@article {pmid40741047,
year = {2025},
author = {Yang, Y and Chen, H and Liu, Q and Niu, Y and Mao, C and Wang, R},
title = {Elucidating molecular pathogenesis and developing targeted therapeutic interventions for cerebrovascular endothelial cell-mediated vascular dementia.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1623050},
pmid = {40741047},
issn = {1663-4365},
abstract = {Vascular dementia (VaD) ranks as the second most prevalent subtype of dementia, surpassed only by Alzheimer's disease (AD). The maintenance of neurological function and cerebral homeostasis critically depends on precisely regulated blood flow within the intricately organized cerebrovascular network. Disruptions in cerebral hemodynamics may impair neurovascular homeostasis, thereby inducing pathophysiological cascades characterized by oxidative stress, neuroinflammation, and neuronal degeneration. Emerging evidence identifies cerebrovascular dysregulation and impaired neurovascular coupling (NVC) as primary pathogenic mechanisms underlying VaD, emphasizing the necessity to elucidate their complex interplay. Cerebrovascular endothelial cells exhibit remarkable heterogeneity, serving dual roles as both architectural components of the blood-brain barrier (BBB) and functional regulators of NVC. Furthermore, pericytes residing abluminal on capillary endothelia demonstrate critical involvement in hemodynamic modulation through contractile regulation of microvascular tone, while concurrently maintaining BBB integrity through dynamic paracrine signaling. This study examines cerebrovascular endothelial-neuronal interactions within the neurovascular unit (NVU) framework, analyzing their bidirectional regulatory mechanisms and therapeutic potential in cognitive dysfunction remediation. The pathophysiological progression of VaD manifests through multiple interdependent pathways, including cerebral hypoperfusion, oxidative stress cascades, neuroinflammatory responses, mitochondrial dysregulation, and electrolyte homeostasis perturbations. Through three interventional axes: (1) BBB fortification strategies; (2) cerebral hemodynamic optimization and NVC enhancement; (3) nanotherapeutic platforms integrating endothelial-specific molecular targets we systematically evaluate endothelial-centric therapeutic paradigms. This multi-modal approach proposes novel mechanistic insights and clinical translation frameworks for VaD management.},
}

@article {pmid40740995,
year = {2025},
author = {Zhang, Y and Zhang, T and Zhao, M and Li, P and Liu, T and Xie, J},
title = {Pharmacological mechanisms and potential clinical applications of Dihydromyricetin in neurological disorders.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1618623},
pmid = {40740995},
issn = {1663-9812},
abstract = {Neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, and stroke) have complex pathogenesis and affect a substantial proportion of the population; yet, available treatments have poor or limited efficacy, and the patients have a poor prognosis, with high morbidity and mortality. Dihydromyricetin (DHM), a flavonoid compound extracted from plants, has received widespread attention in recent years because of its diverse pharmacological effects. In vitro and in vivo studies have revealed its substantial antioxidant, anti-inflammatory, and neuroprotective properties, making it a promising candidate for the treatment of central nervous system disorders through multiple mechanisms and pleiotropic effects. Therefore, there is an urgent need to develop novel therapeutic strategies. DHM is an attractive candidate for the management of neurological disorders, but there is a lack of a systematic summary of the knowledge status and gaps. Therefore, to address this challenge, we systematically reviewed the pharmacological mechanisms of DHM in central nervous system disorders and its potential applications in related conditions. We analyzed the therapeutic potential and current challenges of DHM to provide a reference for its development and application as a novel therapeutic agent. The review suggests that DHM possesses significant potential for the management of neurological disorders.},
}

@article {pmid40740514,
year = {2025},
author = {Wang, J and Mao, Y and Liu, X and Hao, W},
title = {Learning Patient-Specific Spatial Biomarker Dynamics via Operator Learning for Alzheimer's Disease Progression.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {40740514},
issn = {2331-8422},
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with substantial heterogeneity in progression and treatment response. Despite recent therapeutic advances, predictive models capable of accurately forecasting individualized disease trajectories remain limited. Here, we present a machine learning-based operator learning framework for personalized modeling of AD progression, integrating longitudinal multimodal imaging, biomarker, and clinical data. Unlike conventional models with prespecified dynamics, our approach directly learns patient-specific disease operators governing the spatiotemporal evolution of amyloid, tau, and neurodegeneration biomarkers. Using Laplacian eigenfunction bases, we construct geometry-aware neural operators capable of capturing complex brain dynamics. Embedded within a digital twin paradigm, the framework enables individualized predictions, simulation of therapeutic interventions, and in silico clinical trials. Applied to AD clinical data, our method achieves high prediction accuracy exceeding 90% across multiple biomarkers, substantially outperforming existing approaches. This work offers a scalable, interpretable platform for precision modeling and personalized therapeutic optimization in neurodegenerative diseases.},
}

@article {pmid40740460,
year = {2025},
author = {Fu, HX},
title = {Effects of repetitive transcranial magnetic stimulation on electroencephalogram and memory function in patients with mild cognitive impairment.},
journal = {World journal of psychiatry},
volume = {15},
number = {7},
pages = {106761},
pmid = {40740460},
issn = {2220-3206},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a high-risk precursor to Alzheimer's disease characterized by declining memory or other progressive cognitive functions without compromising daily living abilities.

AIM: To investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with MCI.

METHODS: This retrospective analysis involved 180 patients with MCI who were admitted to The First Hospital of Shanxi Medical University from January 2021 to June 2023. Participants were allocated into the research (n = 98, receiving rTMS) and control groups (n = 82, receiving sham stimulation). Memory tests, cognitive function assessments, event-related potential-P300 tests, and electroencephalogram (EEG) examinations were conducted pre-treatment and post-treatment. Further, memory quotient (MQ), cognitive function scores, and EEG grading results were compared, along with adverse reaction incidences.

RESULTS: Pre-treatment MQ scores, long-term and short-term memory, as well as immediate memory scores, demonstrated no notable differences between the groups. Post-treatment, the research group exhibited significant increases in MQ scores, long-term memory, and short-term memory compared to baseline (P < 0.05), with these improvements being statistically superior to those in the control group. However, immediate memory scores exhibited no significant change (P > 0.05). Further, the research group demonstrated statistically better post-treatment scores on the Revised Wechsler Memory Scale than the control group. Furthermore, post-treatment P300 latency and amplitude improved significantly in the research group, surpassing the control group. EEG grading in the research group improved, and the incidence of adverse reactions was significantly lower than in the control group.

CONCLUSION: Patients with MCI receiving rTMS therapy demonstrated improved memory and cognitive functions and EEG grading and exhibited high safety with fewer adverse reactions.},
}

@article {pmid40740038,
year = {2025},
author = {Zheng, M and Yang, M and Li, X and Tian, L and Zhou, S and Wang, G and Gao, W},
title = {Attenuation of Tacrine Combined With Rosmarinic Acid.},
journal = {Phytochemical analysis : PCA},
volume = {},
number = {},
pages = {},
doi = {10.1002/pca.70009},
pmid = {40740038},
issn = {1099-1565},
support = {2060302//Key Project at the Central Government Level/ ; ZYYCXTD-D-202005//Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine/ ; 81872956//National Natural Science Foundation of China/ ; 82173929//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most common forms of dementia among the elderly in the world. With the increase of human life expectancy, its incidence is also increasing year by year. Tacrine (TAC) is the first acetylcholine inhibitor approved for the treatment of AD. Although TAC has obvious anti-AD activity, it was eventually delisted due to acute liver injury caused by its strong hepatotoxicity. Rosmarinic acid (RA) has shown good activity in both neuroprotection and hepatoprotection.

PURPOSE AND STUDY DESIGN: In this study, the combination of RA and TAC was explored, and a high dose of d-galactose was used to build an AD mouse model, which was given at the same time for 4 weeks in order to alleviate TAC hepatotoxicity and enhance the intervention of AD in mice through RA. In particular, we pay attention to the key role of Aβ and microglia in the pathogenesis of AD, so we evaluate the ability of RA combined with TAC in alleviating chronic neuroinflammation induced by Aβ plaque in the brain of AD mice and enhancing the ability of microglia to clear Aβ plaque.

RESULTS: The results show that the combination of RA and TAC has the best intervention effect on AD compared with the single use of the two drugs, and it is basically positively correlated with RA dose. RA + TAC significantly improved body weight, organ index, and behavioral state of AD mice. Further analysis showed that RA + TAC enhanced the antioxidant level of hippocampus and serum of AD mice, alleviated the pathological damage of hippocampus, significantly improved cholinergic system, reduced the expression levels of AB plaque and neurotoxic Aβ1-41 and Aβ1-42 in the brain, and significantly increased the level of neuroprotective protein trigger receptor expressed on myeloid cells 2 (TREM2), which mediated the phagocytosis of microglia. More importantly, the combination therapy of RA and TAC decreased the expression of M1 microglia marker (ionized calcium-binding adapter molecule 1 [Iba-1]), increased the expression of M2 microglia marker Arg-1, and promoted the release of anti-inflammatory compounds. In addition, RA + TAC also inhibited the mRNA expression of TLR4 and NF-κB related to neuroinflammation. In the aspect of liver function, RA reduced cell death mediated by Caspase-3 by regulating the expression of bcl-2/bax, alleviated TAC-induced liver injury in mice, and made the serum indexes of ALT, AST, ALP, TBIL, and γ-GT reflecting liver function closer to the normal range.

CONCLUSION: The combination of RA and TAC shows the potential to reduce the hepatotoxicity of TAC and is expected to enhance its therapeutic effect on AD.},
}

@article {pmid40739944,
year = {2025},
author = {Hardy, J},
title = {Alzheimer's Disease: Treatment Challenges for the Future.},
journal = {Journal of neurochemistry},
volume = {169},
number = {8},
pages = {e70176},
doi = {10.1111/jnc.70176},
pmid = {40739944},
issn = {1471-4159},
mesh = {*Alzheimer Disease/drug therapy/therapy/metabolism ; Humans ; Animals ; Amyloid beta-Peptides/metabolism/immunology/antagonists & inhibitors ; },
abstract = {The approvals of the first anti-amyloid antibodies for the treatment of Alzheimer's disease have changed both the clinical and research landscape for the disease. These antibodies, lecanemab and donanemab, mark a turning point for our understanding of the disease pathogenesis and for the treatment of this prevalent disorder. This review discusses what they imply for disease pathogenesis and what is needed to progress from the current imperfect therapies toward safe and better, disease halting therapies. The research over the next period will involve drug development, largely aimed at reducing the side effects of the anti-amyloid therapies, biomarker and genetic research to try and identify patients earlier in the disease process, and neuropathological research in individuals who have received treatment to try and understand the pathological substrates of the continuing clinical decline in the disease.},
}

*Alzheimer Disease/drug therapy/therapy/metabolism
Humans
Animals
Amyloid beta-Peptides/metabolism/immunology/antagonists & inhibitors

@article {pmid40739673,
year = {2025},
author = {Zheng, X and Yuan, W and Li, L and Ma, H and Zhu, M and Li, X and Feng, X},
title = {Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) to tackle central nervous system diseases: role as a promising approach.},
journal = {European journal of medical research},
volume = {30},
number = {1},
pages = {690},
doi = {10.1186/s40001-025-02937-1},
pmid = {40739673},
issn = {2047-783X},
mesh = {Humans ; *Proprotein Convertase 9/metabolism/genetics ; *PCSK9 Inhibitors/therapeutic use ; *Central Nervous System Diseases/drug therapy/metabolism ; Animals ; },
abstract = {Atherosclerosis-associated disease (ASD) represents a complex pathological condition, characterized by the formation of atherosclerotic plaques within the arterial walls, encompassing cholesterol depositions, which is primarily attributed to elevated levels of low-density lipoprotein-cholesterol (LDL-C). A log-linear association between the absolute magnitude of LDL-C exposure and ASD risk has been widely studied. High levels of LDL-C have been acknowledged as the predominant culprit. The previous research findings have demonstrated that PCSK9 inhibitors (PCSK9i) can remarkably diminish the risk of ASD. The current research has primarily focused on the relevance of PCSK9 to the cardiovascular system and lipid metabolism; however, an increasing body of evidence shows that PCSK9 is pivotal in pathogenic processes in other organ systems. Yet, PCSK9's impact on the brain is complex and not fully clarified, although several recent studies emphasize a putative role of its impact on various neurodegenerative disorders. Among neurological disorders, not only stroke but neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, alcohol use disorder (AUD), amyotrophic lateral sclerosis(ALS), and Alzheimer's Disease (AD) are related to PCSK9. PCSK9 expression in brain is low but greatly upregulated in neurological disorders. Therefore, PCSK9 is a promising pathway for the treatment of central nervous diseases. This review comprehensively describes evidence from the previous research on the effects of PCSK9i on the central nervous system, with a focus on the clinical potential of PCSK9i. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop treatments for the neurological diseases based on PCSK9i.},
}

Humans
*Proprotein Convertase 9/metabolism/genetics
*PCSK9 Inhibitors/therapeutic use
*Central Nervous System Diseases/drug therapy/metabolism
Animals

@article {pmid40737743,
year = {2025},
author = {Liu, J and Liu, K and Cui, X and Ji, Y and Ding, Z and Chang, Z and Zhang, J and Wang, X and Liu, Y},
title = {From gut to brain: donepezil and nimodipine combination therapy improves cognitive deficits in Alzheimer's disease via gut microbiota and metabolites.},
journal = {Biochemical and biophysical research communications},
volume = {778},
number = {},
pages = {152418},
doi = {10.1016/j.bbrc.2025.152418},
pmid = {40737743},
issn = {1090-2104},
abstract = {Donepezil (DNP) is often combined with nimodipine (NMD) for the treatment of Alzheimer's disease (AD). However, its underlying mechanisms remain poorly understood. This study integrated pharmacodynamics, microbiomics, and fecal metabolomics analysis to explore the therapeutic potential and mechanism of DNP + NMD in AD. The results showed that DNP + NMD significantly reduced the contents of serum inflammatory cytokines interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) as well as the contents of nitric oxide synthase (NOS), glycogen synthase kinase-3β (GSK-3β) and acetylcholinesterase (AChE) in the hippocampus, alleviated neuronal damage in hippocampal tissues and effectively improved cognitive deficits of AD rats. Furthermore, DNP + NMD greatly increased the relative abundance of beneficial bacteria (Lactobacillus and Prevotellaceae_Prevotella) and decreased the relative abundance of harmful bacteria (Ruminococcus and Akkermansia). Fecal metabolomic analyses indicated that DNP + NMD regulated 28 fecal differential metabolite levels mainly through six key pathways, including linoleic acid metabolism, arachidonic acid metabolism, unsaturated fatty acid biosynthesis, steroid hormone biosynthesis, saturated fatty acid biosynthesis, primary bile acid biosynthesis, pantothenic acid biosynthesis, and coenzyme A biosynthesis pathway. Moreover, Spearman's correlation analysis revealed significant associations between affected metabolites and specific gut microbes. In general, our research sheds light that DNP + NMD exerts a neuroprotective effect against AD by ameliorating the gut microbiota and fecal metabolic disorders, uncovering novel mechanistic insights and therapeutic targets for AD intervention.},
}

@article {pmid40737409,
year = {2025},
author = {Zou, F and Liu, Y and Luo, Y and Xu, T},
title = {A wearable spatiotemporal controllable ultrasonic device with amyloid-β disaggregation for continuous Alzheimer's disease therapy.},
journal = {Science advances},
volume = {11},
number = {31},
pages = {eadw1732},
pmid = {40737409},
issn = {2375-2548},
mesh = {*Alzheimer Disease/therapy/metabolism/pathology ; Animals ; *Amyloid beta-Peptides/metabolism/chemistry ; Mice ; Disease Models, Animal ; *Wearable Electronic Devices ; Microglia/metabolism ; Humans ; Brain/metabolism/pathology ; Plaque, Amyloid/metabolism ; *Ultrasonic Therapy/instrumentation ; Mice, Transgenic ; *Protein Aggregates ; },
abstract = {The rising prevalence of Alzheimer's disease (AD) due to an aging population has made the search for effective treatments more urgent than ever. Previous studies have demonstrated that continuous ultrasound can depolymerize amyloid proteins, offering potential relief from AD. In this study, we present a portable, fully integrated wearable ultrasound system designed to promote amyloid protein depolymerization. The system comprises a flexible honeycomb ultrasonic array patch, a flexible printed circuit, and an interactive terminal control system to facilitate the treatment process. Our results demonstrate that the system effectively reduces amyloid proteins in the brain, improves cognitive function in a familial Alzheimer's disease (FAD) mouse model, enhances microglial phagocytosis of amyloid-β plaques, and shifts microglia polarization from M1 to M2. These changes contribute to a mitigated inflammatory environment in the brain. This innovative approach may pave the way for noninvasive, personalized treatments for AD, potentially transforming therapeutic strategies in neurodegenerative disorders.},
}

*Alzheimer Disease/therapy/metabolism/pathology
Animals
*Amyloid beta-Peptides/metabolism/chemistry
Mice
Disease Models, Animal
*Wearable Electronic Devices
Microglia/metabolism
Humans
Brain/metabolism/pathology
Plaque, Amyloid/metabolism
*Ultrasonic Therapy/instrumentation
Mice, Transgenic
*Protein Aggregates

@article {pmid40736488,
year = {2025},
author = {Johnston, EM and Lounsbery, JL},
title = {Benzgalantamine (Zunveyl) for the Treatment of Mild to Moderate Alzheimer Disease.},
journal = {American family physician},
volume = {112},
number = {1},
pages = {22-23},
pmid = {40736488},
issn = {1532-0650},
}

@article {pmid40735986,
year = {2025},
author = {Akocak, S and Lolak, N and Ammara, A and Güler, ÖÖ and Supuran, CT},
title = {Exploring the Carbonic Anhydrase Activation Properties of 4-arylazo-3,5- diamino-1H-pyrazoles against hCA I, II, IV, and VII isoenzymes.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266373008250723064558},
pmid = {40735986},
issn = {1873-4294},
abstract = {INTRODUCTION: CAs serve as crucial enzymes involved in a variety of physiological processes, including brain metabolism and cognitive function. hCA VII, a brain-associated isoform, plays an important role in modulating cerebral metabolism. Activating hCA VII may provide therapeutic benefits in Alzheimer's disease and other neurodegenerative or age-related illnesses. This study proposes to add to the growing interest in CAAs by developing innovative drugs with selective activation characteristics that target brain-associated CA isoforms.

METHOD: A series of 4-arylazo-3,5-diamino-1H-pyrazoles have been produced by reacting aniline and aniline derivatives with a malononitrile solution at 0-5 °C, resulting in compounds 1(a-m). Then, arylazo malononitrile compounds were added with hydrazine monohydrate to obtain 4- arylazo-3,5-diamino-1H-pyrazole derivatives 2(a-m). The activity of the synthesized compounds was examined on human CA isoforms I, II, IV, and VII to determine activation potency and selectivity.

RESULTS: The synthesized compounds demonstrated a wide spectrum of strong micromolar activation on human CA isoforms, with particularly encouraging results for hCA VII. The discovered activators showed a high selectivity profile for the brain-associated hCA VII isoform, indicating their potential use in neurological methods of therapy.

DISCUSSION: Among the most compelling findings of this study is the unprecedented potency of several synthesized derivatives, particularly 2i and 2m, in selectively activating hCA VII far beyond the benchmark histamine, positioning them as promising pharmacological candidates for addressing CA-related neurological disorders.

CONCLUSION: The research successfully discovered potent and selective CAAs with specific activity against hCA VII, a key enzyme in brain metabolism. These outcomes offer novel possibilities for developing medicinal products for neurological disorders and provide critical molecules for further study into CAAs. Furthermore, the study advances our understanding of enzyme activation kinetics and gives significant insights into the future of enzyme-based treatment research.},
}

@article {pmid40735980,
year = {2025},
author = {Agarwal, U and Tonk, RK and Verma, S},
title = {Pathogens Association with Alzheimer Disease: Emerging Concepts and New Perspectives.},
journal = {Current gene therapy},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115665232389348250722073721},
pmid = {40735980},
issn = {1875-5631},
abstract = {Alzheimer's Disease (AD) represents a significant global health challenge, distinguished by a complex pathology that involves the accumulation of abnormal proteins in the brain, leading to neuronal loss and brain atrophy. Recent research has indicated a potential association between various pathogens and the development of AD, suggesting that infectious pathogens may play a role in its pathology. The study focuses on the exploration of pathogens linked to AD. It aims to enhance the understanding of the disease's etiopathogenesis, which refers to the causes and development of the condition. The findings from this analysis have the potential to contribute to improved diagnostic methods and treatment strategies for AD. Overall, the manuscript highlights the importance of exploring infectious pathogens relating to neurodegenerative disorders. This comprehensive literature review was conducted using databases such as PubMed and Scopus, focusing on research published up to March 2025. Articles were searched based on keywords related to reviews and research exploring the association/link between different pathogens and AD, emerging interventions, preventive strategies, and limitations in study design. This study indicates that various viruses, bacteria, and fungi are significant contributors to the condition, while parasites and prions play a lesser role. Notably, the variability in pathogen species among patients could provide insights into the evolution and severity of clinical symptoms associated with the disease. Additionally, some studies propose that after modification, certain fungi may actually reduce the amyloid burden in Alzheimer's patients. However, it is crucial to emphasize that there is currently no definitive evidence supporting the notion that treating infections alone can prevent or cure AD. The prevention and treatment of pathogens, including viruses, bacteria, and fungi, as well as infectious prions, may play a significant role in reducing the risk of AD. Effective management of these pathogens can help to control and prevent further damage in individuals who have already been diagnosed with AD. There is a pressing need for additional pre-clinical and clinical research to deepen the understanding of the pathophysiological connections between pathogens and AD.},
}

@article {pmid40735445,
year = {2025},
author = {Khan, W and Khan, MS and Qasem, SN and Ghaban, W and Saeed, F and Hanif, M and Ahmad, J},
title = {An explainable and efficient deep learning framework for EEG-based diagnosis of Alzheimer's disease and frontotemporal dementia.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1590201},
pmid = {40735445},
issn = {2296-858X},
abstract = {The early and accurate diagnosis of Alzheimer's Disease and Frontotemporal Dementia remains a critical challenge, particularly with traditional machine learning models which often fail to provide transparency in their predictions, reducing user confidence and treatment effectiveness. To address these limitations, this paper introduces an explainable and lightweight deep learning framework comprising temporal convolutional networks and long short-term memory networks that efficiently classifies Frontotemporal dementia (FTD), Alzheimer's Disease (AD), and healthy controls using electroencephalogram (EEG) data. Feature engineering has been conducted using modified Relative Band Power (RBP) analysis, leveraging six EEG frequency bands extracted through power spectrum density (PSD) calculations. The model achieves high classification accuracies of 99.7% for binary tasks and 80.34% for multi-class classification. Furthermore, to enhance the transparency and interpretability of the framework, SHAP (SHapley Additive exPlanations) has been utilized as an explainable artificial intelligence technique that provides insights into feature contributions.},
}

@article {pmid40672178,
year = {2025},
author = {Labra, SR and Compher, J and Prabhavalkar, A and Almaraz, M and Kwong, CC and Baal, C and Talantova, M and Dolatabadi, N and Piña-Sanz, J and Wang, Y and Yoon, L and Ghatak, S and Gao, Z and Zhang, Y and Trudler, D and Massey, L and Lin, W and Balistreri, A and Bula, M and Schork, NJ and Mondala, TS and Head, SR and Kelly, JW and Lipton, SA},
title = {Autophagy activators normalize aberrant Tau proteostasis and rescue synapses in human familial Alzheimer's disease iPSC-derived cortical organoids.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {40672178},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is the most common form of dementia worldwide. Despite extensive progress, the cellular and molecular mechanisms of AD remain incompletely understood, partially due to inadequate disease models. To illuminate the earliest changes in hereditary (familial) Alzheimer's disease, we developed an isogenic AD cerebrocortical organoid (CO) model. Our refined methodology produces COs containing excitatory and inhibitory neurons alongside glial cells, utilizing established isogenic wild-type and diseased human induced pluripotent stem cells (hiPSCs) carrying heterozygous familial AD mutations, namely PSEN1[ΔE9/WT], PSEN1[M146V/WT], or APP[swe/WT]. Our CO model reveals time-progressive accumulation of amyloid beta (Aβ) species, loss of monomeric Tau, and accumulation of aggregated high-molecular-weight (HMW) phospho(p)-Tau species. This is accompanied by neuronal hyperexcitability, as observed in early human AD cases on electroencephalography (EEG), and synapse loss. Single-cell RNA-sequencing analyses reveal significant differences in molecular abnormalities in excitatory vs. inhibitory neurons, helping explain AD clinical phenotypes. Finally, we show that chronic dosing with autophagy activators, including a novel CNS-penetrant mTOR inhibitor-independent drug candidate, normalizes pathologic accumulation of Aβ and HMW p-Tau, normalizes hyperexcitability, and rescues synaptic loss in COs. Collectively, our results demonstrate these COs are a useful human AD model suitable for assessing early features of familial AD etiology and for testing drug candidates that ameliorate or prevent molecular AD phenotypes.},
}

@article {pmid40735383,
year = {2025},
author = {Luca, A and Luca, M and Ferri, R and Barbanti, M and Malaguarnera, R and Pecorino, B and Scollo, P and Serretti, A},
title = {Medical Comorbidities in Alzheimer's Disease: An Autopsy Confirmed Study with a Focus on Sex-Differences?.},
journal = {Clinical neuropsychiatry},
volume = {22},
number = {3},
pages = {207-214},
pmid = {40735383},
issn = {2385-0787},
abstract = {OBJECTIVE: Systemic comorbidities are common in Alzheimer's disease (AD) and may influence disease progression, severity, and management. Aim of the study was to assess the prevalence of comorbid medical conditions in a large cohort of AD patients, focusing on sex differences.

METHOD: AD patients from the NIMH Alzheimer Disease Genetics Initiative were enrolled. Data on multimorbidity, demographics, disease characteristics, and clinical assessments were collected from interviews, medical records, and examinations. Univariate and multivariate logistic regression models were performed to identify possible associations between comorbidities and sex. Subgroup analysis was performed for patients with autopsy-confirmed AD.

RESULTS: Four hundred and twenty-four AD patients (295 women; mean age: 78.4±8.3 years) were included. Men had a higher prevalence of heart disease, diabetes, chronic obstructive pulmonary disease and smoking, whereas thyroid disease, hypertension and depression were more common in women (all p<0.05). Except for hypertension, all associations found in the univariate analysis were confirmed in the multivariate analysis after adjustment for age. Subgroup analysis of autopsy-confirmed cases confirmed these findings.

CONCLUSIONS: Our findings support the importance of considering sex-specific comorbidities in AD for precision medicine and emphasize the need for comprehensive assessment of comorbidities to improve clinical outcomes, treatment strategies and health equity.nt.},
}

@article {pmid40734951,
year = {2025},
author = {Yang, JC and Kuo, PJ and Chang, C and Wang, YM and Ou, YC and Cheng, YC and Wu, SC and Chien, PC and Hsieh, CH and Lin, WC},
title = {Linking Lymphedema, Chronic Inflammation, Oxidative Stress, Alzheimer Disease, and Potential Role of Lymphaticovenous Anastomosis.},
journal = {Plastic and reconstructive surgery. Global open},
volume = {13},
number = {7},
pages = {e6955},
pmid = {40734951},
issn = {2169-7574},
abstract = {BACKGROUND: Lymphedema and Alzheimer disease (AD) share common mechanisms involving oxidative stress and chronic inflammation. However, the link between these 2 conditions and the impact of lymphaticovenous anastomosis (LVA) has not been fully explored. This study aimed to evaluate their association by examining changes in AD biomarkers, inflammatory cytokines, and oxidative stress markers before and after LVA.

METHODS: Twenty-four patients with unilateral lower limb lymphedema who underwent LVA as primary treatment and 18 healthy controls were recruited. Exclusion criteria included previous LVA, liposuction, or excisional surgery. Venous blood samples were obtained before and 1 month after LVA.

RESULTS: After matching, 15 patients remained in each group. The lymphedema group had significantly elevated levels of t-tau (p < 0.001), amyloid beta (Aβ)1-40 (P = 0.033), Aβ1-42 (P = 0.033), Aβ1-42 × t-tau (P < 0.001), and Aβ1-42/Aβ1-40 ratio (P = 0.021) compared with controls. One month post-LVA, there were significant reductions in t-tau (P = 0.007) and Aβ1-42 × t-tau (P = 0.002), and a notable increase in brain-derived neurotrophic factor (P = 0.006). Post-LVA samples also showed significant improvements in antioxidative enzymes, antioxidant capacity, and reductions in lipid peroxidation. Inflammatory cytokine levels were also significantly reduced, indicating decreased oxidative stress and inflammation. The median follow-up period was 6.3 months.

CONCLUSIONS: Findings suggest a possible association between lymphedema and increased AD risk possibly linked to elevated oxidative stress and inflammation. LVA may modulate this risk by reducing AD biomarkers and systemic inflammation/oxidative stress, supporting further investigation into its neuroprotective potential.},
}

@article {pmid40734473,
year = {2025},
author = {Prajapat, M and Sarma, P and Kaur, G and Choudhary, G and Jain, S and Kamal, R and Bains, O and Sangwan, N and Prakash, A and Medhi, B},
title = {Therapeutic potential of 6BIO and DKK1-LRP6 inhibitor in Wnt/β-catenin pathway modulation for amyloid-β-induced Alzheimer's disease model.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251362787},
doi = {10.1177/13872877251362787},
pmid = {40734473},
issn = {1875-8908},
abstract = {BackgroundThe Wnt/β-catenin signaling pathway plays a crucial role in central nervous system development, with emerging evidence linking its dysregulation to the progression of Alzheimer's disease (AD).ObjectiveThis study investigates the activation of Wnt signaling by targeting GSK3β and the DKK1/LRP6 interaction using a combination of 6BIO (6Bromoindirubin-3-oxime) and a novel gallocyanine derivative (8e) modulator.MethodsWe identified the interaction energy scores of both modulators with target proteins through an in-silico approach. Furthermore, the effects of 6BIO (10 µM) and 8e (20 µM) were assessed in SH-SY5Y cells treated with Aβ1-42 (20 µM). The efficacy of these modulators was also evaluated in male Wistar rats through dose-ranging studies. An Alzheimer's disease model was established via intracerebroventricular injection of Aβ1-42, followed by treatment with 6BIO (23.8 µg/kg/day, i.p.) and 8e (4.2 mg/kg/day, i.p.).ResultsBoth modulators demonstrated favorable binding energy scores and dynamic simulation results against the targeted proteins. In Aβ1-42-treated SHSY5Y cells, the combination of 6BIO and 8e significantly reduced reactive oxygen species production and apoptotic activity while modulating protein expression. In vivo study, rats treated with combination of 6BIO and 8e modulators exhibited improved neurobehavioral activity compared to AD model rats, along with altered expression of DKK1, β-catenin, p-tau, and pGSK3β. Additionally, decreased oxidative stress and apoptosis markers.ConclusionsThese findings suggest that the combined targeting of GSK3β and LRP6 represents a promising therapeutic strategy for AD. The combination of 6BIO and 8e shows potential as a novel modulator and warrants further investigation in clinical trials to assess its therapeutic efficacy.},
}

@article {pmid40734451,
year = {2025},
author = {Wang, H and Yang, Q and Ge, C and Liu, J and Mistry, H and Jia, YF and He, G},
title = {Integrated transcriptomic and proteomic analysis identifies FBXW7 as a key regulator of tau homeostasis in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251361042},
doi = {10.1177/13872877251361042},
pmid = {40734451},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder driven by complex, incompletely understood genetic and pathogenic factors. E3 ubiquitin ligases (E3s), crucial for protein degradation, are implicated in AD, but their specific contributions to its progression remain to be elucidated.ObjectiveThis study aimed to identify dysregulated E3s in AD and elucidate the role of a hub E3, FBXW7, in its pathogenesis and tau protein regulation.MethodsWe integrated four datasets to identify differentially expressed E3s (DE-E3s) in AD and performed functional enrichment and PPI network analyses. Machine learning identified hub E3s and stratified AD patients into molecular subtypes. Furthermore, we validated the expression and functional role of FBXW7 using western blot, immunoprecipitation-mass spectrometry (IP-MS), and co-immunoprecipitation (Co-IP).ResultsWe identified 42 DE-E3s primarily enriched in protein ubiquitination and Notch signaling pathways. FBXW7 and ENC1 emerged as hub E3s, stratifying patients into two subtypes. Subtype I exhibited enrichment of inflammatory pathways, suggesting immune dysregulation. Conversely, subtype II displayed activation of pathways associated with synaptic dysfunction and neuronal loss, potentially representing distinct primary pathological features. Furthermore, we observed decreased FBXW7 expression in AD models compared to controls. Notably, FBXW7 interacted with Tau protein. Overexpression of FBXW7 reduced the levels of both total Tau and p-Tau Ser262, and this reduction in Tau levels was reversed by MG132 treatment.ConclusionsThis study comprehensively identified E3s associated with AD, with our findings highlighting FBXW7 as a potential key regulator of AD pathogenesis through its modulation of tau protein levels.},
}

@article {pmid40734422,
year = {2025},
author = {Miles, LA and Masters, CL},
title = {The structural foundations of anti-amyloid-β immunotherapies: Unravelling antibody-antigen interactions in Alzheimer's disease treatment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251361049},
doi = {10.1177/13872877251361049},
pmid = {40734422},
issn = {1875-8908},
abstract = {BackgroundAnti-amyloid-β (Aβ) immunotherapies are emerging as treatments for Alzheimer's disease (AD).ObjectiveThis review examines the structure-activity relationships of anti-Aβ therapeutics tested in phase 3 trials.MethodsWe analyzed crystallographic data and molecular models to elucidate the Aβ binding mechanisms of donanemab, lecanemab, aducanumab, bapineuzumab, gantenerumab, solanezumab, and crenezumab.ResultsLecanemab recognizes minimally degraded Aβ missing 1-2 residues, avoiding common Aβ in circulation and further degraded material sequestered in plaques. Bapineuzumab buries the N-terminus of Aβ requiring Asp1 and is reactive with benign, common Aβ. Donanemab buries the truncated N-Glu3 terminus with strong contacts engaging the cyclized pyro-Glu3 modification. Gantenerumab shows lecanemab-like properties but also binds common Aβ. Aducanumab likely needs mAb-mAb cooperation to scavenge a spectrum of Aβ oligomers explaining higher doses. Solanezumab and crenezumab target a pre-amyloid epitope resulting in off-target engagement, including monomers and likely excluding Aβ-ApoE complexes.ConclusionsPreventing primary Aβ nucleation failed due to limitations imposed by the blood-brain barrier, intracellular aggregation routes, and the natural abundance of Aβ. Anti-Aβ monoclonal antibody therapies in clinical use capture Aβ at various stages of decay where post translational modifications have been used effectively as proxies for time spent in vivo. By targeting a relatively labile epitope of aging Aβ, lecanemab selects more biologically active species of Aβ avoiding both benign monomers and old fortified species. This focal point may account for the significant cognitive effects of lecanemab. The structure of aducanumab suggests a broadly neutralizing role has evolved for natural immunity to AD.},
}

@article {pmid40734174,
year = {2025},
author = {Zare, A and Salehi, S and Bader, JM and Wiessler, AL and Prokesch, M and Albrecht, V and Villmann, C and Mann, M and Briese, M and Sendtner, M},
title = {Axonal tau reduction ameliorates tau and amyloid pathology in a mouse model of Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {39},
doi = {10.1186/s40035-025-00499-0},
pmid = {40734174},
issn = {2047-9158},
support = {BR4910/2-2//Deutsche Forschungsgemeinschaft/ ; SE697/5-2//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Animals ; *tau Proteins/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology/genetics ; Disease Models, Animal ; *Axons/metabolism/pathology ; Mice ; Mice, Knockout ; Humans ; *Plaque, Amyloid/pathology/metabolism ; Brain/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Cells, Cultured ; Neurons/metabolism ; Mice, Transgenic ; },
abstract = {BACKGROUND: Pathological deposition of hyperphosphorylated tau in the brain closely correlates with the course of Alzheimer's disease (AD). Tau pathology occurs in axons of affected neurons and tau removal from axons might thus be an early intervention strategy.

METHODS: We investigated the role of the RNA-binding protein hnRNP R in axonal localization and local translation of Mapt mRNA in neurons cultured from hnRNP R knockout mice. hnRNP R knockout mice were crossed with 5×FAD mice, an AD mouse model, and the effects of hnRNP R loss on the deposition of phospho-tau and amyloid-β plaques were evaluated. We designed antisense oligonucleotides (MAPT-ASOs) to block the binding of hnRNP R to Mapt mRNA. Cultured mouse and human neurons were treated with MAPT-ASOs and axonal Mapt mRNA and tau protein levels were quantified. MAPT-ASO was injected intracerebroventricularly into 5×FAD mice followed by quantification of phospho-tau aggregates and amyloid-β plaques in their brains. Protein changes in brains of 5×FAD mice treated with the MAPT-ASO were measured by mass spectrometry.

RESULTS: Mapt mRNA and tau protein were reduced in axons but not cell bodies of primary neurons cultured from hnRNP R knockout mice. Brains of 5×FAD mice deficient for hnRNP R contained less phospho-tau aggregates and amyloid-β plaques in the cortex and hippocampus. Treatment of neurons with MAPT-ASOs to block hnRNP R binding to Mapt similarly reduced axonal tau levels. Intracerebroventricular injection of a MAPT-ASO reduced the phospho-tau and plaque load and prevented neurodegeneration in the brains of 5×FAD mice, accompanied by rescue of proteome alterations.

CONCLUSION: Lowering of tau selectively in axons thus represents an innovative therapeutic perspective for treatment of AD and other tauopathies.},
}

Animals
*tau Proteins/metabolism/genetics
*Alzheimer Disease/metabolism/pathology/genetics
Disease Models, Animal
*Axons/metabolism/pathology
Mice
Mice, Knockout
Humans
*Plaque, Amyloid/pathology/metabolism
Brain/metabolism/pathology
Amyloid beta-Peptides/metabolism
Cells, Cultured
Neurons/metabolism
Mice, Transgenic

@article {pmid40733241,
year = {2025},
author = {Asim, A and Jastrzębski, MK and Kaczor, AA},
title = {Dual Inhibitors of Acetylcholinesterase and Monoamine Oxidase-B for the Treatment of Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {14},
pages = {},
pmid = {40733241},
issn = {1420-3049},
support = {2021/43/B/NZ7/01732//National Science Center/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism/enzymology ; *Monoamine Oxidase Inhibitors/chemistry/therapeutic use/pharmacology ; Humans ; *Cholinesterase Inhibitors/chemistry/therapeutic use/pharmacology ; *Monoamine Oxidase/metabolism/chemistry ; *Acetylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; Animals ; Molecular Structure ; },
abstract = {Alzheimer's disease (AD) is a multi-factorial neurodegenerative disease with a complex pathomechanism that can be best treated with multi-target medications. Among the possible molecular targets involved in AD, acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) are well recognized because they control the neurotransmitters responsible for memory processes. This review discusses the current understanding of AD pathology, recent advances in AD treatment, and recent reports in the field of dual AChE/MAO-B inhibitors for treating AD. We provide a classification of dual inhibitors based on their chemical structure and describe active compounds belonging to, i.a., chalcones, coumarins, chromones, imines, and hydrazones. Special emphasis is given to the computer-aided strategies of dual inhibitors design, their structure-activity relationships, and their interactions with the molecular targets at the molecular level.},
}

*Alzheimer Disease/drug therapy/metabolism/enzymology
*Monoamine Oxidase Inhibitors/chemistry/therapeutic use/pharmacology
Humans
*Cholinesterase Inhibitors/chemistry/therapeutic use/pharmacology
*Monoamine Oxidase/metabolism/chemistry
*Acetylcholinesterase/metabolism/chemistry
Structure-Activity Relationship
Animals
Molecular Structure

@article {pmid40732328,
year = {2025},
author = {Alghamdi, MA},
title = {From Molecules to Medicines: The Role of AI-Driven Drug Discovery Against Alzheimer's Disease and Other Neurological Disorders.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/ph18071041},
pmid = {40732328},
issn = {1424-8247},
support = {IMSIU-DDRSP2501//Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University/ ; },
abstract = {The discovery of effective therapeutics against Alzheimer's disease (AD) and other neurological disorders remains a significant challenge. Artificial intelligence (AI) tools are of considerable interest in modern drug discovery processes and, by exploiting machine learning (ML) algorithms and deep learning (DL) tools, as well as data analytics, can expedite the identification of new drug targets and potential lead molecules. The current study was aimed at assessing the role of AI-based tools in the discovery of new drug targets against AD and other related neurodegenerative diseases and their efficacy in the discovery of new drugs against these diseases. AD represents a multifactorial neurological disease with limited therapeutics available for management and limited efficacy. The discovery of more effective medications is limited by the complicated pathophysiology of the disease, involving amyloid beta (Aβ), neurofibrillary tangles (NFTs), oxidative stress, and inflammation-induced damage in the brain. The integration of AI tools into the traditional drug discovery process against AD can help to find more effective, safe, highly potent compounds, identify new targets of the disease, and help in the optimization of lead molecules. A detailed literature review was performed to gather evidence regarding the most recent AI tools for drug discovery against AD, Parkinson's disease (PD), multiple sclerosis (MLS), and epilepsy, focusing on biological markers, early diagnoses, and drug discovery using various databases like PubMed, Web of Science, Google Scholar, Scopus, and ScienceDirect to collect relevant literature. We evaluated the role of AI in analyzing multifaceted biological data and the properties of potential drug candidates and in streamlining the design of clinical trials. By exploring the intersection of AI and neuroscience, this review focused on providing insights into the future of AD treatment and the potential of AI to revolutionize the field of drug discovery. Our findings conclude that AI-based tools are not only cost-effective, but the success rate is extremely high compared to traditional drug discovery methods in identifying new therapeutic targets and in the screening of the majority of molecules for clinical trial purposes.},
}

@article {pmid40732267,
year = {2025},
author = {Liu, C and Wang, X and Xu, W and Yu, S and Zhang, Y and Xu, Q and Tan, X},
title = {Study on the Pharmacological Efficacy and Mechanism of Dual-Target Liposome Complex AD808 Against Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/ph18070977},
pmid = {40732267},
issn = {1424-8247},
support = {32471351//National Science Foundation of China/ ; },
abstract = {Background/Objectives: To study the efficacy and pharmacological mechanism of the dual-target liposome complex AD808 in the treatment of Alzheimer's disease. Methods: Using APP/PS1 mouse models, the therapeutic efficacy and pharmacological mechanism of AD808 on Alzheimer's disease were studied through water maze tests, brain tissue staining, immunofluorescence, and ELISA for inflammatory and neurotrophic factors. Results: AD808 exhibited significant pharmacodynamic effects in improving behavioral and cognitive abilities (70% reduction in escape latency) and repairing damaged nerve cells (90% reduction in Aβ plaque) in Alzheimer's disease mice. The efficacy of the liposome complex AD808 was significantly better than that of ST707 or gh625-Zn7MT3 alone. AD808 significantly reduced brain inflammation (57.3% and 61.5% reductions in TNF-α and IL-1β, respectively) in AD (Alzheimer's disease) mouse models and promoted the upregulation of neurotrophic factors and nerve growth factors (142.8% increase in BDNF, 275.9% in GDNF, and 111.3% in NGF-1) in brain homogenates. By activating the PI3K/AKT signaling pathway in brain microglia, AD808 upregulated TREM2 protein expression and removed Aβ amyloid plaques in the brain. Additionally, it promoted the transition of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, regulated the M1/M2 balance, released anti-inflammatory and neurotrophic factors, reduced chronic inflammation, and enhanced neurological repair. Based on these results, the potential pharmacological mechanism of AD808 against Alzheimer's disease was proposed. Conclusions: As a dual-target liposome complex, AD808 has shown promising therapeutic potential in the treatment of Alzheimer's disease, providing a new strategy for innovative drug development.},
}

@article {pmid40732244,
year = {2025},
author = {Wiśniewski, K and Zglejc-Waszak, K and Antonowski, T and Szablinska-Piernik, J and Juskiewicz, J and Lahuta, L and Jozwik, M and Wojtkiewicz, J},
title = {Analysis of Scyllo-Inositol in a Wistar Rat Animal Model-A Preliminary Study.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/ph18070954},
pmid = {40732244},
issn = {1424-8247},
support = {RID/SP/0025/2024/01//the Minister of Science under "the Regional Initiative of Excellence Program/ ; },
abstract = {Background: Scyllo-inositol (SCI) is a naturally occurring carbocyclic sugar implicated in many biological processes. Studies have highlighted the potential of using SCI in Alzheimer's therapy. However, in order to fully use this compound in the treatment of neurovegetative diseases, its pharmacokinetics must be thoroughly understood. Objectives: We undertook the task of analyzing SCI in a Wistar rat animal model. The aim of this study was to observe the changes in SCI concentration after oral administration. Methods: All rats received 10 mg/kg of SCI as a solution in distilled water by oral gavage. Estimated parameters were based on the serum concentration of SCI observed in six individual rats with regard to time. Results: The first peak concentration appeared at 30 min for SCI. Thereafter, the serum SCI concentration increased rapidly and reached its highest level after approximately 1.5 h. There was no second peak in SCI concentration. The elimination half-life was determined to be 10.07 h and the mean residence time was 14.52 h. There were no side effects of SCI supplementation noticed during the study. Conclusions: Although our results present an analysis of SCI immediately after oral administration up to 48 h, further studies are necessary.},
}

@article {pmid40731203,
year = {2025},
author = {Gao, H and Jensen, K and Nesbitt, J and Ostroot, M and Cary, GA and Wiley, J and Trushin, S and Watzlawik, JO and Springer, W and Galkin, A and Baloni, P and Funk, C and Trushina, E},
title = {Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70519},
doi = {10.1002/alz.70519},
pmid = {40731203},
issn = {1552-5279},
support = {RF1AG55549/NH/NIH HHS/United States ; RO1AG062135/NH/NIH HHS/United States ; RO1AG59093/NH/NIH HHS/United States ; R01NS112381/NH/NIH HHS/United States ; R01NS131322/NH/NIH HHS/United States ; RF1NS085070/NH/NIH HHS/United States ; R01NS110085/NH/NIH HHS/United States ; U54NS110435/NH/NIH HHS/United States ; R56AG062556/NH/NIH HHS/United States ; Emory-Sage-SGC-JAX U54AG065187//National Institute of Health Target Enablement to Accelerate Therapy Development for Alzheimer's Disease Consortia/ ; W81XWH-17-1-0248//Department of Defense Congressionally Directed Medical Research Programs/ ; //Ted Nash Long Life Foundation/ ; //Michael J. Fox Foundation for Parkinson's Research/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/drug therapy ; *Electron Transport Complex I/deficiency/genetics ; Mice ; Disease Models, Animal ; Female ; Humans ; Male ; Mice, Knockout ; *Mitochondrial Diseases/genetics/metabolism/complications ; Mitochondria/metabolism ; Brain/metabolism ; Transcriptome ; },
abstract = {INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4[-/-] mice, a model of mitochondrial complex I (mtCI) deficiency, and evaluated the therapeutic effects of the neuroprotective mtCI inhibitor CP2.

METHODS: Cortico-hippocampal tissue from Ndufs4[-/-] and wild-type mice was subjected to transcriptomic analysis, followed by cross-species comparisons to human late-onset AD and familial AD mouse datasets.

RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4[-/-] mice showing greater compensatory adaptations and treatment responses.

DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest important considerations for personalized therapeutics.

HIGHLIGHTS: Activity of mitochondrial complex I (mtCI) affects broad mitochondrial and neuronal transcriptional networks. A reduction of mtCI activity is sufficient to induce transcriptomic changes reminiscent of those observed in late-onset Alsheimer's disease (AD) patients and familial mouse models of AD. Pharmacological targeting of mtCI mediates neuroprotective signaling. Male and female mice have differential responses to the loss of mtCI activity and to the mitochondria-targeted therapeutics. Mitochondria play a key role in AD development and treatment.},
}

Animals
*Alzheimer Disease/metabolism/genetics/drug therapy
*Electron Transport Complex I/deficiency/genetics
Mice
Disease Models, Animal
Female
Humans
Male
Mice, Knockout
*Mitochondrial Diseases/genetics/metabolism/complications
Mitochondria/metabolism
Brain/metabolism
Transcriptome

@article {pmid40731005,
year = {2025},
author = {Ghaderi Yazdi, B and Razlighi, QR},
title = {Translation of task-evoked negative BOLD response into aging and Alzheimer's disease: a systematic review of the current literature.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {850},
doi = {10.1186/s12967-025-06721-x},
pmid = {40731005},
issn = {1479-5876},
support = {R01AG085972/AG/NIA NIH HHS/United States ; R01AG057962/AG/NIA NIH HHS/United States ; K01AG044467/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging/blood ; *Magnetic Resonance Imaging ; *Aging/physiology ; *Oxygen/blood ; Cognitive Dysfunction/physiopathology ; },
abstract = {BACKGROUND: Aging, mild cognitive impairment (MCI), Alzheimer's disease (AD), and individuals at risk for AD are associated with impaired negative blood-oxygen-level-dependent (BOLD) response (NBR) in task-evoked functional magnetic resonance imaging (fMRI) studies. In addition, autosomal dominant AD patients have exhibited NBR alterations in the default mode network (DMN) regions nearly a decade before any accumulation of amyloid-β (Aβ) or tau and subsequent memory decline. Studies examining exclusively the NBR are rare in clinical settings, but some existing studies using task-evoked fMRI also report alterations in the NBR. However, in many studies, NBR is often disregarded, left lingering in the shadows, or, more generally, masked out as a bothersome noise.

METHODS: We reviewed the Embase, Scopus, and PubMed databases, and forward and backward citation tracking for studies published up to 6/11/2024. Included articles detailed the use of task-evoked fMRI (tb-fMRI) to investigate aging, AD, mild cognitive impairment (MCI), and early tau or Aβ deposition, with all results reported on NBR.

FINDINGS: From 319 records identified for aging, 154 records for tau or Aβ, and 159 records for AD and MCI, 42, 14, and 9 papers were included, respectively. Forward and backward citation tracking added 44, 3, and 55 papers, respectively resulting in 167 studies with 11310 individuals. A significantly reduced magnitude of NBR in some regions of the DMN in healthy aging compared with young participants and individuals with elevated Aβ levels, MCI, and AD compared to healthy aging was found in 57, 12, 17, and 14 studies, respectively.

INTERPRETATION: This review highlights the DMN NBR's importance in the AD continuum and underscores its potential as an early diagnostic biomarker when pharmacological treatment options can still alter the disease course.},
}

Humans
*Alzheimer Disease/physiopathology/diagnostic imaging/blood
*Magnetic Resonance Imaging
*Aging/physiology
*Oxygen/blood
Cognitive Dysfunction/physiopathology

@article {pmid40730714,
year = {2025},
author = {Xia, X and Aye, S and Frisell, O and Aho, E and Handels, R and Li, Y and Wimo, A and Winblad, B and Eriksdotter, M and Skillbäck, TB and Kern, S and Zetterberg, H and Jönsson, L},
title = {The Cost-Effective Price of Lecanemab for Patients with Early Alzheimer's Disease in Sweden.},
journal = {PharmacoEconomics},
volume = {},
number = {},
pages = {},
doi = {10.1007/s40273-025-01527-7},
pmid = {40730714},
issn = {1179-2027},
support = {101112145//The Innovative Health Initiative Joint Undertaking/ ; 2021-02680//VINNOVA/ ; 2024-03573//Vetenskapsrådet/ ; 2023-00356//Vetenskapsrådet/ ; 2022-01018//Vetenskapsrådet/ ; 2019-02397//Vetenskapsrådet/ ; 2019-02075//Vetenskapsrådet/ ; 2019-02075_15//Vetenskapsrådet/ ; FO2024-0287//Swedish Brain Foundation/ ; FO2024-0097//Swedish Brain Foundation/ ; FO2024-0339//Swedish Brain Foundation/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; ALFGBG-81392//Swedish State Support for Clinical Research/ ; ALFGBG-771071//Swedish State Support for Clinical Research/ ; ALFGBG-1005471//Swedish State Support for Clinical Research/ ; ALFGBG-965923//Swedish State Support for Clinical Research/ ; AF-842471//Alzheimerfonden/ ; AF-737641//Alzheimerfonden/ ; AF-929959//Alzheimerfonden/ ; AF-939825//Alzheimerfonden/ ; 2024-03599//Swedish Research Council/ ; },
abstract = {INTRODUCTION: We sought to estimate the cost-effective price for lecanemab for treating early Alzheimer's disease in Sweden from the perspective of formal care payers.

METHODS: We developed a Markov model with states defined by disease severity and care setting. The model was populated by integrated clinical and economic data from Swedish registers. We included patients with biomarker-confirmed Alzheimer's disease and fitted survival models for transitions between model states. Costs in 2023 Swedish kronor (SEK), life-years (LYs), and quality-adjusted LYs (QALYs) over a 10-year time horizon were estimated for standard of care and for lecanemab in addition to standard of care, assuming a maximum treatment duration of 3 years with lecanemab and no treatment effect after treatment stops. We also explored the impact of different assumptions regarding treatment efficacy and duration.

RESULTS: Treatment with lecanemab over 3 years resulted in 0.13 LYs gained, 0.17 QALYs gained, and a net cost increase of 87,146 SEK (€1 = 11.5 SEK, $US1 = 10.6 SEK) due to administration and monitoring, before considering the cost of drug. The cost-effective price of lecanemab at a willingness-to-pay level of 1 million SEK per QALY was 33,886 SEK per year of treatment. The health gain, net costs, and cost-effective price of lecanemab varied significantly by treatment duration, potential residual effects, and patient characteristics.

CONCLUSIONS: The future price of lecanemab in European countries is unknown. However, treatment with lecanemab is unlikely to be cost effective in Sweden at the levels of current list prices in the USA.},
}

@article {pmid40730660,
year = {2025},
author = {Kumar, S and Song, K and Wang, J and Baghel, MS and Zeng, Y and Shen, K and Zheng, J and Crane, J and Demehri, S and Gao, P and Jain, A and Skolasky, RL and Wong, P and Cao, X and Wan, M},
title = {Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {40730660},
issn = {2662-8465},
support = {R01AG068226//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG072090//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P01AG066603//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on organ aging. Here, we demonstrate that both transgenic Alzheimer's disease (AD) mice and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits. Senescent BMAds acquire a secretory phenotype, markedly increasing secretion of serum amyloid P component (SAP), also known as pentraxin 2 (PTX2). SAP/PTX2 colocalizes with amyloid deposits around senescent BMAds in vivo and promotes insoluble amyloid formation from soluble amyloid-β (Aβ) peptides in in vitro and ex vivo three-dimensional (3D) BMAd-based cultures. Combined SAP/PTX2 and Aβ treatment promotes osteoclastogenesis but inhibits osteoblastogenesis. Transplanting senescent BMAds into the bone marrow cavity of young mice induces bone loss, which is reversed by senolytic treatment. Finally, depleting SAP/PTX2 in aged mice abolishes marrow amyloid deposition and rescues low bone mass. Thus, senescent BMAds drive age-related skeletal amyloidosis and bone deficits via SAP/PTX2.},
}

@article {pmid40730291,
year = {2025},
author = {Magdalena, R and Ferrada, L and Ramírez, E and Smith-Ghiglioto, JF and Salazar, K and Nualart, F},
title = {DEHYDROASCORBIC ACID IMPAIRS NEURITE GROWTH THROUGH RIPK1-ASSOCIATED CASPASE ACTIVATION.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.07.036},
pmid = {40730291},
issn = {1873-4596},
abstract = {Axonal and neurite loss is a common event in neurodegenerative diseases, such as Alzheimer's disease or amyotrophic lateral sclerosis, which are enhanced by oxidative damage and reactive oxygen species (ROS) production. In the central nervous system, vitamin C can be found as ascorbic acid (AA), its reduced form, or dehydroascorbic acid (DHA), its oxidized form. Vitamin C mainly acts as an antioxidant agent, and homeostasis in the brain is maintained through its recycling between neurons and astrocytes. However, DHA accumulation under pathophysiological conditions has been associated with changes in neuronal metabolism and necroptotic cell death through RIPK1 activation. Furthermore, recent studies show that DHA accumulation induces significant neurite loss; however, it is unknown whether this effect is associated with RIPK1 activation. Here, we show that DHA treatment on neurospheres (NE) in vitro induces significant neurite shortening and reduced branching, effects associated with early RIPK1 activation and inhibited through Necrostatin-1s and zVAD-FMK treatment, suggesting the activation of apoptotic mechanisms. Finally, we propose DHA, the oxidized form of vitamin C, impairs neurite growth through ripk1-associated caspase activation.},
}

@article {pmid40729740,
year = {2025},
author = {Hu, L and Li, J and Guo, H and Su, L and Dong, P and Huang, J and Liu, Y and Liu, X and Luo, Z and Xiong, W and Ju, Z and Zhou, Q and Wang, H and Wang, W},
title = {SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e03408},
doi = {10.1002/advs.202503408},
pmid = {40729740},
issn = {2198-3844},
support = {2021YFA08049000//National Key Research and Development Program of China/ ; 32430049//National Natural Science Foundation of China/ ; 82370576//National Natural Science Foundation of China/ ; 82370596//National Natural Science Foundation of China/ ; 32170772//National Natural Science Foundation of China/ ; 32270810//National Natural Science Foundation of China/ ; 92049304//National Natural Science Foundation of China/ ; 82030039//National Natural Science Foundation of China/ ; 82071340//National Natural Science Foundation of China/ ; 82401526//National Natural Science Foundation of China/ ; 2022A1515140040//Guangdong Basic and Applied Basic Research Foundation/ ; 2023B1515120089//Guangdong Basic and Applied Basic Research Foundation/ ; 2021A1515011227//Guangdong Basic and Applied Basic Research Foundation/ ; 2022A0505050041//Guangdong Basic and Applied Basic Research Foundation/ ; },
abstract = {SUMOylation, a reversible post-translational modification, regulates various mitochondrial processes, including biogenesis, dynamics, mitophagy, and the mitochondrial unfolded protein response. Although SUMOylation is shown to be triggered by mitochondrial protein import failure in yeast, its impact on mammalian mitochondrial protein import remains unclear. Here, it is demonstrated that SENP6 knockdown-induced SUMOylation causes loss of mitochondrial proteostasis, which impairs mitochondrial morphology and function. Mechanistically, SENP6 knockdown dampens TOM complex assembly by SUMOylating TOM40, thereby hindering the mitochondrial protein import process, including TOM40 precursor, and ultimately disrupts mitochondrial homeostasis. Additionally, it is observed that CCCP treatment resulted in a decrease of SENP6 within mitochondria fraction, accompanied by increased TOM40 SUMOylation in the brains of 3×Tg-Alzheimer's disease (AD) mice or Aβ1-42 peptide-stimulated cells. Collectively, the results suggest that Aβ1-42 accumulation may enhance TOM40 SUMOylation by suppressing SENP6, thereby impairing mitochondrial homeostasis through protein import failure and potentially contributing to the pathological process of AD. This study elucidates the role of TOM40 SUMOylation/deSUMOylation in regulating the mitochondrial import process during mitochondrial stress.},
}

@article {pmid40728824,
year = {2025},
author = {Helal, MM and Almosilhy, NA and Hamam, NG and Abdelbaset, MAA and Shelbaya, AN and Musse, HAY and Prasad, A},
title = {Sacubitril/Valsartan Reduces the Risk of All-Cause Dementia in Patients with Heart Failure: A Systematic Review and Meta-Analysis.},
journal = {Drugs & aging},
volume = {},
number = {},
pages = {},
doi = {10.1007/s40266-025-01233-1},
pmid = {40728824},
issn = {1179-1969},
abstract = {BACKGROUND: Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), has become a cornerstone therapy for heart failure (HF) since its approval over a decade ago. However, concerns have emerged about potential cognitive risks, as neprilysin inhibition may contribute to the accumulation of amyloid-beta (Aβ) in the brain-a hallmark of Alzheimer's disease, the most common form of dementia.

OBJECTIVE: Given the already elevated risk of dementia in patients with HF and the widespread use of sacubitril/valsartan, this meta-analysis aimed to evaluate whether its use is associated with an increased risk of all-cause dementia in HF populations.

METHODS: A systematic literature search was conducted on 23 March 2025, to identify eligible studies comparing the risk of dementia in patients receiving sacubitril/valsartan versus those receiving placebo, no treatment, or other HF medications. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model.

RESULTS: Six studies, comprising 101,074 participants and published between 2017 and 2024, were included in the meta-analysis. Treatment with sacubitril/valsartan was associated with a significant 15% reduction in the risk of all-cause dementia (RR = 0.85; 95% CI: 0.74-0.98; p = 0.02). Leave-one-out sensitivity and subgroup analyses confirmed the robustness of the findings.

CONCLUSIONS: This meta-analysis suggests that sacubitril/valsartan is associated with a reduced risk of dementia in patients with HF, helping to alleviate previous concerns about potential cognitive adverse effects. These findings support the continued use of sacubitril/valsartan as a foundational therapy in this high-risk population.},
}

@article {pmid40728549,
year = {2025},
author = {Al Saihati, HA and Alazabi, NI and Bakeer, RM and Abol-Fetouh, GM and Ahmed-Farid, OA and Alshedi, AF and Alsabeelah, NF},
title = {Optimizing predictive biomarkers for alzheimer's disease: muscarinic M1 antagonist-induced synaptic signaling disruptions and bee venom intervention through cholinergic modulation and multiregression dose selection.},
journal = {Metabolic brain disease},
volume = {40},
number = {6},
pages = {244},
pmid = {40728549},
issn = {1573-7365},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/chemically induced ; Rats ; *Bee Venoms/pharmacology/therapeutic use ; Biomarkers/metabolism ; Male ; Oxidative Stress/drug effects ; Rats, Wistar ; *Receptor, Muscarinic M1/antagonists & inhibitors/metabolism ; Scopolamine ; Dose-Response Relationship, Drug ; *Muscarinic Antagonists/pharmacology ; Neuroprotective Agents/pharmacology ; Memantine/pharmacology ; Disease Models, Animal ; Brain/metabolism/drug effects ; Maze Learning/drug effects ; },
abstract = {Alzheimer's (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neurochemical imbalances. The present study aims to ensure the correct dosage of scopolamine (SC) for inducing AD using Quality by Design to optimize the predictive biomarker acetylcholine esterase. Further, neuroprotective effects will be assessed with variable doses of bee venom (BV) by analyzing its effect on cognitive function, neurochemical markers, and oxidative stress. The goal of this study is to improve models of AD and learn more about how BV can protect neurons in a dose-dependent way during treatment. Methods: The rats were randomly divided into six groups (n = 6): Control, SC -induced AD, SC + Memantine (1 mg/kg bwt p.o.), and three BV doses (5, 10, 15 µl/kg, i.p, every other day) to study dose-dependent effects combined with SC. Memantine and BV were given to the animals two months before they developed AD, which happened on its own 14 days after treatment. After four days of behavioral assessment using the Morris Water Maze to evaluate cognitive function, the animals were humanely sacrificed. Blood and brain samples were collected for the measurement of serum liver and kidney function markers, oxidative and nitrosative stress parameters, cellular energy metabolites, amino acid profiles, neurotransmitters, and inflammatory markers in brain tissue. Results and Conclusion: The most remarkable neuroprotective effect was found in the group treated with BV medium and high dose showed a plateau, beyond which no more improvement was shown. These findings point toward a promising therapeutic approach for BV in the cognitive decline of AD.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/chemically induced
Rats
*Bee Venoms/pharmacology/therapeutic use
Biomarkers/metabolism
Male
Oxidative Stress/drug effects
Rats, Wistar
*Receptor, Muscarinic M1/antagonists & inhibitors/metabolism
Scopolamine
Dose-Response Relationship, Drug
*Muscarinic Antagonists/pharmacology
Neuroprotective Agents/pharmacology
Memantine/pharmacology
Disease Models, Animal
Brain/metabolism/drug effects
Maze Learning/drug effects

@article {pmid40727792,
year = {2025},
author = {Wang, N and Liu, W and Zhou, L and Liu, W and Liang, X and Liu, X and Xu, Z and Zhong, T and Wu, Q and Jiao, X and Chen, J and Ning, X and Jiang, X and Zhao, Q},
title = {Retraction of "Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3β for the Treatment of Alzheimer's Disease".},
journal = {ACS omega},
volume = {10},
number = {28},
pages = {31208},
doi = {10.1021/acsomega.5c06137},
pmid = {40727792},
issn = {2470-1343},
abstract = {[This retracts the article DOI: 10.1021/acsomega.2c03368.].},
}

@article {pmid40727583,
year = {2025},
author = {Matuszewska, M and Wilkaniec, A and Gąssowska-Dobrowolska, M and Cieślik, M and Olech-Kochańczyk, G and Pałasz, E and Gawinek, E and Strawski, M and Czapski, GA},
title = {Inhibition of BET proteins modulates amyloid-beta accumulation and cognitive performance in middle-aged mice prenatally exposed to maternal immune activation.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1619583},
pmid = {40727583},
issn = {1662-5099},
abstract = {INTRODUCTION: Given the complex etiological basis of Alzheimer's disease (AD), it is reasonable to hypothesize that neuronal dysfunction and death result from the interplay of numerous factors, both genetic and environmental. Accumulating evidence implicates the immune system and inflammation as key components of the pathomechanism of AD. In the present study, we analyzed the effect of maternal immune activation (MIA) on AD-related pathological changes in middle-aged 12-month-old offspring mice. Additionally, we investigated whether the inhibition of bromodomain and extraterminal domain (BET) proteins, which are readers of the histone acetylation code, could influence these changes.

METHODS: In our study, we administered a viral mimetic, polyinosinic-polycytidylic acid (PIC), on gestation day 17 to induce MIA in wild-type C57BL/6J mice. The BET protein inhibitor, OTX-015 (Birabresib), was administered orally to 12-month-old male offspring for 14 days. Subsequently, behavioral, genetic, and immunochemical analyses were conducted.

RESULTS: Our results demonstrated several MIA-evoked molecular alterations in the brains of middle-aged offspring. We observed an increase in App gene expression (qPCR) and amyloid-β (Aβ) levels (ELISA), while the levels and phosphorylation of Tau protein remained unchanged (WB). The mRNA levels of selected microglial markers were also elevated in the MIA group. Treatment with OTX-015 improved memory, as observed in the novel object recognition test, and reduced Aβ levels, but did not alter the expression of inflammatory genes or amyloidogenesis-related genes.

DISCUSSION: Our findings suggest that inhibition of BET proteins may effectively attenuate neuropathological alterations in the aged brain.},
}

@article {pmid40727259,
year = {2025},
author = {Sun, W and Zhu, A and Chang, H and Xia, J and Gao, J and Zhang, Z and Chi, F and Zhu, Y and Bao, X},
title = {Causal associations and shared genetic etiology between neurodegenerative diseases and constipation.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251362469},
pmid = {40727259},
issn = {2542-4823},
abstract = {BACKGROUND: There is increasing evidence suggesting a correlation between neurodegenerative diseases (NDDs) and constipation; however, their genetic relationship and causal mechanisms remain inadequately elucidated.

OBJECTIVE: We aim to investigate the causal link and shared genetic basis between NDDs and constipation.

METHODS: We obtained summary statistics from large-scale genome-wide association studies, encompassing five NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), as well as constipation. The primary analysis employed five Mendelian randomization methods to evaluate causal effects, while linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) were utilized to investigate genetic correlations. Additionally, significant pleiotropic SNPs were identified using pleiotropic analysis under the composite null hypothesis (PLACO) and functional mapping and annotation (FUMA). Finally, enrichment analysis was conducted to explore the biological pathways associated with the identified pleiotropic genes.

RESULTS: MR analysis revealed a significant causal relationship between AD and an enhanced risk of constipation was demonstrated (OR = 1.043, 95% CI: 1.015-1.073, p = 0.003), while no causality was found between PD, MS, ALS, LBD, and the risk of constipation (p > 0.05). LDSC and HDL analysis revealed a significant positive genetic correlation between AD and constipation. Using PLACO combined with FUMA, we identified 30 overlapping pleiotropic loci, with pathway enrichment analysis revealing important biological pathways related to Aβ metabolism and processing, tau protein process, and the complement and coagulation cascades.

CONCLUSIONS: Our study indicates that AD is a contributing factor to constipation and uncovers the complex genetic mechanisms linking AD and constipation, which holds significant implications for diagnosis and treatment of both conditions.},
}

@article {pmid40727044,
year = {2025},
author = {Jiang, Q and Liu, Y and Wei, Y and Kuan, G and Ma, L and Wang, H and Wang, Y and Lou, H},
title = {The underlying mechanism of physical exercise on neurodegenerative diseases: the mediating role of psychological stress and resilience: a systematic review.},
journal = {Frontiers in psychology},
volume = {16},
number = {},
pages = {1474579},
pmid = {40727044},
issn = {1664-1078},
abstract = {Theories and experiments have shown that physical exercise can improve mental resilience and resist the negative effects of psychological stress. Neurodegenerative diseases are a collection of diseases in which progressive changes in the structure and function of neurons result in progressive disorders of cognitive and motor function, greatly reducing the quality of life of the patient. The latest research suggests that psychological factors such as psychological stress and resilience also have an impact on the onset, symptoms, and course of Neurodegenerative diseases. However, the specific mechanisms in the above pathways are unclear, so this study introduced psychological factors such as psychological stress and resilience and explore the mechanism of physical exercise in improving NDDs by influencing psychological factors such as psychological stress and resilience. This review examined four electronic databases (PubMed, Web of Science, Cochrane Library, and CNKI) up to May 2024, selecting a total of 95 articles. A logical analysis approach was employed to evaluate the literature. The findings revealed that: (1) Exercise can enhance resilience by reducing negative emotions or fulfilling individual needs, thereby diminishing the harmful effects of stress, a key risk factor for NDDs. (2) Exercise alleviates NDDs through neurobiological pathways such as improving immune function, regulating endocrine and neurotransmitter levels, and modifying neuronal structure. (3) Long-term, regular high-intensity exercise effectively enhances resilience and helps prevent and treat NDDs. Exercise has a positive impact on the prevention and treatment of NDDs. Clarifying the mechanisms by which exercise improves NDDs is crucial for providing new theoretical insights into the diagnosis, prevention, and treatment of psychologically induced NDDs, as well as offering practical guidance and feasible strategies for using exercise to prevent and mitigate NDDs.},
}

@article {pmid40726797,
year = {2025},
author = {Mondal, S and An, J and Bera, T and Banerjee, M and Debnath, S and Mandal, D and Sikder, A and Guha, S and Kim, JS and Singh, NDP},
title = {Engineering a Green Fluorescent Protein-Core-Inspired NIR-Photocage: Exploring meso-GFP-PRPG toward Alzheimer's Disease Therapeutics.},
journal = {ACS central science},
volume = {11},
number = {7},
pages = {1062-1070},
pmid = {40726797},
issn = {2374-7943},
abstract = {NIR light-activated photocage with inherent protein tagging ability is unprecedented in contemporary photochemistry. Herein, we introduce a series of protein-taggable NIR-photocages derived from green fluorescent protein (GFP) chromophore analogs with spatiotemporal control for releasing the caged bioactive molecules. Through molecular engineering of the GFP chromophoric scaffold, a series of meso-substituted oxazolone-photocages (meso-GFP-PRPG) were judiciously designed and synthesized. These photocages, anchored with electron-donating groups (EDG) and electron-withdrawing groups (EWG), accommodate diverse payloads, including aliphatic carboxylic acids, expanding the possibilities for tailoring their properties and applications. Notably, under anaerobic conditions, irradiation of meso-GFP-PRPG leads to fast and efficient release of caged molecules. Insightful experimental and theoretical investigations revealed that photorelease is predominantly driven by the triplet state photochemistry in anaerobic conditions. The concept's theranostic potential was demonstrated by the conditional release of valproic acid, a neuroprotective agent for Alzheimer's disease (AD) treatment. meso-GFP-PRPG (15E) showed enhanced NIR emission with Aβ oligomers and fibrils (30-37 fold vs ThT) and effectively degraded amyloid fibrils under 640 nm light, offering a promising targeted treatment approach for neurodegenerative disorders.},
}

@article {pmid40726790,
year = {2025},
author = {Ma, M and Zhao, Y},
title = {Protein-Taggable Near-Infrared Photocages for Theranostics of Alzheimer's Disease.},
journal = {ACS central science},
volume = {11},
number = {7},
pages = {1024-1025},
pmid = {40726790},
issn = {2374-7943},
abstract = {Protein-tagged near-infrared-activatable photocages have been developed for the simultaneous diagnosis and treatment of Alzheimer's disease.},
}

@article {pmid40726727,
year = {2025},
author = {Rao, SP and Imam-Fulani, AO and Xie, W and Phillip, S and Chennavajula, K and Bhilare, KD 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 Transgenic Alzheimer's Mice.},
journal = {ACS pharmacology & translational science},
volume = {},
number = {},
pages = {},
pmid = {40726727},
issn = {2575-9108},
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 nonenzymatic 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 reversed 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 that yields key biomarkers linked to the reversal of AD-related metabolic dysregulation. Collectively, this study demonstrates the neuroprotective effect of pro-ψ-GSH in a symptomatic preclinical model of 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 {pmid40726442,
year = {2025},
author = {Ehtezazi, T and Sarker, SD},
title = {Phytochemical Nanoparticles for the Treatment of Neurological Disorders.},
journal = {Phytochemical analysis : PCA},
volume = {},
number = {},
pages = {},
doi = {10.1002/pca.70020},
pmid = {40726442},
issn = {1099-1565},
abstract = {Neurological disorders impose a significant burden on the healthcare systems. The latest published data by WHO indicated that stroke was the second leading cause of death globally in 2020, with Alzheimer's disease (AD) and other dementias in the seventh position. The treatment of neurological disorders is challenging because of the complex nature of the disease, as well as limited accessibility to this target organ due to several biological barriers. There is a wide range of treatment options for neurological disorders. Small drug molecules, antibodies, and stem cells have been employed for the treatment of neurodegenerative diseases such as AD, but currently, there is no effective treatment for AD. As conventional drugs have not been successful in achieving therapeutic outcomes, natural products such as curcumin, stemming from traditional medicines, have been tested for the treatment of neurodegenerative diseases such as AD. However, this compound has not shown significant therapeutic effects for the treatment of brain diseases, mainly due to rapid clearance from the body. Therefore, phytochemical nanoparticles have been developed. In this review article, the rationale has been provided for the use of nanoparticles for the treatment of neurodegenerative diseases with emphasis on phytochemical nanoparticles.},
}

@article {pmid40726148,
year = {2025},
author = {Rahman, AU and Esa, M and Panichayupakaranant, P},
title = {The therapeutic potential of pomegranate in the prevention and management of noncommunicable diseases.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5fo01999k},
pmid = {40726148},
issn = {2042-650X},
abstract = {Noncommunicable diseases (NCDs), including cardiovascular diseases, cancer, respiratory conditions, and metabolic and central nervous system disorders, are the leading causes of morbidity and mortality worldwide. These diseases are primarily driven by unhealthy diets and sedentary lifestyles. Pomegranate (Punica granatum L.), a fruit rich in diverse functional phytoconstituents, has emerged as a promising natural therapeutic agent for the prevention and management of NCDs. Every part of the fruit harbors distinct bioactive compounds that contribute to its health-promoting properties. The peels are particularly rich in punicalagins, the arils are abundant in anthocyanins and ellagic acid, and the seeds contain significant amounts of punicic acid, ellagic acid, and quercetin. Pomegranate peel extracts and juice demonstrate cardioprotective effects through inhibition of angiotensin-converting enzyme (ACE) activity, reduction of inflammatory cytokines, e.g., interleukins and TNF-α, and improvements in lipid profiles. Additionally, their anticancer properties are associated with the upregulation of pro-apoptotic markers (Bax, cytochrome c, caspases 3 and 9, and p53) and the downregulation of tumor-promoting and inflammatory markers (Bcl-2, MMP-2, MMP-9, GOLPH-3, and N-cadherin), as well as the attenuation of reactive oxygen species (ROS) generation. Moreover, pomegranate extracts have exhibited hypoglycemic, nephroprotective, hepatoprotective, antidepressant, anti-Alzheimer's, and anti-Parkinson's properties, as demonstrated in in vitro and in vivo studies, and clinical trials. Recent investigations have identified key bioactive constituents, including punicalagin, ellagic acid, gallic acid, and urolithin A, as major contributors to these therapeutic effects. This review provides an overview of the metabolomic profile of pomegranate, its therapeutic potential, safety, and quality control assessments, and strategies to enhance the stability and bioavailability of its active constituents, thus underscoring its potential as a natural intervention for the prevention and treatment of NCDs.},
}

@article {pmid40725913,
year = {2025},
author = {Ugwu, OP and Okon, MB and Alum, EU and Ugwu, CN and Anyanwu, EG and Mariam, B and Ogenyi, FC and Eze, VHU and Anyanwu, CN and Ezeonwumelu, JOC and Egba, SI and Uti, DE and Onohuean, H and Aja, PM and Ugwu, MN},
title = {Unveiling the therapeutic potential of the gut microbiota-brain axis: Novel insights and clinical applications in neurological disorders.},
journal = {Medicine},
volume = {104},
number = {30},
pages = {e43542},
doi = {10.1097/MD.0000000000043542},
pmid = {40725913},
issn = {1536-5964},
mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; Probiotics/therapeutic use ; *Nervous System Diseases/therapy/microbiology ; *Dysbiosis/therapy/complications ; *Brain ; Fecal Microbiota Transplantation/methods ; Prebiotics/administration & dosage ; *Brain-Gut Axis/physiology ; },
abstract = {Over the last several years, the gut microbiota-brain axis has been the focus of medical study, demonstrating the bidirectional nature of gut and brain communication and the resulting influence on neurological and mental health. Trillions of microorganisms, particularly those found in the gastrointestinal tract, contribute the most to the pathophysiology recovery of organs that are critical to human health, such as digestive processes and metabolism, immune responses, and even cognitive function. Dysbiosis (a disturbance in the microbiome balance) has been identified as one of the risk factors for neuropsychiatric illnesses such as depression, anxiety, autism spectrum disorder, Parkinson's disease, and Alzheimer's disease. Therapeutic strategies aimed at the gut microbiota, such as probiotics, dietary modifications, prebiotics, and fecal microbiota transplantation, will eventually offer ways to alleviate symptoms associated with these disorders by restoring microbial balance, modulating the immune response, and influencing the production of major neurotransmitters. Innovative drug carriers, such as microbially-derived nanoparticles and probiotics that target particular parts of the gut or microbial communities, may improve pharmaceutical treatment efficacy and specificity. The resolution of difficulties such as ethical concerns, unexpected repercussions, and peak performance optimization in a clinical setting is critical for the advancement of this subject.},
}

Humans
*Gastrointestinal Microbiome/physiology
Probiotics/therapeutic use
*Nervous System Diseases/therapy/microbiology
*Dysbiosis/therapy/complications
*Brain
Fecal Microbiota Transplantation/methods
Prebiotics/administration & dosage
*Brain-Gut Axis/physiology

@article {pmid40725728,
year = {2025},
author = {Riachi, R and Khalife, E and Kędzia, A and Niechciał, E},
title = {Understanding Insulin Actions Beyond Glycemic Control: A Narrative Review.},
journal = {Journal of clinical medicine},
volume = {14},
number = {14},
pages = {},
doi = {10.3390/jcm14145039},
pmid = {40725728},
issn = {2077-0383},
abstract = {Insulin, traditionally recognized for its pivotal role in glycemic regulation, exerts extensive effects beyond glucose homeostasis, influencing multiple physiological systems. This narrative review explores the multifaceted actions of insulin, emphasizing its impact on skeletal muscle remodeling, protein and lipid metabolism, growth, reproductive health, and the central nervous system. Methods: An in-depth review of articles with evidence-based research discussing insulin actions beyond glycemic control was conducted in this review paper. Results: Insulin directly influences lipid and protein metabolism as well as growth hormone levels. This hormone provides a protective effect on the skeletal and central nervous systems, helping to maintain homeostasis and potentially reducing the risk of certain disorders such as Alzheimer's disease. The significance of insulin balance in the reproductive system is also crucial, with recent research indicating that insulin plays a role in worsening symptoms and complications associated with polycystic ovary syndrome. This review underscores the importance of maintaining proper insulin levels to lower the risk of insulin resistance. Ongoing research aims to deepen our understanding of insulin's functions, which are essential for preventing specific diseases and developing new treatment strategies. Conclusions: Insulin's action extends far beyond glucose metabolism, affecting many systems and preventing pathological changes in some.},
}

@article {pmid40725270,
year = {2025},
author = {Tahri, A and Niccolai, E and Amedei, A},
title = {Neurosteroids, Microbiota, and Neuroinflammation: Mechanistic Insights and Therapeutic Perspectives.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
doi = {10.3390/ijms26147023},
pmid = {40725270},
issn = {1422-0067},
mesh = {Humans ; *Gastrointestinal Microbiome ; *Neuroinflammatory Diseases/metabolism/microbiology/therapy ; Animals ; *Neurosteroids/metabolism ; *Neurodegenerative Diseases/metabolism/microbiology ; Brain/metabolism ; Inflammation ; },
abstract = {The gut-brain axis (GBA) represents a complex bidirectional communication network that links the gut microbiota (GM) and the central nervous system (CNS). Recent research has revealed that neurosteroids (NSs) play crucial roles in modulating neuroinflammatory responses and promoting neuroprotection. Meanwhile, GM alterations have been associated with various neuroinflammatory and neurodegenerative conditions, such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. This review aims to provide a comprehensive overview of the intricate interactions between NS, GM, and neuroinflammation. We discuss how NS and metabolites can influence neuroinflammatory pathways through immune, metabolic, and neuronal mechanisms. Additionally, we explore how GM modulation can impact neurosteroidogenesis, highlighting potential therapeutic strategies that include probiotics, neuroactive metabolites, and targeted interventions. Understanding these interactions may pave the way for innovative treatment approaches for neuroinflammatory and neurodegenerative diseases, promoting a more integrated view of brain health and disease management.},
}

Humans
*Gastrointestinal Microbiome
*Neuroinflammatory Diseases/metabolism/microbiology/therapy
Animals
*Neurosteroids/metabolism
*Neurodegenerative Diseases/metabolism/microbiology
Brain/metabolism
Inflammation

@article {pmid40725224,
year = {2025},
author = {Scarano, N and Musumeci, F and Casini, B and Brullo, C and D'Ursi, P and Fossa, P and Schenone, S and Cichero, E},
title = {Alzheimer's Disease Etiology Hypotheses and Therapeutic Strategies: A Perspective.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
doi = {10.3390/ijms26146980},
pmid = {40725224},
issn = {1422-0067},
support = {FRA2023//University of Genoa/ ; },
mesh = {*Alzheimer Disease/etiology/therapy/metabolism/drug therapy/pathology ; Humans ; Animals ; Neuroprotective Agents/therapeutic use ; Neurotransmitter Agents/metabolism ; Risk Factors ; Cholinesterase Inhibitors/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a progressive, complex, multifactorial, neurodegenerative disease and accounts for most cases of dementia. The currently approved therapy includes cholinesterase inhibitors, NMDA-receptor antagonists and monoclonal antibodies. However, these medications were gradually discovered to be ineffective in removing the root of AD pathogenesis, having only symptomatic effects. Thus, the priority remains prevention and clarifying AD etiology. A better understanding of the neuroprotective mechanisms undertaken by specific genes is crucial to guide the design of novel therapeutic agents via selective ligands and precision medicine. In this review, we present a perspective of the physiological phase of the AD spectrum, of risk factors in AD with a focus on therapeutic approaches in three categories: neurotransmitters/ion modulations, peptide deposit control and aspecific treatments, followed by a discussion of treatment limitations. An overview of innovative strategies and non-pharmaceutical ancillary support is given.},
}

*Alzheimer Disease/etiology/therapy/metabolism/drug therapy/pathology
Humans
Animals
Neuroprotective Agents/therapeutic use
Neurotransmitter Agents/metabolism
Risk Factors
Cholinesterase Inhibitors/therapeutic use

@article {pmid40725167,
year = {2025},
author = {Abdul-Nasir, S and Chau, CT and Nguyen, TT and Bajgai, J and Rahman, MH and Hwang-Un, K and You, IS and Kim, CS and Seo, BA and Lee, KJ},
title = {Hydrogen Gas Attenuates Toxic Metabolites and Oxidative Stress-Mediated Signaling to Inhibit Neurodegeneration and Enhance Memory in Alzheimer's Disease Models.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
doi = {10.3390/ijms26146922},
pmid = {40725167},
issn = {1422-0067},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy ; *Oxidative Stress/drug effects ; *Hydrogen/pharmacology ; Mice ; Disease Models, Animal ; Astrocytes/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; Hippocampus/metabolism/drug effects ; Mice, Transgenic ; Signal Transduction/drug effects ; Male ; *Memory/drug effects ; Hydrogen Peroxide/metabolism ; Memory Disorders/drug therapy ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition in which amyloid-beta (Aβ) plaques trigger oxidative stress (OS) and neuroinflammation, causing memory loss. OS and neurodegeneration can also be caused by reactive astrocytes, thereby promoting AD via toxic metabolite accumulation in the astrocytic urea cycle. However, the effect of molecular hydrogen (H2) on this cycle remains unknown. Therefore, we investigated whether H2 treatment could reduce OS-induced neurodegeneration and memory loss. 5xFAD (n = 14) and wild-type (n = 15) mice were randomized into four groups and treated with either 3% hydrogen gas (H2) or vehicle for 60 days. Cognitive behaviors were evaluated using the Morris water maze and Y-maze tests. In addition, we used biochemical assays to measure ammonia and hydrogen peroxide (H2O2) levels in the hippocampi of the mice and AβO-treated primary mouse astrocytes. Aβ, γ-aminobutyric acid (GABA), and the expression of inflammatory markers were evaluated using immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR). We observed that H2 treatment significantly prevented cognitive deficits, oxidative stress, the accumulation of toxic metabolites, and the increase in inflammatory markers in 5xFAD mice. These results suggest that H2 therapy can mitigate toxic metabolites in the astrocytic urea cycle, thereby reducing neurodegeneration and memory loss in AD.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy
*Oxidative Stress/drug effects
*Hydrogen/pharmacology
Mice
Disease Models, Animal
Astrocytes/metabolism/drug effects
Amyloid beta-Peptides/metabolism
Hippocampus/metabolism/drug effects
Mice, Transgenic
Signal Transduction/drug effects
Male
*Memory/drug effects
Hydrogen Peroxide/metabolism
Memory Disorders/drug therapy
Maze Learning/drug effects

@article {pmid40725005,
year = {2025},
author = {Heller, E and McGurran, L and Brown, JK and Love, K and Hobbs, M and Kim-Han, JS and Han, BH},
title = {Aβ40 Improves Cerebrovascular Endothelial Function via NOX4-Dependent Hydrogen Peroxide Release.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
doi = {10.3390/ijms26146759},
pmid = {40725005},
issn = {1422-0067},
support = {851-075//A.T. Still University/ ; },
mesh = {*NADPH Oxidase 4/metabolism ; Animals ; *Hydrogen Peroxide/metabolism ; *Amyloid beta-Peptides/pharmacology/metabolism ; Mice ; *Endothelial Cells/metabolism/drug effects ; *Peptide Fragments/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Cell Line ; Nitric Oxide/metabolism ; Brain/metabolism/blood supply ; Alzheimer Disease/metabolism ; Cell Survival/drug effects ; },
abstract = {Alzheimer's disease (AD) is associated with an abnormal accumulation of amyloid β (Aβ) fibrils in the brain parenchyma and cerebrovasculature, which leads to cognitive impairment and cerebrovascular dysfunction. Cerebrovascular endothelial cells play a crucial role in regulating cerebral blood flow, vascular permeability, and neurovascular function. Reactive oxygen species (ROS), particularly those generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), contribute to vascular dysfunction and amyloid deposition in the Alzheimer's disease (AD) brain. However, the role of the NOX4 isoform in AD pathogenesis remains to be examined. In the present study, we found that NOX4 among the NOX isoforms is predominantly expressed in bEnd.3 mouse brain endothelial cells. Treatment with Aβ40 significantly enhanced the release of H2O2 and NO, and increased the endothelial cell viability. To test the involvement of NOX4 in Aβ40-induced H2O2 production, we utilized pharmacological inhibitors of NOX isoforms. Aβ40-induced H2O2 production was attenuated in the presence of the pan-NOX inhibitor, apocynin, or the NOX1/4-selective inhibitors, setanaxib and GKT136901. Since only the NOX4 isoform is expressed in bEnd.3 cells, these results indicate that NOX4 is responsible for the release of H2O2 stimulated by Aβ40. Taken together, the present study demonstrated that Aβ40 peptide exerts beneficial effects in bEnd.3 endothelial cells via the NOX4-dependent mechanism.},
}

*NADPH Oxidase 4/metabolism
Animals
*Hydrogen Peroxide/metabolism
*Amyloid beta-Peptides/pharmacology/metabolism
Mice
*Endothelial Cells/metabolism/drug effects
*Peptide Fragments/pharmacology/metabolism
Reactive Oxygen Species/metabolism
Cell Line
Nitric Oxide/metabolism
Brain/metabolism/blood supply
Alzheimer Disease/metabolism
Cell Survival/drug effects

@article {pmid40724974,
year = {2025},
author = {Gagliardi, S and Hotchkin, T and Hillmer, G and Engelbride, M and Diggs, A and Tibebe, H and Izumi, C and Sullivan, C and Cropp, C and Lantz, O and Marquez, D and Chang, J and Ezaki, J and Zestos, AG and Riley, AL and Izumi, T},
title = {Oxidative Stress in HIV-Associated Neurodegeneration: Mechanisms of Pathogenesis and Therapeutic Targets.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
doi = {10.3390/ijms26146724},
pmid = {40724974},
issn = {1422-0067},
support = {P30AI117970//DC CFAR/ ; 7R15AI172610-02/NH/NIH HHS/United States ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *HIV Infections/complications/metabolism/drug therapy/virology ; Reactive Oxygen Species/metabolism ; *Neurodegenerative Diseases/metabolism/etiology/drug therapy ; Animals ; *AIDS Dementia Complex/metabolism/drug therapy ; Antioxidants/therapeutic use ; },
abstract = {Treatment for HIV infection has become more manageable due to advances in combination antiretroviral therapy (cART). However, HIV still significantly affects the central nervous system (CNS) in infected individuals, even with effective plasma viral suppression, due to persistent viral reservoirs and chronic neuroinflammation. This ongoing inflammation contributes to the development of HIV-associated neurocognitive disorders (HANDs), including dementia and Alzheimer's disease-like pathology. These complications are particularly prevalent among the aging population with HIV. This review aims to provide a comprehensive overview of HAND, with a focus on the contribution of oxidative stress induced by HIV-mediated reactive oxygen species (ROS) production through viral proteins such as gp120, Tat, Nef, Vpr, and reverse transcriptase. In addition, we discuss current and emerging therapeutic interventions targeting HAND, including antioxidant strategies and poly (ADP-ribose) polymerase (PARP) inhibitors. These are potential adjunctive approaches to mitigate neuroinflammation and oxidative damage in the CNS.},
}

Humans
*Oxidative Stress/drug effects
*HIV Infections/complications/metabolism/drug therapy/virology
Reactive Oxygen Species/metabolism
*Neurodegenerative Diseases/metabolism/etiology/drug therapy
Animals
*AIDS Dementia Complex/metabolism/drug therapy
Antioxidants/therapeutic use

@article {pmid40724820,
year = {2025},
author = {Tomaszewska-Zaremba, D and Gajewska, A and Misztal, T},
title = {Anti-Inflammatory Effects of Cannabinoids in Therapy of Neurodegenerative Disorders and Inflammatory Diseases of the CNS.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
doi = {10.3390/ijms26146570},
pmid = {40724820},
issn = {1422-0067},
mesh = {Humans ; *Cannabinoids/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Animals ; *Inflammation/drug therapy ; Central Nervous System/drug effects ; *Central Nervous System Diseases/drug therapy ; },
abstract = {Many neurodegenerative diseases are associated with immune system disorders, while neurodegenerative processes often occur in inflammatory conditions of the Central Nervous System (CNS). Cannabinoids exhibit significant therapeutic potential due to their dual ability to modulate both neural and immune functions. These compounds have a broad spectrum of action, allowing them to target multiple pathological mechanisms underlying neurodegenerative and inflammatory CNS diseases. The present review outlines the therapeutic potential of cannabinoids, with a focus on their anti-inflammatory properties, in the treatment of neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, as well as inflammatory CNS disorders like multiple sclerosis and HIV-associated dementia.},
}

Humans
*Cannabinoids/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy
*Anti-Inflammatory Agents/therapeutic use/pharmacology
Animals
*Inflammation/drug therapy
Central Nervous System/drug effects
*Central Nervous System Diseases/drug therapy

@article {pmid40724803,
year = {2025},
author = {Ivanova, P and Kortenska, L and Angelova, VT and Tchekalarova, J},
title = {The Novel Melatonin Analog Containing Donepezil Fragment Prevents Cognitive Impairments and Associated Oxidative Stress in a Hybrid Rat Model of Melatonin Deficiency and icvAβ1-42.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
doi = {10.3390/ijms26146553},
pmid = {40724803},
issn = {1422-0067},
support = {grant number KP-06-N63/11; 14.12.2022 and IC-SK/03/2025-2026.//the Bulgarian National Science Fund, Bulgarian Academy of Sciences/ ; },
mesh = {Animals ; *Melatonin/analogs & derivatives/pharmacology ; *Donepezil/chemistry/pharmacology ; *Oxidative Stress/drug effects ; Rats ; *Amyloid beta-Peptides/toxicity ; *Cognitive Dysfunction/drug therapy/metabolism/prevention & control ; *Peptide Fragments ; Male ; Disease Models, Animal ; Alzheimer Disease/drug therapy/metabolism ; Hippocampus/metabolism/drug effects ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia in older adults and is becoming a major public health crisis as life expectancy increases worldwide. A major contributor to this disease is a deficiency in melatonin signaling. We have recently synthesised a series of melatonin analogs containing donepezil fragments. These compounds have been tested both in silico and in vitro. In this study, a particularly potent compound, 3a, was evaluated in a hybrid rat model of melatonin deficiency and AD. Rats underwent pinealectomy followed one week later by bilateral intracerebroventricular infusion of Aβ1-42 (1 µg/µL). A 14-day subchronic treatment with compound 3a was started simultaneously with the neurotoxin infusion. Melatonin was used as a reference drug, while a matched sham group received vehicle treatment. One week after the Aβ1-42 infusion, the rats' cognitive functions were assessed using two Y-maze protocols, object recognition and object location tests. Markers of oxidative stress, including hippocampal glutathione, superoxide dismutase, and malondialdehyde, were assessed by ELISA. Compound 3a effectively prevented cognitive impairment induced by the AD model, and its effects were comparable to those of melatonin. In addition, this melatonin analogue with a donepezil fragment reduced AD-associated oxidative stress and suppressed model-associated increased Aβ1-42 levels in the hippocampus. Our findings suggest that melatonin analogs containing donepezil fragments are promising therapeutic options for targeting oxidative stress associated with AD.},
}

Animals
*Melatonin/analogs & derivatives/pharmacology
*Donepezil/chemistry/pharmacology
*Oxidative Stress/drug effects
Rats
*Amyloid beta-Peptides/toxicity
*Cognitive Dysfunction/drug therapy/metabolism/prevention & control
*Peptide Fragments
Male
Disease Models, Animal
Alzheimer Disease/drug therapy/metabolism
Hippocampus/metabolism/drug effects

@article {pmid40723783,
year = {2025},
author = {Muñoz de León-López, CA and Navarro-Lobato, I and Khan, ZU},
title = {The Role of Astrocytes in Synaptic Dysfunction and Memory Deficits in Alzheimer's Disease.},
journal = {Biomolecules},
volume = {15},
number = {7},
pages = {},
doi = {10.3390/biom15070910},
pmid = {40723783},
issn = {2218-273X},
support = {PID2022-136954OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PROYEXCEL-00422//Junta de Andalucía/ ; CTS-586-G-FEDER//Fondo Europeo de Desarrollo Regional/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology/physiopathology ; *Astrocytes/metabolism/pathology ; Humans ; *Synapses/metabolism/pathology ; Animals ; *Memory Disorders/metabolism/pathology ; Neuronal Plasticity ; Synaptic Transmission ; Amyloid beta-Peptides/metabolism ; },
abstract = {Astrocytes are the most abundant glial cells in the brain. They play critical roles in synapse formation and function, neurotransmitter release and uptake, the production of trophic factors, and energy supply for neuronal survival. In addition to producing proteases for amyloid-β degradation, astrocytes express various receptors, transporters, gliotransmitters, and other molecules that enable them to sense and respond to external signals. They are also implicated in amyloid-β clearance. In Alzheimer's disease, excessive accumulation of amyloid-β induces the polarization of astrocytes into the A1 phenotype, promoting the release of inflammatory cytokines and mitochondrial reactive oxygen species, leading to alterations in astrocytic functions. Under such conditions, gliotransmitter release, glutamate neurotransmission, AMPA receptor trafficking, and both Hebbian and non-Hebbian forms of synaptic plasticity-biological activities essential for synaptic functions-are compromised. Moreover, astrocytes are essential for learning, memory, and synaptic plasticity, and alterations in their function are associated with memory deficits in Alzheimer's disease. This review provides an overview of the current understanding of the defects in astrocytes that lead to altered synaptic functions, neuronal structural plasticity, and memory deficits in Alzheimer's disease.},
}

*Alzheimer Disease/metabolism/pathology/physiopathology
*Astrocytes/metabolism/pathology
Humans
*Synapses/metabolism/pathology
Animals
*Memory Disorders/metabolism/pathology
Neuronal Plasticity
Synaptic Transmission
Amyloid beta-Peptides/metabolism

@article {pmid40722053,
year = {2025},
author = {Rajan, R and Singh, M and Suzuki, K and Matsumura, K},
title = {Design of Zwitterionic Conjugated Polymers as Protein Aggregation Inhibitors.},
journal = {Langmuir : the ACS journal of surfaces and colloids},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.langmuir.5c02043},
pmid = {40722053},
issn = {1520-5827},
abstract = {Protein aggregation and misfolding is the root cause of several neurodegenerative diseases, including Alzheimer's disease, and can be mitigated using small molecules, peptides, and conjugated or zwitterionic polymers. However, polymers that are both conjugated and zwitterionic have not been evaluated as protein aggregation/misfolding inhibitors. Herein, to bridge this gap, we prepare polymers with a conjugated backbone bearing zwitterionic sulfobetaine moieties and poly(ethylene glycol) chains and examine their abilities to inhibit protein aggregation. These polymers not only strongly inhibit the aggregation of amyloid β peptide (Aβ42) and other proteins but also actively disrupt and solubilize pre-established amyloid fibrils. This dual functionality enables almost complete fibril disaggregation at concentrations lower than those required for existing alternatives and results in protective capability extension across a broad spectrum of proteins. The results open new avenues for advancing neurodegenerative disease treatment strategies and represent considerable progress in the development of biomedical materials.},
}

@article {pmid40722027,
year = {2025},
author = {Hua, Z and Zhou, N and Zhou, Z and Fu, Z and Guo, R and Akogo, HY and Yang, J and Yu, M and Jiang, Y and Lan, S and Chang, H and Ma, J and Cui, H},
title = {Intranasal administration of stem cell derivatives for the treatment of AD animal models: a systematic review and meta-analysis.},
journal = {Stem cell research & therapy},
volume = {16},
number = {1},
pages = {409},
doi = {10.1186/s13287-025-04555-4},
pmid = {40722027},
issn = {1757-6512},
support = {H2021206321//Natural Science Foundation of Hebei Province/ ; },
}

@article {pmid40716511,
year = {2025},
author = {Feng, NN and Li, L and Liu, LZ and He, RB and Xian, XH and Liu, LR and Hu, YY and Li, WB},
title = {Ceftriaxone ameliorates tau phosphorylation and mislocalization in APP/PS1 AD mice by inhibiting endoplasmic reticulum stress.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110600},
doi = {10.1016/j.neuropharm.2025.110600},
pmid = {40716511},
issn = {1873-7064},
abstract = {Tau phosphorylation and mislocalization are hallmark pathological features of Alzheimer's disease (AD), with endoplasmic reticulum stress (ERS) contributing to tauopathy. We previously showed that ceftriaxone (Cef) improves cognition in APP/PS1 AD mice through regulating GLT-1-mediated glutamate homeostasis. Here, we examined Cef's neuroprotection against ERS-related tauopathy. C57BL/6J and APP/PS1 AD mice were used. Cognitive functions were assessed by new object recognition (NOR), new location recognition (NLR) and Morris water maze (MWM) tests. Hippocampal synaptosomes were isolated using the Syn-PER™ Synaptic Protein Extraction Kit. Western blot analysis evaluates the protein levels of ERS markers, total and phosphorylated tau (Ser396/Ser262/Thr181), and GSK3β. Transmission electron microscopy examined the endoplasmic reticulum ultrastructural changes of the hippocampus. Confocal 3D-reconstructed imaging assessed the phosphorylated tau (Ser396) distribution on the dendrites in the hippocampal region. The results showed that Cef treatment effectively reduced protein levels of ERS markers and restored endoplasmic reticulum ultrastructural integrity of hippocampus. Simultaneously, Cef treatment significantly alleviated tau phosphorylation levels, decreased accumulation of total and phosphorylated tau in synaptosomes, reduced phosphorylated tau (Ser396) distribution in dendritic compartments and inhibited Gsk3β activity in the hippocampus of APP/PS1 AD mice. Tunicamycin, a promoter of ERS, exacerbated cognitive impairments, tau phosphorylation levels and mislocalization, and Gsk3β activity, and notably, this exacerbation was inhibited by Cef treatment. Simultaneously, the ERS activation significantly inhibited Cef's above benefits on APP/PS1 AD mice. In conclusion, Cef improves cognitive impairment by alleviating ERS, decreasing Gsk3β activity, and reducing tau phosphorylation and mislocalization in the hippocampus of APP/PS1 AD mice.},
}

@article {pmid40715899,
year = {2025},
author = {Suk-In, N and Promphet, N and Rodthongkum, N and Ummartyotin, S},
title = {Cellulose nanocrystals from waste cotton fabric and polyvinyl alcohol composite hydrogel for non-invasive colorimetric sensing of cysteine.},
journal = {Mikrochimica acta},
volume = {192},
number = {8},
pages = {526},
pmid = {40715899},
issn = {1436-5073},
mesh = {*Cysteine/urine/analysis ; *Colorimetry/methods ; *Cellulose/chemistry ; *Polyvinyl Alcohol/chemistry ; *Cotton Fiber ; *Nanoparticles/chemistry ; Humans ; Limit of Detection ; *Hydrogels/chemistry ; Copper/chemistry ; },
abstract = {Cellulose nanocrystals (CNCs) were successfully extracted and purified from cotton fabric waste via alkali treatment and acid hydrolysis. The resulting nanostructure was characterized using transmission electron microscopy (TEM) and X-ray diffraction spectroscopy (XRD), confirming the successful isolation of CNCs. A PV/Cu[2+]-CNCs/CNFs/PVA hydrogel was then synthesized through chemical crosslinking of polyvinyl alcohol (PVA), cellulose nanofibrils (CNFs), cellulose nanocrystals (CNCs), and borax. The incorporation of CNCs as a reinforcing agent significantly enhanced the hydrogel's surface area and water absorption capacity, leading to a substantial improvement in the colorimetric sensitivity of the sensor. This hydrogel was employed as a non-invasive colorimetric sensor for urinary cysteine detection, utilizing an indicator-displacement assay (IDA) with pyrocatechol violet/copper ion (PV/Cu[2+]) as the indicator. Upon exposure to cysteine, the sensor exhibited a distinct color change from greenish-blue to orange-red. The sensor demonstrated a linear detection range of 0-0.6 g/L and a limit of detection (LOD) of 0.017 g/L, effectively encompassing the clinical cut-off level for cysteine in human urine (0.25 g/L), relevant for Alzheimer's disease indication. Eventually, this sensor was validated for cysteine determination in artificial urine samples, confirming its practical applicability.},
}

*Cysteine/urine/analysis
*Colorimetry/methods
*Cellulose/chemistry
*Polyvinyl Alcohol/chemistry
*Cotton Fiber
*Nanoparticles/chemistry
Humans
Limit of Detection
*Hydrogels/chemistry
Copper/chemistry

@article {pmid40720733,
year = {2025},
author = {Li, W and Zha, X and Zhang, X and Dai, H and Pu, S and Yao, X and Hui, W and Xu, R and Bao, J and Yu, J and Wei, Y and Huang, J and Guo, N and Xu, M and Zhao, J and Cheng, B and Luo, Z},
title = {Enhanced Positron Emission Tomography Imaging of β-Amyloid through Focused Ultrasound-Mediated Gallium-68 Radiotracer Delivery across the Blood-Brain Barrier.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00476},
pmid = {40720733},
issn = {1948-7193},
abstract = {Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is an innovative approach for enhancing the delivery of central nervous system drugs. [68]Ga radiotracers are advantageous for imaging due to their ideal half-life and imaging properties; however, their limited ability to traverse the BBB constrains their application in brain imaging. This study investigates the application of FUS to selectively deliver the [68]Ga radiotracer, [[68]Ga]STZL4110, into the hippocampus for β-amyloid positron emission tomography (PET) imaging in an Alzheimer's disease (AD) mouse model. The synthesis and radiolabeling of [[68]Ga]STZL4110 were accomplished, demonstrating robust binding to β-amyloid, as validated by Thioflavin T assays and in vitro autoradiography with both wild-type (WT) and APP/PS1 AD mouse brain sections. Cavitation activity measurements confirmed effective and consistent BBB opening post-FUS treatment, ensuring targeted delivery without vascular damage, as supported by histological analysis. Quantitative PET imaging revealed the successful detection of β-amyloid deposition following FUS treatment. Initially, [[68]Ga]STZL4110 showed a low volume of distribution in the right hippocampus of AD mice. FUS application significantly enhanced BBB permeability, leading to a 74% increase in [[68]Ga]STZL4110 uptake in the targeted right hippocampus of APP/PS1 mice compared with the left hippocampus, whereas no significant change was observed in WT mice. These findings suggest that combining FUS with [[68]Ga]STZL4110 could significantly enhance the sensitivity and specificity of [68]Ga PET imaging for β-amyloid. FUS-mediated PET imaging may potentially address the challenge of effective brain imaging with radiotracers that traditionally exhibit a low penetration of the BBB.},
}

@article {pmid40720390,
year = {2025},
author = {Hwang, J and Choi, J and Cha, SY and Lee, IS and Yoon, JH and Jung, DJ and Lee, CW and Kim, SR and Lee, JH and Jeon, B and Park, JH and Maeng, S and Park, H},
title = {Memory improving effect of silkworm larva on insulin resistance related cognitive impairment model.},
journal = {PloS one},
volume = {20},
number = {7},
pages = {e0328847},
pmid = {40720390},
issn = {1932-6203},
mesh = {Animals ; *Bombyx/chemistry ; *Insulin Resistance ; Larva/chemistry ; *Cognitive Dysfunction/drug therapy/physiopathology ; Disease Models, Animal ; Male ; Hippocampus/drug effects/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; *Memory/drug effects ; Rats ; Blood Glucose/metabolism ; Diet, High-Fat/adverse effects ; },
abstract = {Hongjam (HJ) is the steamed and freeze-dried powder of larva-stage silkworm (Bombyx mori) rich in protein, unsaturated fatty acids, and minerals. Silkworm products have traditionally been used for medical purposes, and their effectiveness in diabetic and neurodegenerative diseases has been studied. In particular, the anti-inflammatory-antioxidant, blood sugar-lowering, and neuroprotective effects are expected to be useful for the prevention and treatment of dementia, especially in a model of dementia related to insulin resistance. Most animal models of Alzheimer's disease (AD) are based on genetic factors and research based on these models does not explain the pathophysiology of sporadic AD. Therefore, no drug can effectively delay the progression of AD. We hypothesized that HJ may improve cognitive function in an insulin resistance model which is considered one of the causes of sporadic AD. Insulin resistance was induced by a high-fat diet and streptozotocin injection. Additionally, the effect of HJ was tested in in vitro cultured hippocampal slices treated with an N-methyl-D-aspartate antagonist. At the given dose, HJ did not affect on the body weight but lowered blood glucose concentration, improved spatial memory in the Morris water maze and avoidance memory in the passive avoidance tests which was related to hippocampal brain-derived neurotrophic factor. In hippocampal slices, HJ strengthened long-term potentiation, which was suppressed by AP5. Thus, HJ improved cognitive functions in an insulin-resistance related dementia model and may be useful in treating sporadic AD.},
}

Animals
*Bombyx/chemistry
*Insulin Resistance
Larva/chemistry
*Cognitive Dysfunction/drug therapy/physiopathology
Disease Models, Animal
Male
Hippocampus/drug effects/metabolism
Brain-Derived Neurotrophic Factor/metabolism
*Memory/drug effects
Rats
Blood Glucose/metabolism
Diet, High-Fat/adverse effects

@article {pmid40720331,
year = {2025},
author = {Royall, DR and Palmer, RF},
title = {Affliction class moderates the dementing impact of amyloidopathy.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001021},
pmid = {40720331},
issn = {1931-1559},
support = {//National Institutes of Health; National Institute on Aging/ ; //Julia and Van Buren Parr Endowment/ ; },
abstract = {OBJECTIVE: The treatment of dementia is increasingly likely to focus on dementia-related biomarkers. Unfortunately, there is variability with regard to biomarker-related effects. This analysis tests an algorithm capable of identifying persons adversely impacted by any dementia-related biomarker in this case, amyloidopathy as estimated by positron emission tomography (PET).

METHOD: N = 1,737 subjects of the Alzheimer's disease neuroimaging initiative were assigned to amyloidopathy-affliction classes. Moderation effects were tested by chi-square difference.

RESULTS: 39.3% of subjects with (+) PET results were assigned to the afflicted class. The afflicted subjects had greater dementia severity and higher amyloid burdens. These effects persisted at 36 months. Furthermore, the association between amyloid burden and dementia severity was moderated by affliction class. Afflicted nondemented cases with positive PET findings were more likely to convert to clinical "Alzheimer's disease" over 48 months, by Cox's F: F(312, 154) = 1.27, p = .05. PET assessed amyloid burden was not related to dementia severity in resilient PET (+) cases.

CONCLUSION: Our approach could allow for more accurate prediction of biomarker effects and guide precision interventions against specific biomarkers. (PsycInfo Database Record (c) 2025 APA, all rights reserved).},
}

@article {pmid40720180,
year = {2025},
author = {Mehta, NV and Kapadia, A and Khambete, M and Abhyankar, A},
title = {The Evolution of AChE Inhibitors in Alzheimer's Disease: From Single-Target to Multi-Target Ligands.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {},
number = {},
pages = {e2500053},
doi = {10.1002/cbic.202500053},
pmid = {40720180},
issn = {1439-7633},
abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disease marked by cognitive decline, neuronal degeneration, and the accumulation of intracellular neurofibrillary tangles, extracellular amyloid plaques, and neuroinflammation. Current treatment strategies, such as acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate receptor antagonists, offer symptomatic relief but fail to stop disease progression. The development of multi-target-directed ligands (MTDLs) has gained attention as a method to address the complex pathology of AD. This review provides a detailed account of the journey of AChE inhibitors from single-target ligands to MTDLs, emphasizing the structural changes that improve target specificity, blood-brain barrier penetration, and therapeutic impact. By exploring these advancements, the review highlights the potential of MTDLs to overcome the limitations of traditional single-target approaches and contribute to the discovery of more effective anti-Alzheimer therapies along with discussing potential pitfalls.},
}

@article {pmid40550222,
year = {2025},
author = {Guo, Z and Xu, Q and Zhang, K and Ma, Y and Sheng, S and Jing, D and Sun, X and Kan, C and Yu, X},
title = {Sclerostin: A Potential Link between Osteoporosis and Alzheimer's Disease.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-9},
doi = {10.1159/000547072},
pmid = {40550222},
issn = {1660-2862},
abstract = {BACKGROUND: Osteoporosis and Alzheimer's disease (AD) are age-related disorders with shared risk factors such as aging, oxidative stress, and neuroinflammation. Sclerostin, a glycoprotein secreted by osteocytes, inhibits Wnt/β-catenin signaling, leading to suppressed bone formation and increased resorption in osteoporosis. Recent findings reveal sclerostin is also expressed in the brain, where it may disrupt synaptic function and contribute to AD progression. Romosozumab, an anti-sclerostin monoclonal antibody approved for osteoporosis, is being explored for potential use in AD, though its ability to cross the blood-brain barrier remains a challenge.

SUMMARY: This review highlights the emerging connection between osteoporosis and AD, focusing on sclerostin as a shared molecular mediator. Understanding this link may open new avenues for dual-purpose therapies targeting sclerostin, with the potential to benefit both bone and brain health. Further studies are needed to clarify the causal mechanisms and therapeutic implications.

KEY MESSAGES: This review highlights sclerostin as a key molecular link between osteoporosis and AD, supporting the emerging concept of a bone-brain axis. Anti-sclerostin therapies like romosozumab may offer benefits beyond bone health, with potential in neurodegenerative disease treatment. Sclerostin may drive AD pathology by disrupting Wnt/β-catenin signaling and promoting β-amyloid and tau abnormalities.},
}

@article {pmid40720133,
year = {2025},
author = {Zeltzer, E and Schonhaut, DR and Mundada, NS and Blazhenets, G and Soleimani-Meigooni, DN and Cho, H and Ranasinghe, KG and Windon, C and Yadollahikhales, G and Apgar, C and Gatsonis, C and Carrillo, MC and Hanna, L and Romanoff, J and Hillner, BE and Koeppe, RA and March, A and Siegel, BA and Smith, K and Whitmer, RA and Iaccarino, L and Rabinovici, GD and La Joie, R},
title = {Concordance Between Amyloid-PET Quantification and Real-World Visual Reads.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.2218},
pmid = {40720133},
issn = {2168-6157},
abstract = {IMPORTANCE: With increased payer coverage and the advent of antiamyloid therapies, clinical use of amyloid positron emission tomography (PET) is likely to increase to help guide the diagnosis and treatment of patients with cognitive impairment. However, unlike most previous research studies, in clinical practice, scan acquisition is less standardized, interpretation typically relies purely on visual reads rather than scan quantification, and patients have more frequent comorbidities, all of which might compromise test accuracy.

OBJECTIVE: To compare visual interpretation of amyloid-PET in real-world clinical settings to scan interpretation based on central quantification, in order to assess the accuracy of clinical reads.

This cross-sectional quality improvement study used data from the Imaging Dementia-Evidence for Amyloid Scanning study, collected between February 2016 and January 2018 and analyzed between December 2021 and April 2023. The setting included 294 imaging facilities in the US. Medicare beneficiaries 65 years or older with cognitive decline for whom Alzheimer disease was a diagnostic consideration were recruited by dementia specialists from their clinical practices.

EXPOSURES: Amyloid-PET with [18F]florbetapir, [18F]florbetaben, or [18F]flutemetamol.

MAIN OUTCOMES AND MEASURES: PET scans were visually interpreted as positive or negative by local radiologists or nuclear medicine physicians following approved guidelines. Independently, scans were centrally processed and quantified using the standardized Centiloid (CL) scale. We applied an a priori autopsy-based threshold of 24.4 CL to quantitatively define scan positivity.

RESULTS: Of 18 293 participants included in the parent study, scan images were available for 10 774 (59%), of which Centiloids were successfully calculated for 10 361 (96%). Median (IQR) patient age was 75 (71-80) years; 5245 patients (51%) were female, 6500 (63%) had mild cognitive impairment, and 3861 (37%) had dementia). Participants self-reported the following races and ethnicities: 1 Alaska Native (0%), 23 American Indian (0.2%), 188 Asian (1.8%), 316 Black (3.1%), 449 Hispanic or Latino (4.3%), 8 Native Hawaiian or Other Pacific Islander (0.1%), and 9125 White (88.2%). A total of 6332 scans (61%) were visually read as positive, and 6121 (59%) were quantitatively positive. Agreement between visual reads and quantitative classification was 86.3% (95% CI, 85.7%-87.0%; Cohen κ = 0.72; 95% CI, 0.70-0.73). A total of 5519 (53%) scans were positive visually and quantitatively (V+/Q+), 3416 (33%) were negative by both (V-/Q-), 813 (8%) were V+/Q-, and 602 (6%) were V-/Q+. Female sex (female: 4581/5241 [87.4%]; male: 4354/5109 [85.2%]; P =.001), White race (White race: 7900/9125 [86.6%]; non-White race: 1035/1225 [84.5%]; P =.046), and use of [18F]flutemetamol and [18F]florbetaben ([18F]flutemetamol: 559/628 [89.0%]; [18F]florbetaben: 2664/3032 [87.9%]; [18F]florbetapir: 5712/6690 [85.4%]; P <.001), compared with [18F]florbetapir, were associated with higher visual-quantitative concordance. Scans within a 10- to 40-CL borderline positivity zone were more likely to be discordant.

CONCLUSIONS AND RELEVANCE: This cross-sectional study found high concordance between local visual reads and central quantification of clinical amyloid-PET scans, supporting the validity of amyloid-PET visual reads in real-world clinical practice.},
}

@article {pmid40719892,
year = {2025},
author = {Yu, Q and Li, L and Yu, S and Han, J and Cheng, Q and Cui, Z and Chen, H and Li, M and Lu, Z},
title = {Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.},
journal = {Neurochemical research},
volume = {50},
number = {4},
pages = {251},
pmid = {40719892},
issn = {1573-6903},
support = {tsqnz20240852//Taishan Scholars Program of Shandong Province/ ; 2022CXGC010507//Key Technology Research and Development Program of Shandong Province/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive neurodegeneration and a variety of cognitive deficits. Of note, mitochondrial malfunctions occur early in the disease's development. Mitophagy impairment leads to the build-up of damaged mitochondria inside the cells, causing malfunction and eventual death of the cells. This review summarizes the mechanisms linking mitochondrial damage and autophagy dysregulation to AD and highlights potential therapeutic opportunities. We summarize how mitochondrial dysfunction contributes to AD, including defects in mitochondrial biogenesis, impaired dynamics, the impact of AD-related protein aggregates on mitochondrial integrity, and defective axonal transport. We also explore the roles of mitophagy in AD, including its function in the removal of harmed proteins and organelles. Finally, we highlight the therapeutic strategies for the treatment of AD, targeting molecular components involved in mitochondrial damage and autophagy dysregulation in AD, i.e., antioxidants, mitochondrial modulators, and mitophagy enhancers.},
}

@article {pmid40719827,
year = {2025},
author = {Yde Ohki, CM and Walter, NM and Smigielski, L and Bender, A and Rickli, M and Walitza, S and Grünblatt, E},
title = {Assessing the effects of methylphenidate in proliferation and Wnt activity of neuronal stem cells from attention deficit/hyperactivity disorder patients.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {40719827},
issn = {1435-1463},
abstract = {As the most common neurodevelopmental and mental disorder around the world, attention-deficit/hyperactivity disorder (ADHD) affects primarily children and adolescents. Both genetic (polygenicity) and environmental variables interplay in the etiology of this disorder. The Wnt signaling pathway, which regulates proliferation and differentiation during neurodevelopment, has been implicated in ADHD. Clinically, individuals with ADHD may exhibit delays in structural and functional brain development. Available evidence suggests that methylphenidate (MPH) treatment can potentially improve these delays. However, the molecular and cellular mechanisms underlying ADHD and the therapeutic targets of MPH are not yet completely elucidated. In a pilot investigation, the proliferation of neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) was significantly lowered in ADHD male patients. Yet, we did not observe any variations in proliferation rates during the iPSC stage. To extend the earlier results, we increased the sample size to include females, explored whether MPH may improve NSC proliferation in ADHD and clarified the role of the Wnt pathway. To do so, iPSC and NSC proliferation from five ADHD patients and five controls was assessed. The results corroborated our previous findings of decreased proliferation in ADHD NSCs. Conversely, ADHD NSC proliferation was modestly regulated by MPH treatment at 10 nM, which also showed modulatory effects on Wnt signaling in this group. Interestingly, no increase in proliferation was seen when DKK1 blocked Wnt signaling before MPH treatment. These findings suggest MPH regulates the canonical Wnt pathway and may partially explain ADHD-related neurodevelopmental abnormalities and MPH-specific benefits.},
}

@article {pmid40718958,
year = {2025},
author = {Plantera, L and Immig, K and Fritsche, AK and Reinicke, M and Zemer, A and Monsonego, A and Ceglarek, U and Bechmann, I},
title = {Exploring the Impact of a High-Fat Diet on Brain Homeostasis: A Comprehensive Analysis of the Absence of Inflammation.},
journal = {Molecular nutrition & food research},
volume = {},
number = {},
pages = {e70168},
doi = {10.1002/mnfr.70168},
pmid = {40718958},
issn = {1613-4133},
abstract = {Excessive fat consumption increases the risk of Alzheimer's disease (AD), potentially through diet-induced neuroinflammation. Microglia, the brain's immune cells, are affected by obesity and diet. Phytosterols (PS), plant-derived cholesterol-like compounds, accumulate in the brain with age, and their content correlates with dietary intake. We hypothesize that the accumulation of PS modulates microglial activation and exerts anti-inflammatory effects. We investigated the effects of a normal diet (ND), high-fat diet (HFD), HFD with 2% PS (HFD+2% PS), and HFD with 4% PS (HFD+4% PS) on neuroinflammation in female and male C57BL/6J mice. Flow cytometry (FC) of microglia showed no significant regulation of pro- (IFN-γ, IL-1β, TNF-α) and anti-inflammatory (IL-10) cytokines due to diet, but sex- and age-dependent differences were observed. Immunofluorescence staining showed no TREM2 upregulation, indicating a lack of microglial activation in response to HFD. PS supplementation significantly reduced HFD-induced weight gain, suggesting metabolic effects. Contrary to existing research, we found no evidence of HFD-induced neuroinflammation or microglial activation. However, the reduction in weight gain with PS supplementation suggests potential metabolic benefits, which could have implications for the treatment of obesity. The potential effects on neuroinflammation remain unclear.},
}

@article {pmid40718314,
year = {2025},
author = {Auti, ST and Kulkarni, YA},
title = {Beneficial Effects of Caraway Oil in Aluminium Chloride-Induced Neurotoxicity.},
journal = {Cureus},
volume = {17},
number = {6},
pages = {e86783},
doi = {10.7759/cureus.86783},
pmid = {40718314},
issn = {2168-8184},
abstract = {PURPOSE: Alzheimer's disease (AD) is characterized by cognitive decline and memory impairment, amyloid plaques, and neurofibrillary tangles (NFT). Current therapies provide symptomatic treatment but do not address the exact cause of the disease. Caraway oil, derived from Carum carvi, is rich in carvone and limonene with reported anticholinesterase, antioxidant, and neuroprotective properties. This study aimed to evaluate the neuroprotective effect of caraway oil in an aluminum chloride-induced rat model of neurotoxicity.

METHODS: Albino Wistar rats were randomized into five groups: normal control, disease control (aluminum chloride, 100 mg/kg), standard (donepezil, 1 mg/kg), and caraway oil treatment groups (100 and 200 mg/kg). Treatments were administered orally for 42 days. Behavioral assessments included locomotor activity, the Morris water maze, the elevated plus maze, and passive avoidance tests. Acetylcholinesterase (AChE) activity and oxidative stress markers were assessed in the hippocampus and cortex.

RESULTS: Caraway oil administration significantly improved locomotor activity and spatial memory in rats at 100 mg/kg and 200 mg/kg. The oil showed a significant effect on oxidative stress parameters in the hippocampus and cortex. AChE activity was also improved significantly (p<0.001) after caraway oil treatment.

CONCLUSION: Caraway oil demonstrated significant neuroprotective effects in aluminum chloride-induced neurotoxicity, improving cognitive and behavioral functions and reducing oxidative stress. These findings suggest that caraway oil may have therapeutic potential in the management of AD.},
}

@article {pmid40717971,
year = {2025},
author = {Rong, Y and Li, Q and Du, Y and Wang, W and Su, W and Zhang, J and He, W},
title = {Preclinical evidence and potential mechanisms of tanshinone ⅡA on cognitive function in animal models of Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1603861},
doi = {10.3389/fphar.2025.1603861},
pmid = {40717971},
issn = {1663-9812},
abstract = {BACKGROUND: Tanshinone ⅡA (Tan ⅡA) is a monomer extracted from Salvia miltiorrhiza Bunge. Animal studies have demonstrated its potential in providing cognitive protection in Alzheimer's disease (AD), but the overall effects remain inconclusive, and its multiple mechanisms have not been systematically summarized.

OBJECTIVE: This systematic review and meta-analysis (SR/MA) aimed to evaluate the overall effects of Tan ⅡA on cognitive function in AD animal models and to summarize the mechanisms.

METHODS: Seven databases (PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Chinese Biological Medical Disc, Chongqing VIP, and Wanfang databases) and grey literature were retrieved. Risk of bias was evaluated following the Systematic Review Center for Laboratory Animal Experiments. The mean difference (MD) or standard mean difference (SMD) with 95% confidence intervals (CIs) were used to evaluate the effect of Tan ⅡA on cognitive function, neuropathology, neuroinflammation, oxidative stress, apoptosis, and neural/synaptic plasticity, with P < 0.05 considered a significant difference. The effect and potential mechanisms of Tan ⅡA were demonstrated by performing multiple subgroup analyses.

RESULTS: Nineteen studies involving 581 AD animals were identified. The included studies showed satisfactory reporting quality but had certain risks of bias in methodology. Tan ⅡA ameliorated cognitive deficits, evidenced by reducing escape latency (MD = -17.94 s; 95% CI: -22.92 to -12.96) and increasing time spent in the target quadrant (MD = 10.69 s; 95% CI: 7.32-14.07). It attenuated neuropathological damage by reducing amyloid-β (Aβ) plaques in thioflavine S staining (SMD = -3.46; 95% CI: -5.65 to -1.26) and increasing neuronal density in Nissl staining (SMD = 2.82; 95% CI: 2.11-3.52) and NeuN staining (SMD = 2.89; 95% CI: 1.71-4.08). Tan ⅡA also demonstrated anti-inflammatory effects through downregulation of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6)] and antioxidant stress properties by increasing superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels while reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Additionally, it exhibited antiapoptotic effects by increasing the B-cell lymphoma-2/Bcl-2-associated X protein (Bcl-2/Bax) ratio and decreasing Caspase-3 expression. Moreover, treatment improved neuronal/synaptic plasticity by upregulating postsynaptic density-95 (PSD-95) and brain-derived neurotrophic factor (BDNF) levels.

CONCLUSION: Tan ⅡA could improve cognitive function and neuropathology through multiple mechanisms. This suggests that Tan IIA may serve as a viable candidate for the development of therapeutic strategies for AD.

https://www.crd.york.ac.uk/PROSPERO/view/CRD42024588415.},
}

@article {pmid40717894,
year = {2025},
author = {Yu, M and Ma, H and Lai, X and Wu, J and Shen, M and Yan, J},
title = {Stem cell extracellular vesicles: a new dawn for anti-inflammatory treatment of neurodegenerative diseases.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1592578},
doi = {10.3389/fnagi.2025.1592578},
pmid = {40717894},
issn = {1663-4365},
abstract = {Mesenchymal stem cell-derived extracellular vesicles, as carriers for intercellular communication, are rich in bioactive substances such as proteins and nucleic acids, and show unique potential in the treatment of neurodegenerative diseases. Their vesicular structure, with a diameter of 30-150 nm, can penetrate the blood-brain barrier and modulate the activity of microglia and astrocytes by delivering functional molecules. This process inhibits the release of pro-inflammatory factors and enhances the expression of anti-inflammatory mediators, thereby alleviating neuroinflammation in the pathological process of neurodegenerative diseases. As natural drug carriers, extracellular vesicles can improve the targeted delivery efficiency of therapeutic molecules. However, their specific anti-inflammatory mechanisms remain not fully understood and require further exploration. This article discusses the anti-inflammatory effects in the context of neurodegenerative diseases and provides a summary and outlook on the anti-inflammatory actions associated with extracellular vesicles from past research.},
}

@article {pmid40717814,
year = {2025},
author = {Righes, G and Semenzato, L and Koutsikos, K and Zanato, V and Pinton, P and Giorgi, C and Patergnani, S},
title = {The role of autophagy in the pathogenesis and treatment of multiple sclerosis.},
journal = {Autophagy reports},
volume = {4},
number = {1},
pages = {2529196},
doi = {10.1080/27694127.2025.2529196},
pmid = {40717814},
issn = {2769-4127},
abstract = {Autophagy is a crucial cellular process responsible for the degradation and recycling of damaged or unnecessary components, maintaining cellular homeostasis and protecting against stress. Dysregulation of autophagy has been implicated in a variety of neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Various types of autophagy exist, each with distinct mechanisms, such as macroautophagy, mitophagy, lipophagy, and chaperone-mediated autophagy. These processes are essential for the removal of toxic substrates like protein aggregates and dysfunctional mitochondria, which are vital for neuronal health. In neurodegenerative diseases, the impairment of these clearance mechanisms leads to the accumulation of harmful substances, which accelerate disease progression. Modulating autophagy has emerged as a promising therapeutic strategy, with ongoing studies investigating molecules that can either stimulate or regulate this process. However, despite its potential, significant challenges remain in translating preclinical findings into clinically effective treatments. In this review, we will explore the different types of autophagy, their roles in neurodegenerative diseases, and the therapeutic potential associated with modulating these processes.},
}

@article {pmid40717739,
year = {2025},
author = {Kenaan, N and Alshehabi, Z},
title = {A review on recent advances in Alzheimer's disease: The role of synaptic plasticity.},
journal = {AIMS neuroscience},
volume = {12},
number = {2},
pages = {75-94},
doi = {10.3934/Neuroscience.2025006},
pmid = {40717739},
issn = {2373-7972},
abstract = {Alzheimer's Disease (AD) remains a significant global health challenge, characterized by progressive neurodegeneration and a decline in cognitive abilities such as memory and learning. Despite being the main cause of dementia worldwide, the precise mechanisms that underlie neuronal dysfunction and synaptic plasticity impairment in AD remain elusive. However, while genetic mutations, dietary factors, and immune dysregulation are implicated in AD pathogenesis, the current therapeutic approaches are largely centered around acetylcholinesterase inhibitors (AChEIs). Nevertheless, this cholinergic hypothesis of AD is no longer satisfactory in describing this disease and has demonstrated a limited efficacy. Hence, new treatment approaches should be developed, and that requires us to view AD from a new perspective. Herein, in our review, we present the latest studies that discussed possible AD pathologies and pharmacotherapies. Additionally, we highlight that the emerging treatments that precisely targets brain regions associated with enhancing neuroplasticity have delivered promising results and seem to be more effective than older treatments. Finally, by viewing AD as a complex interplay of various factors that ultimately cause synaptic dysfunction and cognitive decline, we can develop more effective therapeutic interventions and ultimately alleviate the significant burden of this debilitating disease for both patients and their families.},
}

@article {pmid40717666,
year = {2025},
author = {Nakamura, Y and Adachi, J and Hirota, N and Iba, K and Sasajima, C and Shimizu, K and Nakai, M and Takahashi, K},
title = {Brexpiprazole's impacts on patients and caregivers in agitation in Alzheimer's dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70522},
doi = {10.1002/alz.70522},
pmid = {40717666},
issn = {1552-5279},
support = {//Otsuka Pharmaceutical Co., Ltd/ ; },
abstract = {INTRODUCTION: We evaluated the impacts of brexpiprazole treatment on patient neuropsychiatric symptoms and caregiver distress in Japanese patients with agitation in Alzheimer's dementia (AAD).

METHODS: In a phase 2/3 multicenter, double-blind study, patients were randomized to receive brexpiprazole 1 or 2 mg/day, or placebo (3:4:4) for 10 weeks. The Neuropsychiatric Inventory (NPI) was used for evaluation. The areas of patient symptoms and caregiver distress were defined as NPI and NPI-Distress, respectively.

RESULTS: At Week 10, the differences of brexpiprazole 1 and 2 mg versus placebo for NPI total score were -1.2 (p = 0.5891) and -8.4 (p < 0.0001), and those for NPI-Distress total score were -1.1 (p = 0.2292) and -3.9 (p < 0.0001), respectively. In brexpiprazole 2 mg versus placebo, NPI and NPI-Distress agitation/aggression score showed ≥ 2 and ≥ 1 point improvement, respectively.

DISCUSSION: Brexpiprazole is suggested to improve patient symptoms and to reduce caregiver distress in the treatment of AAD in Japanese patients.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03620981 HIGHLIGHTS: Brexpiprazole improved symptoms of patients with agitation in Alzheimer's dementia. The improvements included not only agitation, but also various behavioral and psychological symptoms of dementia scores. The improvements of patient symptoms led to the reduction of caregiver distress. Our study suggests that brexpiprazole is beneficial for both patients and caregivers.},
}

@article {pmid40717576,
year = {2025},
author = {Liu, Y and Sun, Y and Zhao, P and Liu, Z and Wang, Y and Wang, Y and Zhao, R and Wang, C and Wang, S},
title = {Near-Infrared Fluorescent Probe for the Early Diagnosis of Alzheimer's Disease.},
journal = {Medicinal research reviews},
volume = {},
number = {},
pages = {},
doi = {10.1002/med.70000},
pmid = {40717576},
issn = {1098-1128},
support = {//We sincerely thank the Key R&D Program of Gansu Province, under Grant No.24YFWA010; the Talent Innovation and Entrepreneurship Project of Lanzhou City, under Grant No. 2020-RC-43; the Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital, under Grant No. CY2024-MS-A15 and No. CY2024-MS-B17; the Inner Mongolia Science and Technology Plan Project, under Grant No. 2021GG0339./ ; },
abstract = {Alzheimer's disease (AD) is a common progressive neurodegenerative disease characterized by abnormal deposition of amyloid-β protein (Aβ) and the formation of neurofibrillary tangles (NFT). Although there are drugs available for clinical treatment, they do not fundamentally cure AD, so early diagnosis and intervention for AD are essential. In recent years, near-infrared fluorescent (NIRF) probes have been widely used in diagnosing AD due to their advantages of high tissue penetration, low autofluorescence interference, and non-invasiveness. This paper reviewed the recent progress of NIRF probes in AD. We described the effects of NIRF probes on AD biomarkers, including Aβ protein, Tau tangles, mitochondrial viscosity, reactive oxygen species, copper ions, zinc ions, and so on. In detail, we also described the optical properties, in vitro detection, and in vivo imaging of NIRF probes based on different dyes and their derivatives, such as curcumin, Boron dipyrromethene, Quinoline, and Donor-Acceptor. Despite significant progress, NIRF probes remain challenging in imaging and treating AD in vivo. Their selectivity and sensitivity need to be improved due to the complex structure of brain tissue and interfering factors. In conclusion, studying NIRF probes provides us with new ideas. Through further optimization, these probes may be used for early diagnosis and treatment detection of AD to better cope with the challenges brought by AD.},
}

@article {pmid40717475,
year = {2025},
author = {Hsiao, CH and Wu, CE and Wang, CM and Lin, TY and Wu, RY and Wu, MJ and Lin, SH and Sung, PS},
title = {Intracerebral hemorrhage risk in Alzheimer's disease patients on anticoagulants: A nationwide cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251362362},
doi = {10.1177/13872877251362362},
pmid = {40717475},
issn = {1875-8908},
abstract = {BackgroundThe risk of intracerebral hemorrhage (ICH) in Alzheimer's disease (AD) patients undergoing anticoagulation (AC) remains unclear.ObjectiveThis nationwide cohort study assessed ICH risk in AC-treated AD patients.MethodsUsing Taiwan's National Health Insurance Research Database, we identified 1638 AC-treated AD patients and established four matched cohorts: AD with AC, AD without AC, non-AD with AC, and non-AD without AC. We applied inverse probability of treatment weighting (IPTW) and competing risks regression (CRR) to adjust for confounders and mortality risk. Cox proportional hazards regression estimated ICH risk.ResultsThe ICH incidence per 100 person-years was 2.21 in AD patients with AC, 1.03 without AC, 1.71 in non-AD with AC, and 0.28 in non-AD without AC. After IPTW adjustment, compared to non-AD without AC, AD patients with AC had the highest ICH risk (aHR 1.94, 95% CI: 1.44-2.61), followed by non-AD with AC (aHR 1.84, 95% CI: 1.51-2.23) and AD without AC (aHR 1.74, 95% CI: 1.42-2.11). ICH risk in AC-treated AD patients was comparable to non-AD with AC. Subgroup analysis showed higher ICH risk in females and those with hyperlipidemia, diabetes, heart failure, chronic kidney disease, or cancer.ConclusionsAD is associated with increased ICH risk, which is further elevated by AC use. These findings highlight the need for individualized risk-benefit evaluation, particularly in high-risk populations.},
}

@article {pmid40717228,
year = {2025},
author = {Gertz, MA and Aras, MA and Bart, N and Brannagan Iii, TH and Griffin, JM and Kontorovich, AR and Rosen, AM},
title = {Unravelling the myriad physiologic roles of transthyretin: critical considerations for treating transthyretin amyloidosis.},
journal = {Annals of medicine},
volume = {57},
number = {1},
pages = {2536755},
doi = {10.1080/07853890.2025.2536755},
pmid = {40717228},
issn = {1365-2060},
abstract = {BACKGROUND: Transthyretin (TTR) is a highly conserved protein with crucial and broadly protective physiologic roles across organ systems and diseases. Evidence shows that TTR contributes to neuroprotection, cognition, glucose regulation, pregnancy, muscle development, and bone mineralization. In several disease states, including diabetes, Alzheimer's disease, Lewy body dementia, cerebrovascular disease, and osteoporosis, higher TTR levels may be protective. Numerous studies have shown that low levels of TTR are associated with increased mortality overall and in relation to cardiovascular disease and several malignancies.

PURPOSE: There is a growing portfolio of approved and investigational transthyretin amyloidosis (ATTR) treatments that differ in their mechanisms and effects on circulating TTR. When selecting an ATTR therapy, clinicians must decide whether to stabilize and preserve TTR and its functions or knockdown and drastically reduce TTR. This review summarizes the vital physiologic roles of TTR in health and disease. We consider the potential effects on normal biologic pathways that may occur while therapeutically suppressing TTR and discuss clinical decisions concerning ATTR therapies in the context of the summarized literature.

DISCUSSION: TTR is essential for a broad range of physiologic processes and may confer clinically protective effects in neurologic and other organ systems. While a link between low TTR and severe disease and mortality is well established, it remains unclear whether long-term TTR suppression via ATTR therapies increases risk of disease. Clinical decisions in ATTR, however, should reflect the current understanding of the roles of TTR and the patient's clinical history.

CONCLUSION: TTR serves vital physiologic roles across organ systems. Given its clinically protective properties, continued investigation into the potential long-term impact of TTR suppression via knockdown or gene editing therapies is prudent. ATTR treatment selection should reflect an awareness of the physiologic importance of TTR, as well as consideration of the potential long-term impact of chronic TTR suppression.},
}

@article {pmid40715349,
year = {2025},
author = {Ebrahimifar, A and Ahmadi, S and Rostamzadeh, J and Rahimi, K},
title = {Vanadyl sulfate restores memory impairment in streptozotocin-induced rat model of sporadic alzheimer's disease by repressing FoxO1 gene expression.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {27293},
pmid = {40715349},
issn = {2045-2322},
abstract = {Impaired brain insulin signaling is a risk factor for the pathogenesis of Alzheimer's disease (AD). FoxO1 and HMGA1 transcription factors are involved in the pathogenesis of both type 2 diabetes (T2D) and Alzheimer's disease (AD). This study aimed to assess the effect of vanadyl sulfate (VS) on impaired memory and hippocampal FoxO1 and HMGA1 RNA expression in sporadic AD (sAD) model in rats. Thirty-two male Wistar rats (250 ± 10 g) were divided into sham, AD, and VS 0.5 and 0.75 treated groups. The animals were subjected to two bilateral intracerebroventricular (icv) injections of either citrate buffer or streptozotocin (STZ) at 72-hour intervals. The VS-treated groups were treated with either 0.5 or 0.75 mg/ml oral VS for 3 weeks. The target quadrant entry latency, path length, and time and distance traveled in the target quadrants were assessed with the Morris water maze (MWM). Hippocampal tissues were analyzed for FoxO1 and HMGA1 RNA expressions. Group differences and group‒time interactions were analyzed via mixed two-way repeated-measures ANOVA. VS treatment in icv STZ rats restored impaired spatial memory. Hippocampal FOXO1 and HMGA1 RNA expressions were significantly lower in VS-treated and sham groups compared to AD control. VS can restore impaired spatial memory in sAD rats, possibly via the repression of FoxO1 and HMGA1 RNA expression in hippocampus.},
}

@article {pmid40713860,
year = {2025},
author = {Lancaster, TM and Murphy, K and Chandler, H},
title = {Reductions in brainstem volume as a key macrostructural indicator in at-risk populations for Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {177},
doi = {10.1186/s13195-025-01829-0},
pmid = {40713860},
issn = {1758-9193},
support = {PNU-80762-CU-14//European Regional Development Fund/ ; 104943/Z/14/Z//Wellcome Trust/United Kingdom ; 104943/Z/14/Z//Wellcome Trust/United Kingdom ; WT224267//Wellcome/ ; WT224267//Wellcome/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/genetics ; *Brain Stem/pathology/diagnostic imaging ; Aged ; Male ; Female ; Magnetic Resonance Imaging ; Middle Aged ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Organ Size ; },
abstract = {BACKGROUND: Alterations to brain macrostructure, assessed via T1-weighted magnetic resonance imaging are observed in preclinical models of Alzheimer's disease (AD), reflecting susceptibility, prodromal stages of AD or correlates of early AD pathophysiology. While changes in cingulate and medial temporal lobe structures may be functionally implicated in cognitive decline, little is known about the viability of brain-based biomarkers that support autonomic functions implicated in preclinical AD risk such as the brainstem.

METHODS: In a series of multiple linear regressions, we assess the volume of the brainstem in two asymptomatic at-AD-risk samples, assessed via the presence of either mild cognitive impairment (MCI, N = 148), or extremely high polygenic risk (N = 13) with matched demographics (mean age = 67 [range 58-76], in both cases). We further determine the strength of the association, compared to 150 other structural MRI features.

RESULTS: We observed brainstem volume reductions (MCI: b = -0.29, P = 0.018; Genetic risk: b = -1.29, P = 0.002) in both samples. The magnitude of each preclinical AD marker (MCI / AD-polygenic risk)- brainstem association was empirically larger (Z > 2.3, P < 0.05, in both cases) than 150 frequently segmented MRI features. We further replicate the negative AD-polygenic risk score- brainstem association in UK Biobank (N = 31968; b = -0.002, P = 0.03), with weaker evidence that the association was larger than all other MRI features (Z = 1.622; P = 0.052).

CONCLUSIONS: These observations suggest that AD risk, assessed via the presence of MCI or extremely high AD-polygenic risk score is linked to reduced brainstem volume before most typically observed morphological brain alterations. This conforms with evidence implicating the brainstem as one of the earliest sites of morphological neurodegeneration and provides a plausible biological mechanism linking prodromal autonomic symptoms to AD risk in later life. These observations warrant future investigation into the molecular correlates of AD-linked brainstem dysfunction, assessment as a candidate biomarker, and the exploration of brainstem mediated treatment strategies in AD prevention.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/genetics
*Brain Stem/pathology/diagnostic imaging
Aged
Male
Female
Magnetic Resonance Imaging
Middle Aged
*Cognitive Dysfunction/diagnostic imaging/pathology
Organ Size

@article {pmid40713733,
year = {2025},
author = {Li, H and Bai, L},
title = {Advances in mesenchymal stem cell and exosome-based therapies for aging and age-related diseases.},
journal = {Stem cell research & therapy},
volume = {16},
number = {1},
pages = {401},
pmid = {40713733},
issn = {1757-6512},
support = {No. 2022YFA1103803//National Key Research and Development Project/ ; 2021-I2M-1-035//Chinese Academy of Medical Sciences Initiative for Innovative Medicine/ ; },
mesh = {Humans ; *Exosomes/transplantation/metabolism ; *Mesenchymal Stem Cells/metabolism/cytology ; *Aging ; *Mesenchymal Stem Cell Transplantation/methods ; Animals ; *Osteoporosis/therapy ; Primary Ovarian Insufficiency/therapy ; Atherosclerosis/therapy ; *Alzheimer Disease/therapy ; },
abstract = {Mesenchymal stem/stromal cells (MSCs) and their exosomes (MSC-Exos) have great potential for tissue repair and regenerative medicine, which can improve the symptoms and prognosis of aging-related diseases and potentially slow the aging process through multiple pathways. This comprehensive review summarizes the characterization of MSCs and MSC-Exos from various tissue sources and their applications in treating diseases associated with aging, such as premature ovarian failure (POF), Alzheimer's disease (AD), atherosclerosis (AS), and osteoporosis (OP). MSCs exert therapeutic effects through multiple mechanisms, including differentiation into various cell types, secretion of bioactive molecules, and immune response regulation. MSC-Exos, which contain a diverse array of proteins, miRNAs, and other biomolecules, can deliver MSC-derived bioinformatics to target cells and demonstrate comparable therapeutic benefits to MSCs. This review highlights the signaling pathways and molecular mechanisms underlying the therapeutic efficacy of MSCs and MSC-Exos in age-related diseases, and further discusses the importance of MSC and MSC-Exo tissue source selection for specific disease applications and the potential of combination therapies and preconditioning strategies to enhance their therapeutic outcomes. Despite promising preclinical and clinical results, challenges such as uneven distribution, in vivo environmental maladaptation, apoptosis, and immune responses need to be addressed before widespread clinical application. Future research requires multidisciplinary collaboration to further elucidate the mechanisms of action and develop optimized therapeutic strategies for the prevention and treatment of age-related pathologies using MSCs and MSC-Exos.},
}

Humans
*Exosomes/transplantation/metabolism
*Mesenchymal Stem Cells/metabolism/cytology
*Aging
*Mesenchymal Stem Cell Transplantation/methods
Animals
*Osteoporosis/therapy
Primary Ovarian Insufficiency/therapy
Atherosclerosis/therapy
*Alzheimer Disease/therapy

@article {pmid40713730,
year = {2025},
author = {Budda, B and Mitra, A and Park, L and Long, H and Kurnellas, M and Bien-Ly, N and Estacio, W and Burgess, B and Chao, G and Schwabe, T and Paul, R and Kenkare-Mitra, S and Rosenthal, A},
title = {Development of AL101 (GSK4527226), a progranulin-elevating monoclonal antibody, as a potential treatment for Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {174},
pmid = {40713730},
issn = {1758-9193},
support = {R44AG050363//National Institutes of Health/ ; R44AG050363//National Institutes of Health/ ; },
mesh = {*Progranulins/metabolism/blood ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Male ; Rats ; Female ; *Antibodies, Monoclonal/pharmacology/therapeutic use/pharmacokinetics ; Adaptor Proteins, Vesicular Transport/metabolism ; Rats, Sprague-Dawley ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid plaques, tau tangles, and neuronal loss. Progranulin (PGRN) is a secreted immune regulator, lysosomal chaperone, and neuronal survival factor. Genetic polymorphisms that reduce PGRN levels are associated with an increased risk for AD and other neurodegenerative disorders. The receptor sortilin binds and targets PGRN for lysosomal degradation, resulting in a reduction of extracellular PGRN. AL101 (GSK4527226) is a monoclonal antibody that binds to the sortilin receptor and is being developed as a potential PGRN-elevating therapy for AD.

METHODS: Cell-based in vitro studies examined the interaction of AL101 with sortilin and its effect on PGRN levels. In vivo studies evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of AL101 in rats and nonhuman primates. A phase 1 study in healthy volunteers assessed PK, safety, tolerability, and PD biomarkers after intravenous or subcutaneous dosing of AL101.

RESULTS: Cell-based assays showed that AL101 increased PGRN levels by decreasing cell surface sortilin levels and partially blocking the sortilin-PGRN interaction. Preclinical studies in rats and monkeys demonstrated that AL101 decreased cell surface sortilin levels on white blood cells and increased PGRN levels by up to 2-fold in cerebrospinal fluid (CSF) and up to 4-fold in blood. In the phase 1 study in healthy volunteers, both single and multiple doses of AL101 led to significant increases in plasma and CSF PGRN levels, providing additional support for its potential as a PGRN-elevating therapy.

LIMITATIONS: The first-in-human dose-finding study was aimed at investigating the safety and tolerability of AL101 and was not sufficiently powered to detect changes in exploratory outcomes, such as neurodegeneration biomarkers. Clinical studies are needed to evaluate AL101 in AD patients.

CONCLUSIONS: AL101 was shown to bind sortilin and decrease cell surface sortilin levels, leading to consistent elevations of PGRN across in vitro, preclinical, and human studies. These results support continued development of AL101 and its investigation as a potential treatment for AD and other neurodegenerative conditions where PGRN could play a role.

TRIAL REGISTRATION: Clinicaltrials.gov, NCT04111666. Registered on October 1, 2019. https://clinicaltrials.gov/ct2/show/NCT04111666 .},
}

*Progranulins/metabolism/blood
Animals
*Alzheimer Disease/drug therapy/metabolism
Humans
Male
Rats
Female
*Antibodies, Monoclonal/pharmacology/therapeutic use/pharmacokinetics
Adaptor Proteins, Vesicular Transport/metabolism
Rats, Sprague-Dawley

@article {pmid40712813,
year = {2025},
author = {Tan, Q and Liu, Z and Zheng, J and Wang, Y and Wu, H and Wang, Q and Liang, Y},
title = {Experimental validation, molecular docking, proteomic analysis and network pharmacology reveal Morroniside promoting neurogenesis and improving cognitive impairment via Notch1/Hes1 pathway in intracerebroventricular-streptozotocin mice.},
journal = {Journal of ethnopharmacology},
volume = {353},
number = {Pt A},
pages = {120322},
doi = {10.1016/j.jep.2025.120322},
pmid = {40712813},
issn = {1872-7573},
abstract = {ETHNOPHARMACOLOGY RELEVANCE: Alzheimer's disease (AD) is a widely occurred neurodegenerative disease and Notch1/Hes1 pathway based neural stem cell (NSC) proliferation and neurogenesis are very crucial to restore cognitive ability. Cornus officinalis Sieb. et Zucc, a famous traditional Chinese herb remedy was widely used to tonify kidney and essence to ameliorate AD symptoms. Morroniside (MOR), a prominent bioactive component of Cornus officinalis Sieb. et Zucc has demonstrated promising neuroprotective properties, while its function of neurogenesis to improve cognitive ability largely remains unclear.

AIM OF THE STUDY: This study aimed to reveal the role of MOR promoting neurogenesis and improving cognitive function via Notch1/Hes1 pathway thus to discover more neuropharmacological merit of MOR for AD treatment.

MATERIALS AND METHODS: An AD model was induced in C57BL/6 mice by bilateral intracerebroventricular injection of streptozotocin (ICV-STZ). The mice were divided into control, model, low-dose, high-dose, DAPT + MOR, and donepezil groups. Cognitive functions were assessed using open field test, novel object recognition test, and Morris water maze (MWM). Histopathological changes were evaluated by Nissl and hematoxylin-eosin (HE) staining. Immunofluorescence double-labeling was performed to detect the expression of neurogenesis biomarkers in dentate gyrus. qRT-PCR and Western blotting were employed to measure the mRNA levels and Notch1, Hes1 expression. Molecular docking and dynamics simulations were performed to assess the binding affinity and stability between MOR and Notch1/Hes1 proteins. Proteomic analysis combined with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were integrated to verify the effects of MOR on including Notch1/Hes1 pathway for neurogenesis.

RESULTS: MOR (20 and 40 mg/kg) significantly improved cognitive function of ICV-STZ mice from the behavioral tests. Histological analysis showed that MOR enhanced neuronal survival in the hippocampus, improved cellular arrangement and structure, and reduced oxidative stress. Immunofluorescence results indicated that MOR promoted NSC proliferation and neurogenesis, as evidenced by the elevated number of BrdU/Nestin and DCX/Ki67 double-positive cells. Mechanistically, MOR upregulated the mRNA and protein expression of Notch1 and Hes1 in the hippocampus and increased the expression of downstream Cyclin D1 and CDK4. Molecular docking and dynamics simulations further supported stable binding of MOR to Notch1 and Hes1. Proteomics combined with GO and KEGG enrichment further confirmed MOR (40 mg/kg, ∗P < 0.05) could significantly regulated multiple signaling pathways including Notch1 to ameliorate AD symptoms.

CONCLUSION: This work demonstrated MOR could promote neural stem cell proliferation and neurogenesis by activating Notch1/Hes1 pathway, thereby enhancing learning and memory abilities in ICV-STZ mice. Such findings will further promote the clinical application of MOR for AD treatment.},
}

@article {pmid40712769,
year = {2025},
author = {Košak, U and Knez, D and Benetik, SF and Sokolov, PM and Pišlar, A and Horvat, S and Stojan, J and Lv, B and Zhang, W and Wang, Y and Wang, Q and Igert, A and Dias, J and Nachon, F and Brazzolotto, X and Sun, H and Gobec, S},
title = {Chiral switch of a butyrylcholinesterase inhibitor for the treatment of Alzheimer's disease.},
journal = {Chemico-biological interactions},
volume = {420},
number = {},
pages = {111670},
doi = {10.1016/j.cbi.2025.111670},
pmid = {40712769},
issn = {1872-7786},
abstract = {Butyrylcholinesterase (BChE) is a viable drug target to alleviate the symptoms of Alzheimer's disease (AD). We recently developed and biologically evaluated racemic N-benzylpiperidine-based naphthalene-2-sulfonamide 2, a nanomolar BChE inhibitor with procognitive effects. To optimize it, we performed a chiral switch. Using semi-preparative chiral HPLC, we isolated the pure enantiomers (R)-(-)-2 and (S)-(+)-2 and confirmed that (R)-(-)-2 is the eutomer and (S)-(+)-2 is the distomer with respect to human (h)BChE inhibition. Notably, (R)-(-)-2 is a less potent inhibitor of human acetylcholinesterase (hAChE) than both racemate 2 and (S)-(+)-2, which is advantageous, since AChE inhibition is associated with undesirable peripheral parasympathomimetic adverse effects. The crystal structures of hBChE in complexes with each enantiomer revealed distinct binding poses. The crystal structure of hBChE in complex with (R)-(-)-2 confirmed our previous hypothesis that only the (R)-(-)-2 is bound in the active site of hBChE when the racemate is crystallized. The synthesis of (R)-2 hydrochloride has a higher overall yield (73 %) than the synthesis of racemate 2 hydrochloride (64 %) and is safer as it avoids the use of LiAlH4. (R)-(-)-2 has in vivo efficacy in mice with scopolamine-induced AD-like symptoms, and (R)-(-)-2 is less toxic in mice (LD50 = 169 mg/kg) than racemate 2 (LD50 = 112 mg/kg). These results support the chiral switch from racemate 2 to (R)-(-)-2 as a safer and more selective lead compound in the anti-AD drug development pipeline.},
}

@article {pmid40711709,
year = {2025},
author = {Chen, R and Gao, H and Zhu, T and Zheng, N and Jin, Y and Li, M and Lu, Z},
title = {Syringaldehyde Ameliorates Cognitive Dysfunction in APP/PS1 Mice by Stabilizing the NLRP3 Pathway.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40711709},
issn = {1559-1182},
support = {202134029//Jinan Clinical Medical Science and Technology Innovation Plan/ ; tsqnz20240852//Taishan Scholars Program of Shandong Province/ ; 82272414//the National Natural Science Foundation of China/ ; 2022CXGC010507//the Key Research and Development Program of Shandong Province, China/ ; },
abstract = {This study aimed to assess the therapeutic efficacy of syringaldehyde (SYD) in Alzheimer's disease (AD) and to investigate its potential underlying molecular mechanisms. The potential of SYD for AD treatment was first explored through a network pharmacology approach. APPswe/PS1dE9 (APP/PS1) transgenic mice were treated with SYD via intraperitoneal injection for 9 weeks, and cognitive and behavioral functions were evaluated using the Y-maze, Morris water maze, and novel object recognition tests. Histopathological analysis was conducted to assess neuronal changes and amyloid plaque deposition in the hippocampus using immunofluorescence, hematoxylin and eosin staining, Nissl staining, and Congo red staining. RNA sequencing and transcription factor prediction analyses were utilized to identify the potential molecular mechanisms underlying SYD's therapeutic effects. In addition, in vitro experiments were performed on HT22 hippocampal neuronal cells, including ROS assay, TUNEL assay, and quantitative reverse transcription PCR, to validate the mechanisms suggested by the in vivo results. The results demonstrated that SYD treatment significantly reduced amyloid plaque deposition in the hippocampus of APP/PS1 mice, promoted neuronal repair, and improved cognitive performance. Further analysis indicated that these therapeutic effects were mediated by SYD's ability to enhance resistance to oxidative stress, alleviate neuronal damage, and inhibit the NF-κB/IL-1β/NLRP3 inflammatory pathway, thereby counteracting neuroinflammation induced by neuronal activation. In conclusion, this study provides strong evidence for the potential of SYD to ameliorate cognitive impairment and reduce amyloid plaque deposition in AD, highlighting its promising role as a therapeutic agent in the treatment of Alzheimer's disease.},
}

@article {pmid40710322,
year = {2025},
author = {Koch-Paszkowski, J and Sennett, C and Pula, G},
title = {Alzheimer's Disease-Thrombosis Comorbidity: A Growing Body of Evidence from Patients and Animal Models.},
journal = {Cells},
volume = {14},
number = {14},
pages = {},
pmid = {40710322},
issn = {2073-4409},
mesh = {*Alzheimer Disease/complications/epidemiology/pathology ; Humans ; Animals ; Disease Models, Animal ; *Thrombosis/complications/epidemiology/pathology ; Comorbidity ; Brain/pathology/blood supply ; },
abstract = {BACKGROUND/OBJECTIVES: A growing body of evidence is amassing in the literature suggesting a correlation between Alzheimer's disease (AD) and thrombotic vascular complications, which led to the suggestive hypothesis that thrombosis may contribute to AD onset and progression by damaging the neurovasculature and reducing the cerebral blood flow. In turn, low cerebral blood flow is likely to contribute to neurodegeneration by reducing nutrient and oxygen supply and impairing toxic metabolite removal from the brain tissue.

METHODS: We searched the literature for studies in animal models of AD or patients diagnosed with the disease that reported circulating markers of platelet hyperactivity or hypercoagulation, or histological evidence of brain vascular thrombosis.

RESULTS: Platelet hyperactivity and hypercoagulability have been described in multiple animal models of AD, and histological evidence of neurovascular thrombosis has also been reported. Similarly, clinical studies on patients with AD showed circulating markers of platelet hyperactivity and hypercoagulation, or histological evidence of neurovascular thrombosis collected from post-mortem brain tissue samples.

CONCLUSIONS: Taken together, a convincing picture is emerging that suggests a strong correlation between systemic or neurovascular thrombosis and AD. Nonetheless, a mechanistic role for haemostasis dysregulation and neurovascular damage in the onset or the progression of AD remains to be proven. Future research should focus on this important question in order to clarify the mechanisms underlying AD and identify a treatment for this disease.},
}

*Alzheimer Disease/complications/epidemiology/pathology
Humans
Animals
Disease Models, Animal
*Thrombosis/complications/epidemiology/pathology
Comorbidity
Brain/pathology/blood supply

@article {pmid40710114,
year = {2025},
author = {Nazir, S and Dogan, M and Wei, Y and Pan, G},
title = {Electrochemical Immunosensor Using COOH-Functionalized 3D Graphene Electrodes for Sensitive Detection of Tau-441 Protein.},
journal = {Biosensors},
volume = {15},
number = {7},
pages = {},
pmid = {40710114},
issn = {2079-6374},
mesh = {*Graphite/chemistry ; *Biosensing Techniques ; *tau Proteins/analysis ; Humans ; Electrodes ; *Electrochemical Techniques ; Immunoassay ; Alzheimer Disease/diagnosis ; Limit of Detection ; Amyloid beta-Peptides ; },
abstract = {Early diagnosis of Alzheimer's disease (AD) is essential for effective treatment; however current diagnostic methods are often complex, costly, and unsuitable for point-of-care testing. Graphene-based biosensors offer an alternative due to their affordability, versatility, and high conductivity. However, graphene's conductivity can be compromised when its carbon lattice is oxidized to introduce functional groups for biomolecule immobilization. This study addresses this challenge by developing an electrochemical immunosensor using carboxyl-modified commercial graphene foam (COOH-GF) electrodes. The conductivity of graphene is preserved by enabling efficient COOH modification through π-π non-covalent interactions, while antibody immobilization is optimized via EDC-NHS carbodiimide chemistry. The immunosensor detects tau-441, an AD biomarker, using differential pulse voltammetry (DPV), achieving a detection range of 1 fM-1 nM, with a limit of detection (LOD) of 0.14 fM both in PBS and human serum. It demonstrates high selectivity against other AD-related proteins, including tau-217, tau-181, amyloid beta (Aβ1-40 and Aβ1-42), and 1% BSA. These findings underscore its potential as a highly sensitive, cost-effective tool for early AD diagnosis.},
}

*Graphite/chemistry
*Biosensing Techniques
*tau Proteins/analysis
Humans
Electrodes
*Electrochemical Techniques
Immunoassay
Alzheimer Disease/diagnosis
Limit of Detection
Amyloid beta-Peptides

@article {pmid40709649,
year = {2025},
author = {Radanovic, M and Passos Neto, CEB and Monteiro, LH and Forlenza, OV},
title = {Transactive response DNA-binding protein 43 (TDP-43) proteinopathy: the complex biological and clinical findings in limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathological changes, limbic-predominant amnestic neurodegenerative syndrome, and other mixed age-related major neurocognitive disorders.},
journal = {Current opinion in psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1097/YCO.0000000000001025},
pmid = {40709649},
issn = {1473-6578},
abstract = {PURPOSE OF REVIEW: As the term limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE) was coined in 2019, more than 200 articles addressing the subject were published. This review aims to provide an updated synthesis of knowledge regarding LATE-NC as a cause of age-related neurodegeneration and cognitive decline while addressing the challenges posed by overlapping neuropathologies in aging populations.

RECENT FINDINGS: LATE-NC is marked by TDP-43 deposition in limbic structures, such as the amygdala and hippocampus, and is often associated with cognitive decline resembling Alzheimer's disease, though with a slower progression in isolated cases. The frequent coexistence of LATE-NC with other neuropathologies, particularly Alzheimer's disease neuropathologic changes (ADNC) and Lewy body dementia (LBD), exacerbates dementia severity and complicates diagnosis and treatment. Recent efforts have established clinical criteria for in-vivo diagnosis, including neuroimaging markers like hippocampal atrophy and limbic hypometabolism. Genetic studies have identified key risk genes, including GRN, TMEM106B, SORL1, and APOE, while biomarker development in cerebrospinal fluid (CSF) and blood remains in its early stages.

SUMMARY: The review highlights the importance of multidisciplinary research and clinical approaches in addressing the complexities of neurodegenerative diseases involving TDP-43 proteinopathy, enhancing diagnostic accuracy, and developing effective treatments tailored to individual patient profiles.},
}

@article {pmid40709644,
year = {2025},
author = {Radanovic, M and Passos Neto, CEB and Monteiro, LH and Forlenza, OV},
title = {TDP-43 proteinopathy: the complex biological and clinical findings in LATE-NC, LANS, and other mixed age-related major neurocognitive disorders.},
journal = {Current opinion in psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1097/YCO.0000000000001027},
pmid = {40709644},
issn = {1473-6578},
abstract = {PURPOSE OF REVIEW: Since the term limbic-predominant age-related TDP-43 encephalopathy (LATE) was coined in 2019, more than 200 articles addressing the subject were published. This review aims to provide an updated synthesis of knowledge regarding LATE-NC as a cause of age-related neurodegeneration and cognitive decline while addressing the challenges posed by overlapping neuropathologies in aging populations.

RECENT FINDINGS: LATE-NC is marked by TDP-43 deposition in limbic structures, such as the amygdala and hippocampus, and is often associated with cognitive decline resembling Alzheimer's disease, though with a slower progression in isolated cases. The frequent coexistence of LATE-NC with other neuropathologies, particularly Alzheimer's disease neuropathologic changes (ADNC) and Lewy body dementia (LBD), exacerbates dementia severity and complicates diagnosis and treatment. Recent efforts have established clinical criteria for in-vivo diagnosis, including neuroimaging markers like hippocampal atrophy and limbic hypometabolism. Genetic studies have identified key risk genes, including GRN, TMEM106B, SORL1, and APOE, while biomarker development in cerebrospinal fluid (CSF) and blood remains in its early stages.

SUMMARY: The review underscores the need for multidisciplinary research and clinical approaches to address the complexities of neurodegenerative diseases involving TDP-43 proteinopathy, improve diagnostic accuracy, and develop effective treatments tailored to individual patient profiles.},
}

@article {pmid40709598,
year = {2025},
author = {Kaur, G and Mankoo, OK and Kaur, A and Mann, S and Priyadarshi, N and Singh, PP and Goyal, B and Singhal, NK and Goyal, D},
title = {The Synergistic Potential of Rationally Designed Phenol-Triazole Derivatives to Attenuate Aβ/Cu[2+]-Aβ Aggregation and Reactive Oxygen Species.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00386},
pmid = {40709598},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a neurological disorder characterized by a spectrum of symptoms such as memory loss and cognitive decline. AD is a multifaceted disease, and designing multipotent ligands is an effective strategy for AD treatment. In this regard, the pharmacophore moiety of clioquinol (CQ, metal chelator) was employed to design the multifunctional phenol-triazole derivatives 4(a-p). In particular, 4k with an o-I group on the phenyl ring displayed a noteworthy higher inhibition (inhibition efficiency 4k = 90.5%, IC50 = 6.51 ± 0.01 μM) against Aβ42 aggregation as compared to 38.1% noted for CQ. Furthermore, 4k significantly disassembled the preformed Aβ42 fibrils (Aβf, 92.5%), chelated Cu[2+] ions, and inhibited Cu[2+]-mediated Aβ42 aggregation. Compound 4k ceases the production of reactive oxygen species (ROS) as it acts as an antioxidant due to the presence of a phenolic hydroxyl group. Compound 4k has a sufficient safety-efficacy profile and alleviates the cytotoxicity by Aβ42 aggregates in PC-12 cells. For studying the modulation in the fibrillary architecture, hydrodynamic size, and structural transition of Aβ42 in the presence of 4k, we resorted to transmission electron microscopy (TEM), dynamic light scattering (DLS), and circular dichroism (CD), respectively. The molecular dynamics (MD) simulations depicted a notable reduction in the conformational transformations in the Aβ42 monomer (Aβm) and Aβf on the incorporation of 4k. Compound 4k modulates Aβ42 fibrillation by maintaining a helix conformation and simultaneously reduces the sampling of β-sheet structures in Aβm, consistent with the CD results. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis depicted a favorable binding of 4k to Aβm (-42.12 ± 7.14 kcal/mol) and Aβf (-74.42 ± 4.98 kcal/mol) with a significant contribution of van der Waals interactions to the binding free energy. The 4k-induced deformation in Aβf chains noted in the conformational snapshots depicts its destabilization potential against Aβf. Finally, our results uncovered the potential of phenol-triazole derivatives as a promiscuous ligand for targeting various pathological conditions in AD. The key insights into the prevention of conformational transitions in Aβm and destabilization of Aβf by 4k illuminated by experimental and computational studies are central to unraveling the molecular understanding of amyloid aggregation as well as designing future therapeutic candidates against multifaceted AD.},
}

@article {pmid40709526,
year = {2025},
author = {Sharma, N and Kim, D and Sharma, H and Kim, MI and Lee, H and Kim, M and Ryoo, N and Kang, MJ and Pyun, JM and Park, YH and Ryu, J and Oh, HJ and Yang, HS and Kim, HR and Kim, GH and Han, S and Yang, Y and Youn, YC and Teunissen, C and Zetterberg, H and Scheltens, P and An, SSA and Kim, YB and Kim, S and , },
title = {Unveiling blood biomarkers for neuronal hyperplasticity: Insights from AD molecular subtyping, a comprehensive review.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70475},
doi = {10.1002/alz.70475},
pmid = {40709526},
issn = {1552-5279},
support = {RS-2023-00251396//National Research Foundation of Korea/ ; RS-2021-NR060117//Ministry of Education/ ; 2021R1A6A1A03038996//Ministry of Education/ ; RS-2025-02292973//Korea Institute of Marine Science & Technology Promotion (KIMST)/ ; },
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/blood/pathology/classification/diagnosis ; *Neurons/pathology ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, predominantly affecting the aging population. Early detection through biomarkers is essential for early intervention. Recent sub-classification of AD through extensive cerebrospinal fluid (CSF) proteomic analyses revealed distinct characteristics of each subtype, necessitating tailored therapeutic strategies. While CSF proteomics has identified potential biomarkers, the need for non-invasive and cost-effective substitutions highlights the importance of blood-based biomarkers (BBMs). This review is a comprehensive review that categorizes potential BBMs based on neuronal hyperplasticity (subtype 1), underlining their role in refining subtype classification and enabling precision medicine. Early AD is often marked by cortical and hippocampal hyperactivity, followed by hypoactivity during later stages of neurodegeneration. While the exact mechanisms remain unclear, factors like Ca[2+], glutamate, amyloid beta, tau, genetic factors, and impaired glial function play a role. Advancements in blood-based diagnostics would improve detection, individual treatment strategies, and evaluation of therapeutic response, eventually reducing the burden of AD on health-care systems. HIGHLIGHTS: Alzheimer's disease (AD; subtype 1) exhibits neuronal hyperplasticity, mild cortical atrophy, and moderate microglial activation. The neuronal hyperplasticity subtype of AD is characterized by an upregulation of synaptic and plasticity-related proteins, distinguishing it from other AD subtypes. Identifying biomarkers specific to neuronal hyperplasticity would enable real-time monitoring of therapeutic responses, allowing for individualized therapy as opposed to a "one-size-fits-all" strategy. The treatments based on neuronal hyperactivity reduction, restoration of synaptic plasticity, and anti-inflammation/metabolic dysfunction would be useful in this AD subtype. Blood-based biomarkers offer a cost-effective and accessible alternative to cerebrospinal fluid and neuroimaging methods.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/blood/pathology/classification/diagnosis
*Neurons/pathology

@article {pmid40709497,
year = {2025},
author = {Liu, W and Guo, J and Dong, Y and Li, J and Wang, Y},
title = {Efficacy of probiotic supplementation in influencing cognitive function in Alzheimer's disease: A systematic review and meta-analysis.},
journal = {Journal of food science},
volume = {90},
number = {7},
pages = {e70037},
doi = {10.1111/1750-3841.70037},
pmid = {40709497},
issn = {1750-3841},
mesh = {*Probiotics/administration & dosage ; Humans ; *Alzheimer Disease/psychology/drug therapy/microbiology ; *Cognition/drug effects ; Aged ; Gastrointestinal Microbiome/drug effects ; Randomized Controlled Trials as Topic ; *Dietary Supplements ; Male ; Female ; Aged, 80 and over ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral changes. Emerging evidence suggests that the gut microbiota influences central nervous system function. Probiotic interventions may offer a promising therapeutic approach by modulating the gut microbiota composition and potentially improving cognitive outcomes in AD patients. This meta-analysis aimed to assess the effects of probiotic supplementation on cognitive function in AD patients by analyzing randomized controlled trials (RCTs). Following PRISMA 2020 guidelines and registered with PROSPERO (CRD42024508725), we conducted a comprehensive search across PubMed, Embase, Cochrane Library, and ClinicalTrials.gov through April 9th, 2024. Only double-blind RCTs comparing probiotic supplementation to placebo in patients aged 65 or older with clinically diagnosed AD were included. Primary outcomes were cognitive function scores from validated tools like MMSE and TYM. Our stringent inclusion criteria identified four double-blind RCTs with 251 participants aged 65 or older with clinically diagnosed AD. Statistical analysis using a random-effects model revealed significant cognitive improvement in probiotic-treated groups compared to placebo controls (Standardized Mean Difference [SMD] = 0.67; 95% CI [0.14, 1.19]; P < 0.05), though substantial heterogeneity was observed (I[2] = 79.16%). Subgroup analyses indicated that probiotic formulation type, dosage, and baseline AD severity may influence cognitive outcomes. While these findings suggest probiotics may offer cognitive benefits for AD patients, the high heterogeneity and limited study number necessitate additional well-designed clinical trials to confirm these promising results and establish optimal treatment protocols for clinical implementation.},
}

*Probiotics/administration & dosage
Humans
*Alzheimer Disease/psychology/drug therapy/microbiology
*Cognition/drug effects
Aged
Gastrointestinal Microbiome/drug effects
Randomized Controlled Trials as Topic
*Dietary Supplements
Male
Female
Aged, 80 and over

@article {pmid40709486,
year = {2025},
author = {Munn, EE and Montelongo, A and Patel, VK and Fodstad, JC and Ciccarelli, MR and Ptomey, LT and Pangelinan, MM},
title = {A meta-analysis and systematic review of interventions to prevent or treat cognitive decline related to Alzheimer's disease in adults with Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70471},
doi = {10.1002/alz.70471},
pmid = {40709486},
issn = {1552-5279},
mesh = {Humans ; *Down Syndrome/complications ; *Alzheimer Disease/complications/therapy ; *Cognitive Dysfunction/therapy/prevention & control/etiology ; Adult ; Cognitive Behavioral Therapy ; },
abstract = {Down syndrome (DS) is a leading genetic risk factor for Alzheimer's disease (AD). Although prevention and treatment of AD are well documented for those without DS, less is known about individuals with DS. This review evaluates the efficacy of AD and dementia interventions in people with DS. It includes 26 articles with 1417 participants ages 18-69 in the qualitative synthesis and 17 articles with 1118 participants in the meta-analysis. Four types of interventions demonstrated small-to-moderate effects: pharmacological (n = 19), exercise (n = 5), environmental (n = 1), and cognitive training (n = 1). Significant treatment effects were observed across interventions (t(66) = 4.67, p < 0.0001, d = 0.29, 95% confidence interval [CI]: 0.16-0.40); however, high heterogeneity (I[2] = 93.8% CI = 92.8-94.7) was noted, which was not explained by intervention type or outcome. The meta-analysis indicates that interventions enhance AD-related cognitive and behavioral outcomes, emphasizing the need for further research to address heterogeneity. This review was registered with PROSPERO: CRD42024567026. HIGHLIGHTS: This study is the first to comprehensively review both pharmacological and non-pharmacological interventions for Alzheimer's disease (AD) in individuals with Down syndrome (DS), extending previous reviews by including a meta-analysis and examining key mediating variables. Donepezil, the most studied pharmacological treatment, showed significant cognitive and behavioral improvements in individuals with DS, especially with longer treatment periods. However, further trials are needed to explore its efficacy in combination with non-pharmacological interventions. All seven non-pharmacological studies reported significant improvement, suggesting that even small doses of exercise and cognitive training can be effective and feasible for individuals with DS. Online formats may enhance scalability and reduce barriers to participation. Significant heterogeneity in cognitive assessments across studies highlights the need for standardized, sensitive assessments to enable meaningful comparisons of intervention effects. Additional studies are required to determine the long-term efficacy of pharmacological interventions like Donepezil and to assess the sustained impact of non-pharmacological interventions on key AD-related cognitive domains such as memory, language, and executive function.},
}

Humans
*Down Syndrome/complications
*Alzheimer Disease/complications/therapy
*Cognitive Dysfunction/therapy/prevention & control/etiology
Adult
Cognitive Behavioral Therapy

@article {pmid40709360,
year = {2025},
author = {Zhang, Y and Wang, Y and Xu, K and Zhang, C and Lv, P and Bai, Y and Wang, S},
title = {Repetitive transcranial magnetic stimulation across neurodegenerative diseases: a systematic review and dose-response meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1615734},
pmid = {40709360},
issn = {1663-4365},
abstract = {OBJECTIVE: We summarized the existing clinical evidence of repetitive transcranial magnetic stimulation (rTMS) for Parkinson's Disease (PD) and Alzheimer's Disease (AD) and conducted a series of dose-response meta-analyses to determine the curve relationship between the number of pulses and the effect size of the treatment.

METHODS: Existing evidence was retrieved from five databases, and relevant outcome data on rTMS treatment for motor and non-motor symptoms of PD and AD were collected. Data were analyzed using R software to assess effect size using standardized mean differences (SMD) and 95% confidence intervals (CI). Heterogeneity testing was performed to assess differences in efficacy among the evidence, and restricted cubic spline (RCS) was used to fit the dose-response curves.

RESULTS: A total of 51 publications were included, involving 1,938 subjects. We found that for PD patients, the total number of rTMS pulses showed significant bell-shaped curves in TUG (χ[2] = 6.87, df = 2, p = 0.03), FOGQ (χ[2] = 15.17, df = 2, p = 0.001), BDI (χ[2] = 14.33, df = 2, p = 0.001), HAMD (χ[2] = 12.63, df = 2, p = 0.001), and HAMA (χ[2] = 6.06, df = 2, p = 0.04). For AD patients, the total number of rTMS pulses demonstrated significant bell-shaped curves for MMSE (χ[2] = 8.76, df = 2, p = 0.01) and MoCA (χ[2] = 6.79, df = 2, p = 0.03).

CONCLUSION: Our dose-response meta-analysis results show that rTMS demonstrates significant efficacy in certain motor and non-motor symptoms of PD and AD. The number of rTMS pulses presents a typical bell-shaped curve for these symptoms, indicating that more number of rTMS pulses is not always better; beyond a certain threshold, increasing the number of rTMS pulses correlates negatively with therapeutic efficacy.},
}

@article {pmid40709087,
year = {2025},
author = {Wang, G and Zhou, X and Pang, X and Ma, K and Li, L and Song, Y and Hou, D and Wang, X},
title = {Pharmacological effects, molecular mechanisms and strategies to improve bioavailability of curcumin in the treatment of neurodegenerative diseases.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1625821},
pmid = {40709087},
issn = {1663-9812},
abstract = {With the global population aging, the incidence of neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, has been progressively increasing. However, effective therapeutic strategies and clinical drugs for these disorders remain scarce. Curcumin, a natural polyphenolic compound primarily derived from the herbaceous plant Curcuma longa L., has been proposed as a promising candidate for ND treatment based on the excellent antioxidant, anti-inflammatory and neuroprotective properties. Its pharmacological activities encompass scavenging reactive oxygen species, mitigating toxic protein aggregation and cytotoxicity, repairing mitochondrial dysfunction, and inhibiting excessive neuronal apoptosis. Compared with synthetic drugs, curcumin demonstrates a more favorable safety profile with fewer side effects. Nevertheless, its clinical application is substantially hindered by poor bioavailability, which stems from low aqueous solubility, inefficient intestinal absorption, and rapid metabolism and systemic elimination. Conventional administration methods often fail to achieve effective concentrations in vivo. Further clinical trials are also required to validate the therapeutic efficacy and potential adverse effects in human subjects. This article systematically reviews the pathogenesis of NDs and the knowledge on curcumin including pharmacological effects, neuroprotective mechanisms, functions across specific NDs and advanced strategies to enhance the bioavailability, with the aim of promoting the development and clinical translation of curcumin-based therapeutics for NDs.},
}

@article {pmid40708863,
year = {2025},
author = {Nagarajan, R and Lyu, J and Kambali, M and Wang, M and Pearce, RA and Rudolph, U},
title = {Noncanonical sustained actions of propofol reverse surgery-induced microglial activation and cognitive impairment in aged mice.},
journal = {PNAS nexus},
volume = {4},
number = {7},
pages = {pgaf213},
pmid = {40708863},
issn = {2752-6542},
abstract = {Perioperative neurocognitive disorder is a major concern in aged individuals, and currently, treatment options are limited. Chronic intermittent propofol (CIP) has been shown to have neuroprotective effects in aged mice and in a mouse model of Alzheimer's disease. Here, we investigated whether CIP could reverse surgery-induced cognitive deficits and propose a mechanism of action. Male and female mice (21-24 months old) underwent exploratory laparotomy under isoflurane anesthesia. Animals were administered either CIP (75 mg/kg i.p.) or vehicle every fifth day throughout the experiment. Cognitive function was assessed using a battery of behavioral tests: the Y-maze test (spatial working memory), the novel object recognition test (recognition memory), the Morris water maze (spatial learning and memory), and trace and contextual fear conditioning (nondeclarative associative memory). Expression of α5-GABAA receptors, markers of apoptosis, and a microglial activation marker were assessed in the hippocampus using western blotting. The amount of α5-GABAA receptor subunits in cell-surface membranes was determined by biotinylation followed by western blotting. CIP induced a sustained redistribution of α5-GABAA receptors to the cell-surface membranes. Laparotomy led to an increased expression of the microglial activation marker Iba-1 and of proapoptotic markers, and impaired cognitive functions. CIP prevented these molecular and cognitive changes. Perioperative CIP redistributes α5-GABAA receptors to cell-surface membranes and thus prevents or reverses surgery-induced increases in markers of microglial activation, apoptosis, and cognitive dysfunction. Increasing the number or activity of α5-GABAA receptors on cell-surface membranes may be an effective therapeutic strategy to reduce postoperative morbidity in elderly patients.},
}

@article {pmid40708572,
year = {2025},
author = {Pan, Y and Ji, N and Jiang, L and Zhou, Y and Feng, X and Li, J and Zeng, X and Wang, J and Shen, YQ and Chen, Q},
title = {GPCRs identified on mitochondrial membranes: New therapeutic targets for diseases.},
journal = {Journal of pharmaceutical analysis},
volume = {15},
number = {7},
pages = {101178},
pmid = {40708572},
issn = {2214-0883},
abstract = {G protein-coupled receptors (GPCRs) are the largest family of membrane proteins in eukaryotes, with nearly 800 genes coding for these proteins. They are involved in many physiological processes, such as light perception, taste and smell, neurotransmitter, metabolism, endocrine and exocrine, cell growth and migration. Importantly, GPCRs and their ligands are the targets of approximately one third of all marketed drugs. GPCRs are traditionally known for their role in transmitting signals from the extracellular environment to the cell's interior via the plasma membrane. However, emerging evidence suggests that GPCRs are also localized on mitochondria, where they play critical roles in modulating mitochondrial functions. These mitochondrial GPCRs (mGPCRs) can influence processes such as mitochondrial respiration, apoptosis, and reactive oxygen species (ROS) production. By interacting with mitochondrial signaling pathways, mGPCRs contribute to the regulation of energy metabolism and cell survival. Their presence on mitochondria adds a new layer of complexity to the understanding of cellular signaling, highlighting the organelle's role as not just an energy powerhouse but also a crucial hub for signal transduction. This expanding understanding of mGPCR function on mitochondria opens new avenues for research, particularly in the context of diseases where mitochondrial dysfunction plays a key role. Abnormalities in the phase conductance pathway of GPCRs located on mitochondria are closely associated with the development of systemic diseases such as cardiovascular disease, diabetes, obesity and Alzheimer's disease. In this review, we examined the various types of GPCRs identified on mitochondrial membranes and analyzed the complex relationships between mGPCRs and the pathogenesis of various diseases. We aim to provide a clearer understanding of the emerging significance of mGPCRs in health and disease, and to underscore their potential as therapeutic targets in the treatment of these conditions.},
}

@article {pmid40708508,
year = {2025},
author = {Rana, A and Malviya, R and Rajput, S and Sridhar, SB and Wadhwa, T},
title = {Trends in Nanoparticle-based Strategies for the Management of Neuroinflammation.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273373041250707012835},
pmid = {40708508},
issn = {1996-3181},
abstract = {Neuroinflammation, characterised by an overactive immune system in the brain and spinal cord, has now been tied to several neurodegenerative diseases. Here, immune cells invade into the brain, activating astrocytes and microglia. Neuroinflammation is a common symptom of many neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This inflammatory reaction occurs within the central nervous system (CNS). Neurological dysfunction results from the inflammatory response, which arises in reaction to any kind of brain injury. Regulating neuroinflammation can be useful for controlling brain disorders associated with neuroinflammation. Several targeted drug delivery systems attempt to treat neuroinflammation caused by neurodegenerative illnesses or brain tumours by targeting the microglia and other immune cells in the central nervous system. Therefore, biodegradable and biocompatible NPs (nanoparticles) could be developed as a treatment for neurodegenerative diseases caused by neuroinflammation or as a less invasive means of transporting other drugs across the blood-brain barrier. Numerous applications of gold nanoparticles (AuNPs) in the treatment of neurological diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are studied in this article. To prevent neuroinflammation and microglia over-activation, some NPs have recently been found to be effective anti-inflammatory medication carriers that cross the blood-brain barrier.},
}

@article {pmid40707875,
year = {2025},
author = {Wang, C and Bu, X and Cao, M and Lian, Y and Ling, H and You, M and Yi, J and Gao, X and Wu, D and Li, Y},
title = {Mir-199a-3p aggravates neuroinflammation in an Alzheimer's disease transgenic mouse model by promoting M1-polarization microgliaMir-199a-3p M1.},
journal = {BMC neuroscience},
volume = {26},
number = {1},
pages = {45},
pmid = {40707875},
issn = {1471-2202},
support = {yzjj2023qn15//President Foundation of Zhujiang Hospital, Southern Medical University/ ; 2018A0303130216//Natural Science Foundation of Guangdong Province/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *MicroRNAs/metabolism/genetics ; *Microglia/metabolism ; Mice, Transgenic ; Mice ; *Neuroinflammatory Diseases/metabolism/genetics/pathology ; Disease Models, Animal ; Hippocampus/metabolism ; Male ; Cytokines/metabolism ; },
abstract = {Chronic neuroinflammation, driven by M1-polarized microglia, is a core pathological mechanism of Alzheimer's disease (AD). Elevated expression levels of miR-199a-3p and pro-inflammatory cytokines were detected in the hippocampi of AD transgenic mice and in LPS-stimulated BV2 microglial cells. We hypothesized that miR-199a-3p exacerbates neuroinflammation by promoting M1 microglial polarization in AD progression. M1 （AD） 。 AD LPS BV2 miR-199a-3p 。 miR-199a-3p AD M1 。 OBJECTIVE: To explore the role of miR-199a-3p in AD-associated neuroinflammation. miR-199a-3p AD 。 METHODS: AD transgenic (APPswe/PSEN1dE9) mice and LPS-treated BV2 cells were used to assess miR-199a-3p effects in vivo and in vitro. Inflammatory cytokines and markers for microglial cell typing were detected. Transcriptome sequencing was performed on miR-199a-3p-modulated BV2 cells, and the sequencing data were cross-analyzed with public databases to predict miR-199a-3p-mediated pathways.AD （APPswe/PSEN1dE9） LPS BV2 miR-199a-3p 。。 miR-199a-3p BV2 ，， miR-199a-3p 。 RESULTS: Intracerebroventricular administration of miR-199a-3p agomir exacerbated amyloid deposition and impaired cognitive function in AD mice, and promoted microglial polarization toward the M1 phenotype. Conversely, treatment with miR-199a-3p antagomir attenuated AD pathology and suppressed M1 polarization. In LPS treated BV2 cells, miR-199a-3p mimics promoted M1 polarization, while inhibitors reversed this effect. Transcriptome analysis revealed that miR-199a-3p downregulated WDR76, subsequently suppressing cell cycle-associated pathways, IL-17 signaling, and FOXO pathways, resulting in an increase in the proportion of M1 type microglia. miR-199a-3p agomir AD ， M1 。， miR-199a-3p AD M1 。 LPS BV2 ，miR-199a-3p M1 ，。，miR-199a-3p WDR76，、 IL-17 FOXO ， M1 。 CONCLUSION: MiR-199a-3p aggravates neuroinflammation of AD by promoting M1-polarization microglia. These findings highlight miR-199a-3p as a potential therapeutic target for AD.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology
*MicroRNAs/metabolism/genetics
*Microglia/metabolism
Mice, Transgenic
Mice
*Neuroinflammatory Diseases/metabolism/genetics/pathology
Disease Models, Animal
Hippocampus/metabolism
Male
Cytokines/metabolism

@article {pmid40707826,
year = {2025},
author = {Chun, MY and Jeon, J and Chung, SJ and Kim, J},
title = {Association between osteoporosis and risk of dementia: a Korean women nationwide population-based cohort study.},
journal = {Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA},
volume = {},
number = {},
pages = {},
pmid = {40707826},
issn = {1433-2965},
support = {RS-2024-00345524//National Research Foundation of Korea/ ; },
abstract = {UNLABELLED: Brief rationale: dementia and osteoporosis share risk factors and are rising in aging populations.

MAIN RESULTS: osteoporosis significantly increases the risk of all-cause dementia, Alzheimer's disease dementia, and vascular dementia in Korean older women. Significance of the paper: early detection and treatment of osteoporosis may reduce dementia risk.

PURPOSE: Dementia and osteoporosis share common risk factors and are increasing in prevalence in the aging population. This study aimed to investigate the impact of osteoporosis on dementia and its subtypes in women using data from a population-based, health-screening cohort, with a follow-up period of more than 10 years.

METHODS: This retrospective study included 66-year-old Korean women who participated in the "National Screening Program for Transitional Ages" from 2010 to 2011. Participants were categorized based on spine bone mineral density T-scores into three groups: normal (T-score ≥ - 1.0 standard deviation [SD]; 18.7%), osteopenia (- 2.5 SD < T-score < - 1.0 SD; 42.5%), and osteoporosis (T-score ≤ - 2.5 SD; 38.8%). Incident dementia cases were evaluated until 2021 using national healthcare claims databases. Fine-Gray subdistribution hazard models were used to assess the risks of all-cause dementia including Alzheimer's disease (AD) dementia and vascular dementia (VaD), accounting for death as a competing risk.

RESULTS: The study included 131,872 dementia-free women aged 66 years. Over an average follow-up of 10.4 ± 1.8 years, 9399 individuals developed all-cause dementia (7.1%). Osteoporosis was associated with increased risks for all-cause dementia (adjusted subdistribution hazard ratio [asHR] 1.14; 95% confidence interval [CI] 1.08-1.21; p < 0.001), AD dementia (asHR 1.14; 95% CI 1.08-1.22; p < 0.001), and VaD (asHR 1.42; 95% CI 1.08-1.87; p = 0.013), compared to normal.

CONCLUSION: Our findings highlight an association between osteoporosis and increased risks of developing all-cause dementia, AD dementia, and VaD. Further research is needed to explore the effects of early identification and treatment of osteoporosis in preventing dementia.},
}

@article {pmid40706971,
year = {2025},
author = {Alshehri, GH and Al-Kuraishy, HM and Al-Gareeb, AI and Fawzy, MN and Waheed, HJ and Papadakis, M and Alexiou, A and El-Saber Batiha, G},
title = {A novel therapeutic prospect: a dual-acting tirzepatide for Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177979},
doi = {10.1016/j.ejphar.2025.177979},
pmid = {40706971},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, involves microglial activation, pro-inflammatory cytokine release, and impaired insulin signaling via insulin receptor substrate 1 (IRS-1) inhibition. Brain insulin resistance (BIR) is a key factor in AD progression, disrupting synaptic plasticity and neuronal function. Additionally, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) signaling, which regulate insulin pathways, are compromised in AD. GLP-1/GIP receptor activation or their analogs, such as tirzepatide, show potential in mitigating AD neuropathology. However, the precise neuroprotective mechanisms of tirzepatide remain unclear. This mini-review explores tirzepatide's potential therapeutic effects in AD, focusing on its role in restoring insulin signaling, reducing neuroinflammation, and improving cognitive function. Understanding these mechanisms could offer new insights into AD treatment strategies.},
}

@article {pmid40706880,
year = {2025},
author = {Duan, K and Qin, C and Zhang, Y and Li, D and Zhang, J and Li, F},
title = {Scorpion venom heat-resistant synthetic peptide regulates Nrf-2 to alleviate neuronal pyroptosis in an AD model induced by endoplasmic reticulum stress under PM2.5 exposure.},
journal = {Toxicon : official journal of the International Society on Toxinology},
volume = {},
number = {},
pages = {108504},
doi = {10.1016/j.toxicon.2025.108504},
pmid = {40706880},
issn = {1879-3150},
abstract = {In recent years, the impact of fine particulate matter (PM2.5) on the nervous system, particularly on neurodegenerative diseases, has garnered widespread attention. Epidemiological studies have shown that exposure to PM2.5 is closely associated with the development and progression of Alzheimer's disease (AD). However, the mechanisms through which PM2.5 exacerbates AD remain unclear. Scorpion venom heat-resistant synthetic peptide (SVHRSP) is a pharmacologically active product synthesised from the amino acid sequence of scorpion venom heat-resistant peptide. In this study, we investigated the mechanism through which PM2.5 exposure aggravates neuronal pyroptosis and validated the protective effects of SVHRSP against AD. PC12 and HT22 neuronal cells were used to construct in vitro models of AD. Mice were stereotactically injected with Aβ25-35 protein to induce AD. Subsequently, PM2.5 exposure-induced changes in ER stress, pyroptosis, and oxidative stress in AD models, were detected through in vivo and in vitro experiments. The results indicated that PM2.5 exposure aggravated cognitive impairment, ER stress, and pyroptosis in mice with AD. Conversely, treatment with SVHRSP counteracted the damage induced by PM2.5 exposure. At a mechanistic level, PM2.5 might enhance oxidative stress and trigger pyroptosis by suppressing the expression of Nrf-2. These findings offer novel insights into the mechanisms through which PM2.5 exposure hastens the progression of AD and propose a promising strategy for the pharmacological treatment of AD.},
}

@article {pmid40702688,
year = {2025},
author = {Song, X and Wang, Y and Zheng, K},
title = {Taurine ameliorates viral encephalitis by restoring PRKN-mediated mitophagy.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/15548627.2025.2538767},
pmid = {40702688},
issn = {1554-8635},
abstract = {Mitophagy is a selective type of autophagy that removes damaged mitochondria to maintain mitochondrial homeostasis and regulate the antiviral immune response. Despite increasing evidence that herpes simplex virus type 1 (HSV-1) infection causes mitochondrial damage, the regulatory mechanisms governing mitochondrial homeostasis and its biological implications in the context of HSV-1 infection and viral encephalitis remain unclear. In our recent work, we find that HSV-1 infection causes the accumulation of damaged mitochondria via defective mitophagy in vitro and in brain tissue of mice. The viral proteins ICP34.5 and US11 inhibit the EIF2S (eukaryotic translation initiation factor 2 subunit alpha)-ATF4 (activating transcription factor 4) axis to transcriptionally suppress PRKN/Parkin expression and subsequently impede PRKN-dependent mitophagy. Consequently, modulation of mitophagy significantly affects HSV-1 infection and NFKB/NF-κB-mediated neuroinflammation, as well as the severity of viral encephalitis in mice. Moreover, taurine, a metabolite differentially regulated by HSV-1 infection, transcriptionally promotes PRKN-mediated mitophagy, thereby limiting HSV-1 infection both in vitro and in vivo. This work reveals a protective function of mitophagy in restricting viral encephalitis and highlights the ATF4-PRKN axis as a potential therapeutic approach for the treatment of neurotropic virus-related diseases.Abbreviations: Aβ: amyloid β protein; AD: Alzheimer disease; ATF4: activating transcription factor 4; EIF2AK2/PKR: eukaryotic translation initiation factor 2 alpha kinase 2; EIF2S1: eukaryotic translation initiation factor 2 subunit alpha; HSE: herpes simplex encephalitis; HSV-1: herpes simplex virus type 1.},
}

@article {pmid40708156,
year = {2024},
author = {Ghosh, P and Iyer, PK},
title = {Conjugated Polyelectrolytes: Illuminating the Path to Neurodegenerative Disorders Detection and Treatment.},
journal = {ACS applied materials & interfaces},
volume = {16},
number = {16},
pages = {20034-20054},
doi = {10.1021/acsami.3c17890},
pmid = {40708156},
issn = {1944-8252},
mesh = {Humans ; *Polyelectrolytes/chemistry/therapeutic use ; Amyloid beta-Peptides/metabolism/chemistry ; *Neurodegenerative Diseases/diagnosis/drug therapy/metabolism ; Alzheimer Disease/diagnosis/drug therapy/metabolism ; Animals ; },
abstract = {Conjugated polyelectrolytes (CPEs) have gained extensive attention for their potential efficacy in protein misfolding disease (PMD) studies. This comprehensive review article explores the importance of CPEs in PMD research and treatment strategies. CPEs have unique features and capabilities, such as selective binding to disease-specific biomarkers like amyloid-beta (Aβ) aggregates which allows for noninvasive imaging methods to detect and identify early pathological alterations. They also induce unique fluorescence responses upon interaction with Aβ aggregates, enabling real-time monitoring of aggregation kinetics. The exceptional selectivity of CPEs has been demonstrated by their strategic chemical modification, by conjugating them with certain specific ligands, enhancing their diagnostic precision. Thus, CPEs hold immense potential to serve in the diagnosis and treatment of neurodegenerative diseases such as Alzheimer's due to their versatility.},
}

Humans
*Polyelectrolytes/chemistry/therapeutic use
Amyloid beta-Peptides/metabolism/chemistry
*Neurodegenerative Diseases/diagnosis/drug therapy/metabolism
Alzheimer Disease/diagnosis/drug therapy/metabolism
Animals

@article {pmid40706761,
year = {2025},
author = {Ohno, M},
title = {BACE1 as an early biomarker and its relevance to risk factors for Alzheimer's disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111475},
doi = {10.1016/j.brainresbull.2025.111475},
pmid = {40706761},
issn = {1873-2747},
abstract = {While the β-secretase BACE1 is responsible for the rate-limiting initial step to generate amyloid-β (Aβ) peptides, BACE1 inhibitor clinical trials have been halted due to a lack of efficacy and/or safety concerns at symptomatic/prodromal stages of Alzheimer's disease (AD). These trials were often targeted at high levels of BACE1 inhibition (>70%) and ended up with signs of mild cognitive worsening instead of expected improvement. BACE1 concentration and activity are elevated in the cerebrospinal fluid and plasma/serum as well as brains of patients with mild cognitive impairment and AD dementia. Interestingly, recent evidence suggests that these fluid-based biomarkers reflective of BACE1 elevation may be associated with yet asymptomatic pathological changes in preclinical AD populations who are at high-risk for developing AD. Consistent with these findings, it has been demonstrated that exposures to major environmental and genetic risks such as diabetes, sleep disturbances, seizure, vascular disorders, stress, apolipoprotein E4, etc. converge on BACE1 elevation in humans and animal models, which may contribute to triggering sporadic AD. Moreover, vicious cycles exist between BACE1/Aβ elevations and certain prognostic conditions, further accelerating disease progression. Conversely, protective factors for AD are associated with reduced BACE1 level/activity. This review provides an overview of BACE1 alterations as common responses to a broad battery of AD risk and protective factors. The findings validate BACE1 as a biomarker for preclinical AD status that may be useful for earlier diagnosis and identifying subpopulations of individuals under AD risks who would benefit from preventive low-dose BACE1 inhibitor treatment with a higher probability.},
}