@article {pmid41248588,
year = {2025},
author = {Mondal, P and Banerjee, P and Basuli, K},
title = {CPMFD: An algorithm for Classification of Point Mutations together with Frameshift Determination in related mRNA sequences.},
journal = {Mutation research},
volume = {831},
number = {},
pages = {111918},
doi = {10.1016/j.mrfmmm.2025.111918},
pmid = {41248588},
issn = {1873-135X},
abstract = {Mutations are responsible for the genetic origin of various diseases. Existing techniques for mutation identification often fails to detect the full spectrum of mutations in complex genomes hindering progress in diagnosis, treatment and prevention of diseases. Here we propose an algorithm to identify the location and type of mutation occurring in a mutated string with respect to a reference mRNA sequence. In addition to identifying insertion and deletion, by constructing suitable rational combinations of the prime numbers, our algorithm is able to classify point mutations in a novel way by distinguishing missense mutation from silent mutation. Amino acid transformation at each missense mutation site is identified. Moreover, the method allows to locate regions in the sequence undergoing frameshift. It turns out to be efficient when applied on sample dataset. Application of this framework to two haplotypes of the Plasmodium falciparum datasets exhibits different mutation profile to develop similar chloroquine resistance. Despite the overwhelming similarity between the β-globin genes of pygmy and common chimpanzees, our algorithm is able to pinpoint the minute details of the mutations occurring in them differentiating the two species. Additionally, in Alzheimer datasets, the method meticulously identifies true variations in related genes.},
}

@article {pmid41248418,
year = {2025},
author = {Sahin-Lodge, Z and Pisani, S and Nderitu, P and Guu, TW and Aarsland, D and Jackson, TL and Ffytche, D and Venkataraman, AV},
title = {Using retinal diagnostics as a biomarker for neurodegenerative diseases: protocol for a systematic review.},
journal = {BMJ open},
volume = {15},
number = {11},
pages = {e106531},
doi = {10.1136/bmjopen-2025-106531},
pmid = {41248418},
issn = {2044-6055},
mesh = {Humans ; Systematic Reviews as Topic ; *Neurodegenerative Diseases/diagnosis/diagnostic imaging ; Biomarkers ; Tomography, Optical Coherence ; *Retina/diagnostic imaging/pathology ; Research Design ; Electroretinography ; *Retinal Diseases/diagnosis ; },
abstract = {INTRODUCTION: Retinal neurodegeneration has recently been shown to occur in tandem with neurodegenerative disease. In the expectation that disease-modifying treatments for Alzheimer's disease (AD) and Parkinson's disease (PD) will soon become available, it will be important to have clinically useful biomarkers for neurodegenerative disease subtyping to guide early diagnosis, inform on prognosis and stratify subgroups for treatment. Understanding differences in detectable retina changes in individuals with different neurodegenerative disease subtypes is therefore fundamental. The emerging field of oculomics posits that systemic and neurodegenerative disease can be characterised using detectable ocular biomarkers within retinal diagnostics. The aim of this review is to compare the performance of common retinal imaging modalities in neurodegenerative disease detection and subtyping.

METHODS AND ANALYSIS: This protocol has been reported in accordance with the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols) guidelines. A comprehensive literature search will be conducted in PubMed, Web of Science and Scopus. Eligible studies will have reported using retinal diagnostic tools defined as optical coherence tomography (OCT), OCT angiography (OCTA), colour fundus photography (CFP) and electroretinography (ERG) in individuals with neurodegenerative diseases, including AD, PD, dementia with Lewy bodies, frontotemporal dementia, vascular dementia and mild cognitive impairment. There will be no time restrictions placed in these searches. Studies not written in English, not peer-reviewed and grey literature will be excluded. Screening for eligible studies and data extraction will be conducted by two independent reviewers, using predefined inclusion criteria. Any disagreements between the reviewers will be settled by discussion, and if required, third senior reviewer arbitration. The systematic review primary outcome is the performance of retinal diagnostics, namely OCT, OCTA, CFP and ERG in the detection and subtyping of aforementioned neurodegenerative diseases. The secondary outcome is to evaluate the association between changes in retinal diagnostic features (eg, retinal layer thicknesses) and neurodegenerative disease subtypes. The quality of the included studies will be assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluations) tool. A narrative synthesis approach will be used to analyse the results, with meta-analysis performed if there is sufficient data.

ETHICS AND DISSEMINATION: Ethical approval for this manuscript is not required, as this is a protocol for a systematic review and therefore no data are to be collected. Findings for this systematic review will be disseminated as a peer-reviewed publication and presentations at national and international symposiums including International Lewy Body Dementia Conference, International Congress of Parkinson's Disease and Movement Disorders, The Association for Research in Vision and Ophthalmology.

PROSPERO REGISTRATION NUMBER: CRD42023434024.},
}

Humans
Systematic Reviews as Topic
*Neurodegenerative Diseases/diagnosis/diagnostic imaging
Biomarkers
Tomography, Optical Coherence
*Retina/diagnostic imaging/pathology
Research Design
Electroretinography
*Retinal Diseases/diagnosis

@article {pmid41248283,
year = {2025},
author = {Akhter, F and Akhter, A and Zhu, X and Schiff, H and Maffei, A and Douglas, JT and Zhou, Q and Zhao, Z and Zhu, D},
title = {Amyloid-beta glycation induces neuronal mitochondrial dysfunction and Alzheimer's pathogenesis via VDAC1-dependent mtDNA efflux.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {47},
pages = {e2505046122},
doi = {10.1073/pnas.2505046122},
pmid = {41248283},
issn = {1091-6490},
mesh = {Animals ; *Voltage-Dependent Anion Channel 1/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology/genetics ; Mice ; Humans ; *Mitochondria/metabolism/pathology ; *Neurons/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *DNA, Mitochondrial/metabolism/genetics ; Nucleotidyltransferases/metabolism/genetics ; Membrane Proteins/metabolism/genetics ; Receptor for Advanced Glycation End Products/metabolism/genetics ; Glycation End Products, Advanced/metabolism ; Mice, Transgenic ; Glycosylation ; Male ; },
abstract = {Glycation, the nonenzymatic attachment of reactive dicarbonyls to proteins, lipids, or nucleic acids, contributes to the formation of advanced glycation end-products (AGEs). In Alzheimer's disease (AD), amyloid-beta (Aβ) undergoes posttranslational glycation to produce glycated Aβ (gAβ), yet its pathological role remains poorly understood. Here, we demonstrate that gAβ promotes neuronal mitochondrial DNA (mtDNA) efflux via a VDAC1-dependent mechanism, activating the innate immune cGAS-STING pathway. Using aged AD mice and human AD brain samples, we observed cGAS-mtDNA binding and cGAS-STING activation in the neuronal cytoplasm. Knockdown of RAGE, cGAS, or STING, as well as pharmacological inhibition of VDAC1, protected APP mice from mitochondrial dysfunction and Alzheimer's-like pathology. Neuron-specific cGAS knockdown confirmed its pivotal role in driving neuroinflammation and cognitive deficits. Treatment with ALT-711, an AGE cross-link breaker, alleviated gAβ-associated pathology. Furthermore, RAGE inhibition in APP knock-in mice suppressed innate immune activation and disease-associated gene expression, as revealed by spatially resolved transcriptomics. Collectively, our findings establish a mechanistic link between gAβ and innate immune activation, identifying VDAC1, the AGE-RAGE axis, and the cGAS-STING pathway as promising therapeutic targets in AD.},
}

Animals
*Voltage-Dependent Anion Channel 1/metabolism/genetics
*Alzheimer Disease/metabolism/pathology/genetics
Mice
Humans
*Mitochondria/metabolism/pathology
*Neurons/metabolism/pathology
*Amyloid beta-Peptides/metabolism
*DNA, Mitochondrial/metabolism/genetics
Nucleotidyltransferases/metabolism/genetics
Membrane Proteins/metabolism/genetics
Receptor for Advanced Glycation End Products/metabolism/genetics
Glycation End Products, Advanced/metabolism
Mice, Transgenic
Glycosylation
Male

@article {pmid41247815,
year = {2025},
author = {Rathnam, M and Hunter, H and Paul, PS and Schirrmacher, R and Serpe, MJ and Kar, S},
title = {Native PEG-PLGA Attenuates β-Amyloid Aggregation and Toxicity under In Vitro Conditions.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00379},
pmid = {41247815},
issn = {1948-7193},
abstract = {Self-aggregation of amyloid-β (Aβ) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD), the most prevalent cause of dementia affecting the elderly population. The development of an effective treatment for AD pathology remains elusive due to the presence of the blood-brain barrier (BBB) and the heterogeneous nature of disease progression. Recently, we reported that FDA-approved native poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles without any conjugated/encapsulated agent can attenuate Aβ aggregation/toxicity in cellular and animal models of AD. Given the limitation associated with the fast clearance of the native PLGA by the reticuloendothelial system (RES), in the present study, we synthesized PEGylated native PLGA nanoparticles (PEG-PLGA-1) to reduce their clearance via the RES and evaluated their effects on Aβ aggregation/toxicity after biochemical and structural characterization. Determined with Thioflavin T kinetic assay, dynamic light scattering and fluorescence imaging, it was revealed that the native PEG-PLGA-1, which exhibits increased stability, not only inhibits the aggregation of Aβ peptides, but also triggers the disassembly of Aβ aggregates. Additionally, we showed that PEG-PLGA-1 are nontoxic and can significantly enhance the viability of mouse primary cortical cultured neurons against Aβ-mediated toxicity. Collectively, these results suggest that native PEG-PLGA-1 nanoparticles can inhibit Aβ aggregation and trigger disassembly of Aβ aggregates and can protect neurons against Aβ-mediated toxicity, thus suggesting their unique therapeutic potential in the treatment of AD pathology.},
}

@article {pmid41247623,
year = {2025},
author = {Dosseto, A and Tonge, K and Karl, T},
title = {Cannabidiol Modulates Brain Copper Homeostasis in Wild-Type-Like But Not Alzheimer's Disease Transgenic Female Mice: Implications for Neuroprotective Therapy.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {57},
pmid = {41247623},
issn = {1559-1182},
mesh = {Animals ; *Copper/metabolism ; Mice, Transgenic ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Female ; *Cannabidiol/pharmacology/therapeutic use ; *Homeostasis/drug effects ; *Brain/metabolism/drug effects/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Iron/metabolism ; Mice, Inbred C57BL ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and neuroinflammation. Disrupted metal homeostasis-especially copper (Cu), zinc (Zn), and iron (Fe)-is implicated in AD pathogenesis, contributing to amyloid-beta (Aβ) aggregation and oxidative stress. Cannabidiol (CBD), a non-toxic phytocannabinoid with antioxidant and neuroprotective properties, has unclear effects on brain metal regulation. Using high-resolution laser ablation-inductively coupled plasma mass spectrometry (LA‑ICP‑MS), we quantified regional metal distributions in sagittal brain sections from 12‑month‑old female wild‑type (WT) and APP/PS1 transgenic mice treated chronically with CBD or vehicle. CBD significantly elevated whole‑brain Cu in WT mice but not in APP/PS1 mice. Although Zn and Fe concentrations did not differ significantly, effect-size trends revealed regional differences in Cu and Zn patterns across treatment groups, particularly in the hippocampus. Correlation analysis revealed coordinated inter‑regional metal regulation in WT and vehicle‑treated APP/PS1 groups, which was disrupted in CBD‑treated APP/PS1 mice. Additionally, CBD‑treated WT mice exhibited increased variance in cerebellar Cu, suggesting individual differences in response. These findings suggest that CBD influences Cu homeostasis in WT animals, though not significantly altered in transgenic animals under the conditions tested. Our results support integrating spatially resolved metallomics into preclinical AD frameworks and highlight the utility of metrics beyond mean concentration-such as regional ratios, correlation structures, and variability-for detecting subtle treatment effects.},
}

Animals
*Copper/metabolism
Mice, Transgenic
*Alzheimer Disease/metabolism/drug therapy/pathology
Female
*Cannabidiol/pharmacology/therapeutic use
*Homeostasis/drug effects
*Brain/metabolism/drug effects/pathology
*Neuroprotective Agents/pharmacology/therapeutic use
Mice
Iron/metabolism
Mice, Inbred C57BL

@article {pmid41247384,
year = {2025},
author = {Schönberger, A and Schild, AK and Steinmetz, A and Simandi, F and Benson, GS and Hausner, L and Schöttler, M and Hennig, B and Knudsen, A and Maier, F and Frölich, L and Jessen, F},
title = {[Optimization of the work of outpatient memory clinics under aspects of value-based healthcare-An approach from the Center for Memory Disorders of the University Hospital Cologne].},
journal = {Der Nervenarzt},
volume = {},
number = {},
pages = {},
pmid = {41247384},
issn = {1433-0407},
abstract = {BACKGROUND: Memory clinics in Germany are facing major challenges due to increasing numbers of patients and the first available disease-modifying treatments for Alzheimer's disease. Capacities for counselling, biomarker-based diagnostics, drug administration and follow-up examinations must be achieved, which creates the need for modified workflows. Value-based healthcare (VBHC) aims at optimizing the value for patients (outcome in relation to costs) and can serve as a framework for a patient-oriented increase in efficacy.

OBJECTIVE: This project applied approaches of VBHC to analyze and improve the diagnostic processes in our memory clinic in order to achieve a better value for patients and care partners with a more efficient use of existing resources.

METHODS: In a first survey among memory clinic patients and relatives the essential aspects in relation to VBHC were collated and based on the results the existing workflow processes were modified. These modifications were evaluated by a second survey and analysis particularly of process-oriented aspects.

RESULTS: The first survey revealed a general satisfaction with the presentation in the memory clinic. The main point of criticism was the duration of the diagnostic process. After the modification the duration and extent of the diagnostics could be reduced. The second evaluation showed improved patient and care partner satisfaction. The respondents considered the modified trajectories to be better and resources were conserved.

CONCLUSION: In our memory clinic an improvement in the sense of VBHC could be achieved through an increased satisfaction with the treatment (outcome) and reduced personnel binding times (costs). This approach can serve as a model for other memory clinics for the development of a more efficient and patient-centered care.},
}

@article {pmid41246746,
year = {2025},
author = {Bethea, JP and Sharma, H and Doberstein, N and Shenker, T and Gregory, B and Hoffman, R and Aizenman, D and Guirguis, G and Hoffmann, J and Tazani, S and Harris, Z and Costin, J},
title = {Application of Osteopathic Manipulative Treatment (OMT) in Neurodegenerative Disorders: A Scoping Review.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e94748},
doi = {10.7759/cureus.94748},
pmid = {41246746},
issn = {2168-8184},
abstract = {Neurodegenerative diseases are comprised of a host of chronic conditions that impair the central nervous system. Osteopathic manipulative treatment (OMT) consists of many non-invasive modalities that can be used to treat a wide variety of ailments and conditions. OMT is reported to increase the range of motion and lymphatic flow, as well as decrease pain in a wide array of disorders. However, the efficacy of using OMT in neurodegenerative disorders has not been well established. The objective of this scoping review is to map the evidence that pertains to the application of OMT in treating neurodegenerative disorders and identify the gaps in the literature on this subject. This study was designed according to the Joanna Briggs Institute (JBI) guidelines for scoping reviews to gather information on OMT's potential efficacy in managing Parkinson's disease (PD), Alzheimer's disease (AD) dementia, amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Peer-reviewed literature was collected through the Excerpta Medica database (EMBASE), Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), and Web of Science. The criteria were limited to papers in English published between 1999 and 2023. The following search string was utilized: "osteopathic manipulative treatment" OR "osteopathic manipulation" AND "neurodegenerative disorders" OR "Alzheimer's disease" OR "dementia" OR "amyotrophic lateral sclerosis" OR "Parkinson's disease" OR "Huntington's chorea". One hundred and forty-three articles were identified following final screening and critical appraisal, with eleven articles selected for analysis in this study. Data from the selected articles demonstrated that OMT can possibly attenuate symptoms in patients diagnosed with neurodegenerative diseases. Studies in rats showed that OMT techniques were found to alter cholinergic neuronal genes, improve spatial learning and memory, reduce amyloid β protein levels, modulate synaptic transmission, and increase levels of the cytokines IL-1, IL-10, IL-13, RANTES, IL-17A, and EOTAXIN effects in AD dementia. ALS patients demonstrated a high level of satisfaction with OMT and did not report any adverse effects, though there was no decrease in pain or increased quality of life reported. PD patients reported improved postural stability, balance, and gait after OMT. No results were returned regarding OMT's effects on HD. Preliminary results in human PD and ALS patients who received OMT as an adjunct to traditional treatment regimens showed promising results, though few studies were found that address the topic, and the sample sizes of the studies that were found were small. There were no studies of the effects of OMT on human patients with AD or HD found, though preclinical studies in rats supported their trial in subsequent human studies. While current research on the impact of OMT on these neurodegenerative diseases is promising, there remain large gaps in the literature. Further research is necessary to support the use of and long-term efficacy of OMT in neurodegenerative diseases.},
}

@article {pmid41246229,
year = {2025},
author = {Şahin, TÖ and Cemali, Ö and Özdemir, M and Ayten, Ş and Ağagündüz, D},
title = {Flavonoids and phenolic compounds: a promising avenue for neurodegenerative disease therapy.},
journal = {Turkish journal of biology = Turk biyoloji dergisi},
volume = {49},
number = {5},
pages = {635-659},
doi = {10.55730/1300-0152.2767},
pmid = {41246229},
issn = {1303-6092},
abstract = {BACKGROUND/AIM: Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are characterized by a progressive loss of nerve cells, for which no definitive cure currently exists. These conditions share common pathological mechanisms, including chronic neuroinflammation, oxidative stress, protein aggregation, and mitochondrial dysfunction. Flavonoids and other plant-derived phenolic compounds have recently attracted attention for the treatment of such conditions due to their antiinflammatory and antioxidant properties. This review explores the neuroprotective mechanisms of flavonoids and evaluates their potential for the prevention and treatment of neurodegenerative diseases.

MATERIALS AND METHODS: A literature search of the Web of Science, PubMed, and ScienceDirect databases was conducted to evaluate the therapeutic potential of flavonoids and phenolic compounds against neurodegenerative diseases. The search terms included "polyphenols", "flavonoids", and related compounds, along with "Alzheimer's", "Parkinson's", "Huntington's", and "Amyotrophic lateral sclerosis". Eligible studies included clinical trials, randomized controlled trials, and in vitro and in vivo research published in English. Priority was given to studies from the last decade, although older but significant publications were also included.

RESULTS: The findings of multiple studies report the ability of flavonoid compounds such as quercetin, myricetin, apigenin, and epigallocatechin gallate (EGCG) to modulate critical signaling pathways, reduce oxidative stress, prevent the accumulation of neurotoxic proteins, and support mitochondrial function. These bioactive molecules have exhibited significant potential in slowing disease progression and preserving neuronal integrity. Their therapeutic application, however, has been limited by their poor bioavailability, low stability, and rapid metabolism.

CONCLUSION: Flavonoids have shown promise as naturally derived agents with multi-targeted activity against neurodegenerative processes. Enhancing their absorption and stability through novel delivery systems and structural modifications could significantly improve their clinical efficacy. When administered early or as a complementary therapy, flavonoids can be considered a safe and effective approach to the management of neurodegenerative diseases.},
}

@article {pmid41245880,
year = {2025},
author = {Mahdavi, SA and Maghooli, K and Farokhi, F},
title = {A Fuzzy Cognitive Map-based Framework for Alzheimer's Disease Diagnosis Using Multimodal Magnetic Resonance Imaging-Positron Emission Tomography Registration.},
journal = {Journal of medical signals and sensors},
volume = {15},
number = {},
pages = {31},
doi = {10.4103/jmss.jmss_3_25},
pmid = {41245880},
issn = {2228-7477},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive and irreversible brain disorder, characterized by a gradual decline in cognitive and memory function, with memory loss being one of the most prominent symptoms. Accurate and early diagnosis of AD is essential for effective management and treatment. Structural magnetic resonance imaging (sMRI) and positron emission tomography (PET) are widely utilized neuroimaging modalities for diagnosing AD due to their ability to provide complementary structural and functional insights into brain abnormalities.

METHODS: This study introduces a novel computer-aided diagnosis system that integrates sMRI and PET data using Fuzzy Cognitive Maps (FCM) to improve diagnostic accuracy. The research is conducted using the ADNI dataset, where preprocessing of sMRI and PET images is performed using FSL and statistical parametric mapping tools, respectively. In a key innovation, features extracted from both modalities are fused and dimensionality reduction is achieved through an Autoencoder model. The reduced feature set is then classified using FCM, Support Vector Machine, k-Nearest Neighbors, and Multilayer Perceptron.

RESULTS: The FCM-based approach demonstrates superior performance, achieving the highest accuracy of 93.71%, surpassing other classifiers tested.

CONCLUSIONS: This study underscores the effectiveness of integrating FCM with multimodal neuroimaging data and highlights its potential for enhancing the early and reliable diagnosis of AD.},
}

@article {pmid41245492,
year = {2025},
author = {Hines, D and Tobey, H and Dugan, P and Boehringer, S and Helm, R and Anandakrishnan, R and Werre, S and VandeVord, P and Costa, BM},
title = {A preliminary study on the effect of quantified cranial osteopathic manipulation on wild-type and transgenic rat models of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251393742},
doi = {10.1177/25424823251393742},
pmid = {41245492},
issn = {2542-4823},
abstract = {Alzheimer's disease is a chronic progressive neurodegenerative disorder that impairs the meningeal lymphatics, glymphatic system, and compartmental fluid exchange, leading to a decline in cognitive function. Due to the lack of non-pharmacological and physiological treatments, cranial osteopathic manipulation (COM) poses a potential minimally invasive therapeutic choice. To understand the treatment and related effects objectively, we have established a technique to quantify the force applied during COM on an animal model of AD for the first time. Our results indicate that quantified COM can be applied to rodents to study behavioral and biochemical phenotype changes.},
}

@article {pmid41245147,
year = {2025},
author = {Pluta, R},
title = {Direct and indirect role of non-coding RNAs in company with amyloid and tau protein in promoting neuroinflammation in post-ischemic brain neurodegeneration.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1670462},
doi = {10.3389/fncel.2025.1670462},
pmid = {41245147},
issn = {1662-5102},
abstract = {Post-ischemic brain neurodegeneration with subsequent neuroinflammation is a major cause of mortality, permanent disability, and the development of Alzheimer's disease type dementia in the absence of appropriate treatment. The inflammatory response begins immediately after ischemia and can persist for many years. Post-ischemic neuroinflammation plays a dual role: initially, it is essential for brain repair and maintenance of homeostasis, but when it becomes uncontrolled, it causes secondary damage and worsens neurological outcome. Neuroinflammation is a complex phenomenon involving interactions between infiltrating immune cells from the peripheral circulation and resident immune cells in ischemic brain areas. This review focuses on the complex relationship between non-coding RNAs, amyloid accumulation, tau protein modifications, and the development of neuroinflammation in the post-ischemic brain. In particular, it clarifies whether the cooperation of non-coding RNAs with amyloid and tau protein enhances neuroinflammation and whether the vicious cycle of neuroinflammatory responses affects the production, behavior, and aggregation of these molecules. Ultimately, elucidating these interactions is critical, as they may contribute to resolving the phenomenon of post-ischemic brain neurodegenerative mechanisms. Furthermore, this review highlights the role of neuroinflammation as a functionally complex immune response regulated/mediated by transcription factors and cytokines. Additionally, it examines how the presence of non-coding RNAs, amyloid aggregation, and modified tau protein may shape the inflammatory landscape. This review aims to advance our understanding of post-ischemic neuroinflammation and its implications for long-term brain health.},
}

@article {pmid41244831,
year = {2025},
author = {Ye, S and Zhang, S and Zhang, L and Peng, G and Xie, M and Huang, X and Hu, Y},
title = {Screening and experimental validation of modified Gandou Decoction-targeted inhibitors for alleviating AD components via network pharmacology, machine learning, and molecular dynamics simulation.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1685866},
doi = {10.3389/fphar.2025.1685866},
pmid = {41244831},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by abnormal accumulation of β-amyloid (Aβ) and hyperphosphorylation of the Tau protein. Currently, there is a lack of effective and safe therapeutic approaches. In Traditional Chinese medicine (TCM), Gandou Decoction has shown significant efficacy in improving cognitive decline and dementia-related symptoms, but its specific mechanism remains unclear.

METHODS: This study systematically analyzed the active components and anti-AD mechanism of Modified Gandou Decoction (MGD) by integrating network pharmacology, machine learning, molecular docking, molecular dynamics (MD) simulation, and in vitro experimental validation. Obtain the components of Chinese medicines in MGD from TCMSP and screen them via ADMET; obtain AD targets by combining databases and select core targets through machine learning; verify their effects through various analyses and experiments.

RESULTS: A total of 21 potential active molecules of MGD and 68 intersection targets were screened out. Among them, 8 core targets (EIF2AK2, PPARG, BACE1, ESR1, GSK3B, ACE, CASP3, MAPK14) were confirmed to be significantly associated with AD pathology by gene expression difference analysis (P ≤ 0.05). KEGG enrichment analysis showed that MGD mainly intervenes in the amyloid production pathway, the MAPK pathway, and the IL-17 pathway. Molecular docking demonstrated that the majority of the 21 potential active compounds exhibited strong binding affinities to the 8 core targets. Moreover, some potential active molecules exhibited better binding energy and similar binding modes compared with known inhibitors when binding to the corresponding target proteins. Molecular dynamics simulation showed that Alisol B, a potential active component of MGD, could stably bind to BACE1, EIF2AK2, and CASP3. In vitro cell experiments confirmed that Alisol B could significantly reverse okadaic acid-induced damage in SH-SY5Y cells (p < 0.001).

CONCLUSION: MGD exerts its anti-AD effect through its potential active component Alisol B, which binds to target proteins BACE1, EIF2AK2, and CASP3, and synergistically inhibits Aβ production, Tau phosphorylation, and neuroinflammatory processes through multiple pathways. This study provides a foundation for developing MGD-derived natural products for AD treatment, although the precise mechanisms require further experimental validation.},
}

@article {pmid41243261,
year = {2025},
author = {Bramen, JE and Siddarth, P and Popa, ES and Kress, GT and Rapozo, MK and Hodes, JF and Ganapathi, AS and Sparks, WM and Tongson, YM and Torres, AM and Meysami, S and Slyapich, CB and Glatt, RM and Pierce, K and Miller, KJ and Elhelou, SH and Porter, VR and Wong, C and Kim, M and Panos, S and Hirsch, DA and Raji, CA and Bookheimer, SY and Hood, L and Roach, JC and Merrill, DA},
title = {A multi-modal medical management and lifestyle intervention increase cerebral blood flow and lowers diabetic risk in persons with early Alzheimer's disease: Mid-trial results from the PREVENTION trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251388933},
doi = {10.1177/13872877251388933},
pmid = {41243261},
issn = {1875-8908},
abstract = {BackgroundMedical and lifestyle management are crucial for Alzheimer's disease (AD). Cerebral blood flow (CBF), vital for brain health, and influenced by modifiable risk factors, is reduced in AD and may become uncoupled from metabolism due to neurovascular dysfunction in later stages.ObjectiveThis mid-trial analysis tested the hypothesis that a coached, multi-modal intervention (PREVENTION) improved ASL-MRI-measured CBF and diabetic risk (QUICKI) in patients with early AD.MethodsThe control arm received recommendations and medical management for one year; the active arm additionally received coaching, exercise training, and supplementation. We hypothesized that those in (1) the active arm and (2) with higher intervention adherence would have improved post-trial QUICKI and CBF, particularly in regions relevant to exercise, cardiovascular, diabetic, and AD risk. Post-trial CBF was analyzed using a linear model including arm, baseline CBF, adherence, age, education, and depressive symptoms. Change in QUICKI was analyzed using mixed effects general linear models, including arm, adherence, time, and interactions between time and treatment group and time and adherence, controlling for age.ResultsThe active arm (n = 18) showed greater post-trial CBF in regions related to exercise, cardiovascular, diabetic, and AD risk, compared to control (n = 20), but did not differ in global CBF, QUICKI, or adherence. Higher adherence scores were associated with greater regional post-trial CBF and improvement in QUICKI, but not global CBF.ConclusionsIn this small sample, we found evidence that a multi-modal intervention focused on medical management, exercise, and a carbohydrate-restricted diet improved diabetic risk and CBF in patients with AD.},
}

@article {pmid41242500,
year = {2025},
author = {Gungor, D and Muratoglu, S and Aytekin, E and Reçber, T and Telli, G and Akdag, Y and Sahin, S and Gulsun, T},
title = {Assessment of intranasal permeability and pharmacological activity of glyburide-loaded nanosuspension formulation for Alzheimer's disease.},
journal = {Journal of pharmaceutical sciences},
volume = {},
number = {},
pages = {104064},
doi = {10.1016/j.xphs.2025.104064},
pmid = {41242500},
issn = {1520-6017},
abstract = {Glyburide is an anti-diabetic drug with promising potential implications for Alzheimer's disease. This study evaluated the permeability and activity of glyburide via intranasal administration in Alzheimer's disease using both in vivo and ex vivo studies. A glyburide nanosuspension, was used as the drug delivery system. Stability studies demonstrated that the nanosuspension formulation presented suitable stability during in vitro and in vivo studies. The chosen in vivo glyburide dose demonstrated a non-toxic profile via MTT. Additionally, the in vitro permeability of the nanosuspension was assessed. Pharmacological activity was further evaluated through in vivo behavioural tests, including the Morris water maze and novel object recognition tests, and amyloid-beta levels were measured in mice brain tissues with ELISA. Ex vivo quantification of glyburide concentration in various tissues was also conducted. In vitro permeability studies showed that the nanosuspension formulation significantly enhanced permeability of glyburide. In vivo behavioural tests demonstrated that the nanosuspension formulation yielded favourable and promising outcomes even it was administered intranasally. This study suggests that, through the solubility enhancement provided by nanocrystal technology increased the bioavailability of glyburide comparing the intranasal administration of glyburide, leading to improve in vivo activity compared to the raw glyburide suspension in the treatment of Alzheimer's disease.},
}

@article {pmid41242034,
year = {2025},
author = {Bruyère, O and Leroy, L and Olivier, C and Demonceau, C and Buckinx, F and Blavier, M and Lekeu, F},
title = {Exploring the knowledge, attitudes, and practices of physical therapists in care facilities assisting individuals with Alzheimer's disease.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {67},
number = {},
pages = {103710},
doi = {10.1016/j.gerinurse.2025.103710},
pmid = {41242034},
issn = {1528-3984},
abstract = {INTRODUCTION: Physical therapists (PTs) in nursing homes often treat patients with Alzheimer's disease. This study evaluated their knowledge, attitudes, and practices (KAP) concerning Alzheimer's care.

METHODS: A KAP survey-based questionnaire was administered to PTs in Belgian nursing homes and long-term care facilities, focusing on their understanding of Alzheimer's, care approaches, and practical care aspects.

RESULTS: The survey, completed by 133 PTs, revealed strong knowledge and positive attitudes. PTs adapted communication methods, managed treatment refusals, and prioritized fall prevention and safety. Care practices focused on maintaining patient autonomy through exercises for strength, balance, and coordination. Techniques like massage or aromatherapy were less commonly used, despite potential benefits. Notably, knowledge, experience, or exposure to Alzheimer's patients did not significantly influence attitudes or practices.

CONCLUSION: Targeted practical training in dementia care techniques is needed to enhance caregiving skills, despite a solid foundation in knowledge and attitudes. Future research should examine diverse samples and evaluate training impact on practices.},
}

@article {pmid41241266,
year = {2025},
author = {Sharma, A and Singh, TG},
title = {Next-generation neurotherapeutics: mechanistic insights on monoclonal antibodies in Alzheimer's disease.},
journal = {Brain research},
volume = {},
number = {},
pages = {150047},
doi = {10.1016/j.brainres.2025.150047},
pmid = {41241266},
issn = {1872-6240},
abstract = {Monoclonal antibodies (mAbs) for Alzheimer's disease (AD) present a fundamental translational challenge, as demonstrated by amyloid-beta (Aβ)-targeting mAbs that successfully employed Fragment crystallizable gamma receptor (FcγR)/Immunoreceptor tyrosine-based activation motif (ITAM)-mediated microglial phagocytosis yet achieved only modest cognitive improvements while introducing significant Amyloid-related imaging abnormalities (ARIA) risk, thereby highlighting inherent single-therapy limitations. Building on these findings, tau-directed antibodies show preclinical promise by targeting pathological seeding and propagation, but face translational challenges including limited extracellular accessibility and variable efficacy across disease stages, necessitating expansion beyond single-target approaches. Consequently, the translational field is advancing toward innovative multi-mechanistic strategies, including synaptic restoration through anti-PrP and neurotrophic receptor agonists that provide functional benefits independent of plaque reduction, neuroinflammation modulation via anti-CD33 and complement inhibitors requiring careful patient selection due to variable outcomes, and emerging anti-TREM2 and anti-APOE4 mAbs enabling precision medicine tailored to individual genetic profiles. Importantly, comparative studies also reveal that combination therapies-especially dual Aβ/tau targeting-demonstrate superior synergistic effectiveness, driving next-generation engineering advances including Fc modifications that reduce ARIA risk, nanobodies/single-chain variable fragments (scFvs) with enhanced blood-brain barrier (BBB) penetration, cell-penetrating formats for intracellular tau access, and pH-sensitive glycoengineering for optimized tissue-specific binding. Ultimately, successful clinical translation depends on integrating biomarker-guided patient selection, optimized dosing strategies, and disease-stage-appropriate timing, with future progress anticipated through bispecific/multispecific antibodies targeting complementary pathways alongside personalized biomarker approaches, collectively providing realistic potential for achieving genuine neuroprotection and meaningful disease modification beyond symptomatic treatment in AD patients.},
}

@article {pmid41240919,
year = {2025},
author = {Kaila, LV and Ikeda, M and Sultana, J and Chouliaras, L and O'Brien, JT and Taylor, JP},
title = {The evolving therapeutic landscape of dementia with Lewy bodies.},
journal = {The Lancet. Neurology},
volume = {24},
number = {12},
pages = {1038-1052},
doi = {10.1016/S1474-4422(25)00323-0},
pmid = {41240919},
issn = {1474-4465},
mesh = {Humans ; *Lewy Body Disease/therapy/diagnosis ; },
abstract = {Dementia with Lewy bodies has a complex clinical presentation, with symptoms spanning cognitive, neuropsychiatric, motor, autonomic, and sleep domains. The disorder causes high morbidity, is associated with high caregiver burden, and can result in considerable health-care costs. Although symptomatic treatments remain scarce, emerging evidence supports a multipronged approach that integrates pharmacological and non-pharmacological interventions that target different signs and symptoms. Novel frameworks, such as the DIAMOND Lewy toolkit, provide structured management guidance. Beyond symptom control, research is at a turning point, with increasing focus on disease-modifying therapies. Ongoing clinical trials are exploring many therapeutic targets, including α-synuclein aggregation and neuroinflammation. Other potential targets in the treatment of dementia with Lewy bodies include amyloid β, given that the presence of Alzheimer's disease copathology is common in patients with this disease.},
}

Humans
*Lewy Body Disease/therapy/diagnosis

@article {pmid41240389,
year = {2025},
author = {Jahanmehr, D and Ahmadi, A and Fadaei, M and Sangi Nasab Lahijan, A and Shafiee Sabet, M and Kalantari Dehaghi, H and Asadi-Golshan, R},
title = {The Ketogenic Diet: A Possible Intervention for Improving Hippocampal Function in Neurological Disorders.},
journal = {Nutrition reviews},
volume = {},
number = {},
pages = {},
doi = {10.1093/nutrit/nuaf210},
pmid = {41240389},
issn = {1753-4887},
abstract = {With a focus on the hippocampus, in this review we examined the emerging role of the ketogenic diet (KD) in treating neurological disorders. There are multiple pathways through which various versions of the KD influence the hippocampus: energy metabolism shifts, neurotransmitter modulation, neuroinflammation control, and synaptic plasticity and epigenetic regulation modifications. Both animal studies and clinical research, with emphasis on epilepsy and Alzheimer disease, have revealed the therapeutic potential of KDs. By modifying energy metabolism and lowering neuroinflammation, KDs may have therapeutic uses such as treatment of epilepsy and Alzheimer disease. In addition, ketones may stabilize hippocampal neuronal networks and reduce amyloid-beta toxicity. Individualized factors and the duration and timing of KD intervention play critical roles in achieving optimal outcomes, such as enhanced hippocampal function and neuroprotection. While preclinical studies have demonstrated enhanced hippocampal synaptic plasticity and neuroprotection, the long-term neurological and metabolic effects of KDs require further clinical validation. There are still a number of important research gaps, especially with regard to the application of animal findings to humans. Future studies should concentrate on long-term human trials using standardized designs to investigate how KDs can affect the nervous system.},
}

@article {pmid41240365,
year = {2025},
author = {Zammit, MD and Bruzzone, H and Cody, KA and Morse, J and Wilson, R and Bettcher, BT and McLachlan, MJ and McVea, AK and DiFilippo, AH and Carey, FJ and Janelidze, S and Hansson, O and Price, JC and Laymon, CM and Minhas, DS and Luo, W and Rosas, HD and Lai, F and Lee, JH and Lao, PJ and Ances, BM and Krinsky-McHale, SJ and Hom, CL and Hartley, SL and Zaman, SH and Johnson, SC and Cohen, AD and Head, E and Mapstone, ME and Handen, BL and Christian, BT and Tudorascu, DL and Langhough, RE and Betthauser, TJ and , },
title = {The tau biomarker cascade is condensed in Down syndrome compared to sporadic Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf428},
pmid = {41240365},
issn = {1460-2156},
abstract = {Characterizing the timing and progression of Alzheimer's disease biomarker onset in Down syndrome (DS) and contrasting potential timing differences with neurotypical adults is needed to identify optimal Alzheimer's disease therapeutic treatment windows in DS. In this study, 198 adults with DS from the Alzheimer Biomarker Consortium - Down Syndrome and 172 neurotypical adults from the Wisconsin Registry for Alzheimer's Prevention with available longitudinal beta-amyloid PET, tau PET and plasma p-tau217 analyzed on Lilly MSD were included. Individuals with DS had a significantly higher lifetime risk of beta-amyloid plaque onset. Temporal modeling of longitudinal biomarker measures revealed earlier age at positivity of beta-amyloid plaques, p-tau217 and neurofibrillary tau tangles in DS relative to the neurotypical cohort. The onset of p-tau217 and tau PET positivity in DS occurred nearly simultaneously, roughly 4-6 years following beta-amyloid onset, whereas the neurotypical group displayed greater temporal latency between positivity of the two biomarkers. The early and simultaneous onset of these biomarkers in DS highlights the necessity for early therapeutic interventions in this population. This work, combined with the upcoming anti-amyloid safety and efficacy clinical trials for DS will help identify optimal treatment windows for these individuals.},
}

@article {pmid41240244,
year = {2025},
author = {Jayathilaka, NS and Weththasinghe, AV and Amarasekara, CI and Amasha, EADH and Wijekoon, KJ and Firdous, SM},
title = {Targeting the Gut-Brain Axis Through Insulin-like Growth Factors: Therapeutic Implications and Future Directions.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {4},
pages = {150},
pmid = {41240244},
issn = {1559-1166},
mesh = {Humans ; Animals ; *Brain/metabolism ; Gastrointestinal Microbiome ; *Somatomedins/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy/therapy ; *Insulin-Like Growth Factor I/metabolism ; *Brain-Gut Axis ; *Gastrointestinal Tract/metabolism ; Insulin-Like Peptides ; },
abstract = {The gut-brain axis represents a sophisticated bidirectional communication network connecting the gastrointestinal tract and central nervous system through neural, endocrine, and immune pathways. Insulin-like growth factors (IGFs), particularly IGF-1 and IGF-2, function as pivotal mediators within this communication framework. These polypeptide growth factors regulate intestinal barrier integrity, microbiota homeostasis, neurogenesis, and synaptic plasticity mechanisms. Clinical evidence from 1989 to 2024 demonstrates that gut microbiota-derived short-chain fatty acids enhance IGF-1 production through novel molecular mechanisms. This narrative review examines IGF roles in gut-brain communication and evaluates therapeutic potential for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and depression, as well as inflammatory bowel disorders. Current clinical trials investigating IGF-based interventions show preliminary promising results, though studies remain limited in scope and patient numbers. Key therapeutic challenges include delivery mechanisms across biological barriers, oncogenic safety concerns related to cell proliferation, and substantial individual variability in treatment responses. Future directions emphasize development of tissue-specific IGF modulators, microbiome-targeted interventions, and precision medicine approaches utilizing advanced biomarkers. Understanding IGF-mediated gut-brain communication presents therapeutic opportunities for complex pathological conditions simultaneously affecting gastrointestinal and neurological systems.},
}

Humans
Animals
*Brain/metabolism
Gastrointestinal Microbiome
*Somatomedins/metabolism
*Neurodegenerative Diseases/metabolism/drug therapy/therapy
*Insulin-Like Growth Factor I/metabolism
*Brain-Gut Axis
*Gastrointestinal Tract/metabolism
Insulin-Like Peptides

@article {pmid41240183,
year = {2025},
author = {García-Castro, P and Conejo, NM and González-Pardo, H},
title = {Transcranial photobiomodulation therapy in older women regarding cognitive functions: a systematic review.},
journal = {Lasers in medical science},
volume = {40},
number = {1},
pages = {480},
pmid = {41240183},
issn = {1435-604X},
mesh = {Humans ; *Low-Level Light Therapy/methods ; Female ; *Cognition/radiation effects ; Aged ; *Cognitive Dysfunction/therapy ; Animals ; Alzheimer Disease/therapy ; },
abstract = {Transcranial photobiomodulation therapy (tPBM) is a promising non-invasive treatment that uses red or near-infrared light to modulate biological functions and elicit therapeutic effects. This systematic review aimed to summarise the evidence on the effectiveness of tPBM in improving cognitive function in older women, in experimental animal models and in humans, by analyzing the optimal tPBM parameters and behavioral and neurobiological outcomes. tPBM offers advantages specific to older women as a non-invasive brain stimulation technique, applied to a sensitive population with increased risk of ageing-related brain dysfunction due to increased life expectancy. A comprehensive literature search was conducted in PubMed, Scopus, and PsycINFO databases, and only seven articles on older women were included in the review. Studies have shown that tPBM significantly improves cognitive impairment in Alzheimer's disease and related dementias, stroke, cognition and Parkinson's disease in older women. Despite the heterogeneity in the application parameters and limited number of studies, tPBM therapy was preliminarily found to be a safe, feasible, and effective non-pharmacological therapy for several neurological and mental health conditions in older women. Further research is required to establish standardized protocols for optimal therapeutic applications.},
}

Humans
*Low-Level Light Therapy/methods
Female
*Cognition/radiation effects
Aged
*Cognitive Dysfunction/therapy
Animals
Alzheimer Disease/therapy

@article {pmid41239797,
year = {2025},
author = {Garg, N and Dhankhar, S and Dhariya, A and Parkash, C and Chauhan, S and Singh, TG},
title = {Role of Liposomes in the Treatment of Neurodegenerative Disorders: A Comprehensive Review.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {25},
number = {4},
pages = {496-512},
pmid = {41239797},
issn = {1875-6166},
mesh = {Humans ; *Liposomes/metabolism/chemistry ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Drug Delivery Systems/methods ; *Neuroprotective Agents/administration & dosage/therapeutic use ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {The complex etiology and limited therapy options of neurodegenerative illnesses pose daunting challenges to modern medicine. Nonetheless, novel treatment approaches have exciting new possibilities because of developments in nanotechnology. Liposomes have garnered a lot of interest as a potential treatment for neurological illnesses due to the fact that they are able to adapt to their role as nanocarriers. This review article discusses various uses of liposomes, including their ability to help treat neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, as well as their diagnostic and neuroprotective uses. Liposomes allow for the targeted delivery of medicines to specific brain areas with minimal systemic side effects since they encapsulate and carry therapeutic molecules across the blood-brain barrier. Due to the fact that they are biocompatible, have surface features that can be adjusted, and have the ability to co-deliver many drugs, liposomes are excellent candidates for combination therapy and personalized medicine procedures. In spite of this, there is a growing body of research that suggests liposomes could serve as a versatile platform for the improvement of neurodegenerative disease treatment. This is a positive sign for the future results of patients and their quality of life.},
}

Humans
*Liposomes/metabolism/chemistry
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
*Drug Delivery Systems/methods
*Neuroprotective Agents/administration & dosage/therapeutic use
Blood-Brain Barrier/metabolism/drug effects

@article {pmid41239092,
year = {2025},
author = {Kong, W and Miao, X and Dang, R and Jiang, P and Feng, L},
title = {Mechanisms and Clinical Significance of Endosomal Toll-Like Receptors in Neurological Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {54},
pmid = {41239092},
issn = {1559-1182},
support = {82373585//National Natural Science Foundation of China/ ; 2023M741364//the China Postdoctoral Science Foundation/ ; ZR2022MH007//the Natural Science Foundation of Shandong Province/ ; 2022YXNS124//the Jining Key R&D Projects/ ; 2022YXNS137//the Jining Key R&D Projects/ ; 202304040457//the Medical and Health Science and Technology Development Project of Shandong Province/ ; },
mesh = {Humans ; *Toll-Like Receptors/metabolism ; *Endosomes/metabolism ; Animals ; *Nervous System Diseases/metabolism ; Signal Transduction ; Clinical Relevance ; },
abstract = {Neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and epilepsy constitute a major global public health burden, affecting millions of patients. Recent studies have shown that the complex interactions between the immune system and the nervous system play a significant role in these diseases, especially Toll-like receptors (TLRs), among which endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) are crucial in neuroinflammation and disease progression. This review systematically elaborates on the biological characteristics of endosomal TLRs, their distribution, and signaling pathways within the central nervous system, with a particular focus on their "double-edged sword" effect in specific disease contexts: on the one hand, they may provide neuroprotection, while on the other hand, they can exacerbate neural injury and neurodegeneration during immune dysregulation. Furthermore, this article evaluates the potential and challenges of utilizing endosomal TLRs as early diagnostic biomarkers. It summarizes research progress in targeted regulatory strategies as emerging therapeutic approaches, along with the encountered bottlenecks in clinical translation. The review aims to systematically integrate fundamental mechanistic research with clinical application prospects, emphasizing the critical importance of in-depth elucidation of the mechanistic roles of endosomal TLRs in neurological disorders and their translational value in diagnosis and treatment. Clinical trial number: not applicable.},
}

Humans
*Toll-Like Receptors/metabolism
*Endosomes/metabolism
Animals
*Nervous System Diseases/metabolism
Signal Transduction
Clinical Relevance

@article {pmid41239049,
year = {2025},
author = {Ma, H and Cong, C},
title = {Insights and advances of theranostic nanoscale metal-organic frameworks.},
journal = {Mikrochimica acta},
volume = {192},
number = {12},
pages = {809},
pmid = {41239049},
issn = {1436-5073},
mesh = {*Metal-Organic Frameworks/chemistry ; Humans ; *Theranostic Nanomedicine/methods ; Contrast Media/chemistry ; Animals ; },
abstract = {As one class of multifunctional materials, metal-organic frameworks (MOFs) with virtues like large surface area, high porosity, and tailorability have been found in many applications. Particularly, the investigation on health is rapidly growing. Accurate diagnosis and efficient treatment of diseases are increasingly important but challenging. Nanoplatforms based on MOFs are receiving much attention, which has made significant progress in imaging and drug delivery during the past few years. This review article will summarize and discuss the latest development of nanoscale MOFs in the following topics: contrast agents for magnetic resonance imaging (MRI); X-ray computed tomography imaging (CT); optical imaging (OI); photoacoustic imaging (PAI); photothermal imaging (PTI); positron emission tomography (PET); single-photon emission computed tomography (SPECT); and multimodal imaging (MI). In addition, targeting drug delivery by MOFs to treat diseases will be categorized into the followings: cancers; lung diseases; bone diseases; diabetes; infections; wound healing; bowel diseases; Alzheimer's disease; ocular diseases; and atherosclerosis.},
}

*Metal-Organic Frameworks/chemistry
Humans
*Theranostic Nanomedicine/methods
Contrast Media/chemistry
Animals

@article {pmid41238774,
year = {2025},
author = {Cerman, J and Škorvagová, A and Vyhnálek, M and Veverová, K and Dvořák, K and Kozák, Š and Kavka, A and Hort, J},
title = {Concordance between amyloid PET and CSF biomarkers in clinical setting: a cross-platform comparison and in-depth analysis of discordant cases.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39963},
pmid = {41238774},
issn = {2045-2322},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/diagnosis/metabolism ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Female ; *Positron-Emission Tomography/methods ; Aged ; tau Proteins/cerebrospinal fluid ; Middle Aged ; Peptide Fragments/cerebrospinal fluid ; *Amyloid/metabolism ; Aged, 80 and over ; Enzyme-Linked Immunosorbent Assay ; Apolipoprotein E4/genetics ; },
abstract = {Reliable detection of amyloid pathology is essential for Alzheimer's disease (AD) diagnosis and treatment. We directly compared routine ELISA assays and the automated Lumipulse platform against quantitative amyloid PET in a real-world memory clinic cohort. In 153 participants, flutemetamol amyloid PET and CSF biomarkers were assessed across platforms. Concordance with PET and predictors of discordance were evaluated. PET visual reads and Centiloids showed near-perfect agreement (AUC = 0.99). The p-tau181/Aβ42 ratio achieved the highest concordance with PET (OPA 87% ELISA, 92% Lumipulse), while the Lumipulse Aβ42/40 ratio reached 93%. About 6% of participants showed consistent discordance between CSF and PET, associated with APOE ε4 and mixed or non-AD pathologies. Automated CSF assays align strongly with amyloid PET and support biomarker standardization. Persistent discrepancies between CSF and PET likely reflect underlying biological heterogeneity such as mixed or non-AD pathologies and APOE ε4 carriage.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/diagnosis/metabolism
Male
*Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Female
*Positron-Emission Tomography/methods
Aged
tau Proteins/cerebrospinal fluid
Middle Aged
Peptide Fragments/cerebrospinal fluid
*Amyloid/metabolism
Aged, 80 and over
Enzyme-Linked Immunosorbent Assay
Apolipoprotein E4/genetics

@article {pmid41238601,
year = {2025},
author = {Alzarea, SI},
title = {Identification of novel neuraminidase 1 modulators as potential therapeutics for Alzheimer's disease using virtual screening and molecular dynamics simulations.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39901},
pmid = {41238601},
issn = {2045-2322},
support = {KSRG-2024-340//King Salman Center for Disability Research/ ; },
mesh = {*Neuraminidase/antagonists & inhibitors/metabolism/chemistry ; *Alzheimer Disease/drug therapy/enzymology/metabolism ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Humans ; *Enzyme Inhibitors/pharmacology/chemistry ; Drug Evaluation, Preclinical ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder caused by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles, resulting in neuronal dysfunction and cognitive decline. The neuraminidase isoenzyme NEU1 is a most ubiquitous mammalian enzyme, involved in various cellular mechanisms. The deficiency of NEU1 has been implicated in the pathophysiology of AD, significantly in amyloid precursor protein (APP) metabolism and Aβ clearance. Despite extensive research, no potent NEU1 modulator has been developed to regulate its activity for therapeutic intervention in AD. The present work aims to identify potential NEU1 modulators from a library of seaweed Metabolites Database through molecular docking, ADMET analysis, and molecular dynamics (MD) simulations. A library of 1,077 seaweed metabolites was screened, identifying 20 active compounds, of which 4 met Lipinski's Rule of Five criteria. ADMET profiling revealed favorable pharmacokinetic properties for BE003, BS032, and RG007, with good blood-brain barrier permeability and bioavailability. Molecular docking demonstrates that BE003, BS032, RG007, and BD039 metabolites exhibited the highest binding affinities for the NEU1 active site. Additionally, MD simulation and MM-GBSA validated the stability of the metabolite-protein complex, with BE003 demonstrating the most stable interactions. Comparative docking against a natural substrate (Neu5Ac) and a NEU1 inhibitor (17f) revealed that BE003 shares significant interaction, RMSD stability profiles with the substrate and loop conformational dynamics while differing from the inhibitor. Our findings emphasize the potential of this modulator as a novel therapeutic target against NEU1 in AD treatment. Further experimental validation and preclinical studies are needed to confirm its efficacy in modulating NEU1 activity.},
}

*Neuraminidase/antagonists & inhibitors/metabolism/chemistry
*Alzheimer Disease/drug therapy/enzymology/metabolism
Molecular Dynamics Simulation
Molecular Docking Simulation
Humans
*Enzyme Inhibitors/pharmacology/chemistry
Drug Evaluation, Preclinical

@article {pmid41238155,
year = {2025},
author = {Heath, AM and Mojabi, FS and Kraybill, EP and Beard, C and Venkataramanan, V and Cuéllar, V and Piekarski, D and McNerney, MW},
title = {Comparison of treatment schedules on cognitive effects of rTMS in the 3xTg-AD model of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115551},
doi = {10.1016/j.expneurol.2025.115551},
pmid = {41238155},
issn = {1090-2430},
abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a promising non-invasive therapy for improving cognition in Alzheimer's disease (AD), but the optimal treatment parameters have yet to be elucidated. One important parameter is the treatment schedule. In this study, we used an established rodent low intensity rTMS stimulation protocol to compare cognitive and biochemical effects of a intensive treatment protocol (daily for 12 days) to a distributed protocol (twice a week for six weeks) in 12-month-old 3xTg-AD mice and B6 controls. We found that both protocols improved object place memory function, but only the distributed protocol improved working memory as measured with the Y-Maze. We did not find any effect of either rTMS protocol on BDNF or amyloid pathology, although these measures correlated well with activity and cognitive performance, suggesting rTMS improvement was independent of these mechanisms. Intensive rTMS increased choline acetyltransferase-positive neurons in the anterior bed nucleus of the stria terminalis (BNST), which may be due to the function of this region in mediating cognitive and limbic circuitry. These results indicate that while both treatment protocols can improve specific aspects of recognition memory, only distributed rTMS improves working memory function, possibly due to causing less cognitive fatigue and physiological stress. Future studies should examine region specific changes relating working memory function and stress related signaling to further understand the mechanisms behind this important rTMS treatment parameter.},
}

@article {pmid41238102,
year = {2025},
author = {Long, J and Liu, S and Shi, Y and Zhang, C and Qin, L and Ai, Q},
title = {Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical.},
journal = {Metabolism: clinical and experimental},
volume = {},
number = {},
pages = {156436},
doi = {10.1016/j.metabol.2025.156436},
pmid = {41238102},
issn = {1532-8600},
abstract = {The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases-including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)-are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.},
}

@article {pmid41238077,
year = {2025},
author = {Ancy, PM and Sumithra, M},
title = {Development and optimization of flavonoid-enriched solid lipid nanoparticles of Peperomia Pellucida for enhanced brain delivery in Alzheimer's disease: A Quality by Design approach.},
journal = {Annales pharmaceutiques francaises},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.pharma.2025.11.003},
pmid = {41238077},
issn = {2772-803X},
abstract = {OBJECTIVES: The Peperomia pellucida plant exhibits notable neuroprotective potential but has low oral bioavailability in the brain. Herein, we aimed to enhance the oral bioavailability and brain distribution of Peperomia Pellucida, by formulating its flavonoid-enriched fraction into solid lipid nanoparticles as a potential therapeutic approach for Alzheimer' disease.

MATERIALS AND METHODS: Flavonoid-enriched solid lipid nanoparticles of Peperomia pellucida were formulated using an ultrasonication method. A Box-Behnken design was utilized to optimize particle size, entrapment efficiency, and burst release. The optimized formulation was identified via numerical and graphical optimization, and validated through reproducibility studies. Further characterization included scanning electron microscopy and in vivo drug release studies in rats.

RESULTS: Glycerol tripalmitate-based solid lipid nanoparticles exhibited superior entrapment efficiency and reduced burst release. The mean particle size of the solid lipid nanoparticles ranged 110-884 nm, with entrapment efficiency ranging 55-94%. Oral administration of the optimized formulation significantly improved bioavailability in rats and enhanced drug distribution in the cortex and hippocampus of the brain.

CONCLUSION: The results highlight the potential of solid lipid nanoparticles as an effective delivery system for the flavonoid-enriched fraction of Peperomia Pellucida, enhancing its therapeutic impact in the treatment of Alzheimer's disease.},
}

@article {pmid41237463,
year = {2025},
author = {Cho, E and Yi, JH and Jeon, SJ and Kim, DH and Kwon, H and Jeon, J and Kwon, KJ and Jang, DP and Moon, M and Shin, CY and Kim, DH},
title = {Increases in brain catecholamine levels counteract memory deficits and reduces Aβ deposition in 5XFAD male mice.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118764},
doi = {10.1016/j.biopha.2025.118764},
pmid = {41237463},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a degenerative brain disease that presents with neurological symptoms and memory loss, with no clear treatment. Catecholamines, including dopamine, epinephrine, and norepinephrine, can inhibit or degrade the abnormal aggregation of proteins that cause diseases; however, developing these catecholamines as medication is difficult. This study aimed to demonstrate that increasing the levels of catecholamines in the brain may help improve symptoms of AD. We tested whether an increase in catecholamines by bupropion, a dopamine and norepinephrine re-uptake inhibitor, improves the symptoms of AD. Dopamine and norepinephrine showed similar effects in inhibiting amyloid β (Aβ) aggregation and the decomposition of Aβ aggregates as curcumin, a positive control. Dopamine and norepinephrine blocked Aβ aggregates-induced abnormal hippocampal long-term potentiation. The intraperitoneal administration of bupropion increased the concentrations of dopamine and norepinephrine in the hippocampus from 1 to 6 h after administration. In the Aβ-induced memory decline model, bupropion showed a dose-dependent improvement in learning and memory. In 5XFAD mice administered bupropion for 2 months, significant improvements in memory and Aβ deposition were also found compared to vehicle-treated 5XFAD mice. These results suggest that the symptoms of AD can be improved or delayed by increasing the amount of dopamine and norepinephrine using bupropion.},
}

@article {pmid41237058,
year = {2025},
author = {Xu, F and Wang, J and Gao, P and Li, D and Liu, X},
title = {Neuroprotective Effects of Triterpenoids From Rosa laevigata Root: Identification, Molecular Docking, and In Vitro Evaluation for Alzheimer's Disease Treatment.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e02742},
doi = {10.1002/cbdv.202502742},
pmid = {41237058},
issn = {1612-1880},
abstract = {This study investigates the neuroprotective effects of triterpenoid compounds from Rosa laevigata Michx. roots against Alzheimer's disease (AD). A total of 62 compounds were identified using ultra-performance liquid chromatography-Orbitrap-tandem mass spectrometry analysis, which included 55 triterpenoids and seven flavonoids. Among 15 isolated compounds, compound 13 demonstrated the strongest acetylcholinesterase (AChE) inhibitory activity, with an IC50 of 3.38 µmol/L, and a maximum inhibition rate of 87.20%. Compound 13 exhibited favorable and stable binding with AChE in molecular docking studies, whilst demonstrating mixed-type inhibition in enzyme kinetics. In the H2O2-induced SH-SY5Y cell model, compound 13 exhibited 84.45% viability at 25 µmol/L, surpassing Trolox's 74.16%. Research indicates that R. laevigata Michx. root triterpenes exert neuroprotective effects through AChE inhibition and antioxidant activity, with compound 13 potentially serving as a multi-target lead compound for treating AD.},
}

@article {pmid41236865,
year = {2025},
author = {Hanyu, H and Koyama, Y and Momose, T and Watanabe, S},
title = {Patient With Mild Alzheimer's Disease Homozygous for ApoE ε4 Showing Improved Cognition, No Brain Volume Loss, and Complete Amyloid Clearance After Lecanemab Treatment.},
journal = {Geriatrics & gerontology international},
volume = {},
number = {},
pages = {},
doi = {10.1111/ggi.70251},
pmid = {41236865},
issn = {1447-0594},
}

@article {pmid41236362,
year = {2025},
author = {Zide, BS and Barker, MS and Silverman, HE and Manoochehri, M and Fremont, R and Stein, C and Kunicki, ZJ and Lee, S and Devanand, DP and Huey, ED},
title = {Feasibility and tolerability of low-dose lithium for the treatment of agitation and abnormal motor behaviors in Frontotemporal Dementia.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/09540261.2025.2572365},
pmid = {41236362},
issn = {1369-1627},
abstract = {Agitation and abnormal motor behaviors are common, distressing symptoms of Frontotemporal Dementia (FTD). While these symptoms currently lack efficacious and safe pharmacological treatments, case reports in FTD and a clinical trial in Alzheimer's disease suggest that patients may benefit from lithium treatment. We designed a randomized, double-blind, placebo-controlled, 12-week clinical trial to evaluate low-dose lithium for the treatment of agitation and abnormal motor behaviors in FTD. However, the trial did not meet its recruitment target (n = 60). This report assesses the trial's feasibility and tolerability using recruitment, study completion, and safety metrics. Sixteen adults with FTD (median age 59.5 years; 69% female) were enrolled from 2017 to 2021. Fourteen participants (88%) completed the trial. The majority of participants on lithium were taking the maximum daily dose by Week 12 (600 mg), had median (interquartile range) final serum lithium levels of 0.42 (0.37-0.57), and reported minimal side effects, including drowsiness, diarrhea, constipation and insomnia. Preliminary data from intended efficacy outcomes showed no median pre-post changes between treatment groups. Low-dose lithium is feasible and well-tolerated in an FTD population. Further systematic study of lithium and its efficacy to treat agitation and abnormal motor behaviors in FTD is warranted.},
}

@article {pmid41235150,
year = {2025},
author = {Nigdelioglu Dolanbay, S},
title = {Monoterpene-rich essential oil from Artemisia santonicum L. exerts neuroprotective effects in Aβ-induced SH-SY5Y cells: Modulation of tau pathology, neuroinflammation, oxidative stress, and synaptic-metabolic pathways.},
journal = {Toxicology research},
volume = {14},
number = {6},
pages = {tfaf155},
pmid = {41235150},
issn = {2045-452X},
abstract = {Understanding the complex biological mechanisms of ad requires innovative treatment approaches for this disease. In this context, natural compounds, especially monoterpenes, attract attention with their potential for biological activity. In this study, the therapeutic potential of monoterpene rich essential oil obtained from Artemisia santonicum L. for the treatment of ad was comprehensively evaluated. GC-MS analysis showed that the major monoterpenes were limonene, camphor, pinene, terpineol, and carvone in essential oil obtained from A. santonicum L. Possible common targets of monoterpenes with ad were predicted and their PPI networks were analyzed. Furthermore, gene set enrichment analysis was applied to understand the functional roles of these possible common targets and their relationships with biological pathways. Molecular docking studies revealed the binding affinities and interaction abilities of monoterpenes with the predicted possible common targets. The monoterpene rich essential oil obtained from A. santonicum L. used in our study provides a neuroprotective effect by targeting the pathological mechanisms of ad. We designed in vitro experiments to elucidate the mechanism of the mentioned neuroprotective effect. Within the scope of the study, neuroprotective effect analyses were performed to evaluate cell viability rates and in vitro AChE enzyme activity, while the ELISA method was used to determine phosphorylated tau levels and to assess neuroinflammatory responses. In addition, apoptosis levels, MMP changes and intracellular ROS accumulation were examined by flow cytometry analyses. These comprehensive analyses aimed to reveal the molecular mechanisms of the neuroprotective effect of monoterpene rich essential oil obtained from A. santonicum L. and to shed light on its potential therapeutic applications in ad.},
}

@article {pmid41235113,
year = {2025},
author = {Zampieri, TT and Higa, GSV and Borges, FS and Viana, FJC and Cruvinel, E and Bentivoglio, LE and Lugao, AB and Ulrich, H and Britto, LR and Katti, KV and Chesne, AM and de Pasquale, R},
title = {Exposure to β-hydroxybutyrate reduces the operating set point and increases excitability in hippocampal circuitry of healthy mice.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1557612},
pmid = {41235113},
issn = {1663-9812},
abstract = {The ketogenic diet is a therapeutic strategy applied to reduce brain hyperexcitability in conditions such as epilepsy, Parkinson's and Alzheimer's disease, migraines, and autism. This diet reduces circulating glucose levels and increases ketone bodies, with β-hydroxybutyrate (BHB) being one of the leading promoters of the beneficial effects. BHB was previously reported as a mediator of cognitive restoration and memory formation. Herein, we investigate the effect of exogenous BHB on hippocampal neuronal excitability and synaptic plasticity mechanisms, regardless of the pathological or neurodegenerative conditions. Electrophysiological experiments were conducted to explore both passive and active neuronal properties, including action potential firing and spontaneous and evoked postsynaptic responses. Electrical stimulation along the CA3-CA1 pathway enabled the assessment of both short- and long-term synaptic plasticity, as well as the mechanisms mediated by AMPA and NMDA receptors. Experiments were conducted in hippocampal slices treated with 3-β-hydroxybutyrate glycerides (DHB) and niacin (HCAR2 agonist). Although DHB incubation did not alter passive membrane properties, it significantly increased neuronal excitability, reflected in an elevated firing rate upon depolarizing stimulation and enhanced spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons, which were dependent on synaptic inputs. DHB treatment led to a reduction in long-term potentiation (LTP) in CA1 neurons, suggesting a metaplastic effect independent of NMDA receptor activation. Importantly, these DHB-induced neuronal alterations were found to be independent of HCAR2 receptor activation, supporting the involvement of distinct intracellular pathways and long-term modulatory mechanisms. Our findings indicate that DHB exerts a modulatory effect on hippocampal neural activity by enhancing excitability and concurrently promoting a compensatory reduction in LTP, suggesting a homeostatic balancing mechanism.},
}

@article {pmid41234939,
year = {2025},
author = {Wang, R and Peng, S and Zhu, J and Xu, Y and Wang, M and Zhang, L and Qiu, Y and Hou, D and Wang, Q and Liu, R},
title = {Innovations in Alzheimer's disease diagnostic technologies: clinical prospects of novel biomarkers, multimodal integration, and non-invasive detection.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1651708},
pmid = {41234939},
issn = {1664-2295},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) plaques and the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, ultimately leading to cognitive decline and neuronal loss. Current diagnostic methods, including clinical evaluations, neuroimaging examinations, and cerebrospinal fluid biomarker testing, face challenges such as insufficient sensitivity and specificity, as well as operational complexity. In recent years, significant advancements have been made in diagnostic technologies, with the emergence of new biomarkers and detection methods, including blood-based Aβ and tau protein detection, ocular biomarker testing, and non-invasive screening through urine or breath analysis. These innovative developments, combined with multimodal diagnostic technologies that integrate imaging, genomics, and proteomics, have opened new possibilities for the early diagnosis and precise staging of Alzheimer's disease. Furthermore, advancements in microfluidic chips and biosensor technologies have enhanced the capability for rapid, efficient, and cost-effective diagnosis. As research continues to evolve, the gradual application of these advanced technologies in clinical practice is expected to revolutionize the management of Alzheimer's disease, facilitating early intervention and the formulation of individualized treatment strategies.},
}

@article {pmid41234220,
year = {2025},
author = {Fujishiro, H and Kawakami, I and Oshima, K and Torii, Y and Arafuka, S and Iritani, S and Ikeda, K},
title = {Systematized delusions in a patient with covert hepatic encephalopathy: A clinicopathological insight into prodromal dementia with Lewy bodies.},
journal = {PCN reports : psychiatry and clinical neurosciences},
volume = {4},
number = {4},
pages = {e70247},
pmid = {41234220},
issn = {2769-2558},
abstract = {BACKGROUND: Late-onset psychosis is an early clinical manifestation of psychiatric-onset prodromal dementia with Lewy bodies (DLB); however, its underlying neuropathology remains poorly understood. Clinicopathological correlations are often limited by the gap between symptom onset and the autopsy.

CASE PRESENTATION: A 66-year-old man with autopsy-confirmed DLB presented with persistent systematized delusions. After treatment for liver cirrhosis during hospitalization, the patient's physical symptoms improved; however, persecutory delusions developed. The patient was clinically diagnosed with covert hepatic encephalopathy (HE). The delusions were atypical for covert HE, suspecting delusional disorder. His systematized delusions persisted for 3 months until his death, without the development of cognitive decline or Parkinsonism during his lifetime. An autopsy revealed an early transitional type of Lewy body disease with minimal Alzheimer's type II astrocytes indicative of HE. Severe neuronal loss was observed in the locus coeruleus (LC), while the substantia nigra (SN) and nucleus basalis of Meynert (nbM) were preserved. Abundant alpha-synuclein-positive structures were identified in the LC, periaqueductal gray matter, nbM, amygdala, and thalamus, with sparse involvement of the SN, neocortex, peripheral autonomic nervous system, including the heart and gastrointestinal tract.

CONCLUSION: Selective Lewy body involvement, sparing the SN and neocortex, may explain the isolated psychiatric symptoms in the absence of Parkinsonism or dementia. Systemic conditions such as covert HE may have contributed to the emergence of persistent delusions. This case highlights the need for multidisciplinary approaches that integrate psychosomatic assessments with neuropathological investigations to evaluate late-onset psychosis.},
}

@article {pmid41233409,
year = {2025},
author = {Lai, Y and Zhao, H},
title = {Therapeutic efficacy of rehmannioside A on 5×FAD mice in Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39825},
pmid = {41233409},
issn = {2045-2322},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; Oxidative Stress/drug effects ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism/pathology ; Male ; *Saponins/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; Memory/drug effects ; Mice, Transgenic ; Plaque, Amyloid/drug therapy/pathology ; Drugs, Chinese Herbal ; },
abstract = {Alzheimer's disease (AD), characterized by Aβ plaques and cognitive decline, remains a significant therapeutic challenge due to limited efficacy of current pharmacotherapies, while Rehmannioside A (ReA) has shown promising neuroprotective effects against neurodegenerative diseases. This research focuses on investigating the therapeutic effects of ReA on 5×FAD mice, emphasizing its potential application in AD treatment. The 5×FAD mice were divided into experimental groups and treated with ReA at varied dosages or donepezil for a twelve-week continuous treatment period. A series of evaluation methods, including behavioral tests, histopathological analysis, Western blotting, and measurement of oxidative and inflammatory markers, were implemented. The findings demonstrated that optimal ReA doses significantly improved learning, memory, and cognitive functions in 5×FAD mice, reduced Aβ plaque accumulation in the hippocampus, decreased microglial cell counts, increased PSD 95 and synapsin-1 protein expression, mitigated oxidative stress and inflammation, and showed no harmful effects on liver or kidney function. ReA's diverse biological activities suggest its potential in reducing neural damage. More extensive studies are needed to fully understand its molecular mechanisms in AD, which could lead to the development of innovative and effective treatments for this severe neurodegenerative condition.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
Mice
Oxidative Stress/drug effects
Disease Models, Animal
*Neuroprotective Agents/pharmacology/therapeutic use
Hippocampus/drug effects/metabolism/pathology
Male
*Saponins/pharmacology/therapeutic use
Amyloid beta-Peptides/metabolism
Memory/drug effects
Mice, Transgenic
Plaque, Amyloid/drug therapy/pathology
Drugs, Chinese Herbal

@article {pmid41233403,
year = {2025},
author = {Kovač, V and Huntosova, V and Fedorova, V and Georgiou, N and Lai, JZ and Chien, FC and Chen, SJ and Dolenec, F and Siposova, K},
title = {Unraveling the structure-activity relationships of organometallic ferrocene-pyrazole and ferrocene-pyrimidine curcumin analogues in amyloid-β aggregation and glioblastoma treatment.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39867},
pmid = {41233403},
issn = {2045-2322},
support = {HRZZ-IP-2020-02-9162//Hrvatska Zaklada za Znanost/ ; No. 09-I02-03-V01-00021//NextGenerationEU/ ; SAS-NSTC-JRP-2024-03_SUPRA-SIGHT//Slovenská Akadémia Vied/ ; 2/0034/22//Vedecká Grantová Agentúra MŠVVaŠ SR a SAV/ ; No.101007642; PhytoApp//European Union's Horizon 2020 Research and Innovation programme/ ; },
mesh = {Humans ; *Ferrous Compounds/chemistry/pharmacology ; *Glioblastoma/drug therapy/metabolism/pathology ; *Metallocenes/chemistry/pharmacology ; *Curcumin/pharmacology/chemistry/analogs & derivatives ; *Amyloid beta-Peptides/metabolism/chemistry ; *Pyrazoles/chemistry/pharmacology ; *Pyrimidines/chemistry/pharmacology ; Structure-Activity Relationship ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Apoptosis/drug effects ; Protein Aggregates/drug effects ; Cell Survival/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; },
abstract = {Neurodegenerative and oncological disorders, such as Alzheimer's disease (AD) and glioblastoma (GBM), are major global health challenges. Recent evidence indicates shared molecular mechanisms between these diseases, including dysregulated oxidative stress, mitochondrial dysfunction, and protein aggregation. We hypothesized that ferrocene-containing curcumin derivatives could exert dual-functional effects by simultaneously modulating amyloid-β (Aβ) aggregation and inhibiting glioblastoma cell proliferation. This study explores organometallic ferrocene compounds linked to four pyrazole and two pyrimidine analogues of curcumin with different substituents for their effects on amyloid-β-peptide (Aβ) aggregation and glioblastoma. To test this, pyrazole (FcPy-Cur-H, FcPy-Cur-COPh, FcPy-Cur-COFc, FcPy-Cur-Me) and pyrimidine (FcPyn-Cur-O, FcPyn-Cur-S) analogues were synthesized and evaluated. Thioflavin T fluorescence, atomic force microscopy, and single-molecule localization microscopy revealed structure-dependent inhibition of Aβ fibrillogenesis, with FcPyn-Cur-O, FcPyn-Cur-S, and FcPy-Cur-H showing the strongest anti-amyloidogenic activity. Concurrently, these derivatives reduced U87MG glioblastoma cell viability in a dose-dependent manner, inducing apoptotic features, mitochondrial disruption, and α-tubulin destabilization. Our results demonstrate that specific structural modifications of ferrocene-curcumin analogues enhance their dual anti-amyloidogenic and anticancer activities, highlighting the therapeutic potential of multifunctional compounds. This study provides a conceptual advance by combining neurodegenerative and oncological targets within a single chemical framework, offering a promising strategy for the development of multitargeted therapeutics for complex brain disorders.},
}

Humans
*Ferrous Compounds/chemistry/pharmacology
*Glioblastoma/drug therapy/metabolism/pathology
*Metallocenes/chemistry/pharmacology
*Curcumin/pharmacology/chemistry/analogs & derivatives
*Amyloid beta-Peptides/metabolism/chemistry
*Pyrazoles/chemistry/pharmacology
*Pyrimidines/chemistry/pharmacology
Structure-Activity Relationship
Cell Line, Tumor
Cell Proliferation/drug effects
Apoptosis/drug effects
Protein Aggregates/drug effects
Cell Survival/drug effects
*Protein Aggregation, Pathological/drug therapy/metabolism

@article {pmid41233387,
year = {2025},
author = {Park, JS and Kim, S and Jeong, D and Choi, JP and Jeong, H and Park, AJ and Kim, YS and Lee, J and Kim, SH},
title = {Dementia in older adults with schizophrenia: a 12-year analysis of prevalence, incidence, and treatment patterns in South Korea.},
journal = {Schizophrenia (Heidelberg, Germany)},
volume = {11},
number = {1},
pages = {134},
pmid = {41233387},
issn = {2754-6993},
abstract = {Older adults with schizophrenia face a significantly elevated risk of dementia. However, recent trends remain unclear within South Korea's rapidly aging schizophrenia population. This study aimed to quantify the burden of dementia in older schizophrenia patients by examining prevalence, incidence, dementia subtypes, pharmacologic treatment, and healthcare utilization. Using nationwide Health Insurance Review and Assessment (HIRA) data from 2010 to 2021, we identified 220,378 individuals aged ≥50 with schizophrenia. Dementia was diagnosed in 14.6% of patients, with 20.7% of cases occurring before age 60. Patients with dementia were more likely to be female and to have a higher comorbidity burden. Age-standardized all-cause dementia prevalence rose from 11.8% (2010) to 15.8% (2021) in those aged ≥50, and from 24.2% to 32.8% in those aged ≥65-exceeding estimates in the general population. In contrast, incidence declined from 3.4% to 1.7% over the same period. Alzheimer's disease (AD) was the most prevalent subtype (12.2%), followed by vascular dementia (VD, 2.4%), and frontotemporal dementia (0.5%). A lower AD/VD prevalence ratio in schizophrenia (5.3 vs. 8.6 in the general population) suggests a relatively higher burden of vascular pathology. Cognitive enhancer prescriptions increased from 62% to 77% in patients with dementia, compared to 4% to 10% in those without dementia. In 2021, those with dementia were more likely to live in nursing homes (68% vs. 56%) and had greater annual increases in psychiatric hospitalization duration (+2.30 vs. +1.11 days/year). These findings underscore growing care demands and need for integrated treatment strategies for aging schizophrenia patients with dementia.},
}

@article {pmid41233182,
year = {2025},
author = {Nakayama, H},
title = {[Brain Pathology of Cognitive Dysfunction in Aged Non-human Animals].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1241-1247},
doi = {10.11477/mf.188160960770111241},
pmid = {41233182},
issn = {1881-6096},
mesh = {Animals ; *Cognitive Dysfunction/pathology ; *Brain/pathology/metabolism ; *Aging/pathology ; Humans ; Alzheimer Disease/pathology ; Cats ; Amyloid beta-Peptides/metabolism ; },
abstract = {Cognitive dysfunction, characterized by the deposition of amyloid β (Aβ), such as senile plaque (SP) and cerebral amyloid angiopathy (CAA), and phosphorylated tau are observed in several animal species, including primates, dogs, and cats, suggesting that these disorders are universal age-related phenomena in vertebrates. Additionally, argyrophilic neurofibrillary tangles positive for phosphorylated tau have been observed in primates, marine mammals, and felines. Recent findings regarding the pathology of cognitive dysfunction in aged non-human animals provide valuable information from a comparative perspective for advancing research on the pathogenesis, diagnosis, and treatment of Alzheimer's disease.},
}

Animals
*Cognitive Dysfunction/pathology
*Brain/pathology/metabolism
*Aging/pathology
Humans
Alzheimer Disease/pathology
Cats
Amyloid beta-Peptides/metabolism

@article {pmid41233181,
year = {2025},
author = {Yoshiyama, K},
title = {[Agitation].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1231-1240},
doi = {10.11477/mf.188160960770111231},
pmid = {41233181},
issn = {1881-6096},
mesh = {Humans ; *Dementia/therapy/complications ; *Psychomotor Agitation/therapy/etiology ; },
abstract = {Agitation is a behavioral and psychological symptom of dementia (BPSD); however, until recently, there has been no consensus-based definition. When initiating therapeutic interventions, the type of dementia that is the cause of the BPSD must be considered and treatment must be tailored accordingly. As with other types of BPSD, non-pharmacological interventions are considered the first-line treatment for agitation, unless the symptoms present an exceptional level of urgency. Person-centered care is effective as a non-pharmacological intervention for agitation. Other examples include music therapy, animal-assisted therapy, and aromatherapy; however, these are not very effective for agitation. Useful information on non-pharmacological interventions for agitation can be obtained from the website "Ninchisho Chienowa-net," which is a web-based system that collects information on the coping strategies of caregivers for BPSD. If non-pharmacological interventions are ineffective or the symptoms are urgent, pharmacological treatment should be considered. Brexpiprazole has been approved as effective for agitation in Alzheimer's disease. For the treatment of agitation, medications other than brexpiprazole are frequently used in clinical settings and may offer some degree of efficacy.},
}

Humans
*Dementia/therapy/complications
*Psychomotor Agitation/therapy/etiology

@article {pmid41232717,
year = {2025},
author = {Castellano Candalija, A and Díez Porres, L and Notario Leo, H and Roca Martiartu, A and Mayoral Canalejas, N and Alonso Babarro, A},
title = {Prevalence and decision-making in advanced dementia.},
journal = {Revista clinica espanola},
volume = {},
number = {},
pages = {502388},
doi = {10.1016/j.rceng.2025.502388},
pmid = {41232717},
issn = {2254-8874},
abstract = {INTRODUCTION: Dementia is a chronic neurodegenerative disease with a high prevalence and economic cost. Our objective was to evaluate the prevalence of advanced dementia (AD) in patients hospitalized in the Internal Medicine service; to analyze the therapeutic and diagnostic measures implemented, the degree of adequacy of the therapeutic effort and the information of the family.

METHODOLOGY: Descriptive study that included a retrospective analysis of medical records and a telephone interview with family. Patients with GDS 6-7 dementia admitted to Internal Medicine were included, for 3 weeks in 3 different months.

RESULTS: 194 (22%) patients with dementia were included. The prevalence of admissions with AD was 11%. The median age was 87.5 years (QR 81.75-93), 65% women. 45% came from residence for the elderly. The most frequent etiology was Alzheimer's (48%). The most frequent cause of admission was infection (72%). 37% died. Regarding the measures implemented: 100% were treatment intravenous; 89% received anticoagulation; 26% received artificial nutrition; 81% received pharmacological restraint and 63% physical restraint; and 48% underwent invasive diagnostic tests. Regarding adequacy: lipid-lowering treatment was withdrawn in 19%, antidementia drugs in 23%, anticoagulation in 21%; cardiopulmonary resuscitation was not performed in 30%, adequacy of care in 34%, and 13% were assessed by Palliative Care. A telephone interview was conducted with 55 patients. 42% were not aware of any complications. Care planning was carried out in 2 patients.

CONCLUSIONS: The prevalence of admission to AD is high, and almost half of the patients come from residence for the elderly. Associated mortality is high and therapeutic adequacy and planning are very scarce.},
}

@article {pmid41232709,
year = {2025},
author = {Zhou, W and Qu, R and Luo, W and Zhang, H and Gong, L and , },
title = {Identification of cognitive brain diseases using a dual-branch siamese network on structural magnetic resonance imaging data.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.11.011},
pmid = {41232709},
issn = {1873-7544},
abstract = {Early diagnosis of Alzheimer's Disease is crucial for optimizing treatment efficacy, as delayed detection often limits therapeutic outcomes. Traditional diagnostic approaches, such as cognitive assessments, PET scans, and lumbar punctures, are often invasive, costly, and less accessible. To address these limitations, we propose a Dual-Branch Siamese Network aimed at enhancing the classification accuracy of Alzheimer's Disease, Mild Cognitive Impairment, and Cognitively Normal individuals using structural MRI data. Our model integrates neuroimaging features from both Subcortical Segmentation and Cortical Parcellation, leveraging their complementary strengths to improve diagnostic precision. Experimental evaluations demonstrate that our model achieves a classification accuracy of 93% on the original dataset. To further validate the model's generalizability, we tested the trained model on a separate independent test set from the new ADNI4 database (N=191). On this independent cohort, the model achieved a robust classification accuracy of 88.48%, demonstrating its potential for real-world application. Additionally, by implementing network pruning, we reduced the model's complexity by 60% without sacrificing accuracy, thereby enhancing its feasibility for clinical use. Compared to other methods, such as convolutional neural networks and ensemble learning systems, our model demonstrates superior accuracy in multi-class classification and remains competitive in binary classification tasks. Notably, our pruned model balances accuracy with efficiency, outperforming other models in terms of computational feasibility without compromising diagnostic precision. These findings highlight the potential of our approach to facilitate early diagnosis and intervention for neurodegenerative diseases like Alzheimer's Disease.},
}

@article {pmid41232397,
year = {2025},
author = {Zuo, Y and Ding, X and Sun, Y and Wang, L and Song, Y and Zhao, Z and Liu, C},
title = {Critical nodes in precision diagnosis and treatment of Alzheimer's disease: exploration of multidimensional biomarkers and prospects for targeted intervention.},
journal = {Journal of the neurological sciences},
volume = {479},
number = {},
pages = {123734},
doi = {10.1016/j.jns.2025.123734},
pmid = {41232397},
issn = {1878-5883},
abstract = {Alzheimer' s disease (AD), characterized by cognitive decline and progressive neurodegeneration, remains a major clinical and scientific challenge due to its complex pathophysiology and marked heterogeneity. Important signs of the disease, like the buildup of β-amyloid, changes in Tau proteins, inflammation in the brain, and problems with mitochondria, form the basis for developing targeted treatments. This review summarizes recent advances in the identification of therapeutic targets and multi-dimensional biomarkers, such as liquid, imaging, and multi-omics-based markers. These biomarkers hold potential for early diagnosis, disease subtyping, and therapeutic response monitoring. We suggest that combining biomarkers and treatment targets could be a key approach to improving personalized care for AD.},
}

@article {pmid41232357,
year = {2025},
author = {Castillo-Moral, Á and Tchoumtchoua, J and Leonard, K and Del Bas, JM and Ortega, N and Escoté, X and Teichenné, J},
title = {Neuroprotective effects of polyphenol-rich extracts obtained from agricultural by-products in an induced cognitive decline model of zebrafish larvae and in human neurons.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118776},
doi = {10.1016/j.biopha.2025.118776},
pmid = {41232357},
issn = {1950-6007},
abstract = {Neurodegenerative diseases are closely associated with chronic neuroinflammation and oxidative stress, which contribute to progressive neuronal dysfunction and cell death. Due to their antioxidant and anti-inflammatory properties, polyphenols have gained attention as potential neuroprotective agents. Agricultural by-products represent a promising and sustainable source of polyphenols, yet their neuroprotective value remains underexplored. In this study, we evaluated four polyphenol-rich extracts derived from red onion peels (ROPE), olive pruning (OPE), vineyard pruning (VPE) and chicory leaves (CLE), obtained by subcritical water extraction. Their effects were tested in two complementary models of neurodegeneration: in vitro human neurons (SH-SY5Y cells) exposed to D-galactose and a basic cognitive decline model of zebrafish larvae exposed to aluminium chloride (AlCl3). All extracts exhibited anti-inflammatory effects in vitro, significantly reducing IL-1β and IL-8 mRNA expression, at doses ranging 12.5-50 μg/mL in cell medium. In the zebrafish model, treatment with 100 μg/mL ROPE or VPE in medium restored the normal sensorimotor pattern in the Dark-Light-Dark test, while ROPE treatment additionally rescued basal startle responses and enhanced habituation indexes, even surpassing healthy control larvae. Overall, these results highlight the potential of polyphenol-rich agri-food extracts, particularly ROPE, as neuroprotective and cognitive-enhancing compounds and support their further investigation as natural and sustainable interventions to slow or prevent neurodegenerative processes.},
}

@article {pmid41230868,
year = {2025},
author = {Cavagnero, PS and Sánchez, Y and Fell, B and Ramírez Molina, O and Gavilán, J and Polo, EA and Fuentealba, J and Gutierrez, M and Jiménez, CA and López, JJ},
title = {Neuroprotective Activity of 3-((6-(Phenylethynyl)pyridin-3-yl)oxy)quinuclidine: A Potential Ligand for the Treatment of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00527},
pmid = {41230868},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by the accumulation of β-amyloid (Aβ) peptides, which disrupt neuronal homeostasis through their neurotoxic effects. Aβ aggregates interfere with synaptic function by interacting with nicotinic acetylcholine receptors (nAChRs), particularly the α7 subtype, thereby impairing cholinergic signaling, which is crucial for cognition and memory. Pharmacological advancements have identified Positive Allosteric Modulators (PAMs) as promising therapeutic agents to counteract Aβ neurotoxicity. PAMs enhance nAChR activity by binding to allosteric sites, thereby reducing Aβ-induced neurotoxicity without competing with acetylcholine. This study evaluates 3-((6-(phenylethynyl)pyridine-3-yl)oxy)quinuclidine (EQ-04), a novel PAM with high selectivity for the α7 nAChR subtype, demonstrating neuroprotective potential. In vitro analyses using PC-12 cells evaluated the cytotoxic and neuroprotective properties of EQ-04. Cytotoxicity assays confirmed EQ-04's safety, showing no adverse effects on cell viability across concentrations. EQ-04 significantly enhanced cell viability by 37% at 1 nM against Aβ toxicity and inhibited Aβ aggregation. These findings highlight the potential of EQ-04 as a neuroprotective agent for Alzheimer's disease (AD) therapy, warranting further investigation into its pharmacokinetics and in vivo efficacy.},
}

@article {pmid41230514,
year = {2025},
author = {Wang, X and Liu, Y and Fan, S and Zhao, H and Sun, C and Liu, L and Wang, X and Zou, L},
title = {Combined 64-channel EEG and PET evaluation of lecanemab efficacy: Two case reports.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395615},
pmid = {41230514},
issn = {2542-4823},
abstract = {Lecanemab, an anti-amyloid-β (Aβ) monoclonal antibody, has shown potential in slowing Alzheimer's disease (AD) progression. We report divergent responses in two AD patients with similar backgrounds following lecanemab treatment. Subject 1 showed worsened daily functioning, increased Aβ/tau deposition, and elevated electroencephalogram (EEG) slow/fast wave ratios (>30%) in right fronto-occipital regions (Fp2/F8/O1). Subject 2 improved cognitively, with modest Aβ reduction, marked tau suppression, and mixed EEG frontal declines (F3/F7/O1/Pz) and parietal/occipital gains (P3/P4/T3/T6). EEG alterations corresponded with positron emission tomography findings, suggesting its potential for therapeutic monitoring. Multimodal analysis revealed region-specific lecanemab effects, supporting EEG's role in evaluating treatment efficacy.},
}

@article {pmid41230033,
year = {2025},
author = {Oviedo, DC and Haughbrook, R and Culjat, C and Ramirez Surmeier, L and Tratner, AE and Carreira, MB and Villarreal, AE and Harmon, SL and Batista, OI and Meng, Z and Millender, E and Xavier Hall, CD and Britton, GB},
title = {Ethical disclosure of biomarkers for Alzheimer risk in Latin American participants.},
journal = {Frontiers in dementia},
volume = {4},
number = {},
pages = {1672075},
pmid = {41230033},
issn = {2813-3919},
abstract = {INTRODUCTION: In recent years, the disclosure of Alzheimer's disease (AD) biomarkers has become increasingly common, offering critical insights into disease risk and progression. However, in low-resource settings, where healthcare access, provider training, and patient support are often limited, disclosing AD biomarkers presents unique ethical, logistical, and psychological challenges.

OBJECTIVE: This perspective explores the implications of AD biomarker disclosure in these settings, highlighting the potential risks of patient distress, misinformation, and inadequate follow-up care. For this purpose, we conducted a review of available literature, peer-reviewed studies, regional reports, and policy documents addressing AD in Latin America. Our literature search prioritized diagnostic advances, biomarker disclosure, treatment access, and health system challenges, providing a focused evidence base to frame the discussion of regional gaps and opportunities.

DISCUSSION: We discuss strategies to support responsible disclosure practices, including culturally sensitive participant education, enhanced provider training, and policy adaptations to improve accessibility and support systems. Ultimately, we advocate for a careful, context-specific approach to AD biomarker disclosure that prioritizes patient well-being and equity in low-resource environments.},
}

@article {pmid41229208,
year = {2025},
author = {Bosire, EN and Kamau, LW and Kiio, C and Blackmon, K and Taylor, ON and Shah, J and Sokhi, D and Mbugua, S and Meier, I and Hooker, J and Narayan, V and Merali, Z and Udeh-Momoh, C},
title = {Community perceptions and willingness to donate biospecimen for Alzheimer's disease research in Nairobi, Kenya.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389227},
doi = {10.1177/13872877251389227},
pmid = {41229208},
issn = {1875-8908},
abstract = {BackgroundBiomarkers play a critical role in understanding disease mechanisms and advancing diagnostic and treatment options for Alzheimer's disease and related dementias (AD/ADRD). However, in many African countries, biomarker research is limited by insufficient knowledge, infrastructure, funding, and trained personnel.ObjectiveThis study explored community perceptions and willingness to donate biospecimens for AD/ADRD research in Kenya.MethodsEight focus group discussions were conducted in the informal settlements of Mathare and Kibera in Nairobi, Kenya, stratified by age and gender (n = 81). Data were transcribed verbatim and thematically analyzed using QSR Nvivo 14.ResultsParticipants generally expressed a positive attitude toward brain health research and donating biospecimens. Willingness to participate was influenced by altruism, perceived benefits, and improved understanding of AD/ADRD. Non-invasive samples such as saliva, blood, and stool were widely accepted due to perceptions of safety and familiarity. However, several barriers were identified, including cultural beliefs (e.g., fear of witchcraft linked to donating hair), religious beliefs, fear of invasive procedures (spinal taps), and low awareness about biospecimen research. To address these barriers, participants recommended community sensitization, inclusive and transparent research processes, clear communication of benefits, involvement of family members in consenting, and assurance of safety measures for managing potential risks.ConclusionsCommunity willingness to donate biospecimens for AD/ADRD research in Kenya is shaped by a complex interplay of cultural, ethical, and practical considerations. Culturally sensitive, community-driven approaches are essential to enhance participation in AD/ADRD biomarker research in Kenya and similar low-resource settings.},
}

@article {pmid41229078,
year = {2025},
author = {Zhang, N and Liu, Y and Guan, Y},
title = {Piceatannol ameliorates the memory ability and cognitive behavior in Alzheimer's disease mice.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/01616412.2025.2581245},
pmid = {41229078},
issn = {1743-1328},
abstract = {OBJECTIVE: To investigate the effects of different doses of Piceatannol (PIC) on oxidative stress and cognitive function in a mouse model of Alzheimer's disease (AD).

METHODS: Firstly, a mouse model was established by inducing 70 days with D-gal and AlCl3. Sixty male mice are randomly divided into a normal control group (Control), an AD group (AD Model), positive control group (treated with donepezil), an AD model+low-dose group (PIC-L) receiving low-dose piceatannol treatment, an AD model+medium-dose group (PIC-M) receiving medium-dose piceatannol treatment, and an AD model+high-dose group (PIC-H) receiving high-dose piceatannol treatment, with 10 mice in each group. After 35 days of establishing an AD mouse model, different doses of piceatannol are continuously applied for treatment.

RESULTS: After 2 days of treatment, the AD Model had a longer escape latency than the Control. The escape latency time of PIC-L, PIC-M, and PIC-H was below AD Model, (p < 0.05). After treatment for 4d and 5d, the escape latency time of PIC-L, PIC-M, and PIC-H was below the AD Model, and the PIC-H group was even lower, with statistical significance (p < 0.05). PIC-L, PIC-M, and PIC-H crossed the platform more frequently than the AD Model, (p < 0.05). The SOD and GSH-Px levels in AD Model were below the Control, (p < 0.05). The MDA of AD Model exceeded the Control, (p < 0.05). The SOD, and GSH-Px in PIC-L, PIC-M, PIC-H exceeded the AD Model, (p < 0.05).

CONCLUSION: PIC significantly improved memory and cognition in AD mice, elevated serum SOD and GSH-Px, lowered MDA, and attenuated oxidative tissue injury with minimal organ toxicity.},
}

@article {pmid41228597,
year = {2025},
author = {Gomes, ACC and Almeida, A and Freire, CSR and Ferreira, BL},
title = {Chitosan (Nano)formulations as Therapeutic Tools for Neurodegenerative Diseases: A Comprehensive Review.},
journal = {Polymers},
volume = {17},
number = {21},
pages = {},
pmid = {41228597},
issn = {2073-4360},
support = {UIDB/50011/2020 (DOI 10.54499/UIDB/50011/2020)//FCT/MCTES (PIDDAC)/ ; UIDP/50011/2020 (DOI 10.54499/UIDP/50011/2020)//FCT/MCTES (PIDDAC)/ ; LA/P/0006/2020 (DOI 10.54499/LA/P/0006/2020)//FCT/MCTES (PIDDAC)/ ; (UIDP/50017/2020+UIDB/50017/2020+LA/P/0094/2020)//FCT/MCTES (PIDDAC)/ ; 2022.10449.BD (https://doi.org/10.54499/2022.10449.BD)//Fundação para a Ciência e Tecnologia/ ; DOI 10.54499/ND/00464/2017/CP1459/CT0033//Fundação para a Ciência e Tecnologia/ ; DOI: 10.54499/DL57/2016/CP1482/CT0019//National funds (OE), through FCT/ ; },
abstract = {According to the World Health Organization, Alzheimer's disease and other forms of dementia were the seventh leading cause of death in 2021. The prevalence of these disorders is predictable to increase with life expectancy, and their control is hampered by several factors, including late diagnosis due to the lack of specific biomarkers and the absence of disease-modifying treatments, as currently available therapies can only lighten some of the symptoms. Nanotechnology could be the key to overcoming some of the limitations associated with neurodegenerative diseases, as nanomaterials have excellent properties compared to their bulk counterparts and can be used as drug delivery systems, diagnostic tools and platforms for tissue regeneration. Chitosan is a biopolymer with numerous properties that impart it with great potential for biomedical applications, in particular its ability to cross the blood-brain barrier and its versatility in nanoscale design. In this context, the aim of this review is to provide an in-depth analysis of the latest developments and future opportunities for chitosan (nano)formulations for the treatment and management of neurodegenerative diseases.},
}

@article {pmid41228523,
year = {2025},
author = {Liu, Y and Dong, Y and Cao, Z and Ji, Y and Cheng, X and Zheng, X},
title = {The Multi-Dimensional Action Map of Resveratrol Against Alzheimer's Disease: Mechanism Integration and Treatment Strategy Optimization.},
journal = {Nutrients},
volume = {17},
number = {21},
pages = {},
doi = {10.3390/nu17213451},
pmid = {41228523},
issn = {2072-6643},
support = {//the Youth Talent Cultivation Fund Project of Dalian Medical University./ ; },
mesh = {*Resveratrol/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Oxidative Stress/drug effects ; *Antioxidants/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; Plaque, Amyloid/drug therapy ; Energy Metabolism/drug effects ; Mitochondria/drug effects/metabolism ; Neurofibrillary Tangles/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) represents a prevalent neurodegenerative disorder marked by a gradual decline in cognitive and behavioral functions. Despite advancements in elucidating several potential mechanisms underlying the pathogenesis of AD, there remains a limitation in effective supplements or medications for its intervention. Resveratrol, a natural antioxidant, has emerged as a significant player in the treatment of AD. This article reviews the role of resveratrol in four key aspects: amyloid plaque deposition and neurofibrillary tangles, inflammatory response and oxidative stress, energy metabolism and mitochondrial homeostasis, and neuroprotection and regeneration. Furthermore, we also explore treatment strategies to enhance the therapeutic effect of resveratrol.},
}

*Resveratrol/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism
Humans
Oxidative Stress/drug effects
*Antioxidants/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use
Animals
Plaque, Amyloid/drug therapy
Energy Metabolism/drug effects
Mitochondria/drug effects/metabolism
Neurofibrillary Tangles/drug effects/metabolism

@article {pmid41228437,
year = {2025},
author = {Kim, G and Lee, HG and Kwon, S},
title = {Current Utilization and Research Status of the Herbal Medicine Guibi-Tang and Its Variants for Cognitive Impairment: A Scoping Review.},
journal = {Nutrients},
volume = {17},
number = {21},
pages = {},
doi = {10.3390/nu17213365},
pmid = {41228437},
issn = {2072-6643},
support = {RS-2022-KH127675//Korea Health Industry Development Institute/Republic of Korea ; },
mesh = {Humans ; *Cognitive Dysfunction/drug therapy ; *Drugs, Chinese Herbal/therapeutic use/adverse effects ; Aged ; Cognition/drug effects ; Middle Aged ; },
abstract = {Background/Objectives: Guibi-tang (GBT) and its variant Kami-guibi-tang (KGBT) are traditional East Asian multi-herb formulas prescribed for memory loss, insomnia, and fatigue. Preclinical data suggest multimodal neuroprotective actions, including cholinergic signaling modulation and activation of the cAMP response element-binding protein (CREB)/extracellular signal-regulated kinase (ERK) pathway; however, clinical evidence for cognitive disorders remains scattered. This scoping review aimed to map the breadth, design characteristics, efficacy signals, and safety profile of GBT and KGBT across the full spectrum of cognitive impairment. Methods: Following the Arksey-O'Malley framework and PRISMA-ScR guidelines, seven databases were searched (MEDLINE, Embase, Cochrane Library, China National Knowledge Infrastructure, ScienceON, Scopus, Citation Information by the National Institute of Informatics) from inception to 31 January 2025, for human studies evaluating GBT or KGBT in subjective cognitive decline, mild cognitive impairment (MCI), dementia, or post-stroke cognitive impairment (PSCI). Two reviewers independently screened, extracted, and charted data on study design, participants, interventions, outcomes, and adverse events. Results: Fifteen studies met the inclusion criteria-nine randomized controlled trials, one crossover trial, and five observational reports-enrolling 555 participants (age range, 59-87 years). All were conducted in the Republic of Korea, Japan, or China. GBT or KGBT, given as monotherapy or adjunctive therapy for 4 weeks to 9 months, produced modest but consistent improvements in global cognition (Mini-Mental State Examination/Montreal Cognitive Assessment), memory domains, activities of daily living, and neuropsychiatric symptoms across MCI, Alzheimer's disease, and PSCI cohorts. Reported adverse event rates were comparable to or lower than those of placebo, usual care, or conventional drugs, and no serious treatment-related toxicity was identified. Conclusions: Current evidence-although limited by small sample sizes, heterogeneous formulations, short follow-up durations, and regional concentration-indicates that GBT and KGBT are well tolerated and confer clinically meaningful cognitive and functional benefits. Standardized, multicenter, placebo-controlled trials with biomarker end points are warranted to confirm long-term efficacy, clarify mechanisms, and guide integrative clinical use.},
}

Humans
*Cognitive Dysfunction/drug therapy
*Drugs, Chinese Herbal/therapeutic use/adverse effects
Aged
Cognition/drug effects
Middle Aged

@article {pmid41227390,
year = {2025},
author = {Habib, SA and Kamal, MM and Aly, MH and Ghaiad, HR and Rizk, SM and Banks, WA and Erickson, MA},
title = {Streptozotocin Causes Blood-Brain Barrier and Astrocytic Dysfunction In Vitro.},
journal = {Cells},
volume = {14},
number = {21},
pages = {},
doi = {10.3390/cells14211745},
pmid = {41227390},
issn = {2073-4409},
support = {ACOS Research Fund//VA Puget Sound Health Care System/ ; Graduate Scholarship//United States Agency for International Development/ ; },
mesh = {*Blood-Brain Barrier/drug effects/pathology/metabolism ; *Astrocytes/drug effects/pathology/metabolism ; Humans ; *Streptozocin/pharmacology/toxicity ; Endothelial Cells/drug effects/metabolism/pathology ; Induced Pluripotent Stem Cells/drug effects/metabolism ; Glucose Transporter Type 1/metabolism ; Cells, Cultured ; },
abstract = {Streptozotocin (STZ) is an alkylating agent that has neurotoxic effects when injected into the cerebral ventricles (ICV) and also models many other features of Alzheimer's disease. However, the mechanisms of STZ neurotoxicity are not well understood. In this study, we hypothesized that some of the neurotoxic effects of STZ could be due to direct activities on brain endothelial cells and astrocytes, which are key in forming and supporting the functions of the blood-brain barrier (BBB), respectively. To test this hypothesis, we characterized the changes induced by STZ either in cultures of human-induced pluripotent stem cell (iPSC)-derived brain endothelial-like cells (iBECs), which form an in vitro BBB model, or in primary human astrocytes. We found that STZ at a dosage of 5 mM caused a delayed reduction in the transendothelial electrical resistance (TEER) of iBECs at 7-11 days post-treatment, indicating induction of BBB leakage. Additionally, we observed significant increases in albumin leakage across the monolayer, altered iBEC morphology, and reductions in tight junction proteins, suggesting that STZ causes BBB disruption. We further found that the BBB glucose transporter GLUT-1 was reduced in iBECs, as was the total number of iBECs. In astrocytes, the 5 mM dose of STZ reduced the GFAP signal and total number of cells, suggesting that STZ has anti-proliferative and/or toxic effects on astrocytes. Together, these data support that STZ's neurotoxic effects could be due, in part, to its direct toxic activities on brain endothelial cells and astrocytes.},
}

*Blood-Brain Barrier/drug effects/pathology/metabolism
*Astrocytes/drug effects/pathology/metabolism
Humans
*Streptozocin/pharmacology/toxicity
Endothelial Cells/drug effects/metabolism/pathology
Induced Pluripotent Stem Cells/drug effects/metabolism
Glucose Transporter Type 1/metabolism
Cells, Cultured

@article {pmid41226838,
year = {2025},
author = {Zhao, Y and Wang, Z and Xi, E and Yang, F and Gao, N},
title = {Hydrophobic Drug Delivery Platforms Based on Covalent Organic Frameworks for Combined Treatment of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110803},
pmid = {41226838},
issn = {1422-0067},
support = {2022YFB3805902//the National Key R&D Program of China/ ; 22077118//National Natural Science Foundation of China/ ; B18012//the "111" project/ ; 20210101353JC//the National Natural Science Foundation of Jilin Province/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Animals ; *Curcumin/chemistry/administration & dosage/pharmacology/therapeutic use ; Hydrophobic and Hydrophilic Interactions ; Mice ; *Drug Delivery Systems/methods ; *Metal-Organic Frameworks/chemistry ; *Drug Carriers/chemistry ; Humans ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease. The pathogenesis of AD remains incompletely understood. It is characterized by a variety of neuropathological changes, including neuroinflammation, neuronal loss and synaptic damage. Multiple pathological changes make achieving good therapeutic effects with a single drug treatment difficult, and using multiple drugs for combination therapy is currently the most effective method. Currently, the mainstay drugs used for AD treatment are hydrophobic drugs, such as curcumin, donepezil, and resveratrol. Because hydrophobic drugs cannot dissolve in bodily fluids and often aggregate or precipitate, their efficacy is greatly reduced. Therefore, there is an urgent need for a drug carrier that can effectively load and continuously release drugs. However, currently, there are few drug carriers that can achieve efficient co-loading of multiple hydrophobic drugs. Therefore, three of two-dimensional imine covalent organic frameworks (COFs) with different monomers were synthesized through rational design and screening. These three synthesized COFs are simultaneously loaded with curcumin (CUR) and benzofurazan (BZ) to achieve combined therapy. The results indicate that among this series of synthesized COFs, the COF synthesized from 4,4',4″-(1,3,5-Triazine-2,4,6-triyl) trianiline and benzene-1,3,5-tricarboxaldehyde (COF-TB) exhibits optimal hydrophobic drug-loading capacity, enabling effective co-loading of CUR and BZ (BC@COF-TB). After treatment with BC@COF-TB, the cognitive function of 5×FAD mice was significantly improved. The COF platform provides a new way to deliver hydrophobic drugs for AD treatment.},
}

*Alzheimer Disease/drug therapy
Animals
*Curcumin/chemistry/administration & dosage/pharmacology/therapeutic use
Hydrophobic and Hydrophilic Interactions
Mice
*Drug Delivery Systems/methods
*Metal-Organic Frameworks/chemistry
*Drug Carriers/chemistry
Humans
Disease Models, Animal

@article {pmid41226821,
year = {2025},
author = {Paszternák, A and Varga, K and Gyöngyössy, R and Tarnóczi, K and Sikur, N and Szökő, É and Tábi, T},
title = {Resveratrol Analogs Ameliorate Mitochondrial Impairment and Insulin Resistance in a Streptozotocin-Induced In Vitro Model of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110787},
pmid = {41226821},
issn = {1422-0067},
support = {2024-2.1.1-EKÖP-2024-0004 (203)//National Research, Development and Innovation Office/ ; EFOP-3.6.3.-VEKOP-16-2017-00009//National Research, Development and Innovation Office/ ; },
mesh = {*Resveratrol/pharmacology/analogs & derivatives ; *Insulin Resistance ; Humans ; *Alzheimer Disease/metabolism/drug therapy/chemically induced/pathology ; *Mitochondria/drug effects/metabolism/pathology ; Streptozocin/toxicity ; Cell Line, Tumor ; *Neuroprotective Agents/pharmacology/chemistry ; Autophagy/drug effects ; Oxidative Stress/drug effects ; Stilbenes/pharmacology/chemistry ; Antioxidants/pharmacology ; },
abstract = {Alzheimer's disease (AD) is characterized by mitochondrial dysfunction, oxidative stress, insulin resistance, and aberrant protein aggregation. Neurodegeneration model with neuronal insulin resistance was induced in SH-SY5Y human neuroblastoma cells by streptozotocin (STZ). We evaluated the neuroprotective effects of resveratrol (RZV) and three structural analogs: oxyresveratrol (OXI), monomethyl resveratrol (MONO), and trimethyl resveratrol (TRI). Mitochondrial function, plasma membrane integrity, oxidative stress) and autophagy were studied by fluorescent assays. Phosphorylated GSK3 levels were measured by ELISA as an indicator of insulin sensitivity. TRI exhibited significant mitochondrial protective effects and strongly induced autophagy. OXI demonstrated excellent antioxidant activity but showed no detectable mitochondrial protective or autophagy-inducing effects. RZV and MONO exhibited moderate antioxidant effects along with strong insulin-sensitizing and autophagy-inducing properties. Insulin sensitivity was most potently restored by RZV (IC50 = 54 pM) and MONO (IC50 = 50 pM), whereas TRI (IC50 = 160 pM) was less potent, and OXI (IC50 = 97 pM) showed moderate potency. Our findings suggest that the neuroprotective effects of resveratrol analogs significantly depend on their molecular structure and that they exert their beneficial effects through distinct mechanisms. This research may contribute to the development of novel, multi-target compounds for the treatment of neurodegenerative diseases.},
}

*Resveratrol/pharmacology/analogs & derivatives
*Insulin Resistance
Humans
*Alzheimer Disease/metabolism/drug therapy/chemically induced/pathology
*Mitochondria/drug effects/metabolism/pathology
Streptozocin/toxicity
Cell Line, Tumor
*Neuroprotective Agents/pharmacology/chemistry
Autophagy/drug effects
Oxidative Stress/drug effects
Stilbenes/pharmacology/chemistry
Antioxidants/pharmacology

@article {pmid41226793,
year = {2025},
author = {Machowska, M and Leszek, J and Rączy-Krzemianowska, M and Tomasiewicz, B and Hurkacz, M and Rąpała, M and Piechota, J and Głowacka, K and Wiela-Hojeńska, A},
title = {ABC Transporters, APOE, CYP46A1, and LRP1 Gene Polymorphisms as Markers of Dementia Development in Patients with Hyperlipidemia.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110759},
pmid = {41226793},
issn = {1422-0067},
support = {RPDS.01.02.01-02-0002/20//Regional Operational Programme of the Lower Silesian Voivodeship 2014-2020, co-financed by the European Union, European Regional Development Fund/ ; },
mesh = {Humans ; *Hyperlipidemias/genetics/complications ; Male ; Female ; *Apolipoproteins E/genetics ; *Dementia/genetics/etiology ; Aged ; *Polymorphism, Single Nucleotide ; *ATP Binding Cassette Transporter 1/genetics ; Genetic Predisposition to Disease ; *Low Density Lipoprotein Receptor-Related Protein-1/genetics ; Genotype ; Middle Aged ; Alleles ; Gene Frequency ; Biomarkers ; Alzheimer Disease/genetics ; Aged, 80 and over ; *ATP-Binding Cassette Transporters/genetics ; Case-Control Studies ; },
abstract = {In an aging society, solving problems associated with the diagnosis and treatment of dementia-related diseases represents a serious challenge. The aim of the study was to evaluate the possibility of applying molecular biology methods to test polymorphisms recognized in the global literature as potentially useful in assessing the risk of developing dementia in a group of patients with hyperlipidemia. A sample of 203 patients: 109 diagnosed with both dementia and hyperlipidemia, 94 with hyperlipidemia, and 101 individuals as an allele frequency control group-were genotyped. Additional data about cognitive decline and neuropsychological assessment were collected. Among all the studied polymorphisms, the frequency of the ABCA1 rs2230806 polymorphism differed between the analyzed groups. The GG genotype (p = 0.0002, RR = 3.22, CI = 1.63 ÷ 6.37) and the G allele (p = 0.0007, RR = 1.53, CI = 1.19 ÷ 1.97) were more frequent in patients diagnosed with dementia, specifically in those with Alzheimer's disease. Furthermore, the GG genotype was more common in individuals with a shorter disease duration and lower scores on the Montreal Cognitive Assessment (MoCA) scale, and consequently, with greater cognitive function deficits during early stages of the diagnostic process. ABCA1 rs2230806 genotyping is a potential marker for the early identification of dementia risk in patients with hyperlipidemia, which supports the validity of exploring options for incorporating diagnostics based on molecular biology methods.},
}

Humans
*Hyperlipidemias/genetics/complications
Male
Female
*Apolipoproteins E/genetics
*Dementia/genetics/etiology
Aged
*Polymorphism, Single Nucleotide
*ATP Binding Cassette Transporter 1/genetics
Genetic Predisposition to Disease
*Low Density Lipoprotein Receptor-Related Protein-1/genetics
Genotype
Middle Aged
Alleles
Gene Frequency
Biomarkers
Alzheimer Disease/genetics
Aged, 80 and over
*ATP-Binding Cassette Transporters/genetics
Case-Control Studies

@article {pmid41226707,
year = {2025},
author = {Hale, HK and Elias, KM and Ho, S and Kwakye, GF},
title = {Methylene Blue Attenuates 3-Nitropropionic Acid-Induced Oxidative Stress and Mitochondrial Dysfunction in Striatal Cells: Therapeutic Implications in Huntington's Disease Neuropathology.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110672},
pmid = {41226707},
issn = {1422-0067},
support = {Research and Professional Development Portfolio//Oberlin College Arts and Sciences Dean's Office (GFK)/ ; Endowed Professor Research Portfolio//Robert W. & Eleanor H. Biggs Endowed Professor of Neuroscience (GFK)/ ; },
mesh = {*Oxidative Stress/drug effects ; *Huntington Disease/drug therapy/metabolism/pathology ; *Nitro Compounds/toxicity ; *Propionates/toxicity ; *Methylene Blue/pharmacology ; *Mitochondria/drug effects/metabolism/pathology ; Animals ; *Corpus Striatum/drug effects/metabolism/pathology ; Humans ; Reactive Oxygen Species/metabolism ; *Neuroprotective Agents/pharmacology ; Huntingtin Protein/genetics/metabolism ; Cell Survival/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mice ; },
abstract = {There are no disease-modifying treatments available for Huntington's disease (HD), a neurodegenerative disease caused by a genetic mutation in the Huntingtin gene. Previous research suggests that disruptions in the bioenergetics of the mitochondria and increased oxidative stress are potential inducers of HD. Therapies that enhance antioxidant pathways intend to target and attenuate the overproduction of reactive oxygen species associated with mitochondrial dysfunction. We have investigated the effect of Methylene Blue (MB) as a potential therapy for HD. MB is a small molecule demonstrated to exhibit neuroprotective effects in other neurodegenerative disease models, including Parkinson's and Alzheimer's, by attenuating the oxidative stress pathways implicated in their pathophysiology. We used an established striatal cell model of HD expressing wild-type (STHdh[Q7/Q7]) or mutant (STHdh[Q111/Q111]) HTT and a chemical inducer of HD, 3-Nitropropionic acid (3-NPA), to determine the HD-specific mechanisms regulated by 3 h of MB pre-treatment. Upon 24 h of exposure to 3-NPA, mutant HD cells exhibited a significant concentration-dependent decrease in cell survival and a concomitant increase in cell death compared to wild-type, confirming that 3-NPA exacerbates mutant HTT neurotoxicity. Examination of mitochondrial membrane potential and mitochondrial function in the striatal cells by JC-1 and ATP assays, respectively, revealed MB mediated neuroprotection against 3-NPA-induced reduction in mitochondrial activity. Immunoblotting analysis revealed that MB restores baseline expression of oxidative-stress-related proteins, including HO1 and p62, in both wild-type and mutant cells exposed to 3-NPA. Our findings establish a novel neuroprotective role of MB in both genetic and pharmacological models of HD, suggesting that MB might be a promising therapeutic candidate for altering the underlying pathophysiology of HD by improving mitochondrial function.},
}

*Oxidative Stress/drug effects
*Huntington Disease/drug therapy/metabolism/pathology
*Nitro Compounds/toxicity
*Propionates/toxicity
*Methylene Blue/pharmacology
*Mitochondria/drug effects/metabolism/pathology
Animals
*Corpus Striatum/drug effects/metabolism/pathology
Humans
Reactive Oxygen Species/metabolism
*Neuroprotective Agents/pharmacology
Huntingtin Protein/genetics/metabolism
Cell Survival/drug effects
Membrane Potential, Mitochondrial/drug effects
Mice

@article {pmid41226670,
year = {2025},
author = {Bayo Jimenez, MT and Rivas-García, L and Sánchez-González, C and Grosso, G and Lipari, V and Vera-Ramírez, L and Battino, M and Giampieri, F and Quiles, JL and Forbes-Hernández, TY},
title = {Natural Products in Alzheimer's Disease: A Systematic Review of Clinical Trials and Underlying Molecular Mechanisms.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110631},
pmid = {41226670},
issn = {1422-0067},
support = {PID2019-106778RB-I00//MCIN/AEI/10.13039/501100011033 FEDER "Una manera de hacer Europa/ ; Visiting Scholars 2022//Universidad de Granada/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Biological Products/therapeutic use/pharmacology ; Clinical Trials as Topic ; *Plant Extracts/therapeutic use/pharmacology ; Cognitive Dysfunction/drug therapy ; *Neuroprotective Agents/therapeutic use/pharmacology ; Aged ; },
abstract = {This systematic review included 31 clinical trial articles examining the effects of natural compounds on Alzheimer's disease (AD) and mild cognitive impairment (MCI), involving 3582 participants aged 50-90. Treatment durations ranged from 8 weeks to 2 years, with an average of 12.5 months. Notably, 11 studies focused on herbal extracts highlighting their prominence in current research. These extracts showed potential cognitive and neuroprotective benefits, although results varied across compounds and study designs. Other natural compounds-including flavonoids, polyphenols, omega-3 fatty acids, Aloe vera, Spirulina, and citrus phytochemicals-may provide cognitive and neuroprotective benefits, with ginseng and Ginkgo biloba combinations also showing promise. Curcumin and Melissa officinalis had limited effects, resveratrol showed mixed outcomes with some side effects, and matcha green tea may improve cognition and sleep quality. Despite generally favorable results, the studies varied considerably in design and quality; nonetheless, herbal extracts represent a prominent category of natural interventions in AD and MCI, underscoring the need for further large-scale, high-quality clinical trials to confirm their therapeutic potential.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Biological Products/therapeutic use/pharmacology
Clinical Trials as Topic
*Plant Extracts/therapeutic use/pharmacology
Cognitive Dysfunction/drug therapy
*Neuroprotective Agents/therapeutic use/pharmacology
Aged

@article {pmid41226604,
year = {2025},
author = {Hu, C and Lin, M and Wang, C and Zhang, S},
title = {Current Understanding of Protein Aggregation in Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110568},
pmid = {41226604},
issn = {1422-0067},
support = {32170784, 32170707//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; *Protein Aggregates ; *Protein Aggregation, Pathological/metabolism ; Autophagy ; Protein Folding ; },
abstract = {Protein aggregates are central to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. This comprehensive review explores the mechanisms of protein misfolding and aggregation, their prion-like propagation, and the critical role of oligomeric species in neurotoxicity. It further examines cellular clearance pathways, including the ubiquitin-proteasome system and autophagy, alongside the regulatory functions of molecular chaperones. The review also covers advanced diagnostic imaging and biomarker techniques, as well as emerging therapeutic strategies such as pharmacological agents, gene therapy, and immunotherapy. Controversies regarding the toxicity of aggregates and future directions, including novel degradation technologies and targeted therapeutic approaches, are discussed. By integrating current knowledge, this review aims to provide a broad yet detailed overview of the field, highlighting both established concepts and promising avenues for research and treatment.},
}

Humans
*Neurodegenerative Diseases/metabolism/therapy/pathology
Animals
*Protein Aggregates
*Protein Aggregation, Pathological/metabolism
Autophagy
Protein Folding

@article {pmid41226584,
year = {2025},
author = {Costea, D and Dobrin, N and Tataru, CI and Toader, C and Șerban, M and Covache-Busuioc, RA and Munteanu, O and Diaconescu, IB},
title = {The Glymphatic-Venous Axis in Brain Clearance Failure: Aquaporin-4 Dysfunction, Biomarker Imaging, and Precision Therapeutic Frontiers.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110546},
pmid = {41226584},
issn = {1422-0067},
mesh = {Humans ; *Glymphatic System/metabolism/diagnostic imaging ; *Aquaporin 4/metabolism ; Biomarkers/metabolism ; Animals ; *Brain/metabolism/diagnostic imaging/blood supply ; *Neurodegenerative Diseases/metabolism/therapy/diagnostic imaging ; Precision Medicine ; },
abstract = {The identification of brain clearance failure as a precursor to a large variety of neurodegenerative diseases has shifted fluid dynamics from a secondary to a tertiary target of brain health. The identification of the glymphatic system, detailing cerebrospinal fluid entry along perivascular spaces and exit via perivenous and meningeal lymphatic pathways, provided a challenge to previous diffusion models and established aquaporin-4-dependent astroglial polarity as a governing principle of solute transport. Multiple lines of evidence now support a coupled glymphatic-venous axis, wherein vasomotion, venous outflow, and lymphatic drainage are functionally interrelated. Failure of any axis will cascade and affect the entire axis, linking venous congestion, aquaporin-4 disassembly, and meningeal lymphatic failure to protein aggregation, neuroinflammation, edema, and intracranial hypertension. Specific lines of evidence from diffusion tensor imaging along vascular spaces, clearance MRI, and multi-omic biomarkers can provide a measure of transport. Therapeutic strategies are rapidly advancing from experimental strategies to translational approval, including behavioral optimization, closed-loop sleep stimulation, vascular and lymphatic therapies, focused ultrasound, pharmacological polarity recoupling, and regenerative bioengineering. Novel computational approaches, such as digital twin dynamic modeling and adaptive trial designs, suggest that clearance measures may serve as endpoints to be approved by the FDA. This review is intended to bridge relevant mechanistic and translational reviews, focusing on impaired clearance as an exploitable systems defect rather than an incapacitating secondary effect. Improving our understanding of the glymphatic-venous axis Injury may lead to future target strategies that advance cognitive resilience, alleviate disease burden, and improve quality of life. By clarifying the glymphatic-venous axis, we provide a mechanistic link between impaired interstitial clearance and the pathological accumulation of amyloid-β, tau, and α-synuclein in neurodegenerative diseases. The repair of aquaporin-4 polarity, venous compliance, and lymphatic drainage might therefore open new avenues for the diagnosis and treatment of Alzheimer's and Parkinson's disease, supplying both biomarkers of disease progression and new targets for early intervention. These translational implications not only locate clearance failure as an epiphenomenon of neurodegeneration but, more importantly, as a modifiable driver of the course of neurodegeneration.},
}

Humans
*Glymphatic System/metabolism/diagnostic imaging
*Aquaporin 4/metabolism
Biomarkers/metabolism
Animals
*Brain/metabolism/diagnostic imaging/blood supply
*Neurodegenerative Diseases/metabolism/therapy/diagnostic imaging
Precision Medicine

@article {pmid41226231,
year = {2025},
author = {Ananda, SH and Kuragano, M and Tokuraku, K},
title = {Elucidation of the Neuroprotective Effects of Astaxanthin Against Amyloid β Toxicity in the SH-SY5Y Human Neuroblastoma Cell Line.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {21},
pages = {},
pmid = {41226231},
issn = {1420-3049},
support = {SUNBOR GRANT//Suntory Foundation for Life Sciences/ ; JPMJPF2213//Japan Science and Technology Agency/ ; JP24K08627//JSPS KAKENHI/ ; },
mesh = {Humans ; Xanthophylls/pharmacology/chemistry ; *Amyloid beta-Peptides/metabolism/toxicity ; *Neuroprotective Agents/pharmacology ; Cell Line, Tumor ; *Neuroblastoma/metabolism/pathology/drug therapy ; Apoptosis/drug effects ; Cell Movement/drug effects ; Cell Survival/drug effects ; Alzheimer Disease/drug therapy/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, primarily due to amyloid β (Aβ) aggregation in the brain. Astaxanthin (AxN), a xanthophyll carotenoid derived from Haematococcus pluvialis, possesses antioxidant and neuroprotective properties. This study investigated the neuroprotective effects of AxN against Aβ aggregation in human neuroblastoma SH-SY5Y cells. Initially, AxN inhibited Aβ aggregation in DMEM/F12 culture medium but not in PBS, suggesting a medium-dependent effect. Using quantum dot nanoprobes, Aβ aggregation was visualized in the presence of SH-SY5Y cells. AxN treatment (0.032-20 µM) significantly reduced Aβ aggregation and accumulation on SH-SY5Y cells. AxN also prevented Aβ-induced early apoptotic cell death but was less effective against late necrosis. Furthermore, a wound-healing assay showed that AxN restored the impaired cell motility caused by Aβ aggregation. Thioflavin T staining confirmed the reduction in Aβ fibril formation around the cells following AxN treatment. In conclusion, our study suggests that AxN prevents Aβ aggregation and accumulation on the cell surface, thereby restoring cell motility and preventing early apoptosis in neuronal cells.},
}

Humans
Xanthophylls/pharmacology/chemistry
*Amyloid beta-Peptides/metabolism/toxicity
*Neuroprotective Agents/pharmacology
Cell Line, Tumor
*Neuroblastoma/metabolism/pathology/drug therapy
Apoptosis/drug effects
Cell Movement/drug effects
Cell Survival/drug effects
Alzheimer Disease/drug therapy/metabolism

@article {pmid41226137,
year = {2025},
author = {Guaya, D and Espinoza, LC and Jaramillo-Fierro, X and Gualotuña Campoverde, D and Sosa, L and Calpena, AC},
title = {Zinc-Modified Mordenite Zeolite as a Molecular Carrier for Donepezil: A Framework for Drug Delivery Applications.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {21},
pages = {},
pmid = {41226137},
issn = {1420-3049},
support = {PROY_INV_QU_2022_3585//Universidad Técnica Particular de Loja (UTPL)/ ; },
mesh = {*Zeolites/chemistry ; *Donepezil/chemistry/pharmacology/administration & dosage ; *Zinc/chemistry ; *Drug Carriers/chemistry ; *Drug Delivery Systems ; Adsorption ; Drug Liberation ; Kinetics ; Cholinesterase Inhibitors/chemistry ; Hydrogen Bonding ; },
abstract = {The development of advanced drug delivery systems is essential for improving therapeutic efficacy, particularly in the treatment of neurodegenerative disorders such as Alzheimer's disease. This study investigates zinc-modified mordenite zeolite (MR-ZN) as a novel platform for the controlled delivery of donepezil (DPZ), a cholinesterase inhibitor. Natural mordenite was modified with zinc, enhancing its surface area from 62.1 to 85.4 m[2]/g and improving its adsorption properties. Donepezil was successfully loaded at two doses (10 mg and 23 mg), achieving high loading efficiencies of 95% and 94%, respectively. Adsorption kinetics followed a pseudo-second-order model (R[2] > 0.99), indicating that chemisorption predominates through coordination between DPZ functional groups and Zn[2+] sites, while complementary physisorption via hydrogen bonding and van der Waals interactions also contributes to molecular stabilization within the zeolite framework. In vitro release studies under simulated gastrointestinal conditions demonstrated sustained and pH-responsive release profile with 80% and 82% of donepezil released after 24 h for 10 mg and 23 mg formulations, respectively. Density Functional Theory (DFT) calculations revealed favorable adsorption energy (-26.4 kJ/mol), while Bader and Electron Localization Function (ELF) analyses confirmed hydrogen bonding and electrostatic interactions without compromising the zeolite framework. These findings validate MR-ZN as structurally stable, efficient, cost-effective and biocompatible matrix for oral drug delivery. The combination of experimental data and theoretical modeling supports its potential to improve bioavailability and therapeutic performance in neurodegenerative treatment.},
}

*Zeolites/chemistry
*Donepezil/chemistry/pharmacology/administration & dosage
*Zinc/chemistry
*Drug Carriers/chemistry
*Drug Delivery Systems
Adsorption
Drug Liberation
Kinetics
Cholinesterase Inhibitors/chemistry
Hydrogen Bonding

@article {pmid41225966,
year = {2025},
author = {Hayat, MT and Allawi, YM and Alamro, W and Sultan, SM and Abadleh, A and Kang, H and Zreikat, AI},
title = {A Hybrid Convolutional Neural Network-Long Short-Term Memory (CNN-LSTM)-Attention Model Architecture for Precise Medical Image Analysis and Disease Diagnosis.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {21},
pages = {},
pmid = {41225966},
issn = {2075-4418},
support = {PNURSP2025R829//Princess Nourah bint Abdulrahman University/ ; },
abstract = {Background: Deep learning (DL)-based medical image classification is becoming increasingly reliable, enabling physicians to make faster and more accurate decisions in diagnosis and treatment. A plethora of algorithms have been developed to classify and analyze various types of medical images. Among them, Convolutional Neural Networks (CNNs) have proven highly effective, particularly in medical image analysis and disease detection. Methods: To further enhance these capabilities, this research introduces MediVision, a hybrid DL-based model that integrates a vision backbone based on CNNs for feature extraction, capturing detailed patterns and structures essential for precise classification. These features are then processed through Long Short-Term Memory (LSTM), which identifies sequential dependencies to better recognize disease progression. An attention mechanism is then incorporated that selectively focuses on salient features detected by the LSTM, improving the model's ability to highlight critical abnormalities. Additionally, MediVision utilizes a skip connection, merging attention outputs with LSTM outputs along with Grad-CAM heatmap to visualize the most important regions of the analyzed medical image and further enhance feature representation and classification accuracy. Results: Tested on ten diverse medical image datasets (including, Alzheimer's disease, breast ultrasound, blood cell, chest X-ray, chest CT scans, diabetic retinopathy, kidney diseases, bone fracture multi-region, retinal OCT, and brain tumor), MediVision consistently achieved classification accuracies above 95%, with a peak of 98%. Conclusions: The proposed MediVision model offers a robust and effective framework for medical image classification, improving interpretability, reliability, and automated disease diagnosis. To support research reproducibility, the codes and datasets used in this study have been publicly made available through an open-access repository.},
}

@article {pmid41225766,
year = {2025},
author = {Jeon, SY and Byun, MS and Choi, HJ and Kim, YH and Gwag, CH and Oh, Y and Park, JE and Yi, D and Jung, G and Ahn, H and Sohn, BK and Jung, JH and Chang, YY and Kong, N and Choi, H and Kang, KM and Sohn, CH and Lee, DY},
title = {Eligibility for lecanemab and donanemab in Korea under Appropriate Use Recommendations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70875},
doi = {10.1002/alz.70875},
pmid = {41225766},
issn = {1552-5279},
support = {//New Faculty Startup Fund from Seoul National University/ ; //National Research Foundation of Korea/ ; RS-2022-00165636//Ministry of Science and ICT, South Korea/ ; 2014M3C7A1046042//Ministry of Science and ICT, South Korea/ ; //Korea Health Technology R&D Project/ ; //Korea Health Industry Development Institute/ ; HI18C0630//Ministry of Health and Welfare, Republic of Korea/ ; HI19C0149//Ministry of Health and Welfare, Republic of Korea/ ; //Korea Dementia Research Project/ ; //Korea Dementia Research Center (KDRC)/ ; //Ministry of Health & Welfare and Ministry of Science and ICT/ ; RS-2023-KH136195//Republic of Korea/ ; //Basic Science Research Program through the NRF/ ; RS-2023-00210380//Ministry of Education/ ; U01AG072177//National Institute of Aging/ ; //National Institute of AGING/ ; RS-2023-KH136195//Korea Dementia Research Center/ ; HI18C0630//Ministry of Health and Welfare/ ; HI19C0149//Ministry of Health and Welfare/ ; //Seoul National University/ ; },
mesh = {Humans ; Republic of Korea ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Mental Status and Dementia Tests ; Aged, 80 and over ; Brain/diagnostic imaging ; Middle Aged ; Antibodies, Monoclonal, Humanized ; },
abstract = {INTRODUCTION: Appropriate Use Recommendations (AURs) guide real-world use of lecanemab and donanemab in early symptomatic Alzheimer's disease (AD), but their applicability to Asian populations with diverse education backgrounds remains unclear.

METHODS: Among 2726 participants who visited a Korean memory clinic, 1005 amyloid-positive participants with magnetic resonance imaging (MRI) and Clinical Dementia Rating data were included. Eligibility for lecanemab and donanemab was assessed using AUR criteria, including age, Mini-Mental State Examination (MMSE), brain MRI, apolipoprotein E genotype (for donanemab), and anticoagulant use, applying both raw and z-score-based MMSE thresholds.

RESULTS: Among 1005 amyloid-positive participants, 24.6% were eligible for lecanemab and 28.0% for donanemab (9.1% and 10.3% of the initial sample). Applying MMSE z-scores increased eligibility to 38.4% and 33.7%, respectively. Over a third of participants were excluded due to MRI findings, mainly vascular lesions associated with increased amyloid-related imaging-abnormality risks.

DISCUSSION: Incorporating demographically adjusted MMSE z-score threshold improves real-world eligibility and promotes equitable access to anti-amyloid therapies.

HIGHLIGHTS: About a fourth of A+ patients in Korea met AUR criteria for anti-amyloid therapy. Donanemab eligibility slightly exceeded lecanemab despite narrower age criteria. MMSE z-score adjustment increased eligibility in older, less-educated individuals. Over 30% of eligible patients were excluded due to ARIA-related MRI findings. Culturally adapted cognitive thresholds are essential for equitable treatment access.},
}

Humans
Republic of Korea
Male
Female
Magnetic Resonance Imaging
Aged
*Alzheimer Disease/drug therapy/diagnostic imaging
Mental Status and Dementia Tests
Aged, 80 and over
Brain/diagnostic imaging
Middle Aged
Antibodies, Monoclonal, Humanized

@article {pmid41224179,
year = {2025},
author = {Tigro, H and Moëlo, C and Pelcman, J and Paslawski, W and Chen, G and Poska, H and Shimmo, R and Svenningsson, P and Kronqvist, N and Johansson, J},
title = {Bri2 BRICHOS, a molecular chaperone-like domain that can cross brain vascular endothelial cells and deliver proteins into neurons.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114403},
doi = {10.1016/j.jconrel.2025.114403},
pmid = {41224179},
issn = {1873-4995},
abstract = {The transport of biological drugs from the bloodstream into the central nervous system is hindered by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier, creating a need for efficient and safe delivery systems to the brain parenchyma. Recombinant human (rh) BRICHOS, a chaperone-like domain from the protein Bri2, can access the brain after systemic injection and has shown therapeutic efficiency in Alzheimer model mice. Here, we show that rh Bri2 BRICHOS and cargo proteins fused to it are efficiently transcytosed over human BBB models made of cerebral microvascular endothelial cells and astrocytes. Moreover, intravenously injected protein fused with Bri2 BRICHOS can access the brain parenchyma of mice and enter neurons and astrocytes. Our results suggest that rh Bri2 BRICHOS can be harnessed to deliver cargo from the bloodstream into neurons.},
}

@article {pmid41224085,
year = {2025},
author = {Gharedaghi, P and Faridi, N and Wang, P and Bathaie, SZ},
title = {Natural C20 Carotenoids Protect dPC12 Cells from Aβ-Induced Cell Cycle Re-entry, Tau Phosphorylation, and Nrf2 Activation via the Akt/GSK-3β Pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120816},
doi = {10.1016/j.jep.2025.120816},
pmid = {41224085},
issn = {1872-7573},
abstract = {Saffron has been known to improve mood and memory since ancient times. Crocin and Crocetin, bioactive C20 carotenoids, were isolated from saffron stigma and demonstrated multiple biological and pharmacological effects.

AIM OF THE STUDY: We recently demonstrated the effect of Crocin/Crocetin on apoptosis inhibition in an amyloid beta oligomer (AβO)-induced Alzheimer's disease (AD) model using neuronally differentiated PC12 (dPC12) cells. This study investigates their neuroprotective effects on the Akt/GSK-3β pathway in these cells, focusing on NRF2 activity, NQO1 expression, and Tau phosphorylation.

METHODS: dPC12 cells were exposed to AβO to mimic the AD condition. The cells were treated with Crocin/Crocetin before and after to produce preventive and therapeutic modalities. The expression of key pathway markers was evaluated using Western blot and immunocytochemistry. Flow cytometry was employed to assess cell cycle arrest and apoptosis.

RESULTS: Crocin/Crocetin significantly attenuated AβO-induced toxicity in dPC12 cells in both modalities mentioned. The named carotenoids significantly suppressed GSK3β kinase activity and reduced Tau phosphorylation (p-Thr231). Furthermore, they increased AKT phosphorylation, promoted NRF2 translocation into the nucleus, and induced NQO1 expression. These effects were observed in a time-dependent manner. Flow cytometry analyses revealed the involvement of both cell cycle arrest and apoptosis in response to AβO treatment. Crocin and Crocetin inhibited this response.

CONCLUSIONS: Collectively, Crocin/Crocetin effectively mitigated AβO-induced injury in dPC12 cells. Although Crocetin was more effective than Crocin and improved at lower concentrations, both carotenoids exhibited neuroprotective effects against AβO toxicity in preventive and therapeutic modalities via activating the Akt/GSK-3β signaling pathway.},
}

@article {pmid41224062,
year = {2025},
author = {Tiwari, P and Tiwari, S},
title = {Comparative anti-amyloidogenic potential of pristine and nitrogen doped graphene quantum dots against amyloid beta protein.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {148951},
doi = {10.1016/j.ijbiomac.2025.148951},
pmid = {41224062},
issn = {1879-0003},
abstract = {This study investigates the effect of nitrogen doping of graphene quantum dots (GQDs) upon their ability to inhibit the fibrillation of amyloid beta fragments containing 1-42 amino acids (Aβ). Misfolded aggregates of Aβ have been implicated in the pathogenesis of Alzheimer's disease, the most prevalent form of dementia. We employed spectroscopic and microscopic techniques to characterize both quantum dots. Anti-amyloidogenic potential was assessed using circular dichroism (CD) spectroscopy and the thioflavin T (ThT) binding. Atomic force microscopy (AFM) was utilized to characterize the morphological and nanomechanical properties of Aβ fibrils following treatment with the quantum dots. We observed that nitrogen doping significantly alters the absorbance and fluorescence emission profiles, likely due to an increased surface charge density induced by the incorporation of nitrogen atoms. N-GQDs exhibited superior anti-amyloidogenic activity in comparison to pristine quantum dots. This effect varied in accordance to the dose. Using the data of MTT, trypan blue exclusion, differential staining and apoptosis assays on SH-SY5Y neuroblastoma cells, we infer that adsorption of Aβ on doped quantum dots was accompanied with reduction in the stiffness of fibrils and their toxicity to the cells.},
}

@article {pmid41223445,
year = {2025},
author = {Vlachos, I},
title = {Spectral brain connectivity in dementia: Coherence, imaginary coherence and partial coherence analysis of EEG signals.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae1ea1},
pmid = {41223445},
issn = {1741-2552},
abstract = {OBJECTIVE: As the prevalence of dementia continues to rise, the need for accurate and early diagnostic tools becomes increasingly critical. Despite diverse underlying causes, dementia types share common cognitive symptoms, making accurate diagnosis essential for effective treatment.

APPROACH: This study investigates EEG-based spectral brain connectivity in individuals with Alzheimer's disease (AD, N=36), frontotemporal dementia (FTD, N=23), and healthy controls (HC, N=29), with the dual aim of identifying condition-specific connectivity patterns and evaluating three coherence-based connectivity measures: coherence, imaginary coherence, and partial coherence. Resting-state, eyes-closed EEG data (19 channels) were analyzed, and connectivity was estimated across frequencies to assess both global and local network alterations.

MAIN RESULTS: The results indicate that dementias (both AD and FTD) are characterized by decreased connectivity in higher frequency bands and increased connectivity in lower frequencies, reflecting respectively impaired neural communication and neurodegeneration. Moreover, the severity of cognitive impairment correlates with the spatial extent and magnitude of connectivity disruptions. Notably, partial coherence-unlike coherence and imaginary coherence-effectively distinguishes between the AD and FTD groups, suggesting that direct connectivity measures may provide more discriminative information for differential diagnosis.

SIGNIFICANCE: These findings highlight the potential of EEG-based spectral connectivity analysis, particularly partial coherence, as a non-invasive tool to aid in the diagnosis and differential diagnosis of dementia subtypes, supporting early clinical decision-making.},
}

@article {pmid41223194,
year = {2025},
author = {Yoo, SS and Reddy, A and Carroll, W and Ploypradith, K},
title = {Repeated application of transcranial ultrasound maintains spatial and recognition memory in 5xFAD mice with reduction of amyloid-β burden.},
journal = {PloS one},
volume = {20},
number = {11},
pages = {e0336114},
doi = {10.1371/journal.pone.0336114},
pmid = {41223194},
issn = {1932-6203},
abstract = {Pharmacological removal of amyloid beta protofibrils has emerged as a promising therapeutic strategy to delay the onset of Alzheimer's disease (AD) symptoms. As a non-pharmacological and noninvasive alternative, transcranial application of low-intensity ultrasound through intact skull can induce convective acoustic streaming, which has been shown to enhance cerebrospinal fluid solute transport and facilitate the clearance of interstitial solutes. This has led to the development of device-based approaches aimed at removing the precursors of amyloid beta (Aβ) plaques and mitigating cognitive decline in AD. We applied non-thermal, non-cavitational ultrasound (400 kHz frequency) in a pulsed mode (75 ms pulse duration, 2 Hz repetition rate) to the hippocampal region of male 5xFAD mice for 30 minutes weekly, starting at 10 weeks of age and continuing for 15 weeks (until 6 months of age). Spatial and recognition memory performance was assessed monthly using the Y-maze spontaneous alternation (SA) and novel object recognition (NOR) tests. A control group of age-matched mice underwent the same procedures with receiving zero acoustic output. Mice subjected to transcranial ultrasound (tUS) treatment maintained both SA and NOR performance throughout the entire experimental period, whereas mice that received sham tUS exhibited a progressive decline in memory beginning at 3-4 months of age. Congo Red staining of the brain sections revealed a significant (> 40%) reduction in Aβ plaques in the sonicated group. Histological analysis confirmed that repeated ultrasound exposure did not cause any detectable tissue damage. These findings suggest that low intensity tUS may serve as a novel, noninvasive therapeutic strategy to delay the onset of AD symptoms through the reduction of Aβ burden.},
}

@article {pmid41223122,
year = {2025},
author = {Wiest, R and Radojewski, P and Lieb, JM and Psychogios, M and Benzinger, TLS and Franceschi, AM and Wanke, I and Draganski, B and Kurz, FT and Lövblad, KO},
title = {Clinical practice recommendations of the Swiss Society for Neuroradiology*: Neuroimaging standards for enrollment and disease monitoring in Anti-Amyloid Immunotherapies.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-24},
doi = {10.1159/000549521},
pmid = {41223122},
issn = {1660-2862},
abstract = {INTRODUCTION: The Swiss Society for Neuroradiology (SSNR) has established clinical practice recommendations to guide the use of neuroimaging techniques in the enrollment and disease monitoring of patients undergoing anti-amyloid immunotherapies for Alzheimer's disease (AD). In Switzerland, anti-amyloid immunotherapy (AAT) has not been approved by Swissmedic ahead of this publication. This paper therefore reflects the existing international standards of care and will be updated after market clearance of AATs in Switzerland.

BACKGROUND AND RATIONALE: Neuroimaging is a key requirement to assess therapeutic responses and manage potential adverse effects, particularly amyloid-related imaging abnormalities (ARIA). The SSNR recommendations specify the appropriate use of MRI biomarkers to support therapy inclusion, routine monitoring and decision-making in case of manifestations of ARIA-E and ARIA-H during treatment.

CONCLUSIONS: This paper reviews the required image protocols and neuroimaging criteria for patient eligibility and discusses the key findings of ARIA-E and ARIA-H. These findings are required to be recognized by the practicing radiologist to ensure patient safety. The practice recommendations of the SSNR align with previous published recommendations of the American Society of Neuroradiology and the European Society of Neuroradiology. We also provide practical recommendations for workflows and candidate selection to continue or discontinue therapy.},
}

@article {pmid41221473,
year = {2025},
author = {Perez, FP and Bandeira, J and Morisaki, J and Kanakri, H and Rizkalla, M},
title = {Electromagnetic Field Stimulation Effects on Intrinsically Disordered Proteins and Their Role in Aging and Neurodegeneration.},
journal = {Journal of biomedical science and engineering},
volume = {18},
number = {10},
pages = {408-438},
pmid = {41221473},
issn = {1937-6871},
abstract = {There is increasing evidence from preclinical studies. There is growing evidence from preclinical studies in cell cultures and small organisms that exposure to Electromagnetic Fields (EMFs) produces beneficial biological effects. However, controversy persists due to the absence of a clearly defined mechanism. Classical physics, constrained by the non-ionizing nature of these exposures, cannot account for these effects, which do not involve the breaking of chemical bonds to induce conformational changes in proteins. Emerging studies suggest that these effects are mediated through quantum mechanical phenomena-specifically, quantum tunneling and particle-wave duality-acting on the water surrounding proteins at their interfaces. Furthermore, we present evidence of EMF-induced conformational changes in Intrinsically Disordered Proteins (IDPs), including beta-amyloid, tau, alpha-synuclein, and Heat Shock Factor 1 (HSF1). These findings offer a new framework for understanding EMF bioeffects and open promising avenues for research in biophysics and quantum biology. In this context, we address the challenge of reproducibility by examining how variables such as frequency, intensity, Specific Absorption Rate (SAR), and exposure time windows interact, along with how parameters like polarization, phase, pulse modulation, and scheduling influence outcomes. Experimental data identify specific RF frequencies and SAR levels that activate proteostasis and autophagy in cell cultures and small animal models, with potential applications in human treatments that remain consistent with safety thresholds established by regulatory agencies.},
}

@article {pmid41220866,
year = {2025},
author = {Kim, J and Kim, GH and Kang, K and Kim, HJ and Suh, J and Yoon, B and Cho, H and Pyun, JM and Park, YH and Choe, HK and Kim, YK and Lee, KH and Kim, JG and Yang, SJ and Baek, MJ and Chin, J and Jang, H and Moon, SY and , },
title = {Executive Summary of 2025 International Conference of the Korean Dementia Association and International Congress of the Asian Society Against Dementia (IC-KDA/ASAD 2025): A Report From the Academic Committee of the Korean Dementia Association.},
journal = {Dementia and neurocognitive disorders},
volume = {24},
number = {4},
pages = {209-232},
pmid = {41220866},
issn = {2384-0757},
abstract = {The International Conference of the Korean Dementia Association (IC-KDA) 2025 was held jointly with the 19th International Congress of the Asian Society Against Dementia (ASAD) in Seoul, South Korea (May 8-10, 2025), under the theme "Breaking Barriers of Dementia: From Research to Real-world Practice." The program opened with a Pre-Conference Symposium on "Dementia Treatment Update: Lecanemab and NPH" featuring 14 speakers, followed by the main meeting comprising 3 plenary sessions (5 speakers), 7 luncheon-symposium presentations, 16 parallel symposia (48 speakers), a special symposium (2 speakers), and 4 oral-presentation sessions (20 presenters). The congress was attended by 1,052 participants from 27 countries and included 213 poster presentations. Scientific highlights spanned the continuum from discovery to implementation: plasma and imaging biomarkers, retinal and electroencephalogram/voice-based digital biomarkers, and multimodal neuroimaging for risk stratification and outcome prediction; updates on anti-amyloid monoclonal antibodies (MABs) (lecanemab, donanemab), safety/amyloid-related imaging abnormalities management, and real-world data frameworks; mechanistic and multi-omics insights (genetics, metabolomics, epigenomics, transcriptomics); neuroinflammation and glia-mediated pathways; young-onset dementia cohorts across Asia-Pacific; vascular cognitive impairment trials and pathophysiology; neuropsychiatric symptoms and evidence-based behavioral and psychological symptoms of dementia care; lifestyle and multidomain prevention (Mediterranean-Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay-based interventions); dementia-friendly communities and caregiver support; and emerging neuromodulation modalities (low-intensity ultrasound, photobiomodulation, vagus nerve stimulation). Together, the joint IC-KDA & ASAD 2025 meeting emphasized precision medicine and implementation science, bridging laboratory advances with clinical practice and health-system delivery to improve outcomes for people living with dementia and their caregivers.},
}

@article {pmid41220257,
year = {2025},
author = {Wang, HJ and Ruthirakuhan, M and Andreazza, AC and Beroncal, EL and Black, SE and Gallagher, D and Herrmann, N and Kiss, A and Verhoeff, NPLG and Lanctôt, KL},
title = {Identifying a combination of biomarkers to predict treatment response to nabilone for agitation in Alzheimer's disease - an exploratory post hoc analysis.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/17582024.2025.2587549},
pmid = {41220257},
issn = {1758-2032},
abstract = {BACKGROUND: To identify if a combination of blood-based biomarkers related to inflammation and oxidative stress predict treatment response to nabilone for Alzheimer's disease (AD)-associated agitation.

RESEARCH DESIGN AND METHODS: Agitation was assessed using the Cohen-Mansfield Agitation Inventory (CMAI). Serum concentrations of 13 markers were quantified. Univariable and multivariable regression were used to determine differences in CMAI change given nabilone and placebo. A model combining biomarkers with clinical predictors was also evaluated.

RESULTS: Overall, 38 participants enrolled in the original trial (76% male, mean ± SD age 87 ± 10). Nabilone was more efficacious in participants with higher IL-6, higher 8-ISO, higher 24S-OHC, and lower clusterin. Participants in the first tertile (T1) of index scores demonstrated better response to nabilone compared to placebo with a mean difference in CMAI change of -20.6 (95%CI: -30.3, -10.4). During the nabilone phase, 83% of participants in T1 were responders versus 38% in T2 + 3 (Fisher's p = .01). In the combined model, T1 showed better response to nabilone with a mean difference in CMAI change of -26.4 (95%CI: -34.0, -19.6). The proportion of responders was significantly higher in T1 (91%, n = 11) compared to T2 + 3 (32%, n = 19) (Fisher's p = .002).

CONCLUSION: A combination of biomarkers could help characterize responders and non-responders to nabilone.},
}

@article {pmid41219714,
year = {2025},
author = {Blasi, V and Isernia, S and Rossetto, F and Pagliari, C and Borgnis, F and Pirastru, A and Marzulli, M and Foglia, E and Garagiola, E and Baglio, F},
title = {Study protocol for a randomized controlled trial assessing clinical efficacy of digital cognitive rehabilitation for preclinical and mild clinical stages of alzheimer's disease continuum: the MI-RICORDO project.},
journal = {BMC psychiatry},
volume = {25},
number = {1},
pages = {1075},
pmid = {41219714},
issn = {1471-244X},
support = {FP-1321//THCS Horizon Europe Programme/ ; },
abstract = {BACKGROUND: Early or preclinical stages of AD continuum may benefit from lifestyle interventions and cognitive rehabilitation strategies that can delay or prevent progression to dementia. In this context, digital health technologies offer a disruptive potential to expand access to cognitive rehabilitation and meet the increasing demand for early interventions. This study protocol outlines a randomized controlled trial (RCT) designed to evaluate the efficacy and efficiency of a personalized, multidomain digital cognitive rehabilitation approach compared to conventional paper-and-pencil therapy. A secondary objective is to investigate the structural and functional neuroplasticity mechanisms associated with both interventions, using advanced magnetic resonance imaging techniques.

METHODS: The study presents a single-blinded (assessors) 1:1 parallel-arm RCT design involving 102 patients with Subjective Cognitive Decline, o Mild Cognitive Impairment or early-stage dementia. For the experimental intervention group (EG) the digital therapeutic RICORDO-DTx will be employed, while the control group (CG) will perform an unstructured pencil-paper stimulation program. Both interventions will last 5 weeks with 3 session/week. Outcome measures will evaluate efficacy as changes in: behavioural and cognitive abilities, patients' engagement, and structural and functional neuroplasticity mechanisms by means of Magnetic Resonance Imaging. Additional evaluation will include efficiency measures related to usability, acceptability, safety, sustainability and user experience. Patients will be evaluated at baseline (T0), after treatment (T1) and at follow up six months post baseline (T2). Data analyses will involve repeated measures ANOVA models on primary and secondary outcome measures to compare efficacy of intervention between EG and CG. Finally, efficiency measures will be reported with descriptive statistics.

CONCLUSIONS: The expected results lay on the ability of RICORDO DTx, to adapt task difficulty automatically based on patients' performance and perceived difficulty. This adaptive approach is anticipated to yield superior treatment outcomes relative to traditional pencil-and-paper exercises.

TRIAL REGISTRATION: ClinicalTrials.gov NCT07064226. Date of registration 30th July 2025.},
}

@article {pmid41219645,
year = {2025},
author = {Hoang, VD and Nguyen, HMT and Nguyen, TA and Garg, S},
title = {Pharmaceutical Formulations and Analytical Methods of Donepezil.},
journal = {AAPS PharmSciTech},
volume = {27},
number = {1},
pages = {28},
pmid = {41219645},
issn = {1530-9932},
support = {R01AG064688 (Hinton/Nguyen MPI)//the National Institute of Aging (NIA) of the National Institutes of Health (NIH)/ ; },
abstract = {Donepezil is a selective acetylcholinesterase inhibitor widely prescribed for the symptomatic treatment of Alzheimer's disease. As therapeutic needs grow and delivery systems evolve, ensuring product quality, efficacy, safety and patient compliance becomes increasingly important. Meanwhile, pharmaceutical formulation innovations can improve clinical outcomes and usability, and analytical methods help ensure accurate assessment of drug behavior and quality control. This narrative review first provides a concise overview of donepezil's physicochemical properties and synthesis, then focuses on two interrelated domains: (i) pharmaceutical formulations and (ii) analytical methodologies. The former highlights advancements in novel delivery systems-such as liposomes, nanoparticles, microneedles, nasal gels, and long-acting injectable depots-developed to enhance brain targeting, prolong drug release, and reduce systemic side effects. The latter reviews validated analytical methods for quantifying and characterizing donepezil in pharmaceutical and biological matrices, with emphasis on RP-HPLC, LC-MS/MS, chiral separations, and emerging electrochemical and spectroscopic techniques. These analytical strategies are essential for evaluating formulation performance, monitoring drug stability, and ensuring regulatory compliance. Collectively, this review underscores that progress in both formulation design and analytical science is vital to optimizing donepezil-based therapies for Alzheimer's disease management.},
}

@article {pmid41219231,
year = {2025},
author = {Mahadik, N and Paruchuri, SN and Arif, R and Coutts, AS and Barron, GA and Kong Thoo Lin, P and Chatterjee, S and Thompson, CJ},
title = {Evaluation of the toxicity and efficacy of a multi-target polymer-drug nano-polyplex in SH-SY5Y cells and Drosophila model of tauopathy.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39454},
pmid = {41219231},
issn = {2045-2322},
support = {C23-1720928079//Royal Society of Chemistry/ ; C23-1720928079//Royal Society of Chemistry/ ; C23-1720928079//Royal Society of Chemistry/ ; C23-1720928079//Royal Society of Chemistry/ ; C23-1720928079//Royal Society of Chemistry/ ; },
abstract = {Hyperphosphorylated tau contributes to synaptic damage and neuronal dysfunction in neurodegenerative diseases such as Alzheimer's disease (AD), making it a key therapeutic target. This study evaluated the toxicity and therapeutic potential of a novel polymer-drug nano-polyplex, N5NM15, and polyacrylic acid (PAA) in Drosophila tauopathy models and undifferentiated human SH-SY5Y cells. Cellular uptake was demonstrated by N5NM15, and SH-SY5Y cell viability was significantly enhanced (45%, p ≤ 0.0001) under okadaic acid-induced stress, and total tau levels were reduced (1.43-fold, p ≤ 0.01). In comparison, PAA had a modest effect on decreasing tau phosphorylation (1.3-fold) at the pSer202/pThr205 site. Toxicity studies in Drosophila revealed that N5NM15 (3.5:1 and 44:12.5 µg/mL) and PAA (44 µg/mL) were toxic to adult flies expressing the eye-specific driver (GMR-GAL4) but were well-tolerated in flies overexpressing the pan-neuronal driver ELAV-GAL4. Furthermore, treatment with N5NM15 and PAA did not improve the ommatidial arrangement, eye bristle count, or eye length in tauopathy models. Climbing and survival assays indicated a potential mild protective effect at a lower concentration (3.5:1 µg/mL) at the early stage of the disease, but at a higher dose (44:12.5 µg/mL) was significantly toxic, in both wild-type (p ≤ 0.0001) and tauopathy models (p < 0.05). These findings highlight the need for N5NM15 and PAA dose optimisation and reformulation with non-toxic buffers to enhance therapeutic potential while minimising adverse effects in normal and Drosophila tauopathy models for AD treatment.},
}

@article {pmid41219110,
year = {2025},
author = {Rose, DK and Lyketsos, CG and Rosenberg, PB and Nowrangi, MA},
title = {Neuropsychiatric symptoms in Alzheimer's disease: Bridging mechanisms, management, and emerging innovations.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00788},
doi = {10.1016/j.neurot.2025.e00788},
pmid = {41219110},
issn = {1878-7479},
abstract = {Neuropsychiatric symptoms (NPS) are among the most distressing and functionally disruptive features of Alzheimer's disease (AD), affecting the vast majority of individuals across the disease continuum. These symptoms, ranging from apathy and depression to agitation and psychosis, not only worsen quality of life but also predict faster decline, earlier institutionalization, and heightened caregiver burden. Yet, despite their clinical significance, NPS remain under-recognized and undertreated. This review synthesizes current understanding of the biological underpinnings of NPS in AD, highlighting network-level dysfunction, neurotransmitter imbalances, neuroinflammation, and emerging roles for tau pathology and circadian disruption. We critically examine current treatment paradigms, noting that pharmacologic interventions offer benefit but often carry significant risks. In contrast, non-pharmacological approaches, particularly those that integrate caregiver training, environmental design, and sensory engagement, hold promise but are inconsistently applied in routine care. Emerging innovations, including neuromodulation, repurposed agents (e.g., beta-blockers, cannabinoids), and digital therapeutics such as virtual reality and AI-enabled monitoring tools, offer new therapeutic avenues. We call for a paradigm shift toward person-centered, mechanistically-informed care that aligns intervention strategies with biological drivers of NPS. Future progress hinges on inclusive clinical trials, implementation of first-line behavioral strategies, and development of biomarker-guided, precision approaches to symptom management. Effective care for NPS in AD demands integration, not substitution, of pharmacologic and non-pharmacologic strategies, grounded in a deeper understanding of both disease biology and lived patient experience.},
}

@article {pmid41219002,
year = {2026},
author = {Radhakrishna, BK and Kaladiyil, AP and Chakraborty, A and Gautam, V and Muddashetty, RS},
title = {Group 1 mGluR stimulation rescues APOE4-mediated translation defects in neurons.},
journal = {Life science alliance},
volume = {9},
number = {2},
pages = {},
doi = {10.26508/lsa.202503287},
pmid = {41219002},
issn = {2575-1077},
abstract = {The E4 isoform of apolipoprotein (APOE4) is the most recognized risk factor for Alzheimer's disease, implicated in early neurodegeneration and impaired synaptic plasticity. In neurons, exposure to APOE4 disrupts basal and NMDAR-mediated calcium signaling, further disrupting protein synthesis response. Group 1 mGluRs, a major class of glutamate receptors, also play a critical role in synaptic plasticity through activity-dependent protein synthesis. In this study, we examine neuronal protein synthesis response to mGluR stimulation in the background of APOE4 treatment. In DIV15 primary cortical neurons from Sprague-Dawley rat embryos, exposure to APOE4 induces inhibition of protein synthesis, which is rescued by stimulation of mGluRs for 5 min. mGluR stimulation also rescued the APOE4-induced reduction in synaptic activity as measured by the multi-electrode array. This mGluR-mediated rescue is driven by phosphorylation of RPS6, downstream of the mammalian target of rapamycin (mTOR) pathway as it is abolished by rapamycin treatment. This p-RPS6-driven rescue is independent of calcium-mediated translation inhibition induced by APOE4, demonstrating a specific and independent role of mTORC1 activity in maintaining mGluRs' translation capacity under APOE4 exposure. The potential of mGluR-mediated response to compensate for the effect of APOE4 suggests a dynamic mechanism for the induction of plasticity in human APOE4 carriers. This study provokes a critical need to explore the altered synaptic dynamics in the presence of APOE4 and its impact on cognition.},
}

@article {pmid41218737,
year = {2025},
author = {Ahangaran, S and Pourgholaminejad, A and Nosrati, R and Babaei, P},
title = {TLR4 Inhibition Attenuate Facilitatory Effects of JQ1 on Learning & Memory Via Polarization of Microglia, and BDNF Expression in Alzheimer's Disease Model.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115919},
doi = {10.1016/j.bbr.2025.115919},
pmid = {41218737},
issn = {1872-7549},
abstract = {OBJECTIVE: Neuroinflammation is a core event in the pathogenesis of Alzheimer's disease (AD), which is mediated by microglia. The present study aimed to investigate the effect of co-inhibition of Toll-like receptor (TLR4) and chromatin reader of BRD4 on cognition deficit, polarization of microglia, and Brain-derived neurotrophic factor in the hippocampus.

METHODS: Forty male Wistar rats were randomly divided into five groups: saline +saline, Aβ+saline, Aβ+JQ1(BRD4 inhibitor), Aβ+TAK242 (TLR4 inhibitor), Aβ+JQ1+TAK-2452, and received the related treatments. Then cognitive functions were assessed by passive avoidance learning (PAL) and Morris water maze (MWM) tests. Then, the polarization of microglia and BDNF level in the hippocampus, were measured using flow cytometry and western blotting, respectively.

RESULTS: Chronic intracerebroventricular administration of JQ1, either alone or in combination with TAK-242, significantly reduced escape latency and increased the time spent in the target quadrant (TTS) during the probe test of the Morris Water Maze (MWM), compared with the Aβ + saline group (p < 0.05). In contrast, TAK-242 alone prolonged escape latency and reduced TTS (p < 0.05). Moreover, JQ1 treatment markedly elevated the M2/M1 microglial polarization and the mBDNF/proBDNF ratio in the hippocampus (p < 0.05), suggesting that JQ1 promotes neuroprotective and cognitive function mechanisms in this model.

CONCLUSION: Our results indicate that JQ1 successfully improves learning and memory in the rat model of Alzheimer's disease, primarily by inducing the transcription of BDNF expression and suppressing inflammatory factors related to the M1 microglia. In contrast, co-treatment with a TLR4 inhibitor attenuate both spatial and aversive memories, probably through a decrease in BDNF expression.},
}

@article {pmid41218709,
year = {2025},
author = {Ruoff, LK and Bänfer, IWH and Liedtke, DE and China, SE and Wiltfang, J and Bayer, TA and Bock, SF and Spandau, F and Bouter, C and Beindorff, N and Bouter, Y},
title = {Long-term thiethylperazine treatment in the Tg4-42 mouse model of Alzheimer's disease mouse: Therapeutic potential vs. adverse effects.},
journal = {Pharmacology, biochemistry, and behavior},
volume = {},
number = {},
pages = {174127},
doi = {10.1016/j.pbb.2025.174127},
pmid = {41218709},
issn = {1873-5177},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments. Thiethylperazine, a dopamine receptor antagonist with antiemetic and antidopaminergic properties, has been proposed as a potential therapeutic agent for AD. However, its impact on cognitive function in AD remains unclear.

AIMS: This study investigated the long-term effects of thiethylperazine on memory, anxiety-like behavior, motor function, and AD pathology in Tg4-42 mice, a model characterized by Aβ4-42 overexpression and progressive neurodegeneration. Additionally, the impact of prolonged thiethylperazine treatment on behavioral outcomes and cerebral glucose metabolism in healthy adult C57BL/6J wild-type (WT) mice were examined.

METHODS: Tg4-42 and WT mice were treated daily with 10 mg/kg thiethylperazine for 6 months, starting at 10 weeks of age. Memory, anxiety-related, and motor tests were performed at 7.5 months. Immunohistochemical analyses were conducted to quantify effects on Aβ pathology, neurogenesis, neuron number, and neuroinflammation. Additionally, [18]F-FDG-PET imaging was used to evaluate metabolic activity in WT mice following treatment.

RESULTS: Thiethylperazine improved recognition memory in Tg4-42 mice in the Novel Object Recognition test and exhibited anxiolytic properties. However, it impaired spatial learning in the Morris Water Maze (MWM), reduced locomotion, and failed to mitigate motor impairments. No effects on neuron loss or neuroinflammation were observed. In WT mice, thiethylperazine altered learning processes in the MWM, as indicated by shifts in search strategies, induced hypometabolism and increased neurogenesis.

CONCLUSION: Although thiethylperazine offers mild cognitive benefits in Tg4-42, its adverse effects on learning strategies and locomotion raise questions about its potential as a therapeutic option for AD.},
}

@article {pmid41216966,
year = {2025},
author = {Hovde, MJ and Maaser-Hecker, A and Bae, JS and Tanzi, RE},
title = {Inhibition of Acyl-CoenzymeA: Cholesterol Acyltransferase 1 promotes shedding of soluble triggering receptor on myeloid cells 2 (TREM2) and low-density lipoprotein receptor 1 (LRP1)-dependent phagocytosis of amyloid beta protein in microglia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70879},
doi = {10.1002/alz.70879},
pmid = {41216966},
issn = {1552-5279},
support = {//Freedom Together Fund/ ; T32 AG000222-31//Cure Alzheimer's Fund/ ; T32AG000222/AG/NIA NIH HHS/United States ; //NIH/ ; },
abstract = {INTRODUCTION: Lipid regulation is crucial role in Alzheimer's disease (AD) pathogenesis. In AD, microglia show elevated sterol O-acyltransferase 1/Acyl-coenzymeA: Choleseterol Acyltransferase 1 (SOAT1) expression, encoding Acyl-coenzymeA: Cholesterol Acyltransferase 1 (ACAT1), which produces cholesteryl esters (CEs) in lipid droplets. Inhibiting ACAT1 has been shown to reduce amyloid beta (Aβ) pathology, though the mechanism is unclear.

METHODS: We inhibited ACAT1 using avasimibe (AV) in wild-type, triggering receptor expressed on myeloid cells 2 (TREM2) knockout (KO), and low-density lipoprotein receptor related protein 1 (LRP1) KO mouse BV2 and human induced pluripotent stem cell-derived microglia and measured the impact on Aβ uptake to determine the mechanism through which the inhibition of ACAT1 enhances Aβ uptake.

RESULTS: ACAT1 inhibition increased LRP1 levels and soluble TREM2 (sTREM2) release via enhanced TREM2 cleavage by ADAM metallopeptidase domain 10/17 (ADAM10/17). KO of TREM2 or blockade of sTREM2 release prevented AV-enhanced Aβ uptake. This effect was rescued by recombinant sTREM2, but only when LRP1 was present.

DISCUSSION: ACAT1 inhibition promotes microglial Aβ uptake in a sTREM2- and LRP1-dependent manner, offering insights into novel therapeutic strategies for AD.

HIGHLIGHTS: Inhibition of ACAT1, the major enzyme that catalyzes cholesterol storage via esterification enhances microglia-mediated Aβ uptake. Increased Aβ uptake is dependent on the presence of both TREM2 and LRP1. Inhibition of ACAT1 increases cleavage of TREM2 via ADAM10/17 to release sTREM2. Treatment of microglial cells with sTREM2 rescues Aβ uptake in TREM2 KO BV2 cells. Inhibition of ACAT1 promotes Aβ uptake through increased shedding of TREM2, which enhances Aβ uptake through a LRP1-dependent mechanism.},
}

@article {pmid41216919,
year = {2025},
author = {Heikal, SA and Fawi, G and Khedr, EM and Othman, M and Moustafa, SA and Elsheikh, NG and Tawfik, HM and Elfarrash, S and Salama, S and Ali, EM and Hassanin, HI and Salama, M},
title = {The Egyptian Dementia Network (EDN): Baseline characteristics from the first dementia registry in an African Arab country.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70770},
doi = {10.1002/alz.70770},
pmid = {41216919},
issn = {1552-5279},
support = {//100 PhDs for Africa programme/ ; //UM6P- EPFL Excellence in Africa Initiative/ ; //American University in Cairo, Research Support/ ; },
abstract = {INTRODUCTION: Dementia is a growing public health challenge in low- and middle-income countries (LMICs) like Egypt, where data are scarce. The Egyptian Dementia Network (EDN) registry addresses this gap by capturing epidemiological, clinical, and environmental data across Egypt.

METHODS: In this multicenter study, 662 participants from six governorates were enrolled using standardized tools.

RESULTS: The cohort had advanced age (mean 68.3 years), low education (65.9% illiterate), and high comorbidities including hypertension (55%) and diabetes (23%). Alzheimer's disease (62%) and vascular dementia (23%) predominated. Only 24.4% received pharmacological treatment and 2.1% psychosocial support, highlighting care gaps. Household insecticide exposure (20.4%) was notable.

DISCUSSION: EDN demonstrates the feasibility of implementing a national dementia registry in LMICs, generating baseline insights into demographic, clinical, and environmental risks. In addition, registry-linked biosamples have enabled pilot multi‑omics and exposome analyses, underscoring its potential as a scalable scientific platform for future dementia research.

HIGHLIGHTS: Established Egypt's first national, multicenter dementia registry. Aimed to characterize dementia profiles and care gaps across diverse regions. Identified late-stage diagnosis and limited access to dementia interventions. Uncovered unique environmental risk factors relevant to the Egyptian context. Provides a foundation for policy, research, and improved dementia care in Egypt.},
}

@article {pmid41216806,
year = {2025},
author = {Oveisgharan, S and Yu, L and Wang, Y and Yang, J and Vialle, R and Lopes, KP and Tasaki, S and Young-Pearse, TL and De Jager, PL and Petyuk, VA and Schneider, JA and Seyfried, NT and Bennett, DA},
title = {Amyloid beta binding partners in the brain tissue of older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70882},
doi = {10.1002/alz.70882},
pmid = {41216806},
issn = {1552-5279},
support = {P30AG10161/NH/NIH HHS/United States ; P30AG72975/NH/NIH HHS/United States ; R01AG17917. R01AG015819/NH/NIH HHS/United States ; U01AG072572/NH/NIH HHS/United States ; U01AG046152/NH/NIH HHS/United States ; R01AG088643/NH/NIH HHS/United States ; R01AG088643/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: The mechanism linking extracellular amyloid beta (Aβ) with intraneuronal tau tangles, pathological hallmarks of Alzheimer's disease (AD), is not understood; it was tested in the current study through Aβ binding partners.

METHODS: Data were from decedents of community-based clinical-pathological studies. Of 52 Aβ binding partners, suggested by non-human studies, levels of 34 together with total Aβ protein were quantified in the dorsolateral prefrontal cortex. Post mortem pathological assessment immunohistochemically quantified Aβ load and tau tangle density.

RESULTS: The strongest mediations between Aβ and tau tangles were observed for Ras-related C3 botulinum toxin substrate 1 (RAC1) and sodium/potassium-transporting ATPase subunit alpha-3 (ATP1A3), which collectively mediated 10.1% of the association between Aβ and tau tangles. In contrast, Aβ mediated >70% of the associations of matrix proteins with tau tangles.

DISCUSSION: Identification of Aβ binding partners that mediate the association between Aβ and tau tangles may provide new targets for AD treatment.

HIGHLIGHTS: RAC1 linked Aβ with tau tangles. ATP1A3 linked Aβ with tau. RAC1 and ATP1A3 collectively mediated 10.1% of the association between Aβ and tau. Aβ mediated >70% of the associations of matrix proteins, such as APOE, with tau.},
}

@article {pmid41216805,
year = {2025},
author = {Lopergolo, D and Gasparini, D and Bianchi, S and Pucci, B and Tripodi, D and Leoni, V and Chincarini, A and Sestini, S and Zetterberg, H and De Stefano, N and Mignarri, A},
title = {Miglustat in Alzheimer's Disease Associated With Heterozygous NPC1 Mutation: Exploratory Case Series and Preliminary Findings.},
journal = {European journal of neurology},
volume = {32},
number = {11},
pages = {e70419},
doi = {10.1111/ene.70419},
pmid = {41216805},
issn = {1468-1331},
support = {2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; 201809-2016862//Alzheimer Drug Discovery Foundation (ADDF), USA/ ; ADSF-21-831376-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831381-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831377-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-24-1284328-C//AD Strategic Fund and the Alzheimer's Association/ ; 22HLT07//European Partnership on Metrology/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; },
abstract = {INTRODUCTION: Several studies have previously demonstrated an increased risk of dementia and brain amyloid deposition in individuals with heterozygous NPC1 mutations. Moreover, in a recent study, we identified the first family with autosomal dominant late-onset Alzheimer's disease (AD) caused by a heterozygous NPC1 mutation. Unfortunately, there are currently no effective treatments available for this condition. Miglustat, which impacts the metabolism of oxysterols, has been shown to exert an anti-amyloidogenic effect in a human cellular model of AD.

METHODS: In our exploratory uncontrolled study, three patients from the previously published family were orally treated with miglustat for 12 months. They underwent monthly clinical evaluations and routine blood tests. Additionally, neuropsychological evaluations, brain amyloid-PET imaging, and biochemical analyses on plasma and CSF were performed.

RESULTS: All three patients achieved clinical stability, showed a sustained reduction in serum oxysterol levels, and experienced a marked decrease in brain amyloid burden.

DISCUSSION: Based on our preliminary observations and hypothesis-generating findings, along with the growing evidence suggesting AD as a lipid disorder, miglustat should be further tested in a larger cohort of heterozygous NPC1 mutated patients and probably evaluated as a potential disease-modifying treatment for AD.},
}

@article {pmid41216328,
year = {2025},
author = {Mohammadi, S and Zarei, S},
title = {Predicting Alzheimer's disease from environmental risk factors: An fMRI-based functional connectivity and advanced machine learning approach.},
journal = {Journal of environmental health science & engineering},
volume = {23},
number = {2},
pages = {39},
pmid = {41216328},
issn = {2052-336X},
abstract = {Alzheimer's disease (AD) is a prevalent and severe neurodegenerative disorder influenced by both genetic and environmental factors-such as air pollution, toxic elements, pesticides, and infectious agents. In recent years, machine learning techniques have become essential in biomedical research, advancing fields like drug delivery and medical imaging through predictive modeling and pattern recognition. Functional connectivity derived from functional magnetic resonance imaging (fMRI) serves as a promising noninvasive biomarker for AD by mapping the brain's connectome and revealing neural network disruptions. In this study, we employed the Robust Multitask Feature Extraction Method to evaluate six supervised machine learning algorithms logistic regression, naïve Bayes, support vector machine, random forest, XGBoost, and CatBoostmfor AD diagnosis. A dataset of 140 fMRI images from an equal number of AD patients and healthy individuals (mean age 67.3 ± 6.7 years) was analyzed. The XGBoost algorithm demonstrated exceptional performance, achieving an accuracy of 98.2%, a recall of 96.6%, perfect precision (100%), an F1-Score of 98.2%, and a Matthews correlation coefficient of 0.96 effectively minimizing false positives and negatives. Although CatBoost and Random Forest also yielded robust results, logistic regression and naïve Bayes showed lower reliability. Overall, XGBoost emerges as a robust solution for the early and precise prediction of Alzheimer's disease, carrying significant implications for proactive patient care and treatment strategies. Beyond these findings, emerging research is exploring multimodal imaging techniques-such as PET and EEG and deeper neural network architectures to further enhance early diagnostic accuracy and treatment personalization in AD.},
}

@article {pmid41215663,
year = {2025},
author = {Guo, Z and Ni, H and Lu, Y and Cui, Z and Wang, Y and Zhu, Z and Wei, X and Xia, C and Xu, M and Du, L and Yang, Y and Shu, S and Wang, K and Wang, Z and Shan, C and Wang, D},
title = {TNEA Regulates Hippocampal Oscillation by Improving Inhibitory Synaptic Plasticity to Ameliorates Cognitive Impairment in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e10885},
doi = {10.1002/advs.202510885},
pmid = {41215663},
issn = {2198-3844},
support = {62127810//National Natural Science Foundation of China/ ; 82272612//National Natural Science Foundation of China/ ; 82374581//National Natural Science Foundation of China/ ; 21DZ2271000//Shanghai Key Laboratory of Health Identification and Assessment/ ; YC-2023-0604//Pudong New Area of Highland Discipline development program/ ; PWRq2023-36//Pudong New Area Outstanding Young Medical Professionals Training Program/ ; YC-2024-0104//Pudong Traditional Chinese Medicine Standardization & Capacity Building Project/ ; },
abstract = {Three-needle electroacupuncture (TNEA) has demonstrated efficacy in improving cognitive function in both Alzheimer's disease (AD) model animals and patients, although its underlying mechanism remains unclear. Here this work investigates the potential connection between cognitive-enhancing effect and TNEA in 5×familial Alzheimer disease（5xFAD) mice model, a model characterized by Amyloid-beta (Aβ) pathology. This work finds alterations in gamma/theta oscillations and deficits in inhibitory monosynaptic transmission in the hippocampal CA1 region of AD. Parvalbumin-positive (PV[+]) interneurons are crucial for generating gamma oscillations and modulating theta oscillation, thereby maintaining the excitation-inhibition (E/I) balance in local neural circuits. In 5xFAD mice, TNEA modulated PV[+] interneuron function, enhancing gamma oscillations during quiescent states. Furthermore, during the novel object recognition test (NORT), TNEA increased theta oscillation power by strengthening presynaptic inhibitory interneurons involved in monosynaptic connections. Collectively, these findings suggest TNEA is a viable minimally invasive treatment approach for AD.},
}

@article {pmid41215623,
year = {2025},
author = {Li, LL and Wang, RZ and Wang, Z and Hu, H and Xu, W and Zhu, L and Sun, Y and Chen, KL and Chen, SF and He, XY and Yuan, MY and Huang, YY and Liu, X and Liu, P and Ye, QY and Wang, J and Ju, ZZ and Zhang, W and Hu, B and Guo, Y and Cao, XY and Li, YX and Zuo, CT and Cheng, W and Jiang, T and Tan, L and Chen, XC and Zhao, QH and Cui, M and Peng, GP and Xin, JW and Yu, JT},
title = {Safety and short-term outcomes of lecanemab for Alzheimer's disease in China: a multicentre study.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf427},
pmid = {41215623},
issn = {1460-2156},
abstract = {Lecanemab is a newly approved monoclonal antibody targeting amyloid plaques for the treatment of early Alzheimer's disease. This study aimed to evaluate the safety and short-term biomarkers and cognition changes of lecanemab in Chinese clinical practice. This multicenter real-world study involved patients receiving lecanemab treatment across seven hospitals in China. Patients underwent comprehensive assessments before treatment. Lecanemab was administered via intravenous infusion every 2 weeks. Treatment-related symptoms were monitored through self-report, and amyloid-related imaging abnormalities were assessed via magnetic resonance imaging. Amyloid and tau biomarker changes were measured using positron emission tomography imaging or plasma testing. Follow-up cognitive assessments were evaluated after 6 months of treatment. Short-term outcomes were analyzed using linear mixed-effect models, without an untreated control group. A total of 407 patients who received at least one lecanemab infusion were involved in this study, with a mean follow-up time of 5.6±3.39 months. The mean age was 68.08 years, with 67.57% of patients being female. Of the participants, 56.51% were APOE ε4 carriers, and 83.19% were at biological stage C. During the study period, 22.22% of the patients experienced treatment-related symptoms, and 12.15% developed at least one amyloid-related imaging abnormality. Only four symptomatic and seven severe amyloid-related imaging abnormality cases were reported. APOE ε4 status was not related to adverse events in the Chinese population. Patients with a higher number of microhemorrhages at baseline were more likely to develop adverse events. No significant differences in adverse events were observed between the moderate Alzheimer's disease dementia group and the mild cognitive impairment group. By the end of the research period, 9.38% of the patients withdrew from lecanemab. After 6 months of treatment, favourable short-term outcomes in biomarkers and stable cognitive function were observed. This study demonstrates that lecanemab treatment is feasible and well-tolerated among the Chinese population, with lower rates of adverse events and favourable short-term outcomes observed. Administration of lecanemab in moderate AD dementia population was relatively safe and further studies are warranted.},
}

@article {pmid41213497,
year = {2025},
author = {Hu, K and Li, C and Liu, Y and Pan, C and Xie, P and Wen, L and Xu, H and Tang, Y and Zheng, P and Huang, Y},
title = {Arabinoxylan ameliorates memory deficits and amyloid pathology in male 5 × FAD mice via modulation of gut microbiota structure.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.11.010},
pmid = {41213497},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD), a prevalent neurodegenerative disorder, is primarily characterized by β-amyloid (Aβ) deposition. Current therapies alleviate symptoms but lack agents capable of modifying disease progression. Meanwhile, cross-regional studies indicate that AD patients exhibit disrupted gut microbiota composition, which is closely associated with cerebral molecular dysregulation. Building on this gut-brain connection, this study aimed to attenuate AD progression by targeting gut microbiota through microbially metabolized carbohydrates. Specifically, using 5 × FAD mice modeling AD pathology, we conducted 16S rRNA sequencing, targeted metabolomics of microbiota-derived metabolites, and bulk RNA sequencing experiments to investigate gut-brain axis alterations. Our results show that AD mice exhibited gut dysbiosis, depletion of short chain fatty acids (SCFAs), and transcriptomic dysregulation in the hippocampus, particularly affecting aging and synaptic plasticity-related genes. Dietary intervention with arabinoxylan significantly increased SCFAs-producing bacteria (Oscillospiraceae and Eubacterium_coprostanoligenes_group), elevated butyric acid, and thereby reversed expression levels of these aging and synaptic plasticity-related genes. Mechanistically, arabinoxylan alleviated AD-like symptoms by modulating the microbiota-gut-brain (MGB) axis; this beneficial effect occurred through enrichment of probiotic bacteria that produce SCFAs to regulate hippocampal synaptic plasticity genes. Collectively, this work proposes arabinoxylan as a novel prebiotic strategy and identifies candidate therapeutic targets for AD treatment.},
}

@article {pmid41213496,
year = {2025},
author = {Abdulkhaliq, AA and Alasiri, G and Almoghrabi, YM and Kim, B and Khan, J and Ajoolabady, A and Ren, J and Tuomilehto, J and Borai, A and Pratico, D},
title = {Role of TREM2 in neuroinflammation.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115547},
doi = {10.1016/j.expneurol.2025.115547},
pmid = {41213496},
issn = {1090-2430},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is cell surface transmembrane receptor of the TREM family, predominantly expressed on microglia within the central nervous system (CNS). Accumulating evidence has highlighted a critical role for microglial TREM2 in modulating inflammatory signaling pathways, thereby influencing the course of neuroinflammation - a central pathological hallmark of various neurodegenerative and CNS disorders. In this review, we aim to elucidate the molecular mechanisms by which TREM2 regulates neuroinflammatory processes, with a particular focus on the most recent advances in the field. A deeper understanding of TREM2-mediated signaling may uncover novel therapeutic targets and pathways with significant translational potential for treatment of CNS diseases.},
}

@article {pmid41213450,
year = {2025},
author = {Huang, Y and Han, M and Fu, Y and Wang, G and Kong, L and Mo, J and Cao, D and Chu, Z and Li, W},
title = {HY-021068 improves neuronal ferroptosis by activating Nrf2 signaling in APP/PS1 Mice and Aβ1-42-induced HT22 cells.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178349},
doi = {10.1016/j.ejphar.2025.178349},
pmid = {41213450},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unclear pathogenesis and no effective treatment methods. HY-021068 (HY), a novel class I drug, exhibits significant neuroprotective properties in ischemic brain injury. Recent studies suggest that neuronal ferroptosis may be a critical contributor to the onset and progression of AD. However, it is still unclear whether HY treatment has protective effects on AD by inhibiting ferroptosis. In this study, APP/PS1 double transgenic mice were used to investigate the effect and mechanism of HY in AD. In vitro, HT22 cells were stimulated with Amyloid β1-42 (Aβ1-42) (5 μM) to elucidate the therapeutic effect of HY and its potential mechanism. The present study indicated that HY treatment significantly improved cognitive dysfunction, enhanced synaptic integrity by upregulating PSD95 and Synapsin I, and reduced Aβ plaque load, APP, beta-secretase 1 (BACE1) expression, and Tau hyperphosphorylation. Furthermore, HY increased glutathione peroxidase 4 (Gpx4) and Cystine/glutamate transporter (xCT) levels, while reduced DMT1 and transferrin receptor expression, eventually inhibiting neuronal ferroptosis. Mechanistically, HY decreased reactive oxygen species (ROS) accumulation and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by elevating Nrf2, haem oxygenase 1 (HO1), and NAD(P)H quinone oxidoreductase 1 (NQO1) expression. The in vitro study also suggested that the Nrf2 inhibitor ML385 markedly diminished the protective effects of HY, while the Nrf2 activator dimethyl fumarate (DMF) resulted in a significant enhancement of HY's therapeutic effects in Aβ1-42-induced HT22 cells. Molecular docking and cellular thermal shift assay showed that HY had an interaction with Nrf2. These results suggested that HY could ameliorate AD-related cognitive decline and neuronal ferroptosis through activating Nrf2 pathway, positioning it as a promising therapeutic strategy for AD.},
}

@article {pmid41213069,
year = {2025},
author = {Lin, Y and Zhao, H and Meng, D and Wang, M},
title = {The Role of T Cells in Alzheimer's Disease.},
journal = {Critical reviews in immunology},
volume = {45},
number = {6},
pages = {53-67},
doi = {10.1615/CritRevImmunol.2025061107},
pmid = {41213069},
issn = {1040-8401},
abstract = {Alzheimer's disease (AD) is a global neurodegenerative disorder characterized by progressive cognitive decline. Its core pathology involves neurofibrillary tangles mediated by hyperphosphorylated tau protein and senile plaques formed by extracellular deposits of β-amyloid. As the global incidence of AD continues to rise, human health faces a serious threat. However, the complexity of its pathogenesis poses significant challenges to current prevention and treatment strategies. Recent studies reveal that T cells, as key components of the adaptive immune system, exhibit abnormalities in both quantity and function within the brains of AD patients. They infiltrate brain parenchyma through multiple pathways-including the blood-brain barrier, choroid plexus, and meningeal lymphatics-and are deeply involved in AD pathology. In this review, we first introduce recent discoveries in the pathogenesis of AD, including tau protein, β-amyloid plaques, and neuroinflammation. We then describe the immune mechanisms and infiltration pathways of T cells in AD. Finally, we focus on the mechanisms by which different T cell subtypes contribute to brain damage in AD, aiming to provide a theoretical foundation for developing AD therapies guided by neuroimmune homeostasis.},
}

@article {pmid41212646,
year = {2025},
author = {Song, W and Fang, M and Geng, Z and Pang, X and Yang, C and Chen, M and Song, B and Hu, C and Hu, Y and Hu, W and Zhou, S and Yan, Y and Wu, X and Wang, K},
title = {Mechanistic study of Alzheimer's disease with behavioral and psychological symptoms based on electroencephalography microstates.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393715},
doi = {10.1177/13872877251393715},
pmid = {41212646},
issn = {1875-8908},
abstract = {BackgroundBehavioral and psychological symptoms of dementia (BPSD) are common in Alzheimer's disease (AD), yet their mechanisms remain unclear.ObjectiveWe aim to explore the possible neurophysiological mechanisms of BPSD using high temporal resolution electroencephalography (EEG) microstate technology, laying the foundation for clinical evaluation and subsequent treatment.MethodsWe enrolled 52 AD patients (25 with BPSD, 27 without) and 29 age- and gender-matched healthy controls (HC). All participants underwent various neuropsychological assessments and resting-state EEG recordings. Resting-state EEG data were analyzed employing microstate analysis techniques, with a focus on four key microstate parameters: duration, occurrence, coverage, and transition probability. Inter-group comparisons were performed using post-hoc tests, with statistical significance determined through False Discovery Rate (FDR) correction. Furthermore, the correlations between the indicators and neuropsychological assessment scores were analyzed.ResultsCompared to the HC and non-BPSD groups, the BPSD group showed an increase in the transition rate from microstate A to microstate C. Compared to the HC group, the BPSD group showed an extension in the duration of microstate A and a decrease in the frequency of microstate D. Compared to the HC group, the non-BPSD group showed prolonged durations (A, B, mean) and reduced occurrences (C, D, mean).The partial correlation analysis with years of education as a covariate showed that in the BPSD group, the duration of microstate A was correlated with the severity of the Neuropsychiatric Inventory (NPI) and the Hamilton Anxiety Scale (HAMA).ConclusionsAD with and without BPSD exhibits different altered brain dynamics.},
}

@article {pmid41212436,
year = {2025},
author = {Vizuete, AFK and Moreira, AP and Zin, LEF and de Oliveira Marques, C and Pacheco, RF and Leal, MB and Menezes, L and Gonçalves, CA},
title = {Neuroprotective Roles of Metformin in a Streptozotocin-Induced Dementia Model in Rats.},
journal = {Neurotoxicity research},
volume = {43},
number = {6},
pages = {48},
pmid = {41212436},
issn = {1476-3524},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia in humans, with high social and economic costs. AD is predominantly a sporadic disorder, and its risk increases with age and in individuals with type 2 diabetes mellitus (T2DM). Metformin is considered the first line drug for treatment of T2DM and has a plethora of effects in the peripheral and nervous system. However, the neuroprotective mechanism of action of this drug is still under debate. In order to assess the effects of metformin in dementia, we investigated the optimal time to start metformin treatment in animals that were submitted to intracerebroventricular (ICV) administration of streptozotocin (STZ) (3 mg/kg) to induce a sporadic AD-like rodent model of dementia. We used two protocols of metformin administration: early metformin (50 mg/Kg/daily) treatment (2 days after STZ model induction, lasting 28 days) and late metformin (50 mg/Kg/daily) treatment (20 weeks after STZ model induction, lasting 28 days). Both time points improved cognitive behavior in STZ rats, as evaluated by the novel object recognition and Morris's water maze tasks. Moreover, both treatments reduced neuroinflammatory parameters, such as TLR4, RAGE, TNF-α and NF-κB protein expression, induced in STZ animals. Metformin downregulated the methylglyoxal/RAGE/NOX‑2 signaling pathway by restoring glyoxalase 1 activity and GSH levels, which are impaired in the STZ-induced dementia model. Our data contribute to understanding the neuroprotective role of metformin, particularly in conditions involving insulin resistance, such as diabetic encephalopathy and AD.},
}

@article {pmid41212353,
year = {2025},
author = {Shademan, B and Yousefi, H and Sharafkhani, R and Nourazarian, A},
title = {LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {102},
pmid = {41212353},
issn = {1573-6830},
support = {(IR.KHOY.REC.1402.030//Khoy University of Medical Sciences/ ; },
abstract = {Alzheimer's disease (AD) leads to a progressive loss of cognitive abilities and memory. A critical factor now recognized as driving AD pathology is neuroinflammation-inflammation occurring in the nervous system, which contributes to neuronal harm and communication breakdowns. our research investigated the specific effects of neuroinflammation on neuronal signaling pathways. In this study, we primarily employed the SH-SY5Y neuroblastoma cell line as an in vitro neuronal model to investigate inflammatory responses relevant to AD etiology, alongside supplementary observations in primary neurons and 3D spheroids for comparative analysis. Our analysis focused on modifications of key molecules, including the neuroprotective protein Brain-Derived Neurotrophic Factor (BDNF), pro-inflammatory cytokines such as IL-6 and TNF-α, and crucial regulatory kinases. Our results demonstrated that LPS treatment dramatically lowered the vitality and decreased BDNF levels in the SH-SY5Y cells. Furthermore, we observed a considerable elevation in the pro-inflammatory cytokines IL-6 and TNF-α, coupled with elevated levels of COX-2 and iNOS. Gene expression data validated that LPS treatment altered the expression of essential signaling kinases (Protein Kinase A (PKA), Protein Kinase B (AKT), and Mitogen-Activated Protein Kinase (MAPK)). Our first comparative analysis revealed that 3D spheroid cultures may elicit more pronounced inflammatory responses than standard 2D cultures; nevertheless, our detailed investigation primarily focused on the SH-SY5Y model. This study revealed that LPS-induced neuroinflammation affects neuronal signaling in vitro, thereby revealing a relationship between inflammation and neuronal dysfunction in cellular models of neuroinflammation. These findings highlight pathways that may be relevant to AD pathophysiology; however, further in vivo studies are necessary to demonstrate their translational relevance to humans.},
}

@article {pmid41211282,
year = {2025},
author = {Olaolorun, F and Howes, MR and Elufioye, T and Odeku, OA and Olopade, J and Chazot, P},
title = {Iron chelation as a therapeutic target in vanadium neurotoxicity and Parkinson's disease: role of medicinal plants.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1667943},
pmid = {41211282},
issn = {1664-2295},
abstract = {Bioprospecting plant natural products has yielded significant success in the development of symptomatic treatment of neurodegenerative diseases, including the two most common, Alzheimer's and Parkinson's diseases (PD). Dysregulation of iron has been strongly implicated in the pathophysiology of these serious intractable diseases. A series of Nigerian endemic plants' methanolic extracts were explored using a Ferrozine binding iron chelation assay. This identified Spondias purpurea L. (SP) leaves as a potential therapeutic candidate and this was determined by evaluation of oxidative stress in 6-hydroxydopamine (6-OHDA)-exposed monoamine cell culture and Drosophila models of PD and vanadium neurotoxicity. SP treatment protected CAD cells against 6-OHDA toxicity and improved survival in PINK-1 mutant flies, though it had little effect on motor deficits. Furthermore, SP treatment reduced the vanadium-induced reactive oxygen species, and notably, staggered SP treatment significantly extended lifespan in vanadium-treated flies. Overall, Spondias purpurea L. leaf methanolic extract exhibited iron-chelating, antioxidant, neuroprotective, and life-extending properties, relevant to Parkinson's disease and vanadium-induced toxicity.},
}

@article {pmid41211099,
year = {2025},
author = {Viani, A and Custo, A and d'Angremont, E and Garibotto, V and Frisoni, GB and Gutman, BA and Lorenzi, M},
title = {Disease Progression Modeling and Stratification for detecting sub-trajectories in the natural history of pathologies: Application to Alzheimer's disease trajectory modeling.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {3},
number = {},
pages = {},
pmid = {41211099},
issn = {2837-6056},
abstract = {Quantifying the progression of degenerative diseases remains crucial for early diagnosis, prevention, and treatment. However, accurately modeling disease biomarker evolution is hindered by substantial variability in disease trajectories among individuals, driven by demographic, genetic, and lifestyle factors. This variability gives rise to heterogeneous phenotypic manifestations, underscoring the need for stratification based on underlying disease subtypes. Recent advances have shown promise in unsupervised stratification of disease trajectories. Yet, current approaches face significant challenges related to robustness, biomarker specificity, interpretability, and temporal resolution of clustering results. To address these challenges, we introduce Disease Progression Modeling and Stratification (DPMoSt), a new probabilistic model designed to optimize clusters of continuous trajectories along a long-term disease time axis. This approach allows for the determination of subtype-specific biomarkers, improving the accuracy of patient stratification and generalization on external cohorts. We demonstrate DPMoSt on both synthetic and real-world data for the modeling of Alzheimer's disease (AD) evolution. In the synthetic experiments, DPMoSt shows high accuracy in reconstructing trajectory subtypes and identifying the biomarkers' specificity for the clustering problem. Our experiments in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrate the ability of DPMoSt to identify AD subtypes associated with accelerated cognitive decline and higher prevalence of the APOE4 variants. This result was validated on the external memory clinic cohort of the Geneva University Hospitals, confirming the association between cognitive decline and APOE4 in the pathological subtype. These results highlight the robustness of DPMoSt as well as its potential for broader applicability, offering a powerful tool for studying disease progression and subtype differentiation across diverse populations.},
}

@article {pmid41209367,
year = {2025},
author = {Xie, Z and Hu, J and Stallings-Smith, S and Kulshreshtha, A and Hong, YR},
title = {Rural-urban differences in modifiable dementia risk factors among U.S. populations aged 45 years or older.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395318},
pmid = {41209367},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) have become a significant public health concern, and the burden is disproportionately concentrated in rural areas.

OBJECTIVE: To examine rural-urban differences in the prevalence of modifiable dementia risk factors and their treatment among U.S. adults aged 45 years and older, and to investigate how these disparities vary by age group and geographic region.

METHODS: This cross-sectional study analyzed nationally representative data from the 2023 National Health Interview Survey in 2025. Prevalence of 11 modifiable dementia risk factors (hypertension, high cholesterol, diabetes, obesity, hearing loss, visual impairment, traumatic brain injury, low education, depression, social isolation, smoking) and 7 corresponding treatments were assessed via self-report. Adjusted rate ratios (aRR) were estimated using robust Poisson regression models.

RESULTS: The study population consisted of 16,981 individuals (mean age: 62.4, 51.6% female, 68.7% non-Hispanic White, 15.5% in rural areas). Rural residents had significantly higher prevalence of hypertension (aRR, 1.11; 95% CI, 1.06-1.17), obesity (aRR, 1.22; 95% CI, 1.15-1.30), diabetes (aRR, 1.29; 95% CI, 1.15-1.45), and hearing loss (aRR, 1.22; 95% CI, 1.12-1.34) compared to urban residents. Disparities were most significant among adults aged 45-64 years and in South/Midwest regions. Treatment rates for cardiometabolic conditions were high (>85%) and similar across regions, but treatment for sensory/behavioral risk factors remained low.

CONCLUSIONS: Rural U.S. adults face higher burden of modifiable dementia risk factors, particularly cardiometabolic and sensory impairments. Targeted public health strategies are needed to address structural inequities and improve dementia prevention in rural communities.},
}

@article {pmid41208730,
year = {2025},
author = {Ke, J and Ding, J and Xu, Y and Yu, C and Hong, Y and Li, S and Meng, T and Ping, Y and Yuan, H and Hu, F},
title = {Engineering microglial exosome-mediated microRNA-124-3p delivery for Alzheimer's disease combinational therapy.},
journal = {Biomaterials science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5bm01080b},
pmid = {41208730},
issn = {2047-4849},
abstract = {Currently, single-target therapy and difficulty in brain drug delivery gravely impede the treatment of Alzheimer's disease (AD). The promising development of microRNA-124-3p (miR-124-3p) serves as a possibility for multiple therapeutic approaches for AD. However, the effective delivery of miR-124-3p to AD-affected brain regions remains a major challenge, primarily due to the blood-brain barrier (BBB) and the inherent instability of therapeutic miR-124-3p. Herein, we engineered miR-124-3p-enriched microglial exosomes (Exo-124-3p) as a biomimetic nanomedicine for the multifunctional treatment of AD. Exo-124-3p can traverse the BBB and facilitate activated-microglia targeting. Subsequently, the on-demand release of miR-124-3p from Exo-124-3p decreased the aggregation of β-amyloid (Aβ) plaques, attenuated the activation of microglia/astrocytes, and exhibited a valuable neuroprotective effect, thereby remolding the AD focal microenvironment. Notably, the in vivo results demonstrated that Exo-124-3p significantly improved the cognitive function in an AD mouse model. Mechanistically, it was elucidated that Exo-124-3p can bind to the 3'UTR region of MEKK3, ultimately inhibiting the MEKK3/NF-κB signaling pathway, thereby ameliorating AD neuroinflammation. Consequently, this study not only provides a promising therapeutic approach for AD combinational therapy, but also advances the development of miRNA delivery in other brain diseases.},
}