worldwide and is the fifth leading cause of death in the world. Boschniakia rossica (BR) has been used to treat age-related diseases, especially AD in China for centuries, but the material basis and mechanism are unclear. Here, we investigated the effective components and the mechanism of BR in the treatment of AD. The therapeutic effect of BR was verified through pathological and behavioral studies of AD rat model. BR can significantly increase the number of nerve cells in the hippocampus and improve the study and memory ability of AD rats. Subsequently, the active composition and the potential targets of BR were explored by UPLC-Q-Orbitrap-HRMS and network pharmacology. Ursolic acid, baicalein, and salicylic acid were the potential pharmacodynamic components acted on the phosphatidylinositol 3-kinase (PI3 K)/protein kinase B (AKT) pathway, which was verified by further molecular docking and molecular dynamics simulations. The in vivo and in vitro study revealed that BR treat AD by reducing the neurotoxicity of Aβ25-35 induced nerve cells by regulating PI3K/AKT signaling pathway. Our data strongly support a theoretical basis and methodology for the treatment of AD by BR and a reference for its new drug development.}, }
@article {pmid39607970, year = {2024}, author = {El-Shiekh, RA and Atwa, AM and Elgindy, AM and Ibrahim, KM and Senna, MM and Ebid, N and Mustafa, AM}, title = {Current Perspective and Mechanistic Insights on α-Hederin for the Prevention and Treatment of Several Noncommunicable Diseases.}, journal = {Chemistry & biodiversity}, volume = {}, number = {}, pages = {e202402289}, doi = {10.1002/cbdv.202402289}, pmid = {39607970}, issn = {1612-1880}, abstract = {α-Hederin, a naturally occurring compound found in various plant sources, has remarkable properties and therapeutic potential for human health. One notable attribute is its potent anti-inflammatory activity, such as in arthritis, asthma, and inflammatory bowel disease. In addition, it exhibits notable antioxidant effects implicated in the development of chronic diseases, including cardiovascular disorders and certain types of cancer. According to research, it may limit the growth and proliferation of cancer cells, making it a possible candidate for future cancer treatments. Moreover, it is a promising neuroprotective agent and enhances cognitive function, suggesting its potential in the treatment of neurodegenerative illnesses like Alzheimer's and Parkinson's disease. The multifaceted benefits of α-hederin make it an intriguing compound with significant therapeutic implications. As research progresses, exploring its mechanisms of action and clinical applications is warranted. Harnessing the potential of α-hederin may pave the way for innovative treatment strategies and improved outcomes in the battle against various chronic diseases.}, }
@article {pmid39607636, year = {2024}, author = {Dziewa, M and Złotek, M and Herbet, M and Piątkowska-Chmiel, I}, title = {Molecular and Cellular Foundations of Aging of the Brain: Anti-aging Strategies in Alzheimer's Disease.}, journal = {Cellular and molecular neurobiology}, volume = {44}, number = {1}, pages = {80}, pmid = {39607636}, issn = {1573-6830}, mesh = {*Alzheimer Disease/therapy/pathology/metabolism ; Humans ; *Aging/pathology ; *Brain/pathology/metabolism ; Animals ; }, abstract = {Alzheimer's disease (AD) is a condition characterized by the gradual degeneration of the nervous system that poses significant challenges to cognitive function and overall mental health. Given the increasing global life expectancy, there is an urgent need for effective strategies to prevent and manage Alzheimer's disease, with a particular focus on anti-aging interventions. Recent scientific advancements have unveiled several promising strategies for combating Alzheimer's disease (AD), ranging from lifestyle interventions to cutting-edge pharmacological treatments and therapies targeting the underlying biological processes of aging and AD. Regular physical exercise, cognitive engagement, a balanced diet, and social interaction serve as key pillars in maintaining brain health. At the same time, therapies target key pathological mechanisms of AD, such as amyloid-beta accumulation, tau abnormalities, neuroinflammation, mitochondrial dysfunction, and synaptic loss, offering potential breakthroughs in treatment. Moreover, cutting-edge innovations such as gene therapy, stem cell transplantation, and novel drug delivery systems are emerging as potential game-changers in the fight against AD. This review critically evaluates the latest research on anti-aging interventions and their potential in preventing and treating Alzheimer's disease (AD) by exploring the connections between aging mechanisms and AD pathogenesis. It provides a comprehensive analysis of both well-established and emerging strategies, while also identifying key gaps in current knowledge to guide future research efforts.}, }
@article {pmid39607205, year = {2024}, author = {Pinho, RA and Muller, AP and Marqueze, LF and Radak, Z and Arida, RM}, title = {Physical exercise-mediated neuroprotective mechanisms in Parkinson's disease, Alzheimer's disease, and epilepsy.}, journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas}, volume = {57}, number = {}, pages = {e14094}, pmid = {39607205}, issn = {1414-431X}, mesh = {Humans ; *Parkinson Disease/therapy/physiopathology ; *Alzheimer Disease/therapy/physiopathology ; *Epilepsy/therapy/physiopathology ; *Exercise/physiology ; Neuroprotection/physiology ; Neuronal Plasticity/physiology ; Exercise Therapy/methods ; }, abstract = {Research suggests that physical exercise is associated with prevention and management of chronic diseases. The influence of physical exercise on brain function and metabolism and the mechanisms involved are well documented in the literature. This review provides a comprehensive overview of the potential implications of physical exercise and the molecular benefits of exercise in Parkinson's disease, Alzheimer's disease, and epilepsy. Here, we present an overview of the effects of exercise on various aspects of metabolism and brain function. To this end, we conducted an extensive literature search of the PubMed, Web of Science, and Google Scholar databases to identify articles published in the past two decades. This review delves into key aspects including the modulation of neuroinflammation, neurotrophic factors, and synaptic plasticity. Moreover, we explored the potential role of exercise in advancing therapeutic strategies for these chronic diseases. In conclusion, the review highlights the importance of regular physical exercise as a complementary non-pharmacological treatment for individuals with neurological disorders such as Alzheimer's, Parkinson's disease, and epilepsy.}, }
@article {pmid39606633, year = {2024}, author = {Xiang, Q and Xiang, Y and Liu, Y and Chen, Y and He, Q and Chen, T and Tang, L and He, B and Li, J}, title = {Revealing the potential therapeutic mechanism of Lonicerae Japonicae Flos in Alzheimer's disease: a computational biology approach.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1468561}, pmid = {39606633}, issn = {2296-858X}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative brain disease without a cure. Lonicerae Japonicae Flos (LJF), a traditional Chinese herbal medicine, possesses a neuroprotective effect, but its mechanisms for AD are not well understood. This study aimed to investigate potential targets and constituents of LJF against AD.
METHODS: Network pharmacology and bioinformatics analyses were performed to screen potential compounds and targets. Gene Expression Omnibus (GEO) datasets related to AD patients were used to screen core targets of differential expression. Gene expression profiling interactive analysis (GEPIA) was used to validate the correlation between core target genes and major causative genes of AD. The receiver operating characteristic (ROC) analysis was used to evaluate the predictive efficacy of core targets based on GEO datasets. Molecular docking and dynamics simulation were conducted to analyze the binding affinities of effective compounds with core targets.
RESULTS: Network pharmacology analysis showed that 112 intersection targets were identified. Bioinformatics analysis displayed that 32 putative core targets were identified from 112 intersection targets. Only eight core targets were differentially expressed based on GEO datasets. Finally, six core targets of MAPK8, CTNNB1, NFKB1, EGFR, BCL2, and NFE2L2 were related to AD progression and had good predictive ability based on correlation and ROC analyses. Molecular docking and dynamics simulation analyses elucidated that the component of lignan interacted with EGFR, the component of β-carotene interacted with CTNNB1 and BCL2, the component of β-sitosterol interacted with BCL2, the component of hederagenin interacted with NFKB1, the component of berberine interacted with EGFR and BCL2, and the component of baicalein interacted with NFKB1, EGFR and BCL2.
CONCLUSION: Through a comprehensive analysis, this study revealed that six core targets (MAPK8, CTNNB1, NFKB1, EGFR, BCL2, and NFE2L2) and six practical components (lignan, β-carotene, β-sitosterol, hederagenin, berberine, and baicalein) were involved in the mechanism of action of LJF against AD. Our work demonstrated that LJF effectively treats AD through its multi-component and multi-target properties. The findings of this study will establish a theoretical basis for the expanded application of LJF in AD treatment and, hopefully, can guide more advanced experimental research in the future.}, }
@article {pmid39606328, year = {2025}, author = {Cash, DM and Morgan, KE and O'Connor, A and Veale, TD and Malone, IB and Poole, T and Benzinger, TL and Gordon, BA and Ibanez, L and Li, Y and Llibre-Guerra, JJ and McDade, E and Wang, G and Chhatwal, JP and Day, GS and Huey, E and Jucker, M and Levin, J and Niimi, Y and Noble, JM and Roh, JH and Sánchez-Valle, R and Schofield, PR and Bateman, RJ and Frost, C and Fox, NC and , }, title = {Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.12.24316919}, pmid = {39606328}, abstract = {INTRODUCTION: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.
METHODS: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. Sample sizes were computed for detecting a reduction of either absolute levels of AD-related pathology (amyloid, tau) or change over time in neurodegeneration (atrophy, hypometabolism, cognitive change).
RESULTS: Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 47[95%CI 25,104], cortical PIB 49[28,99], CSF p-tau181 74[48,125]) for a four-year trial in presymptomatic individuals (CDR=0) to have 80% power (5% statistical significance) to detect a 25% reduction in absolute levels of pathology, allowing 40% dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50% reduction in rate of change. Sample sizes ranged from 250-900 (examples hippocampal volume: 338[131,2096], cognitive composite: 326[157,1074]). MRI, FDG and cognitive outcomes had lower sample sizes when including indivduals with mild impairment (CDR=0.5 and 1) as well as presymptomatic individuals (CDR=0).
DISCUSSION: Despite the rarity of ADAD, presymptomatic clinical trials with feasible sample sizes given the number of cases appear possible.}, }
@article {pmid39605963, year = {2024}, author = {Ma, K and An, C and Li, M and Zhang, Y and Ren, M and Wei, Y and Xu, W and Wang, R and Bai, Y and Zhang, H and Liu, X and Ji, S and Chen, X and Zhu, K}, title = {Dexmedetomidine Attenuated Neuron Death, Cognitive Decline, and Anxiety-Like Behavior by Inhibiting CXCL2 in CA1 Region of AD Mice.}, journal = {Drug design, development and therapy}, volume = {18}, number = {}, pages = {5351-5365}, pmid = {39605963}, issn = {1177-8881}, mesh = {Animals ; *Dexmedetomidine/pharmacology/administration & dosage ; Mice ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Cognitive Dysfunction/drug therapy ; *Anxiety/drug therapy ; *Chemokine CXCL2/metabolism ; *Neurons/drug effects/metabolism/pathology ; Male ; *Disease Models, Animal ; Neuroprotective Agents/pharmacology ; Cell Death/drug effects ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Mice, Inbred C57BL ; }, abstract = {PURPOSE: β-amyloid overload-induced neuroinflammation and neuronal loss are key pathological changes that occur during the progression of Alzheimer's disease (AD). Dexmedetomidine (Dex) exhibits neuroprotective and anti-inflammatory effects on the nervous system. However, the effect of Dex in AD mice remains unclear, and its neuroprotective regulatory mechanism requires further investigation. This study aimed to reveal how Dex protects against Aβ induced neuropathological changes and behavior dysfunction in AD mice.
METHODS: An AD mouse model was established by the injection of Aβ into the brains of mice, followed by intraperitoneal injection with Dex. CXCL2 overexpression and Yohimbine, a Dex inhibitor, were used to investigate the role of Dex and CXCL2 in the regulation of neuronal loss, cognitive decline, and anxiety-like behavior in AD mice. Behavioral tests were performed to evaluate the cognitive and anxiety status of the mice. Nissl staining and immunofluorescence experiments were conducted to evaluate the status of the hippocampal neurons and astrocytes. qRT-PCR was performed to detect the expression of CXCL2, IL-1β, INOS, SPHK1, Bcl2, IFN-γ, and Caspase 1. The malondialdehyde (MDA) level was detected using an ELISA kit. Terminal TUNEL and Fluoro-Jade C (FJC) staining were used to measure the cell apoptosis rate.
RESULTS: In AD mice, cognitive decline and anxiety-like behaviors were significantly improved by the Dex treatment. The number of neurons was increased in mice in the Dex + AD group compared to those in the AD group, and the number of astrocytes was not significantly different between the two groups. CXCL2, IL-1β, iNOS, and SPHK1 levels were significantly lower in Dex-treated AD mice than those in AD mice. Overloading of CXCL2 or Yohimbine reversed the protective effect of Dex on neuron number and cognitive and anxiety symptoms in AD mice.
CONCLUSION: Our results suggest that Dex exerts neuroprotective effects by downregulating CXCL2. Dex shows potential as a therapeutic drug for AD.}, }
@article {pmid39605544, year = {2024}, author = {Li, B and Wang, S and Kerman, B and Hugo, C and Shwab, EK and Shu, C and Chiba-Falek, O and Arvanitakis, Z and Yassine, H}, title = {Microglia States are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.18.624141}, pmid = {39605544}, issn = {2692-8205}, abstract = {Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD) but much less is known on the key cell types and pathways driving mechanisms of senescence in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed whole transcriptomic data and utilized single-cell RNA seq integration techniques to unveil the convoluted cell-type-specific and sub-cell-type-state-specific senescence pathologies in AD using both ROSMAP and Sea-AD datasets. We identified that microglia are central components to AD associated senescence phenotypes in ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex of 239 AD and 188 non-AD) among non-neuron cell types. We identified that homeostatic, inflammatory, phagocytic, lipid processing and neuronal surveillance microglia states were associated with AD associated senescence in ROSMAP (152,459 microglia nuclei from six regions of brain tissue of 138 early AD, 79 late AD and 226 control subject) and in Sea-AD (82,486 microglia nuclei of 42 dementia, 42 no dementia and 5 reference subjects) via integrative analysis, which preserves the meaningful biological information of microglia cell states across the datasets. We assessed top senescence associated bioprocesses including mitochondrial, apoptosis, oxidative stress, ER stress, endosomes, and lysosomes systems. Specifically, we found that senescent microglia have altered cholesterol related bioprocesses and dysregulated cholesterol. We discovered three gene co-expression modules, which represent the specific cholesterol related senescence transcriptomic signatures in postmortem brains. To validate these findings, the activation of specific cholesterol associated senescence transcriptomic signatures was assessed using integrative analysis of snRNA-seq data from iMGs (microglia induced from iPSCs) exposed to myelin, Abeta, and synaptosomes (56,454 microglia across two replicates of untreated and four treated groups). In vivo cholesterol associated senescence transcriptomic signatures were preserved and altered after treatment with AD pathological substrates in iMGs. This study provides the first evidence that dysregulation of cholesterol metabolism in microglia is a major driver of senescence pathologies in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to slow down AD progression.}, }
@article {pmid39605436, year = {2024}, author = {Rahman, MT and Saeed, F and Bozdag, S and , }, title = {Identifying Alzheimer's disease-associated genes using PhenoGeneRanker.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605436}, issn = {2692-8205}, support = {R35 GM133657/GM/NIGMS NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a neurogenerative disease that affects millions worldwide with no effective treatment. Several studies have been conducted to decipher to genomic underpinnings of AD. Due to its complex nature, many genes have been found to be associated with AD. Despite these findings, the pathophysiology of the disease is still elusive. To discover new putative AD-associated genes, in this study, we integrated multimodal gene and phenotype datasets of AD using network biology methods to prioritize potential AD-related genes. We constructed a multiplex heterogeneous network composed of patient and gene similarity networks utilizing phenotypic and omics datasets of AD patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We applied PhenoGeneRanker to traverse this network to discover potential AD-associated genes. To assess the impact of each network layer and seed gene, we also run PhenoGeneRanker on different variants of the network and seed genes. Our results showed that top-ranked genes captured several known AD-related genes and were enriched in Gene Ontology (GO) terms related to AD. We also observed that several top-ranked genes that are not in AD-associated gene list had literature supporting their potential relevance to AD.}, }
@article {pmid39605111, year = {2024}, author = {Taha, MME and Khalid, A and Elfatih, F and Mohan, S and Sukumaran, SD and Ul-Haq, Z and Aljahdali, IA and Oraibi, O and Oraibi, B and Alfaifi, HA and Alzahrani, AH and Farasani, A and Jerah, AA and Babiker, YOH and Abdelwahab, SI}, title = {Exploring the diverse acetylcholinesterase inhibitory potential of girinimbine: insights from in vitro assays, molecular docking, and simulation studies.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {70}, number = {10}, pages = {154-160}, doi = {10.14715/cmb/2024.70.10.20}, pmid = {39605111}, issn = {1165-158X}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry ; *Molecular Docking Simulation ; *Acetylcholinesterase/chemistry/metabolism ; *Molecular Dynamics Simulation ; Humans ; Tacrine/chemistry/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Protein Binding ; Murraya/chemistry ; }, abstract = {The search for new treatments for Alzheimer's disease (AD) has led to the exploration of plant-based drugs as potential options. Acetylcholinesterase (AChE) inhibitors are widely used as anti-AD medications. This study aimed to investigate the inhibitory mechanism of girinimbine, a constituent of Murraya koenigii, on AChE. AChE inhibition was assessed by in vitro experiments using the modified Ellman method, as well as in silico molecular docking and molecular dynamic simulation. The results were compared to those of the well-known anti-AChE agents tacrine and propidium iodide. Girinimbine, propidium, and tacrine at concentrations of 3.8X10-5M, 1.1x10-5M, and 6.1x10-7M showed percentages of inhibition percentages of 35.6%, 28.2%, and 76.6%, respectively. The docking and molecular dynamics simulation analyses indicated that girinimbine exhibited a higher binding affinity to AChE compared to propidium and tacrine. This finding was further confirmed by the docking, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of rotation analyses. In conclusion, M. koenigii girinimbine shows promise as an acetylcholinesterase inhibitor for Alzheimer's disease. Further research, including in vivo studies and clinical trials, is needed to explore its potential as a plant-based drug candidate for AD treatment.}, }
@article {pmid39604278, year = {2024}, author = {Rao, S and Forns, J and Danysh, HE and Calingaert, B and Dempsey, C and Aquilina, T and Pathak, S and Anthony, MS and Layton, JB}, title = {Natural history and clinical outcomes in patients with Alzheimer's disease-related psychosis by antipsychotic treatment status in the United States.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {102}, number = {4}, pages = {1260-1270}, doi = {10.1177/13872877241297361}, pmid = {39604278}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/epidemiology/drug therapy ; Female ; Male ; *Antipsychotic Agents/therapeutic use/adverse effects ; United States/epidemiology ; Aged ; *Psychotic Disorders/drug therapy/epidemiology ; Aged, 80 and over ; Incidence ; Cohort Studies ; Accidental Falls/statistics & numerical data ; Medicare ; Treatment Outcome ; Fractures, Bone/epidemiology ; }, abstract = {BACKGROUND: While some literature on clinical outcomes in persons with dementia-related psychosis exists, little is known regarding Alzheimer's disease-related psychosis (ADP).
OBJECTIVE: Describe demographic/clinical characteristics of adults with ADP and estimate incidence of clinical events by antipsychotic treatment status.
METHODS: This cohort study identified adults ≥65 years with Alzheimer's disease and incident psychosis (US Medicare database [2013-2018]) and no prior exposure to antipsychotics. Two nonmutually exclusive ADP subcohorts included: patients who initiated treatment with antipsychotic medications (antipsychotic users) and those who remained untreated (antipsychotic nonusers). Baseline characteristics were evaluated before psychosis diagnosis in untreated patients and before antipsychotic initiation in treated patients. Incidence rates were estimated for falls and fractures (composite and separately), seizure/epilepsy (new onset and any), and mortality.
RESULTS: 145,333 ADP antipsychotic nonusers and 49,452 antipsychotic users were identified. Both cohorts had similar baseline demographics; however, antipsychotic users versus nonusers had higher baseline skilled nursing facility use (40.3% and 27.8%), mood (72.7% and 62.1%) and anxiety (70.9% and 57.3%) disorders, falls/fractures (39.5% and 33.8%), urinary tract infections (55.1% and 47.0%), and frailty index scores (76.0% and 69.7%). Crude incidence rates (95% confidence interval)/100 person-years in antipsychotic users and nonusers were 70.0 (68.9-71.2) and 55.8 (55.4-56.1) (falls/fractures composite), 69.0 (67.9-70.1) and 54.9 (54.5-55.2) (falls), 38.6 (38.1-39.0) and 33.0 (32.7-33.2) (mortality), and 45.8 (44.9-46.7) and 54.2 (53.9-54.6) (any seizure/epilepsy).
CONCLUSIONS: Antipsychotic initiators with ADP had a higher burden of some baseline comorbidities; experienced higher incidence of falls, fractures, and mortality; and had lower incidence of seizure/epilepsy than antipsychotic nonusers.}, }
@article {pmid39604076, year = {2024}, author = {Zheng, W and Shi, X and Chen, Y and Hou, X and Yang, Z and Yao, W and Lv, T and Bai, F}, title = {Comparative efficacy of intermittent theta burst stimulation and high-frequency repetitive transcranial magnetic stimulation in amnestic mild cognitive impairment patients.}, journal = {Cerebral cortex (New York, N.Y. : 1991)}, volume = {34}, number = {11}, pages = {}, doi = {10.1093/cercor/bhae460}, pmid = {39604076}, issn = {1460-2199}, support = {LKZ2023014//Jiangsu Province Senior Health Project/ ; BE2023674//Key Research and Development Program of Jiangsu Province/ ; 82371437//National Natural Science Foundation of China/ ; 2022-LCYG-MS-05//Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University/ ; }, mesh = {Humans ; *Cognitive Dysfunction/physiopathology/therapy ; *Transcranial Magnetic Stimulation/methods ; Male ; Female ; Aged ; *Magnetic Resonance Imaging ; *Theta Rhythm/physiology ; Amnesia/physiopathology/therapy/diagnostic imaging ; Middle Aged ; Treatment Outcome ; Brain/physiopathology/diagnostic imaging ; Neuropsychological Tests ; }, abstract = {Intermittent theta burst stimulation, a derivative of repetitive transcranial magnetic stimulation, has been applied to improve cognitive deficits. However, its efficacy and mechanisms in enhancing cognitive function in patients with amnestic mild cognitive impairment compared with traditional repetitive transcranial magnetic stimulation paradigms remain unclear. This study recruited 48 amnestic mild cognitive impairment patients, assigning them to intermittent theta burst stimulation, repetitive transcranial magnetic stimulation, and sham groups (5 times/wk for 4 wk). Neuropsychological assessments and functional magnetic resonance imaging data were collected pre- and post-treatment. Regarding efficacy, both angular gyrus intermittent theta burst stimulation and repetitive transcranial magnetic stimulation significantly improved general cognitive function and memory compared to the sham group, with no significant difference between the 2 treatment groups. Mechanistically, significant changes in brain activity within the temporoparietal network were observed in both the intermittent theta burst stimulation and repetitive transcranial magnetic stimulation groups, and these changes correlated with improvements in general cognitive and memory functions. Additionally, intermittent theta burst stimulation showed stronger modulation of functional connectivity between the hippocampus, parahippocampal gyrus, and temporal regions compared to repetitive transcranial magnetic stimulation. The intermittent theta burst stimulation and repetitive transcranial magnetic stimulation can improve cognitive function in amnestic mild cognitive impairment patients, but intermittent theta burst stimulation may offer higher efficiency. Intermittent theta burst stimulation and repetitive transcranial magnetic stimulation likely enhance cognitive function, especially memory function, by modulating the temporoparietal network.}, }
@article {pmid39603510, year = {2025}, author = {Nath, DK and Lee, Y}, title = {Exploring the multifaceted functions of APPL in metabolism and memory using Drosophila melanogaster.}, journal = {Molecules and cells}, volume = {48}, number = {1}, pages = {100163}, pmid = {39603510}, issn = {0219-1032}, mesh = {Animals ; *Drosophila melanogaster/genetics ; *Drosophila Proteins/metabolism/genetics ; *Memory/drug effects ; Longevity ; Mutation ; Ascorbic Acid/pharmacology/metabolism ; Aging/physiology ; Membrane Proteins ; Nerve Tissue Proteins ; }, abstract = {Amyloid precursor protein (APP) is a single-pass transmembrane protein abundantly expressed in the central nervous system and implicated in familial Alzheimer's disease, a progressive neurodegenerative disorder that impairs memory. Here, we investigated the role of amyloid precursor protein-like (APPL) using the model organism Drosophila melanogaster. In this study, Appl null mutants exhibited a reduced lifespan under normal conditions and increased triglyceride levels, which were mitigated by metformin treatment. Additionally, taste-associative memory impairment in Appl[d] mutants suggested APPL's role in memory formation, which was restored by curcumin supplementation. The Appl[d] mutants also displayed reduced climbing ability, which was improved by supplementation with vitamins C (ascorbic acid) and B2 (riboflavin). These findings suggest that APPL is involved in metabolic regulation, cognition, climbing activity, and aging in Drosophila melanogaster.}, }
@article {pmid39603488, year = {2025}, author = {Wang, Y and Wu, W and Zeng, F and Meng, X and Peng, M and Wang, J and Chen, Z and Liu, W}, title = {The role of kynurenine pathway metabolism mediated by exercise in the microbial-gut-brain axis in Alzheimer's disease.}, journal = {Experimental neurology}, volume = {384}, number = {}, pages = {115070}, doi = {10.1016/j.expneurol.2024.115070}, pmid = {39603488}, issn = {1090-2430}, mesh = {Humans ; *Alzheimer Disease/metabolism ; *Kynurenine/metabolism ; *Gastrointestinal Microbiome/physiology ; *Brain-Gut Axis/physiology ; *Exercise/physiology ; Animals ; Brain/metabolism ; }, abstract = {In recent years, the role of the microbiome-gut-brain axis in the pathogenesis of Alzheimer's disease (AD) has garnered increasing attention. Specifically, tryptophan metabolism via the kynurenine pathway (KP) plays a crucial regulatory role in this axis. This study reviews how exercise regulates the microbiome-gut-brain axis by influencing kynurenine pathway metabolism, thereby exerting resistance against AD. This paper also discusses how exercise positively impacts AD via the microbiome-gut-brain axis by modulating the endocrine, autonomic nervous, and immune systems. Although the specific mechanisms are not fully understood, research indicates that exercise may optimize tryptophan metabolism by promoting the growth of beneficial microbiota and inhibiting harmful microbiota, producing substances that are beneficial to the nervous system and combating AD. The aim of this review is to provide new perspectives and potential intervention strategies for the prevention and treatment of AD by exploring the links between exercise, KP and the gut-brain axis.}, }
@article {pmid39602866, year = {2025}, author = {Zhou, W and Chang, Y and Xiao, Q and Deng, Z and Zhang, L and Yuan, Z and Du, Z}, title = {Structural optimization of naturally derived Ar-turmerone, as novel neuroinflammation suppressors effective in an Alzheimer mouse model.}, journal = {Bioorganic & medicinal chemistry}, volume = {117}, number = {}, pages = {118014}, doi = {10.1016/j.bmc.2024.118014}, pmid = {39602866}, issn = {1464-3391}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; Mice ; Structure-Activity Relationship ; *Disease Models, Animal ; *Lipopolysaccharides/pharmacology/antagonists & inhibitors ; Molecular Structure ; Sesquiterpenes/pharmacology/chemistry/chemical synthesis ; Microglia/drug effects/metabolism ; Male ; Neuroinflammatory Diseases/drug therapy ; Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Mice, Inbred C57BL ; Humans ; Dose-Response Relationship, Drug ; Nitric Oxide/antagonists & inhibitors/metabolism/biosynthesis ; Ketones ; }, abstract = {Microglia-mediated neuroinflammation plays a pivotal role in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. The modulation of chronic and sustained inflammatory processes in the brain with small molecules presents a promising therapeutic strategy for these devastating conditions. Aromatic turmerone (ar-turmerone, ART), an active constituent of turmeric essential oil derived from the edible plant Curcuma longa, has shown substantial potential in mitigating neuroinflammatory responses and associated cognitive deficits. Building on our previous work, we sought to discover more potent neuroinflammation suppressors by designing and synthesizing a series of ar-turmerone derivatives to investigate their structure-activity relationships. Microglia-based cellular evaluations revealed that naphthyl-substituted (7c) and N-substituted amides (7a) demonstrated the most pronounced inhibitory effects against NO, TNF-α, and IL-1β release in vitro. Furthermore, in a lipopolysaccharide (LPS)-induced neuroinflammation model of Alzheimer's disease in mice, these two compounds significantly reduced proinflammatory cytokine release, protected neurons from damage, and ameliorated memory impairments and cognitive deficits in Morris water maze tests. This structural optimization of ar-turmerone yielded highly potent anti-neuroinflammatory compounds, which may serve as promising agents for the treatment of neuroinflammation-related neurodegenerative disorders.}, }
@article {pmid39602498, year = {2024}, author = {Chen, S and Li, R and Liu, Y and Zhang, Z and Fang, M and Huang, S and Li, Y and Geng, L}, title = {Multifunctional Nitrogen-Doped Carbon Dots to Inhibit the Aggregation of Aβ Peptide and Depolymerize the Aβ Fibrils by Modulating Reactive Oxygen Species.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {40}, number = {49}, pages = {26018-26025}, doi = {10.1021/acs.langmuir.4c03454}, pmid = {39602498}, issn = {1520-5827}, mesh = {*Amyloid beta-Peptides/chemistry/antagonists & inhibitors/metabolism ; *Nitrogen/chemistry ; *Reactive Oxygen Species/metabolism ; *Carbon/chemistry ; *Quantum Dots/chemistry ; Protein Aggregates/drug effects ; Peptide Fragments/chemistry ; Humans ; }, abstract = {Multifunctional nitrogen-doped carbon dots (N-CDs) were synthesized, and the morphology, composition, and spectral properties of N-CDs were characterized by multiple characterization techniques. The inhibition of β-amyloid (Aβ) peptide aggregation and the destruction of the Aβ fibril structure by N-CDs were also studied. The conformational transition and morphology of Aβ42 in the presence of N-CDs were monitored by far-UV circular dichroism (CD) spectroscopy and transmission electron microscopy (TEM). The results demonstrated that the prepared N-CDs could effectively inhibit Aβ42 peptide aggregation and depolymerize Aβ fibrils. Furthermore, the inhibition and disaggregation mechanism of existing Aβ42 fibrils by N-CDs was studied by electron paramagnetic resonance spectroscopy (EPR). The results showed that the modulation of reactive oxygen species (ROS) by N-CDs and multiple interactions between N-CDs and Aβ42 fibrils played a crucial part in restraining and reducing the aggregation of Aβ42. Our work demonstrates the therapeutic potential of N-CDs in suppressing Aβ42 peptide aggregation and destroying existing Aβ42 fibrils, which provides a new perspective strategy in the treatment of Alzheimer's disease (AD).}, }
@article {pmid39601452, year = {2025}, author = {Hard, SAAA and Shivakumar, HN and Bafail, DA and Moqbel Redhwan, MA}, title = {Development of in vitro and in vivo evaluation of mucoadhesive in-situ gel for intranasal delivery of vinpocetine.}, journal = {Journal of drug targeting}, volume = {33}, number = {4}, pages = {528-545}, doi = {10.1080/1061186X.2024.2433557}, pmid = {39601452}, issn = {1029-2330}, mesh = {*Administration, Intranasal ; Animals ; *Vinca Alkaloids/administration & dosage/pharmacokinetics/pharmacology ; *Gels ; Rats ; Male ; *Nasal Mucosa/metabolism/drug effects ; Rats, Sprague-Dawley ; Drug Delivery Systems ; Brain/metabolism/drug effects ; Drug Liberation ; Poloxamer/chemistry ; Alzheimer Disease/drug therapy ; Citric Acid/chemistry/administration & dosage ; Rheology ; }, abstract = {Alzheimer's disease (AD), which is marked by gradual neuronal decline and subsequent loss of cognitive functions and memory, poses significant treatment challenges. The present study involved the development, in vitro, and in vivo evaluation of a novel intranasal mucoadhesive in-situ gel of vinpocetine (VIN) with the aim to target the brain. An innovative gel formulation composed of poloxamer 407, HPMC E15 LV, and citric acid as a solubilizer was developed by 2[3] Factorial Design. The developed optimal formulation exhibited favorable rheological properties as it displayed ideal gelation time (31.6 ± 1.52 sec), optimum gelling temperature (32 ± 1.0 °C), enhanced mucoadhesive strength (6622 ± 2.64 dynes/cm[2]), prolonged adhesion (7.22 ± 0.57 hrs) compared with the baseline formulation (F18), and improved drug release in 12 hrs (39.59 ± 1.6%). In vivo, pharmacokinetics revealed a significant increase in Cmax (∼2-fold) and AUC0-t (∼2-fold) in the brain with the in-situ intranasal gel compared to the oral route. In the rat model of AD, in-situ intranasal gel demonstrated significantly greater efficacy (p < 0.001) than oral administration in alleviating AD symptoms as evidenced by behavioral and histological studies. Thus, VIN in-situ gel can be safe and noninvasive for nose-to-brain drug delivery.}, }
@article {pmid39601176, year = {2025}, author = {Yan, L and Xu, K and Liu, C and Yu, F and Guo, J and Hou, L and Feng, Y and Yang, M and Gong, Q and Qin, D and Qin, M and Wang, Y and Su, H and Lu, Y}, title = {Polymer-Formulated Nerve Growth Factor Shows Effective Therapeutic Efficacy for Cerebral Microinfarcts.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {37}, number = {3}, pages = {e2412843}, doi = {10.1002/adma.202412843}, pmid = {39601176}, issn = {1521-4095}, support = {2019YFA0903800//National Key R&D Program of China/ ; 81825007//National Natural Science Foundation of China/ ; 52473137//National Natural Science Foundation of China/ ; 52473137//Innovative Research Group Project of the National Natural Science Foundation of China/ ; 005/2023/SKL [SKL-QRCM(UM)-2023-2025]//State Key Laboratory of Quality Research in Chinese Medicine, University of Macau/ ; 0061/2021/A2//Macau Science and Technology Development Fund/ ; ZYGD23011//1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University/ ; ZYJC21029//1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University/ ; }, mesh = {Animals ; Mice ; *Nerve Growth Factor/therapeutic use/metabolism ; *Polymers/chemistry ; *Blood-Brain Barrier/metabolism ; Microglia/metabolism/drug effects ; Cerebral Infarction/drug therapy/pathology ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; Disease Models, Animal ; Neurons/drug effects/metabolism/pathology ; }, abstract = {Cerebral microinfarcts represent the most prevalent form of ischemic brain injury in the elderly, particularly among those suffering from dementia, Alzheimer's disease, and vascular risk factors. Despite their commonality, effective treatments have remained elusive. Herein, a novel treatment utilizing a polymer-formulated nerve growth factor capable of crossing the blood-brain barrier is reported, which effectively reduced oxidative stress and neuronal apoptosis, reshaped microglia polarization at infarct sites, and decreased the overall microinfarct burden, leading to notable improvements in behavioral and cognitive functions in a mouse model. This work provides a promising new avenue for the treatment of cerebral microinfarcts and other neurodegenerative diseases.}, }
@article {pmid39600701, year = {2024}, author = {Moulton, C and Baroni, A and Quagliarini, E and Leone, L and Digiacomo, L and Morotti, M and Caracciolo, G and Podda, MV and Tasciotti, E}, title = {Navigating the nano-bio immune interface: advancements and challenges in CNS nanotherapeutics.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1447567}, pmid = {39600701}, issn = {1664-3224}, mesh = {Humans ; *Nanoparticles ; Animals ; *Central Nervous System/immunology ; Central Nervous System Diseases/immunology/therapy/drug therapy ; Nanomedicine/methods ; }, abstract = {In recent years, significant advancements have been made in utilizing nanoparticles (NPs) to modulate immune responses within the central nervous system (CNS), offering new opportunities for nanotherapeutic interventions in neurological disorders. NPs can serve as carriers for immunomodulatory agents or platforms for delivering nucleic acid-based therapeutics to regulate gene expression and modulate immune responses. Several studies have demonstrated the efficacy of NP-mediated immune modulation in preclinical models of neurological diseases, including multiple sclerosis, stroke, Alzheimer's disease, and Parkinson's disease. While challenges remain, advancements in NPs engineering and design have led to the development of NPs using diverse strategies to overcome these challenges. The nano-bio interface with the immune system is key in the conceptualization of NPs to efficiently act as nanotherapeutics in the CNS. The biomolecular corona plays a pivotal role in dictating NPs behavior and immune recognition within the CNS, giving researchers the opportunity to optimize NPs design and surface modifications to minimize immunogenicity and enhance biocompatibility. Here, we review how NPs interact with the CNS immune system, focusing on immunosurveillance of NPs, NP-induced immune reprogramming and the impact of the biomolecular corona on NPs behavior in CNS immune responses. The integration of NPs into CNS nanotherapeutics offers promising opportunities for addressing the complex challenges of acute and chronic neurological conditions and pathologies, also in the context of preventive and rehabilitative medicine. By harnessing the nano-bio immune interface and understanding the significance of the biomolecular corona, researchers can develop targeted, safe, and effective nanotherapeutic interventions for a wide range of CNS disorders to improve treatment and rehabilitation. These advancements have the potential to revolutionize the treatment landscape of neurological diseases, offering promising solutions for improved patient care and quality of life in the future.}, }
@article {pmid39600371, year = {2024}, author = {Wen, J and Zhao, M and Xiao, Y and Li, S and Hu, W}, title = {OATP1A2 mediates Aβ1-42 transport and may be a novel target for the treatment of Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1443789}, pmid = {39600371}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with an unknown cause. Many studies have suggested that the imbalance between the clearance and accumulation of β-amyloid protein (Aβ) in the brain of AD patients is the main cause of AD development of AD. Meanwhile, drug transporters play a key role in the transport of drugs and endogenous substances in vivo as well as in the development of many diseases. Could they be related to the imbalance between Aβ clearance and accumulation? OATP1A2 is the most abundant subfamily of organic anion transporting polypeptides (OATPs) that transport amphipathic substrates. Its high bilateral expression in brain endothelial cells suggests it plays a crucial role in delivering drugs and neuroactive peptides to brain tissue. Could it also be involved in mediating the production and accumulation of Aβ in the central system? This could lead to an imbalance between Aβ clearance and accumulation, ultimately resulting in AD development. This hypothesis would be bold and novel in the field of science. In this study, we successfully established the OATP1A2-HEK293T transgenic cell model, and found that the uptake of Aβ1-42 by OATP1A2-HEK293T cells was significantly higher than that of NC-HEK293T control cells and human astrocytes by adding different concentrations of Aβ1-42 to the cells of each group, suggesting that OATP1A2 expressed in the human brain is involved in Aβ amyloid protein transport.}, }
@article {pmid39600269, year = {2024}, author = {Nakashima, M and Suga, N and Fukumoto, A and Yoshikawa, S and Matsuda, S}, title = {Exosomes, Endosomes, and Caveolae as Encouraging Targets with Favorable Gut Microbiota for the Innovative Treatment of Alzheimer's Diseases.}, journal = {Discovery medicine}, volume = {36}, number = {190}, pages = {2132-2142}, doi = {10.24976/Discov.Med.202436190.196}, pmid = {39600269}, issn = {1944-7930}, mesh = {Humans ; *Alzheimer Disease/microbiology/therapy/metabolism/pathology ; *Gastrointestinal Microbiome ; *Endosomes/metabolism ; *Exosomes/metabolism ; *Caveolae/metabolism ; Animals ; Autophagy ; }, abstract = {Neurodegenerative diseases are characterized by progressive damage to specific neuronal cells, resulting in cognitive impairments. Alzheimer's disease is one of the most common types of cognitive impairments. Until recently, strategies that prevent its clinical progression have remained elusive. It has been suggested that oxidative stress, mitochondrial injury, and inflammation might lead to brain cell death in many neurological disorders. Therefore, the identification of effective neuroprotective agents is a research priority, and several autophagy-targeted bioactive compounds are promising candidate therapeutics for the prevention of brain cell damage. Some Alzheimer's disease risk genes expressed within the brain are linked to cholesterol metabolism, lipid transport, endocytosis, exocytosis, and/or caveolae formation, suggesting fruitful therapeutic targets for the treatment of cognitive impairments. Among them, a well-known genetic risk factor for late-onset Alzheimer's disease is allelic variation of the Apolipoprotein E (APOE) genes. APOE proteins may regulate aspects of cellular homeostasis, which is perturbed in the brain in Alzheimer's disease. Interestingly, the Apolipoprotein E ε4 allele (APOE4) protein is related to autophagy and to the biogenesis of caveolae, endosomes, and exosomes, processes which might consequently be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease. Recent research suggests that modification of the diet and/or gut-microbiota could be effective for treatment of various neurodegenerative diseases. Collectively, this research direction has the potential to improve clinical care through disease-modifying treatment strategies with benefits for patients with neurodegenerative diseases.}, }
@article {pmid39600165, year = {2024}, author = {Granberg, T and Börjesson Hanson, A and Fällmar, D and Basun, H and Wahlund, LO}, title = {[New Alzheimer's treatments - a need for national preparations and coordination].}, journal = {Lakartidningen}, volume = {121}, number = {}, pages = {}, pmid = {39600165}, issn = {1652-7518}, mesh = {Humans ; *Alzheimer Disease/diagnosis/drug therapy/therapy ; Sweden ; Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; }, abstract = {Approximately 100,000 persons live with Alzheimer's disease in Sweden. As the population ages, the need for diagnostics and disease-modifying treatment grows. Previously available treatments provide moderate symptom relief but do not affect disease progression. New antibody treatments show promising results and are typically well tolerated. However, adverse events include brain edema and hemorrhages, which can be detected early by MRI. These treatments require substantial resources, including increased use of MRI and radiological expertise. The introduction of new therapies will lead to higher regional healthcare costs and demands for specialized diagnostics. Implementing these therapies therefore necessitates national preparation and planning for coordinated and efficient management, addressing the significant societal and economic challenges posed by Alzheimer's disease.}, }
@article {pmid39599991, year = {2024}, author = {Hoang, PL and Van Vuong, Q}, title = {A Comprehensive Review of the Botany, Bioactive Compounds and Health Benefits of Leptospermum.}, journal = {Chemistry & biodiversity}, volume = {}, number = {}, pages = {e202401335}, doi = {10.1002/cbdv.202401335}, pmid = {39599991}, issn = {1612-1880}, support = {//Vietnamese Government through the Vietnam International Cooperation Department/ ; //Ministry of Education and Training and the University of Newcastle/ ; }, abstract = {There is increasing interest in research and application of natural bioactive compounds due to the growing demand for functional ingredients from the pharmaceutical, cosmetic and food industries. A major challenge is finding suitable natural plant resources for the development of functional ingredients. Leptospermum, a genus of the myrtle family (Myrtaceae), is primarily native to Australia. This genus has been traditionally used for the treatment of a range of ailments, such as colds, fever, constipation, diarrhoea, skin, inflammation, stomach disorder and both internal and external pain. Manuka honey, known for its medicinal properties, is produced from the nectar of Leptospermum flowers, and the leaves of some species are used for essential oil production. Various volatiles, such as pinene, citral and citronellal, have been identified in Leptospermum essential oils. In addition, various non-volatile compounds like leptosperin, cyanidin, quercetin, ellagic acid, delphinidin and myricetin have been isolated from Leptospermum extracts. Preliminary studies have linked Leptospermum essential oils and extracts with various health-promoting properties, such as antimicrobial activity, antidiabetes, anticancer and anti-Alzheimer's disease activities, revealing potential applications of Leptospermum as functional ingredients. To provide a comprehensive understanding of Leptospermum for future research and applications, this review presents an overview of its botanical features, outlines volatile and non-volatile active molecules identified in the genus, reviews potential health benefits and finally proposes trends for future studies on Leptospermum.}, }
@article {pmid39599715, year = {2024}, author = {An, Y and Cao, Z and Du, Y and Xu, G and Wang, J and Zheng, J and Lu, Y}, title = {Bidirectional Two-Sample, Two-Step Mendelian Randomisation Study Reveals Mediating Role of Gut Microbiota Between Vitamin B Supplementation and Alzheimer's Disease.}, journal = {Nutrients}, volume = {16}, number = {22}, pages = {}, pmid = {39599715}, issn = {2072-6643}, support = {2022YFA1103602//This research was funded by the National Key Research and Development Program of China/ ; 82473618//the National Natural Science Foundation of China/ ; 92357305//the National Natural Science Foundation of China/ ; 2020QNRC001//the Young Elite Scientists Sponsorship Program by China Association for Science and Technology/ ; 82103811//the National Natural Science Foundation of China/ ; QML20230301//the Beijing Hospitals Authority Youth Programme/ ; }, mesh = {*Alzheimer Disease/microbiology ; *Gastrointestinal Microbiome/drug effects ; Humans ; *Dietary Supplements ; *Mendelian Randomization Analysis ; *Vitamin B Complex/administration & dosage ; Folic Acid/administration & dosage ; Vitamin B 12/administration & dosage ; Bacteria/genetics/classification/drug effects ; }, abstract = {OBJECTIVES: Alzheimer's disease (AD) is a devastating neurodegenerative disorder with a complex aetiology. The aims of this study were to investigate the relationship between vitamin B supplementation and AD risk and to explore the potential mediating effect of the gut microbiota in this relationship.
METHODS: We employed a Mendelian randomisation analysis to examine the association between different vitamin B supplementation modalities (vitamin B6, folic acid, B12, and vitamin B complex tablets) and AD risk. Univariate Mendelian randomisation with inverse-variance weighting was used. Additionally, mediation analyses were conducted to identify the potential mediating effects of 119 known bacterial genera.
RESULTS: The univariate Mendelian randomisation analyses showed no significant direct associations between individual vitamin B supplements or vitamin B complex tablets and AD risk. However, several gut bacterial genera were significantly associated with AD risk. Lachnospiraceae (NK4A136 group), Paraprevotella, Slackia, and Bifidobacterium were associated with reduced AD risk, while Defluviitaleaceae (UCG011), Desulfovibrio, Eubacterium ventriosum group, and Ruminococcaceae UCG-003 were associated with increased AD risk. The mediation analysis revealed that Lachnospiraceae (NK4A136 group), Defluviitaleaceae (UCG011), and Bifidobacterium fully mediated the causal relationships between vitamin B12, B6, and B complex supplementation, respectively, and AD risk.
CONCLUSIONS: This study provides evidence suggesting that certain gut microbiota genera are significantly associated with AD risk and may mediate the relationship between vitamin B supplementation and AD risk. These findings offer new insights into the variable effectiveness of B vitamins in treating neurodegenerative diseases and suggest potential new strategies for AD treatment and prevention.}, }
@article {pmid39599527, year = {2024}, author = {Farrer, TJ and Moore, JD and Chase, M and Gale, SD and Hedges, DW}, title = {Infectious Disease as a Modifiable Risk Factor for Dementia: A Narrative Review.}, journal = {Pathogens (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {39599527}, issn = {2076-0817}, mesh = {Humans ; *Dementia/epidemiology/prevention & control/etiology ; Risk Factors ; Communicable Diseases/epidemiology ; Alzheimer Disease/prevention & control/epidemiology/etiology ; Vaccination ; Antiviral Agents/therapeutic use ; }, abstract = {This narrative review examines infectious diseases as modifiable risk factors for dementia, particularly in the context of an aging global population. As the prevalence of Alzheimer's disease and related dementias is expected to rise, prevention has become increasingly important due to the limited efficacy of current treatments. Emerging evidence links specific infectious diseases to increased dementia risk, possibly through mechanisms like neuroinflammation and disruption to normal cell function. Here, we review findings on how viral and bacterial infections contribute to dementia and explore potentially preventive measures, including vaccinations and antiviral treatments. Studies indicate that vaccinations against influenza, herpes zoster, and hepatitis, as well as antiviral treatments targeting human herpesvirus, could reduce the incidence of dementia. Additionally, non-pharmaceutical interventions during pandemics and in long-term care settings are highlighted as effective strategies for reducing the spread of infectious diseases, potentially lowering dementia risk. Putative mechanisms underlying the protective effects of these interventions suggest that reducing systemic inflammation may be important to their efficacy. While the currently available evidence suggests at best an association between some infectious diseases and dementia, this narrative review emphasizes the need to incorporate infectious disease prevention into broader public health strategies to potentially mitigate the growing burden of dementia. Further research is required to explore these preventive measures across diverse populations and to deepen our understanding of the biological mechanisms involved.}, }
@article {pmid39598763, year = {2024}, author = {Atanasov, V and Velkova, L and Tancheva, L and Dolashki, A and Kalfin, R and Dolashka, P}, title = {Key Proteins in Rat Cerebral Cortex: Application of Cornu aspersum Extract as a Neuroprotective Agent in Alzheimer's Type Dementia.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {22}, pages = {}, pmid = {39598763}, issn = {1420-3049}, support = {Grant KП-06-H73/5-05.12.2023//Bulgarian National Science Fund/ ; }, mesh = {Animals ; *Cerebral Cortex/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; *Neuroprotective Agents/pharmacology/chemistry ; Disease Models, Animal ; Male ; Proteomics/methods ; }, abstract = {Alzheimer's disease (AD) is the most widespread neurodegenerative disorder. Recently, it was found that mucus extract from Cornu aspersum has beneficial effects on memory and cognitive processes in a rat scopolamine model of AD. The present study elucidated the mechanisms of action of standardized mucus snail extract (SE) enriched with a fraction above 20 kDa on Alzheimer-type dementia in rats. Using proteomic analysis on two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) on rat cortex extracts, we compared protein expression in both groups: the first group was treated intraperitoneally with scopolamine (Sco, 2 mg/kg, 11 days) and the second (Sco + SE) group was treated intraperitoneally with Sco (Sco, 2 mg/kg) and protected by SE (0.5 mL/100 g bw) applied daily orally for 11 days. Brain cortex was separated and the expressions of various proteins related to memory and cognitive functions were identified. We found that the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1, Calbindin, Vacuolar ATP synthase catalytic subunit A, Tropomyosin beta chain, 14-3-3 zeta/delta, Kinesin-1 heavy chain, and Stathmin-4 significantly differs in SE-protected rats as compared to dement animals treated only by Sco, and these brain proteins might be potential therapeutic targets for Alzheimer's-type dementia treatment.}, }
@article {pmid39598746, year = {2024}, author = {Matošević, A and Opsenica, DM and Bartolić, M and Maraković, N and Stoilković, A and Komatović, K and Zandona, A and Žunec, S and Bosak, A}, title = {Derivatives of Amodiaquine as Potent Human Cholinesterases Inhibitors: Implication for Treatment of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {22}, pages = {}, pmid = {39598746}, issn = {1420-3049}, support = {IP-2020-02-9343//Croatian Science Foundation/ ; 451-03-66/2024-03/200026 and 451-03-66/2024-03/200168//MESTD of the Republic of Serbia/ ; 7547552//Special Research Program COVID-19/ ; }, mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Humans ; *Alzheimer Disease/drug therapy ; *Amodiaquine/pharmacology/chemistry ; *Acetylcholinesterase/metabolism/chemistry ; *Butyrylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; Antioxidants/pharmacology/chemistry/chemical synthesis ; Blood-Brain Barrier/metabolism/drug effects ; Molecular Structure ; }, abstract = {As some previously reported studies have proven that amodiaquine, in addition to its primary antimalarial activity, also has potential for new applications such as the inhibition of cholinesterases, in our study we focused on the evaluation of the influence of different substituents in the aminoquinoline part of the amodiaquine structure on the inhibition of human acetylcholinesterase and butyrylcholinesterase to investigate the possibility for their use as drugs for the treatment of AD. We synthesized a series of amodiaquine derivatives bearing H-, F-, CF3-, NO2-, CN-, CO2H- or CH3O- groups on the aminoquinoline ring, and determined that all of the tested derivatives were very potent inhibitors of both cholinesterases, with inhibition constants (Ki) in the nM and low μM range and with prominent selectivity (up to 300 times) for the inhibition of acetylcholinesterase. All compounds displayed an ability to chelate biometal ions Fe[2+], Zn[2+] and Cu[2+] and an antioxidant power comparable to that of standard antioxidants. Most of the compounds were estimated to be able to cross the blood-brain barrier by passive transport and were nontoxic toward cells that represent the models of individual organs. Considering all these beneficial features, our study has singled out compound 5, the most potent AChE inhibitor with a CH3O- on C(7) position, followed by 6 and 14, compounds without substituent or hydroxyl groups in the C(17) position, respectively, as the most promising compounds from the series which could be considered as potential multi-target drugs for the treatment of AD.}, }
@article {pmid39598703, year = {2024}, author = {Angelova, VT and Stoyanov, BP and Simeonova, R}, title = {New Insights into the Development of Donepezil-Based Hybrid and Natural Molecules as Multi-Target Drug Agents for Alzheimer's Disease Treatment.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {22}, pages = {}, pmid = {39598703}, issn = {1420-3049}, support = {KP-06-N63/11; 14.12.2022.//Bulgarian National Science Fund/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Donepezil/therapeutic use/pharmacology/chemistry ; *Biological Products/chemistry/therapeutic use/pharmacology ; Animals ; Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Drug Development ; Drug Design ; }, abstract = {Alzheimer's disease (AD) involves a complex pathophysiology with multiple interconnected subpathologies, including protein aggregation, impaired neurotransmission, oxidative stress, and microglia-mediated neuroinflammation. Current treatments, which generally target a single subpathology, have failed to modify the disease's progression, providing only temporary symptom relief. Multi-target drugs (MTDs) address several subpathologies, including impaired aggregation of pathological proteins. In this review, we cover hybrid molecules published between 2014 and 2024. We offer an overview of the strategies employed in drug design and approaches that have led to notable improvements and reduced hepatotoxicity. Our aim is to offer insights into the potential development of new Alzheimer's disease drugs. This overview highlights the potential of multi-target drugs featuring heterocycles with N-benzylpiperidine fragments and natural compounds in improving Alzheimer's disease treatment.}, }
@article {pmid39598614, year = {2024}, author = {Kim, TK and Hong, JM and Kim, J and Kim, KH and Han, SJ and Kim, IC and Oh, H and Jo, DG and Yim, JH}, title = {Therapeutic Potential of Ramalin Derivatives with Enhanced Stability in the Treatment of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {22}, pages = {}, pmid = {39598614}, issn = {1420-3049}, support = {RS-2021-KS211513//Ministry of Oceans and Fisheries/ ; }, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; *Antioxidants/pharmacology/chemistry/chemical synthesis ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; *tau Proteins/metabolism ; Phosphorylation/drug effects ; Anti-Inflammatory Agents/pharmacology/chemistry/chemical synthesis/therapeutic use ; }, abstract = {Alzheimer's disease (AD) remains a significant public health challenge with limited effective treatment options. Ramalin, a compound derived from Antarctic lichens, has shown potential in the treatment of AD because of its strong antioxidant and anti-inflammatory properties. However, its instability and toxicity have hindered the development of Ramalin as a viable therapeutic agent. The primary objective of this study was to synthesize and evaluate novel Ramalin derivatives with enhanced stabilities and reduced toxic profiles, with the aim of retaining or improving their therapeutic potential against AD. The antioxidant, anti-inflammatory, anti-BACE-1, and anti-tau activities of four synthesized Ramalin derivatives (i.e., RA-Hyd-Me, RA-Hyd-Me-Tol, RA-Sali, and RA-Benzo) were evaluated. These derivatives demonstrated significantly improved stabilities compared to the parent compound, with RA-Sali giving the most promising results. More specifically, RA-Sali exhibited a potent BACE-1 inhibitory activity and effectively reduced tau phosphorylation, a critical factor in AD pathology. Despite exhibiting reduced antioxidant activities compared to the parent compound, these derivatives represent a potential multi-targeted approach for AD treatment, marking a significant step forward in the development of stable and effective AD therapeutics.}, }
@article {pmid39598374, year = {2024}, author = {Li, Y and Fu, J and Wang, H}, title = {Advancements in Targeting Ion Channels for the Treatment of Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {11}, pages = {}, pmid = {39598374}, issn = {1424-8247}, support = {2023YFF1205500//National Key Research and Development Program of China/ ; 82471465//NSFC/ ; C2024202005//Distinguished Young Scholars Science Fund of the Natural Science Foundation of Hebei Province/ ; JZX2023002//Technology Project of Hebei Education Department/ ; 22JCQNJC01110//Tianjin Applied Basic Research Project/ ; 236Z2602G, 246Z2605G, 236Z2401G//the central government guides local funds for science and technology development for Hebei Province/ ; NV20230015//The Key Laboratory of Neural and Vascular Biology, Ministry of Education/ ; }, abstract = {Ion channels are integral membrane proteins embedded in biological membranes, and they comprise specific proteins that control the flow of ion transporters in and out of cells, playing crucial roles in the biological functions of different cells. They maintain the homeostasis of water and ion metabolism by facilitating ion transport and participate in the physiological processes of neurons and glial cells by regulating signaling pathways. Neurodegenerative diseases are a group of disorders characterized by the progressive loss of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Despite significant progress in understanding the pathophysiological processes of various neurological diseases in recent years, effective treatments for mitigating the damage caused by these diseases remain inadequate. Increasing evidence suggests that ion channels are closely associated with neuroinflammation; oxidative stress; and the characteristic proteins in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Therefore, studying the pathogenic mechanisms closely related to ion channels in neurodegenerative diseases can help identify more effective therapeutic targets for treating neurodegenerative diseases. Here, we discuss the progress of research on ion channels in different neurodegenerative diseases and emphasize the feasibility and potential of treating such diseases from the perspective of ion channels.}, }
@article {pmid39598254, year = {2024}, author = {Ebert, ET and Schwinghamer, KM and Siahaan, TJ}, title = {Delivery of Neuroregenerative Proteins to the Brain for Treatments of Neurodegenerative Brain Diseases.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {11}, pages = {}, pmid = {39598254}, issn = {2075-1729}, abstract = {Neurodegenerative brain diseases such as Alzheimer's disease (AD), multiple sclerosis (MS), and Parkinson's disease (PD) are difficult to treat. Unfortunately, many therapeutic agents for neurodegenerative disease only halt the progression of these diseases and do not reverse neuronal damage. There is a demand for finding solutions to reverse neuronal damage in the central nervous system (CNS) of patients with neurodegenerative brain diseases. Therefore, the purpose of this review is to discuss the potential for therapeutic agents like specific neurotrophic and growth factors in promoting CNS neuroregeneration in brain diseases. We discuss how BDNF, NGF, IGF-1, and LIF could potentially be used for the treatment of brain diseases. The molecule's different mechanisms of action in stimulating neuroregeneration and methods to analyze their efficacy are described. Methods that can be utilized to deliver these proteins to the brain are also discussed.}, }
@article {pmid39598187, year = {2024}, author = {İzol, E and Turhan, M}, title = {In-Depth Phytochemical Profile by LC-MS/MS, Mineral Content by ICP-MS, and In-Vitro Antioxidant, Antidiabetic, Antiepilepsy, Anticholinergic, and Antiglaucoma Properties of Bitlis Propolis.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {11}, pages = {}, pmid = {39598187}, issn = {2075-1729}, abstract = {Propolis is very significant in terms of its phytochemical content and biological activity among bee products. In this study, the antioxidant activities (total phenolic and flavonoid, Fe[3+], Cu[2+] (CUPRAC), Fe[3+]-TPTZ (FRAP) reducing, and DPPH[•], ABTS[•+] scavenging assays) of propolis collected from the Bitlis province of Türkiye were determined. In addition, the carbonic anhydrase I and II isoenzymes (hCA I and hCA II), α-glycosidase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibition activity and phytochemical profile of propolis and mineral content were determined by LC-MS/MS and ICP-MS, respectively. In propolis, 31 phytochemicals were found, and the highest concentration of acacetin (23.604 mg/g) was detected. It is seen that the phytochemicals in propolis provide antioxidant properties. The mineral content was screened for 18 elements and determined to be rich in the elements that make up the salt content. Total phenolic content was 215.14 mg GAE/g, and total flavonoid content was 79.11 mg QE/g. The Fe[3+] reduction result was 0.940 (µg/mL), CUPRAC 1.183 (µg/mL), FRAP 0.963 (µg/mL), DPPH[•] scavenging IC50: 16.7 (µg/mL), and ABTS IC50: 8.01 (µg/mL). hCA I enzyme inhibition results in IC50: 7.19 (µg/mL), hCA II 8.15, AChE 5.17, BChE 7.50, and α-Glycosidase 5.72. As a result of this study, it was determined that Bitlis propolis has high antioxidant properties and a rich phytochemical content. It was also observed that it is an effective enzyme inhibitor against epilepsy, glaucoma, Alzheimer's, and diabetes, which are important diseases, and it can be evaluated in the treatment of these diseases and drug production.}, }
@article {pmid39598105, year = {2024}, author = {Alhenaky, A and Alhazmi, S and Alamri, SH and Alkhatabi, HA and Alharthi, A and Alsaleem, MA and Abdelnour, SA and Hassan, SM}, title = {Exosomal MicroRNAs in Alzheimer's Disease: Unveiling Their Role and Pioneering Tools for Diagnosis and Treatment.}, journal = {Journal of clinical medicine}, volume = {13}, number = {22}, pages = {}, pmid = {39598105}, issn = {2077-0383}, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder that presents a significant health concern, often leading to substantial cognitive decline among older adults. A prominent feature of AD is progressive dementia, which eventually disrupts daily functioning and the ability to live independently. A major challenge in addressing AD is its prolonged pre-symptomatic phase, which makes early detection difficult. Moreover, the disease's complexity and the inefficiency of current diagnostic methods impede the development of targeted therapies. Therefore, there is an urgent need to enhance diagnostic methodologies for detection and treating AD even before clinical symptoms appear. Exosomes are nanoscale biovesicles secreted by cells, including nerve cells, into biofluids. These exosomes play essential roles in the central nervous system (CNS) by facilitating neuronal communication and thus influencing major physiological and pathological processes. Exosomal cargo, particularly microRNAs (miRNAs), are critical mediators in this cellular communication, and their dysregulation affects various pathological pathways related to neurodegenerative diseases, including AD. This review discusses the significant roles of exosomal miRNAs in the pathological mechanisms related to AD, focusing on the promising use of exosomal miRNAs as diagnostic biomarkers and targeted therapeutic interventions for this devastating disease.}, }
@article {pmid39597194, year = {2024}, author = {Nanda, SS and Yi, DK}, title = {Exploring the Connection Between Nanomaterials and Neurodegenerative Disorders.}, journal = {Micromachines}, volume = {15}, number = {11}, pages = {}, pmid = {39597194}, issn = {2072-666X}, abstract = {Drug delivery, tissue engineering, and cell promotion in biomedical fields heavily rely on the use of nanomaterials (NMs). When they penetrate cells, NPs undergo degradation and initiate the generation of reactive oxygen species (ROS) by causing changes in the structures of organelles linked to mitochondria. Inside the cell, the excess production of ROS can initiate a chain reaction, along with the autophagy process that helps maintain ROS balance by discarding unnecessary materials. At present, there is no effective treatment for Alzheimer's disease (AD), a progressive neurodegenerative disease. The use of NMs for siRNA delivery could become a promising treatment for AD and other CNS disorders. Recent research demonstrates that the use of combined NPs can induce autophagy in cells. This article emphasizes the importance of the shape of siRNA-encapsulated NMs in determining their efficiency in delivering and suppressing gene activity in the central nervous system. Because of its strict selectivity against foreign substances, the blood-brain barrier (BBB) significantly hinders the delivery of therapeutic agents to the brain. Conventional chemotherapeutic drugs are significantly less effective against brain cancers due to this limitation. As a result, NMs have become a promising approach for targeted drug delivery, as they can be modified to carry specific ligands that direct them to their intended targets. This review thoroughly examines the latest breakthroughs in using NMs to deliver bioactive compounds across the BBB, focusing on their use in cancer treatments. The review starts by examining the structure and functions of the BBB and BBTB, and then emphasizes the benefits that NMs offer.}, }
@article {pmid39596990, year = {2024}, author = {Elariny, HA and Kabel, AM and Selim, HMRM and Helal, AI and Abdelrahman, D and Borg, HM and Elkady, MA and Dawood, LM and El-Badawy, MF and Almalawi, HFA and Arafa, EA and Alsufyani, SE and Arab, HH}, title = {Repositioning Canagliflozin for Mitigation of Aluminium Chloride-Induced Alzheimer's Disease: Involvement of TXNIP/NLRP3 Inflammasome Axis, Mitochondrial Dysfunction, and SIRT1/HMGB1 Signalling.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {11}, pages = {}, pmid = {39596990}, issn = {1648-9144}, support = {TU-DSPP-2024-116//Taif University/ ; }, mesh = {Animals ; *Aluminum Chloride ; *Alzheimer Disease/drug therapy ; *Sirtuin 1/metabolism ; Rats ; *Canagliflozin/pharmacology/therapeutic use ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; HMGB1 Protein/metabolism ; Signal Transduction/drug effects ; Disease Models, Animal ; Mitochondria/drug effects/metabolism ; Male ; Inflammasomes/drug effects/metabolism ; Oxidative Stress/drug effects ; Cell Cycle Proteins/metabolism ; }, abstract = {Background and Objectives: Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world. Due to failure of the traditional drugs to produce a complete cure for AD, the search for new safe and effective lines of therapy has attracted the attention of ongoing research. Canagliflozin is an anti-diabetic agent with proven efficacy in the treatment of neurological disorders in which mitochondrial dysfunction, oxidative stress, apoptosis, and autophagy play a pathophysiological role. Elucidation of the potential effects of different doses of canagliflozin on AD induced by aluminium chloride in rats and exploration of the molecular mechanisms that may contribute to these effects were the primary objectives of the current study. Materials and Methods: In a rat model of AD, the effect of three different doses of canagliflozin on the behavioural, biochemical, and histopathological alterations induced by aluminium chloride was assessed. Results: Canagliflozin administered to aluminium chloride-treated animals induced dose-dependent normalisation in the behavioural tests, augmentation of the antioxidant defence mechanisms, inhibition of TXNIP/NLRP3 inflammasome signalling, modulation of the SIRT1/HMGB1 axis, interference with the pro-inflammatory and the pro-apoptotic mechanisms, and restoration of the mitochondrial functions and autophagy in the hippocampal tissues to approximately baseline values. In addition, canagliflozin exhibited an interesting dose-dependent ability to repress aluminium chloride-induced histopathological changes in the brain. Conclusions: The effects of canagliflozin on oxidative stress, mitochondrial functions, inflammatory pathways, and autophagy signals may open new gates towards the mitigation of the pathologic features of AD.}, }
@article {pmid39596443, year = {2024}, author = {Belousova, E and Salikhova, D and Maksimov, Y and Nebogatikov, V and Sudina, A and Goldshtein, D and Ustyugov, A}, title = {Proposed Mechanisms of Cell Therapy for Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, pmid = {39596443}, issn = {1422-0067}, support = {23-15-00362//Russian Science Foundation/ ; }, mesh = {*Alzheimer Disease/therapy/metabolism ; Humans ; Animals ; *Mitochondria/metabolism ; Cell- and Tissue-Based Therapy/methods ; Stem Cell Transplantation/methods ; Exosomes/metabolism/transplantation ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disorder characterized by mitochondria dysfunction, accumulation of beta-amyloid plaques, and hyperphosphorylated tau tangles in the brain leading to memory loss and cognitive deficits. There is currently no cure for this condition, but the potential of stem cells for the therapy of neurodegenerative pathologies is actively being researched. This review discusses preclinical and clinical studies that have used mouse models and human patients to investigate the use of novel types of stem cell treatment approaches. The findings provide valuable insights into the applications of stem cell-based therapies and include the use of neural, glial, mesenchymal, embryonic, and induced pluripotent stem cells. We cover current studies on stem cell replacement therapy where cells can functionally integrate into neural networks, replace damaged neurons, and strengthen impaired synaptic circuits in the brain. We address the paracrine action of stem cells acting via secreted factors to induce neuroregeneration and modify inflammatory responses. We focus on the neuroprotective functions of exosomes as well as their neurogenic and synaptogenic effects. We look into the shuttling of mitochondria through tunneling nanotubes that enables the transfer of healthy mitochondria by restoring the normal functioning of damaged cells, improving their metabolism, and reducing the level of apoptosis.}, }
@article {pmid39596305, year = {2024}, author = {Mitroshina, EV and Kalinina, EP and Kalyakulina, AI and Teplyakova, AV and Vedunova, MV}, title = {The Effect of the Optogenetic Stimulation of Astrocytes on Neural Network Activity in an In Vitro Model of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, pmid = {39596305}, issn = {1422-0067}, support = {075-15-2022-293//Ministry of Science and Higher Education of the Russian Federation/ ; }, mesh = {*Astrocytes/metabolism ; *Optogenetics/methods ; *Alzheimer Disease/therapy/genetics/metabolism ; Animals ; Mice ; *Hippocampus/metabolism/cytology ; Nerve Net ; Cells, Cultured ; Glial Fibrillary Acidic Protein/metabolism/genetics ; Disease Models, Animal ; Channelrhodopsins/genetics/metabolism ; }, abstract = {Optogenetics is a combination of optical and genetic technologies used to activate or, conversely, inhibit specific cells in living tissues. The possibilities of using optogenetics approaches for the treatment of epilepsy, Parkinson's and Alzheimer's disease (AD) are being actively researched. In recent years, it has become clear that one of the most important players in the development of AD is astrocytes. Astrocytes affect amyloid clearance, participate in the development of neuroinflammation, and regulate the functioning of neural networks. We used an adeno-associated virus carrying the glial fibrillary acidic protein (GFAP) promoter driving the optogenetic channelrhodopsin-2 (ChR2) gene to transduce astrocytes in primary mouse hippocampal cultures. We recorded the bioelectrical activity of neural networks from day 14 to day 21 of cultivation using multielectrode arrays. A single optogenetic stimulation of astrocytes at 14 day of cultivation (DIV14) did not cause significant changes in neural network bioelectrical activity. Chronic optogenetic stimulation from DIV14 to DIV21 exerts a stimulatory effect on the bioelectrical activity of primary hippocampal cultures (the proportion of spikes included in network bursts significantly increased since DIV19). Moreover, chronic optogenetic stimulation over seven days partially preserved the activity and functional architecture of neuronal network in amyloidosis modeling. These results suggest that the selective optogenetic activation of astrocytes may represent a promising novel therapeutic strategy for combating AD.}, }
@article {pmid39596219, year = {2024}, author = {Nguyen, QNS and Yoo, KY and Pham, TTT and Selvaraj, B and Vu, HT and Le, TT and Lee, H and Tran, QL and Thuong, PT and Pae, AN and Jung, SH and Lee, JW}, title = {Neuroprotective Effects of Ethanol Extract Polyscias guilfoylei (EEPG) Against Glutamate Induced Neurotoxicity in HT22 Cells.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, pmid = {39596219}, issn = {1422-0067}, support = {No. NRF-2019K1A3A1A82113697//National Research Foundation of Korea/ ; No. NDT.90.KR/20//Ministry of Science and Technology of Vietnam/ ; }, mesh = {Animals ; *Neuroprotective Agents/pharmacology ; *Glutamic Acid/toxicity/metabolism ; *Reactive Oxygen Species/metabolism ; *Plant Extracts/pharmacology ; Mice ; Rats ; *Oxidative Stress/drug effects ; Cell Line ; Ethanol/toxicity ; Calcium/metabolism ; Neurons/drug effects/metabolism ; Apoptosis/drug effects ; Cell Survival/drug effects ; Male ; Araliaceae/chemistry ; Brain Ischemia/drug therapy/metabolism ; }, abstract = {Oxidative stress induced by glutamate is a significant contributor to neuronal cell damage and can lead to neurodegenerative diseases such as Alzheimer's, Huntington's, and ischemic brain injury. At the cellular level, oxidative stress increases Ca[2+] ion influx and reactive oxygen species (ROS), which activate the MAPK signaling pathway. Additionally, the generation of ROS causes mitochondrial dysfunction, triggering apoptosis by promoting the translocation of AIF to the nucleus from the mitochondria. The neuroprotective potential of Polyscias guilfoylei has not yet been reported. Therefore, in this study, the ethanol extract of Polyscias guilfoylei (EEPG) was examined for its protective effect against oxidative cell damage caused by glutamate in neuronal cells. EEPG treatment increased the viability of HT22 cells exposed to high concentrations of glutamate. Cellular Ca[2+] ion influx and ROS generation decreased with EEPG treatment in glutamate-treated HT22 cells. EEPG treatment inhibited MAPK activation and AIF nuclear translocation. In an in vivo study, EEPG attenuated brain cell death in an ischemic brain injury rat model. This study demonstrates the potential therapeutic effects of Polyscias guilfoylei in the treatment of ischemic brain injury.}, }
@article {pmid39596118, year = {2024}, author = {Armeli, F and Coccurello, R and Giacovazzo, G and Mengoni, B and Paoletti, I and Oddi, S and Maccarrone, M and Businaro, R}, title = {FAAH Inhibition Counteracts Neuroinflammation via Autophagy Recovery in AD Models.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, pmid = {39596118}, issn = {1422-0067}, support = {PRIN 2017- 2017BTHJ4R, Ateneo 2020 RM120172B745088B, Ateneo 2021 RM12117A8166CD9//Ministry of University and Research (MUR), Sapienza University of Rome/ ; }, mesh = {Animals ; *Autophagy/drug effects ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *Carbamates/pharmacology ; *Disease Models, Animal ; *Benzamides/pharmacology ; *Amidohydrolases/metabolism/antagonists & inhibitors ; *Microglia/drug effects/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Mice, Transgenic ; Endocannabinoids/metabolism ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Endocannabinoids have attracted great interest for their ability to counteract the neuroinflammation underlying Alzheimer's disease (AD). Our study aimed at evaluating whether this activity was also due to a rebalance of autophagic mechanisms in cellular and animal models of AD. We supplied URB597, an inhibitor of Fatty-Acid Amide Hydrolase (FAAH), the degradation enzyme of anandamide, to microglial cultures treated with Aβ25-35, and to Tg2576 transgenic mice, thus increasing the endocannabinoid tone. The addition of URB597 did not alter cell viability and induced microglia polarization toward an anti-inflammatory phenotype, as shown by the modulation of pro- and anti-inflammatory cytokines, as well as M1 and M2 markers; moreover microglia, after URB597 treatment released higher levels of Bdnf and Nrf2, confirming the protective role underlying endocannabinoids increase, as shown by RT-PCR and immunofluorescence experiments. We assessed the number and area of amyloid plaques in animals administered with URB597 compared to untreated animals and the expression of autophagy key markers in the hippocampus and prefrontal cortex from both groups of mice, via immunohistochemistry and ELISA. After URB597 supply, we detected a reduction in the number and areas of amyloid plaques, as detected by Congo Red staining and a reshaping of microglia activation as shown by M1 and M2 markers' modulation. URB597 administration restored autophagy in Tg2576 mice via an increase in BECN1 (Beclin1), ATG7 (Autophagy Related 7), LC3 (light chain 3) and SQSTM1/p62 (sequestrome 1) as well as via the activation of the ULK1 (Unc-51 Like Autophagy Activating Kinase 1) signaling pathway, suggesting that it targets mTOR/ULK1-dependent autophagy pathway. The potential of endocannabinoids to rebalance autophagy machinery may be considered as a new perspective for therapeutic intervention in AD.}, }
@article {pmid39596023, year = {2024}, author = {Kciuk, M and Kruczkowska, W and Gałęziewska, J and Wanke, K and Kałuzińska-Kołat, Ż and Aleksandrowicz, M and Kontek, R}, title = {Alzheimer's Disease as Type 3 Diabetes: Understanding the Link and Implications.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, pmid = {39596023}, issn = {1422-0067}, mesh = {*Alzheimer Disease/metabolism/etiology/pathology ; Humans ; *Diabetes Mellitus, Type 2/metabolism ; *Insulin Resistance ; Oxidative Stress ; Animals ; Insulin/metabolism ; }, abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two prevalent conditions that present considerable public health issue in aging populations worldwide. Recent research has proposed a novel conceptualization of AD as "type 3 diabetes", highlighting the critical roles of insulin resistance and impaired glucose metabolism in the pathogenesis of the disease. This article examines the implications of this association, exploring potential new avenues for treatment and preventive strategies for AD. Key evidence linking diabetes to AD emphasizes critical metabolic processes that contribute to neurodegeneration, including inflammation, oxidative stress, and alterations in insulin signaling pathways. By framing AD within this metabolic context, we can enhance our understanding of its etiology, which in turn may influence early diagnosis, treatment plans, and preventive measures. Understanding AD as a manifestation of diabetes opens up the possibility of employing novel therapeutic strategies that incorporate lifestyle modifications and the use of antidiabetic medications to mitigate cognitive decline. This integrated approach has the potential to improve patient outcomes and deepen our comprehension of the intricate relationship between neurodegenerative diseases and metabolic disorders.}, }
@article {pmid39595863, year = {2024}, author = {Fonte, C and Rotundo, G and Varalta, V and Filosa, A and Muti, E and Barletta, C and Evangelista, E and Venturelli, M and Picelli, A and Smania, N}, title = {Combined Effect of tDCS and Motor or Cognitive Activity in Patients with Alzheimer's Disease: A Proof-of-Concept Pilot Study.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595863}, issn = {2076-3425}, abstract = {(1) Background: Alzheimer's disease (AD) accounts for 70% of dementia cases and with no effective pharmacological treatments, new rehabilitation methods are needed. Motor and cognitive activities and transcranial direct current stimulation (tDCS) have shown promise in stabilizing and enhancing cognitive functions. Objective: we want to investigate the effects of tDCS combined with motor or cognitive activity on cognitive functions in AD patients. (2) Methods: Patients with mild or moderate AD were randomized between anodic tDCS groups (MotA or CogA) and sham tDCS groups (MotS or CogS). They received two weeks of treatment (45 min, five days/week), with the first 15 min using tDCS stimulation on the dorsolateral prefrontal cortex. Cognitive assessments were conducted pre-treatment (T0), post-treatment (T1), and one week after (T2). (3) Results: Twenty-three patients were included. Statistical analysis showed significant differences between anodic tDCS groups (MotA + CogA) and sham tDCS groups (MotS + CogS) with advantages for the first in improving global cognitive status (p = 0.042), selective attention (p = 0.012), and sustained attention (p = 0.012). Further analysis indicated no differences between the two anodic tDCS groups between T0 and T1. (4) Conclusions: combined anodal tDCS with motor or cognitive activity could improve global cognitive state and attention, slowing cognitive decline in AD patients. The trial was registered on Clinical Trials: NCT06619795.}, }
@article {pmid39595846, year = {2024}, author = {Costa, ACS}, title = {On the Therapeutic Use of Monoclonal Antibodies Against Amyloid Plaques in Older Adults with Down Syndrome: A Narrative Review and Perspective.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595846}, issn = {2076-3425}, support = {N/A//Center for Neurodegenerative Disorders (CENDIVE) at University Hospitals Cleveland/ ; N/A//Awakening Angels Foundation/ ; R03AG086928/GF/NIH HHS/United States ; 3U24AG057437/GF/NIH HHS/United States ; }, abstract = {Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21 (trisomy 21 or T21) and is associated with an increased risk of early-onset Alzheimer's disease (AD), also known as DS-associated AD (DSAD). Individuals with DS typically develop amyloid neuropathology in their late-thirties to early-forties and the mean age of onset of clinical dementia is approximately 55 years. Recent advances in AD clinical research have focused on monoclonal antibodies (mAbs) targeting amyloid-β (Aβ) plaques as a potential therapeutic approach. Therefore, there has been guarded enthusiasm about using anti-amyloid mAbs in the prevention/treatment of DSAD. This narrative review and perspective explores the current understanding of amyloid pathology in AD and DSAD, the rationale for using anti-amyloid mAbs in the treatment of DSAD, and the challenges and opportunities for research toward the application of this therapeutic strategy to older adults with DS.}, }
@article {pmid39595827, year = {2024}, author = {Wang, M and Dinarvand, D and Chan, CTY and Bragin, A and Li, L}, title = {Photobiomodulation as a Potential Treatment for Alzheimer's Disease: A Review Paper.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595827}, issn = {2076-3425}, support = {RF1 NS033310/NS/NINDS NIH HHS/United States ; 1RF1NS033310-27S1/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent form of dementia, is a leading neurodegenerative disorder currently affecting approximately 55 million individuals globally, a number projected to escalate to 139 million by 2050. Despite extensive research spanning several decades, the cure for AD remains at a developing stage. The only existing therapeutic options are limited to symptom management, and are often accompanied by adverse side effects. The pathological features of AD, including the accumulation of beta-amyloid plaques and tau protein tangles, result in progressive neuronal death, synaptic loss, and brain atrophy, leading to significant cognitive decline and a marked reduction in quality of life.
OBJECTIVE: In light of the shortcomings of existing pharmacological interventions, this review explores the potential of photobiomodulation (PBM) as a non-invasive therapeutic option for AD. PBM employs infrared light to facilitate cellular repair and regeneration, focusing on addressing the disease's underlying biomechanical mechanisms.
METHOD: This paper presents a comprehensive introduction to the mechanisms of PBM and an analysis of preclinical studies evaluating its impact on cellular health, cognitive function, and disease progression in AD.The review provides a comprehensive overview of the various wavelengths and application methods, evaluating their efficacy in mitigating AD-related symptoms.
CONCLUSIONS: The findings underscore the significant potential of PBM as a safe and effective alternative treatment for Alzheimer's disease, emphasizing the necessity for further research and clinical trials to establish its therapeutic efficacy conclusively.}, }
@article {pmid39595812, year = {2024}, author = {Zhang, S and Yang, Y and Lv, X and Zhou, X and Zhao, W and Meng, L and Zhu, S and Zhang, Z and Wang, Y}, title = {Exosome Cargo in Neurodegenerative Diseases: Leveraging Their Intercellular Communication Capabilities for Biomarker Discovery and Therapeutic Delivery.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595812}, issn = {2076-3425}, support = {82171871//National Natural Science Foundation of China/ ; BK20230488//Youth Fund Project of the Jiangsu Province Basic Research Program (Natural Science Foundation)/ ; None//Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)/ ; }, abstract = {The inexorable progression of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, is closely related to irreversible brain decline. Accurately characterizing pathophysiological features and identifying reliable biomarkers for early diagnosis and optimized treatment are critical. Hindered by the blood-brain barrier (BBB), obtaining sensitive monitoring indicators for disease progression and achieving efficient drug delivery remain significant challenges. Exosomes, endogenous nanoscale vesicles that carry key bioactive substances, reflect the intracellular environment and play an important role in cell signaling. They have shown promise in traversing the BBB, serving dual roles as potential biomarkers for NDs and vehicles for targeted drug delivery. However, the specific mechanisms by which exosome influence NDs are not fully understood, necessitating further investigation into their attributes and functionalities in the context of NDs. This review explores how exosomes mediate multifaceted interactions, particularly in exacerbating pathogenic processes such as oxidative stress, neuronal dysfunction, and apoptosis integral to NDs. It provides a comprehensive analysis of the profound impact of exosomes under stress and disease states, assessing their prospective utility as biomarkers and drug delivery vectors, offering new perspectives for tackling these challenging diseases.}, }
@article {pmid39595200, year = {2024}, author = {Qi, X and Nizamutdinov, D and Yi, SS and Wu, E and Huang, JH}, title = {Disease Modifying Monoclonal Antibodies and Symptomatic Pharmacological Treatment for Alzheimer's Disease.}, journal = {Biomedicines}, volume = {12}, number = {11}, pages = {}, pmid = {39595200}, issn = {2227-9059}, abstract = {Alzheimer's Disease (AD) is an irreversible, progressive syndrome characterized by neurocognitive impairment. Two neuropathological features seen in AD are extracellular amyloid plaques consisting of amyloid beta1-40 and 1-42, and intracellular neurofibrillary tangles (NFTs). For decades, neuroscience research has heavily focused on seeking to understand the primary mechanism of AD and searching for pharmacological approaches for the treatment of dementia. Three monoclonal antibodies that act against amyloid beta-aducanumab, lecanemab, and donanemab-have been approved by the Food and Drug Administration (FDA) for the treatment of mild cognitive impairment and mild AD, in addition to medications for cognitive symptom management such as acetylcholinesterase inhibitors and the N-methyl-D-aspartate (NMDA) antagonist. Further trials should focus on the combination of therapies targeting amyloid plaques and tau pathology.}, }
@article {pmid39595072, year = {2024}, author = {Sharbafshaaer, M and Cirillo, G and Esposito, F and Tedeschi, G and Trojsi, F}, title = {Harnessing Brain Plasticity: The Therapeutic Power of Repetitive Transcranial Magnetic Stimulation (rTMS) and Theta Burst Stimulation (TBS) in Neurotransmitter Modulation, Receptor Dynamics, and Neuroimaging for Neurological Innovations.}, journal = {Biomedicines}, volume = {12}, number = {11}, pages = {}, pmid = {39595072}, issn = {2227-9059}, abstract = {Transcranial magnetic stimulation (TMS) methods have become exciting techniques for altering brain activity and improving synaptic plasticity, earning recognition as valuable non-medicine treatments for a wide range of neurological disorders. Among these methods, repetitive TMS (rTMS) and theta-burst stimulation (TBS) show significant promise in improving outcomes for adults with complex neurological and neurodegenerative conditions, such as Alzheimer's disease, stroke, Parkinson's disease, etc. However, optimizing their effects remains a challenge due to variability in how patients respond and a limited understanding of how these techniques interact with crucial neurotransmitter systems. This narrative review explores the mechanisms of rTMS and TBS, which enhance neuroplasticity and functional improvement. We specifically focus on their effects on GABAergic and glutamatergic pathways and how they interact with key receptors like N-Methyl-D-Aspartate (NMDA) and AMPA receptors, which play essential roles in processes like long-term potentiation (LTP) and long-term depression (LTD). Additionally, we investigate how rTMS and TBS impact neuroplasticity and functional connectivity, particularly concerning brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase receptor type B (TrkB). Here, we highlight the significant potential of this research to expand our understanding of neuroplasticity and better treatment outcomes for patients. Through clarifying the neurobiology mechanisms behind rTMS and TBS with neuroimaging findings, we aim to develop more effective, personalized treatment plans that effectively address the challenges posed by neurological disorders and ultimately enhance the quality of neurorehabilitation services and provide future directions for patients' care.}, }
@article {pmid39595009, year = {2024}, author = {Moyano, P and Guzmán, G and Flores, A and García, J and Guerra-Menéndez, L and Sanjuan, J and Plaza, JC and Abascal, L and Mateo, O and Del Pino, J}, title = {Thyroid Hormone Neuroprotection Against Perfluorooctane Sulfonic Acid Cholinergic and Glutamatergic Disruption and Neurodegeneration Induction.}, journal = {Biomedicines}, volume = {12}, number = {11}, pages = {}, pmid = {39595009}, issn = {2227-9059}, support = {PR26/20326//Santander Bank/UCM/ ; 72C126PMA//Alborada Foundation/Cátedra Extraordinaria de Patología y Medioambiente, UCM./ ; }, abstract = {Background: Perfluorooctane sulfonic acid (PFOS), a widely used industrial chemical, was reported to induce memory and learning process dysfunction. Some studies tried to reveal the mechanisms that mediate these effects, but how they are produced is still unknown. Basal forebrain cholinergic neurons (BFCN) maintain cognitive function and their selective neurodegeneration induces cognitive decline, as observed in Alzheimer's disease. PFOS was reported to disrupt cholinergic and glutamatergic transmissions and thyroid hormone action, which regulate cognitive processes and maintain BFCN viability. Objective/Methods: To evaluate PFOS neurodegenerative effects on BFCN and the mechanisms that mediate them, SN56 cells (a neuroblastoma cholinergic cell line from the basal forebrain) were treated with PFOS (0.1 µM to 40 µM) with or without thyroxine (T3; 15 nM), MK-801 (20 µM) or acetylcholine (ACh; 10 µM). Results: In the present study, we found that PFOS treatment (1 or 14 days) decreased thyroid receptor α (TRα) activity by decreasing its protein levels and increased T3 metabolism through increased deiodinase 3 (D3) levels. Further, we observed that PFOS treatment disrupted cholinergic transmission by decreasing ACh content through decreased choline acetyltransferase (ChAT) activity and protein levels and through decreasing muscarinic receptor 1 (M1R) binding and protein levels. PFOS also disrupted glutamatergic transmission by decreasing glutamate content through increased glutaminase activity and protein levels and through decreasing N-methyl-D-aspartate receptor subunit 1 (NMDAR1); effects mediated through M1R disruption. All these effects were mediated through decreased T3 activity and T3 supplementation partially restored to the normal state. Conclusions: These findings may assist in understanding how PFOS induces neurodegeneration, and the mechanisms involved, especially in BFCN, to explain the process that could lead to cognitive dysfunction and provide new therapeutic tools to treat and prevent its neurotoxic effects.}, }
@article {pmid39594648, year = {2024}, author = {El Abiad, E and Al-Kuwari, A and Al-Aani, U and Al Jaidah, Y and Chaari, A}, title = {Navigating the Alzheimer's Biomarker Landscape: A Comprehensive Analysis of Fluid-Based Diagnostics.}, journal = {Cells}, volume = {13}, number = {22}, pages = {}, pmid = {39594648}, issn = {2073-4409}, support = {SRMP-7-6452//Weill Cornell Medicine - Qatar/ ; }, mesh = {*Alzheimer Disease/diagnosis/cerebrospinal fluid/metabolism ; Humans ; *Biomarkers/cerebrospinal fluid/metabolism/blood ; Saliva/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) affects a significant portion of the aging population, presenting a serious challenge due to the limited availability of effective therapies during its progression. The disease advances rapidly, underscoring the need for early diagnosis and the application of preventative measures. Current diagnostic methods for AD are often expensive and invasive, restricting access for the general public. One potential solution is the use of biomarkers, which can facilitate early detection and treatment through objective, non-invasive, and cost-effective evaluations of AD. This review critically investigates the function and role of biofluid biomarkers in detecting AD, with a specific focus on cerebrospinal fluid (CSF), blood-based, and saliva biomarkers.
RESULTS: CSF biomarkers have demonstrated potential for accurate diagnosis and valuable prognostic insights, while blood biomarkers offer a minimally invasive and cost-effective approach for diagnosing cognitive issues. However, while current biomarkers for AD show significant potential, none have yet achieved the precision needed to replace expensive PET scans and CSF assays. The lack of a single accurate biomarker underscores the need for further research to identify novel or combined biomarkers to enhance the clinical efficacy of existing diagnostic tests. In this context, artificial intelligence (AI) and deep-learning (DL) tools present promising avenues for improving biomarker analysis and interpretation, enabling more precise and timely diagnoses.
CONCLUSIONS: Further research is essential to confirm the utility of all AD biomarkers in clinical settings. Combining biomarker data with AI tools offers a promising path toward revolutionizing the personalized characterization and early diagnosis of AD symptoms.}, }
@article {pmid39594552, year = {2024}, author = {Budamagunta, MS and Mori, H and Silk, J and Slez, RR and Bognár, B and Mendiola, UR and Kálai, T and Maezawa, I and Voss, JC}, title = {Nitroxyl Hybrids with Curcumin and Stilbene Scaffolds Display Potent Antioxidant Activity, Remodel the Amyloid Beta Oligomer, and Reverse Amyloid Beta-Induced Cytotoxicity.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {39594552}, issn = {2076-3921}, support = {R01 AG071665/AG/NIA NIH HHS/United States ; NKFI K 137793//National Research, Development, and Innovation Fund of Hungary/ ; P30 AG010129/NH/NIH HHS/United States ; RF1 AG071665/NH/NIH HHS/United States ; }, abstract = {The disorder and heterogeneity of low-molecular-weight amyloid-beta oligomers (AβOs) underlie their participation in multiple modes of cellular dysfunction associated with the etiology of Alzheimer's disease (AD). The lack of specified conformational states in these species complicates efforts to select or design small molecules to targeting discrete pathogenic states. Furthermore, targeting AβOs alone may be therapeutically insufficient, as AD progresses as a multifactorial, self-amplifying cascade. To address these challenges, we have screened the activity of seven new candidates that serve as Paramagnetic Amyloid Ligand (PAL) candidates. PALs are bifunctional small molecules that both remodel the AβO structure and localize a potent antioxidant that mimics the activity of SOD within live cells. The candidates are built from either a stilbene or curcumin scaffold with nitroxyl moiety to serve as catalytic antioxidants. Measurements of PAL AβO binding and remolding along with assessments of bioactivity allow for the extraction of useful SAR information from screening data. One candidate (HO-4450; PMT-307), with a six-membered nitroxyl ring attached to a stilbene ring, displays the highest potency in protecting against cell-derived Aβ. A preliminary low-dose evaluation in AD model mice provides evidence of modest treatment effects by HO-4450. The results for the curcumin PALs demonstrate that the retention of the native curcumin phenolic groups is advantageous to the design of the hybrid PAL candidates. Finally, the PAL remodeling of AβO secondary structures shows a reasonable correlation between a candidate's bioactivity and its ability to reduce the fraction of antiparallel β-strand.}, }
@article {pmid39593736, year = {2024}, author = {Ali, MU and Hussain, SJ and Khalid, M and Farrash, M and Lahza, HFM and Zafar, A}, title = {MRI-Driven Alzheimer's Disease Diagnosis Using Deep Network Fusion and Optimal Selection of Feature.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {11}, number = {11}, pages = {}, pmid = {39593736}, issn = {2306-5354}, abstract = {Alzheimer's disease (AD) is a degenerative neurological condition characterized by cognitive decline, memory loss, and reduced everyday function, which eventually causes dementia. Symptoms develop years after the disease begins, making early detection difficult. While AD remains incurable, timely detection and prompt treatment can substantially slow its progression. This study presented a framework for automated AD detection using brain MRIs. Firstly, the deep network information (i.e., features) were extracted using various deep-learning networks. The information extracted from the best deep networks (EfficientNet-b0 and MobileNet-v2) were merged using the canonical correlation approach (CCA). The CCA-based fused features resulted in an enhanced classification performance of 94.7% with a large feature vector size (i.e., 2532). To remove the redundant features from the CCA-based fused feature vector, the binary-enhanced WOA was utilized for optimal feature selection, which yielded an average accuracy of 98.12 ± 0.52 (mean ± standard deviation) with only 953 features. The results were compared with other optimal feature selection techniques, showing that the binary-enhanced WOA results are statistically significant (p < 0.01). The ablation study was also performed to show the significance of each step of the proposed methodology. Furthermore, the comparison shows the superiority and high classification performance of the proposed automated AD detection approach, suggesting that the hybrid approach may help doctors with dementia detection and staging.}, }
@article {pmid39592934, year = {2024}, author = {Mottolese, N and Loi, M and Trazzi, S and Tassinari, M and Uguagliati, B and Candini, G and Iqbal, K and Medici, G and Ciani, E}, title = {Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder.}, journal = {Journal of neurodevelopmental disorders}, volume = {16}, number = {1}, pages = {65}, pmid = {39592934}, issn = {1866-1955}, mesh = {Animals ; *Spasms, Infantile/drug therapy/genetics ; *Epileptic Syndromes/drug therapy ; Mice ; *Disease Models, Animal ; *Protein Serine-Threonine Kinases/genetics/metabolism ; *Mice, Knockout ; *Ciliary Neurotrophic Factor/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism/drug effects ; Humans ; Neurons/drug effects/metabolism ; Neurogenesis/drug effects ; Male ; }, abstract = {BACKGROUND: Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice. P021, a tetra-peptide derived from the biologically active region of the human ciliary neurotrophic factor (CNTF), was found to enhance neurogenesis and synaptic plasticity by promoting an increase in BDNF expression in preclinical models of brain disorders, such as Alzheimer's disease and Down syndrome, resulting in a beneficial therapeutic effect. Considering the positive actions of P021 on brain development and cognition associated with increased BDNF expression, the present study aimed to evaluate the possible beneficial effect of treatment with P021 in an in vitro and in vivo model of CDD.
METHODS: We used SH-CDKL5-KO cells as an in vitro model of CDD to test the efficacy of P021 on neuronal proliferation, survival, and maturation. In addition, both young and adult Cdkl5 KO mice were used to evaluate the in vivo effects of P021, on neuroanatomical and behavioral defects.
RESULTS: We found that P021 treatment was effective in restoring neuronal proliferation, survival, and maturation deficits, as well as alterations in the GSK3β signaling pathway, features that characterize a human neuronal model of CDKL5 deficiency. Unexpectedly, chronic in vivo P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 KO mice, resulting in limited behavioral benefit.
CONCLUSIONS: At present, it remains to be understood whether initiating the treatment prenatally, or prolonging the duration of treatment will be necessary in order to achieve similar results in vivo in CDD mice to those obtained in vitro.}, }
@article {pmid39592705, year = {2024}, author = {Desarkar, P and Vicario, CM and Soltanlou, M}, title = {Non-invasive brain stimulation in research and therapy.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {29334}, pmid = {39592705}, issn = {2045-2322}, abstract = {Since the introduction of transcranial magnetic stimulation (TMS) almost four decades ago, non-invasive brain stimulation (NIBS) techniques have emerged as promising tools to study brain-behaviour relationships in healthy and impaired states with unprecedented precision. Various NIBS techniques, including TMS, transcranial direct current stimulation (tDCS), and emerging methods such as transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) are employed in both research and clinical settings. TMS has gained regulatory approval for treating conditions like major depressive disorder and migraine, while tDCS is showing efficacy in enhancing cognitive functions in various populations. This collection of articles examines key studies, including the modulation of cognitive-motor functions, optimization of light stimulation for Alzheimer’s therapy, and effects on risk-taking behaviour in violent offenders. Notably, the findings suggest that NIBS can effectively influence executive functions and decision-making processes. They highlight the integration of NIBS with neuroimaging techniques, the importance of personalized targeting, and the potential for combined therapeutic approaches. Future directions include addressing methodological challenges and leveraging artificial intelligence to refine treatment protocols. Collectively, these advancements position NIBS as a transformative tool in both neuroscience research and clinical practice, offering new avenues for understanding and treating complex neuropsychiatric conditions.}, }
@article {pmid39592536, year = {2024}, author = {Nemr, MTM and Abdelaziz, MA and Teleb, M and Elmasry, AE and Elshaier, YAAM}, title = {An overview on pharmaceutical applications of phosphodiesterase enzyme 5 (PDE5) inhibitors.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {39592536}, issn = {1573-501X}, abstract = {Phosphodiesterase enzyme 5 (PDE5) inhibitors have emerged as one of the leading molecules for the treatment of erectile dysfunction (ED). PDE5 inhibitors are categorized structurally into several classes. PDE5 inhibitors have been a multidisciplinary endeavor that attracts the attention of researchers because of their multiple pharmaceutical applications. Beyond their action on ED, PDE5 inhibitors are widely used in treatment of benign prostatic hypertrophy (BPH), Eisenmenger's syndrome, Raynaud's Disease, Intrauterine growth retardation (IUGR), Mountain sickness, Bladder pain syndrome/interstitial cystitis (BPS/IC), pulmonary arterial hypertension and type II diabetes (insulin resistance). In addition, PDE5 inhibitors also show promising antiproliferative activity, anti-Alzheimer and COX-1/COX-2 inhibitory activity (anti-inflammatory). Pharmacokinetics, Pharmacogenetics and toxicity of PDE5 inhibitors were finally explored. The diverse therapeutic applications, the high feasibility of structural modification and the appropriate pharmacokinetic properties of PDE5 inhibitors have motivated researchers to develop new scaffolds that have been either under clinical trials or approved by FDA and utilize them to overcome some recent global concerns, such as COVID-19.}, }
@article {pmid39591987, year = {2024}, author = {Permana, AD and Mahfud, MAS and Munir, M and Aries, A and Rezka Putra, A and Fikri, A and Setiawan, H and Mahendra, I and Rizaludin, A and Ramadhani Aziz, AY and Djabir, YY and Arsyad, A and Harahap, Y and Saputri, WD and Fajarwati, R and Darmawan, N}, title = {A Combinatorial Approach with Microneedle Pretreatment and Thermosensitive Gel Loaded with Rivastigmine Lipid Nanoparticle Formulation Enables Brain Delivery via the Trigeminal Nerve.}, journal = {ACS applied materials & interfaces}, volume = {16}, number = {49}, pages = {68388-68406}, doi = {10.1021/acsami.4c16024}, pmid = {39591987}, issn = {1944-8252}, mesh = {*Rivastigmine/chemistry/pharmacokinetics/pharmacology/administration & dosage ; Animals ; Rats ; *Gels/chemistry ; *Brain/metabolism/drug effects/pathology ; *Nanoparticles/chemistry ; *Trigeminal Nerve/drug effects/metabolism ; Male ; Lipids/chemistry ; Rats, Sprague-Dawley ; Needles ; Drug Delivery Systems ; Alzheimer Disease/drug therapy/pathology/metabolism ; Temperature ; Blood-Brain Barrier/metabolism/drug effects ; Particle Size ; }, abstract = {Alzheimer's disease (AD) often leads to dementia, causing cognitive decline and increased care needs. Rivastigmine (RV) is a key AD treatment, but its brain delivery is limited by the blood-brain barrier (BBB). Aside from oral, olfactory, and intradermal injection (i.d.) routes, the application of polymeric microneedles via the trigeminal nerve on the facial skin as a pretreatment, followed by a solid lipid nanoparticle RV-loaded thermosensitive gel (PMN-SLN-RV-TG), is an alternative to deal with the problems. This study aims to determine the optimal formula for PMN-SLN-RV-TG application and assess its brain delivery ability compared to conventional routes. The optimum SLN-RV formula had a particle size <200 nm and sustained release for 72 h, which was selected for the SLN-RV-TG formulation. SLN-RV-TG was transformed into a gel at normal skin temperature (32-37 °C), with good physical properties and nontoxic behavior. The ideal PMN formula was able to penetrate the dermal layer as an alternative to i.d. administration. Ex vivo dermatokinetics showed significant improvement of PMN-SLN-RV-TG application (p < 0.05) compared to without PMN application. In vivo pharmacokinetic studies on rats also revealed that the PMN-SLN-RV-TG had superior pharmacokinetic parameters (Cmax, AUC, t1/2, and MRT) compared to other groups (p < 0.05). Radiolabeling SLN-RV with [99m]Tc showed good physical properties, with a radiochemical yield of >95%. In vivo distribution studies of PMN-SLN-RV-TG application exhibited a higher brain:blood ratio than i.v. administration after 5 h, as well as being safe for the brain due to a good histological profile. These results show that PMN-SLN-RV-TG application via the trigeminal nerve on the facial skin has strong potential delivery to the brain for AD treatment.}, }
@article {pmid39591666, year = {2024}, author = {Prickaerts, J and Kerckhoffs, J and Possemis, N and van Overveld, W and Verbeek, F and Grooters, T and Sambeth, A and Blokland, A}, title = {Roflumilast and cognition enhancement: A translational perspective.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {181}, number = {}, pages = {117707}, doi = {10.1016/j.biopha.2024.117707}, pmid = {39591666}, issn = {1950-6007}, mesh = {Animals ; Humans ; *Aminopyridines/therapeutic use/pharmacology ; *Benzamides/pharmacology/therapeutic use ; *Cognition/drug effects ; *Cognitive Dysfunction/drug therapy ; Cyclopropanes/therapeutic use/pharmacology/administration & dosage/adverse effects ; Nootropic Agents/therapeutic use/pharmacology ; *Phosphodiesterase 4 Inhibitors/therapeutic use/pharmacology ; Translational Research, Biomedical ; }, abstract = {Cognitive impairment affiliated with neurological disorders has a severe impact on daily life functioning and the quality of life of patients. This is associated with a significant and long-lasting health, social and financial burden, not only for the patients, but also for families and the wider society. However, treatment for cognitive impairment is only available for the indication Alzheimer's disease (AD) and its prodromal stage Mild Cognitive Impairment (MCI), although with major adverse effects, i.e. gastrointestinal effects (drugs) or hemorrhages (antibodies). Roflumilast (selective phosphodiesterase type 4 (PDE4) inhibitor) has been approved as an anti-inflammatory drug for the treatment of chronic obstructive pulmonary disease (COPD), although still 5 % of the patients experience nausea or even vomiting at the approved dose of 500 μg. Nonclinical studies demonstrated that roflumilast appears a promising drug the treat cognitive impairment in healthy rodents and a wide variety of animal models of CNS disorders. These effects are attributed to pro-neuroplasticity and anti-inflammatory effects, which appeared dose dependent. Roflumilast has also been tested in clinical studies and showed cognition enhancement at low dosing (100-250 µg) in healthy adults, healthy elderly, MCI and schizophrenia. Currently, clinical trials are underway for testing the pro-cognitive effects in early AD, post stroke cognitive impairment and Fragile X. Overall, the data showed that roflumilast has beneficial effects on cognitive performance. These cognition-enhancing effects are found at doses that were well-tolerated. Based on this favorable therapeutic window, the repurposing of roflumilast for treating cognitive impairments in CNS diseases may offer an affordable treatment option for patients.}, }
@article {pmid39590293, year = {2024}, author = {Ye, M and Jang, D and Lee, SY and Kim, KR and Rhie, SJ and Oh, JK and Shim, I}, title = {Neuroprotective Effect of Ixeris dentata Extract on Trimethyltin-Induced Memory Impairment in Rats.}, journal = {Current issues in molecular biology}, volume = {46}, number = {11}, pages = {11772-11782}, pmid = {39590293}, issn = {1467-3045}, abstract = {Alzheimer's disease (AD) is a representative neurodegenerative disease characterized by the structural and functional degeneration of neurons. The present study investigated the neuroprotective effect of Ixeris dentata (ID) extract on trimethyltin (TMT)-induced memory deficit in the rat. Cognitive improving effect and neuronal activity of ID were assessed by using Morris water maze (MWM) test and choline acetyltransferase (ChAT), cAMP-response element-binding protein (CREB) immunohistochemistry. Seven days after TMT injection (8.0 mg/kg, i.p.), each group of rats was administered saline, water extract of ID (WID, 400 or 800 mg/kg, p.o.), ethanol extract of ID (EID, 400 or 800 mg/kg, p.o.), or caffeic acid (CAF, 30 mg/kg, i.p.) daily for fourteen days. Results: Treatment with EID and CAF produced a significant improvement in escape latency time of the acquisition, and retention time in the target area of the MWM task. Additionally, administration of EID or CAF markedly alleviated TMT-induced loss of ChAT- and CREB-immunoreactive cells in the hippocampus. The results demonstrated that EID has a protective effect against TMT-induced memory deficit, partly through increasing the CREB and cholinergic signaling pathway in the hippocampus. These results suggest that ethanol extracts of ID might be useful for improving cognitive functions in neurodegenerative diseases such as Alzheimer's disease.}, }
@article {pmid39589986, year = {2024}, author = {Yin, X and Liao, Y and Li, F and Li, J and Du, J}, title = {Enzyme-Assisted Fluorescence Biosensor Based on Circular Single-Stranded DNA Without Group Modification for MicroRNA Detection.}, journal = {Biosensors}, volume = {14}, number = {11}, pages = {}, pmid = {39589986}, issn = {2079-6374}, support = {ZDYF2023SHFZ110//Hainan Province Science and Technology Special Fund/ ; Qhys2022-77//Graduate Students Innovation Research Project of Hainan Province/ ; }, mesh = {*Biosensing Techniques ; *MicroRNAs ; *DNA, Single-Stranded ; Humans ; Fluorescence ; DNA, Circular ; Alzheimer Disease/diagnosis ; }, abstract = {Fluorescent biosensor, which has the characteristics of high sensitivity, specificity, and low cost, can be directly detected in physiological fluids such as blood and serum. Therefore, the development of fluorescence sensor platforms for miRNA detection has a positive effect on the prevention and treatment of various diseases. In this paper, miR-34a was selected as a biological indicator of Alzheimer's disease (AD). We designed a circular single-stranded DNA (CSSD) biosensor, which uses two unmodified single-stranded DNA (ssDNA) with complementary ends, DNAa and DNAb, to form CSSD by DNA sequence pairing to improve thermal stability and achieve signal amplification. At the same time, CSSD can react with miR-34a, and then the DNA of the DNA-RNA chain is hydrolyzed by duplex-specific nuclease (DSN enzyme). Finally, miR-34a is released to partake in the subsequent step, thus realizing cycle amplification. By evaluating the change in fluorescence signal under the optimized conditions, we discovered that this approach exhibits impressive sensitivity, with a detection threshold reaching as low as 0.36 nM. This surpasses the performance of numerous preceding miRNA detection biosensors. Furthermore, the system displays excellent detection capabilities even in intricate settings like serum, showcasing a strong ability to differentiate and choose effectively. In summary, this is a signal-off fluorescent biosensor, which realizes the purpose of double amplification of biosensor signal by using CSSD and enzyme assistance so that it can be used as a valuable tool for early diagnosis of diseases.}, }
@article {pmid39589881, year = {2024}, author = {Jean Gregoire, M and Sirtori, R and Donatelli, L and Morgan Potts, E and Collins, A and Zamor, D and Katenka, N and Fallini, C}, title = {Early disruption of the CREB pathway drives dendritic morphological alterations in FTD/ALS cortical neurons.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {49}, pages = {e2406998121}, pmid = {39589881}, issn = {1091-6490}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; Early Career Development Award//RI-INBRE/ ; R01NS116143//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P20GM103430//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 NS116143/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Dendrites/metabolism ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Neurons/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Signal Transduction ; C9orf72 Protein/genetics/metabolism ; Phosphorylation ; Cerebral Cortex/metabolism/pathology ; }, abstract = {Synaptic loss and dendritic degeneration are common pathologies in several neurodegenerative diseases characterized by progressive cognitive and/or motor decline, such as Alzheimer's disease (AD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). An essential regulator of neuronal health, the cAMP-dependent transcription factor CREB positively regulates synaptic growth, learning, and memory. Phosphorylation of CREB by protein kinase A (PKA) and other cellular kinases promotes neuronal survival and maturation via transcriptional activation of a wide range of downstream target genes. CREB pathway dysfunction has been strongly implicated in AD pathogenesis, and recent data suggest that impaired CREB activation may contribute to disease phenotypes in FTD/ALS as well. However, the mechanisms behind reduced CREB activity in FTD/ALS pathology are not clear. In this study, we found that cortical-like neurons derived from iPSC lines carrying the hexanucleotide repeat expansion in the C9ORF72 gene, a common genetic cause of FTD/ALS, displayed a diminished activation of CREB, resulting in decreased dendritic and synaptic health. Importantly, we determined such impairments to be mechanistically linked to an imbalance in the ratio of regulatory and catalytic subunits of the CREB activator PKA and to be conserved in C9-ALS patient's postmortem tissue. Modulation of cAMP upstream of this impairment allowed for a rescue of CREB activity and an amelioration of dendritic morphology and synaptic protein levels. Our data elucidate the mechanism behind early CREB pathway dysfunction and discern a feasible therapeutic target for the treatment of FTD/ALS and possibly other neurodegenerative diseases.}, }
@article {pmid39589714, year = {2024}, author = {Sun, X and Zhang, W}, title = {Alzheimer's Disease from Modeling to Mechanism Research.}, journal = {Advances in neurobiology}, volume = {41}, number = {}, pages = {153-170}, pmid = {39589714}, issn = {2190-5215}, mesh = {*Alzheimer Disease/metabolism ; Humans ; Animals ; *Disease Models, Animal ; Organoids/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {As our population continues to age, the search for effective therapeutic strategies to combat neurodegenerative diseases, particularly Alzheimer's disease (AD), has become more pressing than ever. For over a decade, researchers have focused on the amyloid cascade hypothesis in their pursuit of new drugs for AD. However, with numerous drugs targeting this hypothesis failing in clinical trials, it is clear that AD's pathogenesis is complex, and each individual may display significant heterogeneity. Consequently, treatment has shifted to focus on multiple targets and early AD detection. Furthermore, there is an urgent need to develop new models that address the shortcomings of current rodent models, which have species differences. The organoid model, a newly developed model, appears to be the future direction, but it must overcome some system immaturity problems.}, }
@article {pmid39589513, year = {2025}, author = {Yang, E and Abd-Elrahman, KS}, title = {Alzheimer's disease treatment landscape: current therapies and emerging mechanism-targeted approaches.}, journal = {Neural regeneration research}, volume = {20}, number = {12}, pages = {3531-3532}, pmid = {39589513}, issn = {1673-5374}, }
@article {pmid39589160, year = {2025}, author = {Wang, Y and Li, D and Xu, K and Wang, G and Zhang, F}, title = {Copper homeostasis and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3124-3143}, pmid = {39589160}, issn = {1673-5374}, abstract = {Copper, one of the most prolific transition metals in the body, is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine, and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline, along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.}, }
@article {pmid39588954, year = {2024}, author = {Lu, X and Sun, W and Leng, L and Yang, Y and Gong, S and Zou, Q and Niu, H and Wei, C}, title = {Ultrasound Stimulation Modulates Microglia M1/M2 Polarization and Affects Hippocampal Proteomic Changes in a Mouse Model of Alzheimer's Disease.}, journal = {Immunity, inflammation and disease}, volume = {12}, number = {11}, pages = {e70061}, pmid = {39588954}, issn = {2050-4527}, support = {//This study was funded by STI2030-Major Projects (No. 2021ZD0201802)./ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/therapy/pathology ; *Microglia/metabolism ; *Hippocampus/metabolism/pathology ; Mice ; *Disease Models, Animal ; *Proteomics/methods ; Amyloid beta-Peptides/metabolism ; Plaque, Amyloid/metabolism/pathology ; Male ; Interleukin-10/metabolism ; Proteome/metabolism ; Ultrasonic Therapy/methods ; Mice, Transgenic ; }, abstract = {BACKGROUND: The effectiveness of ultrasound stimulation in treating Alzheimer's disease (AD) has been reported in previous studies, but the underlying mechanisms remain unclear. This study investigated the effects of ultrasound stimulation on the proportion and function of microglia of different phenotypes, as well as on the levels of inflammatory factors. Additionally, it revealed the alterations in proteomic molecules in the mouse hippocampus following ultrasound stimulation treatment, aiming to uncover potential new molecular mechanisms.
METHODS: Ultrasound stimulation was used to stimulate the hippocampus for 30 min per day for 5 days in the ultrasound stimulation-treated group. Amyloid plaque deposition was measured using immunofluorescence staining. M1 and M2 type microglia were labeled using immunofluorescent double staining, and the ratio was calculated. The levels of Aβ42, IL-10, and TNF-α were determined using ELISA kits. The quantitative proteomics method was employed to explore molecular changes in hippocampal proteins.
RESULTS: Ultrasound stimulation treatment reduced the average fluorescence intensity of amyloid plaques and the concentration of Aβ42. Compared to the AD group, ultrasound stimulation resulted in a 14% reduction in the proportion of M1 microglia and a 12% increase in the proportion of M2 microglia. The concentration of the anti-inflammatory factor IL-10 was significantly increased in the ultrasound stimulation-treated group. Proteomics analysis revealed 753 differentially expressed proteins between the ultrasound stimulation-treated and AD groups, with most being enriched in the oxidative phosphorylation pathway of mitochondria. Additionally, the activity of cytochrome c oxidase, involved in oxidative phosphorylation, was increased after ultrasound stimulation treatment.
CONCLUSIONS: Ultrasound stimulation affects microglial polarization, reduces amyloid plaque load, and enhances levels of anti-inflammatory factors in APP/PS1 mice. Proteomics analysis reveals molecular changes in hippocampal proteins after ultrasound stimulation treatment. The mechanism behind ultrasound stimulation-induced modulation of microglial polarization may be related to changes in mitochondrial oxidative phosphorylation.}, }
@article {pmid39588752, year = {2025}, author = {Chaulagain, B and Singh, J}, title = {Penetratin and Mannose-Functionalized Cannabidiol Lipid Nanoparticles Encapsulating the BDNF Gene Reduce Amyloid-Induced Inflammation.}, journal = {Molecular pharmaceutics}, volume = {22}, number = {1}, pages = {154-167}, pmid = {39588752}, issn = {1543-8392}, support = {R01 AG068034/AG/NIA NIH HHS/United States ; R01 AG083981/AG/NIA NIH HHS/United States ; RF1 AG068034/AG/NIA NIH HHS/United States ; }, mesh = {*Brain-Derived Neurotrophic Factor/genetics/metabolism ; *Nanoparticles/chemistry ; *Cannabidiol/chemistry/pharmacology ; *Mannose/chemistry ; *Amyloid beta-Peptides/metabolism ; Humans ; Animals ; *Inflammation/drug therapy ; *Alzheimer Disease/drug therapy ; Cell-Penetrating Peptides/chemistry ; Lipids/chemistry ; Cell Line ; Mice ; Brain/metabolism/drug effects ; Microglia/drug effects/metabolism ; Gene Transfer Techniques ; Blood-Brain Barrier/metabolism/drug effects ; Liposomes ; }, abstract = {Inflammation is emerging as a critical player in the disease progression of Alzheimer's disease (AD) by its interaction with amyloid beta plaques in a feed-forward loop. There is also a decline in the nourishment and enriching neurotrophic factor, brain-derived neurotrophic factor (BDNF), in the brain. Therefore, supplementing the brain with BDNF by gene delivery and delivering the anti-inflammatory agent, cannabidiol (CBD) in this case, to mitigate inflammation-induced disease cascade offers an attractive treatment strategy. To achieve the brain localization of CBD and pBDNF, lipid nanoparticles (LNPs) functionalized with mannose and penetratin were utilized. CBD and pBDNF were successfully encapsulated in the LNPs (more than 80%) with a size less than 180 nm, polydispersity index less than 0.25, and zeta potential of 23 mV. CBD was released from the formulation over a period of a week. The dual-functionalized LNPs demonstrated higher cellular uptake of CBD and expressed a significantly higher amount of BDNF (p-value <0.05) after transfection than their nonmodified counterparts in four brain cell lines, i.e., brain endothelial cells (b.END3), immortalized microglia cells (IMGs), primary astrocytes, and primary neurons. Similarly, the permeation of CBD through the dual-modified LNPs across the in vitro coculture blood-brain barrier model was significantly higher (p-value <0.05) compared to free CBD or nonfunctionalized nanoparticles. The LNPs demonstrated anti-inflammatory activity against lipopolysaccharides and human amyloid beta1-42 oligomer induction as they reduced the protein and mRNA expression of pro-inflammatory cytokines TNF-α (p < 0.05) and IL-1β (p < 0.05) in IMG cells. In summary, the penetratin and mannose-functionalized LNPs encapsulating CBD and pBDNF could serve as a promising therapy in AD, requiring further validation in animal models.}, }
@article {pmid39588176, year = {2024}, author = {Thulasimani, V and Shanmugavadivel, K and Cho, J and Veerappampalayam Easwaramoorthy, S}, title = {A Review of Datasets, Optimization Strategies, and Learning Algorithms for Analyzing Alzheimer's Dementia Detection.}, journal = {Neuropsychiatric disease and treatment}, volume = {20}, number = {}, pages = {2203-2225}, pmid = {39588176}, issn = {1176-6328}, abstract = {Alzheimer's Dementia (AD) is a progressive neurological disorder that affects memory and cognitive function, necessitating early detection for its effective management. This poses a significant challenge to global public health. The early and accurate detection of dementia is crucial for several reasons. First, timely detection facilitates early intervention and planning of treatment. Second, precise diagnostic methods are essential for distinguishing dementia from other cognitive disorders and medical conditions that may present with similar symptoms. Continuous analysis and improvements in detection methods have contributed to advancements in medical research. It helps to identify new biomarkers, refine existing diagnostic tools, and foster the development of innovative technologies, ultimately leading to more accurate and efficient diagnostic approaches for dementia. This paper presents a critical analysis of multimodal imaging datasets, learning algorithms, and optimisation techniques utilised in the context of Alzheimer's dementia detection. The focus is on understanding the advancements and challenges in employing diverse imaging modalities, such as MRI (Magnetic Resonance Imaging), PET (Positron Emission Tomography), and EEG (ElectroEncephaloGram). This study evaluated various machine learning algorithms, deep learning models, transfer learning techniques, and generative adversarial networks for the effective analysis of multi-modality imaging data for dementia detection. In addition, a critical examination of optimisation techniques encompassing optimisation algorithms and hyperparameter tuning strategies for processing and analysing images is presented in this study to discern their influence on model performance and generalisation. Thorough examination and enhancement of methods for dementia detection are fundamental for addressing the healthcare challenges posed by dementia, facilitating timely interventions, improving diagnostic accuracy, and advancing research in neurodegenerative diseases.}, }
@article {pmid39587940, year = {2024}, author = {Tok, F}, title = {Recent Studies on Heterocyclic Cholinesterase Inhibitors Against Alzheimer's Disease.}, journal = {Chemistry & biodiversity}, volume = {}, number = {}, pages = {e202402837}, doi = {10.1002/cbdv.202402837}, pmid = {39587940}, issn = {1612-1880}, abstract = {Alzheimer's disease is a progressive and neurodegenerative disease characterized by impairment in emotion, language, memory, and cognitive judgment. There are many factors related to Alzheimer's disease, such as amyloid beta plaques (Aβ) due to impaired metabolism of amyloid precursor protein (APP), tau hyperphosphorylation, and accumulation of neurofibrillary tangles, and disruption of the cholinergic system. Disruption of the cholinergic system responsible for cognitive function and memory processes is one of the important causes of Alzheimer's disease. Therefore, cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibitors that maintain choline (acetylcholine and butyrylcholine) levels in the synaptic gap play an important role in the symptomatic treatment of Alzheimer's disease. Numerous studies have been carried out against Alzheimer's disease involving acetylcholinesterase and butyrylcholinesterase inhibitors. However, there are very few drugs (tacrine, rivastigmine, galantamine, and donepezil) approved as cholinesterase inhibitors. Therefore, cholinesterase inhibitors are needed against Alzheimer's disease. This review is focused on using heterocyclic rings that show remarkable cholinesterase inhibitory activity for Alzheimer's disease. In this review, chemical structures and structure-activity relationships of recently reported cholinesterase inhibitors are emphasized. This review will give important ideas to medicinal chemists in the discovery and development of potent cholinesterase inhibitors in their future studies.}, }
@article {pmid39587789, year = {2024}, author = {Bagheri, S and Rashno, M and Salehi, I and Karimi, SA and Raoufi, S and Komaki, A}, title = {Protective effects of geraniol in a male rat model of Alzheimer's disease: A behavioral, biochemical, and histological study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {102}, number = {3}, pages = {646-658}, doi = {10.1177/13872877241290695}, pmid = {39587789}, issn = {1875-8908}, mesh = {Animals ; *Acyclic Monoterpenes/pharmacology ; Male ; *Alzheimer Disease/pathology/drug therapy ; *Rats, Wistar ; *Disease Models, Animal ; *Hippocampus/drug effects/pathology ; Rats ; *Amyloid beta-Peptides/metabolism ; *Terpenes/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Recognition, Psychology/drug effects ; Maze Learning/drug effects ; Behavior, Animal/drug effects ; Peptide Fragments ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) as a neurodegenerative disease can cause behavioral impairments due to oxidative stress. Aging and oxidative conditions are some AD risk factors.
OBJECTIVE: We assessed the influence of geraniol (GR), an acyclic monoterpene alcohol, on behavioral functions, hippocampal oxidative status, and histological alterations in AD rats induced by amyloid-β (Aβ).
METHODS: Male Wistar rats (n = 70) were randomly allocated to the control, sham, AD, control-GR (100 mg/kg; per oral: P.O.), AD-GR (100 mg/kg; P.O.; treatment), GR-AD (100 mg/kg; P.O.; pretreatment), and GR-AD-GR (100 mg/kg; P.O.; pretreatment + treatment) groups. GR administration was done for four continuous weeks. After treatments, novel object recognition (NOR) and Morris water maze (MWM) tests assessed the animals' behavior. Then, hippocampal specimens were collected for biochemical assessment. Finally, the number of intact neurons was identified in the hippocampus using hematoxylin and eosin staining.
RESULTS: Aβ microinjection increased learning and memory deficits in both NOR and MWM tests, oxidative stress status, and neuronal loss. Oral GR administration improved behavioral deficits and reduced oxidative stress status and neuronal loss in the Aβ-infused animals.
CONCLUSIONS: GR ameliorates behavioral impairments through a decrease in neuronal degeneration and oxidative stress.}, }
@article {pmid39587504, year = {2024}, author = {Wang, X and Zhou, J and Zhu, K and Wang, Y and Ma, X and Ren, L and Guo, C and Zhang, Z and Lu, P and Zhang, Q}, title = {Efficacy and safety of Neurocognitive Adaptive Training for Depression combined with SSRIs for treating cognitive impairment among patients with late-life depression: a 12-week, randomized controlled study.}, journal = {BMC psychiatry}, volume = {24}, number = {1}, pages = {848}, pmid = {39587504}, issn = {1471-244X}, support = {2022-3-2124//Capital Health Development Research Special Fund/ ; Discipline Backbones -02-38//Training Plan for High Level Public Health Technical Talents Construction Project/ ; 2022YB68//Central Health Care Research Fund/ ; No. 35 of 2021//the Study to evaluate the efficacy and safety of Sodium Oligomannate (GV-971) in the treatment of mild to moderate Alzheimer's disease with depressive and Anxiety symptoms/ ; }, mesh = {Humans ; Female ; Male ; *Selective Serotonin Reuptake Inhibitors/therapeutic use ; *Cognitive Dysfunction/drug therapy/etiology ; Aged ; *Depressive Disorder, Major/drug therapy/complications ; Combined Modality Therapy ; Middle Aged ; Cognitive Behavioral Therapy/methods ; Treatment Outcome ; Psychiatric Status Rating Scales ; }, abstract = {BACKGROUND: This randomized, open-label study examined the therapeutic effects of Neurocognitive Adaptive Training for Depression (NCAT-D) combined with selective serotonin reuptake inhibitors (SSRIs) on cognitive impairment among patients with late-life depression (LLD).
METHOD: Study data were collected from May 5, 2021, to April 21, 2023. Outpatients who met the diagnostic criteria for major depressive disorder according to the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (i.e., a total score on the 17-item Hamilton Depression Rating Scale (HAMD-17) ≥ 18 and a total score on the Montreal Cognitive Assessment scale (MOCA) < 26) were recruited at Beijing Anding Hospital. These participants were randomly assigned to receive up to 12 weeks of NCAT-D and SSRIs treatment (n = 57) or SSRIs with a control treatment (n = 61). Primary outcomes included changes in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores from baseline to week 12 between the two groups. Assessments were conducted at baseline, after 2 weeks, 4 weeks, 8 weeks, and at 12 weeks. Mixed model repeated measures (MMRM) analysis was performed on modified intention-to-treat (mITT) and completer populations.
RESULTS: The full analysis set (FAS) included 118 patients (NCAT-D and SSRIs group, n = 57; SSRIs and Control group, n = 61). During the 12-week study period, MMRM analysis revealed a significantly greater reduction in cognitive function (as indicated by ADAS-cog total scores) from baseline to post-treatment in the NCAT-D and SSRIs group compared to the SSRIs and Control groups [(F (1,115) = 13.65, least-squares mean difference [95% CI]: -2.77 [- 3.73, - 1.81], p < 0.001)]. The intervention group showed a significantly greater reduction in HAMD-17 scores compared to the control group [MMRM, estimated mean difference (SE) between groups: -3.59 [- 5.02, - 2.15], p < 0.001]. There was no significant difference in the incidence of adverse events between the two groups.
CONCLUSIONS: NCAT-D combined with SSRIs was efficacious and well tolerated in LLD patients with cognitive impairment.
TRIAL REGISTRATION: Registered on October 18, 2022, at ClinicalTrials.gov Identifier: (#NCT05588102).}, }
@article {pmid39587417, year = {2024}, author = {Zimbone, S and Giuffrida, ML and Sciacca, MFM and Carrotta, R and Librizzi, F and Milardi, D and Grasso, G}, title = {A VEGF Fragment Encompassing Residues 10-30 Inhibits Aβ1-42 Amyloid Aggregation and Exhibits Neuroprotective Properties Matching the Full-Length Protein.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {24}, pages = {4580-4590}, doi = {10.1021/acschemneuro.4c00669}, pmid = {39587417}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism ; Humans ; *Vascular Endothelial Growth Factor A/metabolism ; *Peptide Fragments/metabolism ; *Neuroprotective Agents/pharmacology ; Cell Line, Tumor ; Protein Aggregates/drug effects ; Alzheimer Disease/metabolism ; }, abstract = {The intricate relationship between brain vascular diseases and neurodegeneration has garnered increased attention in the scientific community. With an aging population, the incidence of these two conditions is likely to increase, making it imperative to understand the underlying common molecular mechanisms and unveiling novel avenues for therapy. Prompted by the observation that Aβ peptide aggregation has been implicated in the development of cerebral amyloid angiopathy (CAA) and that elevated concentrations of vascular endothelial growth factor (VEGF) in the cerebrospinal fluid (CSF) have been correlated with less cognitive decline in Alzheimer's disease (AD), we demonstrate that a small peptide (Pep9) encompassing the 10-30 sequence of VEGF exhibits significant ability to inhibit the aggregation of the Aβ1-42 peptide, as well as the formation of toxic oligomers. AFM studies confirmed this inhibitory capacity, which is also paralleled by a significant reduction of the random coil to a beta-sheet conformational transition. Further studies have shown that Pep9 protects differentiated neuroblastoma SH-SY5Y cells from Aβ toxicity, being even more effective than full-length protein in preventing amyloid-induced neuronal death. The use of a control peptide wherein two histidines are substituted with glycines (H11G and H12G) suggests a close relationship between the peptide amino acid sequence and its antiaggregating/neuroprotective activity. Overall, this study provides insight into the role of VEGF in AD and suggests that specific VEGF fragments could be beneficial in the treatment of this condition.}, }
@article {pmid39587077, year = {2024}, author = {Sobue, A and Komine, O and Endo, F and Kakimi, C and Miyoshi, Y and Kawade, N and Watanabe, S and Saito, Y and Murayama, S and Saido, TC and Saito, T and Yamanaka, K}, title = {Microglial cannabinoid receptor type II stimulation improves cognitive impairment and neuroinflammation in Alzheimer's disease mice by controlling astrocyte activation.}, journal = {Cell death & disease}, volume = {15}, number = {11}, pages = {858}, pmid = {39587077}, issn = {2041-4889}, support = {JP24wm0425014//Japan Agency for Medical Research and Development (AMED)/ ; JP21wm0425019//Japan Agency for Medical Research and Development (AMED)/ ; JP21wm0425019//Japan Agency for Medical Research and Development (AMED)/ ; None//Takeda Science Foundation/ ; None//Hori Sciences and Arts Foundation (Hori Sciences & Arts Foundation)/ ; None//Hori Sciences and Arts Foundation (Hori Sciences & Arts Foundation)/ ; JPMJM2024//MEXT | Japan Science and Technology Agency (JST)/ ; JP23K14687//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP22H04923//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP22H04923//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy/genetics ; *Astrocytes/metabolism/drug effects ; *Microglia/metabolism/drug effects/pathology ; *Receptor, Cannabinoid, CB2/metabolism/genetics/agonists ; *Cognitive Dysfunction/metabolism/drug therapy/pathology ; Mice ; Humans ; *Mice, Transgenic ; *Cannabinoids/pharmacology ; Neuroinflammatory Diseases/metabolism/drug therapy ; Disease Models, Animal ; Male ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia and is characterized by the accumulation of amyloid β (Aβ) and phosphorylated tau. Neuroinflammation, mainly mediated by glial activation, plays an important role in AD progression. Although there is growing evidence for the anti-neuroinflammatory and neuroprotective effects of the cannabinoid system modulation, the detailed mechanism remains unclear. To address these issues, we analyzed the expression levels of cannabinoid receptor type II (Cnr2/Cb2) in App[NL-G-F/NL-G-F] mice and human AD precuneus, which is vulnerable to amyloid deposition in AD, and the effects of JWH 133, a selective CB2 agonist, on neuroinflammation in primary glial cells and neuroinflammation and cognitive impairment in App[NL-G-F/NL-G-F] mice. The levels of Cnr2/Cb2 were upregulated in microglia isolated from the cerebral cortex of App[NL-G-F/NL-G-F] mice. CNR2 expression was also increased in RNAs derived from human precuneus with advanced AD pathology. Chronic oral administration of JWH 133 significantly ameliorated the cognitive impairment of App[NL-G-F/NL-G-F] mice without neuropsychiatric side effects. Microglia and astrocyte mRNAs were directly isolated from the mouse cerebral cortex by magnetic-activated cell sorting, and the gene expression was determined by quantitative PCR. JWH 133 administration significantly decreased reactive astrocyte markers and microglial C1q, an inducer for the reactive astrocytes in App[NL-G-F/NL-G-F] mice. In addition, JWH133 administration inhibited the expression of p-STAT3 (signal transducer and activator of transcription 3) in astrocytes in App[NL-G-F/NL-G-F] mice. Furthermore, JWH 133 administration suppressed dystrophic presynaptic terminals surrounding amyloid plaques. In conclusion, stimulation of microglial CB2 ameliorates cognitive dysfunction in App[NL-G-F/NL-G-F] mice by controlling astrocyte activation and inducing beneficial neuroinflammation, and our study has implications that CB2 may represent an attractive therapeutic target for the treatment of AD and perhaps other neurodegenerative diseases involving neuroinflammation.}, }
@article {pmid39586557, year = {2025}, author = {Liu, YL and Xu, S and Xu, X and Tang, Y and Shao, J and Chen, J and Li, YG}, title = {Integrating network pharmacology and multi-omics to explore the mechanism of Callicarpa kwangtungensis Chun in ameliorating Alzheimer's disease pathology in APP/PS1 mice.}, journal = {Journal of ethnopharmacology}, volume = {339}, number = {}, pages = {119148}, doi = {10.1016/j.jep.2024.119148}, pmid = {39586557}, issn = {1872-7573}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Network Pharmacology ; Mice ; *Mice, Transgenic ; Male ; Plant Extracts/pharmacology ; Cell Line ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Metabolomics ; Presenilin-1/genetics ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; Multiomics ; }, abstract = {Callicarpa kwangtungensis Chun (CK) is a traditional herb for the treatment of blood stasis, hemostasis, anti-inflammation, and antidepressant. Previous studies have showen that CK extract has significant anti-neuroinflammatory activity. However, the mechanism by which it treats AD is still unclear.
AIM OF STUDY: This study aimed to investigate the effects and mechanisms of CK in ameliorating AD pathology using in vivo and in vitro models, supported by a multi-omics analysis approach.
MATERIALS AND METHODS: The chemical composition of CK was characterized using UPLC-QE Plus-MS/MS. The effects and mechanisms of CK on AD pathology were then investigated using APP/PS1 mice and BV2 and HT22 cell models, with comprehensive insights provided by network pharmacology, transcriptomics, and metabolomics analyses.
RESULTS: This study is the first to report the identification of 146 compounds from CK. CK administration led to significant improvements in cognitive function, reduced amyloid-beta and neurofibrillary tangle formation, and inhibited the activation of microglia and astrocytes in APP/PS1 mice. Comprehensive analyses suggest that CK may modulate the TCA cycle through the PI3K-AKT signaling pathways and inflammation-related MAPK and NF-κB signaling pathways. In vitro studies revealed that CK significantly inhibited LPS-induced inflammation and oxidative stress in BV2 cells, as well as reduced oxidative stress and neuronal apoptosis in HT22 cells.
CONCLUSION: These findings underscore the potential of CK as a therapeutic agent in alleviating AD pathology. This study offers new insights into CK's mechanisms, suggesting that its therapeutic effects may be achieved through the coordinated reduction of neuroinflammation, oxidative stress, and neuronal apoptosis across multiple pathways, collectively working to counteract AD pathology.}, }
@article {pmid39586437, year = {2025}, author = {Mitra, A and Chakraborty, D and Naik, L and Dhiman, R and Sarkar, N}, title = {Anti-amyloidogenic hexapeptide-coated gold nanoparticles for enhanced inhibition of amyloid formation: A promising therapeutic approach.}, journal = {International journal of biological macromolecules}, volume = {284}, number = {Pt 1}, pages = {138002}, doi = {10.1016/j.ijbiomac.2024.138002}, pmid = {39586437}, issn = {1879-0003}, mesh = {*Gold/chemistry ; *Metal Nanoparticles/chemistry ; *Amyloid/chemistry ; *Oligopeptides/chemistry/pharmacology ; Humans ; Hydrogen-Ion Concentration ; }, abstract = {Under specific external stimulus, misfolded and natively disordered globular proteins undergo irreversible transformation into pathogenic β-sheet-rich insoluble fibrillar structure, and deposition of theses fibrils in cells and tissues leads to disorders like Alzheimer's, Dementia, Type II diabetes, and many more. Here, we have developed a positively-charged Arg-containing hexapeptide, SqP7, and elucidated its anti-amyloidogenic propensity on in vitro HEWL amyloid formation under acidic and neutral fibrillation conditions using computational tools and several biophysical techniques. SqP7, at a five-fold molar excess, displayed excellent amyloid inhibition capability at both pH conditions (~83 % and 72 % inhibition under acidic and neutral fibrillation conditions, respectively), and was further chosen as a coating agent on gold nanoparticles. This was done to investigate whether coating of this peptide on gold nanoparticles has any effect on its anti-amyloidogenic efficiency and effective inhibition concentration. The synthesized SqP7-coated gold nanoparticles were characterized to be spherical and highly-dispersed having a mean diameter of 9.12 ± 2.08 nm. The anti-amyloidogenic capability of the synthesized SqP7-coated gold nanoparticles was further evaluated, and a 10-fold reduction in the effective inhibition concentration of SqP7 was observed. This peptide‑gold nanoparticle based integrated approach can lead to the development of highly effective therapeutics for amyloid-related diseases, offering improved prevention and treatment options.}, }
@article {pmid39586209, year = {2025}, author = {Zielinska, Z and Oldak, L and Gorodkiewicz, E}, title = {Biosensing systems for the detection of biomarkers of neurodegenerative diseases: A review.}, journal = {Talanta}, volume = {284}, number = {}, pages = {127247}, doi = {10.1016/j.talanta.2024.127247}, pmid = {39586209}, issn = {1873-3573}, mesh = {*Biosensing Techniques/methods ; Humans ; *Biomarkers/analysis ; *Neurodegenerative Diseases/diagnosis ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) are pathologies associated with neuronal disorders and degradation. They are difficult to detect in their early stages, when it is crucial for appropriate treatment to be implemented. Currently, many biosensors are being developed to enable the determination of compounds characteristic of the aforementioned diseases. This review includes a de-scription of the structure of biosensors, as well as their applications in many areas of qualitative and quantitative analysis, with particular emphasis on diagnostics. The structures of biosensors that can potentially be used for the diagnosis of AD, PD and MS are discussed, as well as their characteristics, which depend on the technique used for the analysis and the type of recognition element capable of specifically binding a given biomarker. A description is also given of biosensors classified according to the type of sample used for quantitative determinations.}, }
@article {pmid39585065, year = {2024}, author = {Fogel, H and Zifman, N and Hallett, M}, title = {Utilization of Single-Pulse Transcranial-Evoked Potentials in Neurological and Psychiatric Clinical Practice: A Narrative Review.}, journal = {Neurology international}, volume = {16}, number = {6}, pages = {1421-1437}, pmid = {39585065}, issn = {2035-8385}, abstract = {Background: The utility of single-pulse TMS (transcranial magnetic stimulation)-evoked EEG (electroencephalograph) potentials (TEPs) has been extensively studied in the past three decades. TEPs have been shown to provide insights into features of cortical excitability and connectivity, reflecting mechanisms of excitatory/inhibitory balance, in various neurological and psychiatric conditions. In the present study, we sought to review and summarize the most studied neurological and psychiatric clinical indications utilizing single-pulse TEP and describe its promise as an informative novel tool for the evaluation of brain physiology. Methods: A thorough search of PubMed, Embase, and Google Scholar for original research utilizing single-pulse TMS-EEG and the measurement of TEP was conducted. Our review focused on the indications and outcomes most clinically relevant, commonly studied, and well-supported scientifically. Results: We included a total of 55 publications and summarized them by clinical application. We categorized these publications into seven sub-sections: healthy aging, Alzheimer's disease (AD), disorders of consciousness (DOCs), stroke rehabilitation and recovery, major depressive disorder (MDD), Parkinson's disease (PD), as well as prediction and monitoring of treatment response. Conclusions: TEP is a useful measurement of mechanisms underlying neuronal networks. It may be utilized in several clinical applications. Its most prominent uses include monitoring of consciousness levels in DOCs, monitoring and prediction of treatment response in MDD, and diagnosis of AD. Additional applications including the monitoring of stroke rehabilitation and recovery, as well as a diagnostic aid for PD, have also shown encouraging results but require further evidence from randomized controlled trials (RCTs).}, }
@article {pmid39585054, year = {2024}, author = {Loukou, S and Papantoniou, G and Pantazaki, A and Tsolaki, M}, title = {The Role of Greek Olive Leaf Extract in Patients with Mild Alzheimer's Disease (the GOLDEN Study): A Randomized Controlled Clinical Trial.}, journal = {Neurology international}, volume = {16}, number = {6}, pages = {1247-1265}, pmid = {39585054}, issn = {2035-8385}, abstract = {Background: Olive leaves are a significant source of biophenols, which have a beneficial impact on cognitive performance. Objective: To examine, for the first time, in humans the effect of the daily consumption of a beverage containing olive leaf extract (OLE) versus a Mediterranean diet (MeDi) on patients diagnosed with mild Alzheimer's Disease (AD), in addition to their regular treatment. Methods: A randomized clinical trial compared OLE's effects on cognitive and functional performance in 55 mild AD patients. Each participant was randomly assigned to two groups: (1) Group 1 was given olive leaves for making a daily beverage and MeDi instructions through monthly diet programs; (2) Group 2 received only the MeDi instructions. After six months, all participants underwent a second neuropsychological evaluation. Results: Group 1 participants had statistically significantly higher MMSE scores compared to Group 2 with a p-value of 0.0135. Specifically, the mean MMSE difference in patients receiving OLE was close to 0, indicating no memory deterioration, whereas in controls it was -4.1, indicative of cognitive decline. The remaining neuropsychological assessments (FRSSD, FUCAS, ADAS-Cog, CDR, GDS, and NPI) revealed better results in the OLE group, except for GDS, which showed no change, but without statistically significant differences between the two groups.}, }
@article {pmid39584354, year = {2025}, author = {Santos, VD and Costa, AC and Junior, NC and Delaere, FJ and Serlet, S and Dourado, MCN}, title = {Virtual reality interventions and their effects on the cognition of individuals with Alzheimer's disease: A systematic review and meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {103}, number = {1}, pages = {68-80}, doi = {10.1177/13872877241299037}, pmid = {39584354}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/psychology/therapy ; *Cognition/physiology ; *Virtual Reality ; Randomized Controlled Trials as Topic ; Virtual Reality Exposure Therapy/methods ; }, abstract = {BACKGROUND: Dementia due to Alzheimer's disease (AD) is the most prevalent neurocognitive disorder in the world and impacts the individual's cognitive functions and functionality in the early stages of the condition. Virtual reality (VR) interventions can assist in non-pharmacological treatment in a more ecological way, positively impacting cognitive abilities. However, there are few studies on VR exclusively involving people with AD in randomized controlled trials.
OBJECTIVE: To evaluate the effects of VR intervention on the cognitive functions of people with AD.
METHODS: A systematically conducted search was carried out in MEDLINE, EMBASE, BVS, Web of Science, and Scopus. Eligible studies were randomized controlled trials comparing the efficacy of VR and traditional cognitive interventions in people with AD. Methodologic quality was assessed with the Cochrane risk of bias tool, and outcomes were calculated as risk ratios (for dichotomous outcomes) and mean differences (for continuous outcomes) with 95% confidence interval.
RESULTS: A total of three randomized controlled trials with 75 participants were included. An improvement in the performance of the VR group was observed in memory, especially when comparing the usual treatment [MD = 0.99; CI95%: 0.33; 1.66; I[2 ]= 0%]. VR has little or no effect on participants' executive function [MD = 1.36; 95%CI: -1.12; 3.85; I[2 ]= 0%] compared to the usual treatment.
CONCLUSIONS: Our study results cautiously suggest, despite the small number of participants, that VR intervention may be a suitable memory treatment for individuals diagnosed with AD.}, }
@article {pmid39584298, year = {2024}, author = {Esmekaya, MA and Ertekin, B}, title = {Neuroprotective effects of coffee-derived exosome-like nanoparticles against Aβ-induced neurotoxicity.}, journal = {General physiology and biophysics}, volume = {43}, number = {6}, pages = {535-543}, doi = {10.4149/gpb_2024025}, pmid = {39584298}, issn = {0231-5882}, mesh = {*Amyloid beta-Peptides/toxicity ; Animals ; *Neuroprotective Agents/pharmacology ; Mice ; *Exosomes/metabolism/drug effects ; *Nanoparticles/chemistry ; *Neurons/drug effects/metabolism ; *Cell Survival/drug effects ; Cell Line ; Coffee/chemistry ; Peptide Fragments/toxicity ; Hippocampus/drug effects/cytology ; Dose-Response Relationship, Drug ; Membrane Potential, Mitochondrial/drug effects ; Alzheimer Disease/metabolism/drug therapy ; }, abstract = {The present study aimed to provide experimental evidence that CDELNs (coffee-derived exosome-like nanoparticles) may be a candidate for the treatment or prevention of amyloid-β (Aβ)-induced Alzheimer's disease (AD). An in vitro Alzheimer's model was created with Aβ-induced toxicity in mouse hippocampal neuronal cells (HT-22). Aβ(1-42)-exposed cells were treated with different concentrations of CDELNs (1-50 μg/ml) and the viability of cells was analyzed. The change in the mitochondrial membrane potential (ΔΨm) of cells was also determined. CDELNs treatment increased the viability of Aβ(1-42)-toxicity-induced HT-22 cells significantly. The increase in the viability of Aβ(1-42)-toxicity-induced cells was correlated with an improvement in ΔΨm. CDELNs treatment restored the dissipated ΔΨm. These results suggested that CDELNs protect neuronal cells against Aβ(1-42)-induced neurotoxicity by repairing mitochondrial dysfunction. CDELNs might be a useful neuroprotective agent for the treatment or prevention of Aβ-induced AD. Further animal and clinical studies should be carried out to investigate the neuroprotective potential of CDELNs against Aβ-induced AD.}, }
@article {pmid39583854, year = {2024}, author = {Cheng, J and Li, W and Wang, L and Gao, Y and Ma, Y and Zhou, M and Yang, T and Yue, C and Yan, L and Lyu, Y}, title = {Jiawei Qifuyin Enhances Immunity and Improves Cognitive Impairment in APP/PS1 Mice Through Modulation of Neuroinflammatory Pathways.}, journal = {Journal of inflammation research}, volume = {17}, number = {}, pages = {9021-9040}, pmid = {39583854}, issn = {1178-7031}, abstract = {PURPOSE: To explore the protective effects and mechanisms of Jiawei Qifuyin on APP/PS1 mice, a model for Alzheimer's disease (AD).
METHODS: Network pharmacology tools were used to predict anti-AD targets and signaling pathways affected by Jiawei Qifuyin. In vitro studies assessed antioxidant and oxygen radical scavenging abilities, immune cell proliferation, and inflammatory cytokine levels in lipopolysaccharide-induced BV2 microglial cells. Cognitive ability in APP/PS1 mice was evaluated using the Morris Water Maze test. mRNA expression of neuroinflammatory factors, changes in intestinal microbiota, and short-chain fatty acid content were analyzed post-treatment.
RESULTS: Network pharmacology predicted that Jiawei Qifuyin affects AKT1, TNF-α, and AGE/RAGE pathways. It showed concentration-dependent antioxidant effects and modulated immune cell proliferation. IL-2, IL-6, and TNF-α levels in LPS-induced BV2 cells were significantly reduced. Treated animals exhibited improved cognitive performance, decreased brain amyloid-beta levels, and downregulated expression of IL-1β, IL-6, RAGE, and NF-κB. Significant changes in intestinal microbiota composition and SCFA content were observed.
CONCLUSION: Jiawei Qifuyin may enhance immunity and improve cognitive impairment in APP/PS1 mice through regulation of inflammatory factors, gut microbiota, and the gut-brain axis.}, }
@article {pmid39583750, year = {2024}, author = {Nakashima, M and Suga, N and Fukumoto, A and Yoshikawa, S and Matsuda, S}, title = {Caveolae with serotonin and NMDA receptors as promising targets for the treatment of Alzheimer's disease.}, journal = {International journal of physiology, pathophysiology and pharmacology}, volume = {16}, number = {5}, pages = {96-110}, pmid = {39583750}, issn = {1944-8171}, abstract = {Alzheimer's disease is the most general type of cognitive impairments. Until recently, strategies that prevent its clinical progression have remained more elusive. Consequently, research direction should be for finding effective neuroprotective agents. It has been suggested oxidative stress, mitochondrial injury, and inflammation level might lead to brain cell death in many neurological disorders. Therefore, several autophagy-targeted bioactive compounds may be promising candidate therapeutics for the prevention of brain cell damage. Interestingly, some risk genes to Alzheimer's disease are expressed within brain cells, which may be linked to cholesterol metabolism, lipid transport, endocytosis, exocytosis and/or caveolae formation, suggesting that caveolae may be a fruitful therapeutic target to improve cognitive impairments. This review would highlight the latest advances in therapeutic technologies to improve the treatment of Alzheimer's disease. In particular, a paradigm that serotonin and N-methyl-d-aspartate (NMDA) receptors agonist/antagonist within caveolae structure might possibly improve the cognitive impairment. Consequently, cellular membrane biophysics should improve our understanding of the pathology of the cognitive dysfunction associated with Alzheimer's disease. Here, this research direction for the purpose of therapy may open the potential to move a clinical care toward disease-modifying treatment strategies with certain benefits for patients.}, }
@article {pmid39583651, year = {2024}, author = {Brendel, M and Parvizi, T and Gnörich, J and Topfstedt, CE and Buerger, K and Janowitz, D and Rauchmann, BS and Perneczky, R and Kurz, C and Mehrens, D and Kunz, WG and Kusche-Palenga, J and Kling, AB and Buchal, A and Nestorova, E and Silvaieh, S and Wurm, R and Traub-Weidinger, T and Klotz, S and Regelsberger, G and Rominger, A and Drzezga, A and Levin, J and Stögmann, E and Franzmeier, N and Höglinger, GU}, title = {Aβ status assessment in a hypothetical scenario prior to treatment with disease-modifying therapies: Evidence from 10-year real-world experience at university memory clinics.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {16}, number = {4}, pages = {e70031}, pmid = {39583651}, issn = {2352-8729}, abstract = {INTRODUCTION: With the advent of disease-modifying therapies, accurate assessment of biomarkers indicating the presence of disease-associated amyloid beta (Aβ) pathology becomes crucial in patients with clinically suspected Alzheimer's disease (AD). We evaluated Aβ levels in cerebrospinal fluid (Aβ CSF) and Aβ levels in positron emission tomography (Aβ PET) biomarkers in a real-world memory-clinic setting to develop an efficient algorithm for clinical use.
METHODS: Patients were evaluated for AD-related Aβ pathology from two independent cohorts (Ludwig Maximilian University [LMU], n = 402, and Medical University of Vienna [MUV], n = 144). Optimal thresholds of CSF biomarkers were deduced from receiver operating characteristic curves and validated against Aβ PET positivity.
RESULTS: In both cohorts, a CSF Aβ42/40 ratio ≥ 7.1% was associated with a low risk of a positive Aβ PET scan (negative predictive value: 94.3%). Implementing two cutoffs revealed 14% to 16% of patients with intermediate results (CSF Aβ42/40 ratio: 5.5%-7.1%), which had a strong benefit from Aβ PET imaging (44%-52% Aβ PET positivity).
DISCUSSION: A two-cutoff approach for CSF Aβ42/40 including Aβ PET imaging at intermediate results provides an effective assessment of Aβ pathology in real-world settings.
HIGHLIGHTS: We evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) amyloid beta (Aβ) biomarkers for Alzheimer's disease in real-world cohorts.A CSF Aβ 42/40 ratio between 5.5% and 7.1% defines patients at borderline levels.Patients at borderline levels strongly benefit from additional Aβ PET imaging.Two-cutoff CSF Aβ 42/40 and PET will allow effective treatment stratification.}, }
@article {pmid39583650, year = {2024}, author = {Fletcher, E and Gavett, B and Farias, ST and Widaman, K and Whitmer, R and Fan, AP and Corrada, M and DeCarli, C and Mungas, D}, title = {A data-driven, multi-domain brain gray matter signature as a powerful biomarker associated with several clinical outcomes.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {16}, number = {4}, pages = {e70026}, pmid = {39583650}, issn = {2352-8729}, support = {R01 AG050782/AG/NIA NIH HHS/United States ; R01 AG052132/AG/NIA NIH HHS/United States ; R01 AG056519/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Characterizing pathological changes in the brain that underlie cognitive impairment, including Alzheimer's disease and related disorders, is central to clinical concerns of prevention, diagnosis, and treatment.
METHODS: We describe the properties of a brain gray matter region ("Union Signature") that is derived from four behavior-specific, data-driven signatures in a discovery cohort.
RESULTS: In a separate validation set, the Union Signature demonstrates clinically relevant properties. Its associations with episodic memory, executive function, and Clinical Dementia Rating Sum of Boxes are stronger than those of several standardly accepted brain measures (e.g., hippocampal volume, cortical gray matter) and other previously developed brain signatures. The ability of the Union Signature to classify clinical syndromes among normal, mild cognitive impairment, and dementia exceeds that of the other measures.
DISCUSSION: The Union Signature is a powerful, multipurpose correlate of clinically relevant outcomes and a strong classifier of clinical syndromes.
HIGHLIGHTS: Data-driven brain signatures are potentially valuable in models of cognitive aging.In previous work, we outlined rigorous validation of signatures for memory.This work demonstrates a signature predicting multiple clinical measures.This could be useful in models of interventions for brain support of cognition.}, }
@article {pmid39582467, year = {2024}, author = {Galvani, F and Cammarota, M and Vacondio, F and Rivara, S and Boscia, F}, title = {Protective Activity of Melatonin Combinations and Melatonin-Based Hybrid Molecules in Neurodegenerative Diseases.}, journal = {Journal of pineal research}, volume = {76}, number = {8}, pages = {e70008}, pmid = {39582467}, issn = {1600-079X}, support = {//This study was supported by EMBO; Regione Emilia-Romagna; Ministero dell'Istruzione, dell'Università e della Ricerca./ ; }, mesh = {*Melatonin/therapeutic use/pharmacology ; Humans ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {The identification of protective agents for the treatment of neurodegenerative diseases is the mainstay therapeutic goal to modify the disease course and arrest the irreversible disability progression. Pharmacological therapies synergistically targeting multiple pathogenic pathways, including oxidative stress, mitochondrial dysfunction, and inflammation, are prime candidates for neuroprotection. Combination or synergistic therapy with melatonin, whose decline correlates with altered sleep/wake cycle and impaired glymphatic "waste clearance" system in neurodegenerative diseases, has a great therapeutic potential to treat inflammatory neurodegenerative states. Despite the protective outcomes observed in preclinical studies, mild or poor outcomes were observed in clinical settings, suggesting that melatonin combinations promoting synergistic actions at appropriate doses might be more suitable to treat multifactorial neurodegenerative disorders. In this review, we first summarize the key melatonin actions and pathways contributing to cell protection and its therapeutic implication in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). We remark the major controversies in the field, mostly generated by the lack of a common consensus for the optimal dosing, molecular targets, and toxicity. Then, we review the literature investigating the efficacy of melatonin combinations with approved or investigational neuroprotective agents and of melatonin-containing hybrid molecules, both in vitro and in animal models of AD, PD, and MS, as well as the efficacy of add-on melatonin in clinical settings. We highlight the rationale for such melatonin combinations with a focus on the comparison with single-agent treatment and on the assays in which an additive or a synergistic effect has been achieved. We conclude that a better characterization of the mechanisms underlying such melatonin synergistic actions under neuroinflammation at appropriate doses needs to be tackled to advance successful clinical translation of neuroprotective melatonin combination therapies or melatonin-based hybrid molecules.}, }
@article {pmid39582341, year = {2025}, author = {Heo, JJ and Han, YE and Kim, MS and Cheong, E and Choi, CW and Oh, SJ}, title = {Suffruticosol B from Paeonia lactiflora Ameliorates Alzheimer's Disease Pathology by Inhibiting MAO-B Activity.}, journal = {Phytotherapy research : PTR}, volume = {39}, number = {2}, pages = {593-603}, doi = {10.1002/ptr.8395}, pmid = {39582341}, issn = {1099-1573}, support = {NRF-2022R1A2C2006229//National Research Foundation of Korea/ ; 2E32851//Korea Institute of Science and Technology/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Paeonia/chemistry ; *Monoamine Oxidase/metabolism ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *Astrocytes/drug effects ; Male ; Monoamine Oxidase Inhibitors/pharmacology/chemistry ; gamma-Aminobutyric Acid/metabolism ; Neuroprotective Agents/pharmacology ; Mice, Inbred C57BL ; Maze Learning/drug effects ; }, abstract = {Monoamine oxidase B (MAO-B) has emerged as a therapeutic target for Alzheimer's disease (AD) due to its involvement in the synthesis of γ-aminobutyric acid (GABA) in reactive astrocytes, which inhibits neuronal activity. Suffruticosol B (Suf-B), isolated from Paeonia lactiflora, is one of the resveratrol oligomers. Although resveratrol oligomers have demonstrated neuroprotective effects, it remains unexplored whether Suf-B exerts therapeutic effects on AD by targeting MAO-B. In this study, we investigated whether Suf-B alleviates AD pathology by mitigating reactive astrogliosis and inhibiting the overproduction of astrocytic GABA. After confirming the MAO-B inhibitory effect of Suf-B through MAO-B enzyme assay, we administered Suf-B to APP/PS1 AD model mice. To test the potential therapeutic action of Suf-B in AD, a series of experiments were conducted, including behavioral tests such as the open field test, novel object recognition test, Barnes maze test, passive avoidance test, as well as immunohistochemistry and whole-cell patch-clamp recordings. We found that Suf-B markedly inhibited MAO-B activity without causing cytotoxicity. Immunohistochemistry and electrophysiology experiments demonstrated that Suf-B significantly reduced astrocyte reactivity, as well as an aberrant increase in GABA production and tonic GABA release from astrocytes in AD. Behavior test results indicated that Suf-B treatment restored cognitive function in APP/PS1 mice. In conclusion, Suf-B effectively reduces excessive GABA production in reactive astrocytes by inhibiting MAO-B, normalizing aberrant inhibition in hippocampal neurons in an AD mouse model. These results suggest that Suf-B has potential as a treatment for AD and may be applicable to other brain diseases associated with reactive astrogliosis.}, }
@article {pmid39582031, year = {2024}, author = {Ji, Q and Lv, Y and Hu, B and Su, Y and Shaikh, II and Zhu, X}, title = {Study on the therapeutic potential of induced neural stem cells for Alzheimer's disease in mice.}, journal = {Biological research}, volume = {57}, number = {1}, pages = {89}, pmid = {39582031}, issn = {0717-6287}, support = {22PJD065//Shanghai Pujiang Program/ ; }, mesh = {Animals ; *Alzheimer Disease/therapy ; *Neural Stem Cells/transplantation ; *Mice, Transgenic ; *Cell Differentiation ; *Valproic Acid/therapeutic use ; *SOXB1 Transcription Factors/metabolism ; Mice ; Disease Models, Animal ; Fibroblasts/transplantation ; Hippocampus/cytology ; Neurons/transplantation ; }, abstract = {Induced neural stem cells (iNSCs), which have similar properties to neural stem cells and are able to self-proliferate and differentiate into neural cell lineages, are expected to be potential cells for the treatment of neurodegeneration disease. However, cell therapy based on iNSCs transplantation is limited by the inability to acquire sufficient quantities of iNSCs. Previous studies have found that mouse and human fibroblasts can be directly reprogrammed into iNSCs with a single factor, Sox2. Here, we induced mouse embryonic fibroblasts (MEFs) into iNSCs by combining valproic acid (VPA) with the induction factor Sox2, and the results showed that VPA significantly improved the conversion efficiency of fibroblasts to iNSCs. The iNSCs exhibited typical neurosphere-like structures that can express NSCs markers, such as Sox2, Nestin, Sox1, and Zbtb16, and could differentiate into neurons, astrocytes, and oligodendrocytes in vitro. Subsequently, the iNSCs were stereotactically transplanted into the hippocampus of APP/PS1 double transgenic mice (AD mice). Post-transplantation, the iNSCs showed long-term survival, migrated over long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Importantly, the cognitive abilities of APP/PS1 mice transplanted with iNSCs exhibited significant functional recovery. These findings suggest that VPA enhances the conversion efficiency of fibroblasts into iNSCs when used in combination with Sox2, and iNSCs hold promise as a potential donor material for transplantation therapy in Alzheimer's disease.}, }
@article {pmid39581531, year = {2025}, author = {Liu, Z and Yoon, CS and Lee, H and Kim, E and Yim, JH and Kim, TK and Oh, H and Lee, DS}, title = {The neuroprotective and anti-neuroinflammatory effects of ramalin synthetic derivatives in BV2 and HT22 cells.}, journal = {Biochemical pharmacology}, volume = {231}, number = {}, pages = {116654}, doi = {10.1016/j.bcp.2024.116654}, pmid = {39581531}, issn = {1873-2968}, mesh = {*Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Animals ; Mice ; Cell Line ; Anti-Inflammatory Agents/pharmacology/chemistry/chemical synthesis ; Cell Survival/drug effects/physiology ; Apoptosis/drug effects ; Coculture Techniques ; NF-kappa B/metabolism/antagonists & inhibitors ; Dose-Response Relationship, Drug ; Neuroinflammatory Diseases/drug therapy/metabolism ; }, abstract = {Ramalin, a strong antioxidant isolated from Antarctic lichens, has been shown to have potential therapeutic effects in the treatment of Alzheimer's disease. However, this compound is readily degraded in aqueous solutions, which restricts its development as a therapeutic agent. With a view toward addressing this problem, in this study, we modified the structure of ramalin to obtain more stable compounds and attempted to identify a derivative with the strongest neuroprotective properties. We synthesized a total of 20 ramalin derivatives, among which, RA-2 N was demonstrated to have the best neuroprotective effects, not only inhibiting inflammation in BV2 cells but also inhibiting inflammation-induced HT22 cell apoptosis in BV2-HT22 co-culture models. Moreover, we established that these effects were associated with an inhibition of the nuclear translocation of nuclear factor kappa-B (NF-κB). Our findings in this study revealed that the synthesis of ramalin derivatives is an effective approach for stabilizing this compound for therapeutic purposes. Given its modified structure, the RA-2 N derivative can inhibit inflammation and protect nerve cells, and thus indicate its potential application as a drug for treating neurodegenerative diseases.}, }
@article {pmid39581354, year = {2025}, author = {Zhang, Y and Chen, J and Li, Y and Jiao, B and Luo, S}, title = {Disease-modifying therapies for Alzheimer's disease: Clinical trial progress and opportunity.}, journal = {Ageing research reviews}, volume = {103}, number = {}, pages = {102595}, doi = {10.1016/j.arr.2024.102595}, pmid = {39581354}, issn = {1872-9649}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors/immunology ; Clinical Trials as Topic ; *Antibodies, Monoclonal, Humanized/pharmacology/therapeutic use ; }, abstract = {The U.S. Food and Drug Administration (FDA) recently approved lecanemab and donanemab for the treatment of early symptomatic Alzheimer's disease (AD) after their phase III trials reached endpoints. These two anti-amyloid β monoclonal antibodies represent the latest promise of disease-modifying therapy (DMT) for AD, which undoubtedly reignites new hope for DMTs to combat the staggering financial and human costs of AD. However, in addition to these two successful antibodies, there have been enormous efforts to develop DMTs in various aspects to meet the therapeutic requirement of AD. In this review, we delineate the core principles and methodologies of diverse DMTs, covering the advances in clinical trials of drug candidates that either have been discontinued, completed, or are ongoing, as well as brain stimulation and lifestyle interventions. In addition, by overseeing the fate of various candidate molecules, we hope to provide references and ideas for prospective approaches and promising applications of DTMs for AD, particularly in terms of universality and clinical application economics, to optimize efficacy and maximize AD patient benefits in the future.}, }
@article {pmid39581349, year = {2025}, author = {Chen, P and Lin, WL and Liu, XY and Li, SJ and Chen, RF and Hu, ZH and Lin, PT and Lin, MH and Shi, MY and Wu, W and Wang, Y and Lin, QS and Ye, ZC}, title = {D30 Alleviates β2-Microglobulin-Facilitated Neurotoxic Microglial Responses in Isoflurane/Surgery-Induced Cognitive Dysfunction in Aged Mice.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {105}, number = {2}, pages = {102190}, doi = {10.1016/j.labinv.2024.102190}, pmid = {39581349}, issn = {1530-0307}, mesh = {Animals ; *Microglia/metabolism/drug effects ; Male ; *Isoflurane/adverse effects/pharmacology ; *Mice, Inbred C57BL ; Mice ; *Postoperative Cognitive Complications/metabolism ; *beta 2-Microglobulin/metabolism ; Humans ; Disease Models, Animal ; Anesthetics, Inhalation/adverse effects ; Cognitive Dysfunction/metabolism ; }, abstract = {Postoperative cognitive dysfunction (POCD) is a common complication with no effective treatment in elderly patients. POCD, Alzheimer disease (AD), and many other cognitive diseases mostly involve neurotoxic microglia response, and recently, β2-microglobulin (B2M) has been suggested to play a pivotal role. A novel pyromeconic acid-styrene hybrid compound D30 was synthesized by our team and shown to be safe and effective in some neurodegenerative mouse models. In this study, we evaluated D30 on POCD and its potential mechanism. Fourteen- to 18-month-old male C57BL/6 mice were used to establish POCD through isoflurane anesthesia and surgery. The plasma of elderly patients was collected pre- and postoperatively. Primary mouse microglia were subjected to various stimulations in multiple experimental designs to imitate in vivo POCD-like conditions. Morris water maze, fear conditioning, western blot, immunofluorescent staining, and blood-brain barrier (BBB) permeability tests were conducted in this study. D30 administration significantly improved learning and memory in aged mice following POCD. Neurotoxic M1 microglia cells were dramatically increased following POCD, manifested as morphologically changing into fewer and shorter branches, enlarged somatic areas, and upregulated expression of iNOS and C1q. Notably, following POCD, B2M was significantly upregulated in the plasma and the brain. D30 treatment significantly suppressed these pathologic changes, by inhibiting the POCD-induced BBB breakdown while suppressing the surge of plasma B2M levels. D30 treatment suppressed POCD-induced surge of B2M and Aβ plaques in the brain and preserved adult hippocampal neurogenesis vulnerable to POCD. Furthermore, postoperative levels of B2M were significantly elevated over the preoperative levels in patients aged 80 years and over. In parallel with mouse plasma after POCD, the postoperative patient plasma was also much more effective at activating M1 microglia. Of note, this POCD plasma-induced activation of M1 microglia was largely prevented by D30 treatment. Taken together, by inhibiting the surge of plasma B2M, protecting BBB integrity, and reducing inflammatory response, D30 protected aged mice from B2M-facilitated POCD.}, }
@article {pmid39580762, year = {2024}, author = {Gwon, HJ and Cho, W and Choi, SW and Lim, DS and Tanriverdi, EÇ and Abd El-Aty, AM and Jeong, JH and Jung, TW}, title = {Donepezil improves skeletal muscle insulin resistance in obese mice via the AMPK/FGF21-mediated suppression of inflammation and ferroptosis.}, journal = {Archives of pharmacal research}, volume = {47}, number = {12}, pages = {940-953}, pmid = {39580762}, issn = {1976-3786}, support = {2022R1A2B5B01001453//National research foundation (KR)/ ; }, mesh = {Animals ; *Donepezil/pharmacology/therapeutic use ; *Insulin Resistance ; Mice ; *Muscle, Skeletal/drug effects/metabolism ; *Inflammation/drug therapy/metabolism ; Male ; *Fibroblast Growth Factors/metabolism ; *Mice, Inbred C57BL ; *Diet, High-Fat/adverse effects ; *AMP-Activated Protein Kinases/metabolism ; *Obesity/drug therapy/metabolism ; Mice, Obese ; Cells, Cultured ; }, abstract = {Donepezil has traditionally been used in Alzheimer's disease treatment and is known for its ability to alleviate neural inflammation and apoptosis. However, its impact on insulin signaling remains unexplored. This study sought to elucidate the novel role of donepezil in mitigating skeletal muscle insulin resistance under hyperlipidemic conditions. Western blot analysis was used to assess the expression of various proteins of interest, whereas a glucose uptake assay was performed in skeletal muscle cells via commercially available kits. An in vitro model of obesity was developed using palmitate. These in vitro findings were corroborated in vivo via insulin resistance models established through high-fat diet (HFD) feeding in mice. Intraperitoneal glucose tolerance tests and insulin tolerance tests were performed on the experimental mice. The results revealed that donepezil treatment improved insulin signaling and inflammation in palmitate-treated C2C12 myocytes and the skeletal muscle of HFD-fed mice. Notably, donepezil treatment augmented FGF21 expression and AMPK phosphorylation in the myocytes and skeletal muscle of HFD-fed mice. Knockdown of FGF21 or AMPK via siRNA reversed the effects of donepezil on insulin signaling and inflammation in cultured myocytes. We also found that donepezil ameliorated skeletal muscle insulin resistance via the FGF21-mediated suppression of ferroptosis under hyperlipidemic conditions. These findings suggest that donepezil enhances the FGF21/AMPK axis, thereby mitigating inflammation and insulin resistance in skeletal muscle. This study introduces a novel therapeutic approach for treating Alzheimer's disease patients with insulin resistance.}, }
@article {pmid39580468, year = {2024}, author = {Kovacech, B and Cullen, NC and Novak, P and Hanes, J and Kontsekova, E and Katina, S and Parrak, V and Fresser, M and Vanbrabant, J and Feldman, HH and Winblad, B and Stoops, E and Vanmechelen, E and Zilka, N}, title = {Post hoc analysis of ADAMANT, a phase 2 clinical trial of active tau immunotherapy with AADvac1 in patients with Alzheimer's disease, positive for plasma p-tau217.}, journal = {Alzheimer's research & therapy}, volume = {16}, number = {1}, pages = {254}, pmid = {39580468}, issn = {1758-9193}, mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/blood/therapy/immunology ; Female ; Male ; Double-Blind Method ; Aged ; Immunotherapy, Active/methods ; Aged, 80 and over ; Middle Aged ; Treatment Outcome ; Biomarkers/blood ; Mental Status and Dementia Tests ; }, abstract = {BACKGROUND: The spread of tau pathology closely correlates with the disease course and cognitive decline in Alzheimer's disease (AD). Tau-targeting immunotherapies are being developed to stop the spread of tau pathology and thus halt disease progression. In this post hoc analysis of the ADAMANT clinical trial, we examined the performance of AADvac1, an active immunotherapy targeting the microtubule-binding region (MTBR) of tau, in a subgroup of participants with elevated plasma p-tau217, indicating AD-related neuropathological changes.
METHODS: ADAMANT was a 24-month, randomized, placebo-controlled, parallel-group, double-blinded, multicenter, phase 2 clinical trial in subjects with mild AD. The trial participants were randomized 3:2 to receive six doses of AADvac1 or placebo at 4-week intervals, followed by five booster doses at 14-week intervals. The primary outcome was safety. The secondary outcomes were the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Alzheimer's Disease Cooperative Study - Activities of Daily Living score for Mild Cognitive Impairment 18-item version (ADCS-ADL-MCI-18), and immunogenicity. Volumetric MRI, plasma neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were exploratory outcomes. The inclusion criterion for this post-hoc analysis was a baseline plasma p-tau217 level above the cutoff for AD.
RESULTS: Among 196 ADAMANT participants, 137 were positive for plasma p-tau217 (mean age 71.4 years, 59% women). AADvac1 was safe and well tolerated in this subgroup. AADvac1 reduced the rate of accumulation of log-plasma NfL by 56% and that of GFAP by 73%. The treatment differences in the CDR-SB and ADCS-ADL-MCI-18 scores favored AADvac1 but were not statistically significant. AADvac1 had no effect on whole-brain volume but nonsignificantly reduced the loss of brain cortical tissue in several regions. Importantly, the impact on the study outcomes was more pronounced in participants with higher anti-tau antibody levels.
CONCLUSIONS: These results suggest that AADvac1 tau immunotherapy can reduce plasma biomarkers of neurodegeneration and neuroinflammation. These findings and possible observations on brain atrophy and cognition are hypothesis-generating and warrant further evaluation in a larger clinical trial.
TRIAL REGISTRATION: EudraCT 2015-000630-30 (primary) and NCT02579252.}, }
@article {pmid39579243, year = {2024}, author = {Alexandre-Silva, V and Soares-Silva, B and Pereira, GC and Custódio-Silva, AC and Carvalhinho-Lopes, PS and Taliano, LO and Lambertucci, RH and Cavalcante, MD and de Souza Araújo, AA and Quintans-Júnior, L and Dos Santos, JR and Ribeiro, AM}, title = {Eplingiella fruticosa leaf essential oil complexed with β-cyclodextrin exerts a neuroprotective effect in an Alzheimer's disease animal model induced by Streptozotocin.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {40}, pmid = {39579243}, issn = {1573-7365}, support = {20/12053-5//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 21/12409-7//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 20/09015-4//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; Finance Code 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 425694/2016-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 303325/2017-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 408377/2021-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 310403/2021-9//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; Male ; *Rats, Wistar ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Streptozocin ; *Oils, Volatile/pharmacology/therapeutic use ; *beta-Cyclodextrins/pharmacology/therapeutic use ; Rats ; *Disease Models, Animal ; *Plant Leaves/chemistry ; *Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Brain/drug effects/metabolism ; tau Proteins/metabolism ; }, abstract = {Alzheimer's Disease (AD) is physiopathologically marked by an accumulation of beta-amyloid peptide (Aβ), hyperphosphorylation of tau protein, inflammation, and oxidative stress in the brain tissue. While new drugs for AD have been approved, novel treatments are still needed. Eplingiella fruticosa (EF) has demonstrated anti-inflammatory and antioxidant properties, which may be beneficial against AD. This study aimed to evaluate the effects of EF leaf essential oil complexed with β-cyclodextrin in a sporadic AD model induced by streptozotocin (STZ). Male Wistar rats (5-6 months old) received an intracerebroventricular STZ injection (3 mg/kg) or vehicle, and were orally treated with vehicle, EF (5 mg/kg), or donepezil (5 mg/kg) for 14 days. Behavioral tests included olfactory discrimination, open field, novel object recognition, sucrose preference, and spontaneous alternation. Upon completion, rats were euthanatized, and their brains were analyzed for Aβ, tau, and IL-1β via immunohistochemistry, and for oxidative stress markers. STZ-treated rats showed memory deficits and anhedonia, accompanied by increased Aβ, tau, and IL-1β immunoreactivity in the olfactory bulb, cortex, hippocampus, and increased TBARS levels in the hippocampus. On the other hand, EF treatment improved short-term and working memory (p < 0.001), and reduced depressive-like behavior (p = 0.02). Additionally, EF treatment decreased Aβ, tau, and IL-1β immunoreactivity in the olfactory bulb, hippocampus and cortex (p < 0.05), and reduced TBARS levels (p = 0.04) and total oxidant status in the hippocampus (p = 0.03), and increased total antioxidant status in the cortex (p = 0.04). These findings suggest EF has neuroprotective effects against STZ-induced damage, indicating its potential as a novel compound for AD treatment.}, }
@article {pmid39577812, year = {2024}, author = {Li, N and Wang, X and Lin, R and Yang, F and Chang, HC and Gu, X and Shu, J and Liu, G and Yu, Y and Wei, W and Bao, Z}, title = {ANGPTL4-mediated microglial lipid droplet accumulation: Bridging Alzheimer's disease and obesity.}, journal = {Neurobiology of disease}, volume = {203}, number = {}, pages = {106741}, doi = {10.1016/j.nbd.2024.106741}, pmid = {39577812}, issn = {1095-953X}, mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Animals ; *Angiopoietin-Like Protein 4/metabolism/genetics ; *Obesity/metabolism ; *Microglia/metabolism ; Mice ; Humans ; Male ; *Lipid Droplets/metabolism ; Female ; Mice, Inbred C57BL ; Aged ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; }, abstract = {Increasing evidence suggests that metabolic disorders such as obesity are implicated in the development of Alzheimer's disease (AD). The pathological buildup of lipids in microglia is regarded as a key indicator in brain aging and the progression of AD, yet the mechanisms behind this process remain uncertain. The adipokine ANGPTL4 is strongly associated with obesity and is thought to play a role in the advancement of neurodegenerative diseases. This study utilized RNA sequencing to identify differential expression in lipid-accumulating BV2 microglia and investigated the potential mechanism through ANGPTL4 overexpression in BV2. Subsequently, animal models and clinical data were employed to further explore alterations in circulating ANGPTL4 levels in AD. RNA sequencing results indicated a correlation between ANGPTL4 and microglial lipid accumulation. The overexpression of ANGPTL4 in microglia resulted in increased secretion of inflammatory factors, elevated oxidative stress levels, and diminished antiviral capacity. Furthermore, when simulating the coexistence of AD and obesity through combined treatment with Amyloid-Beta 1-42 peptide (Aβ) and Free Fatty Acids (FFA) in vitro, we observed a notable upregulation of ANGPTL4 expression, highlighting its potential role in the interplay between AD and obesity. In vivo experiments, we also observed a significant increase in ANGPTL4 expression in the hippocampus and plasma of APP/PS1 mice compared to wild-type controls. This was accompanied by heightened microglial activation and reduced expression of longevity-related genes in the hippocampus. Clinical data from the UK Biobank indicated that plasma ANGPTL4 levels are elevated in patients with AD when compared to healthy controls. Moreover, significantly higher ANGPTL4 levels were observed in obese AD patients relative to their non-obese counterparts. Our findings suggest that ANGPTL4-mediated microglial aging may serve as a crucial link between AD and obesity, proposing ANGPTL4 as a potential biomarker for AD.}, }
@article {pmid39577714, year = {2025}, author = {Wang, L and Li, W and Wu, W and Liu, Q and You, M and Liu, X and Ye, C and Chen, J and Tan, Q and Liu, G and Du, Y}, title = {Effects of electroacupuncture on microglia phenotype and epigenetic modulation of C/EBPβ in SAMP8 mice.}, journal = {Brain research}, volume = {1849}, number = {}, pages = {149339}, doi = {10.1016/j.brainres.2024.149339}, pmid = {39577714}, issn = {1872-6240}, mesh = {Animals ; *Microglia/metabolism ; *Electroacupuncture/methods ; *CCAAT-Enhancer-Binding Protein-beta/metabolism/genetics ; Mice ; *Epigenesis, Genetic ; *Alzheimer Disease/therapy/metabolism/genetics ; *Phenotype ; Male ; Disease Models, Animal ; Cytokines/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), an age-progressive neurodegenerative disease, is featured by a relentless deterioration of cognitive abilities. In parallel with the hypotheses of Aβ and tau, microglia-mediated neuroinflammation is a core pathological hallmark of AD. Promoting the transition of microglia from M1 to M2 phenotype and inhibition of neuroinflammatory response provide new insights into the treatment of AD. And substantial studies have confirmed that overexpression of C/EBPβ accelerates the progression of AD pathology. Acupuncture is renowned for its unique advantages including safety and effectiveness, which has gained wide application in geriatric diseases, and thoroughly exploring the mechanism for its treatment of AD will provide scientific basis for its clinical application.
METHODS: In this study, SAMP8 mice were employed and EA therapy was performed as the main intervention. The combination of behavioural experiments (including water maze and novel objective recognition), Immunofluorescence, Western blot, and Chip-qPCR assay were performed to compare between different groups.
RESULTS: EA therapy facilitates the polarization of microglia from M1 to M2 phenotype, reduces pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) and promotes the expression of anti-inflammatory factors (IL-4 and IL-10), as well as attenuates neuroinflammation. Simultaneously, EA also inhibits the enrichment of H3K9ac at C/EBPβ promoter region and expression of C/EBPβ. Thus, it was evident that EA had a favorable effect on ameliorating cognitive decline in SAMP8 mice.
CONCLUSION: EA therapy may ameliorate cognitive deficits in AD via facilitating microglia shift from M1 to M2 phenotype and epigenetically regulating C/EBPβ. And further studies are required to better understand how the mechanism between microglia and epigenetic modulation of C/EBPβ are effective in reversing AD.}, }
@article {pmid39577557, year = {2025}, author = {Hu, L and Tang, Q and Meng, F and Xu, Y and Chen, W and Xu, S}, title = {TCM-ADIP: A Multidimensional Database Linking Traditional Chinese Medicine to Functional Brain Zones of Alzheimer's Disease.}, journal = {Journal of molecular biology}, volume = {437}, number = {6}, pages = {168874}, doi = {10.1016/j.jmb.2024.168874}, pmid = {39577557}, issn = {1089-8638}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; *Medicine, Chinese Traditional ; *Brain/metabolism/drug effects/pathology ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Databases, Factual ; Computational Biology/methods ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder, with existing therapeutic drugs typically targeting specific disease stages. Traditional Chinese medicine (TCM), known for its multi-target and multi-mechanism therapeutic approach, has demonstrated efficacy in treating various stages of AD. In the present work, through a systematic review of classical Chinese medical texts, the formulae for preventing and treating AD were identified. Meanwhile, the active ingredients within these formulae were extracted and cataloged. A comprehensive bioinformatics analysis of omics data was performed to identify differentially expressed genes across different functional brain zones in AD patients at various stages. Finally, by integrating the multidimensional data, we proposed the first database, TCM-ADIP, dedicated to TCM based AD prevention and treatment, which is freely available at https://cbcb.cdutcm.edu.cn/TCM-ADIP/. TCM-ADIP not only supports interactive searching of multidimensional data, but also provides tools for gene localization and functional enrichment analysis of formulae, herbs, and ingredients for AD intervention in specific brain zones. TCM-ADIP fills a crucial gap in existing databases, offering a comprehensive resource for TCM in the treatment of AD.}, }
@article {pmid39577488, year = {2025}, author = {Pawar, R and Pandey, D and Naqvi, S and Sharma, A}, title = {Critical role of hydrogen sulfide in the management of neurodegenerative disease.}, journal = {Nitric oxide : biology and chemistry}, volume = {154}, number = {}, pages = {77-85}, doi = {10.1016/j.niox.2024.11.006}, pmid = {39577488}, issn = {1089-8611}, mesh = {*Hydrogen Sulfide/metabolism/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Hydrogen sulfide has been known to humans for about 300 years and the previous studies emphasize only on its toxic side effects. In the last two decennium, researchers have varied their perspectives and insights towards H2S biology based on experimental findings. It has been found that H2S is an endogenic gaseous signaling molecule in many organisms and plays a crucial role in many systems and diseases. Early reports suggest that H2S as a neuromodulator influences calcium levels within the brain cells which ultimately control memory, learning, and cognition. It has also been observed that some complications in the pathogenesis of neurodegenerative diseases are due to anomalies in the biosynthesis and metabolism of H2S. This review focuses on the role of H2S in the pathophysiology of major neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Vascular dementia. H2S was observed to have a protective role in the above-mentioned neurological conditions and the H2S donor therapy may help in disease management. The H2S gas displays a neuroprotective role and protects against cellular damage thereby declining the neurological conditions. Some studies have revealed that treatment with H2S donors has improved neuronal damage, restored memory and cognition in animal models. In this review, we have discussed the role of H2S donors as neuroprotective agents with examples of some of the natural and synthetic H2S donors, and also briefly enumerated the molecules used to detect H2S in neurodegenerative diseases.}, }
@article {pmid39577323, year = {2024}, author = {Gao, QC and Liu, GL and Wang, Q and Zhang, SX and Ji, ZL and Wang, ZJ and Wu, MN and Yu, Q and He, PF}, title = {A promising drug repurposing approach for Alzheimer's treatment: Givinostat improves cognitive behavior and pathological features in APP/PS1 mice.}, journal = {Redox biology}, volume = {78}, number = {}, pages = {103420}, pmid = {39577323}, issn = {2213-2317}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *Drug Repositioning ; *Carbamates/pharmacology/therapeutic use ; *Disease Models, Animal ; Humans ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mitochondria/metabolism/drug effects ; Cognition/drug effects ; Amyloid beta-Peptides/metabolism ; Hippocampus/metabolism/drug effects/pathology ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by memory loss, speech and motor defects, personality changes, and psychological disorders. The exact cause of AD remains unclear. Current treatments focus on maintaining neurotransmitter levels or targeting β-amyloid (Aβ) protein, but these only alleviate symptoms and do not reverse the disease. Developing new drugs is time-consuming, costly, and has a high failure rate. Utilizing multi-omics for drug repositioning has emerged as a new strategy. Based on transcriptomic perturbation data of over 40,000 drugs in human cells from the LINCS-L1000 database, our study employed the Jaccard index and hypergeometric distribution test for reverse transcriptional feature matching analysis, identifying Givinostat as a potential treatment for AD. Our research found that Givinostat improved cognitive behavior and brain pathology in models and enhanced hippocampal synaptic plasticity. Transcriptome sequencing revealed increased expression of mitochondrial respiratory chain complex proteins in the brains of APP/PS1 mice after Givinostat treatment. Functionally, Givinostat restored mitochondrial membrane potential, reduced reactive oxygen species, and increased ATP content in Aβ-induced HT22 cells. Additionally, it improved mitochondrial morphology and quantity in the hippocampus of APP/PS1 mice and enhanced brain glucose metabolic activity. These effects are linked to Givinostat promoting mitochondrial biogenesis and improving mitochondrial function. In summary, Givinostat offers a promising new strategy for AD treatment by targeting mitochondrial dysfunction.}, }
@article {pmid39577079, year = {2024}, author = {Sasaki, K and Fujita, H and Sato, T and Kato, S and Takahashi, Y and Takeshita, Y and Kanda, T and Saito, T and Saido, TC and Hattori, S and Hozumi, Y and Yamada, Y and Waki, H}, title = {GLP-1 receptor signaling restores aquaporin 4 subcellular polarization in reactive astrocytes and promotes amyloid β clearance in a mouse model of Alzheimer's disease.}, journal = {Biochemical and biophysical research communications}, volume = {741}, number = {}, pages = {151016}, doi = {10.1016/j.bbrc.2024.151016}, pmid = {39577079}, issn = {1090-2104}, mesh = {Animals ; *Aquaporin 4/metabolism/genetics ; *Astrocytes/metabolism/drug effects ; *Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *Signal Transduction ; *Disease Models, Animal ; *Glucagon-Like Peptide-1 Receptor/metabolism/genetics ; Mice ; Liraglutide/pharmacology ; Mice, Transgenic ; Mice, Inbred C57BL ; Male ; Humans ; Peptide Fragments/metabolism ; Cell Polarity/drug effects ; Cerebral Cortex/metabolism/pathology/drug effects ; }, abstract = {The physiological actions of a gut hormone, glucagon-like peptide-1 (GLP-1), in Alzheimer's disease (AD) brain remain poorly understood, although GLP-1 receptor (GLP-1R) expression in this organ has been shown in several experimental studies. Therefore, we explored whether the GLP-1R signaling promotes the clearance of amyloid β (Aβ) (1-42) which is a core pathological hallmark of AD, focusing on the water channel protein aquaporin 4 (AQP4) localized to astrocyte endfeet perivascular membranes in intact brain. First, we confirmed that Glp1r mRNA is predominantly expressed at perivascular site of astrocytes in normal mouse cerebral cortex through in situ hybridization analysis. Next, we observed that 20-week subcutaneous administration of a GLP-1R agonist (GLP-1RA) liraglutide significantly reduced Aβ (1-42) accumulation in the cerebral cortex and improved spatial working memory in an AD mouse model, App[NL-G-F/NL-G-F] mice. Furthermore, our current data revealed that the 4-week liraglutide treatment relocalized subcellular AQP4 in morphologically injured reactive astrocytes of App[NL-G-F/NL-G-F] mice to the cell surface perivascular site through PKA-mediated AQP4 phosphorylation. Such translocation of phosphorylated AQP4 to astrocyte cell surface following incubation with liraglutide was observed also in the present in vitro study using the cell line in which AQP4 cDNA was introduced into immortalized human astrocyte. These results suggest that enhanced intracerebral GLP-1R signaling following peripheral administration of GLP-1RA restores AQP4 subcellular polarization in reactive astrocytes and would promote Aβ excretion possibly through increasing AQP4-mediated intracerebral water flux in the brain in AD.}, }
@article {pmid39576427, year = {2024}, author = {Cui, T and Yu, P and Feng, X and Song, Q and Yang, D and Li, M and Feng, L}, title = {Elucidation of the inhibitory effects of Jiedu Yizhi formula on neuronal apoptosis in the treatment of Alzheimer's disease based on network pharmacology and in vivo experiments.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {38}, pmid = {39576427}, issn = {1573-7365}, support = {ZR2023QH159//Natural Science Foundation of Shandong/ ; 202313011384//Shandong Province Medical Health Science and Technology Development Plan Project/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Apoptosis/drug effects ; *Network Pharmacology ; Mice ; *Neurons/drug effects/metabolism ; *Molecular Docking Simulation ; Male ; Protein Interaction Maps/drug effects ; Hippocampus/drug effects/metabolism ; }, abstract = {OBJECTIVE: This study aimed to investigate the mechanism of action of Jiedu Yizhi formula (JDYZF) in the treatment of Alzheimer's disease (AD) through network pharmacology, molecular docking technology, and in vivo experiments.
METHOD: The main active ingredients of seven herbs in the Chinese Medicine compound JDYZF were identified by searching the TCMSP database, PubChem database, CNKI, and other sources. Disease targets of AD were obtained from databases such as OMIM, TDD, DisGeNET, and DrugBank. A protein‒protein interaction (PPI) network was constructed using the STRING platform, and core targets were identified through topological analysis using Cytoscape software. Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the relevant targets were performed using the Metascape database. The main active ingredients of JDYZF and potential core targets were identified based on degree values. Molecular docking technology was used to verify the interactions between the main active ingredients and potential core targets. Furthermore, water maze tests and hematoxylin-eosin (HE) staining of brain and liver tissues were performed to evaluate the effects of JDYZF on cognitive dysfunction in AD mice and neuronal damage in hippocampal brain tissue and to assess drug toxicity. PCR was performed to determine the expression levels of the apoptosis-related genes Bcl-2, Bax, and caspase-3 and to investigate the effect of JDYZF on hippocampal apoptosis in AD mice. Results. One hundred twelve core PPI target proteins, including CASP3, TP53, and VEGFA, were found between JDYZF and AD. The KEGG pathway enrichment analysis showed significant enrichment of the MAPK signaling pathway, PI3K/AKT signaling pathway and so on. Water maze tests revealed that the high-dose JDYZF treatment significantly improved the escape latency of AD model mice. The HE staining results showed that JDYZF exerted a protective effect on neuronal damage in the hippocampus of AD mice. JDYZF could upregulate the expression of the anti-apoptotic factor Bcl-2 while downregulating the expression of the proapoptotic factors Bax and caspase-3. Conclusion. JDYZF can improve the cognitive function of AD mice by suppressing cell apoptosis.}, }
@article {pmid39576418, year = {2024}, author = {Koike, S and Tsurudome, S and Okano, S and Kishida, A and Ogasawara, Y}, title = {Dimethyl Fumarate Reduces Methylglyoxal-derived Carbonyl Stress Through Nrf2/GSH Activation in SH-SY5Y Cells.}, journal = {Neurochemical research}, volume = {50}, number = {1}, pages = {28}, pmid = {39576418}, issn = {1573-6903}, support = {21K06652//JSPS KAKENHI/ ; 22K06780//JSPS KAKENHI/ ; }, mesh = {*Dimethyl Fumarate/pharmacology ; *NF-E2-Related Factor 2/metabolism ; *Pyruvaldehyde/metabolism ; Humans ; *Glutathione/metabolism ; Cell Line, Tumor ; Glycation End Products, Advanced/metabolism ; Oxidative Stress/drug effects ; Protein Carbonylation/drug effects ; }, abstract = {Carbonyl stress refers to the excessive accumulation of advanced glycation end products (AGEs) in mammalian tissues. This phenomenon plays a significant role in the pathogenesis of various diseases, including diabetes, chronic renal failure, arteriosclerosis, and central nervous system (CNS) disorders. We have previously demonstrated that an increase in glutathione concentration, dependent on the nuclear factor erythroid 2-related factor 2 (Nrf2) system, provides a potent cytoprotective effect against Methylglyoxal (MGO)-induced carbonyl stress. Meanwhile, dimethyl fumarate (DMF), known for its Nrf2-activating effects, was recently approved as a treatment for multiple sclerosis (MS), a neurodegenerative disease. DMF is a first line therapy for relapsing-remitting MS and may also be effective for other neurodegenerative conditions. However, the detailed mechanisms by which DMF mitigates neurodegenerative pathologies remain unclear. This study investigates the impact of DMF on anticarbonyl activity and its underlying mechanism focusing on the accumulation of carbonyl protein in the cell. MGO, a glucose metabolite, was used to induce carbonylation in the neuronal cell line. MGO is a typical carbonyl compound that readily reacts with arginine and lysine residues to form AGE-modified proteins. Methylglyoxal-derived hydroimidazolone 1 (MG-H1) often forms uncharged, hydrophobic residues on the protein surface, which can affect protein distribution and lead to misfolding. Our findings indicate that DMF increases levels of glutathione (GSH), glutamate cysteine ligase modifier subunit (GCLM), and nuclear Nrf2 in SH-SY5Y cells. Importantly, DMF pretreatment significantly reduced the accumulation of MG-H1-modified proteins. Furthermore, this effect of DMF was diminished when Nrf2 expression was suppressed and when GCL, a rate-limiting enzyme in GSH synthesis, was inhibited. Thus, the increase in GSH levels, leading to the activation of the Nrf2 pathway, a key factor in DMF's ability to suppress the accumulation of MG-H1-modified proteins. This study is the first to demonstrate that DMF possesses strong anticarbonyl stress activity in neuronal cells. Therefore, future research may extend the application of DMF to other CNS diseases associated with carbonyl stress, such as Alzheimer's and Parkinson's disease.}, }
@article {pmid39576095, year = {2025}, author = {Lee, J and Ju, IG and Lim, YJ and Kim, JH and Lee, S and Choi, Y and Oh, MS and Kim, J and Kim, D}, title = {Dimethysiloxane polymer for the effective transdermal delivery of donepezil in Alzheimer's disease treatment.}, journal = {Biomaterials science}, volume = {13}, number = {5}, pages = {1189-1198}, doi = {10.1039/d4bm01368a}, pmid = {39576095}, issn = {2047-4849}, mesh = {*Donepezil/administration & dosage/chemistry/pharmacology/pharmacokinetics ; Animals ; *Alzheimer Disease/drug therapy ; *Administration, Cutaneous ; Mice ; *Siloxanes/chemistry/administration & dosage ; Polymers/chemistry/administration & dosage ; Cholinesterase Inhibitors/administration & dosage/chemistry/pharmacology/pharmacokinetics ; Disease Models, Animal ; Drug Carriers/chemistry ; Male ; Humans ; }, abstract = {Donepezil (DNZ) has been used to treat dementia associated with mild, moderate, or severe Alzheimer's disease (AD). DNZ uptake can alleviate cognitive symptoms in AD patients via acetylcholinesterase (AChE) inhibition. However, oral administration of DNZ has limitations, including first-pass metabolism, difficulties with swallowing, and low patient compliance. In this work, we disclose a novel transdermal DNZ delivery system utilizing T2 polymer, synthesized via the ring-opening polymerization of 2,2,5,5-tetramethyl-2,5-disila-1-oxacyclopentane with trifluoroacetic acid (TFA). In the in vivo studies in an AD animal model, the DNZ-loaded T2 polymer (DNZ@T2) facilitated efficient transdermal DNZ delivery to the bloodstream and improved spatial working memory and long-term memory of the AD mouse model. Both the T2 polymer and DNZ@T2 exhibited low cytotoxicity and non-significant in vivo toxicity. This research highlights a promising transdermal delivery strategy for AD treatment, potentially enhancing therapeutic efficacy and patient compliance.}, }
@article {pmid39575672, year = {2025}, author = {Mares, J and Kumar, G and Sharma, A and Emrani, S and McIntire, LB and Guo, J and Menon, V and Nuriel, T and , }, title = {APOE ε4-associated heterogeneity of neuroimaging biomarkers across the Alzheimer's disease continuum.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {1}, pages = {e14392}, pmid = {39575672}, issn = {1552-5279}, support = {R01 AG066831/AG/NIA NIH HHS/United States ; R01 AG078800/AG/NIA NIH HHS/United States ; R01 AG070202/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; K01 AG061264/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging/pathology/metabolism ; Female ; Male ; Aged ; *Apolipoprotein E4/genetics ; *Biomarkers ; *Neuroimaging ; *Brain/diagnostic imaging/pathology/metabolism ; *Amyloid beta-Peptides/metabolism ; *Cognitive Dysfunction/genetics/diagnostic imaging ; tau Proteins/metabolism ; Positron-Emission Tomography ; Aged, 80 and over ; Heterozygote ; Magnetic Resonance Imaging ; }, abstract = {INTRODUCTION: While the role of apolipoprotein E (APOE) ε4 in Alzheimer's disease (AD) susceptibility has been studied extensively, much less is known about the differences in disease presentation in APOE ε4 carriers versus non-carriers.
METHODS: To help elucidate these differences, we performed a broad analysis comparing the regional levels of six different neuroimaging biomarkers in the brains of APOE ε4 carriers versus non-carriers who participated in the Alzheimer's Disease Neuroimaging Initiative (ADNI).
RESULTS: We observed significant APOE ε4-associated heterogeneity in regional amyloid beta deposition, tau accumulation, glucose uptake, brain volume, cerebral blood flow, and white matter hyperintensities within each AD diagnostic group. We also observed important APOE ε4-associated differences in cognitively unimpaired individuals who converted to mild cognitive impairment/AD versus those who did not convert.
DISCUSSION: This observed heterogeneity in neuroimaging biomarkers between APOE ε4 carriers versus non-carriers may have important implications regarding the prevention, diagnosis, and treatment of AD in different subpopulations.
HIGHLIGHTS: An extensive study was performed on the apolipoprotein E (APOE) ε4-associated heterogeneity in neuroimaging biomarkers from the Alzheimer's Disease Neuroimaging Initiative. Robust APOE ε4-associated increases in amyloid beta (Aβ) deposition throughout the brain, in every diagnostic group, were observed. APOE ε4-associated increases in tau pathology, decreases in glucose uptake, and increases in brain atrophy, which expand in regional scope and magnitude with disease progression, were observed. Significant sex- and age-related differences in APOE ε4-associated neuroimaging biomarker heterogeneity, with overall increases in pathological presentation in female APOE ε4 carriers, were observed. Regional differences in Aβ deposition, tau accumulation, glucose uptake, ventricle size, and white matter hyperintensities were observed in cognitively normal participants who converted to mild cognitive impairment/Alzheimer's disease, which may hold potential predictive value.}, }
@article {pmid39574978, year = {2024}, author = {Olukorode, JO and Orimoloye, DA and Nwachukwu, NO and Onwuzo, CN and Oloyede, PO and Fayemi, T and Odunaike, OS and Ayobami-Ojo, PS and Divine, N and Alo, DJ and Alex, CU}, title = {Recent Advances and Therapeutic Benefits of Glucagon-Like Peptide-1 (GLP-1) Agonists in the Management of Type 2 Diabetes and Associated Metabolic Disorders.}, journal = {Cureus}, volume = {16}, number = {10}, pages = {e72080}, pmid = {39574978}, issn = {2168-8184}, abstract = {Glucagon-like peptide-1 (GLP-1) agonists have emerged as a groundbreaking class of medications for managing type 2 diabetes and associated metabolic disorders. These agents not only improve glycemic control by increasing insulin secretion and reducing glucagon levels but also promote significant weight loss, enhance cardiovascular and renal health, and offer potential neuroprotective benefits. Their multifaceted mechanisms include appetite suppression, increased energy expenditure, and direct neuroprotective effects. GLP-1 agonists have shown recent benefits in Obstructive Sleep Apnea, and the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as reducing the risk of stroke. This review highlights the therapeutic potential of GLP-1 agonists in diabetes management and beyond, advocating for continued research to optimize their clinical use and explore new therapeutic avenues.}, }
@article {pmid39574868, year = {2024}, author = {Kac, PR and Alcolea, D and Montoliu-Gaya, L and Fernández, S and Rodriguez, JL and Maure, L and González-Ortiz, F and Benejam, B and Turton, M and Barroeta, I and Harrison, P and Videla, L and Ashton, NJ and Lleó, A and Zetterberg, H and Carmona-Iragui, M and Karikari, TK and Fortea, J and Blennow, K}, title = {Plasma p-tau212 as a biomarker of sporadic and Down Syndrome Alzheimer's disease.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39574868}, support = {R01 AG075336/AG/NIA NIH HHS/United States ; R01 AG081394/AG/NIA NIH HHS/United States ; R01 AG083874/AG/NIA NIH HHS/United States ; R01 AG072641/AG/NIA NIH HHS/United States ; RF1 AG061566/AG/NIA NIH HHS/United States ; RF1 AG056850/AG/NIA NIH HHS/United States ; R01 MH108509/MH/NIMH NIH HHS/United States ; RF1 AG025516/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P01 AG025204/AG/NIA NIH HHS/United States ; R61 AG066543/AG/NIA NIH HHS/United States ; R01 MH121619/MH/NIMH NIH HHS/United States ; R37 AG023651/AG/NIA NIH HHS/United States ; U24 AG082930/AG/NIA NIH HHS/United States ; R21 AG056974/AG/NIA NIH HHS/United States ; R01 AG073267/AG/NIA NIH HHS/United States ; R01 AG025516/AG/NIA NIH HHS/United States ; RF1 AG052525/AG/NIA NIH HHS/United States ; R01 AG053952/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: All individuals with Down Syndrome (DS) will develop full-blown Alzheimeŕs disease (AD) pathology by age 40, decades before the occurrence of sporadic late-onset AD. Understanding this strong biological relation between age and AD pathology risk in DS is important to accelerate diagnostics, disease monitoring, and treatment. Several genes encoded in chromosome 21 including dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) have been proven to contribute to the pathology. A recently validated plasma immunoassay to measure tau phosphorylation at threonine-212 (p-tau212) has very high diagnostic accuracy in detecting AD. P-tau212 is also very sensitive to DYRK1A phosphorylation and is increased in DSAD brain lysates. Here, we assessed the potential of this biomarker in DSAD and sporadic AD.
METHODS: Using Simoa technology, we tested p-tau212 and p-tau181 (n=245 for plasma, n=114 matching cerebrospinal fluid (CSF) samples). We used AUC-ROC to examine diagnostic performance and the DeLong test to compare the AUC-ROC differences between methods. Spearman correlation is used to examine correlations. Fold changes relative to median levels were calculated for their respective asymptomatic groups. ANCOVA followed by Tukey posthoc test was used to calculate differences across groups. LOESS was used to determine the temporality of plasma biomarker changes.
RESULTS: We have confirmed that p-tau212 has extremely high accuracy in detecting AD-related changes in euploid controls. For the DS population, we observed a strong correlation between plasma and CSF p-tau212 (r=0.867; p<0.001). In prodromal DS (pDS) and dementia DS (dDS), we observed significantly elevated levels of p-tau212 in reference to asymptomatic DS (aDS). The diagnostic accuracy to differentiate between aDS and dDS was AUC=0.91 and AUC = 0.86 in discriminating between DS amyloid positive and amyloid negative participants. Plasma p-tau212 started increasing approximately when people became amyloid PET-positive.
CONCLUSIONS: We have confirmed that the levels of plasma p-tau212 are increased in the DS population and sporadic AD cases including prodromal and MCI states. Plasma p-tau212 might have utility for theragnostic, monitoring therapy efficacy, and as a target engagement biomarker in clinical trials both in sporadic and DSAD.}, }
@article {pmid39574862, year = {2024}, author = {Guan, H and Novoa-Laurentiev, J and Zhou, L}, title = {SCD-Tron: Leveraging Large Clinical Language Model for Early Detection of Cognitive Decline from Electronic Health Records.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39574862}, support = {R01 AG080429/AG/NIA NIH HHS/United States ; R44 AG081006/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Early detection of cognitive decline during the preclinical stage of Alzheimer's disease is crucial for timely intervention and treatment. Clinical notes, often found in unstructured electronic health records (EHRs), contain valuable information that can aid in the early identification of cognitive decline. In this study, we utilize advanced large clinical language models, fine-tuned on clinical notes, to improve the early detection of cognitive decline.
METHODS: We collected clinical notes from 2,166 patients spanning the 4 years preceding their initial mild cognitive impairment (MCI) diagnosis from the Enterprise Data Warehouse (EDW) of Mass General Brigham (MGB). To train the model, we developed SCD-Tron, a large clinical language model on 4,949 note sections labeled by experts. For evaluation, the trained model was applied to 1,996 independent note sections to assess its performance on real-world unstructured clinical data. Additionally, we used explainable AI techniques, specifically SHAP values, to interpret the models predictions and provide insight into the most influential features. Error analysis was also facilitated to further analyze the model's prediction.
RESULTS: SCD-Tron significantly outperforms baseline models, achieving notable improvements in precision, recall, and AUC metrics for detecting Subjective Cognitive Decline (SCD). Tested on many real-world clinical notes, SCD-Tron demonstrated high sensitivity with only one false negative, crucial for clinical applications prioritizing early and accurate SCD detection. SHAP-based interpretability analysis highlighted key textual features contributing to model predictions, supporting transparency and clinician understanding.
CONCLUSION: SCD-Tron offers a novel approach to early cognitive decline detection by applying large clinical language models to unstructured EHR data. Pretrained on real-world clinical notes, it accurately identifies early cognitive decline and integrates SHAP for interpretability, enhancing transparency in predictions.}, }
@article {pmid39574684, year = {2024}, author = {Chamberlin, S and Zweig, JA and Neff, CJ and Marney, L and Choi, J and Yang, L and Maier, CS and Soumyanath, A and McWeeney, S and Gray, NE}, title = {Multi-omics analysis in mouse primary cortical neurons reveals complex positive and negative biological interactions between constituent compounds in Centella asiatica.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39574684}, issn = {2692-8205}, support = {P30 AG066518/AG/NIA NIH HHS/United States ; S10 RR027878/RR/NCRR NIH HHS/United States ; U19 AT010829/AT/NCCIH NIH HHS/United States ; }, abstract = {BACKGROUND: A water extract of the Ayurvedic plant Centella asiatica (CAW) improves cognitive function in mouse models of aging and Alzheimer's disease, and affects dendritic arborization, mitochondrial activity and oxidative stress in mouse primary neurons. Triterpenes (TT) and caffeoylquinic acids (CQA) are constituents associated with these bioactivities of CAW although little is known about how interactions between these compounds contribute to the plant's therapeutic benefit.
METHODS: Mouse primary cortical neurons were treated with CAW, or equivalent concentrations of four TT combined, eight CQA combined, or these twelve compounds combined (TTCQA). Treatment effects on the cell transcriptome (18,491 genes) and metabolome (192 metabolites) relative to vehicle control were evaluated using RNAseq and metabolomic analyses respectively.
RESULTS: Extensive differentially expressed genes (DEGs) were seen with all treatments, as well as evidence of interactions between compounds. Notably many DEGs seen with TT treatment were not observed in the TTCQA condition, possibly suggesting CQA reduced the effects of TT. Moreover, additional gene activity seen with CAW as compared to TTCQA indicate the presence of additional compounds in CAW that further modulate TTCQA interactions. Weighted Gene Correlation Network Analysis (WGCNA) identified 4 gene co-expression modules altered by treatments that were associated with extracellular matrix organization, fatty acid metabolism, cellular response to stress and stimuli, and immune function. Compound interaction patterns were seen at the eigengene level in these modules. Interestingly, in metabolomics analysis, the TTCQA treatment saw the highest number of changes in individual metabolites (20), followed by CQA (15), then TT (8) and finally CAW (3). WGCNA analysis found two metabolomics modules with significant eigenmetabolite differences for TT and CQA, and possible compound interactions at this level.
CONCLUSIONS: Four gene expression modules and two metabolite modules were altered by the four types of treatments applied. This methodology demonstrated the existence of both negative and positive interactions between TT, CQA and additional compounds found in CAW on the transcriptome and metabolome of mouse primary cortical neurons.}, }
@article {pmid39574505, year = {2024}, author = {Yakemow, G and Kolesar, TA and Wright, N and Beheshti, I and Choi, EH and Ryner, L and Chaulk, S and Patel, R and Ko, JH}, title = {Investigating neural markers of Alzheimer's disease in posttraumatic stress disorder using machine learning algorithms and magnetic resonance imaging.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1470727}, pmid = {39574505}, issn = {1664-2295}, abstract = {INTRODUCTION: Posttraumatic stress disorder (PTSD) is a mental health disorder caused by experiencing or witnessing traumatic events. Recent studies show that patients with PTSD have an increased risk of developing dementia, including Alzheimer's disease (AD), but there is currently no way to predict which patients will go on to develop AD. The objective of this study was to identify structural and functional neural changes in patients with PTSD that may contribute to the future development of AD.
METHODS: Neuroimaging (pseudo-continuous arterial spin labeling [pCASL] and structural magnetic resonance imaging [MRI]) and behavioral data for the current study (n = 67) were taken from our non-randomized open label clinical trial (ClinicalTrials.gov Identifier: NCT03229915) for treatment-seeking individuals with PTSD (n = 40) and age-matched healthy controls (HC; n = 27). Only the baseline measures were utilized for this study. Mean cerebral blood flow (CBF) and gray matter (GM) volume were compared between groups. Additionally, we utilized two previously established machine learning-based algorithms, one representing AD-like brain activity (Machine learning-based AD Designation [MAD]) and the other focused on AD-like brain structural changes (AD-like Brain Structure [ABS]). MAD scores were calculated from pCASL data and ABS scores were calculated from structural T1-MRI images. Correlations between neuroimaging data (regional CBF, GM volume, MAD scores, ABS scores) and PTSD symptom severity scores measured by the clinician-administered PTSD scale for DSM-5 (CAPS-5) were assessed.
RESULTS: Decreased CBF was observed in two brain regions (left caudate/striatum and left inferior parietal lobule/middle temporal lobe) in the PTSD group, compared to the HC group. Decreased GM volume was also observed in the PTSD group in the right temporal lobe (parahippocampal gyrus, middle temporal lobe), compared to the HC group. GM volume within the right temporal lobe cluster negatively correlated with CAPS-5 scores and MAD scores in the PTSD group.
CONCLUSION: Results suggest that patients with PTSD with reduced GM volume in the right temporal regions (parahippocampal gyrus) experienced greater symptom severity and showed more AD-like brain activity. These results show potential for early identification of those who may be at an increased risk for future development of dementia.}, }
@article {pmid39574332, year = {2024}, author = {Chen, Z and Qi, B and Jing, B and Dong, R and Chen, R and Feng, P and Shou, Y and Li, H}, title = {A multi-modal and multi-stage region of interest-based fusion network convolutional neural network model to differentiate progressive mild cognitive impairment from stable mild cognitive impairment.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877241295287}, doi = {10.1177/13872877241295287}, pmid = {39574332}, issn = {1875-8908}, abstract = {BACKGROUND: Accurately differentiating stable mild cognitive impairment (sMCI) from progressive MCI (pMCI) is clinically relevant, and identification of pMCI is crucial for timely treatment before it evolves into Alzheimer's disease (AD).
OBJECTIVE: To construct a convolutional neural network (CNN) model to differentiate pMCI from sMCI integrating features from structural magnetic resonance imaging (sMRI) and positron emission tomography (PET) images.
METHODS: We proposed a multi-modal and multi-stage region of interest (ROI)-based fusion network (m2ROI-FN) CNN model to differentiate pMCI from sMCI, adopting a multi-stage fusion strategy to integrate deep semantic features and multiple morphological metrics derived from ROIs of sMRI and PET images. Specifically, ten AD-related ROIs of each modality images were selected as patches inputting into 3D hierarchical CNNs. The deep semantic features extracted by the CNNs were fused through the multi-modal integration module and further combined with the multiple morphological metrics extracted by FreeSurfer. Finally, the multilayer perceptron classifier was utilized for subject-level MCI recognition.
RESULTS: The proposed model achieved accuracy of 77.4% to differentiate pMCI from sMCI with 5-fold cross validation on the entire ADNI database. Further, ADNI-1&2 were formed into an independent sample for model training and validation, and ADNI-3&GO were formed into another independent sample for multi-center testing. The model achieved 73.2% accuracy in distinguishing pMCI and sMCI on ADNI-1&2 and 75% accuracy on ADNI-3&GO.
CONCLUSIONS: An effective m2ROI-FN model to distinguish pMCI from sMCI was proposed, which was capable of capturing distinctive features in ROIs of sMRI and PET images. The experimental results demonstrated that the model has the potential to differentiate pMCI from sMCI.}, }
@article {pmid39574131, year = {2024}, author = {Li, L and Sun, J and Chen, F and Xiong, L and She, L and Hao, T and Zeng, Y and Li, L and Wang, W and Zhao, X and Liang, G}, title = {Pedunculoside alleviates cognitive deficits and neuronal cell apoptosis by activating the AMPK signaling cascade.}, journal = {Chinese medicine}, volume = {19}, number = {1}, pages = {163}, pmid = {39574131}, issn = {1749-8546}, support = {2021C03041 to G.L.//Zhejiang Key Laboratory of Pathophysiology/ ; LQ23H090018 to X.Z.//Natural Science Foundation of Zhejiang Province/ ; }, abstract = {BACKGROUND: Mitochondrial dysfunction emerges as an early pathological hallmark of Alzheimer's disease (AD). The reduction in mitochondrial membrane potential and the elevation of reactive oxygen species (ROS) production are pivotal in the initiation of neuronal cell apoptosis. Pedunculoside(Ped), a novel triterpene saponin derived from the dried barks of Ilex rotunda Thunb, exhibits a potent anti-inflammatory effect. In the course of drug screening, we discovered that Ped offers significant protection against apoptosis induced by Aβ1-42. Nevertheless, the role and mechanism of Ped in AD are yet to be elucidated.
METHODS: Oxidative stress was evaluated by measuring mitochondrial membrane potential and intracellular ROS production. The expression of proteins associated with apoptosis was determined using western blot analysis and flow cytometry. In vivo, the pathological characteristics of AD were investigated through Western blot and tissue immunofluorescence techniques. Cognitive function was assessed using the Morris Water Maze and Novel Object Recognition tests.
RESULTS: We demonstrated that Ped decreased apoptosis in PC12 cells, reduced the generation of intracellular ROS, and restored mitochondrial membrane potential. Mechanistically, we found that the protective effect of Ped against Aβ-induced neurotoxicity was associated with activation of the AMPK/GSK-3β/Nrf2 signaling pathway. In vivo, Ped alleviated memory deficits and inhibited neuronal apoptosis, inflammation, and oxidative stress in the hippocampus of 3 × Tg AD mice, along with the activation of the AMPK signaling pathway.
CONCLUSION: The findings indicate that Ped exerts its neuroprotective effects against oxidative stress and apoptosis through the AMPK signaling cascade. The results demonstrate that Ped is a potential candidate for the treatment of AD.}, }
@article {pmid39573867, year = {2024}, author = {Tang, M and Guo, JJ and Guo, RX and Xu, SJ and Lou, Q and Hu, QX and Li, WY and Yu, JB and Yao, Q and Wang, QW}, title = {Progress of research and application of non-pharmacologic intervention in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {102}, number = {2}, pages = {275-294}, doi = {10.1177/13872877241289396}, pmid = {39573867}, issn = {1875-8908}, mesh = {*Alzheimer Disease/therapy ; Humans ; Quality of Life ; }, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disease characterized by amyloid-β (Aβ) deposition and neurofibrillary tangles formed by high phosphorylation of tau protein. At present, drug therapy is the main strategy of AD treatment, but its effects are limited to delaying or alleviating AD. Recently, non-pharmacologic intervention has attracted more attention, and more studies have confirmed that non-pharmacologic intervention in AD can improve the patient's cognitive function and quality of life. This paper summarizes the current non-pharmacologic intervention in AD, to provide useful supplementary means for AD intervention.}, }
@article {pmid39573866, year = {2024}, author = {Zhang, X and Lv, R and Sun, Y and Liu, TC}, title = {The safety and effectiveness of 40 Hz γ-tACS in Alzheimer's disease: A meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {102}, number = {2}, pages = {295-307}, doi = {10.1177/13872877241289397}, pmid = {39573866}, issn = {1875-8908}, mesh = {*Alzheimer Disease/therapy ; Humans ; *Transcranial Direct Current Stimulation/methods ; Cognition/physiology ; Treatment Outcome ; Memory/physiology ; }, abstract = {BACKGROUND: The efficacy and safety of 40 Hz gamma transcranial alternating current stimulation (γ-tACS) in Alzheimer's disease (AD) are still uncertain.
OBJECTIVE: This meta-analysis was conducted to investigate the therapeutic potential and safety of 40 Hz γ-tACS for AD.
METHODS: The meta-analysis was conducted by systematically searching four databases from their start to 28 December 2023. Subgroup analyses were performed to identify the intervention effects of γ-tACS.
RESULTS: Of the 7 included studies, γ-tACS has a notable impact on improving overall cognition [standardized mean difference (SMD): 0.49, 95% CI: 0.09 to 0.89], memory (SMD: 0.79, 95% CI: 0.18 to 1.41), and cholinergic transmission (weighted mean difference: -0.40, 95% CI: -0.43 to -0.37). Furthermore, subgroup analysis revealed that γ-tACS treatment had a substantial impact on enhancing memory targeting the left angular gyrus in both home (SMD: 3.12, 95% CI: 1.54 to 4.70) and non-home settings (SMD: 0.53, 95% CI: 0.24 to 0.82). However, γ-tACS had a positive effect on overall cognition in non-home settings (SMD: 0.55, 95% CI 0.11 to 0.98), but not in home settings (SMD: 0.22, 95% CI -0.76 to 1.20). Additionally, targeting temporo-frontal or bitemporal γ-tACS treatment resulted in improvement in overall cognition (SMD: 0.61, 95% CI: 0.06 to 1.16), but not targeting the left angular gyrus (SMD: 0.22, 95% CI: -0.76 to 1.20).
CONCLUSIONS: γ-tACS could be beneficial in enhancing cognition, memory and restoring cholinergic dysfunction in AD. The different selection of stimulation sites plays distinct roles. Meanwhile, AD patients are recommended to receive γ-tACS treatment at home.}, }
@article {pmid39572624, year = {2024}, author = {Mirzaei, M and Ahmadi, N and Bagheri Fahraji, B and Ardekani, AM and Rahimdel, A and Soltani, MH and Ardekani, SMY and Bidaki, R and Kasnavie, FH and Dastjerdi, G and Aboutorabi, M and Mirzaei, H}, title = {A randomized clinical trial evaluating Hydralazine's efficacy in early-stage Alzheimer's disease: The EHSAN Study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28837}, pmid = {39572624}, issn = {2045-2322}, support = {IR.NIMAD.REC.1398.424//National Institute for Medical Research Development/ ; IR.NIMAD.REC.1398.424//National Institute for Medical Research Development/ ; IR.NIMAD.REC.1398.424//National Institute for Medical Research Development/ ; IR.NIMAD.REC.1398.424//National Institute for Medical Research Development/ ; IR.NIMAD.REC.1398.424//National Institute for Medical Research Development/ ; IR.NIMAD.REC.1398.424//National Institute for Medical Research Development/ ; IR.NIMAD.REC.1398.424//National Institute for Medical Research Development/ ; IR.NIMAD.REC.1398.424//National Institute for Medical Research Development/ ; IR.NIMAD.REC.1398.424//National Institute for Medical Research Development/ ; IR.NIMAD.REC.1398.424//National Institute for Medical Research Development/ ; IR.NIMAD.REC.1398.424//National Institute for Medical Research Development/ ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease/drug therapy ; Antihypertensive Agents/therapeutic use ; Cognition/drug effects ; Double-Blind Method ; *Hydralazine/therapeutic use ; Treatment Outcome ; Randomized Controlled Trials as Topic ; }, abstract = {Alzheimer's Disease (AD), a neurodegenerative disorder escalating worldwide, remains incurable with existing interventions merely mitigating symptoms. Hydralazine, an antihypertensive agent, has displayed neuroprotective potential in AD animal models via amplification of mitochondrial functionality and stimulation of stress management and repair pathways. Nevertheless, its effectiveness and tolerability in human AD cohorts are yet to be confirmed. This study protocol describes the design of an ongoing, single-center, randomized, triple-blind, placebo-controlled trial to assess hydralazine's effects on cognitive function in mild to moderate -stage AD patients. We will enroll 424 patients aged 50 and older, meeting NINCDS-ADRDA criteria for probable AD with Mini-Mental State Examination scores from 12-26. They'll be randomly assigned to receive either hydralazine HCL (25 mg, thrice daily) or a placebo for 12 months. The primary outcome is the Alzheimer's Disease Assessment Scale change from baseline to 12 months. Secondary outcomes include various measures using Lawton instrumental activities of daily living scale, neuropsychiatry inventory, and caregiver activity survey. This trial will explore the potential benefits and risks of hydralazine in mild to moderate AD treatment. It's the first trial examining hydralazine's impact on mild to moderate -stage AD in human and is registered at the Iranian Registry of Clinical Trials (IRCT20200711048075N1, registered 29/07/2020) and ClinicalTrials.gov (NCT 04,842,552AQ, registered 13/04/2021). Ethics approval was granted by the Research Ethics Committee of the National Institute for Medical Research Development (IR.NIMAD.REC.1398.424), following the SPIRIT Statement guidelines. Findings will be disseminated via peer-reviewed publications and conferences. This inaugural human clinical trial evaluates hydralazine's impact on patients in the mild to moderate AD. Executed with a randomized, triple-blind, placebo-controlled methodology, this study incorporates a significant sample size and an extended monitoring duration. Multiple parameters, including cognitive capabilities, will be assessed. Potential limitations include the inherent homogeneity of the AD cohort, the lack of biomarker assays, and the unpredictable progression of the disease. Notably, the study might not elucidate the protracted effects of hydralazine beyond a 12-month period. Another limitation of our clinical trial is that patients were diagnosed with Alzheimer's disease based solely on clinical evaluation and MRI findings, without the inclusion of specific biomarkers, which may impact the accuracy and specificity of the diagnosis. Trial registration: Iranian Registry of Clinical Trials (IRCT20200711048075N1, registered 29/07/2020) and ClinicalTrials.gov (NCT 04,842,552, registered 13/04/2021).}, }
@article {pmid39571960, year = {2025}, author = {Zheng, Y and Yu, X and Li, W and Wu, F and Gu, Y and Liu, K and Tao, S and Liu, Y and Wang, Q}, title = {HLA is a potent immunoinflammatory target in asymptomatic Alzheimer's disease.}, journal = {Neuroscience}, volume = {565}, number = {}, pages = {386-398}, doi = {10.1016/j.neuroscience.2024.11.049}, pmid = {39571960}, issn = {1873-7544}, mesh = {*Alzheimer Disease/immunology/metabolism/drug therapy ; Animals ; Humans ; Mice ; *Mice, Transgenic ; Neuroinflammatory Diseases/drug therapy/immunology/metabolism ; Microglia/metabolism/drug effects/immunology ; Inflammation/metabolism/immunology ; Hippocampus/metabolism/drug effects/immunology ; Astrocytes/metabolism/drug effects/immunology ; Transcriptome ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disease, neuroinflammation is an early pathological feature of AD. However, the alteration of the immune microenvironment in asymptomatic AD was not fully explained. In this study, we aimed to utilize the transcriptome data of AD patients in public databases to reveal the change of immune microenvironment in asymptomatic AD and screen the potential drug targets. A series of bioinformatics analyses were done, including differentially expressed genes (DEGs) screening, enrichment analysis, PPI network construction, and hub gene identification. Meanwhile, the selected hub genes were validated in APP/PS-1(AD) mice. Importantly, seven enrichment pathways and eight hub genes associated with inflammation were identified in asymptomatic AD. Correspondingly, more hub genes were increased in the hippocampus in AD mice compared to the other four brain regions. Accompanied by the activation of microglia and astrocytes, the inflammatory cytokines were increased in the hippocampus of AD mice. Subsequently, the relationship between HLA-C and inflammation was evaluated in AD mice. HLA-C was correlated with the activation of microglia, and HLA-DRB1 with IL-6 in the hippocampus. Moreover, HLA-C is expressed in the microglia cells and astrocytes. Further, five FDA-approved drugs (Itrazole, Dfo, Syrosingopine, Cefoperazone, and Pradaxa) were predicted as the common drug targeting HLA-C and HLA-DRB1 by molecular docking. Taken together, the results revealed the changes in the immune microenvironment of asymptomatic AD and provided a new perspective for the development of anti-inflammatory drugs for AD early treatment.}, }
@article {pmid39571644, year = {2024}, author = {Olatunde, OO and Oyetunde, KS and Han, J and Khasawneh, MT and Yoon, H and , }, title = {Multiclass classification of Alzheimer's disease prodromal stages using sequential feature embeddings and regularized multikernel support vector machine.}, journal = {NeuroImage}, volume = {304}, number = {}, pages = {120929}, doi = {10.1016/j.neuroimage.2024.120929}, pmid = {39571644}, issn = {1095-9572}, mesh = {*Alzheimer Disease/diagnostic imaging/classification ; Humans ; *Support Vector Machine ; *Cognitive Dysfunction/diagnostic imaging/classification ; *Magnetic Resonance Imaging/methods ; Aged ; *Prodromal Symptoms ; Female ; Male ; Positron-Emission Tomography/methods ; Brain/diagnostic imaging ; Image Interpretation, Computer-Assisted/methods ; }, abstract = {The detection of patients in the cognitive normal (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD) stages of neurodegeneration is crucial for early treatment interventions. However, the heterogeneity of MCI data samples poses a challenge for CN vs. MCI vs. AD multiclass classification, as some samples are closer to AD while others are closer to CN in the feature space. Previous attempts to address this challenge produced inaccurate results, leading most frameworks to break the assessment into binary classification tasks such as AD vs. CN, AD vs. MCI, and CN vs. MCI. Other methods proposed sequential binary classifications such as CN vs. others and dividing others into AD vs. MCI. While those approaches may have yielded encouraging results, the sequential binary classification method makes interpretation and comparison with other frameworks challenging and subjective. Those frameworks exhibited varying accuracy scores for different binary tasks, making it unclear how to compare the model performance with other direct multiclass methods. Therefore, we introduce a classification framework comprising unsupervised ensemble manifold regularized sparse low-rank approximation and regularized multikernel support vector machine (SVM). This framework first extracts a joint feature embedding from MRI and PET neuroimaging features, which were then combined with the Apoe4, Adas11, MPACC digits, and Intracranial volume features using a regularized multikernel SVM. Using that framework, we achieved a state-of-the-art (SOTA) result in a CN vs. MCI vs. AD multiclass classification (mean accuracy: 84.87±6.09, F1 score: 84.83±6.12 vs 67.69). The methods generalize well to binary classification tasks, achieving SOTA results in all but the CN vs. MCI category, which was slightly lower than the best score by just 0.2%.}, }
@article {pmid39571412, year = {2025}, author = {Kang, SJ and Kim, YH and Nguyen-Phuong, T and Kim, Y and Oh, JM and Go, JC and Kim, D and Park, CG and Lee, H and Kim, HJ}, title = {Immune cell-enriched single-cell RNA sequencing unveils the interplay between infiltrated CD8[+] T resident memory cells and choroid plexus epithelial cells in Alzheimer's disease.}, journal = {Journal of neuroimmunology}, volume = {398}, number = {}, pages = {578488}, doi = {10.1016/j.jneuroim.2024.578488}, pmid = {39571412}, issn = {1872-8421}, mesh = {Animals ; *Choroid Plexus/immunology/metabolism ; Mice ; *Alzheimer Disease/immunology/genetics/pathology ; *CD8-Positive T-Lymphocytes/immunology ; *Mice, Transgenic ; *Memory T Cells/immunology/metabolism ; *Epithelial Cells/metabolism/immunology ; *Single-Cell Analysis ; Sequence Analysis, RNA/methods ; Mice, Inbred C57BL ; Male ; }, abstract = {Alzheimer's disease (AD) is a progressive neurological disorder and the leading cause of dementia. Despite significant efforts, treatment strategies targeting amyloid-β have been less successful than anticipated. Recently, the role of neuroinflammation and adaptive immune response in AD pathogenesis has gained attention. Here, we performed immune cell-enriched single-cell RNA sequencing of brain parenchymal cells from 12-month-old 5xFAD, an AD mouse model. We analyzed 11,587 single cells and found distinct differences in T cell and choroid plexus cell populations between 5xFAD mouse and littermate control. Subsequent sub-clustering of T cells in the 5xFAD mouse revealed distinct subtypes, with CD8[+] resident memory T cells (TRM) being the most prevalent T cell type. In addition, we observed an increase in T cell exhaustion markers, including Pdcd1, Ctla4, and Havcr2, with a particularly significant elevation of PD-1 and TIM-3 in CD8[+] TRM in 5xFAD mouse. Furthermore, choroid plexus (ChP) epithelial cells showed altered gene expression patterns, with higher expression of MHC class I and Type I IFN-stimulated genes in 5xFAD mouse compared to the control mouse, suggesting an association with clonal expansion of AD-specific T cells in the brain. Through single-cell RNA sequencing (scRNA-seq) analysis, our study highlights the potential role of resident memory CD8[+] T cell and their possible interactions with ChP epithelial cells. This study provides an exploration of the brain microenvironment landscape in AD, revealing critical insights into its underlying mechanisms.}, }
@article {pmid39571302, year = {2024}, author = {Zhai, B and Hao, Q and Wang, M and Luo, Z and Yang, R and Yang, J and Cao, Y}, title = {Discovery of new 4-aminoquinoline derivatives containing an amine or hydroxamic acid terminal as multifunctional agents for the treatment of Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {153}, number = {}, pages = {107954}, doi = {10.1016/j.bioorg.2024.107954}, pmid = {39571302}, issn = {1090-2120}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Aminoquinolines/chemistry/pharmacology/chemical synthesis ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; *Acetylcholinesterase/metabolism ; *Butyrylcholinesterase/metabolism ; *Hydroxamic Acids/chemistry/pharmacology/chemical synthesis ; Humans ; Structure-Activity Relationship ; Molecular Structure ; Animals ; *Amines/chemistry/pharmacology/chemical synthesis ; *Molecular Docking Simulation ; Dose-Response Relationship, Drug ; Drug Discovery ; Neuroprotective Agents/chemistry/pharmacology/chemical synthesis ; Mice ; }, abstract = {Due to the multifactorial nature of Alzheimer's disease (AD), effective multi-targeted directed ligands (MTDLs) are urgently needed for its treatment as single-target drugs currently encounter therapeutic challenges. Two series of new 4-aminoquinoline derivatives containing an amine or hydroxamic acid terminal were designed, synthesized and evaluated for their cholinesterase inhibition, antioxidant and metal-ion chelation properties. Among them, hydroxamic acid-containing compounds 7r and 7f exhibited the best inhibitor activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), respectively, with the corresponding IC50 values of 0.41 and 1.06 μM, which were superior to those of rivastigmine (IC50 = 5.26, 2.02 μM, respectively). Moreover, compounds 7r and 7f presented excellent ABTS radical scavenging efficiency and selective metal-ion chelation ability such as Cu[2+] and Fe[2+]. Both molecular docking and enzyme kinetic analysis revealed that compound 7r was a mixed-type inhibitor of AChE. Additionally, the ADME prediction indicated that compounds 7r and 7f have suitable pharmacokinetic and drug-like properties. Furthermore, they demonstrated good safety and blood-brain barrier permeability in cytotoxicity assays and in vivo experiments, respectively. These findings strongly suggest that the 4-aminoquinoline derivatives containing a hydroxamic acid terminal have great potential as promising MTDLs for the treatment of AD, opening new avenues for future therapeutic strategies.}, }
@article {pmid39571180, year = {2025}, author = {Kodali, M and Madhu, LN and Somayaji, Y and Attaluri, S and Huard, C and Panda, PK and Shankar, G and Rao, S and Shuai, B and Gonzalez, JJ and Oake, C and Hering, C and Babu, RS and Kotian, S and Shetty, AK}, title = {Residual microglia following short-term PLX5622 treatment in 5xFAD mice exhibit diminished NLRP3 inflammasome and mTOR signaling, and enhanced autophagy.}, journal = {Aging cell}, volume = {24}, number = {2}, pages = {e14398}, pmid = {39571180}, issn = {1474-9726}, support = {R01 AG075440/AG/NIA NIH HHS/United States ; RF1 AG074256/AG/NIA NIH HHS/United States ; R01AG075440-02/AG/NIA NIH HHS/United States ; RF1AG074256-02/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Microglia/metabolism/drug effects ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Mice ; *TOR Serine-Threonine Kinases/metabolism ; *Autophagy/drug effects ; *Inflammasomes/metabolism ; *Signal Transduction ; Female ; Mice, Transgenic ; Alzheimer Disease/metabolism/pathology/drug therapy ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism/antagonists & inhibitors ; Organic Chemicals ; }, abstract = {While moderately activated microglia in Alzheimer's disease (AD) are pivotal in clearing amyloid beta (Aβ), hyperactivated microglia perpetuate neuroinflammation. Prior investigations reported that the elimination of ~80% of microglia through inhibition of the colony-stimulating factor 1 receptor (CSF1R) during the advanced stage of neuroinflammation in 5xFamilial AD (5xFAD) mice mitigates synapse loss and neurodegeneration. Furthermore, prolonged CSF1R inhibition diminished the development of parenchymal plaques. Nonetheless, the effects of short-term CSF1R inhibition during the early stages of neuroinflammation on residual microglia are unknown. Therefore, we investigated the effects of 10-day CSF1R inhibition using PLX5622 in three-month-old female 5xFAD mice, a stage characterized by the onset of neuroinflammation and minimal Aβ plaques. We observed ~65% microglia depletion in the hippocampus and cerebral cortex. The leftover microglia displayed a noninflammatory phenotype with reduced NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complexes. Moreover, plaque-associated microglia were reduced with diminished Clec7a expression. Additionally, phosphorylated S6 ribosomal protein and the protein sequestosome 1 analysis suggested reduced mechanistic targets of rapamycin (mTOR) signaling and autophagy in microglia and neurons within the hippocampus and cerebral cortex. Biochemical assays validated the inhibition of NLRP3 inflammasome activation, decreased mTOR signaling in the hippocampus and cerebral cortex, and enhanced autophagy in the hippocampus. However, short-term CSF1R inhibition did not influence Aβ plaques, soluble Aβ-42 levels, astrocyte hypertrophy, or hippocampal neurogenesis. Thus, short-term CSF1R inhibition during the early stages of neuroinflammation in 5xFAD mice promotes the retention of homeostatic microglia with diminished inflammasome activation and mTOR signaling, alongside increased autophagy.}, }
@article {pmid39571156, year = {2024}, author = {Wang, Z and Zhou, L and Zhao, N and Zhang, Z and Zhang, J and Ren, QG}, title = {Bidirectional Crosstalk between the Heart and Brain in Alzheimer's Disease.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.1132}, pmid = {39571156}, issn = {2152-5250}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder condition linked to various systemic comorbidities. Numerous studies have shown bidirectional crosstalk between the heart and the brain, but the specifics of how these interactions occur in AD are poorly understood. This narrative review summarizes the clinical evidence for a firm link between AD and cardiovascular health and discusses the bidirectional roles of AD and the cardiovascular system. AD pathogenic proteins, AD risk genes, neurohormones, the autonomic nervous system, and neurotransmitters may affect cardiovascular health, and cardiac-derived proteins, neurohormones, vascular function, inflammation, and other potential specific molecules or neural pathways may also influence AD pathology and cognitive function. Additionally, we propose potential AD intervention strategies based on the heart-brain axis to provide novel insights into AD prevention and treatment.}, }
@article {pmid39570769, year = {2024}, author = {Shuja, MH and Imran, H and Abid, M and Ibrahim Ahmed, F}, title = {Evaluating Donanemab: Advances and Challenges in Alzheimer Disease Treatment.}, journal = {American journal of therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1097/MJT.0000000000001848}, pmid = {39570769}, issn = {1536-3686}, }
@article {pmid39570454, year = {2024}, author = {Zheng, M and Wang, C and Hu, M and Li, Q and Li, J and Quan, S and Zhang, X and Gu, L}, title = {Research progress on the association of insulin resistance with type 2 diabetes mellitus and Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {35}, pmid = {39570454}, issn = {1573-7365}, mesh = {*Alzheimer Disease/metabolism ; *Diabetes Mellitus, Type 2/metabolism ; Humans ; *Insulin Resistance/physiology ; Animals ; Brain/metabolism ; Hypoglycemic Agents/therapeutic use/pharmacology ; Signal Transduction/physiology ; Insulin/metabolism ; }, abstract = {Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. It is also known to be a risk factor for Alzheimer's disease (AD). Insulin plays a crucial role in regulating the body's metabolism and is responsible for activating the Phosphoinotide-3-Kinase (PI3K)/Protein Kinase B (Akt) signaling pathway. This pathway is activated when insulin binds to the insulin receptor on nerve cells, and it helps regulate the metabolism of glucose and lipids. Dysfunction in the insulin signaling pathway can lead to a decrease in brain insulin levels and insulin sensitivity, thereby inducing disruptions in insulin signal transduction and leading to disorders in brain energy metabolism. Moreover, these dysfunctions also contribute to the accumulation of β-amyloid (Aβ) deposition and the hyperphosphorylation of Tau protein, both of which are characteristic features of AD. Therefore, this article focuses on insulin resistance to reveal the complex mechanism between brain insulin resistance and AD occurrence in T2DM. On this basis, this article further summarizes the biological effects and mechanisms of antidiabetic drugs on the two diseases, aiming to provide new ideas for the discovery of drugs for the treatment of T2DM combined with AD.}, }
@article {pmid39568583, year = {2024}, author = {Fu, Y and Xu, Q and Zhang, J and Kang, C and Yang, C and Guo, L and Zhang, C and Zhou, T and Xiao, C}, title = {Identifying the quality markers and optimizing the processing of Gastrodiae rhizoma to treat brain diseases.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1396825}, pmid = {39568583}, issn = {1663-9812}, abstract = {BACKGROUND: Gastrodiae rhizoma (GR) refers to the dried tuber of Gastrodia elata Bl. and has been used for many centuries to treat brain diseases, such as Alzheimer's disease, major depressive disorder, and cerebral ischemia. However, the processing of GR is complex and varied, resulting in unstable clinical treatment effects. The processing protocols significantly affect the active ingredients and curative effects of GR. We can optimize the processing of GR by identifying quality markers to treat brain diseases.
METHODS: Fresh tubers of G. elata Bl. were processed under eight different protocols, and their resulting contents of potentially bioactive compounds were compared using liquid chromatography mass spectrometry to screen the potential quality markers of GR through stoichiometric analysis. The potential quality markers of GR targeting Alzheimer's disease, major depressive disorder, and cerebral ischemia were identified by network pharmacology, and the potentially neuroprotective effects of these components were validated through simulated docking to likely protein targets. Finally, a fit degree analysis was carried out using different composition ratios and proportions of the disease component degree value, and the therapeutic effects of different processing methods on Alzheimer's disease, major depressive disorder, and cerebral ischemia were outlined clearly.
RESULTS: We identified 32 potential therapeutic components and screened 13 quality markers in GR, of which five quality markers (galactinol, glucosyringic acid, parishins C and E, and S-(4-hydroxybenzyl)-glutathione) showed efficacy against all three brain diseases. Furthermore, steaming and microwave-drying during processing can optimize the components of these quality markers for treating the three diseases.
CONCLUSION: Processing protocols significantly affect the therapeutic components of GR and may also impact its effectiveness in treating brain diseases. Accordingly, optimizing the processing methods of GR to correspond to different therapeutic purposes may improve its efficacy against brain diseases.}, }
@article {pmid39568081, year = {2024}, author = {Zhu, J and Wu, C and Yang, L}, title = {Cellular senescence in Alzheimer's disease: from physiology to pathology.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {55}, pmid = {39568081}, issn = {2047-9158}, support = {32100918//National Natural Science Foundation of China/ ; 32300959//National Natural Science Foundation of China/ ; 2021M690060//China Postdoctoral Science Foundation/ ; 2022T150227//China Postdoctoral Science Foundation/ ; SL2024A04J00578//Guangzhou Scientific Research Grant/ ; 22KJ04//SCNU Young Faculty Development Program/ ; }, mesh = {*Alzheimer Disease/pathology/metabolism ; Humans ; *Cellular Senescence/physiology ; Animals ; Brain/pathology/metabolism ; }, abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, characterized by the accumulation of Aβ and abnormal tau hyperphosphorylation. Despite substantial efforts in development of drugs targeting Aβ and tau pathologies, effective therapeutic strategies for AD remain elusive. Recent attention has been paid to the significant role of cellular senescence in AD progression. Mounting evidence suggests that interventions targeting cellular senescence hold promise in improving cognitive function and ameliorating hallmark pathologies in AD. This narrative review provides a comprehensive summary and discussion of the physiological roles, characteristics, biomarkers, and commonly employed in vivo and in vitro models of cellular senescence, with a particular focus on various cell types in the brain, including astrocytes, microglia, oligodendrocyte precursor cells, neurons, and endothelial cells. The review further delves into factors influencing cellular senescence in AD and emphasizes the significance of targeting cellular senescence as a promising approach for AD treatment, which includes the utilization of senolytics and senomorphics.}, }
@article {pmid39567497, year = {2024}, author = {Zhu, Z and Song, M and Ren, J and Liang, L and Mao, G and Chen, M}, title = {Copper homeostasis and cuproptosis in central nervous system diseases.}, journal = {Cell death & disease}, volume = {15}, number = {11}, pages = {850}, pmid = {39567497}, issn = {2041-4889}, mesh = {Humans ; *Copper/metabolism ; *Homeostasis ; *Central Nervous System Diseases/metabolism/pathology ; Animals ; }, abstract = {Copper (Cu), an indispensable micronutrient for the sustenance of living organisms, contributes significantly to a vast array of fundamental metabolic processes. The human body maintains a relatively low concentration of copper, which is mostly found in the bones, liver, and brain. Despite its low concentration, Cu plays a crucial role as an indispensable element in the progression and pathogenesis of central nervous system (CNS) diseases. Extensive studies have been conducted in recent years on copper homeostasis and copper-induced cell death in CNS disorders, including glioma, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease, and stroke. Cuproptosis, a novel copper-induced cell death pathway distinct from apoptosis, necrosis, pyroptosis, and ferroptosis, has been identified as potentially intricately linked to the pathogenic mechanisms underlying various CNS diseases. Therefore, a systematic review of copper homeostasis and cuproptosis and their relationship with CNS disorders could deepen our understanding of the pathogenesis of these diseases. In addition, it may provide new insights and strategies for the treatment of CNS disorders.}, }
@article {pmid39566741, year = {2024}, author = {Niu, Q and Li, D and Zhang, J and Piao, Z and Xu, B and Xi, Y and Mohamed Kamal, NNSN and Lim, V and Li, P and Yin, Y}, title = {The new perspective of Alzheimer's Disease Research: Mechanism and therapeutic strategy of neuronal senescence.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102593}, doi = {10.1016/j.arr.2024.102593}, pmid = {39566741}, issn = {1872-9649}, mesh = {*Alzheimer Disease/therapy/metabolism/pathology ; Humans ; *Cellular Senescence/physiology ; *Neurons/pathology/metabolism ; Animals ; Aging/physiology/pathology ; Brain/pathology/metabolism ; }, abstract = {Alzheimer's disease (AD), commonly known as senile dementia, is a neurodegenerative disease with insidious onset and gradually worsening course. The brain is particularly sensitive to senescence, and neuronal senescence is an important risk factor for the occurrence of AD. However, the exact pathogenesis between neuronal senescence and AD has not been fully elucidated so far. Neuronal senescence is characterized by the permanent stagnation of the cell cycle, and the changes in its structure, function, and microenvironment are closely related to the pathogenesis and progression of AD. In recent years, studies such as the Aβ cascade hypothesis and Tau protein phosphorylation have provided new strategies for the therapy of AD, but due to the complexity of the etiology of AD, there are still no effective treatment measures. This article aims to deeply analyze the pathogenesis between AD and neuronal senescence, and sort out various existing therapeutic methods, to provide new ideas and references for the clinical treatment of AD.}, }
@article {pmid39566720, year = {2025}, author = {North, R and Liu, AJ and Pieper, C and Danus, S and Thacker, CR and Ashner, M and Colón-Emeric, C and Lee, RH}, title = {Effect of donepezil on bone metabolism among older adults with Alzheimer's disease.}, journal = {Contemporary clinical trials}, volume = {148}, number = {}, pages = {107748}, pmid = {39566720}, issn = {1559-2030}, support = {R21 AG078982/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Alzheimer Disease/drug therapy/metabolism ; Bone and Bones/metabolism/drug effects ; *Bone Density/drug effects ; Bone Remodeling/drug effects ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; *Donepezil/therapeutic use/pharmacology ; Double-Blind Method ; Fractures, Bone/prevention & control ; Indans/therapeutic use/pharmacology ; Randomized Controlled Trials as Topic ; }, abstract = {Older adults with Alzheimer's disease (AD), in addition to significant cognitive disability, have twice the risk of fracture compared to those with normal cognition. Fractures among older adults with AD are associated with substantial morbidity, loss of physical function, and significant mortality. Prior studies have shown a decreased risk of fracture among those taking acetylcholinesterase inhibitors, such as donepezil. With both cognitive and non-cognitive benefits, donepezil would be a valuable component in a fracture prevention program for older adults with AD. Though anti-amyloid therapies are now clinically available, donepezil may still have non-cognitive benefits. However, the specific effects of donepezil on bone metabolism are unknown. We have designed this randomized, double-blind, placebo-controlled clinical trial to investigate the effect of AD treatment with donepezil on bone metabolism. The study will measure the change in bone mineral density, bone turnover markers, and bone quality related to 12-months of donepezil therapy. This will be the first known study of changes in bone metabolism among older adults with AD.}, }
@article {pmid39566583, year = {2025}, author = {Poceviciute, I and Brazaityte, A and Buisas, R and Vengeliene, V}, title = {Scopolamine animal model of memory impairment.}, journal = {Behavioural brain research}, volume = {479}, number = {}, pages = {115344}, doi = {10.1016/j.bbr.2024.115344}, pmid = {39566583}, issn = {1872-7549}, mesh = {Animals ; *Scopolamine/pharmacology ; Male ; *Disease Models, Animal ; *Rats, Wistar ; *Memory Disorders/chemically induced/drug therapy ; *Recognition, Psychology/drug effects ; Female ; Aging/drug effects/physiology ; Rats ; Maze Learning/drug effects ; Motor Activity/drug effects ; Alzheimer Disease/chemically induced/drug therapy/physiopathology ; Exploratory Behavior/drug effects ; Memory, Short-Term/drug effects ; }, abstract = {In this study, we reassessed the suitability of a commonly used pharmacological animal model of Alzheimer's disease (AD) - scopolamine-induced memory impairment. The goal of the study was to explore if this animal model induces other behavioral changes associated with AD. One of the key behavioral features of AD, manifesting already during the early stages of the illness, is apathy-like behavior. We also evaluated how behavioral alterations induced by scopolamine compare to those seen in healthy aging animals. To achieve these goals, locomotor activity and short-term memory of young male Wistar rats were tested in the open field, novel object recognition (NOR) and T-maze spontaneous alternation tests before, during and after 21 daily administrations of scopolamine. Three-, ten- and nineteen-month-old male and female rats were used to measure age-related changes in these behaviors. Our data showed that although both scopolamine treatment and aging reduced the number of approaches to the objects and their exploration time during the NOR test, correlation with impaired object recognition memory was only observed in the scopolamine treated animals. Furthermore, treatment with scopolamine significantly increased the locomotor activity, which could be observed even one week after treatment discontinuation. Contrary, locomotor activity in older rats was significantly lower than that of younger rats. These findings demonstrate that the animal model of scopolamine-induced memory impairment fails to incorporate apathy-like symptoms characteristic to the AD and age-related reduction in physical activity of older rats.}, }
@article {pmid39566555, year = {2025}, author = {Soukhaklari, R and Pirsalami, F and Moezi, L and Moosavi, M}, title = {Curcumin ameliorates aluminum oxide nanoparticle-induced memory deficit by regulating the hippocampal p38 signaling pathway in mice.}, journal = {Neurological research}, volume = {47}, number = {1}, pages = {15-22}, doi = {10.1080/01616412.2024.2430998}, pmid = {39566555}, issn = {1743-1328}, mesh = {Animals ; *Curcumin/pharmacology ; Male ; *Memory Disorders/chemically induced ; *Hippocampus/drug effects/metabolism ; Mice ; *MAP Kinase Signaling System/drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; Nanoparticles ; Avoidance Learning/drug effects ; Maze Learning/drug effects ; Disease Models, Animal ; Signal Transduction/drug effects ; Dose-Response Relationship, Drug ; }, abstract = {OBJECTIVES: Exposure to aluminum (Al) has been shown to be strongly associated with the pathogenesis of Alzheimer's disease (AD). Recent evidence indicates that the toxicity of Al nanoparticle (Al-NP) is far greater than Al itself due to its particle size. Epidemiological studies suggest that curcumin lower the prevalence of AD. MAPKs (ERK, p38 and JNK) were suggested to be involved in AD pathology and memory impairment. The present study aimed to evaluate if curcumin has the ability to protect against behavioral deficits induced by subcutaneously administered Al-NP in mice. Furthermore, the levels of phosphorylated and total hippocampal MAPKs were assessed using western blottechnique.
METHODS: Al-NP (10 mg/kg/s.c.) was administered to adult male NMRI mice for 10 days with or without curcumin in doses of 2.5 or 25 mg/kg/oral gavage). Memory was assessed using passive avoidance apparatus and anxiety-like behavior was evaluated using elevated plus maze. Following the behavioral tasks, western blot analysis was performed on the hippocampal tissues to detect the levels of phosphorylated and total MAPKs.
RESULTS: The results revealed that Al-NP deteriorated memory with no significant effect on anxiety-like behaviors. Additionally, it activated hippocampal p38 signaling pathway with no effect on ERK and JNK. Curcumin treatment at the dose of 25 mg/kg restored memory and p38 activation.
DISCUSSION: This study suggests that subcutaneous Al-NP administration impairs memory and hippocampal p38 signaling with no effect on ERK and JNK. Co-administration of curcumin restored Al-NP induced memory impairment and hippocampal p38 phosphorylation.}, }
@article {pmid39566031, year = {2025}, author = {Colín-Martínez, E and Arias, C}, title = {Involvement of the VGF/BDNF axis in the neuropathology of Alzheimer's disease and its potential role in diagnosis and treatment.}, journal = {Reviews in the neurosciences}, volume = {36}, number = {3}, pages = {267-278}, pmid = {39566031}, issn = {2191-0200}, mesh = {*Alzheimer Disease/metabolism/diagnosis/pathology/therapy ; Humans ; *Brain-Derived Neurotrophic Factor/metabolism ; Animals ; *Brain/metabolism/pathology ; Signal Transduction/physiology ; }, abstract = {The brain is a highly plastic organ that continually receives and integrates signals to generate functional and structural changes and homeostatic adaptations throughout life. Alterations in some signaling pathways that mediate these responses can impact brain plasticity, accelerate brain aging and potentially lead to neurodegeneration. There is substantial evidence that two important signaling pathways activated by neurotrophins, nonacronymic (VGF) and brain-derived neurotrophic factor (BDNF), are involved in substantial functions stimulating neuronal growth, differentiation, and circuit establishment during development and neuronal maintenance and plasticity in the mature brain. In this review, we present evidence that these two pathways and their interactions are central players in cognitive performance and alterations in pathological aging, particularly in conditions such as Alzheimer's disease (AD). Finally, we suggest specific avenues for future research on the basis of recent findings suggesting these molecules are diagnostic biomarkers and putative therapeutic tools to prevent, delay or improve AD neuropathology.}, }
@article {pmid39565645, year = {2025}, author = {Ye, W and Tao, Y and Wang, W and Yu, Y and Li, X}, title = {Periodontitis associated with brain function impairment in middle-aged and elderly individuals with normal cognition.}, journal = {Journal of periodontology}, volume = {96}, number = {3}, pages = {290-300}, doi = {10.1002/JPER.24-0264}, pmid = {39565645}, issn = {1943-3670}, support = {2022AH051138//Scientific Research Project of the University in Anhui Province/ ; 81901726//National Natural Science Foundation of China/ ; 82071905//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Middle Aged ; Male ; Female ; *Periodontitis/physiopathology/complications ; Aged ; *Magnetic Resonance Imaging ; *Cognition/physiology ; *Brain/physiopathology/diagnostic imaging ; }, abstract = {BACKGROUND: The present study aimed to investigate changes in intranetwork functional connectivity (FC) and internetwork FC in middle-aged and elderly individuals with normal cognition (NC) and varying degrees of periodontitis to determine the effects of periodontitis on brain function.
METHODS: Periodontal findings and resting-state functional magnetic resonance imaging data were acquired from 51 subjects with NC. Independent component analysis and correlation analysis were used for the statistical analysis of the data.
RESULTS: Differences in intranetwork FC were observed among groups in the anterior default-mode network (aDMN), dorsal attention network and dorsal sensorimotor network (dSMN). Compared with the nonperiodontitis (NP) group or the mild-periodontitis group, the analysis of internetwork FC showed increased FC between the auditory network and the ventral attention network (VAN), between the aDMN and the salience network (SN), and between the SN and the VAN and decreased FC between the posterior default-mode network and the right frontoparietal network in the moderate-to-severe periodontitis group. Additionally, internetwork FC between the dSMN and the VAN was also increased in the moderate-to-severe periodontitis group compared to the NP group. The altered intra- and internetwork FC were significantly correlated with the periodontal clinical index.
CONCLUSION: Our results confirmed that periodontitis was associated with both intra- and internetwork FC changes even in NC. The present study indicates that periodontitis might be a potential risk factor for brain damage and provides a theoretical clue and a new treatment target for the early prevention of Alzheimer disease.
PLAIN LANGUAGE SUMMARY: Recent research has proposed that periodontitis is a potential risk factor for Alzheimer disease (AD). However, the relationship between periodontitis and the brain function of middle-aged and elderly individuals with normal cognition (NC) remains unclear. Analyzing the effect of periodontitis on brain function in the NC stage can provide clues to AD development and help achieve early prevention of dementia. The present study aimed to investigate changes in brain functional connectivity (FC) in NC with different severity of periodontitis to determine the effects of periodontitis on brain function. Both changed intranetwork FC and internetwork FC were found in the moderate-to-severe periodontitis group, and periodontitis was associated with brain network function impairment in NC. The present study indicates that periodontitis might be a potential risk factor for brain damage even in NC stage, and provides a theoretical clue and a new treatment target for the early prevention of AD.}, }
@article {pmid39565643, year = {2024}, author = {Fukumoto, H and Kao, TH and Tai, CY and Jang, MK and Miyamoto, M}, title = {High-molecular-weight oligomer tau (HMWoTau) species are dramatically increased in Braak-stage dependent manner in the frontal lobe of human brains, demonstrated by a novel oligomer Tau ELISA with a mouse monoclonal antibody (APNmAb005).}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {22}, pages = {e70160}, pmid = {39565643}, issn = {1530-6860}, support = {P30 AG072980/AG/NIA NIH HHS/United States ; //Michael J. Fox Foundation for Parkinson's Research (MJFF)/ ; //APRINOIA Therapeutics/ ; P30 AG19610/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *tau Proteins/metabolism/immunology ; *Enzyme-Linked Immunosorbent Assay/methods ; Mice ; *Antibodies, Monoclonal/immunology ; Animals ; *Alzheimer Disease/metabolism/pathology ; *Frontal Lobe/metabolism/pathology ; Female ; Molecular Weight ; Male ; Aged ; Aged, 80 and over ; }, abstract = {Disease-specific oligomers Tau assay system is anticipated in Alzheimer disease (AD) to elucidate their etiological roles. We developed a highly sensitive and selective ELISA for high-molecular-weight oligomer tau (HMWoTau) with LLOQ of 0.3 pg/well for the first time, using a novel mouse monoclonal antibody APNmAb005. The target molecule was identified as HMWoTau with circa 2000 kD as a minimum size and the more oligomerized species (>5000 kD), in combination analysis with Size-Exclusion-Chromatography and Sucrose-Density-Gradient-Centrifugation for both recombinant human (rh) Tau-derived aggregates and AD brain-lysates in PBS(-). HMWoTau was labeled by Thioflavin S and visualized as a homogeneous globular particle (about 30 nm in diameter) by two different technologies of atomic force microscopy and dSTORM-Nanoimager. Specific quantitation was also confirmed by immune-absorption, rhHMWoTau-spiked, and cross-reactivity studies. APNmAb005 failed to detect the HMWoTau signal by treatment with DTT/SDS under no influence on the pan-tau antibody, indicating its conformation-specific recognition. APNmAb005-ELISA showed AD-specific and statistically significant ELISA signals from 1 ng brain lysate protein/well. Analysis of the frontal neocortex (N = 40, Braak stage I-VI) by ELISA revealed the detection-limit levels of HMWoTau species at stage I-III, and drastic and statistically significant increases at stage V/VI (AD). By contrast, total Tau and p181 Tau showed 1/4-1/5 levels of AD even at Stage I, while both tau species also showed a statistically significant increase in AD. In sum, our novel APNmAb005-ELISA clarified the disease-specific increase in HMWoTau species and will be useful for not only further etiological elucidation but also the potential diagnostics in AD and relevant tauopathy.}, }
@article {pmid39565424, year = {2024}, author = {Verma, H and Kaur, S and Jeeth, P and Kumar, P and Kadhirvel, S and Dhiman, M and Mantha, AK}, title = {Understanding Aβ25-35 peptide altered exosomal proteome and associated pathways linked with the Alzheimer's disease pathogenesis using human neuroblastoma SH-SY5Y Cells.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {25}, pmid = {39565424}, issn = {1573-7365}, support = {CRG/2021/002524//SERB, Govt. of India/ ; CRG/2021/002524//SERB, Govt. of India/ ; }, mesh = {Humans ; *Exosomes/metabolism/drug effects ; *Amyloid beta-Peptides/metabolism ; *Proteome/drug effects/metabolism ; *Alzheimer Disease/metabolism ; *Peptide Fragments/metabolism ; Cell Line, Tumor ; *Neuroblastoma/metabolism ; *Oxidative Stress/drug effects ; Proteomics ; Neuroprotective Agents/pharmacology ; Neurons/drug effects/metabolism ; Coumaric Acids ; }, abstract = {The central nervous system (CNS) involves a complex interplay of communications between the neurons and various glial cells, which is crucial for brain functions. The major interactomes are exosomes that transmit sundry molecules (DNA, miRNAs, and proteins) between the cells and thus alter cell physiology. Exosomes can act as neuroprotective or neurodegenerative agents depending on the microenvironment of cells secreting them. Therefore, revealing exosome proteome becomes important to understand donor cells' physiology and its effect on the recipient cell. In this study, oxidative stress was induced by Aβ25-35 in the human neuroblastoma SH-SY5Y cells and the protective effects of phytochemical ferulic acid (FA) were evaluated alone and in combination with Aβ25-35 (pre-treated for 3 h before Aβ25-35 exposure) and proteome of their secreted exosomes was analyzed, which was carried out via a high-resolution LC-MS Triple-ToF and further network-based analysis has been carried out using various bioinformatics tools. The proteomic profiling enlightened the multiple roles of exosomes as proteins associated with the various pathways advocate that exosomes can mediate a wide range of effects, from normal physiological processes like synaptic plasticity, neuronal metabolic support, nerve regeneration, DNA repair, axon guidance, and long-term potentiation (LTP) to abnormal pathological processes like inflammatory responses, oxidative stress, apoptosis, and formation of neutrophil extracellular traps (NETs). On comparison, treatment with Aβ25-35 resulted in a significant modulation of the exosomal proteome, promoting pathways associated with neurodegeneration. Conversely, the phytochemical FA displayed a protective effect by effectively countering Aβ25-35-induced oxidative stress responses linked with neurodegeneration, as seen in Alzheimer's disease (AD). Taken together, this study highlights the dual role of exosomes in physiological and pathophysiological neurodegenerative AD, which intricately depend on the particular cellular milieu.}, }
@article {pmid39565401, year = {2024}, author = {Tavares, J and Oliveira, AV and de Souza Nascimento, T and Gomes, JMP and Parente, ACB and Bezerra, JR and da Costa, MDR and de Aguiar, MSS and Sampaio, TL and Lima, FAV and de Barros Viana, GS and de Andrade, GM}, title = {Aqueous extract of Spirulina exerts neuroprotection in an experimental model of Alzheimer sporadic disease in mice induced by Streptozotocin.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {26}, pmid = {39565401}, issn = {1573-7365}, mesh = {Animals ; *Spirulina/chemistry ; *Streptozocin ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Male ; Mice ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Disease Models, Animal ; Oxidative Stress/drug effects ; Plant Extracts/pharmacology/therapeutic use ; Brain/drug effects/metabolism/pathology ; Hippocampus/drug effects/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes gradual memory loss and cognitive impairment. Intracerebroventricular injections of streptozotocin (ICV-STZ) have been used as an experimental model of sporadic Alzheimer's disease (SAD) because they produce deficits in brain insulin signaling, oxidative stress, neuroinflammation, and neurodegeneration, resulting in cognitive decline and memory impairment. Spirulina platensis (SPI) is a nutraceutical with anti-inflammatory, antioxidant, and neuroprotective properties. The objective of this work was to study the effects of SPI on cognitive deficits and neuronal damage in mice submitted to the experimental model of SAD induced by ICV-STZ. Male Swiss mice (25-35 g) received ICV-STZ (3 mg/Kg) bilaterally on days 1 and 3, SPI (50 and 100 mg/Kg, o.p.) or vehicle (saline) was administered 2 h after the second surgery, and once a day for 16 days. SPI treatment prevented working, episodic, spatial, and aversive memory deficits. Locomotor activity was not altered. ICV-STZ caused an increase in MDA, nitrite, and superoxide anion, while decreasing GSH. SPI treatment protected against GSH increase in the prefrontal cortex and hippocampus, and inhibited AChE activity in the prefrontal cortex. SPI prevented astrogliosis and microgliosis induced by ICV-STZ. These findings highlight the therapeutic potential of SPI for the treatment of SAD, indicating that its neuroprotective action is linked to antioxidant, anti-inflammatory, and AChE inhibitory activity.}, }
@article {pmid39565006, year = {2024}, author = {Arumugam, P}, title = {Investigating the neuroprotective effects of alkaloids from Galanthus woronowii as a potential treatment for Alzheimer's disease.}, journal = {Natural product research}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/14786419.2024.2431124}, pmid = {39565006}, issn = {1478-6427}, }
@article {pmid39564918, year = {2024}, author = {Collij, LE and Bollack, A and La Joie, R and Shekari, M and Bullich, S and Roé-Vellvé, N and Koglin, N and Jovalekic, A and Garciá, DV and Drzezga, A and Garibotto, V and Stephens, AW and Battle, M and Buckley, C and Barkhof, F and Farrar, G and Gispert, JD and , }, title = {Centiloid recommendations for clinical context-of-use from the AMYPAD consortium.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {20}, number = {12}, pages = {9037-9048}, pmid = {39564918}, issn = {1552-5279}, support = {P30 AG062422/AG/NIA NIH HHS/United States ; 115952//Innovative Medicines Initiative/ ; //European Union's Horizon 2020/ ; 115952//Innovative Medicines Initiative 2 Joint Undertaking/ ; //EFPIA/ ; }, mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/pathology ; *Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Biomarkers/cerebrospinal fluid ; Brain/pathology/diagnostic imaging ; Disease Progression ; *Positron-Emission Tomography ; }, abstract = {Amyloid-PET quantification through the tracer-independent Centiloid (CL) scale has emerged as an essential tool for the accurate measurement of amyloid-β (Aβ) pathology in Alzheimer's disease (AD) patients. The AMYPAD consortium set out to integrate existing literature and recent work from the consortium to provide clinical context-of-use recommendations for the CL scale. Compared to histopathology, visual reads, and cerebrospinal fluid, CL quantification accurately reflects the amount of AD pathology. With high certainty, a CL value below 10 excludes the presence of Aβ pathology, while a value above 30 corresponds well with pathological amounts. Values falling in between these two cutoffs ("intermediate range") are related to an increased risk of disease progression. Together, CL quantification is a valuable adjunct to visual assessments of amyloid-PET images. An abnormal amyloid biomarker assessment is a key criterion to determine eligibility for anti-amyloid disease-modifying therapies, and amyloid-PET quantification can add further value by precisely monitoring amyloid clearance, and hence guiding patient management decisions. HIGHLIGHTS: Centiloid (CL) quantification robustly reflects of the amount of Aβ pathology. CL < 10/CL > 30 reflects Aβ-negativity/positivity thresholds with high certainty. CL quantification is a valuable adjunct to visual assessments of amyloid-PET. CL quantification can support trial design and treatment management. CL quantification could support the identification of early or emerging Aβ pathology.}, }
@article {pmid39564756, year = {2024}, author = {Sun, Z and Liu, J and Chen, Z and So, KF and Hu, Y and Chiu, K}, title = {Lycium barbarum Extract Enhanced Neuroplasticity and Functional Recovery in 5xFAD Mice via Modulating Microglial Status of the Central Nervous System.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {11}, pages = {e70123}, pmid = {39564756}, issn = {1755-5949}, support = {LHJJ24JH13//Joint Founding Project of Innovation Research Institute/ ; MRP-092-17X//Midstream Research Program for Universities/ ; 14151281//Health and Medical Research Fund, Hong Kong, China/ ; }, mesh = {Animals ; *Microglia/drug effects/metabolism ; *Neuronal Plasticity/drug effects/physiology ; *Mice, Transgenic ; Mice ; *Recovery of Function/drug effects/physiology ; *Lycium/chemistry ; *Alzheimer Disease/drug therapy/pathology ; Plant Extracts/pharmacology ; Male ; Central Nervous System/drug effects ; Maze Learning/drug effects/physiology ; Amyloid beta-Peptides/metabolism ; Brain/drug effects/metabolism/pathology ; Presenilin-1/genetics ; }, abstract = {OBJECTIVE: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with limited treatment options. This study aimed to investigate the effects of Lycium barbarum extract (LBE), a Chinese herb, on the central nervous system (CNS)-including the retina, brain, and spinal cord-in 5xFAD transgenic mice after the onset of AD.
METHODS: Starting at 6 months of age, 5xFAD mice received daily intragastric gavage of LBE (2 g/kg) for 2 months. At 8 months, behavioral tests were conducted to assess cognition, motor function, and visual function. These included the Morris water maze, novel object recognition, and Y-maze tests for cognition; the beam walking balance and clasping tests for motor function; and electroretinogram (ERG) for visual function. Immunohistochemistry, western blotting, and ELISA were used to evaluate Aβ deposition, microglial morphology, neuroinflammation, and neuroprotective signaling pathways. Primary microglia and the IMG cell line were used to study LBE's effects on Aβ uptake and degradation in vitro.
RESULTS: After 2 months of LBE treatment, the decline in cognition, motor, and visual functions in 5xFAD mice was significantly slowed. Microglia in the brain, spinal cord, and retina exhibited a neuroprotective state, with reduced Aβ deposition, decreased inflammatory cytokine levels (e.g., TNF-α, IL-1β, IL-6), increased Arg-1/iNOS ratio, and enhanced phagocytic capacity. LBE also promoted Aβ uptake and degradation in primary microglia and the IMG cell line. Neuroprotective signals such as p-Akt, p-Erk1/2, and p-CREB were elevated. Additionally, LBE treatment restored synaptic protein expression and enhanced neuroplasticity.
CONCLUSION: The findings suggest that LBE treatment can enhance neuroplasticity, reduce systemic inflammation, and improve phagocyte clearance of Aβ deposition via inducing a neuroprotective microglial phenotype throughout CNS. As an upper-class Chinese medicine, appropriate intake of LBE may serve as a beneficial antiaging strategy for AD.}, }
@article {pmid39563977, year = {2024}, author = {Ohashi, K and Takahashi-Iwata, I and Jieyu, Z and Sakushima, K and Yabe, I and Ogasawara, K}, title = {Are There Shortages and Regional Disparities in Lecanemab Treatment Facilities? A Cross-Sectional Study.}, journal = {Health services insights}, volume = {17}, number = {}, pages = {11786329241299312}, pmid = {39563977}, issn = {1178-6329}, abstract = {INTRODUCTION: Alzheimer disease (AD) is the most common type of dementia, affecting 70% of patients with dementia. In Japan, over 5 million people aged 65 years and older had dementia in 2018, and this figure is expected to rise to 25% to 30% of this age group by 2045. In Japan, lecanemab, which was approved in 2023, is expected to be a new treatment for AD. However, lecanemab requires stringent management, including amyloid PET scans and MRI monitoring, necessitating specialized facilities, creating concerns regarding the lack of treatment facilities and poor treatment access.
METHODS: This study assessed spatial accessibility to lecanemab in Hokkaido, Japan, using geographic information system data. Hospitals were categorized into 3 scenarios based on their capacity to meet the treatment criteria. Service area analysis in each scenario evaluated the population coverage within 30-, 60-, and 120-minute travel times. The inverted two-step floating catchment area method was used to calculate the potential high-demand areas index (PHDI) for each hospital.
RESULTS: Population coverage ranged from 56% to 97%, depending on the scenario and travel time. Coverage for the most feasible scenario (Scenario 1) was 56%, 73.9%, and 88.3% within 30, 60, and 120 minutes, respectively. Northern and southern Hokkaido had the lowest coverage. PHDI analysis identified high-demand areas, with Sapporo facing potential overcapacity issues.
CONCLUSION: Lecanemab highlights the need for strategic resource allocation to enhance accessibility and capacity. Establishing additional treatment centers, particularly in areas with poor accessibility and capacity, is crucial to maximize the benefits of treatment for dementia.}, }
@article {pmid39563830, year = {2024}, author = {Rosse, G}, title = {Novel Aminopyrazole Inhibitors of PDE11A for the Treatment of Alzheimer's Disease and Other Types of Dementia.}, journal = {ACS medicinal chemistry letters}, volume = {15}, number = {11}, pages = {1828-1829}, pmid = {39563830}, issn = {1948-5875}, }
@article {pmid39563827, year = {2024}, author = {Rosse, G}, title = {Azaspirooctane-carboxylates as Novel Activators/Modulators of M4 for the Treatment of Alzheimer's Disease and Parkinson's Disease.}, journal = {ACS medicinal chemistry letters}, volume = {15}, number = {11}, pages = {1830-1831}, pmid = {39563827}, issn = {1948-5875}, abstract = {Novel azaspirooctane-carboxylates are described for potential treatment of Alzheimer's disease and Parkinson's disease, among other conditions.}, }
@article {pmid39563448, year = {2024}, author = {Cheng, J and Zhao, H}, title = {NEK7 induces lactylation in Alzheimer's disease to promote pyroptosis in BV-2 cells.}, journal = {Molecular brain}, volume = {17}, number = {1}, pages = {81}, pmid = {39563448}, issn = {1756-6606}, mesh = {Animals ; *NIMA-Related Kinases/metabolism ; *Alzheimer Disease/pathology/metabolism ; *Pyroptosis/drug effects ; *Amyloid beta-Peptides/metabolism ; *Mice, Transgenic ; Histones/metabolism ; Mice ; Cell Line ; Disease Models, Animal ; Male ; Mice, Inbred C57BL ; Lysine/metabolism ; }, abstract = {Alzheimer's disease (AD), an age-related neurodegenerative disorder, is characterized by irreversible brain tissue degeneration. The amyloid-β (Aβ) cascade hypothesis stands as the predominant paradigm explaining AD pathogenesis. This study aimed to elucidate the mechanisms underlying Aβ-induced pyroptosis in AD. AD models were established using amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and Aβ-treated BV-2 cells (5 µM, 24 h). NEK7 expression was evaluated in vitro and in vivo. Cell pyroptosis was assessed before and after NEK7 expression was inhibited in BV-2 cells. Adeno-associated virus (AAV) vectors carrying short hairpin RNA (shRNA) against NEK7 (AAV-sh-NEK7) were administered to mice to knockdown NEK7 in vivo. Spatial learning and memory abilities were evaluated using the Morris water maze test. The interaction between NEK7 and histone H4 lysine 12 lactylation (H4K12la) were then investigated. The results suggested that NEK7 expression was markedly elevated in both in vitro and in vivo AD models. Treatment with Aβ significantly reduced cell viability and enhanced pyroptosis in BV-2 cells; these effects were reversed by inhibiting NEK7. Furthermore, AD mice with NEK7 knockdown exhibited shorter escape latencies and increased time spent in the target quadrant, suggesting that NEK7 inhibition improved cognitive function and memory retention. Mechanistically, Aβ treatment induced histone lactylation in BV-2 cells, and suppression of lactylation attenuated NEK7 transcriptional activity and mRNA levels. In summary, elevated NEK7 expression promoted histone lactylation in BV-2 cells, thereby facilitating pyroptosis. Inhibition of NEK7 conferred protection against Aβ-induced cellular damage and enhanced cognitive performance and memory retention in AD model mice. Collectively, targeting NEK7 represents a potential therapeutic strategy for alleviating AD symptoms.}, }
@article {pmid39563240, year = {2024}, author = {Peterson, IL and Liktor-Busa, E and Karlage, KL and Young, SJ and Scholpa, NE and Schnellmann, RG and Largent-Milnes, TM}, title = {Formoterol dynamically alters endocannabinoid tone in the periaqueductal gray inducing headache.}, journal = {The journal of headache and pain}, volume = {25}, number = {1}, pages = {200}, pmid = {39563240}, issn = {1129-2377}, support = {IK2BX005218//U.S. Department of Veterans Affairs/ ; I01 BX004868/BX/BLRD VA/United States ; T32-HL007249/NH/NIH HHS/United States ; R01 NS126752/NS/NINDS NIH HHS/United States ; 1R01NS126752-01A1/NH/NIH HHS/United States ; I01BX004868//U.S. Department of Veterans Affairs/ ; }, mesh = {Animals ; *Endocannabinoids/metabolism ; Female ; *Periaqueductal Gray/metabolism/drug effects ; *Formoterol Fumarate/pharmacology ; Mice ; Mice, Inbred C57BL ; Hyperalgesia/chemically induced/metabolism ; Adrenergic beta-2 Receptor Agonists/pharmacology ; Headache/chemically induced/metabolism/drug therapy ; Disease Models, Animal ; }, abstract = {BACKGROUND: Headache is a pain disorder present in populations world-wide with a higher incidence in females. Specifically, the incidences of medication overuse headache (MOH) have increased worldwide. Comorbidities of MOH include photosensitivity, anxiety, "brain fog", and decreased physical activity. The FDA-approved long-lasting selective β2-adrenergic receptor agonist, formoterol, is currently approved for use in severe asthma and chronic obstructive pulmonary disease. Recently, interest in repurposing formoterol for use in other disorders including Alzheimer's disease, and neuropathic pain after spinal cord injury and traumatic brain injury has gained traction. Thus, revisiting known side-effects of formoterol, like headache and anxiety, could inform treatment paradigms. The endocannabinoid (eCB) system is implicated in the etiology of preclinical headache, with observed decreases in the circulating levels of endogenous cannabinoids, referred to as Clinical Endocannabinoid Deficiency. As cross-talk between the eCB system and adrenergic receptors has been reported, this study investigated the role of the eCB system and ability of formoterol to induce headache-like periorbital allodynic behavior.
METHODS: Female 8-week-old C57Bl/6J mice were treated daily with formoterol (0.3 mg/kg, i.p.) for up to 42-days, during which they were assessed for periorbital allodynia, open field/novel object recognition, and photosensitivity. At the end of the study, the periaqueductal grey (PAG), a brain region known to contribute to both headache induction and maintenance, was collected and subjected to LC-MS to quantify endocannabinoid levels.
RESULTS: Mice exhibited periorbital allodynia at nearly all time points tested and photosensitivity from 28-days onward. Levels of endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), along with cannabinoid receptor 1 (CB1R) expression were altered by both age and upon treatment with formoterol. Administration of FAAH/MAGL inhibitors, to target the eCB system, and a non-selective cannabinoid receptor agonist, WIN 55,212 reversed the formoterol-induced periorbital allodynia.
CONCLUSIONS: These results suggest that formoterol is dysregulates eCB tone to drive headache-like periorbital allodynic behaviors. These results could help inform preventative treatment options for individuals receiving formoterol, as well as provide information on the interaction between the eCB and adrenergic system.}, }
@article {pmid39562463, year = {2024}, author = {Martínez, A and Hillyard, SA and Javitt, DC}, title = {Visual Neurophysiological Biomarkers for Patient Stratification and Treatment Development Across Neuropsychiatric Disorders.}, journal = {Advances in neurobiology}, volume = {40}, number = {}, pages = {757-799}, pmid = {39562463}, issn = {2190-5215}, mesh = {Humans ; *Visual Pathways/diagnostic imaging/physiopathology ; *Biomarkers/metabolism ; *Mental Disorders/physiopathology/diagnostic imaging ; Electroencephalography ; Visual Cortex/diagnostic imaging/physiopathology/metabolism ; Visual Perception/physiology ; Evoked Potentials, Visual/physiology ; }, abstract = {The human visual system begins in the retina and projects to cortex through both the thalamocortical and retinotectal visual pathways. The thalamocortical system is divided into separate magnocellular and parvocellular divisions, which engage separate layers of the lateral geniculate nucleus (LGN) and project preferentially to the dorsal and ventral visual streams, respectively. The retinotectal system, in contrast, projects to the superior colliculus, pulvinar nucleus of the thalamus and amygdala. The pulvinar nucleus also plays a critical role in the integration of information processing across early visual regions.The functions of the visual system can be assessed using convergent EEG- and functional brain imaging approaches, increasingly supplemented by simultaneously collected eye-tracking information. These approaches may be used for tracing the flow of information from retina through early visual regions, as well as the contribution of these regions to higher-order cognitive processing. A pathway of increasing interest in relationship to neuropsychiatric disorders is the primate-specific "third visual pathway" that relies extensively on motion-related input and contributes preferentially to social information processing. Thus, disturbances in the brain's responsiveness to motion stimuli may be especially useful as biomarkers for early visual dysfunction related to impaired social cognition.Visual event-related potentials (ERPs) can be collected with high-fidelity and have proven effective for the study of neuropsychiatric disorders such as schizophrenia and Alzheimer's disease, in which alterations in visual processing may occur early in the disorder, andautism-spectrum disorder (ASD), in which abnormal persistence of early childhood patterns may persist into adulthood, leading to impaired functioning of visual social pathways. The utility of visual ERPs as biomarkers for larger clinical studies is limited at present by the need for standardization of visual stimuli across laboratories, which requires specialized protocols and equipment. The development of optimized stimulation protocols as well as newer headset-based systems may increase the clinical utility of present stimulation approaches.}, }
@article {pmid39562009, year = {2024}, author = {Koch, G and Altomare, D and Benussi, A and Bréchet, L and Casula, EP and Dodich, A and Pievani, M and Santarnecchi, E and Frisoni, GB}, title = {The emerging field of non-invasive brain stimulation in Alzheimer's disease.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {12}, pages = {4003-4016}, pmid = {39562009}, issn = {1460-2156}, support = {//European Union's Horizon 2020 research and innovation programme/ ; //Italian Ministry of University/ ; }, mesh = {*Alzheimer Disease/therapy/physiopathology ; Humans ; *Transcranial Direct Current Stimulation/methods ; *Transcranial Magnetic Stimulation/methods ; Animals ; Brain/physiopathology ; }, abstract = {Treating cognitive impairment is a holy grail of modern clinical neuroscience. In the past few years, non-invasive brain stimulation is increasingly emerging as a therapeutic approach to ameliorate performance in patients with cognitive impairment and as an augmentation approach in persons whose cognitive performance is within normal limits. In patients with Alzheimer's disease, better understanding of brain connectivity and function has allowed for the development of different non-invasive brain stimulation protocols. Recent studies have shown that transcranial stimulation methods enhancing brain plasticity with several modalities have beneficial effects on cognitive functions. Amelioration has been shown in preclinical studies on behaviour of transgenic mouse models for Alzheimer's pathology and in clinical studies with variable severity of cognitive impairment. While the field is still grappling with issues related to the standardization of target population, frequency, intensity, treatment duration and stimulated region, positive outcomes have been reported on cognitive functions and on markers of brain pathology. Here we review the most encouraging protocols based on repetitive transcranial magnetic stimulation, transcranial direct current stimulation, transcranial alternating current stimulation, visual-auditory stimulation, photobiomodulation and transcranial focused ultrasound, which have demonstrated efficacy to enhance cognitive functions or slow cognitive decline in patients with Alzheimer's disease. Beneficial non-invasive brain stimulation effects on cognitive functions are associated with the modulation of specific brain networks. The most promising results have been obtained targeting key hubs of higher-level cognitive networks, such as the frontal-parietal network and the default mode network. The personalization of stimulation parameters according to individual brain features sheds new light on optimizing non-invasive brain stimulation protocols for future applications.}, }
@article {pmid39561994, year = {2025}, author = {Wang, X and Zhang, S and Li, Y and Zhang, Y}, title = {The regulation of miRNAs using curcumin and other polyphenols during the prevention and treatment of Alzheimer's disease.}, journal = {Human molecular genetics}, volume = {34}, number = {2}, pages = {117-127}, doi = {10.1093/hmg/ddae154}, pmid = {39561994}, issn = {1460-2083}, mesh = {*Alzheimer Disease/genetics/drug therapy/metabolism ; *MicroRNAs/genetics/metabolism ; Humans ; *Curcumin/therapeutic use/pharmacology ; *Polyphenols/pharmacology/therapeutic use ; *Gene Expression Regulation/drug effects ; *Autophagy/drug effects ; Animals ; }, abstract = {Alzheimer's disease (AD), a prevalent neurodegenerative disorder, predominantly affects individuals over the age of 65 and poses significant challenges in terms of effective management and treatment. The disease's pathogenesis involves complex molecular pathways including misfolded proteins accumulation, neuroinflammation, and synaptic dysfunction. Recent insights have highlighted the role of microRNAs (miRNAs) as critical regulators within these pathways, where they influence gene expression and contribute to the pathophysiological landscape of AD. Notably, emerging research has demonstrated that polyphenols, including curcumin, might modulate miRNA activity, thus offering a novel approach to mitigate AD symptoms and progression. This review explores the potential mechanisms through which polyphenols regulate miRNA expression and activity, specifically focusing on autophagy enhancement and inflammation reduction in the context of AD. We provide a detailed examination of key studies linking miRNA dysregulation to AD pathogenesis and discuss how polyphenols might correct these aberrations. The findings presented here underscore the therapeutic potential of polyphenols in AD treatment via miRNA modulation, pointing to new directions in disease management strategies and highlighting the need for targeted research into miRNA-based interventions.}, }
@article {pmid39561662, year = {2025}, author = {Thai, QM and Nguyen, TH and Lenon, GB and Thu Phung, HT and Horng, JT and Tran, PT and Ngo, ST}, title = {Estimating AChE inhibitors from MCE database by machine learning and atomistic calculations.}, journal = {Journal of molecular graphics & modelling}, volume = {134}, number = {}, pages = {108906}, doi = {10.1016/j.jmgm.2024.108906}, pmid = {39561662}, issn = {1873-4243}, mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology ; *Machine Learning ; *Molecular Docking Simulation ; *Molecular Dynamics Simulation ; *Acetylcholinesterase/chemistry ; Ligands ; Protein Binding ; Humans ; Databases, Chemical ; Binding Sites ; }, abstract = {Acetylcholinesterase (AChE) is one of the most successful targets for the treatment of Alzheimer's disease (AD). Inhibition of AChE can result in preventing AD. In this context, the machine-learning (ML) model, molecular docking, and molecular dynamics calculations were employed to characterize the potential inhibitors for AChE from MedChemExpress (MCE) database. The trained ML model was initially employed for estimating the inhibitory of MCE compounds. Atomistic simulations including molecular docking and molecular dynamics simulations were then used to confirm ML outcomes. In particular, the physical insights into the ligand binding to AChE were clarified over the calculations. Two compounds, PubChem ID of 130467298 and 132020434, were indicated that they can inhibit AChE.}, }
@article {pmid39561115, year = {2024}, author = {Jang, S and Choi, B and Lim, C and Kim, M and Lee, JE and Lee, H and Baek, E and Cho, KS}, title = {Neuronal fatty acid-binding protein enhances autophagy and suppresses amyloid-β pathology in a Drosophila model of Alzheimer's disease.}, journal = {PLoS genetics}, volume = {20}, number = {11}, pages = {e1011475}, pmid = {39561115}, issn = {1553-7404}, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *Autophagy/genetics ; *Disease Models, Animal ; *Amyloid beta-Peptides/metabolism/genetics ; *Neurons/metabolism ; *Drosophila Proteins/genetics/metabolism ; Humans ; *Fatty Acid-Binding Proteins/genetics/metabolism ; Brain/metabolism/pathology ; Drosophila melanogaster/genetics/metabolism ; Fatty Acid Binding Protein 3/metabolism/genetics ; }, abstract = {Fatty acid-binding proteins (FABPs) are small cytoplasmic proteins involved in intracellular lipid transport and bind free fatty acids, cholesterol, and retinoids. FABP3, the major neuronal FABP in the adult brain, is upregulated in the CSF of patients with Alzheimer's disease (AD). However, the precise role of neuronal FABPs in AD pathogenesis remains unclear. This study investigates the contribution of fabp, the Drosophila homolog of FABP3 and FABP7, to amyloid β (Aβ) pathology using a Drosophila model. Neuronal knockdown of fabp shortened the lifespan of flies and increased age-related protein aggregates in the brain. In an AD model, fabp knockdown in neurons increased Aβ accumulation and Aβ-induced neurodegeneration, whereas fabp overexpression ameliorated Aβ pathology. Notably, fabp overexpression stimulated autophagy, which was inhibited by the knockdown of Eip75B, the Drosophila homolog of the peroxisome proliferator-activated receptor (PPAR). The PPAR activator rosiglitazone restored autophagy impaired by fabp knockdown and reduced fabp knockdown-induced increased Aβ aggregation and cell death. Furthermore, knockdown of either fabp or Eip75B in the wing imaginal disc or adult fly brain reduced the expression of Atg6 and Atg8a. Additionally, treatment of the fabp knockdown AD model flies with polyunsaturated fatty acids, such as docosahexaenoic acid or linoleic acid, partially alleviated cell death in the developing eye, restored impaired autophagy flux, reduced Aβ aggregation, and attenuated Aβ-induced cell death. Our results suggest that Drosophila fabp plays an important role in maintaining protein homeostasis during aging and protects neurons from Aβ-induced cell death by enhancing autophagy through the PPAR pathway. These findings highlight the potential importance of neuronal FABP function in AD pathogenesis.}, }
@article {pmid39560943, year = {2024}, author = {Lee, YC and Shi, SM and Sison, SM and Park, CM and Oh, G and Jeong, S and McCarthy, EP and Kim, DH}, title = {Discontinuation of Cholinesterase Inhibitors Following Initiation of Memantine and Admission to Long-Term Care Among Older Adults.}, journal = {JAMA network open}, volume = {7}, number = {11}, pages = {e2445878}, pmid = {39560943}, issn = {2574-3805}, mesh = {Humans ; *Memantine/therapeutic use ; Female ; Male ; *Cholinesterase Inhibitors/therapeutic use ; Aged ; *Long-Term Care/statistics & numerical data ; Aged, 80 and over ; Retrospective Studies ; United States/epidemiology ; *Dementia/drug therapy ; Medicare/statistics & numerical data ; Propensity Score ; Withholding Treatment/statistics & numerical data ; }, abstract = {IMPORTANCE: Discontinuing cholinesterase inhibitors when initiating memantine in patients with dementia may be reasonable to reduce treatment burden, costs, and the risk of adverse drug events.
OBJECTIVE: To assess the association of cholinesterase inhibitor discontinuation on long-term care institutionalization among older adults with dementia who initiate memantine.
This retrospective propensity score-matched cohort study used Medicare claims data from January 2014 to December 2019. Participants included fee-for-service Medicare beneficiaries with dementia. Data were analyzed from September 2021 to August 2024.
EXPOSURES: Discontinuation vs continuation of cholinesterase inhibitor.
MAIN OUTCOMES AND MEASURES: The primary outcome was 1-year long-term care institutionalization-free days. Secondary outcomes include all-cause death and adverse drug events over 1 year. We performed subgroup analyses based on age, sex, dementia type (Alzheimer disease vs other), frailty, and dementia severity (mild vs moderate or severe) based on claims-based algorithms. The primary outcome was analyzed using nonparametric restricted mean survival time analysis.
RESULTS: Among 16 292 beneficiaries who initiated memantine, 1820 (11.2%) discontinued cholinesterase inhibitors. In the propensity score-matched cohort of 3612 beneficiaries, the mean (SD) age was 80.7 (6.7) years, 2261 (62.6%) were female, and 1989 (55.0%) had a diagnosis of Alzheimer disease. Over 1 year, long-term care institutionalization occurred in 51 of 1806 beneficiaries (2.8%) who discontinued cholinesterase inhibitors (3.4 per 100 person-years) and 62 of 1806 beneficiaries (3.4%) who continued (4.1 per 100 person-years). There was no statistically significant difference in the 1-year mean institutionalization-free days between discontinuation and continuation groups (360.6 [95% CI, 359.3 to 362.0] days vs 359.1 [95% CI, 357.5 to 360.6] days; mean difference, 1.5 [95% CI,-0.5 to 3.6] days). The mean difference in the long-term care institutionalization-free days did not differ by age category, sex, dementia type, frailty, or dementia stage. Individuals who discontinued had a lower rate of fall-related injury (0.9 vs 2.0 per 100 person-years; hazard ratio [HR], 0.47 [95% CI, 0.25 to 0.88]). There was no difference between the discontinuation and continuation groups in all-cause death (10.4 vs 11.6 per 100 person-years; HR, 0.89 [95% CI, 0.72 to 1.10]).
CONCLUSIONS AND RELEVANCE: In this study, discontinuing cholinesterase inhibitors upon memantine initiation was not associated with an increased risk of long-term care institutionalization but with a lower risk of fall-related injury among older adults with dementia. These findings offer valuable insights for clinicians aiming to reduce treatment burden in this population.}, }
@article {pmid39560812, year = {2024}, author = {Davri, AS and Katsenos, AP and Tulyaganova, GK and Tzavellas, NP and Simos, YV and Kanellos, FS and Konitsiotis, S and Dounousi, E and Niaka, K and Bellou, S and Lekkas, P and Bekiari, C and Batistatou, A and Peschos, D and Tsamis, KI}, title = {The SGLT2 inhibitor empagliflozin exerts neuroprotective effect against hydrogen peroxide-induced toxicity on primary neurons.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {15}, pmid = {39560812}, issn = {1573-7365}, mesh = {Animals ; *Glucosides/pharmacology ; *Benzhydryl Compounds/pharmacology/toxicity ; *Neuroprotective Agents/pharmacology ; *Neurons/drug effects/metabolism/pathology ; *Hydrogen Peroxide/toxicity ; Rats ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Oxidative Stress/drug effects ; Cells, Cultured ; Rats, Transgenic ; Hippocampus/drug effects/metabolism ; Cell Survival/drug effects ; }, abstract = {Oxidative stress has been implicated in several chronic pathological conditions, leading to cell death and injury. Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) have several overlapping mechanisms as they are both characterized by increased oxidative stress, inflammation, insulin resistance, and autophagy dysfunction. The objective of this study was to elucidate the possible neuroprotective effect of empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), against hydrogen peroxide-induced neurotoxicity in primary hippocampal neurons derived from wild-type (WT) and transgenic AD rats (TgF344-AD). An in vitro oxidative stress model was established using hydrogen peroxide to induce damage to neurons. Empagliflozin pretreatment was tested on this model initially through a cell viability assay. Flow cytometry and cell sorting were employed to discriminate the apoptotic and necrotic neuronal cell populations. Finally, the morphological and morphometric features of the neurons, including dendritic length and spine density, were evaluated using the SNT ImageJ plug-in following immunostaining with GFP. Sholl analysis was used to evaluate the impact of empagliflozin and hydrogen peroxide on dendritic arborization. Empagliflozin tended to ameliorate hydrogen peroxide-induced toxicity in primary neurons derived from WT rats and led to the preservation of dendritic spine density in both WT and TgF344-AD neurons (one-way ANOVA, p < 0.05). A modest improvement in dendrites' length was also observed. Empagliflozin pretreatment can partially mitigate dendritic and spine alterations induced by hydrogen peroxide in primary neurons. These results underscore the impact of empagliflozin on neuronal morphology and highlight its potential as a candidate for the treatment and/or prevention of AD.}, }
@article {pmid39559896, year = {2024}, author = {Zhao, Q and Baranova, A and Cao, H and Zhang, F}, title = {Evaluating Causal Effects of Gut Microbiome on Alzheimer's Disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {11}, number = {6}, pages = {1843-1848}, doi = {10.14283/jpad.2024.113}, pmid = {39559896}, issn = {2426-0266}, mesh = {*Alzheimer Disease/microbiology ; *Gastrointestinal Microbiome ; Humans ; *Genome-Wide Association Study ; Mendelian Randomization Analysis ; }, abstract = {BACKGROUND: The preceding evidence indicates a close correlation between imbalances in the gut microbiome and Alzheimer's disease (AD), yet the direct causal relationship remains unclear. Our objective is to investigate this potential causal connection.
METHODS: We obtained summary results from two significant genome-wide association studies (GWAS) on gut microbiota (the MibioGen consortium and the Dutch Microbiome Project), along with one GWAS summary result for AD. Using a two-sample Mendelian randomization (TSMR) analysis, we examined the potential causal effects of gut microbiota on AD.
RESULTS: Our TSMR analysis revealed that 16 gut bacterial taxa were linked to a reduced risk of AD. These included phylum Tenericutes, classes Bacilli and Clostridia along with its order Clostridiales, family Bacteroidaceae, genus Bacteroides, and species Bifidobacterium bifidum (OR: 0.867~0.971, P ≤ 0.045). Conversely, the presence of 12 taxa correlated with an increased risk of AD. These comprised class Actinobacteria and its family Coriobacteriaceae, as well as class Betaproteobacteria, its order Burkholderiales, and its family Sutterellaceae (OR: 1.042~1.140, P ≤ 0.035).
CONCLUSION: Our research uncovered evidence suggesting certain gut bacterial species might play a causal role in AD risk, providing a fresh angle for AD treatment strategies.}, }
@article {pmid39559892, year = {2024}, author = {Vijverberg, E and de Haan, W and Scheijbeler, E and Hamby, ME and Catalano, S and Scheltens, P and Grundman, M and Caggiano, AO}, title = {A Pilot Electroencephalography Study of the Effect of CT1812 Treatment on Synaptic Activity in Patients with Mild to Moderate Alzheimer's Disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {11}, number = {6}, pages = {1809-1817}, pmid = {39559892}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology ; *Electroencephalography ; Double-Blind Method ; Male ; Female ; Aged ; *Cross-Over Studies ; Pilot Projects ; Aged, 80 and over ; Middle Aged ; Synapses/drug effects/physiology ; }, abstract = {BACKGROUND: CT1812 is a first-in-class, sigma-2 receptor ligand, that prevents and displaces binding of amyloid beta (Aβ) oligomers. Normalization of quantitative electroencephalography (qEEG) markers suggests that CT1812 protects synapses from Aβ oligomer toxicity.
OBJECTIVES: Evaluate CT1812 impact on synaptic function using qEEG measurements.
DESIGN: Phase 2, randomized, double-blind, placebo-controlled, 4-week crossover study.
SETTING: VU University Medical Center and Brain Research Center Amsterdam, The Netherlands.
PARTICIPANTS: Adults with mild or moderate Alzheimer's disease (AD).
INTERVENTION: A daily 300 mg dose of CT1812 or placebo for 4 weeks.
MEASUREMENTS: A resting-state, eyes closed qEEG assessment occurred on Day 1 and on Day 29 of Treatment Periods 1 and 2, and at follow-up. The primary endpoint was global relative theta power (4-8 Hz), along with secondary EEG measures including global alpha corrected Amplitude Envelope Correlation (AEC-c). Cognitive and functional assessments, fluid biomarkers, and safety and tolerability were assessed.
RESULTS: 16 patients were randomized, and 15 completed. A non-significant (p=0.123) but consistent reduction occurred in global relative theta power and in relative theta power in frontal, temporal, parietal, occipital and central (p<0.006) brain regions with CT1812. A nominally significant (p=0.034) improvement was observed in global alpha AEC-c. Adverse events occurred in 11 patients with CT1812 and 6 with placebo - most commonly nausea, diarrhea, and procedural headache. No severe or serious AEs, deaths or discontinuations were reported.
CONCLUSION: CT1812 improved established EEG markers of spontaneous brain activity (spectral power, functional connectivity) in patients with mild-to-moderate AD, suggesting improved neuronal/synaptic function within a 4-week timespan.}, }
@article {pmid39559889, year = {2024}, author = {Ren, L and Zhang, Q and Zhou, J and Wang, X and Zhu, D and Chen, X}, title = {Leveraging Diverse Regulated Cell Death Patterns to Identify Diagnosis Biomarkers for Alzheimer's Disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {11}, number = {6}, pages = {1775-1788}, pmid = {39559889}, issn = {2426-0266}, mesh = {*Alzheimer Disease/genetics/diagnosis ; Humans ; *Biomarkers/metabolism ; Cluster Analysis ; Cell Death/genetics ; Machine Learning ; Cohort Studies ; Gene Expression Profiling ; Algorithms ; }, abstract = {BACKGROUND: The functions of regulated cell death (RCD) are closely related to Alzheimer's disease (AD). However, very few studies have systematically investigated the diagnosis and immunologic role of RCD-related genes in AD patients.
METHODS: 8 multicenter AD cohorts were included in this study, and then were merged into a meta cohort. Then, an unsupervised clustering analysis was carried out to detect unique subtypes of AD based on RCD-related genes. Subsequently, differently expressed genes (DEGs) and weighted correlation network analysis (WGCNA) between subtypes were identified. Finally, to establish an optimal risk model, an RCD.score was constructed by using computational algorithm (10 machine-learning algorithms, 113 combinations).
RESULTS: We identified two distinct subtypes based on RCD-related genes, each exhibiting distinct hallmark pathway activity and immunologic landscape. Specifically, cluster.A patients had a higher immune infiltration, a higher immune modulators and poor AD progression. Utilizing the shared DEGs and WGCNA of these subtypes, we constructed an RCD.score that demonstrated excellent predictive ability in AD across multiple datasets. Furthermore, RCD.score was identified to exhibit the strongest association with poor AD progression. Mechanistically, we observed activation of signaling pathways and effective immune infiltration and immune modulators in the high RCD.score group, thus leading to a poor AD progression. Additionally, Mendelian randomization screening revealed four genes (CXCL1, ENTPD2, METTL7A, and SERPINB6) as feature genes for AD.
CONCLUSION: The RCD model is a valuable tool in categorizing AD patients. This model can be of great assistance to clinicians in determining the most suitable personalized treatment plan for each individual AD patient.}, }
@article {pmid39559887, year = {2024}, author = {Meng, F and Zhang, X}, title = {Unveiling Potential Biomarkers in Cerebrospinal Fluid for Amyloid Pathological Positivity in Non-Demented Individuals.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {11}, number = {6}, pages = {1759-1766}, doi = {10.14283/jpad.2024.129}, pmid = {39559887}, issn = {2426-0266}, mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid ; Female ; Male ; Aged ; *Chitinase-3-Like Protein 1/cerebrospinal fluid ; Apolipoproteins E/genetics ; Alzheimer Disease/cerebrospinal fluid/diagnosis/pathology ; Disease Progression ; Middle Aged ; Positron-Emission Tomography ; Calcium-Binding Proteins/cerebrospinal fluid ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque accumulation and neurofibrillary tangles. The recent approval of anti-amyloid therapeutic medications highlights the crucial need for early detection of Aβ pathological abnormalities in individuals without dementia to facilitate timely intervention and treatment.
OBJECTIVE: The primary aim of this study was to identify cerebrospinal fluid (CSF) biomarkers strongly associated with Aβ pathological positivity in a non-demented cohort and evaluate their clinical values.
METHODS: A comprehensive analysis was conducted on 51 CSF proteins (excluding Aβ42, pTau, and Tau) obtained from 474 non-demented participants sourced from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. By utilizing the Least Absolute Shrinkage and Selection Operator (LASSO) regression, we identified potential proteins indicative of Aβ pathological positivity and evaluated their performance in tracking longitudinal pathological progression.
RESULTS: Our LASSO analysis unveiled three candidates: apolipoprotein E (APOE), chitinase-3-like protein 1 (CHI3L1), and SPARC-related modular calcium-binding protein 1 (SMOC1). While SMOC1 did not correlate with Aβ42-related cognitive alterations, it displayed better abilities in discriminating both CSF-Aβ positivity and Aβ-positron emission tomography (PET) positivity than the other two candidates. It could precisely predict longitudinal Aβ-PET status conversion. Notably, SMOC1 was the only protein showing associations with longitudinal Aβ-PET trajectory and enhancing the diagnostic accuracy of Aβ42. The assessment of combined Aβ42 and SMOC1 yielded valuable clinical insights.
CONCLUSION: Our findings elucidated SMOC1 as a potential biomarker for detecting Aβ abnormalities. Aβ42 combining SMOC1 offered critical implications in AD pathological diagnosis and management.}, }
@article {pmid39559880, year = {2024}, author = {Aschenbrenner, AJ and Hassenstab, JJ and Schindler, SE and Janelidze, S and Hansson, O and Morris, JC and Grober, E}, title = {Free Recall Outperforms Story Recall in Associations with Plasma Biomarkers in Preclinical Alzheimer Disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {11}, number = {6}, pages = {1696-1702}, pmid = {39559880}, issn = {2426-0266}, support = {P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/blood/psychology ; *Biomarkers/blood ; *Mental Recall ; *Amyloid beta-Peptides/blood ; Aged ; Female ; *Memory, Episodic ; Male ; *tau Proteins/blood ; Longitudinal Studies ; Peptide Fragments/blood ; Neuropsychological Tests ; Neurofilament Proteins/blood ; Prodromal Symptoms ; }, abstract = {BACKGROUND: A decline in episodic memory is one of the earliest cognitive characteristics of Alzheimer disease and memory tests are heavily featured in cognitive composite endpoints that are used to demonstrate treatment efficacy. Assessments of episodic memory can take many forms including free recall, associate learning, and paragraph or story recall. Plasma biomarkers of Alzheimer disease are now widely available and will likely form the backbone of cohort enrichment strategies for future clinical trials. Thus, it is critical to evaluate which episodic memory measures are most sensitive to plasma markers of Alzheimer disease pathology.
OBJECTIVES: To compare the associations of common episodic memory tests with plasma biomarkers of Alzheimer disease.
DESIGN: Longitudinal cohort study.
SETTING: Academic medical center in the midwestern United States.
PARTICIPANTS: A total of 161 cognitively normal older adults with at least one plasma biomarker assessment and two or more annual clinical and cognitive assessments which included up to three different tests of episodic memory.
MEASUREMENTS: Episodic memory performance using free recall, paired associates recall or paragraph recall. Plasma Aβ42, Aβ40, ptau217, and neurofilament light chain were measured.
RESULTS: Free recall on the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT + IR) was substantially more sensitive to longitudinal cognitive change associated with abnormal baseline plasma Aβ42/Aβ40 and ptau217 compared to other measures of episodic memory. A cognitive composite that included only free recall showed larger decline associated with baseline Aβ42/Aβ40 when compared to those that included paragraph recall. Differences in decline across composites were minimal when considering baseline ptau217 or NfL.
CONCLUSION: Episodic memory is a critical domain to assess in preclinical Alzheimer disease. Methods of assessing memory are not equal and longitudinal change in free recall substantially outperformed both paired associates and paragraph recall. Clinical trial results will depend critically on the episodic memory test(s) that are chosen for a composite endpoint and free recall from the FCSRT + IR is an optimal memory measure to include rather than paired associates or paragraph recall.}, }
@article {pmid39559879, year = {2024}, author = {Lin, M and Yu, JX and Zhang, WX and Lao, FX and Huang, HC}, title = {Roles of TREM2 in the Pathological Mechanism and the Therapeutic Strategies of Alzheimer's Disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {11}, number = {6}, pages = {1682-1695}, pmid = {39559879}, issn = {2426-0266}, mesh = {*Alzheimer Disease/metabolism/pathology/drug therapy ; *Receptors, Immunologic/metabolism ; Humans ; *Membrane Glycoproteins/metabolism ; *Microglia/metabolism ; Animals ; }, abstract = {Alzheimer's disease (AD) is an age-related degenerative disease, which is characteristic by the deposition of senile plaques (SP) outside the cells, the neurofibrillary tangles (NFTs) inside the neurons, and the loss of synapse and neurons. Neuroinflammation may play an important role in the pathogenesis of AD. Microglia are the immune cells in the central nervous system. However, microglia might become disease-related microglia (DAMs) when stimulated by the external environment. DAMs have been shown to be involved in a series of events of AD development including Aβ accumulation and tau phosphorylation. The triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor that is mainly expressed by microglia in the central nervous system (CNS). TREM2 plays an important role in the physiological function of microglia, and the dyshomeostasis of TREM2 is related to the development of late-onset AD. This article summarized the latest advances in TREM2 biology and its impact on the roles of microglia in AD development, with a particular emphasis on the structure, ligands, signal transduction, and the agonistic antibodies of TREM2 for AD treatment. We further discussed the survival, migration, phagocytosis, inflammation, and cellular metabolism of microglia, as well as the role of sTREM2 in neuroprotection and as a biomarker for AD. It provides a reference for further research on the molecular mechanism of microglial TREM2 in the occurrence and development of AD and on the therapeutic strategies targeted on the microglial TREM2.}, }
@article {pmid39559876, year = {2024}, author = {Sternberg, Z and Podolsky, R and Yu, J and Hua, S and Halvorsen, S and Hojnacki, D and Schaller, BJ}, title = {Anti-Hypertensives Reduce the Rate of Alzheimer's Disease Progression: A Cohort Study Linked with Genetic and Neuropathological Analyses.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {11}, number = {6}, pages = {1634-1646}, pmid = {39559876}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy/pathology ; *Disease Progression ; Male ; Female ; *Antihypertensive Agents/therapeutic use ; Aged ; *Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; *tau Proteins/cerebrospinal fluid ; Cohort Studies ; Hypertension/drug therapy ; Peptide Fragments/cerebrospinal fluid ; Brain/pathology ; Hippocampus/pathology ; Aged, 80 and over ; }, abstract = {BACKGROUND: Arterial hypertension contributes to both the development and progression of dementia due to both Alzheimer's disease (A.D.) and vascular pathology. However, the effects of different classes of anti-hypertensives (A.H.T.s), on the rate of dementia progression and brain neuropathology are unknown.
OBJECTIVE: To investigate the effect of each class of A.H.T., both as single and combined, on the rate of dementia progression. In addition, we analyzed the effect of A.H.T.s on brain neuropathology in AD participants, indicated by Braak staging, hippocampal atrophy, and baseline CSF levels of A-β42, total (T) tau, and P-181 tau.
METHODS: We have used the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS).
RESULTS: A.H.T.s were associated with reduced yearly increase in the CDR-SOB scores of 1.025 during a 10-year follow-up (P<0.001). The overall survival rate was higher in A.H.T. users than non-users [HR: 0.912: 0.860, 0.967) P=0.002]. These trends continued when stratifying participants by age, gender, and APOE4 allele. Participants who did not use A.H.T.s had a mean yearly increase of 1.71±1.7 in the CDR-SOB scores. This value was reduced to 1.48±1.6, P=0.006 and 1.45±1.6, P=0.024 for participants with documented use of βB and A.R.B.s, respectively. Combining diuretics with α1-AB or ACEI led to synergistic effects in reducing the rise in CDR-SOB scores. The proportion of participants who were diagnosed having AD postmortem with severe Braak staging was significantly lower in A.H.T.-users than non-users. The severity of Braak staging, and hippocampal atrophy differed in participants> 70 vs. <70 years old, in both males and females. A significant relationship was observed between hippocampal atrophy and Braak staging; and between hippocampal atrophy and baseline CSF levels of P-181 tau.
CONCLUSION: Our results could have implications for halting the progression of dementia regardless of the etiology being related to AD or vascular pathology. The choice of combination of A.H.T. therapy should also consider the combination which would lead to an optimum benefit in slowing the progression of dementia. Additionally, our results underline a more complex A.D. disease model than previously thought, which opens new treatment options.}, }
@article {pmid39559868, year = {2024}, author = {Shields, LBE and Hust, H and Cooley, SD and Cooper, GE and Hart, RN and Dennis, BC and Freeman, SW and Cain, JF and Shang, WY and Wasz, KM and Orr, AT and Shields, CB and Barve, SS and Pugh, KG}, title = {Initial Experience with Lecanemab and Lessons Learned in 71 Patients in a Regional Medical Center.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {11}, number = {6}, pages = {1549-1562}, pmid = {39559868}, issn = {2426-0266}, mesh = {Humans ; Aged ; Female ; Male ; Retrospective Studies ; Aged, 80 and over ; Middle Aged ; *Alzheimer Disease/drug therapy ; Cognitive Dysfunction/drug therapy ; Antibodies, Monoclonal, Humanized/therapeutic use ; Positron-Emission Tomography ; }, abstract = {BACKGROUND AND OBJECTIVES: On July 6, 2023 the U.S. Food and Drug Administration approved the anti-amyloid monoclonal antibody lecanemab (Leqembi®) for treatment of patients with mild cognitive impairment or mild dementia due to Alzheimer's disease (AD). Our early experience and lessons learned with lecanemab in a regional community medical center are described.
This retrospective observational study highlights the first 71 patients treated with lecanemab at our multidisciplinary Norton Neuroscience Institute Memory Center. All patients had positive cerebrospinal fluid biomarkers for AD and underwent at least 1 lecanemab infusion. Two patients had additional amyloid PET scans which were positive.
RESULTS: The mean age was 72 years (49-90 years), and 44 (62%) patients were female. Most were Caucasian (68 [96%]), and 54 [76%] were referred to our Memory Center by their primary care provider. Comorbidities were common, including hypertension (34 [48%]), hypercholesterolemia (51 [72%]), diabetes mellitus (17 [24%]), and cardiovascular disease excluding hypertension (22 [31%]). The mean body mass index was 27.0 (range: 17.8-45.0). A total of 36 (51%) patients were heterozygous for the ApoE4 genotype, and 9 (13%) were homozygous. A total of 61 [86%] patients had been treated with donepezil; 40 (56%) patients had received memantine. Of the 50 patients who completed 1 or more safety monitoring brain MRIs following infusion, 12 (24%) had amyloid-related imaging abnormalities (ARIA) detected: solitary ARIA-H (hemorrhage) in 5, solitary ARIA-E (edema) in 3, and both ARIA-H and ARIA-E in 4. Of the 12 patients with ARIA, 9 were asymptomatic, 4 were homozygous for the ApoE4 genotype, and 6 were heterozygous for the ApoE4 genotype. Of the 9 who were homozygous for the ApoE4 genotype in this study, 4 (44%) had evidence of ARIA. Of the 36 who were heterozygous for the ApoE4 genotype, 6 (17%) were diagnosed with ARIA. Twenty-six (37%) patients experienced infusion reactions after their first lecanemab infusion: headaches (12 patients) and shaking/chills/rigors (11 patients) were most common. Twenty-three (88%) of these 26 patients reported the side effects either at the infusion center or within the first 24 hours post-infusion. One patient died shortly after the first lecanemab infusion of a myocardial infarction. It is uncertain whether or not this death was related to lecanemab treatment.
CONCLUSION: Through our early experience with lecanemab, we have recognized several areas of improvement which have clarified and enhanced the lecanemab infusion experience.}, }
@article {pmid39559708, year = {2024}, author = {van Dorst, MEG and Rensen, YCM and Nijsten, JMH and Janssen, GTL and Kessels, RPC}, title = {Towards a Non-pharmacological Intervention on Apathy in Korsakoff's Syndrome: A Systematic Narrative Review Across Different Clinical Conditions.}, journal = {Neuropsychiatric disease and treatment}, volume = {20}, number = {}, pages = {2125-2144}, pmid = {39559708}, issn = {1176-6328}, abstract = {ABSTRACT: Apathy is a quantitative reduction of goal-directed activity, which can be observed in relation to behavior, cognition, emotions and social interaction. It is an invalidating behavioral symptom that is frequently present across different psychiatric conditions and neurocognitive disorders including Korsakoff's Syndrome (KS). In fact, apathy is one of the most severe behavioral symptoms of KS and has a major impact on the lives of patients and their relatives and other informal caregivers. However, guidelines for the treatment of apathy in KS are currently not available. This systematic narrative review provides a transdiagnostic overview of the effectiveness of different types of non-pharmacological interventions on apathy across different study populations that at symptom-level share characteristics with KS. This evidence may inform the development of an intervention targeting apathy in KS. The included study populations are dementia (due to Alzheimer's disease, or vascular dementia), Parkinson's disease, schizophrenia and traumatic brain injury. Through a stepped selection approach and with regard to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 22 systematic reviews and 32 empirical articles on the non-pharmacological treatment of apathy were identified. The results show a variety of effective non-pharmacological interventions on apathy. In conditions with severe cognitive impairments, successful interventions did not rely on intrinsic motivation, self-monitoring, or illness insight of the patients, but depend on external stimulation and behavioral activation. Since apathy is a multidimensional construct, identification of the extent and type of apathetic behavior before starting an intervention is highly recommended. Furthermore, it is important to adjust the treatment to the patients' personal interests and needs and embedded in daily care.
TRIAL REGISTRATION: CRD42022298464 (PROSPERO).}, }
@article {pmid39558496, year = {2024}, author = {Tripathi, S and Sharma, Y and Kumar, D}, title = {Exploring the Therapeutic Potential of Noncoding RNAs in Alzheimer's Disease.}, journal = {Protein and peptide letters}, volume = {31}, number = {11}, pages = {862-883}, doi = {10.2174/0109298665335550241011080252}, pmid = {39558496}, issn = {1875-5305}, mesh = {*Alzheimer Disease/genetics/metabolism ; Humans ; MicroRNAs/genetics ; RNA, Untranslated/genetics/metabolism ; Amyloid beta-Peptides/metabolism/genetics ; RNA, Long Noncoding/genetics/metabolism ; Biomarkers/metabolism ; Animals ; tau Proteins/metabolism/genetics ; Amyloid beta-Protein Precursor/genetics/metabolism ; Gene Expression Regulation ; RNA, Circular/genetics/metabolism ; }, abstract = {Despite significant research efforts, Alzheimer's disease (AD), the primary cause of dementia in older adults worldwide, remains a neurological challenge for which there are currently no effective therapies. There are substantial financial, medical, and personal costs associated with this condition.Important pathological features of AD include hyperphosphorylated microtubule-associated protein Tau, the formation of amyloid β (Aβ) peptides from amyloid precursor protein (APP), and continuous inflammation that ultimately results in neuronal death. Important histological markers of AD, amyloid plaques, and neurofibrillary tangles are created when Aβ and hyperphosphorylated Tau build-up. Nevertheless, a thorough knowledge of the molecular players in AD pathophysiology is still elusive. Recent studies have shown how noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), regulate gene expression at the transcriptional and posttranscriptional levels in a variety of diseases, including AD. There is increasing evidence to support the involvement of these ncRNAs in the genesis and progression of AD, making them promising as biomarkers and therapeutic targets. As a result, therapeutic approaches that target regulatory ncRNAs are becoming more popular as potential means of preventing the progression of AD. This review explores the posttranscriptional relationships between ncRNAs and the main AD pathways, highlighting the potential of ncRNAs to advance AD treatment. In AD, ncRNAs, especially miRNAs, change expression and present potential targets for therapy. MiR-346 raises Aβ through APP messenger Ribonucleic Acid (mRNA), whereas miR-107 may decrease Aβ by targeting beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). They are promising early AD biomarkers due to their stability in cerebrospinal fluid (CSF) and blood. Furthermore, additional research is necessary to determine the role that RNA fragments present in AD-related protein deposits play in AD pathogenesis.}, }
@article {pmid39557438, year = {2024}, author = {Luo, YY and Shan, XQ and Song, JJ and Hao, N and Zhao, L}, title = {[Research progress of mechanism of acupuncture and moxibustion on prevention and treatment of Alzheimer's disease based on the neuronal cell cycle re-entry].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {49}, number = {11}, pages = {1205-1212}, doi = {10.13702/j.1000-0607.20230547}, pmid = {39557438}, issn = {1000-0607}, mesh = {*Alzheimer Disease/therapy/metabolism/genetics ; Humans ; *Moxibustion ; *Acupuncture Therapy ; *Neurons/metabolism ; *Cell Cycle ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism/genetics ; }, abstract = {Alzheimer's disease (AD) is the most common type of dementia. Studies have shown that neuronal cell cycle re-entry is an abnormal change in the early stage of AD, and it is also one of the key reasons for mediating neuronal death. The mechanism of acupuncture and moxibustion in treating AD may be related to the regulation of abnormal cell cycle. In this article, we reviewed the occurrence of AD neuronal cell cycle re-entry and its mediated cell death mechanism, listed the factors affecting neuronal cell cycle re-entry, explored the possible mechanism of acupuncture and moxibustion in preventing and treating AD by regulating AD cell cycle protein, AD neuronal cell cycle re-entry influencing factors (β-amyloid protein and Tau protein phosphorylation level, oxidative stress, brain-derived neurotrophic factor), the multi-target regulation of neuronal cell cycle re-entry, so as to provide reference for the application and research of acupuncture and moxibustion in preventing and treating AD.}, }
@article {pmid39557220, year = {2025}, author = {Wu, Q and Shan, X and Li, X and Guan, J and Song, F and Zhou, X and Fan, Y and Guo, L}, title = {Salidroside ameliorates neuroinflammation in autistic rats by inhibiting NLRP3/Caspase-1/GSDMD signal pathway.}, journal = {Brain research bulletin}, volume = {220}, number = {}, pages = {111132}, doi = {10.1016/j.brainresbull.2024.111132}, pmid = {39557220}, issn = {1873-2747}, mesh = {Animals ; *Phenols/pharmacology ; *Glucosides/pharmacology/therapeutic use ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Rats ; *Signal Transduction/drug effects ; *Caspase 1/metabolism ; Female ; Rats, Sprague-Dawley ; Hippocampus/drug effects/metabolism ; Neuroinflammatory Diseases/drug therapy/metabolism ; Pyroptosis/drug effects ; Pregnancy ; Disease Models, Animal ; Male ; Autism Spectrum Disorder/drug therapy/metabolism ; Autistic Disorder/drug therapy/metabolism ; }, abstract = {BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that place a huge economic and emotional burden on society. Salidroside (Sal) has been reported to have therapeutic effects in a variety of neurological disorders such as Alzheimer's disease （AD） and Parkinson's disease (PD), however no studies have been conducted to show whether salidroside is effective in ASD. Pyroptosis is involved in the pathology of a variety of neurological disorders, but has not been reported in ASD.
OBJECTIVES: The aim of this study was to investigate whether pyroptosis is involved in the pathological mechanisms of ASD, and whether salidroside has an impact on the pathological process of ASD by regulating pyroptosis.
METHODS: We obtained a rat model of offspring ASD by prenatal intraperitoneal administration of valproic acid (VPA, 500 mg/kg) to pregnant rats, and we treated seven-day-old offspring ASD with salidroside (Sal, 30 mg/kg once daily) by gavage for 28 days as the salidroside treatment group. We examined the hippocampal state of ASD rats and the effect of salidroside on the hippocampus of VPA-induced ASD rats. In addition, in BV2 cells treated with LPS/Nig, we explored the mechanisms by which salidroside regulates neuroinflammation and pyroptosis in vitro.
RESULTS: In vivo, we observed VPA-induced hippocampal neuronal damage and activation of the NLRP3/Caspase-1/GSDMD signalling pathway in ASD rats, while salidroside alleviated neuronal damage in ASD rats. In vitro, we found that salidroside inhibited LPS/Nig-induced neuroinflammation and activation of the NLRP3/Caspase-1/GSDMD signalling pathway. These results suggest that the therapeutic effect of salidroside on hippocampal damage in ASD rats may be related to NLRP3/Caspase-1/GSDMD-mediated pyroptosis.
CONCLUSIONS: Our work showed that salidroside ameliorates hippocampal neurological damage in ASD rats by targeting NLRP3/Caspase-1/GSDMD-mediated pyroptosis, providing a potential therapy drug for ASD.}, }
@article {pmid39556640, year = {2024}, author = {Jarrett, JB and Infante, AF}, title = {Brexpiprazole (Rexulti) for the Treatment of Agitation Associated With Alzheimer Disease.}, journal = {American family physician}, volume = {110}, number = {5}, pages = {537-538}, pmid = {39556640}, issn = {1532-0650}, }
@article {pmid39556451, year = {2025}, author = {Farnum, Z and Mani, R and Bindoff, A and Wilson, R and Fiotakis, A and Stephens, J and Cho, E and Mackay-Sim, A and Sinclair, D}, title = {Convergent effects of synthetic glucocorticoid dexamethasone and amyloid beta in human olfactory neurosphere-derived cells.}, journal = {Journal of neurochemistry}, volume = {169}, number = {2}, pages = {e16263}, doi = {10.1111/jnc.16263}, pmid = {39556451}, issn = {1471-4159}, support = {//Dementia Australia Research Foundation/ ; }, mesh = {Humans ; *Amyloid beta-Peptides/metabolism ; *Dexamethasone/pharmacology ; *Glucocorticoids/pharmacology ; *Olfactory Mucosa/drug effects/metabolism ; *Peptide Fragments ; Male ; Cells, Cultured ; Female ; Adult ; Middle Aged ; Receptors, Glucocorticoid/metabolism ; Proteome/drug effects/metabolism ; }, abstract = {Stressful life events and glucocorticoid (stress) hormones appear to increase the risk of Alzheimer's disease and hasten its progression, but the reasons for this remain unclear. One potential explanation is that when amyloid β (Aβ) pathology is accumulating in the preclinical disease stage, glucocorticoid receptor signalling during stressful events exacerbates cellular dysfunction caused by Aβ. Alternatively, Aβ may disrupt glucocorticoid receptor signalling. To explore these possibilities, we investigated whether the synthetic glucocorticoid dexamethasone and Aβ have overlapping effects on the cellular proteome and whether Aβ influences canonical glucocorticoid receptor function. Human olfactory neurosphere-derived (ONS) cells, collected from the olfactory mucosa of six adult donors, were treated with soluble Aβ40 or Aβ42 followed by dexamethasone. Proteins were quantified by mass spectrometry. After 32 h treatment, Aβ40 and Aβ42 both induced profound changes in innate immunity-related proteins. After 72 h, Aβ42 formed widespread aggregates and induced few proteomic changes, whereas Aβ40 remained soluble and altered expression of mitochondrial and innate immunity-related proteins. ONS cells revealed overlapping impacts of Aβ40 and dexamethasone, with 23 proteins altered by both treatments. For 16 proteins (including eight mitochondrial proteins) dexamethasone counteracted the effects of Aβ40. For example, caspase 4 and methylmalonate-semialdehyde dehydrogenase were increased by Aβ40 and decreased by dexamethasone. Consistent with this finding, Aβ40 increased, but dexamethasone decreased, ONS cell proliferation. For seven proteins, including superoxide dismutase [Mn] mitochondrial, dexamethasone exacerbated the effects of Aβ40. For some proteins, including complement C3, the effects of dexamethasone differed depending on whether Aβ40 was present or absent. Neither Aβ species influenced glucocorticoid receptor nuclear translocation. Overall, this study revealed that glucocorticoid receptor signalling modifies the intracellular effects of Aß40, counteracting some effects and exacerbating others. It suggests that cellular mechanisms through which glucocorticoid receptor signalling influences Alzheimer's disease risk/progression are complex and determined by the balance of beneficial and detrimental glucocorticoid effects.}, }
@article {pmid39556389, year = {2025}, author = {Salloway, S and Wojtowicz, J and Voyle, N and Lane, CA and Klein, G and Lyons, M and Rossomanno, S and Mazzo, F and Bullain, S and Barkhof, F and Bittner, T and Schneider, A and Grundman, M and Aldea, R and Boada, M and Smith, J and Doody, R}, title = {Amyloid-Related Imaging Abnormalities (ARIA) in Clinical Trials of Gantenerumab in Early Alzheimer Disease.}, journal = {JAMA neurology}, volume = {82}, number = {1}, pages = {19-29}, pmid = {39556389}, issn = {2168-6157}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/cerebrospinal fluid/genetics ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Female ; Male ; Aged ; Middle Aged ; Aged, 80 and over ; *Amyloid beta-Peptides/cerebrospinal fluid ; Double-Blind Method ; *Magnetic Resonance Imaging ; Brain/diagnostic imaging/pathology/drug effects ; }, abstract = {IMPORTANCE: Data from 2 phase 3 studies of gantenerumab, GRADUATE I/II, and their open-label extensions represent a resource to further characterize amyloid-related imaging abnormalities (ARIA), including long-term sequelae.
OBJECTIVES: To describe the characteristics of ARIA and risk factors and clinical consequences of ARIA-edema (ARIA-E).
Secondary data collection from the GRADUATE I/II phase 3 randomized, double-blind, placebo-controlled, 116-week parallel-group studies and their open-label extensions, including PostGraduate, with up to 210 (mean, 125) weeks of total gantenerumab treatment were conducted between 2018 and 2023. The study included multicenter trials at 288 sites across 30 countries. GRADUATE I/II enrolled 985 and 980 participants, respectively, with early symptomatic Alzheimer disease (AD) and amyloid-beta (Aβ) pathology who were aged 50 to 90 years. PostGraduate enrolled 1382 participants (671 previously randomized to gantenerumab). Data were analyzed from November 2, 2022, to October 10, 2023.
INTERVENTIONS: GRADUATE I/II participants were randomized 1:1 to gantenerumab or placebo. Nine-month uptitration was used to mitigate ARIA risk.
MAIN OUTCOMES AND MEASURES: Postbaseline safety monitoring, including brain magnetic resonance imaging (MRI) findings, and adverse events and cognitive assessments.
RESULTS: The safety-evaluable MRI population of GRADUATE I/II comprised 1939 participants (mean age, 71.7 years; 1105 female [57.0%]). Severity of AD-related Aβ neuropathology (lower cerebrospinal fluid [CSF] Aβ42, hazard ratio [HR] for CSF Aβ42: 0.4; 95% CI, 0.2-0.7) and comorbid cerebrovascular pathology (Fazekas score: HR, 1.6; 95% CI, 1.3-2.0; total superficial siderosis count: HR, 1.9; 95% CI, 1.3-2.6; total microhemorrhage count: HR, 1.3; 95% CI, 1.0-1.5) may be important baseline risk factors for ARIA-E, in addition to apolipoprotein E (APOE) ε4 status (APOE ε4 heterozygous carrier: HR, 2.0; 95% CI, 1.4-2.8 and APOE ε4 homozygous carrier: HR, 4.7; 95% CI, 3.2-6.7). At the group level, ARIA-E did not impact long-term cognitive and functional performance (relative difference in adjusted means for Clinical Dementia Rating-Sum of Boxes was -9% in pooled GRADUATE analysis at week 116 and when censored at first ARIA-E). While taking gantenerumab, ARIA-E and ARIA-hemosiderin occurred in 24.9% (247 of 993) and 22.9% (227 of 993) participants, respectively; first ARIA-E occurred by week 64 in 86.2% (213 of 247) of participants with ARIA-E. Narratives are provided for all serious symptomatic ARIA-E cases.
CONCLUSIONS AND RELEVANCE: These results show that in addition to APOE ε4 allele count, severity of Aβ neuropathology and comorbid cerebrovascular pathology may be relevant for clinicians prescribing anti-Aβ monoclonal antibodies for early AD and developing individualized safety monitoring plans. Evaluation of these risk factors in other anti-Aβ monoclonal antibodies is recommended.
TRIAL REGISTRATIONS: ClinicalTrials.gov Identifiers: NCT03444870, NCT03443973, NCT04374253.}, }
@article {pmid39556273, year = {2024}, author = {Zhu, H and Zhang, T and Li, R and Ren, D and Xu, J and Xiao, L}, title = {Bushen Huoxue acupuncture ameliorates Alzheimer's disease by upregulating MARCHF3 to induce NLRP3 ubiquitination and inhibit caspase-1-dependent pyroptosis.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {11}, pmid = {39556273}, issn = {1573-7365}, support = {2021JJ31029, 2023JJ30862//Hunan Provincial Natural Science Foundation of China/ ; }, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Pyroptosis/drug effects/physiology ; *Alzheimer Disease/metabolism/therapy ; Mice ; *Caspase 1/metabolism ; *Acupuncture Therapy ; *Ubiquitination/drug effects ; Male ; Ubiquitin-Protein Ligases/metabolism ; Hippocampus/metabolism/drug effects ; Up-Regulation/drug effects ; Humans ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder that places a heavy burden on patients and society. Hippocampal neuronal loss is a hallmark of AD progression. Therefore, understanding the mechanism underlying hippocampal neuronal death would be of great importance for the diagnosis and treatment of AD. This study aimed to explore the molecular mechanism via which Bushen Huoxue Acupuncture inhibits hippocampal neuronal pyroptosis in AD. Senescence-accelerated mouse prone 8 (SAMP8) mice were used as a model of AD. Bushen Huoxue Acupuncture was performed in four acupoints: "Baihui acupoint" (GV20), "Shenshu acupoint" (BL23), "Xuehai acupoint" (SP10), and "Geshu acupoint" (BL17). Morris water maze was used to test cognitive function in mice. IHC staining was used to test mice's Aβ1-42, MARCHF1 and MARCHF3 expression. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining was used for observing hippocampal neuronal apoptosis. The mRNA expression levels of pyroptosis markers MARCHF1, MARCHF3, NLRP3, caspase-1, GSDMD, IL-1β, and IL-18 mRNA in AD mice were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The protein expression of NLRP3, caspase-1 and GSDMD-N was tested by Western blotting. IL-1β and IL-18 protein levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA). SH-SY5Y cells were used to establish an AD model following Aβ1-42 treatment. Western blot was used to detect the NLRP3, MARCHF1 and MARCHF3 proteins following Aβ1-42 treatment. The endogenous Co-IP assay in combination with immunoblotting for ubiquitin signals was used to detect of NLRP3 ubiquitination level. We found that Bushen Huoxue Acupuncture protected cognitive impairment in AD mice. Bushen Huoxue Acupuncture inhibited hippocampal neuronal pyroptosis and the secretion of inflammatory cytokines in vivo. In SH-SY5Y cells, we found that Aβ1-42 decreased the binding of E3 ubiquitin-protein ligase MARCHF1 or MARCHF3 with NLRP3, and the ubiquitination of NLRP3. In conclusion, Bushen Huoxue Acupuncture ameliorates AD by upregulating MARCHF3 to induce NLRP3 ubiquitination and inhibits caspase-1-dependent pyroptosis.}, }
@article {pmid39556267, year = {2024}, author = {Dastan, M and Rajaei, Z and Sharifi, M and Salehi, H}, title = {Gallic acid ameliorates LPS-induced memory decline by modulating NF-κB, TNF-α, and Caspase 3 gene expression and attenuating oxidative stress and neuronal loss in the rat hippocampus.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {12}, pmid = {39556267}, issn = {1573-7365}, support = {3400804//Isfahan University of Medical Sciences/ ; }, mesh = {Animals ; *Gallic Acid/pharmacology/therapeutic use ; Male ; *Oxidative Stress/drug effects ; *Rats, Wistar ; *Hippocampus/drug effects/metabolism ; *Tumor Necrosis Factor-alpha/metabolism ; *NF-kappa B/metabolism ; Rats ; *Lipopolysaccharides/toxicity ; *Caspase 3/metabolism ; *Memory Disorders/drug therapy/chemically induced/metabolism ; *Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Lipid Peroxidation/drug effects ; Gene Expression/drug effects ; Maze Learning/drug effects ; }, abstract = {Neuroinflammation and apoptosis play critical roles in the pathogenesis of Alzheimer's disease (AD), which is responsible for most cases of dementia in the elderly people. Gallic acid is a phenolic compound with radical scavenging, anti-inflammatory and anti-apoptotic activities. This study aimed to explore the protective effects of gallic acid on LPS-induced spatial memory impairment and find the underlying mechanisms. Gallic acid was orally administered (100 mg/kg) to male Wistar rats for 12 days. LPS was injected intraperitoneally at a dose of 1 mg/kg on days 8-12. Morris water maze paradigm was used to evaluate spatial learning and memory. The mRNA level of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α) and Caspase 3, lipid peroxidation and total thiol level was assessed in the rat hippocampus. Neuronal loss and histological changes were also evaluated in the brain. LPS treatment resulted in spatial learning and memory impairment, upregulation of NF-κB, TNF-α, and Caspase 3 mRNA expression, increased lipid peroxidation, decreased total thiol level, and neuronal loss in the hippocampus. Moreover, treatment with gallic acid at a dosage of 100 mg/kg ameliorated memory decline, reduced the mRNA level of NF-κB, TNF-α, and Caspase 3, decreased lipid peroxidation and increased total thiol level in the hippocampus. Gallic acid also prevented LPS-induced neuronal loss and histological changes in the brain. Conclusively, our study demonstrated that gallic acid exerts neuroprotective effect against LPS-induced memory decline in rats. This outcome could be due to anti-inflammatory, antioxidant, and anti-apoptotic activities of gallic acid.}, }
@article {pmid39556154, year = {2024}, author = {Chowdhury, MR and Karamveer, K and Tiwary, BK and Nampoothiri, NK and Erva, RR and Deepa, VS}, title = {Integrated systems pharmacology, molecular docking, and MD simulations investigation elucidating the therapeutic mechanisms of BHD in Alzheimer's disease treatment.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {8}, pmid = {39556154}, issn = {1573-7365}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Molecular Docking Simulation ; Humans ; *Molecular Dynamics Simulation ; Protein Interaction Maps/drug effects ; Plant Extracts/therapeutic use/pharmacology/chemistry ; Network Pharmacology ; Diosgenin/therapeutic use/pharmacology ; }, abstract = {Alzheimer's disease (AD) poses a longstanding health challenge, prompting a century-long exploration into its etiology and progression. Despite significant advancements in medical science, current AD treatments provide only symptomatic relief, urging a shift towards innovative paradigms. This study, departing from the amyloid hypothesis, integrates Systems Pharmacology, Molecular Docking and Molecular Dynamic Simulations to investigate a polyherbal phytoformulation (US 7,273,626 B2) rooted in Ayurveda for AD, consisting of Bacopa monnieri, Hippophae rhamnoides, and Dioscorea bulbifera (BHD). Diosgenin emerges as a crucial compound, aligning with previous studies, yet recognizing its limitations in explaining BHD's mechanism, this research delves into the intricate network of interactions. Protein-Protein Interaction (PPI) network analysis identifies hub genes (ALOX5, GSK3B, ACHE, SRC, AKT1, EGFR, PIK3R1, ESR1 and APP), suggesting a systems-level modulation of AD. Enrichment analyses unveil 370 AD-associated genes and key terms like "Cellular Response to Chemical Stimulus" and "Regulation of Biological Quality." KEGG pathway analysis underscores BHD's potential in Alzheimer's disease pathway (hsa05010), Endocrine resistance (hsa01522), and PI3K-Akt signaling (hsa04151). Molecular docking, carefully selecting compounds (Kaempferol, Quercetin, Myricetin, Isorhamnetin, Beta-Sitosterol, Stigmasterol, Emodin and Diosgenin) and top modulated targets, validates interactions with high dock scores, providing promising therapeutic avenues. Two core targets, Acetylcholinesterase (AChE) and Estrogen Receptor 1 (ESR1), were identified for further investigation due to their critical roles in Alzheimer's disease. To validate the molecular docking results, Molecular Dynamics (MD) simulations were performed on the AChE complexes with Myricetin, Beta-Sitosterol, and Stigmasterol, as well as the ESR1 complexes with Emodin, Diosgenin, and Beta-Sitosterol. These simulations were then compared to the interactions observed with the marketed drugs Donepezil and Estradiol, which are commonly used in Alzheimer's treatment. The MD simulations provided detailed insights into the stability and behavior of these complexes over time. The findings indicated that Myricetin and Emodin not only maintained stable interactions with AChE and ESR1 but also exhibited greater stability than Donepezil and Estradiol at specific time points and protein regions, as demonstrated by lower RMSD and RMSF values. These results suggest that natural compounds hold promise as potential therapeutic agents in the treatment of Alzheimer's disease, offering new avenues for drug development, while the formulation BHD shows potential as an adjuvant in integrative medicine alongside standard Alzheimer's treatments, effectively targeting related pathways and genes.}, }
@article {pmid39556113, year = {2025}, author = {Yeganeh Markid, T and Pourahmadiyan, A and Hamzeh, S and Sharifi-Bonab, M and Asadi, MR and Jalaiei, A and Rezazadeh, M and Ghafouri-Fard, S}, title = {A special focus on polyadenylation and alternative polyadenylation in neurodegenerative diseases: A systematic review.}, journal = {Journal of neurochemistry}, volume = {169}, number = {2}, pages = {e16255}, doi = {10.1111/jnc.16255}, pmid = {39556113}, issn = {1471-4159}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *Polyadenylation ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) are one of the prevailing conditions characterized by progressive neuronal loss. Polyadenylation (PA) and alternative polyadenylation (APA) are the two main post-transcriptional events that regulate neuronal gene expression and protein production. This systematic review analyzed the available literature on the role of PA and APA in NDDs, with an emphasis on their contributions to disease development. A comprehensive literature search was performed using the PubMed, Scopus, Cochrane, Google Scholar, Embase, Web of Science, and ProQuest databases. The search strategy was developed based on the framework introduced by Arksey and O'Malley and supplemented by the inclusion and exclusion criteria. The study selection was performed by two independent reviewers. Extraction and data organization were performed in accordance with the predefined variables. Subsequently, quantitative and qualitative analyses were performed. Forty-seven studies were included, related to a variety of NDDs, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Disease induction was performed using different models, including human tissues, animal models, and cultured cells. Most investigations were related to PA, although some were related to APA or both. Amyloid precursor protein (APP), Tau, SNCA, and STMN2 were the major genes identified; most of the altered PA patterns were related to mRNA stability and translation efficiency. This review particularly underscores the key roles of PA and APA in the pathogenesis of NDDs through their mechanisms that contribute to gene expression dysregulation, protein aggregation, and neuronal dysfunction. Insights into these mechanisms may lead to new therapeutic strategies focused on the modulation of PA and APA activities. Further research is required to investigate the translational potential of targeting these pathways for NDD treatment.}, }
@article {pmid39555293, year = {2024}, author = {Yan, S and Yang, X and Duan, Z}, title = {Controlling Alzheimer's disease by deep brain stimulation based on a data-driven cortical network model.}, journal = {Cognitive neurodynamics}, volume = {18}, number = {5}, pages = {3157-3180}, pmid = {39555293}, issn = {1871-4080}, abstract = {This work aims to explore the control effect of DBS on Alzheimer's disease (AD) from a neurocomputational perspective. Firstly, a data-driven cortical network model is constructed using the Diffusion Tensor Imaging data. Then, a typical electrophysiological feature of EEG slowing in AD is reproduced by reducing the synaptic connectivity parameters. The corresponding changes in kinetic behavior mainly include an oscillation decrease in the amplitude and frequency of the pyramidal neuron population. Subsequently, DBS current with specific parameters is introduced into three potential targets of the hippocampus, the nucleus accumbens and the olfactory tubercle, respectively. The results indicate that applying DBS to simulated mild AD patients induces an increase in relative alpha power, a decrease in relative theta power, and a significant rightward shift of the dominant frequency. This is consistent with the EEG reversal in pharmacological treatments for AD. Further, the optimal stimulation strategy of DBS is investigated through spectral and statistical analyses. Specifically, the pathological symptoms of AD could be alleviated by adjusting the critical parameters of DBS, and the control effect of DBS on various targets is that the hippocampus is superior to the olfactory tubercle and nucleus accumbens. Finally, using correlation analysis between the power increments and the nodal degrees, it is concluded that the control effect of DBS is related to the importance of the nodes in the brain network. This study provides a theoretical guidance for determining DBS targets and parameters, which may have a substantial impact on the development of DBS treatment for AD.}, }
@article {pmid39555281, year = {2024}, author = {Wang, R and He, Q and Shi, L and Che, Y and Xu, H and Song, C}, title = {Automatic detection of Alzheimer's disease from EEG signals using an improved AFS-GA hybrid algorithm.}, journal = {Cognitive neurodynamics}, volume = {18}, number = {5}, pages = {2993-3013}, pmid = {39555281}, issn = {1871-4080}, abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by energy diffusion and partial disconnection in the brain, with its main feature being an insidious onset and subtle clinical symptoms. Electroencephalogram (EEG) as a primary tool for assessing and aiding in the diagnosis of brain diseases has been widely used in AD detection. Accurate diagnosis is crucial for preventing the transition from early cognitive impairment to AD and providing early treatment for AD patients. This study aims to establish a hybrid model based on the Improved Artificial Fish Swarm Algorithm (IAFS) and Genetic Algorithm (GA)-IAFS-GA, to determine the optimal channel combination for AD detection under multiple EEG signals. Geometric features and complexity features of AD EEG signals were extracted using Second Order Difference Plot (SODP) and entropy analysis across the full frequency band. Subsequently, Pearson correlation was used for feature ranking, selecting the six least correlated features for each channel. The Relief algorithm was then used to fuse these selected features, with one fused feature representing one channel. Based on this, a feature selection optimization algorithm, IAFS-GA, combining the improved artificial fish swarm algorithm and genetic algorithm, was proposed. Finally, the feature combination was input into a Naive Bayes classifier for the identification of AD patients and normal controls. The feature combination was input into a Naive Bayes classifier for the identification of AD patients and normal controls. Using a five-fold cross-validation strategy across the entire frequency band, the classification accuracy reached 93.53%, with a sensitivity of 98.74%, specificity of 98.25%, and an AUC area of 97.82%. This framework can quickly select appropriate brain channels to enhance the efficiency of detecting AD and other neurological diseases. Moreover, it is the first time that an improved artificial fish swarm genetic combination algorithm and SODP features has been used for channel selection in EEG, proving to be an effective method for AD detection. It is based on SODP analysis, entropy analysis, and intelligent algorithms, which can assist clinicians in rapidly diagnosing AD, reducing the misdiagnosis rate of false positives, and expanding our understanding of brain function in patients with neurological diseases.}, }
@article {pmid39555263, year = {2024}, author = {Kachare, PH and Sangle, SB and Puri, DV and Khubrani, MM and Al-Shourbaji, I}, title = {STEADYNet: Spatiotemporal EEG analysis for dementia detection using convolutional neural network.}, journal = {Cognitive neurodynamics}, volume = {18}, number = {5}, pages = {3195-3208}, pmid = {39555263}, issn = {1871-4080}, abstract = {Dementia is a neuro-degenerative disorder with a high death rate, mainly due to high human error, time, and cost of the current clinical diagnostic techniques. The existing dementia detection methods using hand-crafted electroencephalogram (EEG) signal features are unreliable. A convolution neural network using spatiotemporal EEG signals (STEADYNet) is presented to improve the dementia detection. The STEADYNet uses a multichannel temporal EEG signal as input. The network is grouped into feature extraction and classification components. The feature extraction comprises two convolution layers to generate complex features, a max-pooling layer to reduce the EEG signal's spatiotemporal redundancy, and a dropout layer to improve the network's generalization. The classification processes the feature extraction output nonlinearly using two fully-connected layers to generate salient features and a softmax layer to generate disease probabilities. Two publicly available multiclass datasets of dementia are used for evaluation. The STEADYNet outperforms existing automatic dementia detection methods with accuracies of 99.29 % , 99.65 % , and 92.25 % for Alzheimer's disease, mild cognitive impairment, and frontotemporal dementia, respectively. The STEADYNet has a low inference time and floating point operations, suitable for real-time applications. It may aid neurologists in efficient detection and treatment. A Python implementation of the STEADYNet is available at https://github.com/SandeepSangle12/STEADYNet.git.}, }
@article {pmid39555102, year = {2024}, author = {Wei, Y and Li, H and Li, Y and Zeng, Y and Quan, T and Leng, Y and Chang, E and Bai, Y and Bian, Y and Hou, Y}, title = {Advances of curcumin in nervous system diseases: the effect of regulating oxidative stress and clinical studies.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1496661}, pmid = {39555102}, issn = {1663-9812}, abstract = {In recent years, researchers have highly observed that neurological disorders (NSDs) with the aging of the population are a global health burden whose prevalence is increasing every year. Previous evidence suggested that the occurrence of neurological disorders is correlated with predisposing factors such as inflammation, aging, and injury. Particularly, the neuronal cells are susceptible to oxidative stress, leading to lesions caused by high oxygen-consuming properties. Oxidative stress (OS) is a state of peroxidation, which occurs as a result of the disruption of the balance between oxidizing and antioxidizing substances. The oxidative intermediates such as free radicals, hydrogen peroxide (H2O2), and superoxide anion (O[2]-) produced by OS promote disease progression. Curcumin, a natural diketone derived from turmeric, is a natural antioxidant with a wide range of neuroprotective, anti-inflammatory, anti-tumor, anti-aging, and antioxidant effects. Fortunately, curcumin is recognized for its potent antioxidant properties and is considered a promising candidate for the prevention and treatment of neurological diseases. Consequently, this review elucidates the mechanisms by which curcumin mitigates oxidative stress and emphasizes the potential in treating nervous system disorders, including depression, Alzheimer's disease, Parkinson's disease, epilepsy, subarachnoid hemorrhage, and glioblastoma. We aim to provide a new therapeutic option for the management of neurological diseases.}, }
@article {pmid39554484, year = {2024}, author = {Wu, P and Lv, Z and Bi, Y and Li, Y and Chen, H and Jiang, J and Pang, S and Zhao, X and Jiang, W}, title = {Network-based statistics reveals an enhanced subnetwork in prefrontal cortex in mild cognitive impairment: a functional near-infrared spectroscopy study.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1416816}, pmid = {39554484}, issn = {1663-4365}, abstract = {BACKGROUND: Mild cognitive impairment (MCI) is generally considered to have a high risk of progression to Alzheimer's disease. Our study aimed to investigate the abnormal functional connectivity (FC) in prefrontal cortex (PFC) in patients with MCI and explore the relationship between the observed changes and cognitive function.
METHODS: Sixty-seven patients with MCI and 71 healthy individuals were recruited for this study. All participants underwent the Montreal Cognitive Assessment (MoCA) and functional near-infrared spectroscopy (fNIRS) examinations.
RESULTS: Compared with healthy controls (HC), the patients with MCI exhibited significantly lower MoCA scores (p < 0.001). Through FC analysis, an enhanced subnetwork was observed in the right prefrontal cortex of the MCI group, covering four pairs of channel connections: CH12-CH15, CH12-CH16, CH13-CH15, and CH13-CH16. Moreover, the FC values of these four channel pairs and the education duration were significantly correlated with MoCA scores. Subsequently, a multiple linear regression model was performed to observe the independent factors of cognition decline, serving the education duration and the average FC values of subnetwork as independent variables and the MoCA scores as the dependent variable. The regression model showed a total of 25.7% explanation power (adjusted R[2] = 0.257, F = 24.723, p < 0.001).
CONCLUSION: Our study suggested that the enhanced subnetwork within the right PFC may be involved in the pathophysiology of MCI and serve as a potential target for the treatment of MCI.}, }
@article {pmid39554422, year = {2024}, author = {Pirota, V and Stritto, AD and Magnaghi, LR and Biesuz, R and Doria, F and Mella, M and Freccero, M and Crespan, E}, title = {A Novel G-Quadruplex Structure within Apolipoprotein E Promoter: A New Promising Target in Cancer and Dementia Fight?.}, journal = {ACS omega}, volume = {9}, number = {45}, pages = {45203-45213}, pmid = {39554422}, issn = {2470-1343}, abstract = {Human apolipoprotein E (APOE) is a crucial lipid transport glycoprotein involved in various biological processes, including lipid metabolism, immune response, and neurodegeneration. Elevated APOE levels are linked to poor prognosis in several cancers and increased risk of Alzheimer's disease (AD). Therefore, modulating APOE expression presents a promising therapeutic strategy for both cancer and AD. Considering the pivotal role of G-quadruplex (G4) structures in medicinal chemistry as modulators of gene expression, here, we present a newly discovered G-quadruplex (G4) structure within the ApoE gene promoter. Bioinformatic analysis identified 21 potential G4-forming sequences in the ApoE promoter, with the more proximal to the transcription start site, pApoE, showing the highest G-score. Biophysical studies confirmed the folding of pApoE into a stable parallel G4 under physiological conditions, supported by circular dichroism, NMR spectroscopy, UV-melting, and a quantitative PCR stop assay. Moreover, the ability to modulate pApoE-G4 folding was demonstrated by using G4-stabilizing ligands (HPHAM, Braco19, and PDS), which increased the thermal stability of pApoE-G4. In contrast, peptide nucleic acid conjugates were synthesized to disrupt G4 formation, effectively hybridizing with pApoE sequences, and confirming the potential to unfold G4 structures. Overall, our findings provide a mainstay for future therapeutic approaches targeting ApoE-G4s to regulate APOE expression, offering potential advancements in cancer and AD treatment.}, }
@article {pmid39554174, year = {2024}, author = {Podlesny-Drabiniok, A and Romero-Molina, C and Patel, T and See, WY and Liu, Y and Marcora, E and Goate, AM}, title = {Cytokine-induced reprogramming of human macrophages toward Alzheimer's disease-relevant molecular and cellular phenotypes in vitro.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39554174}, issn = {2692-8205}, support = {R56 AG081417/AG/NIA NIH HHS/United States ; RF1 AG054011/AG/NIA NIH HHS/United States ; U01 AG058635/AG/NIA NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; }, abstract = {Myeloid cells including brain-resident (microglia) and peripheral macrophages play a crucial role in various pathological conditions, including neurodegenerative disorders like Alzheimer's disease (AD). They respond to disruption of tissue homeostasis associated with disease conditions by acquiring various transcriptional and functional states. Experimental investigation of these states is hampered by the lack of tools that enable accessible and robust reprogramming of human macrophages toward Alzheimer's disease-relevant molecular and cellular phenotypes in vitro. In this study, we investigated the ability of a cytokine mix, including interleukin-4 (IL4), colony stimulating factor 1 (CSF1/MCSF), interleukin 34 (IL34) and transforming growth factor beta (TGFβ), to induce reprogramming of cultured human THP-1 macrophages. Our results indicate this treatment led to significant transcriptomic changes, driving THP-1 macrophages towards a transcriptional state reminiscent of disease-associated microglia (DAM) and lipid-associated macrophages (LAM) collectively referred to as DLAM. Transcriptome profiling revealed gene expression changes related to oxidative phosphorylation, lysosome function, and lipid metabolism. Single-cell RNA sequencing revealed an increased proportion of DLAM clusters in cytokine mix-treated THP-1 macrophages. Functional assays demonstrated alterations in cell motility, phagocytosis, lysosomal activity, and metabolic and energetic profiles. Our findings provide insights into the cytokine-mediated reprogramming of macrophages towards disease-relevant states, highlighting their role in neurodegenerative diseases and potential for therapeutic development.}, }
@article {pmid39554163, year = {2024}, author = {Rao, NR and DeGulis, O and Nomura, T and Lee, S and Hark, TJ and Dynes, JC and Dexter, EX and Dulewicz, M and Ge, J and Upadhyay, A and Fornasiero, EF and Vassar, R and Hanrieder, J and Contractor, A and Savas, JN}, title = {Levetiracetam prevents Aβ42 production through SV2a-dependent modulation of App processing in Alzheimer's disease models.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39554163}, issn = {2692-8205}, support = {S10 OD032464/OD/NIH HHS/United States ; P20 AG068053/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; R21 AG080705/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; T32 AG020506/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; F31 AG079653/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P20 AG068077/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; R01 AG078796/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; RF1 AG022560/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; P30 CA060553/CA/NCI NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; }, abstract = {In Alzheimer's disease (AD), amyloid-beta (Aβ) peptides are produced by proteolytic cleavage of the amyloid precursor protein (APP), which can occur during synaptic vesicle (SV) cycling at presynapses. Precisely how amyloidogenic APP processing may impair presynaptic proteostasis and how to therapeutically target this process remains poorly understood. Using App knock-in mouse models of early Aβ pathology, we found proteins with hampered degradation accumulate at presynaptic sites. At this mild pathological stage, amyloidogenic processing leads to accumulation of Aβ42 inside SVs. To explore if targeting SVs modulates Aβ accumulation, we investigated levetiracetam (Lev), a SV-binding small molecule drug that has shown promise in mitigating AD-related pathologies despite its mechanism of action being unclear. We discovered Lev reduces Aβ42 levels by decreasing amyloidogenic processing of APP in a SV2a-dependent manner. Lev corrects SV protein levels and cycling, which results in increased surface localization of APP, where it favors processing via the non-amyloidogenic pathway. Using metabolic stable isotopes and mass spectrometry we confirmed that Lev prevents the production of Aβ42 in vivo. In transgenic mice with aggressive pathology, electrophysiological and immunofluorescent microscopy analyses revealed that Lev treatment reduces SV cycling and minimizes synapse loss. Finally, we found that human Down syndrome brains with early Aβ pathology, have elevated levels of presynaptic proteins, confirming a comparable presynaptic deficit in human brains. Taken together, we report a mechanism that highlights the therapeutic potential of Lev to modify the early stages of AD and represent a promising strategy to prevent Aβ42 pathology before irreversible damage occurs.}, }
@article {pmid39554109, year = {2024}, author = {Charli, A and Luo, J and Palanisamy, B and Malovic, E and Riaz, Z and Miller, C and Chang, YT and Samidurai, M and Zenitsky, G and Jin, H and Anantharam, V and Kanthasamy, A and Kanthasamy, AG}, title = {Mitochondrial Stress Disassembles Nuclear Architecture through Proteolytic Activation of PKCδ and Lamin B1 Phosphorylation in Neuronal Cells: Implications for Pathogenesis of Age-related Neurodegenerative Diseases.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.01.621517}, pmid = {39554109}, issn = {2692-8205}, abstract = {Mitochondrial dysfunction and oxidative stress are hallmarks of pathophysiological processes in age-related neurodegenerative diseases including Parkinson's, Alzheimer's and Huntington's diseases. Neuronal cells are highly vulnerable to mitochondrial stress, however, the cellular and molecular mechanisms underlying the enhanced vulnerability are not well understood. Previously, we demonstrated that the novel PKC isoform PKCδ is highly expressed in dopamin(DA)ergic neurons and plays a key role in inducing apoptotic cell death during neurotoxic stress via caspase-3-mediated proteolytic activation. Herein, we further uncovered a key downstream molecular event of PKCδ signaling following mitochondrial dysfunction that governs neuronal cell death by dissembling nuclear architecture. Exposing N27 DAergic cell line to the mitochondrial complex-1 inhibitor tebufenpyrad induced PKCδ phosphorylation at the T505 activation loop accompanied by caspase-3-dependent proteolytic activation of the kinase. Subcellular analysis using high-resolution 3D confocal microscopy revealed that proteolytically activated cleaved PKCδ translocates to the nuclear compartment, colocalizing with Lamin B1. Electron microscopy also enabled the visualization of nuclear membrane damage triggered by subjecting the DAergic neuronal cells by Tebufenpyrad (Tebu) toxicity. In silico analyses identified that the threonine site on Lamin B1 (T575) is likely phosphorylated by PKCδ, suggesting that Lamin B1 serves as a key downstream target of the kinase. Interestingly, N27 DAergic cells stably expressing the PKCδ proteolytic cleavage site-resistant mutant failed to induce nuclear damage, PKCδ activation, and Lamin B1 phosphorylation. Furthermore, CRISPR/Cas9-based stable knockdown of PKCδ greatly attenuated Tebu-induced Lamin B1 phosphorylation. Also, studies using Lamin B1 [T575G] mutated at phosphorylation and PKCδ-ΔNLS-overexpressing N27 cells showed that PKCδ activation and translocation to the nuclear membrane are critically required for phosphorylating Lamin B1 at T575 to induce nuclear membrane damage during Tebu insult. Additionally, Tebu failed to induce Lamin B1 damage and Lamin B1 phosphorylation in organotypic midbrain slices cultured from PKCδ [-/-] mouse pups. More importantly, we observed higher PKCδ activation, Lamin B1 phosphorylation and Lamin B1 loss in nigral DAergic neurons from the postmortem brains of PD patients as compared to age-matched healthy control brains, thus providing translational relevance of our finding. Collectively, our data reveal that PKCδ functions as a Lamin B1 kinase to disassemble the nuclear membrane during the neuronal cell death process triggered by mitochondrial stress. This mechanistic insight may have important implications for the etiology of age-related neurodegenerative diseases resulting from mitochondrial dysfunction as well as for the development of novel treatment strategies.}, }
@article {pmid39553925, year = {2024}, author = {Birnbaum, EM and Xie, L and Serrano, P and Rockwell, P and Figueiredo-Pereira, ME}, title = {BT-11 repurposing potential for Alzheimer's disease and insights into its mode of actions.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.10.29.620882}, pmid = {39553925}, issn = {2692-8205}, support = {R01 AG057555/AG/NIA NIH HHS/United States ; }, abstract = {Neuroinflammation is a key pathological hallmark of Alzheimer's disease (AD). Investigational and FDA approved drugs targeting inflammation already exist, thus drug repurposing for AD is a suitable approach. BT-11 is an investigational drug that reduces inflammation in the gut and improves cognitive function. BT-11 is orally active and binds to lanthionine synthetase C-like 2 (LANCL2), a glutathione-s-transferase, thus potentially reducing oxidative stress. We investigated the effects of BT-11 long-term treatment on the TgF344-AD rat model. BT-11 reduced hippocampal-dependent spatial memory deficits, Aβ plaque load and neuronal loss in males, and mitigated microglia numbers in females. BT-11 treatment led to hippocampal transcriptomic changes in signaling receptor, including G-protein coupled receptor pathways. We detected LANCL2 in hippocampal nuclear and cytoplasmic fractions with potential different post-translational modifications, suggesting distinct functions based on its subcellular localization. LANCL2 was present in oligodendrocytes, showing a role in oligodendrocyte function. To our knowledge, these last two findings have not been reported. Overall, our data suggest that targeting LANCL2 with BT-11 improves cognition and reduces AD-like pathology by potentially modulating G-protein signaling and oligodendrocyte function. Our studies contribute to the field of novel immunomodulatory AD therapeutics, and merit further research on the role of LANCL2 in this disease.}, }
@article {pmid39553038, year = {2024}, author = {Thakor, VS and Tyagi, A and Lee, JM and Coffman, F and Mittal, R}, title = {Alois Alzheimer (1864-1915): The Father of Modern Dementia Research and the Discovery of Alzheimer's Disease.}, journal = {Cureus}, volume = {16}, number = {10}, pages = {e71731}, pmid = {39553038}, issn = {2168-8184}, abstract = {Alois Alzheimer was a German psychologist and neuropathologist who significantly advanced the study of dementia with his discovery of Alzheimer's disease (AD). Based on his assessment of a 51-year-old female patient with symptoms of presenile dementia and after conducting a postmortem autopsy of her brain, Alzheimer distinguished two neurological substances - senile plaques and neurofibrillary tangles - as unique markers of what was later deemed as AD. He recognized that dementia is not a natural consequence of age but rather a recognizable neurocognitive disorder. Despite the long-lasting criticism of his findings, Alzheimer's discovery fundamentally altered the landscape of neuropathological studies by establishing that AD was a clinically identifiable disease with distinct markers that could be targeted for treatment. Today, modern research on AD continues to build on the foundation laid by Alzheimer's discovery.}, }
@article {pmid39552578, year = {2024}, author = {Rakshit, D and Goyal, R and Yadav, V and Gore, SK and Sen, S and Ranjan, OP and Mishra, A}, title = {Nanoformulated fisetin ameliorates Alzheimer's disease via reducing proinflammatory cytokines and activating the NRF2/HO-1 pathway.}, journal = {Nanomedicine (London, England)}, volume = {19}, number = {30}, pages = {2537-2553}, doi = {10.1080/17435889.2024.2419814}, pmid = {39552578}, issn = {1748-6963}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Flavonols/pharmacology ; Mice ; *Cytokines/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Oxidative Stress/drug effects ; Male ; Flavonoids/pharmacology/chemistry/administration & dosage ; Heme Oxygenase-1/metabolism ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/chemistry/administration & dosage ; Chitosan/chemistry ; Amyloid beta-Peptides/metabolism ; Nanoparticles/chemistry ; Humans ; Signal Transduction/drug effects ; Peptide Fragments/chemistry/metabolism ; Hippocampus/drug effects/metabolism ; Brain/drug effects/metabolism/pathology ; }, abstract = {Aim: The study aimed to evaluate the neuroprotective effect of a chitosan-coated fisetin nanoformulation in an experimental Alzheimer's disease (AD) model, focusing on improving fisetin's pharmacokinetics and exploring its impact on both brain and colon pathology.Materials & methods: AD was induced in mice by intracerebroventricular administration of Aβ1-42. Mice were treated with either fisetin or a fisetin nanoformulation (5 mg/kg/day, orally) for 21 days. Behavioural assessments were conducted to evaluate memory impairment, motor deficits, and depression-like behaviour. Oxidative stress markers and pro-inflammatory cytokines were measured in the cortex, hippocampus and colon. The changes in cortical and hippocampal AChE levels were also recorded. Histological studies were performed on the cortex, hippocampus (dentate gyrus), and proximal colon.Results: The fisetin nanoformulation significantly improved neurobehavioral outcomes, reducing memory impairment, motor deficits and depression-like symptoms induced by Aβ1-42. It also decreased oxidative and nitrosative stress, along with pro-inflammatory cytokine levels in the cortex, hippocampus and colon. Histological analyses revealed improved brain and colon tissue architecture after treatment with the nanoformulation.Conclusion: The chitosan-coated fisetin nanoformulation enhanced the neuroprotective effects of fisetin in an AD model, likely by improving its pharmacokinetic profile. The findings also suggest a potential link between colon health and Aβ-induced AD pathology, underscoring the therapeutic potential of fisetin nanoformulations in AD management.}, }
@article {pmid39552492, year = {2024}, author = {Kashif, M and Chandrabose, K and Pandurangan, AK}, title = {Plausible Action of N-(3,4-Dimethoxy-Phenyl)-6,7-Dimethoxyquinazoline-4-Amine (TKM01) as an Armor Against Alzheimer's Disease: In Silico and In Vivo Insights.}, journal = {Journal of biochemical and molecular toxicology}, volume = {38}, number = {12}, pages = {e70048}, doi = {10.1002/jbt.70048}, pmid = {39552492}, issn = {1099-0461}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Zebrafish ; *Molecular Docking Simulation ; *Quinazolines/pharmacology/chemistry ; *Amyloid beta-Peptides/metabolism ; *Acetylcholinesterase/metabolism ; Humans ; Molecular Dynamics Simulation ; Cholinesterase Inhibitors/pharmacology/chemistry ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) affects millions of people and has limited treatment options, thus making it a global health concern. Amyloid β (Aβ), a disrupted cholinergic system with high acetylcholinesterase (AChE), oxidative stress (OS), reduced antioxidants, and neuroinflammation are key factors influencing AD progression. Prior research has shown that AChE can interact with Aβ and increase its accumulation and neurotoxicity, so targeting AChEs and Aβ could be a potential therapeutic approach for AD treatment. It has been known that nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit Aβ accumulation. Previously, TKM01, a derivative of 4-anilinoquinazoline, has demonstrated inhibitory effects against GSK-3β-a regulator in AD progression. The current research included molecular docking studies of NSAIDs and TKM01 with Aβ and AChEs as targets. TKM01 exhibited a higher binding affinity with Aβ among all tested compounds. Molecular dynamic (MD) simulations confirmed the stability of the protein-TKM01 complexes. TKM01 also exhibited favorable drug-likeness properties, and no hepatoxicity was visualized in comparison with other compounds. Further, in vitro assay showed an inhibitory action of TKM01 (50-1200 µg/mL) on AChEs. In the in vivo studies on zebrafish larvae brains, we found that TKM01 (120 and 240 µg/mL) reduced the levels of AChEs and lipid peroxidation (LPO) and increased antioxidant superoxide dismutase (SOD) and catalase (CAT) in AlCl3(80 µM)-induced AD-like model. Additionally, TKM01 treatment was found to decrease pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. The current study demonstrates that TKM01 can be used to treat AD. Nonetheless, experimental validation is needed to reveal the cellular, sub-cellular, and molecular mechanisms and possible implications at a clinical stage.}, }
@article {pmid39551957, year = {2024}, author = {Liu, W and Lv, H and Zhou, Y and Zuo, X and Wang, X}, title = {Comprehensive Analysis of the Gene Expression Profiles of Rat Brain Tissues under Environmental Exposure to Nicotine.}, journal = {Pakistan journal of biological sciences : PJBS}, volume = {27}, number = {11}, pages = {547-566}, doi = {10.3923/pjbs.2024.547.566}, pmid = {39551957}, issn = {1812-5735}, mesh = {Animals ; *Nicotine ; *Brain/metabolism/drug effects ; Rats ; *Gene Expression Profiling ; *Transcriptome/drug effects ; *Protein Interaction Maps ; *Environmental Exposure/adverse effects ; Computational Biology/methods ; Gene Regulatory Networks ; Signal Transduction/drug effects ; }, abstract = {Background and Objective: Nicotine-relevant smoking causes many serious issues of environmental pollution and complicated harm to human health. The present study aimed to evaluate the experimental effects of exposure to nicotine on the gene expression profiles of rat brain tissues with differentially expressed genes (DEGs). Materials and Methods: The rat gene expression profiles of environmental exposure to nicotine were initially screened and retrieved from the microarray dataset GSE59895 in the GEO database. Next, it was analyzed with an integrated bioinformatics pipeline. The DEGs were analyzed in Limma and functional enrichment analyses of GO terms and KEGG pathways were performed with clusterProfiler. The STRING online tools and Cytoscape StringApp were subsequently employed to construct the protein-protein interaction (PPI) network, whereas key modules and hub genes were finally explored and visualized. Results: There was total of 382 shared DEGs between different case groups in the experiment, whereas 9 common shared DEGs were found among all three groups. The significant enrichments of 28 GO terms and 3 KEGG pathways were comprehensively analyzed with corresponding functionally enriched genes. Then, 3 key modules and 10 hub genes were further identified and explored in the resulted PPI network. In the disease-related signaling pathways, eleven potential neuropathic disease-related genes may complement the treatment of neurodegenerative diseases. Conclusion: The study found that chronic exposure to nicotine would result in the differential expression of the disease-related genes, whereas these DEGs might increase the environmental risks of Huntington's disease, Alzheimer's disease and other multiple neurodegenerative diseases.}, }
@article {pmid39551742, year = {2024}, author = {Özdemir, AY and Hofbauerová, K and Kopecký, V and Novotný, J and Rudajev, V}, title = {Different amyloid β42 preparations induce different cell death pathways in the model of SH-SY5Y neuroblastoma cells.}, journal = {Cellular & molecular biology letters}, volume = {29}, number = {1}, pages = {143}, pmid = {39551742}, issn = {1689-1392}, support = {SVV-260683//Přírodovědecká Fakulta, Univerzita Karlova/ ; }, mesh = {*Amyloid beta-Peptides/metabolism/pharmacology ; Humans ; *Neuroblastoma/pathology/metabolism ; Cell Line, Tumor ; *Peptide Fragments/pharmacology ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; Cell Death/drug effects ; Alzheimer Disease/metabolism/pathology ; Mitochondria/metabolism/drug effects ; Necroptosis/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Amyloid β42 (Aβ42) plays a decisive role in the pathology of Alzheimer's disease. The Aβ42 peptide can aggregate into various supramolecular structures, with oligomers being the most toxic form. However, different Aβ species that cause different effects have been described. Many cell death pathways can be activated in connection with Aβ action, including apoptosis, necroptosis, pyroptosis, oxidative stress, ferroptosis, alterations in mitophagy, autophagy, and endo/lysosomal functions. In this study, we used a model of differentiated SH-SY5Y cells and applied two different Aβ42 preparations for 2 and 4 days. Although we found no difference in the shape and size of Aβ species prepared by two different methods (NaOH or NH4OH for Aβ solubilization), we observed strong differences in their effects. Treatment of cells with NaOH-Aβ42 mainly resulted in damage of mitochondrial function and increased production of reactive oxygen species, whereas application of NH4OH-Aβ42 induced necroptosis and first steps of apoptosis, but also caused an increase in protective Hsp27. Moreover, the two Aβ42 preparations differed in the mechanism of interaction with the cells, with the effect of NaOH-Aβ42 being dependent on monosialotetrahexosylganglioside (GM1) content, whereas the effect of NH4OH-Aβ42 was independent of GM1. This suggests that, although both preparations were similar in size, minor differences in secondary/tertiary structure are likely to strongly influence the resulting processes. Our work reveals, at least in part, one of the possible causes of the inconsistency in the data observed in different studies on Aβ-toxicity pathways.}, }
@article {pmid39551061, year = {2024}, author = {Jessen, F and Frölich, L and Hort, J and Winblad, B and Fortea, J}, title = {Amyloid-lowering treatment in Alzheimer's disease.}, journal = {Lancet (London, England)}, volume = {404}, number = {10468}, pages = {2161-2162}, doi = {10.1016/S0140-6736(24)02510-8}, pmid = {39551061}, issn = {1474-547X}, }
@article {pmid39550828, year = {2024}, author = {Dou, RX and Zhang, YM and Hu, XJ and Gao, FL and Zhang, LL and Liang, YH and Zhang, YY and Yao, YP and Yin, L and Zhang, Y and Gu, C}, title = {Aβ1-42 promotes microglial activation and apoptosis in the progression of AD by binding to TLR4.}, journal = {Redox biology}, volume = {78}, number = {}, pages = {103428}, pmid = {39550828}, issn = {2213-2317}, mesh = {*Toll-Like Receptor 4/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; *Apoptosis ; *Alzheimer Disease/metabolism/pathology/genetics ; *Peptide Fragments/metabolism ; *Microglia/metabolism ; Humans ; Animals ; tau Proteins/metabolism/genetics ; Disease Progression ; Protein Binding ; }, abstract = {Alzheimer's disease (AD) is one of the most common age-related neurodegenerative diseases and the most devastating form of senile dementia. It has a complex mechanism and no effective treatment. Exploring the pathogenesis of AD and providing ideas for treatment can effectively improve the prognosis of AD. Microglia were incubated with β-amyloid protein 1-42 (Aβ1-42) to construct an AD cell model. After microglia were activated, cell morphology changed, the expression level of inflammatory factors increased, cell apoptosis was promoted, and the expression of microtubule-associated protein (Tau protein) and related proteins increased. By up-regulating and down-regulating Toll-like receptor 4 (TLR4), the cells were divided into TLR4 knockdown negative control group(Lv-NC group), TLR4 knockdown group(Lv-TLR4 group), TLR4 overexpression negative control group(Sh-NC group), and TLR4 overexpression group(Sh-TLR4 group). The expression of inflammatory factors was detected again. It was found that compared with the Lv-NC group, the expression of various inflammatory factors in the Lv-TLR4 group decreased, cell apoptosis was inhibited, and the expression of Tau protein and related proteins decreased. Compared with the Sh-NC group, the expression of inflammatory factors in the Sh-TLR4 group increased, cell apoptosis was promoted, and the expression of Tau protein and related proteins increased. These results indicate that Aβ1-42 may promote microglial activation and apoptosis by binding to TLR4. Reducing the expression of TLR4 can reduce the occurrence of inflammatory response in AD cells and slow down cell apoptosis. Therefore, TLR4 is expected to become a new target for the prevention and treatment of AD.}, }
@article {pmid39550564, year = {2024}, author = {Castilla-Martí, L and García-Sánchez, A and Martínez, J and Rosende-Roca, M and Vargas, L and Tartari, JP and Casales, F and Rodríguez, JN and Bein, N and Alegret, M and Ortega, G and Espinosa, A and Sanabria, Á and Pérez-Cordón, A and Muñoz, N and García-Gutiérrez, F and Blazquez-Folch, J and Miguel, A and de Rojas, I and García-González, P and Puerta, R and Olivé, C and Capdevila, M and Muñoz-Morales, Á and Bayón-Buján, P and Cano, A and Fernández, V and Valero, S and Tárraga, L and Ruiz, A and Boada, M and Castilla-Martí, M and Marquié, M}, title = {Changes in choroidal thickness quantified by Optical Coherence Tomography across cognitive impairment: data from the NORFACE cohort.}, journal = {Alzheimer's research & therapy}, volume = {16}, number = {1}, pages = {249}, pmid = {39550564}, issn = {1758-9193}, mesh = {Humans ; *Tomography, Optical Coherence/methods ; Male ; Female ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Aged ; *Choroid/diagnostic imaging/pathology ; Cohort Studies ; Middle Aged ; Aged, 80 and over ; Alzheimer Disease/diagnostic imaging/pathology ; Cerebrovascular Disorders/diagnostic imaging/pathology ; }, abstract = {BACKGROUND: Optical coherence tomography (OCT) enables high-resolution imaging of ocular structures in health and disease. Choroid thickness (CT) is a key vascular retinal parameter that can be assessed by OCT and might be relevant in the evaluation of the vascular component of cognitive decline. We aimed to investigate CT changes in a large cohort of individuals cognitive unimpaired (CU), with mild cognitive impairment due to Alzheimer's (MCI-AD), mild cognitive impairment due to cerebrovascular disease (MCI-Va), Alzheimer's disease dementia (ADD), and vascular dementia (VaD).
METHODS: Clinical, demographical, ophthalmological and OCT data from the Neuro-ophthalmological Research at Fundació ACE (NORFACE) project were analyzed. CT was assessed in the macula across nine Early Treatment Diabetic Retinopathy Study (ETDRS) quadrants, average thickness, total volume, and subfoveal choroidal thickness. Differences of CT among the five diagnostic groups were assessed in a multivariate regression model, adjusting for demographic and cardiovascular risk factors and OCT image quality. A comparison between manual and automatic CT measurements in a subset of participants was also performed.
RESULTS: The study cohort comprised 1,280 participants: 301 CU, 196 MCI-AD, 112 MCI-Va, 578 ADD, and 93 VaD. CT was significantly increased in individuals with cognitive impairment compared to those CU, particularly in the VaD and MCI-Va groups and in the peripheral ETDRS regions. No significant differences were found in inner superior, center and subfoveal choroidal thickness. The interaction of sex and diagnosis had no effect in differentiating CT. Mini-Mental State Examination (MMSE) scores were not correlated to CT. Manual and automated CT measurements showed good reliability.
DISCUSSION: Our findings indicated that peripheral choroidal thickening, especially in patients with cerebrovascular disease, may serve as a potential choroidal biomarker for cognitive decline and suggest different pathogenic pathways in AD and VaD. Further research is required to explore CT as a reliable ocular biomarker for cognitive impairment.}, }
@article {pmid39550061, year = {2025}, author = {Cao, W and Zhu, B and Liu, Z and Jia, X and Zhao, H and Gu, N and Chang, H and Xi, J and Li, R and Guo, K and Shen, J and Ding, L and Sun, F and Di, Z}, title = {Comparison of the efficacy of updated drugs for the treatment on the improvement of cognitive function in patients with Alzheimer 's disease: A systematic review and network meta- analysis.}, journal = {Neuroscience}, volume = {565}, number = {}, pages = {29-39}, doi = {10.1016/j.neuroscience.2024.11.029}, pmid = {39550061}, issn = {1873-7544}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Network Meta-Analysis ; *Cognition/drug effects ; Nootropic Agents/therapeutic use ; Treatment Outcome ; Randomized Controlled Trials as Topic/methods ; }, abstract = {BACKGROUND: The recent emergence of updated drugs for the treatment of Alzheimer's disease (AD) has produced encouraging cognitive and clinical results in clinical trials, but there is still controversy over how to choose effective treatment options among these numerous drugs. The purpose of this network meta-analysis (NMA) is to compare and rank these drugs based on their efficacy.
METHODS: We systematically searched in PubMed, Web of Science databases and Cochrane LIbrary, gov for randomized controlled trials for data from 2020 to 2024, and then performed a random-effect network meta-analysis.
RESULTS: Our NMA results showed that in several main indicators ADAS-cog, CDR-SB and ADCS-ADL. GV-971 (MD -2.36, 95 % CI -5.08, 0.35), Lecanemab (MD -2.00, 95 % CI -5.25, 1.26), Donanemab (MD -1.45, 95 % CI -4.70, 1.81), Masupirdine (MD -0.83, 95 % CI -3.49, 1.84) were more effective than placebo in improving ADAS-cog. In terms of CDR-SB, Lecanemab (MD -3.11,95 % CI -5.23, -0.99) was more effective. Compared with placebo, Donanemab was more effective in ADCS-ADL (MD 3.26,95 % CI 1.48,5.05). SUCRA values showed that GV-971 (76.1 % and 68.7 %) could achieve better therapeutic effects in ADAS-cog) and NPI, and Lecanema (98.1 %) was more effective in improving CDR-SB scores than other drugs. Donanemab (99.8 %) may be the most promising way to slow down the decline in ADCS-ADL scores. The effect of Masupirdine (80.7 %) on MMSE was significantly better than that of several other drugs.
CONCLUSION: Donanemab and Lecanemab showed good efficacy in ADCS-ADL and CDR-SB, respectively. GV-971 is the best choice to improve ADAS cogs and NPI.}, }
@article {pmid39550057, year = {2025}, author = {Zhu, H and Xu, G}, title = {Electrochemical biosensors for dopamine.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {566}, number = {}, pages = {120039}, doi = {10.1016/j.cca.2024.120039}, pmid = {39550057}, issn = {1873-3492}, mesh = {*Dopamine/analysis ; Humans ; *Biosensing Techniques/methods ; *Electrochemical Techniques ; }, abstract = {Dopamine (DA), a key catecholamine, plays a pivotal role in the regulation of human cognition and emotions. It has profound effects on the hormonal, memory, and cardiovascular systems. Anomalies like Alzheimer's, Parkinson's, schizophrenia, and senile dementia are linked to abnormal DA levels. Consequently, the precise determination of DA levels in biological systems is critical for the accurate diagnosis and treatment of these disorders. Among all analytical techniques, electrochemical studies provide the most selective and highly sensitive methods for detecting DA in biological samples. Ascorbic acid and uric acid are two examples of small biomolecules that can obstruct the detection of DA in biological fluids. To address this issue, numerous attempts have been made to modify bare electrodes to separate the signals of these substances and enhance the electrocatalytic activity towards DA. Various surface modifiers, including coatings, conducting polymers, ionic liquids, nanomaterials, and inorganic complexes, have been employed in the modification process. Despite the reported success in DA detection using electrochemical sensors, many of these approaches are deemed too complex and costly for real-world applications. Therefore, this review aims to provide an overview of DA electrochemical biosensors that are practical for real-world applications.}, }
@article {pmid39549949, year = {2025}, author = {El-Desouky, S and Abdel-Halim, M and Fathalla, RK and Abadi, AH and Piazza, GA and Salama, M and El-Khodery, SA and Youssef, MA and Elfarrash, S}, title = {A novel phosphodiesterase 5 inhibitor, RF26, improves memory impairment and ameliorates tau aggregation and neuroinflammation in the P301S tauopathy mouse model of Alzheimer's disease.}, journal = {Experimental neurology}, volume = {384}, number = {}, pages = {115058}, doi = {10.1016/j.expneurol.2024.115058}, pmid = {39549949}, issn = {1090-2430}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *tau Proteins/metabolism ; *Phosphodiesterase 5 Inhibitors/pharmacology ; *Memory Disorders/drug therapy/etiology ; *Tauopathies/drug therapy ; *Disease Models, Animal ; *Neuroinflammatory Diseases/drug therapy ; Mice, Transgenic ; Male ; Maze Learning/drug effects ; }, abstract = {Phosphodiesterase-5 (PDE5) inhibitors are primarily used in the treatment of erectile dysfunction and pulmonary hypertension, but have also been reported to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD). This is likely to be through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling by elevating cGMP, a secondary messenger involved in processes of neuroplasticity. In the present study, we evaluated the efficacy of a novel PDE5 inhibitor, RF26, using P301S tauopathy mice model. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, including AD, Frontotemporal dementia (FTD), Supranuclear palsy and others. RF26 successfully targeted NO/cGMP signaling pathway and showed a significant improvement of spatial memory task performance of P301S mice using Morris Water Maze and T-maze. Furthermore, RF26 -treated mice showed a significant reduction of phosphorylated tau load, gliosis and downregulated pro-inflammatory cytokines. The presented data support the efficacy of RF26 as a potent PDE5 inhibitor and calls for further investigation as a potential therapeutic drug for Alzheimer's and other tauopathy related neurological disorders.}, }
@article {pmid39549875, year = {2025}, author = {Bajwa, IK and Sharma, P and Goyal, R}, title = {Modulation of tyrosine receptor imposed by estrogen in memory and cognition in female rats.}, journal = {Behavioural brain research}, volume = {479}, number = {}, pages = {115340}, doi = {10.1016/j.bbr.2024.115340}, pmid = {39549875}, issn = {1872-7549}, mesh = {Animals ; Female ; *Rats, Wistar ; *Estrogens/pharmacology/metabolism ; *Ovariectomy ; *Cognition/drug effects/physiology ; Rats ; *Imatinib Mesylate/pharmacology ; Memory Disorders/metabolism ; Maze Learning/drug effects/physiology ; Oxidative Stress/drug effects/physiology ; Estradiol/pharmacology/metabolism ; Brain/metabolism/drug effects ; Memory/drug effects/physiology ; Protein-Tyrosine Kinases/metabolism ; Protein Kinase Inhibitors/pharmacology ; }, abstract = {The present study aimed to investigate the potential role of estrogen in modulating the pathogenesis of dementia-type-AD phenotype, possibly by tyrosine kinase. Female Wistar rats were ovariectomized (OVX) and were treated with Diethylstilbesterol (DES), an estrogen analogue (20 μg/kg/day, i.m.), and Imatinib, a tyrosine kinase inhibitor (30 mg/kg/day, orally), for two months. Animals underwent surgical ovariectomy exhibited significant memory deficits in spatial memory assessment as mean dwell time, short-term memory as spontaneous alteration, and novel object recognition after a chronic period of 4 weeks. OVX animals administered with DES produced significant restoration of memory dysfunction in comparison to OVX, as exhibited by Morris water maze (p=0.0003), Y maze (p<0.0001), and NORT. Imatinib prior to DES treatment in OVX animals showed significant decline in memory functions, which confirms the potential involvement of tyrosine receptor kinase activity in improved memory functions offered by estrogen. Levels of estradiol were significantly (p<0.0001) lower in the OVX group compared to normal which was significantly (p<0.0001) restored in the OVX+E group. Biochemical estimations of TBARS, glutathione, and acetylcholinesterase levels in the brain showed a significant increase in oxidative stress among the OVX group. However, a significant restoration of oxidative changes with TBARS (p=0.0496), glutathione (p<0.0001), and acetylcholinesterase activity (p=0.0201) of OVX animals receiving DES was observed in comparison to animals receiving imatinib followed by DES. These implications in the brain signify that estrogen and tyrosine kinase play an important role in the pathogenesis of dementia. In conclusion, estrogen offers neurochemical mediation for cognition and memory possibly via modulation of tyrosine kinase signaling in female subjects.}, }
@article {pmid39549715, year = {2024}, author = {Heneka, MT and Morgan, D and Jessen, F}, title = {Passive anti-amyloid β immunotherapy in Alzheimer's disease-opportunities and challenges.}, journal = {Lancet (London, England)}, volume = {404}, number = {10468}, pages = {2198-2208}, doi = {10.1016/S0140-6736(24)01883-X}, pmid = {39549715}, issn = {1474-547X}, mesh = {*Alzheimer Disease/therapy/immunology ; Humans ; *Amyloid beta-Peptides ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Immunization, Passive/methods ; }, abstract = {With the advent of the first disease-modifying, anti-amyloid β-directed passive immunotherapy for Alzheimer's disease, questions arise who, when, and how to treat. This paper describes shortly the pathogenic basis of and preclinical data, which have, more than two decades ago, initiated the development of this vaccination therapy. We discuss clinical trial results of aducanumab, lecanemab, and donanemab. We also review appropriate use recommendations of these novel treatments on patient selection and safety monitoring. Furthermore, estimations of numbers of patient who will qualify for treatment regarding inclusion and exclusion criteria and estimations on readiness of health-care systems for identifying the right patients and for providing the treatment are reported. In our view, we are experiencing a fundamental shift from syndrome-based Alzheimer's dementia care to early, biomarker-guided treatment of Alzheimer's disease. This shift requires substantial adjustments of infrastructure and resources, but also holds promise of eventually achieving substantial slowing of disease progression and delaying dementia.}, }
@article {pmid39549628, year = {2025}, author = {Nguyen, HD and Vu, GH and Kim, WK}, title = {The molecular mechanisms of steroid hormone effects on cognitive function.}, journal = {Archives of gerontology and geriatrics}, volume = {129}, number = {}, pages = {105684}, doi = {10.1016/j.archger.2024.105684}, pmid = {39549628}, issn = {1872-6976}, mesh = {Humans ; *Cognition/drug effects ; *MicroRNAs/metabolism ; *Cognitive Dysfunction/drug therapy ; Testosterone ; Progesterone ; Estrogens ; }, abstract = {OBJECTIVE: There is a lack of information on the molecular mechanisms by which steroid hormones (testosterone, estrogen, and progesterone) regulate cognitive impairment. Thus, we aimed to identify the protective effects of steroid hormones on cognitive function.
METHODS: We analyzed the literature on the molecular mechanisms, biological activities, physicochemical properties, and pharmacokinetics of steroid hormones.
RESULTS: Steroid hormones can protect against cognitive impairment by regulating key genes (INS, TNF, STAT3, ESR1). Specific microRNAs, namely hsa-miR-335-5p, hsa-miR-16-5p, and hsa-miR-26b-5p, along with transcription factors NFKB1, PPARG, NR3C1, GATA2, EGR1, ATF3, and CEBPA, play a significant role in this protective mechanism. The involvement in cognitive processes, regulation of phosphorylation, neuronal apoptosis, and signaling pathways related to Alzheimer's disease significantly influence the protein-protein interaction network underlying these effects. Additionally, steroid hormones exhibit anti-hypercholesterolemic properties, anti-inflammatory activity, antitoxic properties, and function as inhibitors of acetylcholine neuromuscular transmission. They also hold promise as therapeutic agents for the treatment of dementia. Promising therapeutic interventions for cognitive impairment include the use of miRNA sponges targeting hsa-miR-16-5p, along with the administration of capsaicin, minocycline, dopamine, sertraline, and minaprine. The gut microbiota species Lactobacillus amylovorus, Paraprevotella clara, Libanicoccus massiliensis, Prevotella oris, Turicibacter sanguinis, and Dubosiella newyorkensis were identified as significant contributors to cognitive impairment and altered levels of steroid hormones.
CONCLUSION: Steroid hormones are promising compounds for improving cognitive function. Further research is needed to validate these findings through focused investigations into apoptosis, regulation of neuronal cell death, miRNA sponges, interactions with gut microbiota, and the potential efficacy of pharmaceutical agents.}, }
@article {pmid39548663, year = {2024}, author = {Yue, Q and Leng, X and Xie, N and Zhang, Z and Yang, D and Hoi, MPM}, title = {Endothelial Dysfunctions in Blood-Brain Barrier Breakdown in Alzheimer's Disease: From Mechanisms to Potential Therapies.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {11}, pages = {e70079}, pmid = {39548663}, issn = {1755-5949}, support = {0035/2020/AGJ//The Science and Technology Development Fund (FDCT), Macau SAR/ ; 0023/2020/AFJ//The Science and Technology Development Fund (FDCT), Macau SAR/ ; 82061160374//National Natural Science Foundation of China/ ; 82404892//National Natural Science Foundation of China/ ; 21623114//Fundamental Research Funds for the Central Universities/ ; 2024A1515012818//Natural Science Foundation of Guangdong Province/ ; MYRG-CRG2022-00010-ICMS//The University of Macau Research Grant/ ; MYRG2022-00248-ICMS//The University of Macau Research Grant/ ; }, mesh = {*Blood-Brain Barrier/metabolism/pathology ; Humans ; *Alzheimer Disease/metabolism/pathology ; Animals ; *Endothelial Cells/metabolism/drug effects ; }, abstract = {Recent research has shown the presence of blood-brain barrier (BBB) breakdown in Alzheimer's disease (AD). BBB is a dynamic interface consisting of a continuous monolayer of brain endothelial cells (BECs) enveloped by pericytes and astrocytes. The restricted permeability of BBB strictly controls the exchange of substances between blood and brain parenchyma, which is crucial for brain homeostasis by excluding blood-derived detrimental factors and pumping out brain-derived toxic molecules. BBB breakdown in AD is featured as a series of BEC pathologies such as increased paracellular permeability, abnormal levels and functions of transporters, and inflammatory or oxidative profile, which may disturb the substance transportation across BBB, thereafter induce CNS disorders such as hypometabolism, Aβ accumulation, and neuroinflammation, eventually aggravate cognitive decline. Therefore, it seems important to protect BEC properties for BBB maintenance and neuroprotection. In this review, we thoroughly summarized the pathological alterations of BEC properties reported in AD patients and numerous AD models, including paracellular permeability, influx and efflux transporters, and inflammatory and oxidative profiles, and probably associated underlying mechanisms. Then we reviewed current therapeutic agents that are effective in ameliorating a series of BEC pathologies, and ultimately protecting BBB integrity and cognitive functions. Regarding the current drug development for AD proceeds extremely hard, this review aims to discuss the therapeutic potentials of targeting BEC pathologies and BBB maintenance for AD treatment, therefore expecting to shed a light on the future AD drug development by targeting BEC pathologies and BBB protection.}, }
@article {pmid39548583, year = {2024}, author = {Ishii, A and Pathoulas, JA and MoustafaFathy Omar, O and Ge, Y and Yao, AY and Pantalena, T and Singh, N and Zhou, J and He, W and Murphy, P and Yan, R and Hu, X}, title = {Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer's disease.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {83}, pmid = {39548583}, issn = {1750-1326}, support = {RF1NS074256/NS/NINDS NIH HHS/United States ; RF1-NS117449/NS/NINDS NIH HHS/United States ; RF1AG046929/AG/NIA NIH HHS/United States ; RF1AG058261/AG/NIA NIH HHS/United States ; RF1AG025493/AG/NIA NIH HHS/United States ; AG059124-01A1/AG/NIA NIH HHS/United States ; 1F30AG081134-01/AG/NIA NIH HHS/United States ; 23PRE1027078//American Heart Association/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Amyloid Precursor Protein Secretases/metabolism ; Mice ; *Oligodendroglia/metabolism ; *Aspartic Acid Endopeptidases/metabolism ; *Disease Models, Animal ; *Plaque, Amyloid/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Mice, Knockout ; Mice, Transgenic ; }, abstract = {BACKGROUND: The accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer's disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits. Understanding the physiological role of BACE1 in individual cell types is essential for developing effective BACE inhibitors for the treatment of AD. Recent single-cell RNA transcriptomic assays revealed that oligodendrocytes are enriched with genes required for generating Aβ. However, the contribution of oligodendrocytes to amyloid plaque burden in AD and the side effects of oligodendrocyte-specific Bace1 deletion remain to be explored.
METHODS: We generated an oligodendrocyte-specific Bace1 knockout model (Bace1[fl/fl];Olig2-Cre) to monitor potential disruptions in myelination using standard electron microscopy. Long-term potentiation (LTP) was monitored to measure synaptic integrity. We crossed the Bace1[fl/fl];Olig2-Cre model with heterozygous App[NL-G-F/wt] knock-in AD mice to generate AD mice lacking oligodendrocyte Bace1 (Bace1[fl/fl];Olig2-Cre; App[NL-G-F/wt]) and examined amyloid plaque number and insoluble Aβ levels and gliosis in these animals. Single nuclei RNA sequencing experiments were conducted to examine molecular changes in response to Bace1 deficiency in oligodendrocytes in the wild type or APP knock-in background.
RESULTS: Bace1 deletion in oligodendrocytes caused no change in myelin thickness in the corpus callosum but a marginal reduction in myelin sheath thickness of the optic nerve. Synaptic strength measured by LTP was not different between Bace1[fl/fl];Olig2-Cre and age-matched Bace1[fl/fl] control animals, suggesting no major effect on synaptic plasticity. Intriguingly, deletion of Bace1 in 12-month-old heterozygous AD knock-in mice (Bace1[fl/fl];Olig2-Cre; App[NL-G-F/wt] mice) caused a significant reduction of amyloid plaques by ~ 33% in the hippocampus and ~ 29% in the cortex compared to age-matched AD mice (Bace1[fl/fl];App[NL-G-F/wt]). Insoluble Aβ1-40 and Aβ1-42 levels were reduced comparably while more astrocytes and microglia were observed in surrounding amyloid plaques. Unbiased single-nuclei RNA sequencing results revealed that deletion of oligodendrocyte Bace1 in APP[NL-G-F/wt] knock-in mice increased expression of genes associated with Aβ generation and clearance such as ADAM10, Ano4, ApoE, Il33, and Sort1.
CONCLUSION: Our results provide compelling evidence that the amyloidogenic pathway in oligodendrocytes contributes to Aβ plaque formation in the AD brain. While specifically targeting BACE1 inhibition in oligodendrocytes for reducing Aβ pathology in AD is likely challenging, this is a potentially explorable strategy in future studies.}, }
@article {pmid39547733, year = {2025}, author = {Patil, S and Ayubcha, C and Teichner, E and Subtirelu, R and Cho, JH and Ghonim, M and Ghonim, M and Werner, TJ and Høilund-Carlsen, PF and Alavi, A and Newberg, AB}, title = {Clinical Applications of PET Imaging in Alzheimer's Disease.}, journal = {PET clinics}, volume = {20}, number = {1}, pages = {89-100}, doi = {10.1016/j.cpet.2024.09.015}, pmid = {39547733}, issn = {1879-9809}, support = {T32 GM144273/GM/NIGMS NIH HHS/United States ; }, mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; *Positron-Emission Tomography/methods ; *Brain/diagnostic imaging ; Cognitive Dysfunction/diagnostic imaging ; Radiopharmaceuticals ; }, abstract = {Alzheimer's disease (AD) involves a complex pathophysiology of neurodegeneration that leads to severe cognitive deficiencies. Understanding the molecular alterations that underlie this disease is fundamental to clinical management and therapeutic innovation. Functional imaging with positron emission tomography (PET) enables a visualization of these impaired pathways, such as cerebral hypometabolism, amyloid and tau accumulation, and neurotransmitter dysfunction. This review discusses the clinical applications of PET in AD and mild cognitive impairment, focusing on relevant original research studies for disease diagnosis, progression, and treatment response.}, }
@article {pmid39547338, year = {2024}, author = {Wang, ZJ and Han, WN and Chai, SF and Li, Y and Fu, CJ and Wang, CF and Cai, HY and Li, XY and Wang, X and Hölscher, C and Wu, MN}, title = {Semaglutide promotes the transition of microglia from M1 to M2 type to reduce brain inflammation in APP/PS1/tau mice.}, journal = {Neuroscience}, volume = {563}, number = {}, pages = {222-234}, doi = {10.1016/j.neuroscience.2024.11.022}, pmid = {39547338}, issn = {1873-7544}, mesh = {Animals ; *Glucagon-Like Peptides/pharmacology ; *Microglia/drug effects/metabolism ; *Mice, Transgenic ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Mice ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Presenilin-1/genetics ; Encephalitis/drug therapy/metabolism ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics/metabolism ; Neuroprotective Agents/pharmacology ; Male ; Brain/drug effects/metabolism/pathology ; Mice, Inbred C57BL ; }, abstract = {A growing number of studies show that the diabetes drug Semaglutide is neuroprotective in Alzheimer's disease (AD) animal models, but its mode of action is not fully understood. In order to explore the mechanism of Semaglutide, 7-month-old APP/PS1/tau transgenic (3xTg) mice and wild-type (WT) mice were randomly divided into four groups: control group (WT + PBS), AD model group (3xTg + PBS), Semaglutide control group (WT + Semaglutide) and Semaglutide treatment group (3xTg + Semaglutide). Semaglutide (25 nmol/kg) or PBS was administered intraperitoneally once every two days for 30 days, followed by behavioral and molecular experiments. The results show that Semaglutide can improve working memory and spatial reference memory of 3xTg-AD mice, promote the release of anti-inflammatory factors and inhibit the production of pro-inflammatory factors in the cortex and hippocampus, and reduce Aβ deposition in the hippocampal CA1 region of 3xTg mice. Semaglutide can inhibit the apoptosis of BV2 cells induced by Aβ1-42 in a dose-dependent manner and promote the transformation of microglia from M1 to M2, thereby exerting anti-inflammatory and neuroprotective effects. Therefore, we speculate that Semaglutide shows an anti-inflammatory effect by promoting the transformation of microglia from M1 to M2 type in the brain of 3xTg mice, and thus exerts a neuroprotective effect.}, }
@article {pmid39546937, year = {2025}, author = {Ihsan, NSMN and Abdul Sani, SF and Looi, LM and Pathmanathan, D and Cheah, PL and Chiew, SF and Chio-Srichan, S and Soontaranon, S and Bradley, DA}, title = {Supramolecular arrangements in human amyloid tissues using SAXS.}, journal = {Biophysical chemistry}, volume = {316}, number = {}, pages = {107349}, doi = {10.1016/j.bpc.2024.107349}, pmid = {39546937}, issn = {1873-4200}, mesh = {Humans ; *Scattering, Small Angle ; *X-Ray Diffraction ; *Amyloid/chemistry ; Kidney/chemistry/metabolism ; }, abstract = {Amyloid diseases are characterized by the accumulation of misfolded protein aggregates in human tissues, pose significant challenges for both diagnosis and treatment. Protein aggregations known as amyloids are linked to several neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, and systemic amyloidosis. The key goal of this research is to employ Small-Angle X-ray Scattering (SAXS) to examine the supramolecular structures of amyloid aggregates in human tissues. We present the structural analysis of amyloid using SAXS, which is employed directly to analyze thin tissue samples without damaging the tissues. This technique provides size and shape information of fibrils, which can be used to generate low-resolution 2D models. The present study investigates the structural changes in amyloid fibril axial d-spacing and scattering intensity in different human tissues, including kidney, heart, thyroid, and others, while also accounting for the presence of triglycerides in these tissues. Tissue structural components were examined at momentum transfer values between q = 0.2 nm[-1] and 1.5 nm[-1]. The d-spacing is a critical parameter in SAXS that provides information about the periodic distances between structures within a sample. From the supramolecular SAXS patterns, the axial d-spacing of fibrils in amyloid tissues is prominent and exists within the 3rd to 10th order, compared to that of healthy tissues which do not have notable peak orders. The axial period of fibrils in amyloid tissues is within the scattering vector range 57.40-64.64 nm[-1] while in normal tissues the range is between 60.68 and 61.41 nm[-1], which is 3.0 nm[-1] smaller than amyloid-containing tissues. Differences in d-spacing are often correlate with distinct pathological mechanisms or stages of disease progression. The application of SAXS to investigate amyloid structures in human tissues has enormous potential to further knowledge of amyloid disorders. This work will open the path for novel diagnostic instruments and therapeutic strategies meant to reduce the burden of amyloid-related diseases by offering a thorough structural examination of amyloid aggregates.}, }
@article {pmid39546224, year = {2025}, author = {Yan, Q}, title = {Personality, Aging, and Alzheimer's Disease: Implications for Psychoneuroimmunology and Personalized Medicine.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2868}, number = {}, pages = {37-48}, pmid = {39546224}, issn = {1940-6029}, mesh = {Humans ; *Aging ; *Alzheimer Disease/diagnosis/immunology/psychology ; *Biomarkers ; Brain-Gut Axis ; Hypothalamo-Hypophyseal System/metabolism ; *Personality ; Pituitary-Adrenal System/metabolism ; *Precision Medicine/methods ; *Psychoneuroimmunology/methods ; }, abstract = {Psychoneuroimmunology (PNI) advancements may revolutionize personalized medicine by identifying systemic biomarkers that enhance diagnosis and treatment. Inflammatory pathways connect personality traits with cognitive performance, aging-related disorders, and mortality risks. Studies have demonstrated the critical interactions between personality and various biological systems like the hypothalamic-pituitary-adrenal (HPA) axis. The gut-brain axis also affects behaviors and psychological states in older adults, with specific gut microbiota influencing cognition, mood, and personality. These findings underscore the practical implications of understanding personality-biology interactions. They can support preventive and personalized medicine for aging-associated disorders. Specifically, personality changes are prevalent in Alzheimer's disease (AD) patients, impacting clinical management and caregiver stress. Non-cognitive factors, such as personality traits and psychiatric symptoms, may serve as early markers of AD. Traits like high Neuroticism and low Openness can predict initial AD stages, often before a formal diagnosis. Personality alterations in AD are also linked to cerebrospinal fluid (CSF) and vascular imaging biomarkers, which can track AD pathology and serve as predictors. Dynamic personality assessment can aid in timely diagnosis, monitoring progression, and evaluating treatments of AD. Understanding personality traits is crucial for predicting burnout, lifespan, and intervention success. Integrating personality and PNI biomarkers into patient profiles will support the development of personalized and systems medicine.}, }
@article {pmid39545607, year = {2024}, author = {Zheng, J and Zhao, G and Hu, Z and Jia, C and Li, W and Peng, Y and Zheng, J}, title = {Metabolic Activation and Cytotoxicity of Donepezil Induced by CYP3A4.}, journal = {Chemical research in toxicology}, volume = {37}, number = {12}, pages = {2003-2012}, doi = {10.1021/acs.chemrestox.4c00357}, pmid = {39545607}, issn = {1520-5010}, mesh = {*Donepezil/metabolism/pharmacology/chemistry ; Animals ; *Cytochrome P-450 CYP3A/metabolism ; Rats ; Humans ; *Hepatocytes/drug effects/metabolism ; *Piperidines/pharmacology/chemistry/metabolism ; Male ; *Rats, Sprague-Dawley ; *Indans/chemistry/toxicity/pharmacology ; Cholinesterase Inhibitors/toxicity/chemistry/metabolism ; Microsomes, Liver/metabolism ; Activation, Metabolic ; Glutathione/metabolism ; Ketoconazole/pharmacology ; Cytochrome P-450 CYP3A Inhibitors/pharmacology/chemistry ; Tandem Mass Spectrometry ; }, abstract = {Donepezil (DNP) is a selective cholinesterase inhibitor widely used for the therapy of Alzheimer's disease. Instances of liver injury correlated with DNP treatment have been reported, yet the underlying hepatotoxic mechanism remains to be elucidated. This study aimed to explore the contribution of metabolic activation to the hepatotoxicity of DNP. The structure of 6-O-desmethyl DNP (M1), the oxidative metabolite of DNP, was characterized by chemical synthesis, LC-MS/MS, and nuclear magnetic resonance. A reactive quinone methide resulting from the metabolism of DNP was captured by glutathione (GSH) fortified in liver microsomal incubations after exposure to DNP, and the resulting GSH conjugate (M2) was detected in the bile of rats receiving DNP. Recombinant human P450 enzyme incubation studies demonstrated that CYP3A4 was the principal enzyme responsible for the production of M1 and M2. The generation of M2 declined in rat primary hepatocytes pretreated with ketoconazole, an inhibitor of CYP3A4, which also decreased the vulnerability of rat primary hepatocytes to DNP-caused cytotoxicity. These findings suggest that the quinone methide metabolite may contribute to the cytotoxicity and hepatotoxicity caused by the DNP.}, }
@article {pmid39545328, year = {2025}, author = {DeCarli, C and Rajan, KB and Jin, LW and Hinman, J and Johnson, DK and Harvey, D and Fornage, M and , }, title = {WMH Contributions to Cognitive Impairment: Rationale and Design of the Diverse VCID Study.}, journal = {Stroke}, volume = {56}, number = {3}, pages = {758-776}, pmid = {39545328}, issn = {1524-4628}, support = {UF1 NS125513/NS/NINDS NIH HHS/United States ; RF1 AG071665/AG/NIA NIH HHS/United States ; RF1 NS130659/NS/NINDS NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; R01 AG065359/AG/NIA NIH HHS/United States ; UF1 NS100614/NS/NINDS NIH HHS/United States ; U19 NS115388/NS/NINDS NIH HHS/United States ; RF1 AG077639/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; R01 AG052132/AG/NIA NIH HHS/United States ; P01 AG025532/AG/NIA NIH HHS/United States ; R01 AG075758/AG/NIA NIH HHS/United States ; RF1 AG056519/AG/NIA NIH HHS/United States ; R01 AG073627/AG/NIA NIH HHS/United States ; U19 NS120384/NS/NINDS NIH HHS/United States ; RF1 AG052132/AG/NIA NIH HHS/United States ; UF1 NS100608/NS/NINDS NIH HHS/United States ; R01 AG058679/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Cognitive Dysfunction ; Female ; *Magnetic Resonance Imaging ; Male ; Aged ; Risk Factors ; Middle Aged ; White Matter/diagnostic imaging ; Aged, 80 and over ; Prospective Studies ; Hispanic or Latino ; Cohort Studies ; Dementia/diagnostic imaging ; White ; }, abstract = {As awareness of dementia increases, more individuals with minor cognitive complaints are requesting clinical assessment. Neuroimaging studies frequently identify incidental white matter hyperintensities, raising patient concerns about their brain health and future risk for dementia. Moreover, current US demographics indicate that ≈50% of these individuals will be from diverse backgrounds by 2060. Racial and ethnic minority populations bear a disproportionate burden of vascular risk factors magnifying dementia risk. Despite established associations between white matter hyperintensities and cognitive impairment, including dementia, no study has comprehensively and prospectively examined the impact of individual and combined magnetic resonance imaging measures of white matter injury, their risk factors, and comorbidities on cognitive performance among a diverse, nondemented, stroke-free population with cognitive complaints over an extended period of observation. The Diverse VCID (Diverse Vascular Cognitive Impairment and Dementia) study is designed to fill this knowledge gap through 3 assessments of clinical, behavioral, and risk factors; neurocognitive and magnetic resonance imaging measures; fluid biomarkers of Alzheimer disease, vascular inflammation, angiogenesis, and endothelial dysfunction; and measures of genetic risk collected prospectively over a minimum of 3 years in a cohort of 2250 individuals evenly distributed among Americans of Black/African, Latino/Hispanic, and non-Hispanic White backgrounds. The goal of this study is to investigate the basic mechanisms of small vessel cerebrovascular injury, emphasizing clinically relevant assessment tools and developing a risk score that will accurately identify at-risk individuals for possible treatment or clinical therapeutic trials, particularly individuals of diverse backgrounds where vascular risk factors and disease are more prevalent.}, }
@article {pmid39545066, year = {2024}, author = {Zou, Y and Wang, C and Li, H and Zhong, M and Lin, J and Hu, Y and Chen, Z and Gan, CL}, title = {Epileptic seizures induced by pentylenetetrazole kindling accelerate Alzheimer-like neuropathology in 5×FAD mice.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1500105}, pmid = {39545066}, issn = {1663-9812}, abstract = {Clinical studies have shown that epileptic seizures worsen Alzheimer's disease (AD) pathology and related cognitive deficits; however, the underlying mechanism is unclear. To assess the effects of seizures on the progression of AD, chronic temporal lobe epilepsy was induced in five familial AD mutation (5×FAD) mice by kindling with the chemoconvulsant pentylenetetrazole (PTZ) at 3-3.5 months of age. The amyloidogenic pathway, tauopathy, synaptic damage, neuronal death, neurological inflammatory response and associated kinase signaling pathway dysregulation were examined at 9 months of age. We found that APP, p-APP, BACE1, Aβ and kinase-associated p-tau levels were elevated after PTZ kindling in 5×FAD mice. In addition, PTZ kindling exacerbated hippocampal synaptic damage and neuronal cell death, as determined by scanning electron microscopy and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, respectively. Finally, the levels of the neuroinflammation markers GFAP and Iba1, as well as the inflammatory cytokine IL-1β, were increased after PTZ insult. PTZ kindling profoundly exacerbated extracellular regulated kinase (ERK)-death-associated protein kinase (DAPK) signaling pathway overactivation, and acute ERK inhibitor treatment downregulated Aβ production and p-APP and p-tau levels in epileptic 5×FAD mice. In addition, long-term use of the antiseizure drug carbamazepine (CBZ) alleviated seizure-induced accelerated amyloid and tau pathology and ERK-DAPK overactivation in 5×FAD mice. Collectively, these results demonstrate that seizure-induced increases in AD-like neuropathology in 5×FAD mice are partially regulated by the ERK-DAPK pathway, suggesting that the ERK-DAPK axis could be a new therapeutic target for the treatment of AD patients with comorbid seizures.}, }
@article {pmid39545064, year = {2024}, author = {Ren, H and Tang, L and Yuan, Z and Liu, Y and Zhou, X and Xiao, X and Wu, X and Chen, W and Chen, Y and Wang, H and Xue, Q and Xu, X}, title = {Combined administration of catalpol, puerarin, gastrodin, and borneol modulates the Tlr4/Myd88/NF-κB signaling pathway and alleviates microglia inflammation in Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1492237}, pmid = {39545064}, issn = {1663-9812}, abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disorder affecting millions of people worldwide, with no effective treatment currently available. In recent decades, various traditional Chinese medicines (TCMs) and their active ingredients have shown the potential to attenuate the pathogenesis of AD in cellular and animal models. However, the effects of TCM formulas, which are typically administered in practice, have been less studied. This study aims to investigate the therapeutic effects of several formulas consisting of 4 components herbal components: catalpol, puerarin, gastrodin, and borneol, on streptozotocin (STZ)-induced AD models in cells and rats. The new object recognition (NOR), elevated plus maze (EMP), and Morris water maze (MWM) tests were used to evaluate the cognitive functions of rats. Golgi staining, Haematoxylin and Eosin (HE) staining, and Nissl staining analyses were employed assess the physiology of hippocampal tissues. Gene expression profiles were analyzed used transcriptomics and reverse transcription quantitative polymerase chain reaction analysis, while protein expression levels were determined using immunoblotting, immunohistochemical, and immunofluorescence. The production of cytokines was evaluated with enzyme-linked immunosorbent assay. The results demonstrated that the combined administration of these 4 components (CPGB) had superior mitigating effects on AD cell model, as evidenced by the reduced pro-inflammatory cytokine production and decreased deposition of Aβ protein. Further in vivo and in vitro experiments confirmed that varying doses of CPGB formula effectively ameliorated STZ-induced cognitive deficits, as shown by NOR, MWM, and EMP tests, as well as pathological changes in hippocampal tissues and a 3-dimensional brain neurovascular unit (3D-NVU) model, including decreased deposition of Aβ protein and formation of plaques. Transcriptome sequencing and analysis identified 35 genes with significantly altered expression levels due to STZ and CPGB treatment in hippocampal tissues, which were enriched in the Tlr4/Myd88/NF-κB signaling pathway. Interference with this pathway significantly influenced the therapeutic effects of CPGB in the 3D-NVU model. Collectively, these findings suggest that the combined administration of catalpol, puerarin, gastrodin, and borneol offers superior therapeutic effects on AD by modulating the Tlr4/Myd88/NF-κB signaling pathway. This study strengthens the theoretical foundation for using TCMs to treat AD, proving new insights and references for alleviating and treating AD.}, }
@article {pmid39544911, year = {2024}, author = {Kodosaki, E and Bell, R and Sogorb-Esteve, A and Wiltshire, K and Zetterberg, H and Heslegrave, A}, title = {More than microglia: myeloid cells and biomarkers in neurodegeneration.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1499458}, pmid = {39544911}, issn = {1662-4548}, abstract = {The role of myeloid cells (granulocytes and monocytes) in neurodegeneration and neurodegenerative disorders (NDD) is indisputable. Here we discuss the roles of myeloid cells in neurodegenerative diseases, and the recent advances in biofluid and imaging myeloid biomarker research with a focus on methods that can be used in the clinic. For this review, evidence from three neurodegenerative diseases will be included, Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). We discuss the potential for these biomarkers to be used in humans with suspected NDD as prognostic, diagnostic, or monitoring tools, identify knowledge gaps in literature, and propose potential approaches to further elucidate the role of myeloid cells in neurodegeneration and better utilize myeloid biomarkers in the understanding and treatment of NDD.}, }
@article {pmid39544104, year = {2024}, author = {Fabrizi, E and Ancidoni, A and Locuratolo, N and Piscopo, P and Della Gatta, F and Salemme, S and Pani, SM and Marconi, D and Vignatelli, L and Sagliocca, L and Caffarra, P and Secreto, P and Guaita, A and Stracciari, A and Vanacore, N and Lacorte, E and , }, title = {The Italian guideline on diagnosis and treatment of dementia and mild cognitive impairment.}, journal = {Age and ageing}, volume = {53}, number = {11}, pages = {}, pmid = {39544104}, issn = {1468-2834}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis/therapy/psychology ; *Dementia/therapy/diagnosis/psychology ; Italy ; *Caregivers/psychology ; Consensus ; }, abstract = {INTRODUCTION: Approximately 2 million people in Italy are currently living with dementia or mild cognitive impairment (MCI), and 4 million are involved as family members or caregivers. Considering the significant impact of dementia, the Italian Ministry of Health entrusted the Italian National Institute of Health (Istituto Superiore di Sanità) with the development of a guideline within the Italian National Guideline System (Sistema Nazionale Linee Guida, SNLG) on the diagnosis and treatment of dementia and MCI. The main objective was to provide evidence-based recommendations aimed at reducing the variability and ensuring the appropriateness of clinical practices throughout the whole care process from identification and diagnosis to the end of life for people with dementia (PwD) or MCI and their families/caregivers.
METHODS: The GRADE-ADOLOPMENT approach was used to adopt, adapt and update the guideline developed by the National Institute for Health and Care Excellence in 2018 (NG97). The methodology was based on the Methodological Handbook produced by the SNLG. A multidisciplinary panel of 29 experts and four representatives of family members/caregivers discussed and approved 47 review questions. Of these, 34 questions were adopted from the NG97, and 13 were new questions, including 10 questions referring to MCI. Systematic literature reviews were performed for each question, and a team of methodological and clinical experts qualitatively assessed and summarised results from included studies based on the GRADE approach. To facilitate the implementation and dissemination of the contents of this guideline, a care pathway and a leaflet dedicated to PwD or MCI and their families/caregivers were also developed.
RESULTS: The literature review for this guideline included studies published up to November 2023. More than 1000 peer-reviewed publications were included, covering the following areas: (i) identification, diagnosis and post-diagnostic support; (ii) care models and care coordination; (iii) pharmacological interventions for cognitive symptoms; (iv) non-pharmacological interventions for cognitive symptoms; (v) non-cognitive symptoms, intercurrent illnesses and palliative care. The multidisciplinary panel discussed and approved 167 clinical practice recommendations and 39 research recommendations.
COMMENTARY: Italy's first National Guideline on dementia and MCI addresses diagnosis, treatment and care within the National Healthcare System. It includes recommendations on pharmacological and non-pharmacological approaches, and emphasises tailored interventions, comprehensive cognitive assessment, staff training and palliative care. The guideline also underlines the need to involve PwD in decision-making and supporting caregivers throughout the entire course of the disease.
CONCLUSIONS: Structured strategies for the dissemination and implementation of the guideline will be defined within the Italian Fund for Alzheimer and other Dementias 2024-2026. An interactive care pathway and a leaflet dedicated to PwD and their carers are already available. The guideline will be updated starting January 2027, but early updates may be planned in case of breakthrough advancements.}, }
@article {pmid39544007, year = {2024}, author = {Ke, C and Shan, S and Yu, J and Wei, X and Pan, J and Zhang, W}, title = {Acupuncture for patients with Alzheimer's disease: An evidence map of randomized controlled trials, systematic reviews, and meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {102}, number = {4}, pages = {924-942}, doi = {10.1177/13872877241295400}, pmid = {39544007}, issn = {1875-8908}, mesh = {Humans ; *Acupuncture Therapy/methods ; *Alzheimer Disease/therapy ; Meta-Analysis as Topic ; Randomized Controlled Trials as Topic ; Systematic Reviews as Topic ; }, abstract = {Background: Acupuncture is an effective complementary treatment for Alzheimer's disease (AD). This review aims to summarize the available evidence provided by randomized controlled trials (RCTs) and systematic reviews (SRs) or meta-analyses (MAs) on the effect of acupuncture on AD. Objective: To systematically summarize and combine clinical research evidence on AD distribution. Methods: We conducted a comprehensive search of various databases, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang Data, Chinese BioMedical Literature Database (CBM) and Chonqing VIP (CQVIP), from their inception to September 2023. Relevant literature about acupuncture for AD was included, and the characteristics of the evidence map were presented through charts and textual analyses. Results: In total, 117 RCTs and 17 SRs or MAs were included. The results were divided into three categories: basic characteristics of the included literature, clinical characteristics and quality assessment of the included RCTs, and clinical characteristics and quality assessment of the included SRs and MAs. Conclusions: Acupuncture as a therapeutic measure for AD has some advantages in improving cognition and quality of life; thus, it is imperative to conduct multi-center, large-scale RCTs to enhance the evidence supporting the use of acupuncture in AD. This is the first evidence map exploring acupuncture treatment for AD, providing insights into the current clinical research landscape on acupuncture treatment for AD. Furthermore, the findings of this study highlight research gaps in this field and serve as a valuable reference for guiding the planning and selection of topics for future research.}, }
@article {pmid39543508, year = {2024}, author = {Wang, X and Liu, Y and Qin, G and Yu, Y}, title = {Robust double machine learning model with application to omics data.}, journal = {BMC bioinformatics}, volume = {25}, number = {1}, pages = {355}, pmid = {39543508}, issn = {1471-2105}, support = {ZD2021CY001//Shanghai Municipal Science and Technology Major Project/ ; 82473724//National Natural Science Foundation of China/ ; 82273730//National Natural Science Foundation of China/ ; 21QA1401300//Shanghai Rising-Star Program/ ; 22ZR1414900//Shanghai Municipal Natural Science Foundation/ ; GWVI-11.2-XD10//the Three-Year Public Health Action Plan of Shanghai/ ; }, mesh = {*Machine Learning ; Humans ; *Alzheimer Disease/genetics/metabolism ; *DNA Methylation ; Algorithms ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Genomics/methods ; }, abstract = {BACKGROUND: Recently, there has been a growing interest in combining causal inference with machine learning algorithms. Double machine learning model (DML), as an implementation of this combination, has received widespread attention for their expertise in estimating causal effects within high-dimensional complex data. However, the DML model is sensitive to the presence of outliers and heavy-tailed noise in the outcome variable. In this paper, we propose the robust double machine learning (RDML) model to achieve a robust estimation of causal effects when the distribution of the outcome is contaminated by outliers or exhibits symmetrically heavy-tailed characteristics.
RESULTS: In the modelling of RDML model, we employed median machine learning algorithms to achieve robust predictions for the treatment and outcome variables. Subsequently, we established a median regression model for the prediction residuals. These two steps ensure robust causal effect estimation. Simulation study show that the RDML model is comparable to the existing DML model when the data follow normal distribution, while the RDML model has obvious superiority when the data follow mixed normal distribution and t-distribution, which is manifested by having a smaller RMSE. Meanwhile, we also apply the RDML model to the deoxyribonucleic acid methylation dataset from the Alzheimer's disease (AD) neuroimaging initiative database with the aim of investigating the impact of Cerebrospinal Fluid Amyloid β 42 (CSF A β 42) on AD severity.
CONCLUSION: These findings illustrate that the RDML model is capable of robustly estimating causal effect, even when the outcome distribution is affected by outliers or displays symmetrically heavy-tailed properties.}, }
@article {pmid39543022, year = {2025}, author = {Güzel, Ö and Kehoe, PG}, title = {The Contribution of the Renin-Angiotensin System to Alzheimer's Disease.}, journal = {Current topics in behavioral neurosciences}, volume = {69}, number = {}, pages = {107-127}, pmid = {39543022}, issn = {1866-3370}, mesh = {*Alzheimer Disease/drug therapy/metabolism/physiopathology/genetics ; Humans ; *Renin-Angiotensin System/physiology/drug effects ; Animals ; }, abstract = {The renin-angiotensin system (RAS) is becoming increasingly recognised as a biochemical pathway relevant to the development and progression of Alzheimer's disease (AD). RAS involvement in AD was initially linked to AD via numerous genetic association studies and more recent Genome-Wide Association Studies (GWAS), and in some cases in relation to classical hallmarks of AD pathology. Since these initial findings, which will be summarised here, several complementary areas of research are converging in support of what has been proposed as the Angiotensin Hypothesis for Alzheimer's disease. This hypothesis proposes how the RAS and disease-associated changes to the normal balance between opposing regulatory pathways within RAS warrant careful consideration in the pathogenesis of AD and its pathology. We discuss some of these in relation to RAS-targeting therapeutics, originally developed for the treatment of cardiovascular conditions, and how they might be repurposed as interventions for AD.}, }
@article {pmid39542999, year = {2025}, author = {Dhurandhar, Y and Tomar, S and Namdeo, KP and Bodakhe, SH}, title = {Excitatory amino acids as therapeutic agents: Reversing neurodegenerative trajectory by tackling excitotoxicity.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {2}, pages = {549-560}, pmid = {39542999}, issn = {1590-3478}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Excitatory Amino Acids/metabolism ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; }, abstract = {Neurodegenerative diseases pose significant challenges to healthcare systems globally due to their complex etiology and relentless progression, often rendering conventional treatments ineffective. Recent advances have spotlighted excitatory amino acids, particularly D-amino acids, once considered as products of metabolism of the microbiota or deriving from food intake. This review explores the role of D-amino acids in mitigating excitotoxicity-a process characterized by excessive calcium influx through aberrant N-methyl-D-aspartate receptor (NMDAR) activation, which is implicated in the pathogenesis of diseases like Alzheimer's disease. By providing alternative pathways for neuronal signaling and protecting against excitotoxic damage, D-amino acids offer a novel approach to reversing neurodegenerative trajectories. Future research should focus on elucidating the detailed mechanisms of action of these compounds, evaluating their therapeutic potential through rigorous preclinical and clinical trials, and developing effective delivery systems to optimize their neuroprotective effects. This emerging field holds promise for developing innovative treatment strategies that could significantly improve outcomes for patients with neurodegenerative disorders.}, }
@article {pmid39542878, year = {2024}, author = {Hossain, MS and Haque, MA and Park, IS}, title = {Novel role of curcumin as inhibitor of β-amyloid-induced lamin fragmentation.}, journal = {Histochemistry and cell biology}, volume = {163}, number = {1}, pages = {2}, pmid = {39542878}, issn = {1432-119X}, mesh = {*Curcumin/pharmacology/chemistry ; Humans ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Lamins/metabolism/antagonists & inhibitors ; Cell Survival/drug effects ; Cathepsin L/antagonists & inhibitors/metabolism ; Peptide Fragments/metabolism/antagonists & inhibitors ; Tumor Cells, Cultured ; }, abstract = {Oligomer amyloid beta 42 (Aβ) is considered the key pathogenic molecule in Alzheimer disease (AD) and causes specific lamin fragmentation. Curcumin has been recognized for its protective effects against Aβ-induced toxicity in AD, though its underlying mechanism remains unclear. In this study, the inhibitory mechanism of curcumin against Aβ-induced lamin fragmentation and cell death was investigated. Human neuroblastoma cells were used to examine Aβ-induced lamin fragmentation and lamin deformation by immunoblotting and confocal microscopy, while cell viability was measured using MTT and alamarBlue assay. Caspase and cathepsin L activity were assessed by spectrofluorometry, and Aβ aggregation was evaluated by ThT assay. Our results demonstrated that curcumin inhibited Aβ aggregation, reducing intracellular Aβ uptake by 45% compared to Aβ-treated cells. Curcumin also inhibited the Aβ-induced intracellular calcium rise, subsequently leading to a onefold reduction in cathepsin L activity. This reduction in cathepsin L activity by curcumin blocked the Aβ-induced lamin fragmentation. Collectively, these findings suggest that curcumin inhibits Aβ-induced cell death by preventing Aβ entry and lamin cleavage, providing potential new insights for AD treatment.}, }
@article {pmid39542700, year = {2025}, author = {Collij, LE and Bischof, GN and Altomare, D and Bader, I and Battle, M and Vállez García, D and Lopes Alves, I and Wolz, R and Gismondi, R and Stephens, A and Walker, Z and Scheltens, P and Nordberg, A and Gispert, JD and Drzezga, A and Perissinotti, A and Morbelli, S and Buckley, C and Garibotto, V and Frisoni, GB and Farrar, G and Barkhof, F and , }, title = {Quantification Supports Amyloid PET Visual Assessment of Challenging Cases: Results from the AMYPAD Diagnostic and Patient Management Study.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {66}, number = {1}, pages = {110-116}, pmid = {39542700}, issn = {1535-5667}, mesh = {Humans ; *Positron-Emission Tomography ; Male ; Female ; Aged ; *Amyloid/metabolism ; Retrospective Studies ; Alzheimer Disease/diagnostic imaging ; Middle Aged ; Image Processing, Computer-Assisted ; }, abstract = {Several studies have demonstrated strong agreement between routine clinical visual assessment and quantification, suggesting that quantification approaches could support assessment by less experienced readers or in challenging cases. However, all studies to date have implemented a retrospective case collection, and challenging cases were generally underrepresented. Methods: We included all participants (n = 741) from the AMYPAD diagnostic and patient management study with available baseline amyloid PET quantification. Quantification was done with the PET-only AmyPype pipeline, providing global Centiloid and regional z scores. Visual assessment was performed by local readers for the entire cohort. From the total cohort, we selected a subsample of 85 cases for which the amyloid status based on the local reader's visual assessment and the Centiloid classification (cutoff = 21) was discordant or that were assessed with low confidence (i.e., ≤3 on a 5-point scale) by the local reader. In addition, concordant negative (n = 8) and positive (n = 8) scans across tracers were selected. In this sample (n = 101 cases; [[18]F]flutemetamol, n = 48; [[18]F]florbetaben, n = 53), the visual assessments and corresponding confidence by 5 certified independent central readers were captured before and after disclosure of the quantification results. Results: For the whole AMYPAD diagnostic and patient management study cohort, overall assessment by local readers highly agreed with Centiloid status (κ = 0.85, 92.3% agreement). This was consistently observed within disease stages (subjective cognitive decline-plus, κ = 0.82, 92.3% agreement; mild cognitive impairment, κ = 0.80, 89.8% agreement; dementia, κ = 0.87, 94.6% agreement). Across all central reader assessments in the challenging subsample, quantification of global Centiloid and regional z scores was considered supportive of visual reads in 70.3% and 49.3% of assessments, respectively. After disclosure of the quantitative results, we observed improvement in concordance across the 5 readers (baseline κ = 0.65, 65.3% agreement; κ after disclosure = 0.74, 73.3% agreement) and a significant increase in reader confidence (baseline mean (M) = 4.0 vs. M after disclosure = 4.34, Wilcoxon statistic (W) = 101,056, P < 0.001). Conclusion: In this clinical study enriched for challenging amyloid PET cases, we demonstrate the value of quantification to support visual assessment. After disclosure, both interreader agreement and confidence showed significant improvement. These results are important considering the arrival of antiamyloid therapies, which used the Centiloid metric for trial inclusion and target engagement. Moreover, quantification could support determination of amyloid-β status with high certainty, an important factor for treatment initiation.}, }
@article {pmid39542412, year = {2025}, author = {Li, Y and Zhang, J and Zhang, L and Hu, C and Zhou, L and Cheng, Y and Liu, Q}, title = {Ellagic acid(EA) ameliorates Alzheimer's disease by reducing Aβ levels, oxidative stress and attenuating inflammation.}, journal = {European journal of pharmacology}, volume = {986}, number = {}, pages = {177099}, doi = {10.1016/j.ejphar.2024.177099}, pmid = {39542412}, issn = {1879-0712}, mesh = {Animals ; *Ellagic Acid/pharmacology/therapeutic use ; *Oxidative Stress/drug effects ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *Amyloid beta-Peptides/metabolism ; Male ; Disease Models, Animal ; Inflammation/drug therapy/metabolism/pathology ; Mice, Transgenic ; Memory/drug effects ; Hippocampus/drug effects/metabolism/pathology ; Maze Learning/drug effects ; }, abstract = {BACKGROUND: Ellagic acid (EA) serves as a pivotal coenzyme for various dehydrogenases, influencing diverse biological processes. Recognized for its potential in impeding disease progression, EA's effectiveness and mechanism in treating 5xFAD remain elusive.
AIM OF THE STUDY: This study aims to investigate EA's potential roles and underlying mechanisms in mitigating symptoms associated with 5xFAD.
MATERIALS AND METHODS: 5 × FAD mice underwent a 12-week EA treatment regimen. The efficacy of EA against 5 × FAD was assessed through in vivo experiments, including Morris water maze and contextual fear conditioning tests for learning and memory abilities. Immunofluorescence (IF) and thioflavin staining examined changes in Aβ/neurons in brain tissue. RT‒qPCR evaluated inflammatory cytokine expression, while Bcl2/Bax protein levels were analyzed via Western blot (WB).
RESULTS: EA demonstrates promise in alleviating symptoms associated with 5xFAD. It significantly reduced the mice's escape latency in the Morris water maze, increased the frequency of crossings in the target quadrant, and prolonged freezing time in the contextual fear memory test. EA also improved neuronal pathology in the hippocampus and cortex, decreased neuronal loss, and reduced Aβ levels. Moreover, EA significantly increased MDA and SOD levels, effectively modulated the Bcl2/Bax ratio, and decreased the production of proinflammatory factors in brain tissue of 5xFAD model mice.
IN CONCLUSION: Our findings highlight the potential therapeutic efficacy of EA in addressing 5xFAD-related nervous system disorders by targeting Aβ levels, oxidative stress, and inflammation.}, }
@article {pmid39542342, year = {2024}, author = {Khandayataray, P and Murthy, MK}, title = {Dietary interventions in mitigating the impact of environmental pollutants on Alzheimer's disease - A review.}, journal = {Neuroscience}, volume = {563}, number = {}, pages = {148-166}, doi = {10.1016/j.neuroscience.2024.11.020}, pmid = {39542342}, issn = {1873-7544}, mesh = {*Alzheimer Disease/prevention & control ; Humans ; *Environmental Pollutants/toxicity ; Animals ; Diet, Mediterranean ; Oxidative Stress/drug effects/physiology ; Dietary Approaches To Stop Hypertension ; }, abstract = {Numerous studies linking environmental pollutants to oxidative stress, inflammation, and neurotoxicity have assigned pollutants to several neurodegenerative disorders, including Alzheimer's disease (AD). Heavy metals, pesticides, air pollutants, and endocrine disruptor chemicals have been shown to play important roles in AD development, with some traditional functions in amyloid-β formation, tau kinase action, and neuronal degeneration. However, pharmacological management and supplementation have resulted in limited improvement. This raises the interesting possibility that activities usually considered preventive, including diet, exercise, or mental activity, might be more similar to treatment or therapy for AD. This review focuses on the effects of diet on the effects of environmental pollutants on AD. One of the primary issues addressed in this review is a group of specific diets, including the Mediterranean diet (MeDi), Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH intervention for Neurodegenerative Delay (MIND), which prevent exposure to these toxins. Such diets have been proven to decrease oxidative stress and inflammation, which are unfavorable for neuronal growth. Furthermore, they contribute to positive changes in the composition of the human gut microbiota and thus encourage interactions in the Gut-Brain Axis, reducing inflammation caused by pollutants. This review emphasizes a multi-professional approach with reference to nutritional activities that would lower the neurotoxic load in populations with a high level of exposure to pollutants. Future studies focusing on diet and environment association plans may help identify preventive measures aimed at enhancing current disease deceleration.}, }
@article {pmid39542176, year = {2024}, author = {Tian, Z and Zhang, Q and Wang, L and Li, M and Li, T and Wang, Y and Cao, Z and Jiang, X and Luo, P}, title = {Progress in the mechanisms of pain associated with neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102579}, doi = {10.1016/j.arr.2024.102579}, pmid = {39542176}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Pain/physiopathology/metabolism/etiology ; Animals ; Neuroinflammatory Diseases ; }, abstract = {Neurodegenerative diseases (NDDs) represent a class of neurological disorders characterized by the progressive degeneration or loss of neurons, impacting millions of individuals globally. In addition to the typical manifestations, pain is a prevalent symptom associated with NDDs, seriously impacting the quality of life for patients. The pathogenesis of pain associated with NDDs is intricate and multifaceted. Currently, the clinical management of NDDs-related pain symptoms predominantly relies on conventional pharmacological agents or physical therapy. However, these approaches often fail to produce satisfactory outcomes. This article summarizes the underlying mechanisms of major NDDs-associated pain: Neuroinflammation, Brain and spinal cord dysfunctions, Mitochondrial dysfunction, Risk gene and pathological protein, as well as Receptor, channel, and neurotransmitter. While numerous studies have investigated the downstream pathological processes associated with these mechanisms, there remains a significant gap in identifying the key initiating factors. Specifically, there is insufficient evidence for the upstream elements that activate microglia and astrocytes in neuroinflammation leading to pain in NDDs. Likewise, there is an absence of upstream factors elucidating how dysfunctions in the brain and spinal cord, as well as mitochondrial impairments, contribute to the development of pain. Furthermore, the specific mechanisms through which hallmark pathological proteins related to NDDs contribute to these pathological processes remain inadequately understood. The objective of this article is to synthesize the existing mechanisms underlying pain associated with NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Schizophrenia, Amyotrophic lateral sclerosis, and Multiple sclerosis, while also identifying gaps and deficiencies in these mechanisms. This paper offers insights for future research trajectories. Given the intricate pathogenesis of NDDs-related pain, it emphasizes that a promising short-term strategy is combination therapy-intervening concurrently in multiple pathological processes-akin to the cocktail approach utilized in treating acquired immunodeficiency syndrome (AIDS). For long-term advancements, achieving breakthroughs in the treatment of the NDDs themselves will remain essential for alleviating accompanying pain symptoms.}, }
@article {pmid39541666, year = {2024}, author = {Zhu, C and Wang, S and Ma, S and Zhang, S and Wang, Y and Li, B and Zhang, W and Sun, Z}, title = {Gastrodin reduces Aβ brain levels in an Alzheimer's disease mouse model by inhibiting P-glycoprotein ubiquitination.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {135}, number = {}, pages = {156229}, doi = {10.1016/j.phymed.2024.156229}, pmid = {39541666}, issn = {1618-095X}, mesh = {*Glucosides/pharmacology ; Animals ; *Ubiquitination/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism ; *Disease Models, Animal ; *Benzyl Alcohols/pharmacology ; *ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Mice ; *Blood-Brain Barrier/drug effects/metabolism ; *Brain/drug effects/metabolism ; Molecular Docking Simulation ; Male ; Mice, Transgenic ; }, abstract = {BACKGROUND: Studies have demonstrated the potential of gastrodin in the treatment of Alzheimer's disease (AD), however, its mechanism of action remains elusive. Currently, the Amyloid-β (Aβ) cascade hypothesis continues to be the prevailing theory regarding AD etiology. The ubiquitination of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) contributes to the accumulation of Aβ in the brain during AD.
PURPOSE: To investigate the mechanism of gastrodin intervention in AD.
METHODS: The molecular docking, molecular dynamics simulations, and microscale thermophoresis (MST) were employed to identify the action target of gastrodin. The western blot (WB) was performed to detect the protein expression level, the ubiquitination level of P-gp was d