@article {pmid41527747,
year = {2026},
author = {Heo, RJ and Negida, A and Barrett, MJ and Chrenka, EA and Bayram, E and Kane, JPM and Werner, AM and Rossom, RC and Wyman-Chick, KA},
title = {Cholinesterase inhibitors for patients with dementia: Patterns of prescribing and disparities in treatment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411418},
doi = {10.1177/13872877251411418},
pmid = {41527747},
issn = {1875-8908},
abstract = {BackgroundCholinesterase inhibitors (ChEIs) are cornerstones of the symptomatic treatment of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and are also prescribed for vascular dementia (VaD). Despite their widespread use, patterns of ChEI prescribing are unclear.ObjectiveOur objective was to examine the prevalence, timing, and types of ChEI prescriptions before and after dementia diagnosis.MethodsWe analyzed electronic health record and claims data for patients diagnosed with AD, DLB, or VaD between October 2015 and August 2022 from a large U.S. healthcare system. ChEI claims (donepezil, rivastigmine, galantamine) were identified in the ±3 years surrounding dementia diagnosis. Repeated measures logistic regression was used to estimate the likelihood of ChEI fills by time-period, dementia type, and time x dementia type interaction to determine if change in prescription patterns significantly differed by diagnosis.ResultsAmong 3166 eligible patients, DLB had the highest prevalence of ChEIs both pre-and post-diagnosis compared to patients with AD and VaD. Post-diagnosis, donepezil was the most common, while galantamine use was sparse. After adjusting for demographics, patients with VaD had lower rates of ChEIs relative to AD (OR: 0.34, 95% CI 0.26-0.45). In the fully adjusted model, females (OR: 0.81, 95% CI: 0.71-0.91) and patients from ethnoracially minoritized populations (OR: 0.74, 95% CI: 0.62-0.88) were less likely to fill ChEI prescriptions.ConclusionsDonepezil was the most frequently filled ChEI across dementias. Patients with DLB had the highest prevalence of ChEIs pre- and post-diagnosis. The potential disparities in treatment we identified should be investigated further.},
}

@article {pmid41527739,
year = {2026},
author = {Le, J and Hu, X and Jiang, Y and Wang, Q and Ma, Q and Cui, W},
title = {Insights into phosphoproteomic studies and prospects of phosphoproteins as biomarkers for brain disorders.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411546},
doi = {10.1177/13872877251411546},
pmid = {41527739},
issn = {1875-8908},
abstract = {The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.},
}

@article {pmid41527682,
year = {2026},
author = {Zohud, O and Lone, IM and Midlej, K and Iraqi, FA},
title = {The complexity of dementia development and its comorbidities: The collaborative cross-mouse population for multivarious tasks approach.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.70131},
pmid = {41527682},
issn = {2576-2095},
support = {//A core fund from Tel Aviv University/ ; },
abstract = {The rising incidence of dementia and associated neurodegenerative disorders poses a growing public health challenge. These conditions have traditionally been studied as isolated central nervous system disorders; however, emerging evidence suggests that broader systemic factors, including chronic inflammation, immune dysregulation, metabolic dysfunction, and genetic susceptibility, may also play a role. This review examines the interconnection between autoimmune diseases and metabolic syndromes in the pathogenesis and exacerbation of neurodegeneration. Conditions such as rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus have been associated with a heightened risk of developing dementia through chronic immune activation, blood-brain barrier disruption, and neuroinflammatory signaling. Similarly, metabolic disorders such as diabesity promote insulin resistance and oxidative stress, accelerating cognitive decline. The review also discusses glaucoma as a neurodegenerative condition with autoimmune features, underscoring the need for expanded classification and treatment strategies. A key focus is the utilization of the Collaborative Cross (CC) mouse model, which enables the study of gene-environment interactions across genetically diverse backgrounds. Findings from CC mice reveal strain-dependent susceptibility to inflammation, cognitive impairment, and gut-brain axis dysfunction, providing a translational bridge to human variability. This review highlights the importance of integrating precision-based approaches to dementia research that consider systemic influences. Advancing our understanding of these multiorgan interactions holds potential for designing precision-based therapeutic approaches to postpone the onset or reduce the incidence of neurodegenerative conditions.},
}

@article {pmid41527663,
year = {2025},
author = {Barbati, SA and Carota, G and Partsinevelos, K and Di Pietro, L and Privitera, A and Cardaci, V and Graziani, A and Mangione, R and Lazzarino, G and Tavazzi, B and Di Pietro, V and Maiani, E and Bellia, F and Amorini, AM and Lazzarino, G and Baba, SP and Caruso, G},
title = {Preclinical evidence and therapeutic perspectives on carnosine for the treatment of neurodegenerative disorders.},
journal = {AIMS neuroscience},
volume = {12},
number = {4},
pages = {444-513},
doi = {10.3934/Neuroscience.2025025},
pmid = {41527663},
issn = {2373-7972},
abstract = {Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide widely distributed in mammalian tissues, especially skeletal and cardiac muscle cells, and, to a lesser extent, in the brain. While early interest in carnosine was given because of its role in muscle cell metabolism and athletic performance, it has more recently gained attention for its potential application in several chronic diseases. Specifically, brain aging and neurodegenerative disorders have received particular attention, as a marked reduction in carnosine levels has been described in these conditions. Carnosine exerts a wide range of biological activities, including antioxidant, anti-inflammatory, anti-glycation, metal-chelating, and neuroprotective properties. Mechanistically, it acts by inhibiting the production of advanced glycation end products (AGEs), buffering cellular pH, and regulating intracellular nitric oxide signaling and mitochondrial function. Its safety profile, the lack of toxicity, and significant side effects support its application for long-term therapeutic use. In this review, we aim to recapitulate and discuss the effects, dosages, and administration routes of carnosine in preclinical in vivo models, with a particular focus on neurodegenerative disorders where it has been shown to reduce oxidative stress, suppress neuroinflammation, modulate protein aggregation, and preserve cognitive function, all key features of neurodegeneration. Despite promising findings, there are gaps in the knowledge on how carnosine affects synaptic plasticity, neuronal remodeling, and other processes that play a central role in the pathophysiology of neurodegenerative disorders. Additionally, clinical translation remains challenging due to inconsistencies across in vivo studies in terms of dosage, treatment duration, routes of administration, and disease models, which affect reproducibility and cross-study comparability. Therefore, while carnosine emerges as a multifunctional and well-tolerated molecule, further research is needed to clarify its therapeutic relevance in human diseases. In this review, we also address future perspectives and key methodological challenges that must be overcome to effectively translate carnosine's biological potential into clinical practice.},
}

@article {pmid41527522,
year = {2026},
author = {Richardson, TI and Klein, RC and Huang, K and Zhang, J and Mesecar, AD and Dage, JL and Clayton, B and Lamb, BT and Palkowitz, AD},
title = {Next-generation Alzheimer's therapeutics: target assessment and enablement at the Indiana University School of Medicine-Purdue University TREAT-AD Center.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e70964},
doi = {10.1002/alz.70964},
pmid = {41527522},
issn = {1552-5279},
support = {U54AG065181/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Drug Discovery/methods ; Indiana ; United States ; National Institute on Aging (U.S.) ; Schools, Medical ; },
abstract = {The incidence of Alzheimer's disease (AD) continues to increase, despite decades of effort to develop disease-modifying therapies. In response, the National Institute on Aging (NIA) established the TaRget Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) centers to address the gap between basic research and translational drug discovery. Situated within a robust AD research environment, the Indiana University School of Medicine (IUSM)-Purdue University TREAT-AD Center is one of two National Institutes of Health (NIH)-supported centers funded to accomplish this mission. With a focus on novel biological targets beyond amyloid and tau, our center has assembled the necessary components of a drug discovery engine: project and data management, bioinformatics and computational science, structural biology and biochemistry, assay development and pharmacology, and molecular design and synthesis of small molecules, antibodies, and oligonucleotides. Our objective is to deliver Target Enabling Packages (TEPs) within an open science framework, making data, methods, and research tools broadly accessible through the AD Knowledge Portal. HIGHLIGHTS: The Indiana University School of Medicine (IUSM)-Purdue TREAT-AD Center develops Target Enabling Packages (TEPs) to advance novel targets for the treatment of Alzheimer's disease (AD). The center is overseen by an administrative core and operates through four technical cores - bioinformatics, structural biology, assay development, and medicinal chemistry - within a milestone-driven and open science framework. Multi-omics, systems biology, and machine learning (ML) approaches guide the nomination of high-priority targets beyond amyloid and tau. Cross-core workflows provide structural insights into novel biological targets, validated assays, biomarkers, and molecular probes that enable lead optimization. All data, methods, and tools are openly shared through the AD Knowledge Portal to accelerate global efforts in AD drug discovery.},
}

*Alzheimer Disease/drug therapy
Humans
*Drug Discovery/methods
Indiana
United States
National Institute on Aging (U.S.)
Schools, Medical

@article {pmid41527496,
year = {2026},
author = {Kalita, T and Shakya, A and Ghosh, SK and Singh, UP and Bhat, HR},
title = {Microwave-Assisted Synthesis and In Vitro Anti-Alzheimer Evaluation of Novel 1,3,5-Triazine-Nicotinic Hydrazide Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {1},
pages = {e70685},
doi = {10.1002/jbt.70685},
pmid = {41527496},
issn = {1099-0461},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Butyrylcholinesterase/metabolism/chemistry ; *Alzheimer Disease/drug therapy/enzymology ; *Acetylcholinesterase/metabolism/chemistry ; Animals ; Humans ; *Triazines/chemistry/pharmacology/chemical synthesis ; *Microwaves ; Cell Line, Tumor ; Molecular Docking Simulation ; Male ; *Hydrazines/chemistry/pharmacology/chemical synthesis ; Rats ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder posing major global health challenges due to its complex pathophysiology and increasing prevalence among the elderly. In the present work, the molecular hybridization technique was utilized to design and synthesize nicotinic hydrazide-1,3,5-triazine hybrids. Accordingly, this study aimed to design, perform in silico screening, synthesize, and evaluate the in vitro and in vivo anti-AD potential of the proposed compounds. Docking studies revealed that the compounds displayed key interactions with catalytic site and peripheral anionic site residues. Based on binding affinity, ten compounds were synthesized and characterized using different spectroscopic techniques. In vitro AChE and BChE inhibitory assays revealed that the compound 4A36 showed the highest inhibitory ability with log IC50 values of 5.97 μM against AChE and 4.57 μM against BChE. In addition, cytotoxicity screening revealed that 4A36 was non-toxic in SH-SY5Y neuroblastoma cells in the concentration range of 15.625-250 µg/mL. Acute oral toxicity evaluation of the compound revealed no adverse effects up to 175 mg/kg b.w. Further, in vivo studies using the scopolamine-induced model further validated the therapeutic promise of the compound. At a dose of 30 mg/kg b.w., the compound demonstrated significant improvements in learning and memory, reduced MDA levels with concurrent elevation of antioxidant enzymes SOD and Catalase, and reduced AChE activity in hippocampal tissue. Histopathological observations revealed that treatment groups, especially at higher dose (30 mg/kg b.w.), preserved the granular layer of the dentate gyrus and improved neuronal integrity compared to the disease control. These findings indicate that 4A36 at a dose of 30 mg/kg b.w. may be considered as a promising lead compound in AD.},
}

*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry
*Butyrylcholinesterase/metabolism/chemistry
*Alzheimer Disease/drug therapy/enzymology
*Acetylcholinesterase/metabolism/chemistry
Animals
Humans
*Triazines/chemistry/pharmacology/chemical synthesis
*Microwaves
Cell Line, Tumor
Molecular Docking Simulation
Male
*Hydrazines/chemistry/pharmacology/chemical synthesis
Rats

@article {pmid41527161,
year = {2026},
author = {Cheng, CM and Tsai, MJ and Tseng, CC and Lin, YS and Lin, YS and Chen, LY and Liu, MN and Fuh, JL},
title = {Pharmacological management of agitation in dementia: An evidence-based review with expert consensus.},
journal = {Journal of the Chinese Medical Association : JCMA},
volume = {},
number = {},
pages = {},
doi = {10.1097/JCMA.0000000000001342},
pmid = {41527161},
issn = {1728-7731},
abstract = {Agitation is a frequently occurring and challenging neuropsychiatric symptom of Alzheimer's disease (AD) that substantially affects quality of life, caregiver burden, and healthcare utilization. Non-pharmacological interventions, especially trigger identification, environmental adjustments, and supportive activities, remain the first-line approach for treating agitation. Pharmacological treatment should be considered only when non-drug measures are insufficient or when agitation causes severe distress or safety risks. This consensus integrates evidence up to June 2025, the Taiwan Ministry of Health and Welfare approvals, and Taipei Veterans General Hospital expert opinion. Among the approved agents, brexpiprazole demonstrated the strongest evidence and most favorable safety profile. Risperidone and aripiprazole are effective, but require careful monitoring for cerebrovascular and extrapyramidal risks. Selected antidepressants, particularly citalopram and agomelatine, should be considered when safety is prioritized. Anticonvulsants, acetylcholinesterase inhibitors, and memantine have limited efficacy and should be reserved for refractory cases. Long-term or routine pharmacological use is not supported by current evidence. Future research should focus on identifying responsive patient subgroups, optimizing dosing strategies, and integrating medications into individualized, multidisciplinary care plans.},
}

@article {pmid41526725,
year = {2026},
author = {Li, R and Berlowitz, D and Mez, J and Silver, B and Wang, X and Hu, W and Goodwin, R and Keating, H and Liu, W and Lin, H and Yu, H},
title = {Early prediction of Alzheimer's disease using longitudinal electronic health records of US military veterans.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {23},
pmid = {41526725},
issn = {2730-664X},
abstract = {BACKGROUND: Early prediction of Alzheimer's disease is important for timely intervention and treatment. We examine whether machine learning on longitudinal electronic health record notes can improve early prediction of Alzheimer's disease.

METHODS: From Veterans Health Administration records (2000 to 2022), we studied 61,537 individuals diagnosed with Alzheimer's disease and 234,105 without, aged 45-103 years, 98.4% were male. From clinical notes, we quantified the frequency of subjective cognitive decline and Alzheimer's disease-related keywords, and applied statistical machine learning models to assess their ability to predict future diagnosis.

RESULTS: Here we show that Alzheimer's-related keywords (e.g., "concentration," "speaking"), occur more often in notes of individuals who later develop Alzheimer's disease than in controls. In the 15 years preceding diagnosis, cases demonstrate an exponential increase in keyword mentions (from 9.4 to 57.7 per year), whereas controls show a slower, linear increase (8.2 to 20.3). These trends are consistent across demographic subgroups. Random forest models using these keywords for prediction achieve an area under receiver operating characteristic curve from 0.577 at ten years before diagnosis to 0.861 one day before diagnosis, consistently outperforming models using only structured data.

CONCLUSIONS: Signs and symptoms of early Alzheimer's disease are reported in clinical notes many years before a clinical diagnosis is made and the frequency of these signs and symptoms, approximated by keywords, increases the closer one is to the diagnosis. A simple keyword-based approach can capture these signals and can help identify individuals at high risk of future Alzheimer's disease.},
}

@article {pmid41524953,
year = {2026},
author = {O'Mara, A and Mody, BP and Mammi, M and Simjian, T and Ghattas, K and Kaliki, S and Le, NPM and Liew, A and Migliore, M and Mekary, RA},
title = {The effect of GLP-1 receptor agonists on cognition in nondiabetic patients with mild cognitive impairment or alzheimer's disease: a meta-analysis of randomized controlled trials.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {1},
pages = {149},
pmid = {41524953},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Cognitive Dysfunction/drug therapy ; *Glucagon-Like Peptide-1 Receptor Agonists ; Randomized Controlled Trials as Topic ; *Cognition/drug effects ; },
abstract = {BACKGROUND: Currently, the cognitive impact of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) remains unclear in non-diabetic patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI), despite their widespread use for type 2 diabetes. This meta-analysis summarized cognitive outcomes from randomized controlled trials (RCTs) of GLP-1 RAs in non-diabetic patients with AD or MCI.

METHODS: PubMed, Cochrane Library, and Embase were searched for studies through October 27, 2024. Pooled standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated using random-effects models. Sensitivity analyses addressed variations in cognitive assessment methodologies. Between-study heterogeneity was evaluated using the I² index.

RESULTS: Four RCTs comprising 112 patients (61 placebo, 51 treatment) were included. For cognitive tests where higher scores indicate better outcomes, no significant difference was observed between GLP-1 RA and placebo groups (pooled SMD: -0.10, 95% CI: -0.53, 0.34; I² = 23.9%). Sensitivity analyses yielded consistent results. Analysis of the Alzheimer's Disease Assessment Scale-Cognitive subscale from two studies, where lower scores indicate better outcomes, similarly showed no significant treatment effect (SMD: 0.07, 95% CI: -0.47, 0.62; I² = 0%).

CONCLUSION: There was no evidence that GLP-1 RAs improved cognitive outcomes compared to placebo in non-diabetic patients with AD or MCI. Further research is needed to clarify their neuroprotective potential and explore alternative therapeutic strategies for cognitive decline.},
}

Humans
*Alzheimer Disease/drug therapy
*Cognitive Dysfunction/drug therapy
*Glucagon-Like Peptide-1 Receptor Agonists
Randomized Controlled Trials as Topic
*Cognition/drug effects

@article {pmid41524814,
year = {2026},
author = {Tripathi, P and Shah, J},
title = {Valacyclovir Mitigates Amyloid Plaque Deposition, P-Tau Aggregation, and Neuroinflammation in Streptozotocin induced Alzheimer's Disease Rat Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {356},
pmid = {41524814},
issn = {1559-1182},
support = {GSBTM/MD/PROJECTS/SSA/4887/2016-17//Gujarat State Biotechnology Mission, Government of Gujarat, India./ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; *tau Proteins/metabolism ; Streptozocin ; Male ; *Valacyclovir/pharmacology/therapeutic use ; Disease Models, Animal ; *Plaque, Amyloid/drug therapy/metabolism/pathology ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Rats ; Amyloid beta-Peptides/metabolism ; Rats, Wistar ; *Protein Aggregates/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's Disease (AD), a leading cause of dementia, is a known neurodegenerative disorder. Affecting millions of people worldwide, AD pathogenesis involves diverse risk factors such as lifestyle, environmental, and metabolic conditions that accelerate sporadic AD. Very recently, backed with substantial evidence, herpes simplex virus-1 (HSV-1) has been recognized as a potential causative factor that may play a pivotal role in sporadic AD. Latent virus is estimated to activate key underlying pathways, preferably Aβ and p-tau, to cause AD. Additionally, Antivirals such as Valacyclovir have emerged to impart a potential neuroprotective role in AD. Present research aimed to explore the neuroprotective role and mechanism of Valacyclovir in the streptozotocin-induced Alzheimer's disease model in rats. A single dose of 3 mg/kg ICV (intracerebroventricular) Streptozotocin (STZ) was administered to induce AD in rats. Two doses of Valacyclovir, i.e., 100 mg/kg and 150 mg/kg were evaluated with Donepezil 5 mg/kg as standard. Post 21 days of treatment, Valacyclovir demonstrated dose-dependent improvement in neurobehavioral parameters. Further, AD-specific parameters i.e. Aβ1-40 and Aβ1-42, p-tau, and BACE-1 were significantly (p < 0.001) reduced with parallel reduction in inflammatory (p < 0.001) and oxidative stress markers. Additionally, Valacyclovir also increased the levels of amyloid clearance enzymes i.e., neprilysin (NEP) (p < 0.001) and insulin-degrading enzyme (IDE) (p < 0.001). Results suggest promising neuroprotective action of valacyclovir via reducing Aβ-amyloid protein, p-Tau, BACE-1, as well as demonstrating anti-inflammatory and antioxidant activity.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
*tau Proteins/metabolism
Streptozocin
Male
*Valacyclovir/pharmacology/therapeutic use
Disease Models, Animal
*Plaque, Amyloid/drug therapy/metabolism/pathology
*Neuroinflammatory Diseases/drug therapy/metabolism/pathology
Rats
Amyloid beta-Peptides/metabolism
Rats, Wistar
*Protein Aggregates/drug effects
Neuroprotective Agents/pharmacology/therapeutic use
Oxidative Stress/drug effects

@article {pmid41524585,
year = {2026},
author = {Hu, G and Li, W and Lei, X and Yao, Y and Ye, S},
title = {Aloe-emodin attenuated Aβ-induced tau phosphorylation by autophagy-NLRP3 inflammasome pathway.},
journal = {Neuroreport},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNR.0000000000002246},
pmid = {41524585},
issn = {1473-558X},
support = {82205235//the National Natural Science Foundation of China/ ; 2022AH050502//The Key Project Foundation of Natural Science Research of Anhui University of Chinese Medicine/ ; 2022rcyb028//The Talent Support Program of Anhui University of Traditional Chinese Medicine/ ; YQYB2024028//Anhui Province 2024 Action Project for Training Young and Middle aged Teachers in Universities/ ; },
abstract = {OBJECTIVE: Anthraquinone derivative aloe-emodin, extracted from Chinese herbs has been confirmed with various pharmacological effects, including anti-inflammatory and neuroprotective properties, particularly in Alzheimer's disease, but the exact mechanism of action remains unclear.

METHODS: In this study, the PC12 cells were induced by amyloid β-protein (Aβ) to establish an in vitro model of Alzheimer's disease. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine staining, transmission electron microscopy, real-time quantitative PCR, western blot, ELISA, coimmunoprecipitation (Co-IP), and immunofluorescence were employed to evaluate effect of aloe-emodin on the survival and expression of related genes and proteins in PC12 cells induced by Aβ.

RESULTS: We found that 5 μM aloe-emodin significantly enhanced cell survival and proliferation. It also increased the mRNA and protein expression of Beclin-1 and LC3II, while decreasing the mRNA expression of P62, PI3K, AKT, mechanistic target of rapamycin (mTOR), NOD-like receptor protein 3 (NLRP3), and caspase-1, as well as the protein expression of P62, NLRP3, cleaved-caspase-1, p-PI3K, p-AKT, p-mTOR, interleukin-18 (IL-18), and IL-1β. Additionally, aloe-emodin reduced the intensity of p-tau fluorescence. The Co-IP results demonstrated a direct interaction between NLRP3 and LC3. Interestingly, aloe-emodin exhibited effects comparable to those of RAPA, an mTOR inhibitor.

CONCLUSION: These findings demonstrate that aloe-emodin offers neuroprotective benefits by reducing NLRP3-mediated inflammation and promoting autophagy, thereby providing a novel perspective on the treatment of Alzheimer's disease.},
}

@article {pmid41524357,
year = {2025},
author = {Guzanova, EV and Zorkova, AV and Sorokina, TA and Goncharov, VV and Voronina, DS and Beschastnova, IA},
title = {[Frequency of nutritional deficiency in patients with Alzheimer's disease and Parkinson's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {125},
number = {12},
pages = {113-119},
doi = {10.17116/jnevro2025125121113},
pmid = {41524357},
issn = {1997-7298},
mesh = {Humans ; Aged ; *Parkinson Disease/complications ; *Alzheimer Disease/complications ; Male ; Female ; Middle Aged ; Aged, 80 and over ; *Malnutrition/epidemiology/etiology/diagnosis/diet therapy ; Nutritional Status ; Nutrition Assessment ; Incidence ; Body Mass Index ; },
abstract = {OBJECTIVE: To determine the incidence of nutritional deficiencies in patients with Alzheimer's disease (AD) and Parkinson's disease (PD) and, if identified, to correct them.

MATERIAL AND METHODS: 111 patients with neurodegenerative diseases AD and PD aged 50 to 89 years) were examined. Patients were examined twice: at the initial visit and 2 months later. During the first visit, a neurological examination and neuropsychological assessment were performed, and anxiety and depression levels were determined. Nutritional status was assessed using the Mini Nutritional Assessment (MNA) questionnaire, and body mass index (BMI) was calculated. For laboratory confirmation of malnutrition, hemoglobin, albumin, lipid profile, urea, and creatinine levels were assessed. All patients at risk of malnutrition were given dietary recommendations. The patient's family discussed adherence to a dietary regimen and maintaining a nutritious diet. To treat malnutrition, patients were also recommended to receive enteral nutrition supplements at a rate of 30-35 kcal/kg of body weight for outpatients (a total of at least 400 kcal/day) and 1 g of protein/kg of body weight/day. For this purpose, Fresubin protein was used, individually adjusted from 2 to 6 measuring spoons (12-36 g of protein). In the presence of dysphagia, depending on the severity of the swallowing disorder, a diet with a modified consistency was prescribed: Fresubin Cream 2 kcal, Fresubin Yogurt, Fresubin Condensed Level 2, and Fresubin Condensed Level 1. At the second visit (2 months later), treatment effectiveness was assessed.

RESULTS: Among the examined patients, AD was diagnosed in 66 (59.5%) patients, and PD in 45. (40.5%). malnutrition/risk of malnutrition was detected in 31 (28%) patients. In the group of patients with AD who had malnutrition/risk of malnutrition, 15 (62.5%) patients had malnutrition, 9 (37.5%) had the risk of malnutrition. Among patients with PD, 3 (42.9%) patients were diagnosed with malnutrition, 4 (57.1%) had the risk of malnutrition. Patients with AD who had moderate and severe dementia had significantly more often malnutrition and risk of malnutrition (p<0.05). Patients with PD at a more severe stage of the disease and, accordingly, with more pronounced movement disorders, had significantly more often malnutrition and the risk of malnutrition (p<0.05). A moderate correlation was obtained between dysphagia, oral apraxia, tooth loss, chewing disorder and malnutrition and the risk of malnutrition in patients with AD and PD (r=0.3, p<0.001). The value of laboratory parameters, such as increased creatinine, decreased albumin and hemoglobin, statistically significantly correlated with malnutrition and the risk of malnutrition (p<0.05). The study found a statistically significant association between depression, affective disorders, and malnutrition and the risk of malnutrition in patients with AD and PD (p<0.05). When examining patients malnutrition and the risk of malnutrition at the second visit, BMI increased in all patients.

CONCLUSION: Malnutrition and the risk of malnutrition occur in more than a quarter of patients with AD and PD. The risk of malnutrition increases in moderate and severe stages of the disease. Malnutrition is more common in AD compared to PD. Malnutrition and the risk of malnutrition were significantly associated with the presence of depression, affective disorders, as well as with chewing disorders, tooth loss, dysphagia, and oral apraxia. Early recognition of the risks of malnutrition is important for the timely correction of modifiable factors for the development of malnutrition, including the organization of adequate nutrition for the patient, dental prosthetics, Adjustment of the treatment regimen for the underlying disease, treatment of depressive episodes, and affective disorders. If a diagnosis of malnutrition is made, it is necessary to calculate and replenish the patient's energy and fluid needs, including the inclusion of additional enteral nutrition in the comprehensive treatment strategy.},
}

Humans
Aged
*Parkinson Disease/complications
*Alzheimer Disease/complications
Male
Female
Middle Aged
Aged, 80 and over
*Malnutrition/epidemiology/etiology/diagnosis/diet therapy
Nutritional Status
Nutrition Assessment
Incidence
Body Mass Index

@article {pmid41524345,
year = {2025},
author = {Yusupov, FA and Abdykadyrov, MS},
title = {[Neurogenesis in neurodegeneration: multifactorial regulation, mechanisms of impairment, and therapeutic strategies].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {125},
number = {12},
pages = {14-21},
doi = {10.17116/jnevro202512512114},
pmid = {41524345},
issn = {1997-7298},
mesh = {Humans ; *Neurogenesis/physiology ; *Alzheimer Disease/physiopathology/metabolism/therapy ; *Neurodegenerative Diseases/physiopathology/therapy ; *Parkinson Disease/physiopathology/therapy/metabolism ; Animals ; },
abstract = {OBJECTIVE: To systematize current data on neurogenesis and its role in the pathogenesis of neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease, with a focus on molecular mechanisms of regulation, the nature of disorders in neurodegeneration, and the evaluation of therapeutic approaches aimed at stimulating neurogenesis.

MATERIAL AND METHODS: Research papers published in scientific databases, mainly Scopus, PubMed, and Google Scholar, over the past 5 years were used for this review. Special attention was paid to studies on neurogenesis and its role in the pathogenesis of neurodegenerative diseases. The review included studies that met the following criteria: publications from the past five years reporting current neurogenesis data, using clearly identified experimental and clinical techniques, published in peer-reviewed international journals with a high impact factor, and providing reliable statistics to support the results.

UNLABELLED: Studies with a limited sample size and insufficient statistical significance, those lacking a transparent methodology or exhibiting a low level of data reproducibility, reviews without a clear focus on neurogenesis or its connection to neurodegenerative diseases, and studies providing insufficient information on the applied technologies and analysis methods were excluded.

RESULTS: Modern research has significantly expanded the understanding of neurogenesis and its role in neurodegenerative diseases. Neurogenesis has been confirmed to occur in specific areas of the adult brain, including the hippocampus, where it is involved in cognitive processes such as learning, memory consolidation, spatial adaptation, cognitive flexibility, and regulation of affective behavior. However, the extent and functional significance of neurogenesis in different brain regions remain a matter of debate. The effect of neurodegenerative diseases on neurogenesis varies: in Alzheimer's disease, studies in animal models demonstrate its impairment; however, data on humans are inconsistent: a decrease in neurogenesis is observed in the early stages of the disease, but in some cases, its increase is reported, likely as a compensatory mechanism. Factors influencing neurogenesis in Alzheimer's disease include β-amyloid and tau protein accumulation, neuroinflammation, mitochondrial dysfunction, and oxidative stress. Parkinson's disease is associated with a decrease in neurogenesis in the subventricular zone and hippocampus due to the degeneration of dopaminergic neurons and the accumulation of α-synuclein; however, deep brain stimulation is able to enhance neuronal proliferation. Therapeutic strategies include pharmacological approaches aimed at stimulating neurogenesis, such as the use of neurotrophic factors, acetylcholinesterase inhibitors, selective serotonin reuptake inhibitors, Wnt and EGFR signaling pathway modulators, uric acid, and MFG-E8, as well as non-pharmacological methods, including physical activity, enriched environment, cognitive training, electrical stimulation, and music therapy.

CONCLUSION: Neurodegenerative diseases are a significant problem in modern healthcare, requiring an in-depth study of the mechanisms of neurogenesis and its role in pathogenesis. Despite conflicting evidence on neurogenesis in adult humans, animal model studies and cellular technologies demonstrate prospects for its therapeutic stimulation. Pharmacological and non-pharmacological methods, including the use of neurotrophic factors, electrical stimulation, and cognitive training, as well as cellular and gene therapy, are the basis of new intervention strategies. However, the issues of controlling the differentiation and integration of new neurons, as well as the ethical aspects associated with the use of stem cells, remain unresolved. Further interdisciplinary research aimed at studying the regulatory mechanisms of neurogenesis and its therapeutic potential may lead to the development of effective treatment strategies that can slow or even reverse the progression of neurodegenerative diseases. It highlights the need to integrate advanced technologies and approaches in modern neuroscience and clinical practice.},
}

Humans
*Neurogenesis/physiology
*Alzheimer Disease/physiopathology/metabolism/therapy
*Neurodegenerative Diseases/physiopathology/therapy
*Parkinson Disease/physiopathology/therapy/metabolism
Animals

@article {pmid41523330,
year = {2025},
author = {Raphael, DL},
title = {Neuropsychiatric symptoms in mild cognitive impairment and early Alzheimer's disease: Clinical pattern and diagnostic implications.},
journal = {AIMS neuroscience},
volume = {12},
number = {4},
pages = {676-705},
pmid = {41523330},
issn = {2373-7972},
abstract = {BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are widely recognized for their hallmark cognitive deficits, typically characterized by progressive cognitive deterioration. However, neuropsychiatric symptoms (NPS), including depression, apathy, anxiety, irritability, and sleep disturbances, are increasingly prevalent in the early stages of these conditions and significantly influence the disease trajectory and patient outcomes. Importantly, neuropsychiatric symptoms often precede overt memory loss by several years, with subtle mood and behavioral disturbances serving as early pre-diagnostic markers of an underlying Alzheimer's pathology. Their presence complicates the diagnosis, accelerates the disease progression, and intensifies the caregiver burden. However, distinguishing NPS arising from neurodegeneration and primary psychiatric disorders remains a profound diagnostic challenge, thus delaying timely intervention and obscuring early disease recognition.

OBJECTIVE: This structured narrative review examines the diagnostic complexities, clinical impact, and current management of NPS in early-stage Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI), alongside the biological underpinnings, clinical relevance, diagnostic challenges, and treatment perspectives. We argue that understanding and managing NPS is essential to improve the clinical outcomes, reduce the caregiver burden, and guide therapeutic innovation.

METHODS: A structured narrative review of peer-reviewed studies published between 2012 and 2025 was conducted using PubMed, MEDLINE, Scopus, PsycINFO, Google Scholar, and CINAHL. The included studies investigated NPS prevalence, neurobiological correlations, and management strategies in individuals with AD or MCI.

FINDINGS: NPS affects up to 80% of individuals with early AD or MCI, often preceding cognitive decline. The current management strategies heavily rely on non-pharmacological interventions such as caregiver support, behavioral activation, and structured routines, while pharmacological options remain limited by modest efficacy and safety concerns.

DISCUSSION: Advancing knowledge of NPS and their association with cognitive decline is critical to establish more precise diagnostic criteria and to inform personalized therapeutic approaches. Future research should emphasize biomarker-driven diagnostics and the development of novel, targeted interventions that simultaneously address cognitive and neuropsychiatric domains to optimize outcomes for patients and caregivers. This study contributes to the field by reframing NPS as potential early biomarkers in the trajectory of MCI and dementia progression.},
}

@article {pmid41522467,
year = {2026},
author = {Williams, DM and Heikkinen, S and Hiltunen, M and , and Davies, NM and Anderson, EL},
title = {The proportion of Alzheimer's disease attributable to apolipoprotein E.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {1},
pmid = {41522467},
issn = {3005-1940},
abstract = {Variation in the APOE gene strongly affects Alzheimer's disease (AD) risk. However, the proportion of AD burden attributable to this variation requires clarification, which would help to elucidate the scope of strategies targeting apolipoprotein E (APOE) for AD prevention and treatment. We estimated the extents to which clinically diagnosed AD, AD neuropathology and all-cause dementia are attributable to the common APOE alleles in four large studies. First, we used data on 171,105 and 289,150 participants aged ≥60 years from UK Biobank (UKB) and FinnGen, respectively. AD and all-cause dementia were ascertained from linked electronic health records in these cohorts. Second, we examined amyloid-β positivity from amyloid positron emission tomography scans of 4415 participants of the A4 Study. Third, we analysed data from the Alzheimer's Disease Genetics Consortium (ADGC), where neuropathologically confirmed AD cases were compared to pathology-negative, cognitively intact controls (N = 5007). In each analysis, we estimated outcome risk among carriers of APOE risk alleles ε3 and ε4, relative to individuals with an ε2/ε2 genotype, and calculated attributable fractions to show the proportions of the outcomes due to ε3 and ε4. For AD, fractions ranged from 71.5% (95% confidence interval: 54.9%, 81.7%) in FinnGen to 92.7% in the ADGC (82.4, 96.5%). In A4, 85.4% (17.5, 94.5%) of cerebral amyloidosis was attributable to ε3 and ε4. The proportions of all-cause dementia attributable to ε3 and ε4 in UKB and Fin-Gen were 44.4% (95% CI: 18.2%, 62.2%) and 45.6% (30.6%, 56.9%), respectively. Without strong underlying risks from APOE ε3 and ε4, almost all AD and half of all dementia would not occur. Intervening on APOE should be prioritised to facilitate dementia prevention.},
}

@article {pmid41522370,
year = {2026},
author = {Foley, KE and Weekman, EM and Wilcock, DM},
title = {Acute anti-Aβ antibody exposure induces microglial changes and significantly alters chemokine signaling.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70201},
pmid = {41522370},
issn = {2352-8737},
abstract = {INTRODUCTION: While the anti-amyloid-lowering immunotherapies provide the first disease-targeting therapies for the treatment of Alzheimer's disease, there remain harmful adverse events causing hesitation among patients, families, physicians, and regulatory bodies. Though these drugs have been repeatedly proven to lower brain amyloid plaque burden, the specific cellular mechanisms and pathways by which the immunotherapy impacts the brain remain unclear.

METHODS: This study aimed to transcriptionally profile the brain's immediate immune response to anti-amyloid beta (anti-Aβ) antibodies. To evaluate acute cellular priorities, we intracranially injected anti-Aβ antibody (3D6) or an isotype-matched control immunoglobulin G (IgG) antibody and performed single-cell sequencing analysis after 3 days.

RESULTS: We found reduced numbers of a motile microglia cluster and homeostatic microglia in the 3D6 antibody-injected cortex compared to the IgG-injected cortex. It was also found that chemokine/cytokine signaling was enriched across homeostatic-proinflammatory microglia, interferon-responding microglia, and disease-associated microglia 2 (DAM2) following 3D6 antibody injection. We explored "CCL" signaling, which suggested a change in outgoing signaling coordinated by all microglia types targeting homeostatic microglia, surprisingly not targeting DAM1 or DAM2. We then analyzed enriched signaling pathways clustered by k-means river plots and identified pathways enriched and dampened with acute 3D6 treatment.

DISCUSSION: Together these data supply evidence for significant involvement of microglia in the anti-Aβ response in the brain after just 3 days. Most interestingly, there are changes in cytokine/chemokine signaling across microglia subtypes, specifically with communication in CCL pathways targeting homeostatic microglia and T cells. These acute signaling changes provide novel insights and generate unique hypotheses on the brain's immediate immune reaction to anti-Aβ antibody.

HIGHLIGHTS: Intracranially injected anti-amyloid beta (anti-Aβ) antibody promotes an immediate microglial response.3D6 exposure resulted in fewer homeostatic and motile microglia subtypes.Acute 3D6 enriches for chemokine/cytokine signaling pathways.},
}

@article {pmid41522368,
year = {2026},
author = {Scheltens, P and Atri, A and Feldman, HH and Zetterberg, H and Sano, M and Johannsen, P and Colombo, TL and Bardtrum, L and Jeppesen, R and Hansen, CT and Cummings, JL},
title = {Baseline characteristics from evoke and evoke+: Two phase 3 randomized placebo-controlled trials of semaglutide in participants with early-stage symptomatic Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70200},
pmid = {41522368},
issn = {2352-8737},
abstract = {INTRODUCTION: The glucagon-like peptide-1 receptor agonist semaglutide may impact neuroinflammation and reduce neurodegeneration. We present baseline characteristics of participants enrolled in the evoke (NCT04777396) and evoke+ (NCT04777409) trials, referred to as "evoke (+)" hereafter.

METHODS: Evoke (+) are two ongoing global, multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trials investigating semaglutide in participants with early-stage symptomatic Alzheimer's disease (AD) with confirmed amyloid positivity (by positron emission tomography or cerebrospinal fluid testing). Inclusion criteria are the same for both trials, except that by design, evoke+ also includes participants with significant small vessel pathology. Both trials include a 12-week screening phase before randomization (1:1) to receive oral semaglutide titrated to 14 mg or placebo for 156 weeks. Baseline data were summarized and analyzed descriptively. Additionally, data were pooled and assessed by five main geographical regions.

RESULTS: Evoke (+) recruited 9996 participants from 566 sites in 40 countries. The mean (standard deviation) age of participants was 71.8 (7.1) and 72.6 (7.1) years in evoke and evoke+, respectively; more participants were female than male (female: 53.0% and 51.9%, respectively) and most had a Clinical Dementia Rating (CDR) global score of 0.5 (72.8% and 71.4%; CDR global score of 1: 26.5% and 27.6%). Both trial populations had similar demographics, and clinical and cognitive baseline characteristics, except that 2.8% of participants in evoke+ had magnetic resonance imaging-documented significant small vessel pathology as per protocol inclusion criteria. Regional-level data demonstrated some differences in AD treatment characteristics, including cholinesterase inhibitor use of 41.7% in North America versus 61.6% in Asia.

DISCUSSION: Evoke (+) are the only large-scale, phase 3 trials investigating the longer-term efficacy and safety of semaglutide in early AD as a potential disease-modifying treatment. The baseline characteristics from evoke (+) reflect a varied, global population with early-stage symptomatic AD. Primary readouts are expected in the second half of 2025.

HIGHLIGHTS: evoke and evoke+ are the only large-scale randomized controlled trials (RCTs) investigating the longer-term efficacy and safety of semaglutide in early AD.Baseline characteristics reflect a varied, global population.The trials' primary readouts are expected in the second half of 2025.},
}

@article {pmid41521630,
year = {2026},
author = {K, A and B, SK and Reddy, SG and Kugabalasooriar, S},
title = {Innovations in Nanobot and Microbot Propulsion for Targeted CNS Drug Delivery Across the Blood-Brain Barrier.},
journal = {Critical reviews in analytical chemistry},
volume = {},
number = {},
pages = {1-30},
doi = {10.1080/10408347.2025.2612631},
pmid = {41521630},
issn = {1547-6510},
abstract = {The transport of therapeutic molecules to the brain is one of the largest challenges of contemporary medicine because of the restrictive nature of the blood-brain barrier (BBB), which blocks the penetration of almost all biological therapeutics and most small-molecule drugs. This is a major limitation to the treatment of such neurological diseases as Parkinson's disease (PD), glioblastoma, and Alzheimer's disease. To beat these obstacles, there must be advanced delivery systems that can be precise, be released under control, and move without being invasive. Over the past decade, there have been innovations in micro and nanorobotic technologies, which provide a groundbreaking model that incorporates innovations in materials science, analytical chemistry, and biomedical engineering. Such engineered nanorobots are magnetically controlled, polymeric, or biologically derived nanorobots, which can be magnetically, acoustically, optically, or chemically controlled, and can cross the BBB with greater specificity. It has also been possible to follow the behavior of nanorobots at a direct visualization level in biological systems due to the development of analytical tools, especially imaging, real-time monitoring, and in situ sensing, which allows the behavior of nanorobots to be evaluated rigorously in terms of motions, shape transformation, and drug release profiles. The present review gives a detailed description of the propulsion-based nanorobotic drug delivery systems to the central nervous system (CNS), including structural components, modes of actuation, and protocols of analysis. The review explains that the combined effects of physicochemical features, external stimuli, and interactions between biointerfaces influence permeability via the BBB and accuracy of therapeutic response.},
}

@article {pmid41521126,
year = {2026},
author = {Sankhe, K and Ruthirakuhan, M and Andreazza, AC and Brawman-Mintzer, O and Craft, S and Herrmann, N and Ismail, Z and Lerner, AJ and Levey, AI and Mintzer, J and Padala, PR and Perin, J and Porsteinsson, AP and Rosenberg, PB and Shade, D and Tumati, S and van Dyck, CH and Lanctôt, KL},
title = {Peripheral biomarkers associated with apathy and predicting response to methylphenidate: Secondary analysis of the Apathy in Dementia Methylphenidate Trial 2 (ADMET2) study.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100181},
doi = {10.1016/j.inpsyc.2025.100181},
pmid = {41521126},
issn = {1741-203X},
abstract = {BACKGROUND: In Apathy in Dementia Methylphenidate Trial 2 (ADMET2), apathy in Alzheimer's disease improved with methylphenidate (MPH) in a randomized, placebo-controlled trial, though response varied. Here we evaluated serum biomarkers for their association with apathy and with treatment response.

METHODS: All ADMET2 participants with available blood samples were included. Markers of inflammation [interleukin (IL)-6, IL-10, Tumor Necrosis Factor (TNF)], oxidative stress [lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane (8-ISO)] and neuronal injury [neurofilament light (NfL), S100B] were assessed and values log-transformed. Neuropsychiatric Inventory-apathy (NPI-A) measured apathy. Least Absolute Shrinkage and Selection Operator (LASSO) regression was performed for feature selection of baseline markers predicting NPI-A at Month-6 (M6). Univariate analyses examined individual biomarker effects and multivariable models evaluated their combined effects. Treatment interactions, baseline and change in biomarker levels in treatment responders (≥4 change in NPI-A) and remitters (M6 NPI-A=0) were explored.

RESULTS: In the ADMET2 biomarker subset (n = 44, MPH:21, age:75 years, MMSE:20.2), higher baseline TNF was associated with higher M6 NPI-A [B(SE)= 6.86 (1.71), p = .0003], and multivariable models found lower baseline TNF [B(SE)= 8.28(1.61), p < .001] and higher baseline S100B [B(SE)= -6.41(1.95), p = .002] were associated with lower M6 NPI-A. Exploratory analyses suggested that higher baseline NfL significantly interacted with treatment to predict lower M6 NPI-A [B(SE)= -8.36(4.21), p = .05], only when adjusting for cognition. MPH remitters had lower baseline TNF [B(SE)= -0.27(0.10), p = .02], higher baseline NfL [B(SE)= 0.33(0.14), p = .03], and a greater decrease in IL-6 [B(SE)= -0.44 (0.17), p = .02].

CONCLUSIONS: Inflammatory and neuronal injury biomarkers may have prognostic value and may potentially inform treatment response and remission outcomes in apathy. Apathy in Dementia Methylphenidate Trial 2 (ADMET2), NCT02346201, https://clinicaltrials.gov/study/NCT02346201.},
}

@article {pmid41520868,
year = {2026},
author = {Bajinka, O and Jallow, L and Ozdemir, G},
title = {A multi-target therapeutic framework for Alzheimer's disease: an integrative mechanistic review.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.01.010},
pmid = {41520868},
issn = {1873-7544},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a multifactorial network disorder in which amyloid and tau pathology interact with mitochondrial dysfunction, neuroinflammation, metabolic impairment, vascular dysregulation, and synaptic failure. This review provides an integrative, systems-level synthesis of these mechanisms with emphasis on diagnostic and therapeutic implications.

METHODS: A structured narrative review was conducted using PubMed, Scopus, Web of Science, and Embase (2010-2025). Eligible studies included clinical trials, biomarker validation studies, cohort analyses, and mechanistic investigations. Evidence was synthesized by mechanistic domain with focus on cross-system interactions and translational relevance.

FINDINGS: Convergent data indicate that soluble Aβ species, tau propagation, glial dysregulation, insulin resistance, mitochondrial bioenergetic failure, lipid imbalance, and BBB dysfunction form a self-reinforcing neurodegenerative network. Diagnostic advances-including plasma p-tau181/217, Aβ42/40 ratio, GFAP, sTREM2, neuronal exosomes, and multimodal machine-learning models-enable earlier staging and refinement of therapeutic selection. Therapeutic development is shifting from linear amyloid removal to multi-target strategies incorporating anti-tau agents, glial-modulating compounds, metabolic and microbiome interventions, medical nutrition, and multidomain lifestyle programs. Across trials, combined strategies targeting interacting mechanisms demonstrate stronger biomarker and cognitive effects than single-axis approaches.

CONCLUSIONS: AD management requires a systems-oriented therapeutic architecture in which interventions are selected based on mechanistic dominance, biomarker stage, and potential synergy. We outline a multi-target strategy integrating amyloid/tau modulation, neuroimmune regulation, metabolic-vascular stabilization, and synaptic support. Future work should prioritize biomarker-guided stratification, treatment sequencing, and prevention-oriented combination designs.},
}

@article {pmid41520543,
year = {2025},
author = {Xue, R and Wang, F and Zhang, B and Wu, J and Zhang, N and Sun, C},
title = {Carrier-free nanoassembly with dual antioxidant and anti-inflammatory activities camouflaged by melanoma cell membrane for tau-targeted therapy of Alzheimer's disease.},
journal = {Biomaterials},
volume = {329},
number = {},
pages = {123970},
doi = {10.1016/j.biomaterials.2025.123970},
pmid = {41520543},
issn = {1878-5905},
abstract = {Targeting phosphorylated tau (p-tau) across the blood-brain barrier (BBB) represents a critical prerequisite for attenuating tau pathology and disease progression in Alzheimer's disease (AD) by alleviating oxidative stress and neuroinflammation. To address this challenge, we developed a novel carrier-free selenium-based nanoassembly stabilized by hydroxyl-rich fingolimod (FTY720), a sphingosine analogue. Following camouflaging with melanoma cell membranes and further functionalizing with T807, the resulting nanocomposite (FSMT) demonstrated robust capacity for BBB crossing and target p-tau both in vitro and in vivo. Additionally, FTY720 and nano-selenium exert remarkable antioxidant and anti-inflammatory effects by modulating the GSK-3β and NF-κB signaling pathways, respectively, thereby attenuating tau hyperphosphorylation and preventing neuronal cell death. In an okadaic acid-induced AD mouse model, the FSMT treatment not only significantly ameliorated oxidative stress and neuroinflammation, but also improved spatial learning and memory impairments. The reduction in abnormal tau aggregation following treatment was confirmed by PET-CT imaging. Overall, this p-tau-targeted biomimetic nanocomposite demonstrated excellent biocompatibility and therapeutic efficacy, presenting a translatable strategy for treating AD and other neurological disorders through analogous mechanisms.},
}

@article {pmid41520099,
year = {2026},
author = {Mao, C and Wang, W and Huang, X and Wu, M and Wang, Y and Wang, T and Qiu, Y and Chu, S and Jin, W and Jiang, Y and Bao, J and You, Y and Li, Y and Dong, L and Feng, F and Huo, L and Qiu, L and Gao, J},
title = {Real world clinical practice of lecanemab at PUMCH dementia cohort: focus on dynamic imaging and biomarker evolution.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01943-z},
pmid = {41520099},
issn = {1758-9193},
support = {2021-I2M-1-020//CAMS Innovation fund for medical sciences (CIFMS)/ ; 2022-PUMCH-A-254//National High Level Hospital Clinical Research Funding/ ; 2020YFA0804500, 2020YFA0804501//National Key Research and Development Program of China/ ; },
abstract = {BACKGROUND: Lecanemab is an anti-Aβ antibody approved in China for mild cognitive impairment (MCI) and mild dementia. Real-world application requires comprehensive assessment beyond MMSE scores, considering factors like ARIA risk. This single-center, real-world study aims to evaluate its efficacy in an expanded population, observe biomarker changes, and assess its safety profile in clinical practice.

METHODS: We recruited adults aged 40-90 with early AD from the PUMCH Dementia Cohort. A total of 42 patients received lecanemab treatment, of whom 29 completed the 6-month treatment evaluation. Participants had confirmed amyloid and tau pathology and met clinical criteria (CDR ≤ 1, CDR-SB ≤ 8and MMSE ≥ 18). Comprehensive assessments included neuropsychological testing, CSF and plasma biomarkers (Lumipulse G1200), multi-sequence 3T MRI (volumetric and ALPS index analysis), and amyloid/tau PET imaging (Centiloid quantification). All were monitored for adverse reactions. Matched control groups (matched for sex, age, APOE genotype, disease severity, and baseline therapy) were established for comparison of longitudinally changes in cognitive function, daily living ability and structure MRI.

RESULTS: Treatment was effective even for patients with lower MMSE scores but still classified as having mild dementia by CDR. A significant median Centiloid reduction of 30.9 was observed, with a 24.1% amyloid PET negativity rate after six months. While scores on cognitive and functional scales (CDR-SB, ADL) significantly worsened, indicating disease progression, the rate of progression was significantly slower compared to the control group. Structural MRI showed significant volume reduction in multiple brain regions and increased ventricular volume post-treatment, with no statistically significant change in the ALPS value. The rate of brain volume reduction is faster than that in the control group. Plasma biomarker dynamics (Aβ42, GFAP) indicated effective disease-modifying therapy. Greater Centiloid reduction was linked to more brain volume loss, higher baseline Centiloid levels, higher plasma Aβ42 increase and older age of onset. APOE ɛ4 homozygotes showed less Centiloid reduction. A favorable safety profile was observed, with a 7.1% incidence of asymptomatic, mild ARIA.

CONCLUSIONS: This study confirms the clinical efficacy, biomarker changes, and safety profile of lecanemab treatment over a 6-month period, demonstrating its positive therapeutic value and a favorable safety profile in the Chinese population with AD.},
}

@article {pmid41519279,
year = {2026},
author = {Cai, M and Wang, S and Liu, M and Lai, B and Chen, C and Ding, J and Wang, X},
title = {Elevated FKBP5 expression associates with epilepsy-related molecular changes and promotes neuronal hyperexcitability.},
journal = {Brain research},
volume = {},
number = {},
pages = {150157},
doi = {10.1016/j.brainres.2026.150157},
pmid = {41519279},
issn = {1872-6240},
abstract = {OBJECTIVE: Epilepsy is one of the neurological disorders, characterized by recurrent, spontaneous seizures arising from neuronal hyperexcitability and hypersynchrony in the brain. The mechanisms of epilepsy are intricate and remain elusive. FKBP5 has emerged as a significant protein implicated in neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). This study aims to investigate the role of FKBP5 in a kainic acid (KA)-induced intrahippocampal epilepsy model and assessed how FKBP5 gain-of-function and FKBP51 inhibition influence neurotransmitter dynamics and neuronal excitability.

METHODS: We examined the expression of FKBP5 in the hippocampus of the kainic acid (KA)-induced epilepsy model. To explore the impact of FKBP5 on neuronal activity, we overexpressed FKBP5 in primary cortical neurons and astrocytes, assessing extracellular glutamate levels in neuron-astrocytes co-cultures with or without the FKBP51-selective inhibitor SAFit2 (250 nM). Intrinsic excitability, voltage-gated Na[+] currents, and network activity were evaluated using whole-cell patch-clamp recordings and high-density microelectrode arrays (HD-MEAs).

RESULTS: We observed an elevated level of FKBP5 in the hippocampus of a kainic acid (KA)-induced chronic epilepsy mouse model, whereas cortical FKBP5 did not show clear changes across the examined post-insult time points.. Moreover, FKBP5 overexpression induced a remarkable increase in the extracellular glutamate level in co-cultured primary cortical neurons and astrocytes. Intriguingly, FKBP5 overexpression modifies the electrophysiological properties of primary neurons, resulting in increased intrinsic excitability and enhanced Na[+] currents. Additionally, the network activity exhibits hyperexcitability with FKBP5 overexpression. Notably, SAFit2 treatment was also associated with elevated extracellular glutamate in the co-culture system, while intracellular FKBP5 and EAAT2 protein levels showed no significant group differences in the current dataset.

CONCLUSION: These findings suggested that FKBP5 played a significant role in regulating neuronal excitability and extracellular glutamate homeostasis. However, due to discrete sampling and the lack of continuous seizure monitoring, the present in vivo data do not establish a definitive causal contribution of FKBP5 to epileptogenesis, warranting future studies integrating longitudinal EEG and cell-type-specific manipulations.},
}

@article {pmid41519243,
year = {2026},
author = {Sharma, K and Shahid, M and Patel, R and Islam, A},
title = {Insights into Mechanism of Ionic Liquids for Protein Stability: Future Implications for Neurodegeneration Treatment.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103024},
doi = {10.1016/j.arr.2026.103024},
pmid = {41519243},
issn = {1872-9649},
abstract = {Neurodegenerative diseases are characterized by a gradual loss of neurons, cellular dysfunction, loss of intricate synaptic networks and brain damage, which are going to be the second leading cause of death in future. These proteinopathies are marked by abnormal amyloid fibril deposition, aberrant aggregation of misfolded proteins via polymerization, where protein aggregates serve as key pathological hallmarks in Alzheimer's, Parkinson's, and multiple system atrophy disorders. These toxic aggregates accumulate in the brain and disrupt neuronal function targeting motor neurons, spinal cord, and ultimately leading to respiratory failure and death. As population age, the prevalence of these neuronal disorders rises significantly, emphasizing to approach effective treatment for risk reduction. In the pursuit of developing effective anti-amyloidogenesis therapeutic agents, ionic liquids (ILs) continue to receive least attention. ILs have emerged as promising substitute for conventional solvents, owing to their unique physicochemical properties that facilitate protein refolding, mitigate denaturation, amyloidogenesis, and prevent aggregation. This review critically addresses intricate IL-protein interactions, dictated by anions-cations composition of ILs, their polarity, hydrophobicity, kosmotropicity, chaotropicity, amphiphillicity, and network, which modulate protein behavior and support structural and functional integrity. This article also underscores the need for precision in IL selection, ensuring their properties align with the desired structural outcome. We showcase ILs as a promising therapeutic avenue for neurodegenerative diseases, demonstrating their potential to modulate pathological protein aggregation and enhance protein homeostasis. Lastly, this review of outstanding research works, account for current lacunae that will guide future perspectives for the rational designing of IL for protein stabilization and offers new strategies for addressing underlying mechanism of ageing disorders.},
}

@article {pmid41519166,
year = {2026},
author = {Zhao, P and Cao, Z and Rozpędek-Kamińska, W},
title = {Receptor Tyrosine Kinases in Alzheimer's Disease: Mechanistic Insights and Therapeutic Implications.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106117},
doi = {10.1016/j.neuint.2026.106117},
pmid = {41519166},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis remains incompletely understood. It is considered one of the most costly, fatal, and socially burdensome diseases of the twenty-first century. Previous studies have shown that receptor tyrosine kinases (RTKs) play an important role in the pathological progression of AD. RTKs regulate amyloid-beta (Aβ) deposition and Tau hyperphosphorylation, thereby influencing neuronal survival, synaptic plasticity, and spatial cognitive function in patients with AD. From a therapeutic perspective, RTK-targeted interventions offer new avenues for AD treatment. Inhibiting specific RTKs can reduce Aβ production and pathological Tau phosphorylation, thereby slowing disease progression. Conversely, activating selected neuroprotective RTKs can promote neuronal survival, restore synaptic function, and ameliorate cognitive impairment. Several small-molecule inhibitors and monoclonal antibodies targeting RTKs have already demonstrated promising therapeutic potential in preclinical studies. Overall, this review systematically summarizes the clinical features and mechanisms of AD, as well as the current applications and future challenges of RTK-based research in neurodegenerative diseases, providing theoretical guidance for the development and repurposing of novel multi-pathway RTK-directed therapies.},
}

@article {pmid41518900,
year = {2025},
author = {Loraine, A and Farr, SA and Niehoff, ML and Larrea, IG and Ganev, Y and Samanta, J and Rahman, K and Crider, AM and Sandoval, K and Witt, KA},
title = {Dual sigma receptor 1 and 2 modulator improves memory behavior in mouse model of age-related cognitive decline.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {393},
number = {2},
pages = {103795},
doi = {10.1016/j.jpet.2025.103795},
pmid = {41518900},
issn = {1521-0103},
abstract = {Sigma-1 (S1R) and sigma-2 (S2R) receptors are promising targets for treating Alzheimer disease (AD), playing important roles in cognitive function, with potential to mitigate neuropathology. The dual S1R/S2R receptor modulator (+/-)-cis-1-n-Butyl-8-methoxy-1,2,3a,4,5,9b-hexahydrobenz[e]indole hydrochloride (BBZI) was evaluated in the senescence-accelerated mouse prone 8 model of cognitive decline and AD as to behavior and hippocampal expression effects. Chronic BBZI treatment (0, 0.001, 0.01, 0.1, 1.0, or 10 mg/kg, i.p. daily, 27-days) was evaluated using a behavioral battery including open field activity (day-15), elevated plus maze (day-16), Y-maze (day-22), T-maze foot-shock avoidance (days 20 and 27), and novel object recognition (days 23 and 24). No changes were observed in open field, elevated plus maze, Y-maze, or novel object recognition tests at any dose of BBZI as compared with vehicle. BBZI enhanced T-maze foot-shock memory retention at 0.1 (P < .05, Bonferroni) and 1.0 mg/kg (P < .001, Bonferroni) compared with vehicle (day-27). In a separate cohort, a single-injection of BBZI (0, 0.001, 0.01, 0.1 & 1.0 μg, i.c.v.) with testing 7-days later showed a significant effect in the T-maze foot-shock test (P = .011) and enhanced memory retention behavior at 0.01 μg compared with vehicle (P < .05, Bonferroni). Poly(A) RNA sequencing evaluation of hippocampal tissue 24-hours after intracerebroventricular administered BBZI (1.0 μg/μL) versus vehicle showed unique gene expression changes, with notable effects relevant to mitochondrial energetics and synaptic function. Gene enrichment analysis identified affiliations with pathways involved in neurodegenerative disease. This data supports dual S1R/S2R receptor modulation as a promising strategy for AD treatment and identifies potential gene pathways involved. SIGNIFICANCE STATEMENT: Dual sigma receptor 1 and 2 modulator BBZI improved memory behavior in senescence-accelerated mouse prone 8 mice. Evaluation of senescence-accelerated mouse prone 8 hippocampal tissue 24 hours after BBZI (1.0 μg/μL i.c.v.) versus vehicle administration identified gene changes related to mitochondrial energetics and synaptic function. BBZI to mitigates cognitive decline behavior, impacting hippocampal genes critical for brain function.},
}

@article {pmid41518808,
year = {2026},
author = {Qu, J and Jiang, X and Ma, Y and Sheng, X and Pi, C and Wang, Y and Xu, Q and Li, R and Wang, P and Qian, D and Wang, J and Yi, Z and Yi, J and Wen, L and Liu, S},
title = {Unveiling the gut-brain axis: How chronic exposure to arsenic-induced microglial pyroptosis drives Alzheimer's disease-like pathology.},
journal = {Journal of hazardous materials},
volume = {503},
number = {},
pages = {141087},
doi = {10.1016/j.jhazmat.2026.141087},
pmid = {41518808},
issn = {1873-3336},
abstract = {Arsenic, a pervasive environmental contaminant in groundwater, poses a severe global threat to public health. Chronic arsenic exposure has been linked to neurological impairment, however, its specific pathogenic mechanism and whether the gut-brain axis plays a key role remain unclear. This study investigated the role of gut microbiota and its metabolite indoxyl sulfate (IS) in mediating chronic exposure to arsenic-induced cognitive impairment and Alzheimer's disease (AD)-like pathology, with a specific focus on microglial pyroptosis. We found that chronic arsenic exposure induced cognitive dysfunction and intestinal barrier injury, disrupted gut microbiota composition, promoted IS accumulation in serum and brain, and activated the AhR/NF-κB/NLRP3 signaling pathway, triggering microglial pyroptosis and elevating AD-like pathological markers in mice. Meanwhile, fecal microbiota transplantation (FMT) from arsenic-exposed mice recapitulated cognitive impairment, elevated IS levels, and neuroinflammation in recipient mice. Furthermore, arsenic upregulated hepatic IS-synthesis genes (CYP2E1, Sult1d1) and downregulated renal IS-excretion gene (ABCG2). In vitro, arsenic and IS co-exposure promoted M1 polarization and enhanced pyroptosis by activating the AhR/NF-κB/NLRP3 signaling pathway, while suppressing phagocytosis-related proteins (TREM2, SYK and CD36). Furthermore, SiAhR treatment could alleviated microglial inflammatory injury and enhancing the microglia's phagocytic capacity induced by arsenic and IS co-exposure in BV2 cells through inhibiting the AhR/NF-κB/NLRP3-mediated pyroptosis signaling pathway. In conclusion, chronic arsenic exposure induced cognitive impairment and AD-like pathological via the gut microbiota-AhR-pyroptosis cascade, where in IS accumulation served a key mediator. These findings provide new insights into preventing arsenic-related cognitive damage.},
}

@article {pmid41518572,
year = {2026},
author = {Zhang, Z and Zhang, M and Cao, Z and Zhao, H and Li, X and Luo, P},
title = {Fibrillarin: bridging ribosome biogenesis and apoptosis in cellular stress and disease.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {1},
pages = {11},
pmid = {41518572},
issn = {1573-675X},
support = {82171363//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Apoptosis/genetics ; *Ribosomes/metabolism/genetics ; *Neoplasms/genetics/metabolism/pathology ; *Stress, Physiological ; Animals ; Tumor Suppressor Protein p53/metabolism/genetics ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Cell Nucleolus/metabolism ; Signal Transduction ; Chromosomal Proteins, Non-Histone ; },
abstract = {Nucleolar stress has emerged as a critical regulatory mechanism linking ribosome biogenesis defects to apoptotic cell death in various pathological conditions. Fibrillarin (FBL), the catalytic component of box C/D small nucleolar ribonucleoproteins, participates in multiple forms of programmed cell death through both p53-dependent and p53-independent pathways across diverse disease contexts including cancer and neurodegeneration. In malignancies including breast cancer, colorectal cancer, and hepatocellular carcinoma, FBL overexpression promotes apoptosis resistance, whereas in Alzheimer's disease and ALS/FTD, FBL dysfunction contributes to pathological neuronal death. Dysregulation of FBL can lead to excessive apoptosis or apoptosis resistance depending on cellular context and disease state. Various cellular stressors trigger aberrant FBL function, disrupting rRNA processing and ribosome assembly, which then activates nucleolar stress responses that culminate in cell death through ribosomal protein-MDM2-p53 axis activation or selective translational control of survival factors in a context-dependent manner. Therefore, targeting FBL-mediated apoptotic pathways is considered an important avenue for the treatment of various cancers and neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of FBL-regulated apoptosis in disease pathogenesis and provide a systematic overview of current therapeutic strategies targeting nucleolar stress pathways, including RNA polymerase I inhibitors and precision medicine approaches based on p53 status, which may provide important therapeutic targets that merit further investigation.},
}

Humans
*Apoptosis/genetics
*Ribosomes/metabolism/genetics
*Neoplasms/genetics/metabolism/pathology
*Stress, Physiological
Animals
Tumor Suppressor Protein p53/metabolism/genetics
*Neurodegenerative Diseases/genetics/metabolism/pathology
Cell Nucleolus/metabolism
Signal Transduction
Chromosomal Proteins, Non-Histone

@article {pmid41518096,
year = {2026},
author = {Mai, D and Li, Z and Cao, Z and Lin, P and Tan, J and Li, R and Ye, Q},
title = {Metabolomics-Driven Integration of Traditional Chinese Medicine for Neurological Disorders: From Precision Diagnosis to Therapeutic Innovation.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70182},
pmid = {41518096},
issn = {1099-1573},
support = {20251026//Guangdong Provincial Department of Traditional Chinese Medicine/ ; SEZYY2023A13//the Second Traditional Chinese Medicine Hospital of Guangdong Province/ ; },
abstract = {Neurological disorders are leading causes of disability and death worldwide, yet many patients still face delayed diagnosis, limited disease-modifying options and substantial treatment-related adverse effects. Traditional Chinese medicine (TCM) provides holistic, multi-target interventions through acupuncture, herbal formulas and adjunctive therapies, but its mechanisms remain insufficiently defined. Metabolomics, which enables system-wide profiling of small-molecule metabolites, offers an objective way to characterise disease-related metabolic networks and quantify the global effects of TCM. We systematically searched PubMed, Web of Science and China National Knowledge Infrastructure for studies published between January 2005 and June 2025 that evaluated TCM-related interventions for neurological disorders and reported metabolomic outcomes. Peer-reviewed animal and clinical studies were included, whereas reviews, conference abstracts, methodological-only papers and non-neurological studies were excluded. Across Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), ischaemic stroke (IS), epilepsy and high-altitude cerebral oedema (HACE), consistent alterations were identified in amino acid, lipid and energy-related pathways, such as nicotinamide and lysophosphatidylcholine species in AD, branched-chain amino acids in PD and phenylalanine and asymmetric dimethylarginine in MS. Metabolomics studies indicate that acupuncture and herbal formulas can jointly modulate neurotransmitter balance, cerebral energy metabolism, oxidative stress, neuroinflammation and blood-brain barrier integrity. Emerging spatial metabolomics based on mass spectrometry imaging links individual TCM components, including ginsenosides and Astragalus membranaceus-Carthamus tinctorius decoctions, to region-specific metabolic reprogramming in the cortex, hippocampus and thalamus. However, most metabolite-disease associations are correlative and are constrained by small sample sizes, heterogeneous designs and lack of technical standardisation. Metabolomics therefore provides a quantitative framework to dissect the multi-target mechanisms of TCM in neurology and to connect molecular changes with functional outcomes. Standardised workflows, larger multicentre clinical studies and integration of spatial metabolomics, multi-omics and artificial-intelligence-based analysis are required to translate these findings into TCM-informed precision diagnosis and personalised treatment for neurological disorders.},
}

@article {pmid41517979,
year = {2026},
author = {Bachhav, SS and Florian, H and Boiser, J and Wang, Y and Shiller, DD and Graab, U and Lynch, SY and Graff, O and Xiong, H},
title = {Safety, Tolerability, and Pharmacokinetics of Single Doses of ABBV-916, an Anti-Amyloid Antibody, in Healthy Participants.},
journal = {Clinical and translational science},
volume = {19},
number = {1},
pages = {e70419},
pmid = {41517979},
issn = {1752-8062},
mesh = {Humans ; Male ; Female ; Double-Blind Method ; Healthy Volunteers ; Adult ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Middle Aged ; Dose-Response Relationship, Drug ; *Antibodies, Monoclonal, Humanized/administration & dosage/pharmacokinetics/adverse effects ; Infusions, Intravenous ; Alzheimer Disease/drug therapy ; Injections, Subcutaneous ; Young Adult ; },
abstract = {Amyloid-beta (Aβ) plaque brain clearance is one of the promising disease-modifying treatment approaches to slow cognitive decline in Alzheimer's disease (AD). ABBV-916, an anti-amyloid antibody, was being developed as an early AD disease-modifying treatment. A phase 1, randomized double-blind, placebo-controlled single ascending dose (SAD) study investigated the safety, tolerability, pharmacokinetics (PK), and immunogenicity of ABBV-916 in healthy participants. Five groups of participants were enrolled and randomized 6:2 to receive ABBV-916 (100, 300, 1000, or 3000 mg) or placebo by intravenous (IV) infusion or subcutaneous (SC) injection (300-mg dose only). After dosing, participants were followed for 20 weeks for assessments. Cerebrospinal fluid (CSF) samples were collected after dosing 1000 mg IV for determination of ABBV-916 levels in the CSF. ABBV-916 single doses up to 3000 mg were well tolerated in healthy participants. No clinically significant laboratory findings, amyloid-related imaging abnormalities, or serious adverse events were reported. The ABBV-916 PK profile exhibited dose-related increases in maximum concentration and area under the plasma concentration-time curve with terminal elimination half-life ranging from 29 to 40 days across the cohorts. The estimated absolute bioavailability after SC dosing was 51%. The average CSF-to-serum partition ratio was 0.12% (range 0.10%-0.21%). Positive anti-drug antibody was detected in < 7% of participants, which was transient, at low titer, and did not affect ABBV-916 PK. This study demonstrated desirable safety, tolerability, and PK profile of ABBV-916 after single-dose administration in healthy participants. The data supported further evaluation of ABBV-916 multiple IV and SC doses in patients with AD.},
}

Humans
Male
Female
Double-Blind Method
Healthy Volunteers
Adult
*Amyloid beta-Peptides/immunology/antagonists & inhibitors
Middle Aged
Dose-Response Relationship, Drug
*Antibodies, Monoclonal, Humanized/administration & dosage/pharmacokinetics/adverse effects
Infusions, Intravenous
Alzheimer Disease/drug therapy
Injections, Subcutaneous
Young Adult

@article {pmid41517961,
year = {2026},
author = {Vilor-Tejedor, N and Danso, S and Albanus, RD and Billingsley, K and Evans, TE and Lee, LY and Wang, S and Jiang, J and Liu, H and Ross, J and Chilla, G},
title = {Advancing global dementia research through equity and inclusion.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71069},
pmid = {41517961},
issn = {1552-5279},
support = {//Alzheimer's Disease Data Initiative/ ; RYC2022-038136-I//Spanish Ministry of Science and Innovation-State Research Agency,/ ; PID2022-143106OA-I00//European Union FSE+/ ; 23S06083-001//European Union FEDER/ ; //Ajuntament de Barcelona/ ; //la Caixa Foundation/ ; VCID-UMD-26-1514428//AD Strategic Fund: Vascular Contributions to Cognitive Impairment and Dementia-Understanding Mechanisms of Dysfunction/ ; 25AARF-1377279 (2025-2029)//Alzheimer's Association Research postdoctoral fellowship/ ; WE.03-2024-07(2025-2027)//Alzheimer's Association Research postdoctoral fellowship/ ; //Intramural Research Programs of the National Institute on Aging (NIA)/ ; //National Institute of Neurological Disorders and Stroke (NINDS)/ ; Z01-AG000949//National Institutes of Health (NIH), Department of Health and Human Services/ ; 1ZIANS003154//National Institutes of Health (NIH), Department of Health and Human Services/ ; P30AG072976//National Institutes of Health (NIH), Department of Health and Human Services/ ; R01AG081693//National Institutes of Health (NIH), Department of Health and Human Services/ ; },
mesh = {Humans ; *Dementia ; *Biomedical Research ; Global Health ; },
abstract = {Despite the global burden of dementia, research remains dominated by high-income, Western populations, limiting the generalizability and equity of findings. In this Perspective, we highlight the importance of diversity and inclusion in dementia research, not only in study participants but also in the researchers, study design, and funding priorities. We describe how the lack of representation creates knowledge gaps and delays progress in prevention, diagnosis, and treatment. We also present examples of initiatives that are working to change this, including the Alzheimer's Disease Data Initiative and the William H. Gates Sr. Fellowship program, which supports open science, international collaboration, and early-career researchers from underrepresented regions. These efforts demonstrate that diversity is not only an ethical goal, but a scientific need. More inclusive and global research could lead to discoveries that are more generalizable, more globally applicable, and better able to inform strategies to address dementia across all communities. HIGHLIGHTS: Prioritize representation in datasets across ethnicity, geography, sex/gender, and socio-economic status. Support early-career researchers from underrepresented regions with long-term funding and mentorship. Standardize and adapt tools (cognitive, clinical, genomic) across cultural and linguistic contexts. Promote open science through equitable, federated data sharing platforms, and embed community engagement from research design to dissemination. Value diversity as a driver of discovery, not as a confounder.},
}

Humans
*Dementia
*Biomedical Research
Global Health

@article {pmid41517810,
year = {2026},
author = {Lee, S and Chang, JW},
title = {From Ablation to Neuromodulation Platform: The Evolving Role of Magnetic Resonance-Guided Focused Ultrasound in Functional Neurosurgery.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {1},
pages = {17-41},
doi = {10.3988/jcn.2025.0563},
pmid = {41517810},
issn = {1738-6586},
support = {/HI/NHLBI NIH HHS/United States ; },
abstract = {Magnetic resonance-guided focused ultrasound (MRgFUS) has rapidly evolved from an experimental concept into a versatile platform in functional neurosurgery. Initially pioneered as a noninvasive thermal ablation modality for essential tremor, MRgFUS has since gained regulatory approval and demonstrated durable long-term efficacy. Its clinical applications have expanded to include Parkinson's disease, chronic pain, psychiatric disorders, and investigational use in dystonia, epilepsy, and brain tumors. Beyond lesioning, low-intensity focused ultrasound enables reversible neuromodulation and transient blood-brain barrier opening, facilitating drug and gene delivery in conditions such as Alzheimer's disease and glioblastoma. Comparative analyses highlight MRgFUS as an incisionless alternative to traditional modalities like deep brain stimulation, radiofrequency ablation, and radiosurgery, offering unique advantages in precision, safety, and patient acceptability while retaining certain limitations, including irreversibility and eligibility constraints due to skull properties. Emerging innovations-such as dual-target strategies, staged bilateral procedures, adaptive focusing technologies, and integration with immuno- or gene therapies-are expanding its therapeutic potential. Collectively, these advances position MRgFUS as not only an ablative tool but also a transformative neuromodulation platform with broad implications for the treatment of movement disorders, neuropsychiatric disease, and neurodegeneration.},
}

@article {pmid41517524,
year = {2025},
author = {Abboud, I and Xu, E and Xu, S and Alhasany, A and Wang, Z and Wu, X and Astraea, N and Jiang, F and Hu, ZJ and Chan, JW},
title = {Emerging Oculomic Signatures: Linking Thickness of Entire Retinal Layers with Plasma Biomarkers in Preclinical Alzheimer's Disease.},
journal = {Journal of clinical medicine},
volume = {15},
number = {1},
pages = {},
pmid = {41517524},
issn = {2077-0383},
support = {UL1 TR001872/NH/NIH HHS/United States ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is the leading cause of dementia, which is an inevitable consequence of aging. Early detection of AD, or detection during the pre-AD stage, is beneficial, as it enables timely intervention to reduce modifiable risk factors, which may help prevent or delay the progression to dementia. On the one hand, plasma biomarkers have demonstrated great promise in predicting cognitive decline. On the other hand, in recent years, ocular imaging features, particularly the thickness of retinal layers measured by spectral-domain optical coherence tomography (SD-OCT), are emerging as possible non-invasive, non-contact surrogate markers for early detection and monitoring of neurodegeneration. This pilot study aims to identify retinal layer thickness changes across the entire retina linked to plasma AD biomarkers in cognitively healthy (CH) elderly individuals at risk for AD. Methods: Eleven CH individuals (20 eyes total) were classified in the pre-AD stage by plasma β-amyloid (Aβ)42/40 ratio < 0.10 and underwent SD-OCT. A deep-learning-derived automated algorithm was used to segment retinal layers on OCT (with manual correction when needed). Multiple layer thicknesses throughout the entire retina (including the inner retina, the outer retina, and the choroid) were measured in the inner ring (1-3 mm) and outer ring (3-6 mm) of the Early Treatment Diabetic Retinopathy Study (ETDRS). Relationships between retinal layers and plasma biomarkers were analyzed by ridge regression/bootstrapping. Results: Results showed that photoreceptor inner segment (PR-IS) thinning had the largest size effect with neurofilament light chain. Additional findings revealed thinning or thickening of the other retinal layers in association with increasing levels of glial fibrillary acidic protein and phosphorylated tau at threonine 181 and 217 (p-tau181 and p-tau217). Conclusions: This pilot study suggests that retinal layer-specific signatures exist, with PR-IS thinning as the largest effect, indicating neurodegeneration in pre-AD. Further research is needed to confirm the findings of this pilot study using larger longitudinal pre-AD cohorts and comparative analyses with healthy aging adults.},
}

@article {pmid41516328,
year = {2026},
author = {Cipriano, GL and Floramo, A and Argento, V and Oddo, S and Artimagnella, O},
title = {Mutant Tau (P301L) Enhances Global Protein Translation in Differentiated SH-SY5Y Cells by Upregulating mTOR Signalling.},
journal = {International journal of molecular sciences},
volume = {27},
number = {1},
pages = {},
pmid = {41516328},
issn = {1422-0067},
support = {RRC-2025-23686388//Ministero della Salute/ ; },
mesh = {Humans ; *TOR Serine-Threonine Kinases/metabolism/genetics ; *tau Proteins/genetics/metabolism ; *Protein Biosynthesis ; *Signal Transduction ; Up-Regulation ; Cell Line, Tumor ; *Mutation ; Neurons/metabolism ; Sirolimus/pharmacology ; Cell Differentiation ; },
abstract = {Altered protein synthesis plays a key role in ageing and multiple neurodegenerative diseases. In Alzheimer's disease and other tauopathies, the intracellular accumulation of hyperphosphorylated Tau disrupts several cellular processes, including mRNA translation. Although Tau interacts with ribosomal proteins and modulates translational selectivity, its effects on global protein synthesis remain poorly understood. Studies report reduced translation in later disease stages but increased translation early in pathology. To clarify Tau's impact in human neurons, we used SH-SY5Y cells overexpressing the P301L mutant form of Tau and quantified global protein synthesis using the SUnSET (Surface Sensing of Translation) puromycin-incorporation assay. We found that Tau-P301L expression greatly increased global translation by upregulating mTOR/S6 pathway. These effects were abolished by rapamycin treatment, indicating that Tau-driven translational upregulation is mTOR-dependent. Given that impaired translational control can disrupt synaptic plasticity and memory, Tau-induced alterations in protein synthesis may contribute to tauopathy progression and identify mTOR signalling as a potential therapeutic target.},
}

Humans
*TOR Serine-Threonine Kinases/metabolism/genetics
*tau Proteins/genetics/metabolism
*Protein Biosynthesis
*Signal Transduction
Up-Regulation
Cell Line, Tumor
*Mutation
Neurons/metabolism
Sirolimus/pharmacology
Cell Differentiation

@article {pmid41516246,
year = {2025},
author = {Kvetnoy, I and Kheyfets, O and Safaniev, L and Kheifets, V and Mironova, E and Kvetnaia, T and Mazzoccoli, G and Prashchayeu, K and Gavrilova, A},
title = {Signaling Molecules and Diagnosis of Cognitive Disorders: Current State and Prospects.},
journal = {International journal of molecular sciences},
volume = {27},
number = {1},
pages = {},
pmid = {41516246},
issn = {1422-0067},
mesh = {Humans ; Biomarkers/metabolism ; *Signal Transduction ; *Alzheimer Disease/metabolism/diagnosis ; Dementia, Vascular/metabolism/diagnosis ; *Cognition Disorders/diagnosis/metabolism ; *Cognitive Dysfunction/diagnosis/metabolism ; },
abstract = {Cognitive disorders present significant medical and social challenges nowadays, due to their high prevalence, progressive course and a lack of effective methods for treatment of neurodegenerative diseases and comorbid pathologies. An important area of research is the identification of molecular biomarkers that reflect early pathophysiological changes and facilitate a more accurate biological characterization of cognitive impairment. This study provides an overview of the most relevant signaling molecules for diagnosing cognitive disorders. It presents data on the effectiveness of using comprehensive panels of molecular biomarkers in clinical practice, including β-amyloid, CD34, claudin, DRP1, endothelin-1, NF-kB, PINK1, RAGE, S100, α-synuclein, and tau protein, in patients with Alzheimer's disease (AD) and vascular dementia (VD). The study results demonstrate that cumulative changes in the expression of signaling molecules reflect various neurodegenerative and vascular-associated biological processes. The data obtained are comparative in nature and require further validation before potential clinical application.},
}

Humans
Biomarkers/metabolism
*Signal Transduction
*Alzheimer Disease/metabolism/diagnosis
Dementia, Vascular/metabolism/diagnosis
*Cognition Disorders/diagnosis/metabolism
*Cognitive Dysfunction/diagnosis/metabolism

@article {pmid41515488,
year = {2026},
author = {Huang, Y and Li, X and Dai, L and Cheng, M and Zhao, L and Shen, Y and Xie, J and Luo, X},
title = {Antioxidant, Anti-Inflammatory, and Chemical Composition Analysis of In Vitro Huperzia serrata Thallus and Wild Huperzia serrata.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {1},
pages = {},
pmid = {41515488},
issn = {1420-3049},
support = {20232ACB2050009//Natural Science Foundation of Jiangxi Province, China/ ; 32060074//National Natural Science Foundation of China/ ; 20204BCJ22024//Major Academic and Technical Leader Training Project of Jiangxi Province/ ; },
mesh = {*Antioxidants/pharmacology/chemistry ; *Anti-Inflammatory Agents/pharmacology/chemistry ; *Huperzia/chemistry ; Animals ; *Plant Extracts/chemistry/pharmacology ; Mice ; Sesquiterpenes/pharmacology/chemistry ; Alkaloids/pharmacology/chemistry ; RAW 264.7 Cells ; },
abstract = {Huperzine A is a preferred treatment option for Alzheimer's disease. Huperzia serrata (Thunb. ex Murray) Trev. (H. serrata) has garnered significant attention for its ability to produce Huperzine A (HupA). However, natural populations of wild H. serrata (WH) are rapidly declining. Fortunately, our group obtained two types of H. serrata thalli (OT and ST) capable of stably producing Huperzine A, which have the potential to serve as an alternative resource to WH. To evaluate the feasibility of this strategy, we conducted a comprehensive assessment of both WH and H. serrata thallus. The results indicated that compared to WH, ST and OT exhibited stronger anti-inflammatory and antioxidant activities, with lower cytotoxicity. Notably, ST demonstrated a strong radical scavenging activity, reaching 93.23% (DPPH at 0.2 μg/mL) and 99.87% (ABTS at 4 μg/mL), and reduced nitrite production from 10.29 μM to 6.51 μM at 50 µg/mL. GC-MS and widely targeted metabolomics analyses revealed that the higher antioxidant and anti-inflammatory activities for ST and OT were due to higher concentrations of phenolic acids and flavonoids compared to WH. In addition, the HupA content in ST reached 36.56% of that found in WH. KEGG enrichment analysis revealed that the flavonoid, phenylalanine, and phenylpropanoid biosynthesis pathways may be involved in regulating the antioxidant activity. P-coumaroyl quinic acid and caffeoyl quinic acid are the crucial metabolites for antioxidant activity. These findings suggested that the H. serrata thallus could serve as a sustainable alternative to WH.},
}

*Antioxidants/pharmacology/chemistry
*Anti-Inflammatory Agents/pharmacology/chemistry
*Huperzia/chemistry
Animals
*Plant Extracts/chemistry/pharmacology
Mice
Sesquiterpenes/pharmacology/chemistry
Alkaloids/pharmacology/chemistry
RAW 264.7 Cells

@article {pmid41514478,
year = {2026},
author = {Noman, M and Qadir, H and Ahmed, S and Rehman, NU and Shah, FA and Riaz, M and Ahmad, N and Ul-Haq, Z and Irshad, N},
title = {Santonin Attenuates Alzheimer's-Like Pathology via Multitarget Modulation of the NLRP3 Inflammasome, BDNF Signaling, and Amyloidogenic Pathways: An Integrated Experimental and Computational Study.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00957},
pmid = {41514478},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant cause of dementia, characterized by amyloid β (Aβ) plaques and tau tangles that disrupt neurons in memory-related brain regions. This study explores the therapeutic potential of santonin using integrated in silico, in vitro, and in vivo approaches. Molecular docking identified santonin as a promising acetylcholinesterase, NOD-like receptor family, pyrin domain-containing 3 (NLRP3), brain-derived neurotrophic factor (BDNF), and nuclear factor kappa B (NF-κB) ligand with significant binding affinities and supportive interaction scores supported by molecular dynamics simulations with significant multitarget therapeutic relevance. In vitro assays demonstrated that santonin has measurable inhibition of cholinesterase enzymes, showing significant effects on butyrylcholinesterase and acetylcholinesterase enzymes. Behavioral analysis revealed that santonin produced dose-dependent improvements in memory and exploratory behaviors, indicating significant neuroprotective effects against streptozotocin (STZ)-induced impairments. Histological analysis showed that santonin preserved neuronal architecture, enhanced neuronal density, and reduced Aβ deposition in STZ-treated brains using hematoxylin and eosin, Congo red, and Nissl analysis. These effects were evident in the cortical and hippocampal regions. Santonin exhibited strong antioxidant effects, mitigating induced enzyme depletion and oxidative marker elevation. Santonin effectively mitigated STZ-induced Aβ buildup and provided protective effects. Santonin modulated marker expression in STZ-treated brains by reducing the amyloid precursor protein, Tau, toll-like receptor 4, NLRP3, discs large MAGUK scaffold protein 4, and BDNF. Santonin reduces neuroinflammation and neurotrophic signaling in the early stages of AD, which suggests that it may be used as a treatment. However, more research is needed to confirm its effectiveness.},
}

@article {pmid41514416,
year = {2026},
author = {Tian, Q and Liu, M and Zhong, F and Liu, X and Lü, Y},
title = {Lecanemab treatment for mild alzheimer's disease with high risk of cerebral hemorrhage: a case report.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-025-04581-y},
pmid = {41514416},
issn = {1471-2377},
abstract = {BACKGROUND: Lecanemab has been approved for the treatment of mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia based on the efficacy in slowing cognitive decline and preliminary safety data from the phase Ⅲ Clarity AD trial. However, this trial excluded patients with high risk of cerebral hemorrhage, such as individuals with intracranial aneurysms or > 4 microhemorrhages.

CASE PRESENTATION: A 70-year-old male with mild AD, intracranial aneurysm, microhemorrhages, and APOE ε3/ε4 genotype received lecanemab after multidisciplinary evaluation and informed consent. Over six months of intensive monitoring, cognitive function stabilized with no deterioration, daily activities were preserved, microhemorrhages remained stable (with one new small lesion noted at 3 months), and no aneurysm rupture or severe adverse events (including amyloid-related imaging abnormalities) occurred.

CONCLUSIONS: This case suggests that, despite hemorrhage risks, lecanemab may have a manageable risk-benefit profile in selected real-world AD patients under intensive monitoring and multidisciplinary care, with its application beyond clinical trial criteria requiring more nuanced and individualized consideration.},
}

@article {pmid41513640,
year = {2026},
author = {Abdulkhaliq, AA and Kim, B and Almoghrabi, YM and Khan, J and Ajoolabady, A and Ren, J and Bahijri, S and Tuomilehto, J and Borai, A and Pratico, D},
title = {Amyloid-β and Tau in Alzheimer's disease: pathogenesis, mechanisms, and interplay.},
journal = {Cell death & disease},
volume = {17},
number = {1},
pages = {21},
pmid = {41513640},
issn = {2041-4889},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Animals ; Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disease and the most prevalent type of dementia characterized by pathological deposition of amyloid-β plaques/deposits and tau tangles within the brain parenchyma. This progressive ailment is featured by irreversible cognitive impairment and memory loss, often misdiagnosed as the consequence of old age in elderlies. Pathologically, synaptic dysfunction occurs at the early stages and then progresses into neurodegeneration with neuronal cell death in later stages. In this review, we aimed to critically discuss and highlight recent advances in the pathological footprints of amyloid-β and tau in AD. Specifically, we focused our attention on the interplay and synergistic effects of amyloid-β and tau in the pathogenesis of AD. We hope that our paper will provide new insights and perspectives on these pathological features of AD and spark new ideas and directions in AD research and treatment.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
Animals
Brain/metabolism/pathology

@article {pmid41513181,
year = {2026},
author = {Vyas, J and Jamenis, AS and Kaku, K and Shah, Y and Miner, KM and Bhatia, TN and Kim, RE and Bai, R and Hamel, E and Leak, RK and Gangjee, A},
title = {Discovery of multitargeting single agents as a novel route to the potential treatment of neurodegenerative diseases.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {133},
number = {},
pages = {130536},
doi = {10.1016/j.bmcl.2026.130536},
pmid = {41513181},
issn = {1464-3405},
abstract = {There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical options will likely require two or more agents with different mechanisms of action. However, drug combinations have significant drawbacks, including overlapping toxicities and unique pharmacokinetic properties, particularly the rate and extent of central nervous system (CNS) penetration. A single agent with multiple mechanisms of action could overcome these drawbacks. We have recently discovered first-in-class novel single agents (compounds 1 and 2) that mildly inhibit clinically important kinases and subtly favor microtubule stability at concentrations that show no evidence of neuronal toxicity in primary neurons, while maintaining their ability to penetrate the CNS in vivo. It is important to note that the effects of these analogs are mild and are predicated on avoiding neurotoxicity. These multitargeting single agents provide a new structural modality with the potential to influence treatments for Parkinson's and Alzheimer's disease and serve as lead compounds for further optimization.},
}

@article {pmid41511604,
year = {2026},
author = {Babaker, MA and Alazabi, NI and Yousef, EM and Haredy, SA and Algohary, AM and Mansour, DF and Ahmed-Farid, OA},
title = {Taurine Mitigates Spironolactone-Induced Hyperkalemia and Cognitive Dysfunction: A Biochemical and Histological Study in a Rat Model.},
journal = {Applied biochemistry and biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s12010-025-05513-9},
pmid = {41511604},
issn = {1559-0291},
abstract = {Spironolactone (SPR), a widely used potassium-sparing diuretic, frequently causes hyperkalemia, leading to significant cardiovascular and neurological complications. Taurine, a semi-essential amino acid with known antioxidant and neuroprotective effects, was hypothesized to mitigate these adverse effects. This study investigated taurine's efficacy against SPR-induced hyperkalemia and associated cognitive dysfunction in a rat model. Adult male Sprague-Dawley rats were treated for four weeks with SPR, SPR + galantamine (an AChE inhibitor widely used in the treatment of Alzheimer's disease), or SPR + varying concentrations of taurine, followed by assessment of cognitive, biochemical, and histopathological alterations. SPR administration significantly increased serum potassium levels (~7.5 mEq/L), induced cognitive deficits, disrupted neurotransmitter balance (e.g., altered GABA and glutamate levels), and caused reactive astrocytic swelling in key brain regions. Taurine demonstrated a dose-dependent protective effect against SPR-induced neurotoxicity by mitigating hyperkalemia and associated cognitive impairments. Biochemically, taurine restored neurotransmitter balance by increasing GABA and reducing the excitotoxic glutamate levels. Histological analysis further confirmed taurine's neuroprotective effects, showing preserved cortical structures and reduced astrogliosis, especially at the highest concentration (5%). Our correlation analysis reveals complex regulatory mechanisms underlying neurotransmitter balance in the brain. These findings suggest taurine as a promising therapeutic agent for alleviating SPR-induced neurological side effects. Further studies are needed to explore taurine's long-term effects and clinical applications in managing hyperkalemia-related cognitive dysfunctions.},
}

@article {pmid41511339,
year = {2025},
author = {Yu, H and Josi, RR and Khanna, A and Khismatullin, DB},
title = {Low-Density Lipoproteins Induce a Pro-Inflammatory, Chemotactic Mox-like Phenotype in THP-1-Derived Human Macrophages.},
journal = {Cells},
volume = {15},
number = {1},
pages = {},
pmid = {41511339},
issn = {2073-4409},
support = {1R01HL127092-01A1/NH/NIH HHS/United States ; },
mesh = {Humans ; *Lipoproteins, LDL/pharmacology ; *Macrophages/metabolism/drug effects ; *Chemotaxis/drug effects ; Phenotype ; THP-1 Cells ; *Inflammation/pathology/metabolism ; Mast Cells/metabolism/drug effects ; Interleukin-6/metabolism ; Cytokines/metabolism ; Cell Differentiation/drug effects ; },
abstract = {Murine macrophages exposed to oxidized low-density lipoprotein (oxLDL) polarize into a distinct Mox phenotype characterized by impaired phagocytic and chemotactic function. Although implicated in atherosclerosis, this phenotype has not been confirmed in human macrophages. Drawing parallels to human tumor-associated macrophages, and in contrast to the murine cell response, we hypothesize that LDL/oxLDL induces a hybrid Mox-like state in human macrophages, marked by the simultaneous secretion of pro-inflammatory cytokines and anti-inflammatory factors, potentially exacerbating vascular inflammation and atherogenesis. To test this, THP-1 human monocytes were differentiated into resting macrophages, then polarized into M1-like and M2-like phenotypes, followed by treatment with native LDL, oxLDL, IL-6, or their combinations. ELISA results showed that oxLDL or LDL with IL-6 polarized resting and M1-like macrophages into a Mox-like phenotype that secreted TNF-α and TGF-β1 at levels comparable to M1- and M2-like cells, respectively. The pro-inflammatory nature of Mox-like macrophages was supported by increased THP-1 adhesion to vascular endothelial cells exposed to the macrophage-conditioned media. In microfluidic assays, LUVA human mast cells migrated toward media from Mox-like macrophages, indicating enhanced chemotaxis. In summary, the pro-inflammatory Mox-like state is triggered in human macrophages by oxLDL or LDL combined with IL-6, a key regulator of the inflammatory acute-phase response. Unlike in murine cells, this state is marked by high chemotactic activity driven by TGF-β1 secretion, which promotes mast cell recruitment and contributes to atherosclerotic plaque development and Alzheimer's disease.},
}

Humans
*Lipoproteins, LDL/pharmacology
*Macrophages/metabolism/drug effects
*Chemotaxis/drug effects
Phenotype
THP-1 Cells
*Inflammation/pathology/metabolism
Mast Cells/metabolism/drug effects
Interleukin-6/metabolism
Cytokines/metabolism
Cell Differentiation/drug effects

@article {pmid41510854,
year = {2026},
author = {Tyagi, S and Murali, N and Singh, SK and Babtiwale, SR and Padhi, BK and Lakshmi, NRA and Gandhi, AP},
title = {A Systematic Review to Evaluate the Effect of Neflamapimod on Cognitive Function and Progression of Dementia.},
journal = {Neurology India},
volume = {74},
number = {1},
pages = {12-19},
doi = {10.4103/neurol-india.Neurol-India-D-25-00227},
pmid = {41510854},
issn = {1998-4022},
mesh = {Humans ; *Cognition/drug effects ; Disease Progression ; *Dementia/drug therapy ; *Alzheimer Disease/drug therapy ; *Lewy Body Disease/drug therapy ; },
abstract = {Treatment options for dementia mainly comprise of symptomatic treatment, as no disease-modifying therapy currently exists that directly reduces the pathology. This systematic review assessed the effectiveness of neflamapimod (VX-745), a p38α kinase inhibitor, as a therapeutic agent for treating dementia, including Alzheimer's disease (AD) and Lewy Body Dementia (LBD). The systematic review evaluated the therapeutic effect of neflamapimod on dementia. Five electronic databases were included in the systematic review: PubMed, Embase, ProQuest, Cochrane Library, and Web of Science, which were searched until May 5, 2024. Two independent reviewers conducted title and abstract screening, followed by full-text review and data extraction, with disagreements resolved by a third reviewer. The risk of bias in the included studies was assessed using the ROB 2.0 tool. PROSPERO Registration ID: CRD42024542377. The review identified clinical results, biomarker effects, and mechanistic insights from two key trials. Due to the inclusion of only two eligible studies with varying methodologies and outcome measures, a meta-analysis could not be performed. While the primary cognitive outcomes, such as "neuropsychological test battery (NTB)" and "Hopkins Verbal Learning Test-Revised (HVLT-R)" were not statistically different, episodic memory, executive function, attention, gait dysfunction, and motor issues showed improvements, especially in patients with elevated plasma tau181, a marker for AD pathology. Biomarker analysis also indicated a statistically significant reduction in cerebrospinal fluid (CSF) tau and phosphorylated tau biomarkers, which are closely related to neuroinflammation and synaptic impairment in dementia. The findings of the current review suggested that while the cognitive effects of neflamapimod remain uncertain, its ability to influence disease-specific biomarkers makes it a potential drug to be used in dementia. This review connects biological and clinical outcomes, paving the way for future advancements in dementia treatment strategies.},
}

Humans
*Cognition/drug effects
Disease Progression
*Dementia/drug therapy
*Alzheimer Disease/drug therapy
*Lewy Body Disease/drug therapy

@article {pmid41510732,
year = {2026},
author = {Adhikari, B and Venkatesh, DN and Puri, V and Sharma, A},
title = {Therapeutic Implications of Nutraceutical Nanotechnology for the Treatment of Chronic Diseases.},
journal = {Current drug metabolism},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892002415344251122122358},
pmid = {41510732},
issn = {1875-5453},
abstract = {Nanotechnology possesses therapeutic value in managing chronic disease, but it has limitations like as solubility, stability, and targeted delivery in clinical applications. The review explores how nanotechnology-based delivery systems improve the efficacy, bioavailability, and targeted actions of nutraceutical compounds. Health benefits, sustainable nanotechnology, market size, and growth forecasts have shown positive results in this industry over the last two decades. The disease-like respiratory, diabetes, Alzheimer's and Parkinson's, and breast cancer top focused sectors for this nutraceuticals sector. Most literature has been collected from 2020-2025 using PubMed, Scopus, Google Scholar, and Web of Science. The different criteria included preclinical, clinical, and nanotechnology-integrated nutraceutical studies. The liposomes, dendrimers, nanoemulsions, and polymeric nanoparticles significantly enhance the stability and delivery of key bioactive as example like curcumin, resveratrol, and omega-3. Early-stage clinical trials show promise for diseases like Alzheimer's, diabetes, and cancer. Nanotechnology is the reshaping of nutraceutical therapy, through regulatory, toxicology, and large-scale validation gaps persist. Future work must focus on green synthesis, long-term safety, and harmonized approval pathways. Despite this, the industry still needs collaboration between academic researchers, scientists, and regulatory bodies to start the next generation of clinical trials and treatments that can reduce the risk of diseases and death in the future.},
}

@article {pmid41510728,
year = {2026},
author = {González-Jiménez, KA and Herrera-Mayorga, EV and Paredes Sánchez, FA and Niño-García, N and Torres-Castillo, JA and Martínez-Padrón, HY and Sánchez-Sánchez, M},
title = {New Drug Therapies Against Targeting Neurodegenerative Diseases: A Comprehensive Review.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249397580251117044621},
pmid = {41510728},
issn = {1875-6166},
abstract = {Neurodegenerative diseases encompass well-characterized behavioral, cognitive, and movement disorders that affect older people, impacting all facets of daily life. In Alzheimer's disease, specific antibodies targeting the β-amyloid protein (aducanumab, lecanemab, and others) are gaining special interest due to the approval of the first particular drugs against this disease. In Parkinson's disease, most drugs were approved several decades ago; however, new Phase II clinical trials point to monoclonal antibodies as a promising approach, and the report of alkaloids also suggests various therapeutic targets against this disease. Pick's disease has a low prevalence; currently, no drugs are approved by government agencies. However, thanks to molecular tools, it has been possible to elucidate therapeutic targets implicated in the appearance of the disease. α-synuclein is the main therapeutic target in Lewy body disease; most of the reported molecules are in clinical Phases I and II. Additionally, drug repositioning may emerge as a viable option in the search for effective treatments against this disease. In amyotrophic lateral sclerosis, the appearance of newly approved drugs such as tofersen and edaravone, and some others in clinical Phase II (bosutinib), opens a new era in the understanding and treatment of this condition. Altered emotions and progressive damage in some brain regions characterize schizophrenia and vascular dementia. Combinations of tricyclic drugs are a trend that aims to increase the cognitive performance of patients with schizophrenia. In vascular dementia, numerous in vivo trials with molecules of different natures (flavonoids and lactones) have yielded positive results, delaying the progression of the disease. This review examines recent reports on molecules evaluated in vivo and in vitro models of the primary neurodegenerative diseases.},
}

@article {pmid41510718,
year = {2026},
author = {Prabakaran, A and Sivaperuman, A and Natarajan, R and Nagarajan, NC and Solomon, VR},
title = {Innovative Approaches to Alzheimer's Treatment: Utilizing Tacrine Hybrids to Inhibit Amyloid Beta Aggregation as a Strategic Focus.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575422492251116190843},
pmid = {41510718},
issn = {1875-5607},
abstract = {Alzheimer's disease (AD) is a complex and progressive brain disorder marked by memory loss, cognitive decline, and behavioral changes. One of its defining features is the build-up of amyloid plaques, clumps of β-amyloid (Aβ) peptides, in the brain, along with the formation of neurofibrillary tangles. These Aβ peptides are generated when the amyloid precursor protein (APP) is cleaved by enzymes, with β-secretase (BACE1) playing a key role in the first step of this process. Because BACE1 starts the cascade that leads to harmful Aβ build-up, it has become an important target in the search for effective Alzheimer's treatments. As Aβ accumulates in neurons, it disrupts communication between brain cells and triggers oxidative stress, which worsens damage and accelerates disease progression. This is often exacerbated by imbalances in metal ions, such as copper and iron. While tacrine, an early acetylcholinesterase inhibitor, has shown benefits in managing AD symptoms, its limitations have led researchers to explore improved versions. One promising direction is the development of tacrine-based hybrid molecules. By combining tacrine with other chemical groups that have anti-β-amyloid (Aβ) effects, antioxidant properties, and metal-chelating properties, scientists aim to create compounds that target multiple aspects of the disease simultaneously. This review examines the emerging potential of tacrine hybrids, particularly their capacity to inhibit BACE1 and prevent Aβ aggregation, providing new hope for more effective and disease-modifying therapies for Alzheimer's disease.},
}

@article {pmid41510716,
year = {2026},
author = {Bano, A and Khan, AA and Kushwaha, SP and -, A and Zaidi, SMH and Misbahul Hasan, S and Fatima, A},
title = {Indole Scaffolds in Neurological Therapeutics: Synthesis, Structure-Activity Relationships and Drug-Receptor Interactions.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575415521251021091530},
pmid = {41510716},
issn = {1875-5607},
abstract = {INTRODUCTION: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.

METHODS: A detailed literature survey was conducted using databases such as Google Scholar, Elsevier, PubMed, ACS, PubChem, ScienceDirect, and RSC to understand the structural modifications of indole derivatives and their therapeutic potential. Both research and review articles related to indole- based compounds were thoroughly studied to prepare this review article.

RESULTS: There are over 40 FDA-approved drugs containing an indole nucleus used to treat various diseases, underscoring its potential in neurotherapeutics. This review highlights innovative synthetic strategies, including green chemistry approaches, that improve the drug-likeness and bioavailability of indole derivatives. Indole continues to be an indispensable scaffold in the development of novel therapeutics aimed at addressing the growing burden of neurological disorders.

DISCUSSION: This review aims to provide a comprehensive analysis of the therapeutic potential of indole-based compounds for the treatment of neurological disorders. However, challenges like blood-brain barrier permeability and long-term safety must be addressed for clinical success. Nonetheless, this review will help in designing and developing newer indole-based molecules in the discovery of neurological drug development.

CONCLUSION: Due to its broad spectrum of biological activities and favorable pharmacokinetic properties, indole is an impressive scaffold for the treatment of various neurological disorders. Indole demonstrates remarkable therapeutic potential against a range of central nervous system-related conditions, including Alzheimer's disease, epilepsy, migraine, stroke, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and Huntington's disease.},
}

@article {pmid41510572,
year = {2026},
author = {Tang, C and Han, K and Wen, X and Zhang, J and Sun, W and Yue, X and Shi, L and Liu, Z and Zhao, J and Yan, C and Liu, M and Yao, Z and Kong, Z and Liu, Y and Fu, Z and Zhao, X and Yang, Z and Han, M and Chen, C and Xing, Z and Zhou, X and Yang, F and Zhang, Y and Jiang, X},
title = {Synthetic Disaggregators Enhance Central-Peripheral Amyloid-β Clearance in Alzheimer's Disease.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e20002},
doi = {10.1002/adma.202520002},
pmid = {41510572},
issn = {1521-4095},
support = {2024YFA0918400//National Key Research and Development Program of China/ ; 82350125//National Natural Science Foundation of China/ ; 82425056//National Natural Science Foundation of China/ ; 82173763//National Natural Science Foundation of China/ ; 82303810//National Natural Science Foundation of China/ ; ZR2022ZD18//Fundamental Research Funds of Shandong Province/ ; ZR2023QH224//Natural Science Foundation of Shandong Province/ ; 2022M721967//China Postdoctoral Science Foundation/ ; 2024T170524//China Postdoctoral Science Foundation/ ; SYS202202//Shandong Provincial Laboratory Project/ ; NO.tsqnz20221165//Taishan Scholar Foundation of Shandong Province/ ; 2025CXPT177//Key R&D Program of Shandong Province/ ; 2025CXPT177//Key R&D Program of Shandong Province/ ; },
abstract = {Pathogenic amyloid-β (Aβ) accumulation defines Alzheimer's disease (AD), directly inflicting neuronal damage and driving chronic neuroinflammation. While both central microglia and peripheral macrophages are critical for Aβ clearance, their functional impairment in AD inexorably leads to escalating Aβ burden and disease progression. We here report an in situ engineered synthetic Aβ disaggregator (SAD) delivered to macrophages via neuroprotective DHA-based lipid nanoparticles (DLNPs). This platform transcends current therapeutic limitations by not only potently dismantling neurotoxic Aβ aggregates but also by fundamentally reprogramming peripheral macrophages to enhance Aβ clearance. Specifically, our results demonstrate that DLNPs effectively reprogram peripheral macrophages to produce and secrete cerebral-penetrating SAD both in vitro and in vivo. The SAD can promote cerebral Aβ disaggregation, thereby inhibiting neuroinflammatory pathology progression. Moreover, the DLNPs efficiently reprogram the peripheral macrophages to enhance phagocytosis, further facilitating drainage of Aβ and reducing cerebral Aβ accumulation in mouse models. Collectively, these findings uncover a dual-action mechanism of SAD through the synergistic interplay of direct Aβ disaggregation and enhanced macrophage-mediated clearance. In sum, our findings establish that the central-peripheral targeting therapeutic strategy significantly reversed AD pathology, highlighting the therapeutic potential of mRNA-based in situ fusion protein in AD treatment.},
}

@article {pmid41510365,
year = {2026},
author = {Wang, Y and Alexander, GC and Mehta, HB},
title = {Treatment of type 2 diabetes among medicare beneficiaries with and without alzheimer's disease: A retrospective cohort study.},
journal = {Journal of diabetes and metabolic disorders},
volume = {25},
number = {1},
pages = {25},
pmid = {41510365},
issn = {2251-6581},
abstract = {PURPOSE: While Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) commonly co-occur in older adults, little is known regarding whether and how the treatment of T2DM varies by AD status. This study aimed to compare and contrast T2DM treatment among individuals with and without AD.

METHODS: We conducted a retrospective cohort study using 20% Medicare Fee-for-Service claims data from 2016 to 2020. The primary outcome was initiation of any antidiabetic medication within one year of T2DM diagnosis, and we also examined initiation patterns across specific drug classes. We used multivariable logistic regression to estimate adjusted odds ratios for the association between AD and treatment initiation.

RESULTS: Among 388,359 beneficiaries newly diagnosed with T2DM, 9,584 had AD. Within one year, overall treatment initiation was lower for individuals with AD compared to those without. At initiation, individuals with AD were more likely to receive insulin and less likely to receive metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists. In adjusted models, AD was associated with lower odds of antidiabetic treatment initiation, and among those initiating treatment, lower odds of initiating newer agents such as GLP-1 receptor agonists and SGLT2 inhibitors.

CONCLUSION: Beneficiaries with AD were less likely to initiate antidiabetic therapy, particularly newer agents. Future work could explore the basis for these differences.},
}

@article {pmid41510304,
year = {2025},
author = {Wang, Y and Zhou, M and Tang, Z and Xiong, C and Asken, B and Yang, B and Su, J and Zhou, X and Song, Q},
title = {CauReL: Dynamic Counterfactual Learning for Precision Drug Repurposing in Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8206648/v1},
pmid = {41510304},
issn = {2693-5015},
abstract = {Alzheimer's disease has few effective therapies, and decades of amyloid- and tau-focused trials have delivered only modest benefit with substantial toxicity. Drug repurposing using real-world data offers a faster and lower-risk route to new treatments, yet current approaches typically average effects across populations, model disease onset and progression separately, and provide little insight into which patients are most likely to benefit. We present CauReL, a dynamic counterfactual representation learning framework that enables transparent, patient specific estimation of treatment effects from large-scale electronic health records for precision drug repurposing in AD. CauReL first learns balanced latent representations of treated and untreated patients using Integral Probability Metric regularization, then jointly predicts two clinically linked outcomes, incident AD and time from mild cognitive impairment (MCI) to AD, to generate paired counterfactual outcomes for every individual. A counterfactual explanation module quantifies how clinical features shape benefit at the patient level, and uplift trees transform complex heterogeneity into simple, rule-based subgroups suitable for trial enrichment and clinical decision support.Using independent cohorts from OneFlorida + and All of Us, we screened outpatient prescriptions with at least 20 percent exposure among 28,605 individuals with mild cognitive impairment, of whom 4,990 progressed to Alzheimer's disease. CauReL substantially improved covariate balance and distributional overlap across drug cohorts and achieved strong predictive accuracy for both incidence (AUC greater than 0.90) and progression timing (C index 0.81 to 0.84; Spearman 0.80 to 0.86). Twenty drugs showed consistent protective associations, with four emerging as highly reproducible across both networks, the metabolic agents liraglutide and empagliflozin and the neuroactive agents entacapone and amantadine. These drugs were associated with meaningful absolute risk reductions and clinically significant delays in progression from mild cognitive impairment to Alzheimer's disease. Metabolic drugs produced the strongest benefits in individuals with diabetes, obesity, or cardiovascular disease, whereas neuroactive drugs provided broadly consistent protection across most subgroups.CauReL is available as an open source Python package with a companion web server for direct application to new cohorts or disease settings (https://caurel.site/). This work delivers a scalable and interpretable framework for prioritizing repurposable drugs and designing targeted clinical trials for the patients most likely to benefit.},
}

@article {pmid41510223,
year = {2025},
author = {Jiang, L and Tucker, A and Sepehri, C and Patel, D and Wang, Q and Yuan, S and Sherman, E and Chen, Y and Beh, J and Downey, A and Goldberg, D and Gniadzik, W and Ma, X},
title = {Inhibition of N6-Methyladenosine Accumulation by Targeting METTL3 Mitigates Tau Pathology and Cognitive Decline in Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8379573/v1},
pmid = {41510223},
issn = {2693-5015},
abstract = {Dysregulation of N6-methyladenosine (m6A) modification of RNA has emerged as a novel feature of Alzheimer's disease (AD). Here, we investigate the relationship between m6A modification and AD pathology, and the therapeutic potential of modulating excessive m6A via its "writer" methyltransferase METTL3 in a humanized P301S tau transgenic mouse model of AD (PS19). We observed significantly elevated m6A levels in human post-mortem AD frontal cortex tissue compared to healthy controls, which positively correlated with hyperphosphorylated tau and amyloid-β (Aβ) deposition. These effects were recapitulated in the PS19 tau mice model of AD. Importantly, treatment of PS19 mice with the METTL3 inhibitor STM2457 reduced excessive m6A, alleviated tau pathology, and attenuated neurodegeneration. Behavioral assessments further demonstrated that STM2457-treated PS19 mice exhibited significantly improved learning and memory relative to untreated PS19 mice. Our results identify m6A as a critical contributor to AD pathogenesis and demonstrate that pharmacological inhibition of METTL3 represents a promising therapeutic strategy to improve cognition in AD.},
}

@article {pmid41509358,
year = {2026},
author = {Jati, S and Kal, S and Munoz-Mayorga, D and Tang, K and Sahoo, D and Chen, X and Mahata, SK},
title = {Catestatin ameliorates tauopathy and amyloidogenesis via adrenergic inhibition.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.04.697519},
pmid = {41509358},
issn = {2692-8205},
abstract = {Neurodegenerative disorders like Alzheimer's disease (AD), Corticobasal Degeneration (CBD), and Progressive Supranuclear Palsy (PSP) are characterized by Tau aggregation, synaptic dysfunction, neuroinflammation, and progressive cognitive decline. Although metabolic dysregulation and neuropeptide imbalance have been linked to these disorders, the functional consequences of such imbalance and its potential for therapeutic reversal remain poorly understood. Our previous work identified chromogranin A (CgA), which encodes a pro-hormone for several metabolic peptides, as a key regulator of Tau pathology. Here, we investigate Catestatin (CST), a CgA-derived peptide that is a potent inhibitor of catecholamine release and has been shown to increase insulin sensitivity and lower peripheral blood pressure. We report significant reductions in CST levels in the hippocampus and cortex of AD brains, as well as in the frontal cortex of CBD and the basal ganglia of PSP. Supplementing CST in cortical neuronal cultures and organotypic slice cultures (OTSC) decreased Tau phosphorylation and aggregation. In vivo , CST administration in PS19 Tauopathy mice reduced pathological Tau species, attenuated gliosis, and improved cognitive function. CST treatment also lowered amyloid plaque burden and neuroinflammation in 5xFAD mice. Mechanistically, CST decreased epinephrine (EPI) levels in both PS19 and 5xFAD mice and suppressed downstream protein kinase A (PKA) hyperactivation in PS19 and OTSC. These findings reveal a previously unrecognized neuropeptidergic mechanism linking CST deficiency to elevated adrenergic receptor (ADR)-EPI-PKA stress signaling and Tauopathy-driven neurodegeneration, suggesting CST replacement as a promising therapeutic approach.},
}

@article {pmid41509252,
year = {2026},
author = {Jesudason, CD and Rangel-Barajas, C and Beach, CJ and Beck, DE and Caballero-Floran, IH and Clayton, WB and Da Silva, L and David, JC and Doolen, S and Faulkner, AN and Hamdani, AK and Huhe, H and Huynh, K and Imhoff, RD and Javens-Wolfe, J and Mason, ER and Moussaif, M and Singhal, K and Soni, DM and van Buuren-Milne, M and Williams, SP and Angus, SP and Chu, S and Dage, JL and Hipskind, PA and Johnson, TS and Kaddurah-Daouk, R and Lamb, BT and Meikle, PJ and Mesecar, AD and Palkowitz, AD and Quinney, SK and Sukoff Rizzo, SJ and Oblak, AL and Richardson, TI},
title = {Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer's Disease Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41509252},
issn = {2692-8205},
abstract = {Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1), encoded by the gene INPP5D, is a lipid phosphatase that negatively regulates immune receptor signaling in hematopoietic cells and microglia. Here, we describe a pyridyl-pyrazole-piperidine scaffold and the lead compound 3-((2-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine (32), which demonstrates SHIP1 target engagement, brain exposure, and evidence of a central pharmacodynamic response in vivo. Structure-activity relationship studies, guided by biochemical and cellular assays using multiple human and murine protein constructs and cells, identified SHIP1-active ligands. A thermal shift assay using full-length SHIP1 was used to assess compounds for cellular target engagement, while studies in IL-4 conditioned THP-1 cells was used to demonstrate changes in downstream AKT signaling. Targeted lipidomics revealed changes in the overall phosphoinositide pool consistent with SHIP1 target engagement and reduction of phospho-AKT levels. In a protein-lipid overlay assay, compound 32 induced changes in the relative association of SHIP1 with multiple phosphatidylinositols on a membrane surface. In high-content cellular imaging assays, compound 32 enhanced the uptake of myelin/membrane debris and fibrillar amyloid by primary murine microglia, phenocopying a genetic model with reduced SHIP1 expression. Finally, oral administration of compound 32 resulted in brain exposure sufficient to alter gene expression and reduce IL-1β levels as pharmacodynamic markers of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimer's disease. Collectively, these results define a scaffold with SHIP1 target engagement, CNS exposure, and in vivo activity, providing a foundation for the optimization of brain-penetrant SHIP1 ligands suitable for further mechanistic studies and therapeutic development for the treatment of Alzheimer's disease.},
}

@article {pmid41509242,
year = {2025},
author = {Kumari, R and Bowen, C and Srivastava, U and Brandelli, AD and Kumar, P and Kour, D and Malepati, S and Jang, WE and Bromwich, M and Zeng, H and Sing, A and Sloan, SA and Wulff, H and Rangaraju, S},
title = {Kv1.3 inhibition alleviates neuropathology via neuroinflammatory and resilience pathways in a mouse model of Aβ pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.25.696456},
pmid = {41509242},
issn = {2692-8205},
abstract = {Inhibition of voltage-gated potassium channel Kv1.3 is a therapeutic strategy to curb microglia-mediated neuroinflammation in neurodegeneration, although the cellular and signaling mechanisms of disease-modification by Kv1.3 blockers are unclear. In this study, we delineate protective mechanisms of Kv1.3 blockade in a mouse model of Alzheimer's disease (AD) pathology using comprehensive transcriptomics and proteomics profiling of brain, corresponding with neuropathological effects of two translationally relevant Kv1.3 blockers, namely small molecule PAP-1 and peptide ShK-223. Following 3 months of treatment, both molecules reduced Ab plaque burden. Single nuclear RNA seq (snRNA seq) of brain nuclei showed that PAP-1 disproportionately impacted oligodendrocytes and microglia and increased crosstalk between neurons and astrocytes with endothelial cells. In contrast, ShK-223 had pronounced effects on glutamatergic neurons and astrocytes. Both blockers increased expression of myelination genes in oligodendrocytes and synaptic genes in neurons. Neuroprotective effects of PAP-1 were further confirmed by bulk brain transcriptomics and proteomics whereby PAP-1 increased levels of synaptic, cognitive resilience and mitochondrial proteins, while decreasing glial and immune pathways including STAT1/3 phosphorylation. Using proximity labeling and co-immunoprecipitation, we found that Kv1.3 interacts with STAT1/3 in microglia. Using microglial cell lines and primary microglia, we discovered a preferential functional coupling between Kv1.3 and type 2 but not type 1 IFN signaling. Brain-level disease modification by Kv1.3 blockade was reflected in the cerebrospinal fluid (CSF) via reduced levels of neurofilament-light (NEFL) and resilience protein RPH3A, both of which are increased in human AD CSF. Together, this study demonstrates functional links between Kv1.3 channels and type 2 IFN signaling and reveals distinct cellular effects of Kv1.3 blockers in AD pathology that correspond with reduced neuropathology and neuroinflammation, augmentation of resilience and neuro-vascular pathways, along with biomarkers of therapeutic effect.},
}

@article {pmid41508224,
year = {2025},
author = {Ma, YJ and Deng, SX and Liao, ZH and Gao, MH and Ding, HX and Xu, ZQ and Lu, YT and Yang, C and Wang, Q},
title = {[Treatment of Alzheimer's disease from gut-brain interactions based on theory of "spleen deficiency leading to obstruction of nine orifices"].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {19},
pages = {5330-5339},
doi = {10.19540/j.cnki.cjcmm.20250618.501},
pmid = {41508224},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy/physiopathology/metabolism ; Humans ; *Brain/physiopathology/drug effects/metabolism ; *Spleen/physiopathology/drug effects ; Animals ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use ; Gastrointestinal Microbiome ; },
abstract = {Alzheimer's disease(AD) is the most common form of dementia. The decline in sensory function is associated with pathological damage in specific brain regions during the early stages of AD. Such decline often precedes cognitive impairment, worsens as the pathology progresses, and constitutes a high-risk factor for the onset of AD. According to traditional Chinese medicine(TCM), all orifices are connected to the brain, and the brain governs all orifices. The mind originates from and depends on both the brain and orifices, with their physiological and pathological states being closely interconnected. In AD, dysfunction of the sensory orifices is closely linked to the later-stage manifestations of impaired mental clarity and consciousness. The theory that "spleen deficiency leading to obstruction of nine orifices" emphasizes that insufficiency of the spleen and stomach is the root cause of orifice dysfunction. Both internal and external pathogenic factors in AD can damage the spleen and stomach, leading to the abnormal movement of turbid substances generated by these organs, which may transform into turbid toxins. This, in turn, gradually impairs the orifices, brain, and mind, thereby exacerbating the progression of AD. The digestive, absorptive, and transport functions of the spleen and stomach are similar to those of the gut microbiota. Spleen deficiency is a core pathological factor in diseases associated with gut microbiota dysbiosis. Such dysbiosis can lead to dysfunction in the neural, metabolic, and immune pathways involved in gut-brain interactions, constituting the biological basis for the TCM concept that "spleen deficiency leading to obstruction of nine orifices". Under the guidance of this theory, employing spleen-strengthening and cognition-enhancing drugs alongside aromatic orifice-opening drugs to support spleen function, and using ingredients that promote dampness elimination, lubrication, and blood stasis resolution to dispel pathogenic factors from the orifices, can help restore the structural balance of the gut microbiota, regulate related metabolic and immune dysfunctions, and ultimately delay the progression of AD. This article explores the etiology, pathogenesis, and therapeutic strategies of AD based on the theory of "spleen deficiency leading to obstruction of nine orifices", and interprets its biological significance from the perspective of gut-brain interactions, aiming to provide new insights for the prevention and treatment of AD.},
}

*Alzheimer Disease/drug therapy/physiopathology/metabolism
Humans
*Brain/physiopathology/drug effects/metabolism
*Spleen/physiopathology/drug effects
Animals
Medicine, Chinese Traditional
Drugs, Chinese Herbal/therapeutic use
Gastrointestinal Microbiome

@article {pmid41508200,
year = {2025},
author = {Zhang, YX and Wang, J and Chen, QQ and Zhang, JL and Wang, Q and Long, YL and Zhou, SJ and Gong, ZP and Zheng, L and Huang, Y and Li, YT},
title = {[Study on quality markers of Pleione yunnanensis for "same treatment for different diseases" in liver inflammation and Alzheimer's disease based on UHPLC fingerprint and network pharmacology].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {20},
pages = {5684-5696},
doi = {10.19540/j.cnki.cjcmm.20250710.202},
pmid = {41508200},
issn = {1001-5302},
mesh = {Network Pharmacology ; *Drugs, Chinese Herbal/chemistry/therapeutic use ; *Alzheimer Disease/drug therapy/genetics/metabolism ; Chromatography, High Pressure Liquid/methods ; Humans ; Molecular Docking Simulation ; Biomarkers/analysis ; Quality Control ; },
abstract = {This study aims to screen quality markers(Q-markers) of Pleione yunnanensis for the treatment of liver inflammation and Alzheimer's disease(AD) based on the concept of "same treatment for different diseases" using ultra-high-performance liquid chromatography(UHPLC) fingerprinting combined with network pharmacology and molecular docking, and to perform quantitative analysis of the identified Q-markers. The UHPLC fingerprints of 15 batches of P. yunnanensis were established and subjected to similarity evaluation, cluster analysis(CA), principal component analysis(PCA), and orthogonal partial least squares discriminant analysis(OPLS-DA) to identify characteristic components responsible for quality variations. Network pharmacology and molecular docking were employed to explore the potential active components, related targets, and signaling pathways underlying the "same treatment for different diseases" mechanism for liver inflammation and AD. Based on the criteria of effectiveness, specificity, and measurability, Q-markers of P. yunnanensis were identified and quantified. Ten common peaks were identified in the UHPLC fingerprints of 15 batches, with eight components identified. Similarity scores ranged from 0.774 to 0.987. Chemical pattern recognition analysis identified that shancigusin H, militarine, and gymnoside Ⅴ were the major characteristic components contributing to quality differences among batches. RESULTS:: of network pharmacology and molecular docking revealed that dactylorhin A and militarine were the key active components exerting anti-inflammatory and neuroprotective effects. These components acted on 13 core targets, including SRC, CASP3, and CTNNB1, and regulated signaling pathways such as the PI3K-Akt signaling pathway and arachidonic acid metabolism. Based on the effectiveness, specificity, and measurability of Q-marker, dactylorhin A and militarine were selected as the Q-markers of P. yunnanensis. Quantitative analysis demonstrated that the content of dactylorhin A ranged from 0.527% to 2.21%, and militarine ranged from 0.731% to 2.58% across the 15 batches. The UHPLC fingerprint method and Q-marker-based quantification approach are robust and reliable, providing experimental evidence for quality control and standardization of P. yunnanensis.},
}

Network Pharmacology
*Drugs, Chinese Herbal/chemistry/therapeutic use
*Alzheimer Disease/drug therapy/genetics/metabolism
Chromatography, High Pressure Liquid/methods
Humans
Molecular Docking Simulation
Biomarkers/analysis
Quality Control

@article {pmid41508178,
year = {2025},
author = {Hou, WX and Liu, YX and Miao, JR and Zhu, ZK and Yin, Y and Liu, JL and Zhao, DY},
title = {[Mechanism of Liuwei Dihuang Pills in enhancing GPNMB expression to regulate FcγRⅡB/c-Src pathway for prevention and treatment of Alzheimer's disease].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {21},
pages = {6062-6071},
doi = {10.19540/j.cnki.cjcmm.20250805.401},
pmid = {41508178},
issn = {1001-5302},
mesh = {Animals ; *Drugs, Chinese Herbal/administration & dosage ; *Alzheimer Disease/drug therapy/genetics/metabolism/prevention & control ; Male ; Mice ; *Membrane Glycoproteins/genetics/metabolism ; Humans ; Signal Transduction/drug effects ; *src-Family Kinases/metabolism/genetics ; Hippocampus/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Memory/drug effects ; Eye Proteins ; },
abstract = {This study investigated the effect of Liuwei Dihuang Pills on the Fcγ receptor Ⅱ-b(FcγRⅡB)/c-Src tyrosine kinase(c-Src) pathway in senescence-accelerated mouse prone 8(SAMP8) by regulating the expression of the glycoprotein non-metastatic melanoma protein B(GPNMB) and explored the mechanism of the kidney-tonifying and essence-strengthening therapy in the treatment of Alzheimer's disease.(1) For the effects of Liuwei Dihuang Pills on the learning and memory ability, hippocampal β-amyloid protein(Aβ), GPNMB, and autophagy function in SAMP8 mice, eight seven-month-old male senescence-accelerated mouse resistant 1(SAMR1) mice were used as a control group, and 16 male SAMP8 mice of the same age were randomly divided into a model group and a Liuwei Dihuang Pills group. The Liuwei Dihuang Pills group was given 2.36 g·kg~(-1) concentrated Liuwei Dihuang Pills solution by gavage, while the control group and the model group were given the same volume of normal saline twice a day for four consecutive weeks. The learning and memory ability of mice in each group was detected by the Morris water maze experiment; the expression level of Aβ in the hippocampus of mice were detected by enzyme-linked immunosorbent assay(ELISA) and immunohistochemistry; the expression of GPNMB in the hippocampus of mice was detected by immunofluorescence and Western blot; the expression level of ubiquitin-binding protein p62 and microtubule-associated protein light chain 3(LC3) Ⅱ/LC3Ⅰ in the hippocampus of mice was measured by Western blot.(2) For the regulatory effect of GPNMB on the FcγRⅡB/c-Src pathway, eight seven-month-old male SAMR1 mice were used as a control group, and 24 male SAMP8 mice of the same age were randomly divided into a model group, an LV-Vector group, and an LV-GPNMB~(OE) group. The bilateral hippocampus of the LV-Vector group and LV-GPNMB~(OE) group was injected with LV-Vector and LV-GPNMB~(OE) of 2 μL/each side, respectively. Western blot was used to detect the expression level of p62, LC3Ⅱ/LC3Ⅰ, FcγRⅡB, Src homology 2 protein tyrosine phosphatase 1(SHP-1), and c-Src proteins in the hippocampus of mice.(3) For the effect of Liuwei Dihuang Pills in regulating the FcγRⅡB/c-Src pathway by increasing the GPNMB expression, 32 seven-month-old male SAMP8 mice were randomly divided into a model group, a Liuwei Dihuang Pills group, a Liuwei Dihuang Pills + LV-NC group, and a Liuwei Dihuang Pills + LV-shGPNMB group. The bilateral hippocampus of the Liuwei Dihuang Pills + LV-NC group and Liuwei Dihuang Pills + LV-shGPNMB group was injected with LV-NC and LV-shGPNMB, respectively, before the drug treatment. Western blot was used to detect the expression level of p62, LC3Ⅱ/LC3Ⅰ, FcγRⅡB, SHP-1, and c-Src proteins in the hippocampus of mice. The results showed that(1) compared with those of the control group, the escape latency of the model group was significantly increased, and the time spent in the target quadrant and the effective area was significantly decreased. The expression level of Aβ, GPNMB, and p62 in the hippocampus was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. Compared with those of the model group, the escape latency of the Liuwei Dihuang Pills group was significantly shortened, and the time spent in the target quadrant and the effective area was significantly increased. The level of Aβ was significantly decreased, and the expression level of GPNMB was significantly increased. The expression level of p62 was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased.(2) Compared with those of the control group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src proteins in the hippocampus of the model group was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. Compared with those of the model group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the LV-GPNMB~(OE) group was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased.(3) Compared with those of the model group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the Liuwei Dihuang Pills group was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased. Compared with those of the Liuwei Dihuang Pills group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the Liuwei Dihuang Pills + LV-shGPNMB group was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. These results indicate that Liuwei Dihuang Pills can inhibit the FcγRⅡB/c-Src pathway by up-regulating the GPNMB expression, thereby increasing autophagy levels, enhancing neuroprotective ability, and alleviating Alzheimer's disease.},
}

Animals
*Drugs, Chinese Herbal/administration & dosage
*Alzheimer Disease/drug therapy/genetics/metabolism/prevention & control
Male
Mice
*Membrane Glycoproteins/genetics/metabolism
Humans
Signal Transduction/drug effects
*src-Family Kinases/metabolism/genetics
Hippocampus/drug effects/metabolism
Amyloid beta-Peptides/metabolism
Memory/drug effects
Eye Proteins

@article {pmid41508060,
year = {2025},
author = {Sun, CX and Han, XY and Xiao, YT and Liu, YX and Ye, TY},
title = {[Research progress on prevention and treatment of Alzheimer's disease with Danggui Shaoyao San].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {22},
pages = {6215-6226},
doi = {10.19540/j.cnki.cjcmm.20250626.601},
pmid = {41508060},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy/prevention & control/metabolism ; *Drugs, Chinese Herbal/therapeutic use/administration & dosage ; Humans ; Animals ; },
abstract = {Alzheimer's disease is a neurodegenerative disorder associated with aging. In traditional Chinese medicine(TCM), it is classified as a syndrome of root deficiency and branch excess. Danggui Shaoyao San, a classic formula traditionally used to treat gynecological disorders, has the effects of promoting blood circulation, removing blood stasis, opening orifices, awakening the mind, strengthening the spleen, resolving phlegm, and tonifying Qi to nourish the spirit. Modern clinical studies have found that Danggui Shaoyao San can slow the progression of Alzheimer's disease and has great potential for clinical application. Recent studies indicate that Danggui Shaoyao San treats Alzheimer's disease through multi-target and multi-level mechanisms. These include clearing amyloid β(Aβ) plaques and abnormally phosphorylated tau protein, maintaining brain-gut homeostasis, reducing oxidative stress, and regulating autophagy. Its key components, paeoniflorin and ferulic acid, have also been reported to exert antioxidant, anti-inflammatory, and anti-apoptotic effects, eliminate pathological products, and regulate the cholinergic system in the brain. This paper traces the classic formula of Danggui Shaoyao San, conducts a theoretical integration of ancient and modern medical systems, and systematically summarizes and analyzes the research related to the treatment of Alzheimer's disease using Danggui Shaoyao San and its key components. It aims to provide a valuable reference for further research and modern application of Danggui Shaoyao San in the treatment of Alzheimer's disease.},
}

*Alzheimer Disease/drug therapy/prevention & control/metabolism
*Drugs, Chinese Herbal/therapeutic use/administration & dosage
Humans
Animals

@article {pmid41507065,
year = {2026},
author = {De Rui, M and Salerno Trapella, G and Ceolin, C and Ceccato, F and Antonelli, G and Ravelli, A and Andreuzza, R and Conti, E and Sarlo, M and Coin, A and Zanforlini, BM and Bertocco, A and Curreri, C and Tizianel, I and Mapelli, D and Sergi, G and Devita, M},
title = {Effect of cognitive training on cortisol levels in patients with neurocognitive disorders.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {81},
number = {2},
pages = {},
pmid = {41507065},
issn = {1758-5368},
mesh = {Humans ; *Hydrocortisone/metabolism/analysis ; Male ; Female ; Aged ; Saliva/chemistry ; *Neurocognitive Disorders/therapy/metabolism ; Middle Aged ; Italy ; *Cognitive Behavioral Therapy/methods ; Hypothalamo-Hypophyseal System/metabolism ; Case-Control Studies ; Cognitive Training ; },
abstract = {OBJECTIVES: Elevated cortisol levels are linked to a greater risk and faster progression of neurocognitive disorders (NCDs). While interventions such as exercise and mindfulness have shown benefits in reducing cortisol, the impact of cognitive training (CT) on cortisol regulation remains unexplored. This study investigated whether CT affects cortisol levels and secretion patterns in individuals with minor or major NCD and compared its effects with those of pharmacological treatment.

METHODS: Sixty-two older adults with NCD and 43 healthy controls were recruited from the University Hospital of Padua in Italy. Among patients with NCD, 34 underwent CT (CT-NCD group), and 28 received pharmacological treatment (PH-NCD group). Salivary cortisol was measured at six points during the day, at baseline, and at 3 months (T1) and 6 months (T2) post-intervention.

RESULTS: Compared with pharmacological treatment (PH), CT showed a larger percentage decrease of daily cortisol exposure area under the curve (AUC) from baseline; however, the between-group difference did not remain statistically significant after covariate adjustment, and the only robust time-point effect was in the afternoon (F(1,47)=5.13; p = .028). Morning values decreased within groups, but between-group differences in the CAR were not significant; at bedtime, CT showed only a trend towards lower cortisol than PH (p = .071). Median morning values changed from 7.75 to 6.20 in CT and from 5.80 to 5.15 in PH.

DISCUSSION: Cognitive training may help lower cortisol levels and enhance cognitive function in NCD patients, suggesting its potential as a nonpharmacological tool to modulate hypothalamic-pituitary-adrenal axis activity. Larger randomized studies are needed to confirm and extend these findings.},
}

Humans
*Hydrocortisone/metabolism/analysis
Male
Female
Aged
Saliva/chemistry
*Neurocognitive Disorders/therapy/metabolism
Middle Aged
Italy
*Cognitive Behavioral Therapy/methods
Hypothalamo-Hypophyseal System/metabolism
Case-Control Studies
Cognitive Training

@article {pmid41506734,
year = {2026},
author = {, and , },
title = {[Guidelines for the management of chronic insomnia comorbid with common neuropsychiatric disorders in adults (2025 edition)].},
journal = {Zhonghua nei ke za zhi},
volume = {65},
number = {1},
pages = {18-44},
doi = {10.3760/cma.j.cn112138-20250911-00539},
pmid = {41506734},
issn = {0578-1426},
support = {2021YFC2501400//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Sleep Initiation and Maintenance Disorders/therapy/epidemiology/complications ; *Mental Disorders/therapy/complications/epidemiology ; Comorbidity ; Adult ; Parkinson Disease ; },
abstract = {Chronic insomnia frequently co-occurs with common neuropsychiatric disorders, including migraine, stroke, Alzheimer's disease, Parkinson's disease, epilepsy, generalized anxiety disorder, depressive disorder, body distress disorder, post-traumatic stress disorder, and disorders due to use of alcohol. The prevalence of these neuropsychiatric disorders is hiher among patients with chronic insomnia than in the general population, and the conditions mutually exacerbate each other. Comorbidities not only exacerbate the severity and increases the relapse risk of each condition but also lead to a poorer prognosis, more severe impairment of social functioning, a higher all-cause mortality risk, and greater treatment challenges. Therefore, the Sleep Disorders Group, Chinese Society of Neurology and Sleep Medicine Group,China Neurologist Association have convened experts in relevant fields, based on current medical evidence, to establish guideline for the management of Chinese adults with chronic insomnia comorbid with the aforementioned 10 categories of common neuropsychiatric disorders. The aim is to standardize clinical practice and improve treatment effectiveness and cure rates.},
}

Humans
*Sleep Initiation and Maintenance Disorders/therapy/epidemiology/complications
*Mental Disorders/therapy/complications/epidemiology
Comorbidity
Adult
Parkinson Disease

@article {pmid41506537,
year = {2026},
author = {Liang, YZ and Jiang, MZ and Xu, XT and Zhu, T and Guo, H and Ding, L and Zhong, H and Bao, J and Qin, LQ and Li, YH},
title = {Ameliorating effect and mechanism of p-coumaric acid liposome on cognitive dysfunction and mitochondrial damage under intermittent hypoxia.},
journal = {Life sciences},
volume = {387},
number = {},
pages = {124197},
doi = {10.1016/j.lfs.2026.124197},
pmid = {41506537},
issn = {1879-0631},
abstract = {AIMS: Alzheimer's disease (AD) has become a global public health problem. Mitochondrial dysfunction contributes to AD pathogenesis, and adequate oxygen supply is essential to maintain mitochondrial homeostasis. P-coumaric Acid (CA) is a polyphenol with anti-hypoxia and anti-AD properties. In this study, CA was formulated into a biomimetic liposome (CA-Lip) to enhance its therapeutic efficacy, and the underlying mechanisms were studied.

MATERIALS AND METHODS: APP/PS1 mice were divided into four groups: AD group, hypoxia treatment group (AD-HY group), hypoxia + CA treatment group (CA group), hypoxia + CA-Lip treatment group (CA-Lip group). Age-matched wild-type littermates were used as controls. Mice in the hypoxia treatment groups were exposed to a hypoxia chamber for 6 h daily for 8 weeks. Cognitive performance and mitochondrial function were subsequently evaluated to determine the ameliorating effects and mechanisms of CA-Lip.

RESULTS: Cognitive impairment and mitochondrial dysfunction were more pronounced in the AD-HY group than in the AD group. CA-Lip produced greater neuroprotective effects than CA. Mechanistic analyses showed that CA-Lip reduced amyloid-β (Aβ) accumulation, enhanced mitochondrial biogenesis (upregulation of PGC-1α expression), maintained mitochondrial dynamics (upregulation of MFN2 expression, and downregulation of DRP1 expression), inhibited excessive mitophagy (downregulation of PINK1 and Parkin expression), enhanced cell autophagy (upregulation of ATG7 and LC3B expression and downregulation of mTOR and P62 expression), and reduced neuronal apoptosis.

CONCLUSIONS: CA-Lip effectively ameliorates hypoxic cognitive impairment by reducing Aβ generation and improving mitochondrial function.},
}

@article {pmid41505228,
year = {2026},
author = {Head, E and Cohen, A and Fortea, J and McGlinchey, E},
title = {Novel insights into Alzheimer's disease through the study of individuals with Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71074},
pmid = {41505228},
issn = {1552-5279},
support = {U19AG068054//NIH/NIA/ ; U19AG068054//NIH/NIA/ ; P30AG066519//NIH/NIA/ ; RF1AG079519//NIH/NIA/ ; U19AG068054//NIH/NIA/ ; P30AG066519//NIH/NIA/ ; RF1AG079519//NIH/NIA/ ; R01AG056850//NIH/NIA/ ; R21AG056974//NIH/NIA/ ; R01AG061566//NIH/NIA/ ; 1R01AG081394//NIH/NIA/ ; R61AG066543//NIH/NIA/ ; //Fondo de Investigaciones Sanitario/ ; INT21/00073//Carlos III Health Institute/ ; PI20/01473//Carlos III Health Institute/ ; PI23/01786//Carlos III Health Institute/ ; //Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Program 1/ ; //Fondo Europeo de Desarrollo Regional/ ; SLT006/17/00119//Department de Salut de la Generalitat de Catalunya/ ; //Fundación/ ; IIBSP-DOW-2020-151//Tatiana Pérez de Guzmán el Bueno/ ; H2020-SC1-BHC-2018-2020//Horizon 2020-Research and Innovation Framework Programme/ ; HPE-ADRD 24HPE1284307//Alzheimer Association/ ; },
}

@article {pmid41505203,
year = {2026},
author = {Lyketsos, CG and Peters, ME},
title = {Neuropsychiatric symptoms in Alzheimer's disease: Past, present, and future.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71077},
pmid = {41505203},
issn = {1552-5279},
support = {P30AG066507//Johns Hopkins Alzheimer's Disease Research Center/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/complications ; *Cognitive Dysfunction/psychology ; Disease Progression ; *Depression/etiology ; },
abstract = {Noncognitive neuropsychiatric symptoms (NPS; e.g., depression, agitation) are nearly universal throughout the course of Alzheimer's disease (AD), cause significant adverse impact to patients and caregivers, and are associated with more rapid progression to severe dementia. Although the importance and presence of NPS was recognized by Dr. Alois Alzheimer himself, it was a series of research roundtables in the 2010s that propelled the understanding and treatment of NPS in AD forward. The mild behavioral impairment (MBI) construct was developed as a complementary behavioral analogue to mild cognitive impairment, solidifying the importance of NPS prior to dementia onset. Neurobiological underpinnings of NPS are being studied and the NPS treatment pipeline includes novel therapeutics, repurposing of existing pharmaceuticals, and non-pharmacologic interventions. The Alzheimer's Disease Research Centers and The National Alzheimer's Coordinating Center, being recognized in this special issue, have played a pivotal role in the recognition and study of NPS in AD. HIGHLIGHTS: Noncognitive neuropsychiatric symptoms (NPS) are nearly universal throughout the course of Alzheimer's disease (AD), cause significant adverse impact to patients and caregivers, and are associated with more rapid progression to severe dementia. A series of research roundtables in the last decade and a half have propelled the understanding and treatment of NPS in AD forward. The mild behavioral impairment (MBI) construct was developed as a complementary behavioral analogue to mild cognitive impairment, solidifying the importance of NPS prior to dementia onset. Neurobiological underpinnings of NPS are being studied and the treatment pipeline includes novel therapeutics, repurposing of pharmaceuticals, and non-pharmacologic interventions. The Alzheimer's Disease Research Centers and The National Alzheimer's Coordinating Center have played a pivotal role in the recognition and study of NPS in AD.},
}

Humans
*Alzheimer Disease/psychology/complications
*Cognitive Dysfunction/psychology
Disease Progression
*Depression/etiology

@article {pmid41502736,
year = {2025},
author = {Biswal, B and Pattnaik, S and Satapathy, BS and Maharana, L},
title = {Luliconazole-Loaded Nanoliposomes as a Repurposing Strategy to Combat Memory Dysfunction in LPS-Induced Alzheimer's Rats.},
journal = {ACS omega},
volume = {10},
number = {48},
pages = {59655-59674},
pmid = {41502736},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder with no definitive cure. Out of several proposed pathophysiology, microbial infection has recently been identified as one of the key pathogenic contributors for the development and progression of AD. In this context, the present study aims at a repurposing strategy through luliconazole (a potent imidazole derivative)-loaded optimized nanoliposomal carriers to treat AD. Optimized luliconazole-loaded nanoliposomes (LuNLs) were developed by the conventional thin-film hydration method followed by characterization in terms of FESEM, AFM, zeta potential, average size, loading %, and drug release (in vitro). The in vivo effectiveness of the LuNLs was investigated in LPS-induced AD rats. Molecular docking and simulation analysis demonstrated a favorable docking score between luliconazole and selected AD proteins. Spherical, nanosized (52.42 nm), negatively charged (-29.9 mV) LuNLs were reported showing a sustained drug release up to 24 h. An in vivo behavioral study depicted improved cognitive behavior in the LuNLs-treated group as compared to control groups. In vivo antioxidant activity in terms of SOD, MDA, and GSH inhibition by LuNLs was found comparable to that of standard formulation-treated groups, depicting the neuroprotective behavior of LuNLs. The histopathological observation of brain tissue in the LuNLs/control group further substantiated the in vivo behavioral study data. Based on the reports, luliconazole may be used as a viable, efficacious alternative for the treatment of AD, though further preclinical studies are highly warranted.},
}

@article {pmid41502722,
year = {2025},
author = {Wu, H and Huang, N and Wang, K and Mi, J and Liu, Z and Wang, J and Sang, Z and Tan, Z},
title = {Development of Novel 3‑Phenylpropanamide Derivatives as BChE Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {ACS omega},
volume = {10},
number = {48},
pages = {59522-59534},
pmid = {41502722},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative degenerative disorder among the elderly, featured by progressive cognitive decline and memory impairment. Due to its complex pathogenesis, there is still no effective therapeutic drug to date. Recently, selective BChE inhibition has been regarded as a potent approach for treating AD. In this work, we conducted structural optimization and structure-activity relationship studies on the previously obtained lead compound EMC-4f, and obtained the potential selective BChE inhibitor 12a (eqBChE, IC50 = 1.3 μM; huBChE, IC50 = 0.95 μM). The in vitro results exhibited that 12a showed good BBB permeability. Moreover, 12a demonstrated significant neuroprotective effects on l-Glu/Aβ25-35-induced HT22 cells injury. Further, the in vivo tests suggested that 12a remarkably alleviated mice cognitive impairment induced by scopolamine. Therefore, these data present that 12a is a promising BChE inhibitor against AD.},
}

@article {pmid41502346,
year = {2026},
author = {Chang, YY and Zheng, XH and Wang, MW and Zhang, QW and Gao, YT and Wang, YN and Sun, YT and Fan, HH and Li, X and Du, LD and Xie, XM and Pang, XB},
title = {Morroniside Modulates Microglia Polarization via the CX3CL1/CX3CR1/PU.1 Axis in ApoE4 Transgenic Mice.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70177},
pmid = {41502346},
issn = {1099-1573},
support = {251111313400//Key R&D Program of Henan Province/ ; 252300421379//Natural Science Foundation of Henan/ ; 25B350004//Key Scientific Research Projects of Henan Higher Education Institutions/ ; 82501727//Natural Science Foundation of China/ ; 22508091//Natural Science Foundation of China/ ; },
abstract = {Microglia monitor disease stimulation, neuronal apoptosis, and neural repair, and their overactivation-induced inflammation plays a key role in the pathogenesis of Alzheimer's disease (AD). Morroniside (Mor), an iridoid glycoside compound in Cornus officinalis, is one of the effective active components. The effects of Mor on antioxidant stress, antiapoptosis, and nerve repair function have been widely studied, but the mechanism of Mor in AD treatment remains unclear. To study the neuroprotective effects of Mor and elucidate the molecular mechanisms underlying its improvement of AD symptoms, we used ApoE4 transgenic mice and ApoE4-transfected BV2 cells as models of AD, focusing on microglia phenotype, function, and neuroinflammation. The 10-month-old mice were randomly divided into the ApoE3 control group (ApoE3 + Veh), the ApoE4 model group (ApoE4 + Veh), and the ApoE4 + Mor 10, 20, and 40 mg/kg groups as in vivo models. The in vitro BV2-ApoE model was constructed via lentiviral transfection. The effects of Mor on cognitive function of AD models were assessed through behavioral tests, western blot, immunofluorescence staining, and ELISA to measure changes of related pathological and inflammatory factors. Mor improved the cognitive function of ApoE4 transgenic mice by reducing Aβ plaques in the brain, improving the structural lesions of hippocampal neurons, and increasing synaptic plasticity in the brain of AD mice. In addition, Mor promoted the transformation of microglia from the M1 to the M2 phenotype, inhibited the activation of the CX3CR1/PU.1 signaling axis, and alleviated the dysfunction of microglia both in vitro and in vivo. CX3CR1 siRNA and PU.1 siRNA were used further to verify the regulatory effect of Mor on microglia phenotype. Our findings indicate that Mor can inhibit neuroinflammation, reduce Aβ accumulation, and improve synaptic damage in ApoE4 mice via the CX3CL1/CX3CR1/PU.1 pathway regulating the phenotype and function of microglia. This study provides a new therapeutic candidate for the prevention and treatment of AD.},
}

@article {pmid41502301,
year = {2026},
author = {Abhyankar, SD and Xiao, Y and Mahajan, N and Luo, Q and Cummins, TR and Oblak, AL and Lamb, BT and Corson, TW and Bhatwadekar, AD},
title = {Müller Glial Kir4.1 Channel Dysfunction in APOE4-KI Model of Alzheimer's Disease.},
journal = {Glia},
volume = {74},
number = {3},
pages = {e70119},
pmid = {41502301},
issn = {1098-1136},
support = {R01EY027779-S1/EY/NEI NIH HHS/United States ; R01EY032080/EY/NEI NIH HHS/United States ; //Research to Prevent Blindness, Unrestricted Grant/ ; DK064466/DK/NIDDK NIH HHS/United States ; G20240315-8762//Sigma Xi Grants in Aid of Research/ ; //NIH T32, Peter J. Roach Award, Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine/ ; },
mesh = {Animals ; *Potassium Channels, Inwardly Rectifying/metabolism/genetics ; *Alzheimer Disease/metabolism/genetics/pathology ; *Ependymoglial Cells/metabolism/pathology/drug effects ; *Apolipoprotein E4/genetics/metabolism ; Kcnj10 Channel ; Disease Models, Animal ; Mice, Transgenic ; Rats ; Mice ; Mitochondria/metabolism ; Oxidative Stress/physiology ; Retina/metabolism/pathology ; Mice, Inbred C57BL ; },
abstract = {Alzheimer's disease (AD), particularly late-onset AD (LOAD), affects millions worldwide, with the apolipoprotein ε4 (APOE4) allele being a significant genetic risk factor. Retinal abnormalities are a hallmark of LOAD, and our recent study demonstrated significant age-related retinal impairments in APOE4-knock-in (KI) mice, highlighting that retinal impairments occur before the onset of cognitive decline in these mice. Müller cells (MCs), key retinal glia, are vital for retinal health, and their dysfunction may contribute to retinal impairments seen in AD. MCs maintain potassium balance via specialized inwardly rectifying K[+] channels 4.1 (Kir4.1). This study posits that Kir4.1 channels will be impaired in APOE4-KI, resulting in MC dysfunction. Additionally, we demonstrate that MC dysfunction in APOE4-KI stems from alterations in mitochondrial dynamics and oxidative stress. Kir4.1 expression and function were studied using immunofluorescence and through the whole-cell voltage clamp, respectively. In parallel, rat Müller cells (rMC-1) were used to create an in vitro model for further mechanistic studies. MitoQ was used to evaluate its potential to mitigate APOE4-induced deficits. APOE4 retinas and APOE4-transfected rMC-1 significantly reduced Kir4.1 expression, K+ buffering capacity, and increased mitochondrial damage. APOE4-transfected rMC-1 showed reduced mitochondrial membrane potential (ΔΨm) and increased mitochondrial reactive oxygen species (ROS). MitoQ treatment significantly reduced mitochondrial ROS and restored Kir4.1 expression in APOE4-expressing cells. Our results demonstrate that APOE4 causes mitochondrial dysfunction and MC impairment, which may contribute to retinal pathology in AD. MitoQ restored mitochondrial health and Kir4.1 expression in APOE4-expressing rMC-1, suggesting targeting mitochondria may offer a promising therapeutic strategy for AD.},
}

Animals
*Potassium Channels, Inwardly Rectifying/metabolism/genetics
*Alzheimer Disease/metabolism/genetics/pathology
*Ependymoglial Cells/metabolism/pathology/drug effects
*Apolipoprotein E4/genetics/metabolism
Kcnj10 Channel
Disease Models, Animal
Mice, Transgenic
Rats
Mice
Mitochondria/metabolism
Oxidative Stress/physiology
Retina/metabolism/pathology
Mice, Inbred C57BL

@article {pmid41501928,
year = {2026},
author = {Li, E and Song, F and Coppola, Q and Yack, L and Le, M and Javed, S and Pandher, N and Prufer, I and Mayzel, O and Heuer, HH and Koestler, M and Miller, BL and Boxer, AL and Vandevrede, L and Grinberg, LT and Walsh, CM and Neylan, TC},
title = {Treatment of Disturbed Sleep in Progressive Supranuclear Palsy: a randomized, remote, double-blinded, 6-week cross-over design study protocol comparing zolpidem, suvorexant, and placebo.},
journal = {Trials},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13063-025-09382-9},
pmid = {41501928},
issn = {1745-6215},
support = {A130340//Rainwater Charitable Foundation/ ; },
abstract = {BACKGROUND: Prior research identified profound sleep disruption in progressive supranuclear palsy (PSP). The hypothalamus and brainstem, areas that help regulate sleep/wake patterns, are among the earliest affected brain regions in PSP disease progression. Comparing polysomnography and quantitative-neuropathology metrics, we identified relative sparing of wake-promoting nuclei in PSP compared to Alzheimer's disease, though PSP had more disrupted sleep. It led to the hypothesis that PSP patients have hyperinsomnia (or hyposomnia, little sleep) due to degeneration of sleep nuclei with a preservation of sleep neurons, causing a system unbalance. A higher neuronal count of wake-promoting nuclei was associated with greater nocturnal wake, regardless of disease. Specifically, orexinergic wake-promoting neurons in the lateral hypothalamus, previously described as the sleep-on/off switch, are relatively spared in PSP. Thus, we hypothesized that an orexinergic antagonist may be more effective in treating sleep/wake issues in PSP than other hypnotic medications. This study protocol was established to test the safety and efficacy of an orexinergic antagonist (suvorexant) targeting the wake-promoting system and contrasts it with a GABAergic receptor agonist (zolpidem) targeting sleep-promoting systems and placebo.

METHODS: This is a remote clinical trial, designed as a double-blind, cross-over, within-subject 6-week trial, with 3 one-week-long conditions, separated by 1-week washout periods. The order of the 3 regimens is randomized and counterbalanced: placebo (microcrystalline cellulose), 15 mg/day suvorexant, 5 mg/day zolpidem. Participants are recruited from doctor and study referrals, registries, and support groups. Once onboarded, the trial coordinator maintains communication with the participant/caregiver throughout the 6 weeks. Assessments include neurological interviews, cognitive testing, and subjective questionnaire packets. Sleep and circadian rhythms are assessed through ambulatory EEG and actigraphy monitoring devices worn by the participant throughout the trial.

DISCUSSION: The study design aims to reduce participant and caregiver burden, while improving accessibility to such a study. Administering a remote clinical trial for a rare disease, however, creates unique issues that would otherwise be absent from in-person studies. Particularly, a symptom rather than disease-modifying trial is challenging to recruit for when potential disease-modifying therapeutics are available. Needing to coordinate with non-associated medical offices to attain medical records or prescriptions can cause frustrations for the potential participant, medical office, and study team. In recruitment, onboarding, and trial maintenance, this study design relies on consistent communication to support participant enrollment and satisfaction.

TRIAL REGISTRATION: Treatment of Disturbed Sleep in Progressive Supranuclear Palsy (PSP); NCT04014389. Registered on June 2, 2019.},
}

@article {pmid41501420,
year = {2026},
author = {Wang, XY and Zhou, WS and Gaur, U and Zhen, XC and Zheng, WH},
title = {Sigma-1 receptor positive allosteric modulator promotes neuronal survival and improves cognitive deficits in AD mice via sigma-1 receptor/ERK pathway.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {41501420},
issn = {1745-7254},
abstract = {The sigma-1 receptor is an important new therapeutic drug target for Alzheimer's disease (AD). Here, we reported that SOMCL-668, a novel selective and potent sigma-1 receptor allosteric modulator, is neuroprotective in AD both in vitro and in vivo. SOMCL-668 promoted PC12 cells against Aβ-induced intracellular reactive oxygen species (ROS) accumulation, mitochondrial membrane potential hyperpolarization and neuronal apoptosis. Similar results were obtained in SH-SY5Y and primary cortical culture neurons. The mechanistic study showed that SOMCL-668 stimulated the phosphorylation of ERK and CREB, while pharmacological inhibition or knockout of ERK via CRISPR-Cas9 attenuated its protective effects. Further studies with the sigma-1 receptor agonists/antagonists and knockout of sigma-1 receptor via CRISPR-Cas9 indicated that the sigma-1 receptor is essential for the effect of SOMCL-668. In 3xTg-AD mice, SOMCL-668 improved the learning and memory deficits, inhibited neuronal apoptosis and oxidative stress, reduced Aβ deposition and tau protein phosphorylation via ERK/CREB pathway. Moreover, pretreatment with sigma-1 receptor antagonist BD1047 blocked the effect of SOMCL-668. These results demonstrated that SOMCL-668 provides neuroprotection in AD and its effect is mediated by the sigma-1 receptor/ERK/CREB pathway. Our findings support that SOMCL-668 can be utilized as a potential drug for the prevention and treatment of Alzheimer's disease.},
}

@article {pmid41499862,
year = {2025},
author = {Nadais, A and Castro, C and Martins, I and Trigo, D and Nunes, C and Henriques, AG and de Lourdes Pereira, M and da Cruz E Silva, OAB},
title = {Nanoparticle-mediated Zn delivery impacts neural protein phosphatase activity.},
journal = {Biomaterials advances},
volume = {182},
number = {},
pages = {214675},
doi = {10.1016/j.bioadv.2025.214675},
pmid = {41499862},
issn = {2772-9508},
abstract = {In recent years, the use of nanoparticles (NPs) in diagnosis and treatment of different disorders has been a matter of intensive research. Due to their physical and chemical properties, zinc oxide nanoparticles (ZnO NP) have been explored in a range of biological applications, including cancer and neurological diseases. Regarding the latter, while some studies report protective effects of ZnO NP in cultured cells and animal models, others indicate that these NPs have a harmful impact on the brain, such as promoting oxidative stress and cell death. Previous results from our group have suggested beneficial effects for zinc (Zn) cations in both modulating protein aggregation and on Alzheimer's disease (AD) pathology. In this context, the effect of encapsulated Zn as a nanoparticle on protein aggregation and its influence on protein phosphorylation events associated with AD were explored. The results herein presented show that ZnO NP contributed to a decrease in protein aggregation in neuronal cells. However, these NPs were also found to decrease PP1 and PP2A activity, potentially contributing to increased phosphorylation of tau and APP, which are AD pathology hallmarks. In conclusion, while the use of NPs as a Zn delivery system may offer benefits by reducing aggregate formation, they also appear to induce undesired molecular changes, like those observed in AD. Therefore, a holistic approach should be incorporated as we move forward in this research line, as their effects on distinct cellular processes may be dual edged.},
}

@article {pmid41499318,
year = {2026},
author = {Melrose, J},
title = {Roles for Electrochemical Proton Gradients in Mitochondrial Energy Production and Neurosensory Processes in Health and Disease.},
journal = {Developmental neurobiology},
volume = {86},
number = {1},
pages = {e70006},
doi = {10.1002/dneu.70006},
pmid = {41499318},
issn = {1932-846X},
support = {//Melrose Personal Research Fund/ ; },
mesh = {Humans ; Animals ; *Mitochondria/metabolism ; *Energy Metabolism/physiology ; *Protons ; *Proton-Motive Force/physiology ; *Nervous System Diseases/metabolism ; Oxidative Stress/physiology ; },
abstract = {This study reviews the roles of proton electrochemical gradients in ubiquitous mitochondrial energy production systems in cellular activation and functions in neurosensory signaling. Proton electrochemical gradients crucially shaped the evolution of life. The emergence of the proton-motive force in mitochondria was fundamental in energy production and central to the function of eukaryotic cells. Dysfunctional mitochondria, however, result in impaired formation of proton gradients and a wide spectrum of diseases. This is particularly prominent in tissues with high energetic demands, such as muscle and nervous tissues. Oxidant stress generated by dysfunctional proton conductance in the brain results in Alzheimer's and Parkinson's disease, muscular sclerosis, amyotrophic sclerosis, and Huntington's disease. In these disorders, oxidative stress, protein misfolding, and neuroinflammation lead to dysfunctional neuronal activity, neuronal damage, and death. Advancements in nanozyme-engineered synthetic enzymes offer a promising innovative approach to the treatment of these disorders. Nanozymes target proton conductance and the oxidant species they generate, scavenging oxygen free radicals and restoring redox balance, and offer neuronal protection and functional recovery of brain tissues. Neural injury and associated neurological diseases affect almost 1 billion people globally, so there is a clear need to develop effective methods that stimulate neural repair and regeneration. Glycosaminoglycans with proton capture and transport properties regulate intercellular signaling processes, synaptic functions, and cellular communication. Electroconductive hydrogels are showing impressive results in neural repair and regeneration. Glycosaminoglycans, particularly keratan sulfate, show useful electroconductive proton capture and transport properties, suggesting they may be worth evaluation in such procedures.},
}

Humans
Animals
*Mitochondria/metabolism
*Energy Metabolism/physiology
*Protons
*Proton-Motive Force/physiology
*Nervous System Diseases/metabolism
Oxidative Stress/physiology

@article {pmid41499301,
year = {2026},
author = {Mohasel-Roodi, M and Nozari, M and Shamsara, A and Basiri, M and Mirzaie, V and Baghalishahi, M},
title = {Effects of Dexmedetomidine on the Behavioral Outcomes in Streptozotocin-Induced Alzheimer's Disease Rats.},
journal = {Brain and behavior},
volume = {16},
number = {1},
pages = {e71196},
pmid = {41499301},
issn = {2162-3279},
support = {402000357//Kerman Neuroscience Research Center, Kerman University of Medical Sciences/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced ; *Dexmedetomidine/pharmacology/administration & dosage ; Streptozocin/pharmacology ; Rats, Wistar ; Male ; Rats ; *Behavior, Animal/drug effects ; Anxiety/drug therapy ; Maze Learning/drug effects ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; *Adrenergic alpha-2 Receptor Agonists/pharmacology ; Cognitive Dysfunction/drug therapy ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive and prevalent neurodegenerative disorder characterized by progressive cognitive decline and memory impairment. Intracerebroventricular (ICV) administration of streptozotocin (STZ) in rodents recapitulates key features of sporadic AD, including brain insulin resistance and oxidative stress. Dexmedetomidine (Dex), a highly selective α2-adrenergic receptor agonist, has demonstrated neuroprotective and anti-inflammatory properties, suggesting its potential utility as a therapeutic approach for AD.

METHODS: Seventy adult male Wistar rats were randomly allocated to seven experimental groups: Control, Sham, STZ, Sham + Dex (25 µg/kg), and STZ + Dex (25, 50, 100 µg/kg). Cognitive performance and anxiety-like behaviors were evaluated using the open-field test (OFT), elevated plus maze (EPM), Y-maze test, and Morris water maze (MWM).

RESULTS: In the Y-maze, STZ-treated rats exhibited significant reductions in spontaneous alternation behavior (p = 0.002), which were significantly reversed by Dex (25 µg/kg, p = 0.002). In the MWM, the STZ administration resulted in prolonged escape latencies and increased path lengths compared with Control animals (p < 0.05). Treatment with Dex (25 µg/kg) significantly improved spatial learning and memory retention (p < 0.05). No significant differences were observed in locomotor activity and anxiety-related behaviors in the OFT or EPM.

CONCLUSIONS: These findings indicate that Dex at 25 µg/kg attenuates STZ-induced cognitive deficits, likely through neuroprotective and anti-inflammatory mechanisms. The results highlight Dex as a promising candidate for AD therapy, though further research is required to elucidate its underlying molecular pathways. The study supports the potential repurposing of Dex for neurodegenerative disorders.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced
*Dexmedetomidine/pharmacology/administration & dosage
Streptozocin/pharmacology
Rats, Wistar
Male
Rats
*Behavior, Animal/drug effects
Anxiety/drug therapy
Maze Learning/drug effects
Disease Models, Animal
Neuroprotective Agents/pharmacology
*Adrenergic alpha-2 Receptor Agonists/pharmacology
Cognitive Dysfunction/drug therapy

@article {pmid41498900,
year = {2026},
author = {Lin, ZY and Cai, LL and Lin, JX and Zheng, GY},
title = {Tiaobu Xinshen Recipe Improves Cognitive Deficits by Alleviating Synaptic Ultrastructure Degradation and Reducing Amyloid β in Transgenic Mice of Alzheimer's Disease.},
journal = {Chinese journal of integrative medicine},
volume = {},
number = {},
pages = {},
pmid = {41498900},
issn = {1993-0402},
abstract = {OBJECTIVE: To investigate the effect of Tiaobu Xinshen Recipe (TXR) on cognitive function of 5xFAD transgenic mice and explore the potential mechanisms.

METHODS: Six-month-old male wild-type (WT) mice and 5xFAD transgenic mice were randomly divided into vehicle (0.9% NaCl), TXR (granules, 4.18 g/kg) and donepezil (0.625 mg/kg) groups using a random number table, respectively, which were given intragastric administration once a day for 60 d. Spatial learning and memory performance was tested with modified Morris water maze (MMWM) test. Synaptic ultrastructure in the hippocampal CA1 region was observed by transmission electron microscopy. The levels of amyloid β (Aβ), the major amyloid precursor protein (APP)-cleaving enzymes and Aβ-degrading enzymes including β-secretase, α-secretase, neprilysin (NEP) and insulin-degrading enzyme (IDE), were detected by immunohistochemistry staining and Western blot, respectively.

RESULTS: In MMWM test, when compared with the 5xFAD-vehicle group, 5xFAD-TXR group demonstrated a significantly shorter escape latency to the platform and increased number of platform crossings and time spent in target quadrant (P<0.05 or P<0.01). The ultrastructure of synapse in the hippocampal CA1 region of mice in the 5xFAD-TXR group was significantly changed, including increased numbers of mitochondria and synaptic vesicles, intact synaptic membrane, and thickened postsynaptic density. The Aβ load was markedly decreased in the cerebral cortex and hippocampus CA1 subregion of TXR-treated 5xFAD mice (P<0.05). TXR treatment decreased APP levels and increased IDE expression in brains of 5xFAD mice (P<0.01). However, TXR treatment had no effect on α- and β-secretase, and NEP in 5xFAD mice (P>0.05).

CONCLUSION: TXR improves cognitive dysfunction in 5xFAD mice by alleviating synaptic ultrastructure degradation and reducing Aβ.},
}

@article {pmid41498480,
year = {2026},
author = {Goodall, LS and Lennon, MJ and Sachdev, PS and Gorelick, PB and Kovacic, JC and Samaras, K},
title = {Current and Emerging Therapeutic Approaches for Vascular Cognitive Impairment and Dementia.},
journal = {Journal of the American College of Cardiology},
volume = {87},
number = {1},
pages = {77-100},
doi = {10.1016/j.jacc.2025.09.1502},
pmid = {41498480},
issn = {1558-3597},
mesh = {Humans ; *Dementia, Vascular/therapy/prevention & control ; *Cognitive Dysfunction/therapy ; },
abstract = {Cardiovascular risk factors contribute to the majority of dementia cases, with about 20% directly attributable to vascular cognitive impairment and dementia (VCID). VCID treatment developments have been slow compared with Alzheimer's disease (AD), which now has several FDA-approved symptom- and disease-modifying agents. In the second part of this JACC Seminar Series, advances and new perspectives on the management and prevention of VCID are reviewed. There is reasonable evidence that cognitive enhancers (donepezil, galantamine, and memantine) modestly improve cognition in vascular dementia (VaD), the most severe form of VCID, especially if there is associated AD pathology. Antidepressants may benefit those with depression and stroke, but they have poor efficacy in those with depression and VaD alone. Behavioral, social, and environmental interventions are first-line therapies for managing VCID-associated agitation and psychosis. Second-line antipsychotics have not been trialed in those with VaD alone, but are beneficial where AD and VaD co-exist, with risperidone and quetiapine effective in reducing psychosis and agitation. Primary prevention of VCID includes identifying and managing cardiometabolic risk factors along with manifestations of covert cerebrovascular disease. Both primary and secondary VCID prevention involve management of cardiovascular risks, specifically hypertension, diabetes mellitus, smoking, atrial fibrillation, obesity, and sedentariness. Management of vascular risk factors may moderately reduce the risk of incident cognitive impairment. Novel interventions currently being evaluated in clinical trials are discussed. The discovery and utilization of VCID and AD biomarkers will enhance the specificity and effectiveness of interventions such that a precision-medicine approach to disease-specific medical therapy may be taken.},
}

Humans
*Dementia, Vascular/therapy/prevention & control
*Cognitive Dysfunction/therapy

@article {pmid41498479,
year = {2026},
author = {Sachdev, PS and Bentvelzen, AC and Gustafson, D and Hansra, GK and Hosoki, S and Jiang, J and Lennon, MJ and Moro, MA and Saks, DG and Samaras, K and Kovacic, JC and Kalaria, R},
title = {Vascular Cognitive Impairment and Dementia: Clinical Features, Neuropathology, and Biomarkers.},
journal = {Journal of the American College of Cardiology},
volume = {87},
number = {1},
pages = {52-76},
doi = {10.1016/j.jacc.2025.11.008},
pmid = {41498479},
issn = {1558-3597},
mesh = {Humans ; Biomarkers/metabolism ; *Dementia, Vascular/diagnosis/pathology ; *Cognitive Dysfunction/diagnosis/etiology ; Risk Factors ; *Brain/pathology ; },
abstract = {Vascular cognitive impairment and dementia (VCID), ie, cognitive impairment secondary to cerebrovascular disease (CeVD), is the second most common form of dementia after Alzheimer's disease (AD), accounting for 15% to 20% of all cases. CeVD, in fact, contributes to dementia alongside other neuropathologies in up to 75% of dementia cases. CeVD and AD not only frequently co-occur in the brain, but they may also interact, and some VCID risk factors (midlife hypertension and diabetes) also increase AD risk. Because CeVD and cardiovascular disease share risk factors and pathophysiology, the cardiovascular clinician is likely to encounter both in the clinic. Moreover, common cardiac disorders, such as atrial fibrillation, heart failure, acute coronary syndrome, and valvular disease, increase VCID risk. There have been recent developments in the diagnostic criteria for VCID, with advances in risk biomarkers, treatment, and prevention of cognitive impairment and dementia. The diagnosis of VCID is a 2-step process, with the initial identification of a cognitive syndrome followed by the establishment of a predominantly vascular etiology, guided by clinical history and examination and substantiated by neuroimaging, preferably magnetic resonance imaging. Clinical presentations include an acute onset, a stepwise decline, a fluctuating course if caused by multiple strokes, or a gradual slow progression if attributable to cerebral small vessel disease. Cognitive deficits can be found in several domains, such as information-processing speed, attention, executive function, and emotional lability, sometimes referred to as the subcortical syndrome, often seen in the early stages of VCID without cortical infarcts. The diagnosis is supported by the identification of large and small infarcts, lacunes, white matter hyperintensities, dilated perivascular spaces and cerebral microbleeds using magnetic resonance imaging. This part 1 of a 2-part JACC review series describes the clinical features, pathophysiology, and biomarkers of VCID for cardiovascular clinicians who have a critical role in its early identification, management, and prevention in their patients.},
}

Humans
Biomarkers/metabolism
*Dementia, Vascular/diagnosis/pathology
*Cognitive Dysfunction/diagnosis/etiology
Risk Factors
*Brain/pathology

@article {pmid41496378,
year = {2026},
author = {Zhao, Y and Lu, H and Jiang, X},
title = {Advance in neuroprotective effects of proanthocyanidins (PCs): Structure, absorption, bioactivities, mechanism, and perspectives.},
journal = {Pharmacological research},
volume = {223},
number = {},
pages = {108082},
doi = {10.1016/j.phrs.2025.108082},
pmid = {41496378},
issn = {1096-1186},
mesh = {*Proanthocyanidins/chemistry/pharmacology/pharmacokinetics/therapeutic use ; Humans ; *Neuroprotective Agents/chemistry/pharmacokinetics/pharmacology/therapeutic use ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; Gastrointestinal Microbiome/drug effects ; },
abstract = {With the global population growing and aging, along with increasing environmental, metabolic, and lifestyle-related risk factors, the worldwide incidence of stroke, Alzheimer's disease (AD) and other dementias, meningitis, and other neurological disorders-along with associated mortality-has risen significantly. Proanthocyanidins (PCs), which are oligomers and polymers of flavan-3-ols, are widely distributed across the plant kingdom, including in grape seeds, cinnamon, apples, cranberries, lotus seeds, and pine bark. They represent the second most abundant class of polyphenols in nature, after lignin. A substantial body of preclinical evidence indicates that PCs exert significant neuroprotective effects through multiple mechanisms. This review provides a systematic overview of the sources, structural characteristics, and bioavailability of PCs, with a focus on their pharmacological mechanisms in nervous system disease. Specifically, it examines their roles in regulating oxidative stress, neuroinflammation, protein homeostasis, apoptosis, autophagy, and key signaling pathways, including Nrf2/HO-1, CREB/BDNF, PI3K/Akt, MAPK, and NF-κB. Furthermore, this review systematically summarized the distinct structural forms of PCs, including monomers, dimers, trimers, and polymers, and explores their structure-activity relationships (SARs) in modulating the gut-brain axis. Additionally, recent advances in PCS-based nano-delivery systems and clinical studies related to neurological disorders are summarized. Growing evidence indicates that microbial metabolism in the gut serves as a key mechanism underlying their neuroprotective effects. Finally, the potential applications of PCs as promising dietary supplements or therapeutic agents for the prevention and treatment of nervous system diseases are discussed, along with existing challenges and future perspectives.},
}

*Proanthocyanidins/chemistry/pharmacology/pharmacokinetics/therapeutic use
Humans
*Neuroprotective Agents/chemistry/pharmacokinetics/pharmacology/therapeutic use
Animals
*Nervous System Diseases/drug therapy/metabolism
Gastrointestinal Microbiome/drug effects

@article {pmid41496364,
year = {2026},
author = {Facchinetti, R and Valenza, M and Ciarla, C and Steardo, L and Serviddio, G and Palombelli, G and Verkhratsky, A and Steardo, L and Canese, R and Cassano, T and Scuderi, C},
title = {Ultramicronized palmitoylethanolamide restores astrocyte-neuron metabolic coupling and Klotho/FGF21 signaling in a triple-transgenic mouse model of Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {118965},
doi = {10.1016/j.biopha.2025.118965},
pmid = {41496364},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD), a multifactorial neurodegenerative disorder, is characterized by metabolic deficiency, neuroinflammation, and synaptic impairment. Astrocyte-neuron metabolic coupling regulates cerebral energy homeostasis through key metabolites such as lactate, glutamate, and taurine. We investigated the therapeutic potential of ultramicronized-palmitoylethanolamide (um-PEA) in restoring the homeostasis of these metabolites in the triple transgenic (3 ×Tg-AD) mouse model of AD. Using in vivo magnetic resonance imaging and spectroscopy (MRI/MRS) combined with Western blot, we evaluated the effects of chronic um-PEA treatment on lactate-glutamate dynamics and taurine metabolism in the frontal cortex and hippocampus of 6- and 12 month-old mice. Our findings demonstrate that 3 ×Tg-AD mice exhibit lactate accumulation, glutamine/glutamate imbalance, and taurine depletion, alongside reduced expression of metabolic processes regulators such as FGF21, Klotho, and insulin receptor. Treatment with um-PEA successfully restored these metabolic changes by: (i) rebalancing lactate-glutamate metabolism, (ii) increasing taurine synthesis and transport, (iii) upregulating FGF21, Klotho, and insulin receptor expression, and (iv) modulating the metalloproteases ADAM10 and ADAM17, which regulate Klotho processing. These results identify um-PEA as a promising metabolic modulator capable of mitigating AD-related neurodegenerative processes. By targeting astrocyte-neuron metabolism and enhancing both FGF21 and Klotho pathways, um-PEA holds significant potential as an adjunctive therapeutic strategy for AD.},
}

@article {pmid41496361,
year = {2026},
author = {Huzián, O and Nagy, LI and Hackler, L and Knapp, L and Kocsis, ÁK and Szöts, I and Tamás, G and Puskás, LG and Molnár, G},
title = {Novel drug candidate binds to delta subunit containing GABAA receptors and improves spatial memory.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {118970},
doi = {10.1016/j.biopha.2026.118970},
pmid = {41496361},
issn = {1950-6007},
abstract = {The hydroxyquinoline derivative Q134R is a promising drug candidate for the treatment of Alzheimer's disease with cytoprotective and cognition-enhancing properties. Radioligand binding assays showed that Q134R reduced [[35]S]TBPS binding, consistent with modulation of the picrotoxin site or conformational states that regulate TBPS accessibility. Electrophysiological recordings in mouse brain slices revealed that Q134R significantly increased tonic inhibitory currents in cortical neurogliaform and dentate gyrus granule cells, both known to express delta subunit-containing GABAA receptors. This effect was abolished in mice deficient in the GABAA delta subunit confirming the delta subunit dependency of Q134R's action. Furthermore, in a scopolamine-induced amnesia model, Q134R treatment significantly improved spatial memory performance in wild-type mice, but not in mice lacking in the delta subunit. These results suggest that Q134R enhances tonic inhibition through delta subunit-containing GABAA receptors, which may contribute to the modulation of memory processes and serve as a protective mechanism in early-stage neurodegenerations. These receptor-mediated effects likely contribute to its broader therapeutic efficacy and may complement its previously reported interactions with signaling pathways such as NFAT and HIF-1.},
}

@article {pmid41495612,
year = {2025},
author = {Yang, G and Zhu, D and Zhang, K},
title = {Nose-brain axis: A bridge from the nasal cavity to the central nervous system.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01770},
pmid = {41495612},
issn = {1673-5374},
abstract = {The nose-brain axis is a direct pathway linking the nasal cavity to the central nervous system. Odors, as well as exogenous substances such as pathogens, inflammatory mediators, and drugs, can enter the cranial cavity through pathways including the olfactory nerve, trigeminal nerve, and humoral routes, thereby enabling signal transmission and material exchange from the peripheral nasal cavity to the central nervous system. In recent years, advances in multimodal visualization technologies have made it possible to dynamically monitor the nose-brain axis from the molecular level to the tissue level, providing important means for revealing its functional characteristics and pathological changes. Owing to the existence of the nose-brain axis, nasal inflammation can, through neuro-immune interactions, activate central microglia and astrocytes and induce neuroinflammation, thus promoting the onset and progression of central nervous system diseases. In addition, the nose-brain axis offers a unique route for the treatment of central nervous system disorders. Intranasal drug delivery can bypass the blood-brain barrier, act directly on the central nervous system, increase intracranial drug bioavailability, and produce rapid effects, providing new ideas for treating cross-system diseases. This review systematically summarizes the anatomical pathways of the nose-brain axis, visualization monitoring technologies, and mechanisms by which nasal inflammation affects the central nervous system. It also reviews advances in intranasal drug delivery for emotional disorders, migraine, Parkinson's disease, and Alzheimer's disease, aiming to provide new strategies for studying the mechanisms by which nasal inflammation influences the central nervous system and for cross-system targeted therapy.},
}

@article {pmid41495456,
year = {2026},
author = {Chen, Z and Bi, S and Shan, Y and Wang, F and Wang, Y and Qi, Z and Wang, T and Li, X and Li, S and Xiao, H and Wang, S and Cui, B and Qi, Z and Han, Y and Yan, S and Lu, J and , },
title = {MRI-to-PET synthesis via deep learning for amyloid-β quantification in Alzheimer's disease.},
journal = {European radiology},
volume = {},
number = {},
pages = {},
pmid = {41495456},
issn = {1432-1084},
support = {82102010//National Natural Science Foundation of China/ ; 82394434//National Natural Science Foundation of China/ ; },
abstract = {OBJECTIVES: Amyloid-β (Aβ) PET is crucial for diagnosing and monitoring Alzheimer's disease (AD), but its high cost and radiation exposure limit its use. Deep learning techniques make it possible to generate PET from structured MRI data. In this study, we built a deep learning model to generate 3D synthetic Aβ PET images from structural MRI.

MATERIALS AND METHODS: The generative adversarial network with share parameters (ShareGAN) model was trained and tested with 1009 Aβ PET and paired MRI images from the Alzheimer's Disease Neuroimaging Initiative database and three tertiary hospitals in China. The 3D synthetic model operates on the whole volume rather than 2D image slices, realistically reproducing minor discrepancies between neighboring image planes. ShareGAN-based PET images were evaluated using quantitative metrics and visual assessment. Pearson correlation coefficient and Bland-Altman analyses were used to assess the correlation and concordance between synthetic and real PETs.

RESULTS: 3D Synthetic PET images showed high similarity and correlation with real Aβ PET in external testing sets 1 and 2 in terms of structural similarity index measure (0.898, 0.899), peak signal-to-noise ratio (34.690, 34.725), mean absolute error (0.031, 0.031), and standardized uptake value ratio (R = 0.758, 0.828). The diagnostic accuracy of PET positive or negative status in external testing sets 1 and 2 was 88.5% and 89.4%, respectively.

CONCLUSION: MRI-based 3D synthetic Aβ PET images can serve as a safe and cost-effective tool for Aβ status visualization, providing PET-eligible patients with Aβ PET-like imaging analysis to guide subsequent real Aβ PET scans.

KEY POINTS: Question Amyloid-β (Aβ) PET limitations (high cost, radiation, limited access) hinder early Alzheimer's disease (AD) detection. Clinical practice urgently requires a suitable supplementary method for Aβ pathology assessment. Findings AI-synthesized 3D Synthetic Aβ PET from structural MRI demonstrated strong consistency with real PET and effectively triaged high-risk patients for confirmatory scans. Clinical relevance This non-invasive, cost-effective method holds the promise of enabling wider Aβ pathology screening, reduces unnecessary PET scans, and supports early intervention in resource-limited settings, while preserving diagnostic rigor for treatment decisions.},
}

@article {pmid41494605,
year = {2026},
author = {Viqueira, L and Navarro, E and Negredo, P and Bernal, JA and Rodríguez-Franco, MI and Tortosa, E and López, MG},
title = {Long-term NRF2-driven microglial repopulation mitigates microgliosis, neuronal loss and cognitive deficits in tauopathy.},
journal = {Brain, behavior, and immunity},
volume = {133},
number = {},
pages = {106253},
doi = {10.1016/j.bbi.2026.106253},
pmid = {41494605},
issn = {1090-2139},
abstract = {Tauopathies, including Alzheimer's disease, feature chronic microglial reactivity that drives neuroinflammation and disease progression. Pharmacological microglial depletion and subsequent repopulation using colony-stimulating factor 1 receptor inhibitors have emerged as a potential therapeutic strategy to reprogram dysfunctional microglia. Despite promising short-term results, the long-term efficacy and pharmacological modulation of repopulated microglia remain poorly understood. Here, we investigated the long-term effects of microglial repopulation alone and in combination with the activation of the cytoprotective nuclear factor erythroid 2 p45-related factor 2 (NRF2) in an in vivo AAV-hTau[P301L] induced model. Integrating different behavioural, immunohistological and transcriptomic analysis, we evaluated cognitive function, tau pathology, neuronal survival and glial reactivity. We found that, whereas microglial repopulation alone did not significantly affect disease progression, NRF2-driven microglial replenishment sustained cognitive function, prevented hippocampal neuronal loss and restored microglial phenotype. Transcriptomic analyses further revealed that the combined treatment modulated tau- associated mitochondrial gene expression changes. These results highlight the importance of shaping the fate of self-renewed microglia and propose NRF2-mediated microglial repopulation as a potential pharmacological strategy for the treatment of tauopathies.},
}

@article {pmid41493713,
year = {2026},
author = {Hoveizi, E and Doraghi, K and Rostami, E},
title = {Fabrication and Characterization of Resveratrol-Loaded Solid Lipid Nanoparticles: Evaluation of Neuroprotective, Neurobehavioral, and Molecular Outcomes.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {346},
pmid = {41493713},
issn = {1559-1182},
support = {SCU.SB1403.12464//Shahid Chamran University of Ahvaz/ ; },
mesh = {*Resveratrol/pharmacology/administration & dosage/chemistry ; Animals ; *Nanoparticles/chemistry/ultrastructure ; *Neuroprotective Agents/pharmacology/administration & dosage/chemistry ; Male ; Rats ; Oxidative Stress/drug effects ; *Lipids/chemistry ; Antioxidants/pharmacology ; Neural Stem Cells/drug effects/metabolism ; *Behavior, Animal/drug effects ; Rats, Sprague-Dawley ; Interleukin-1beta/metabolism ; Memory/drug effects ; },
abstract = {Neurodegenerative processes involve oxidative stress, inflammation, and disrupted signaling, which contribute to cognitive decline. Resveratrol offers neuroprotection but suffers from poor solubility and bioavailability. Solid lipid nanoparticles (SLNs) can improve solubility, stability, and neural targeting, thereby enhancing efficacy. This study investigates whether SLN/resveratrol treatment modulates neuroprotective targets (HSP70, IL-1β) and antioxidant enzymes (CAT, GPX, SOD) in vitro and whether it improves inactive avoidance memory in an animal model. SLNs were produced by melting tripalmitin and palmitic acid, adding resveratrol, Tween, and butanol, then combining with water and stirring for 1 day. The resulting formulations were characterized using FTIR, electron microscopy, and DLS. Neural stem cells (NSCs) were treated with SLNs, resveratrol, and SLN/resveratrol, and the expression of oxidative stress enzymes, HSP70, and IL-1β was analyzed. In vivo, a passive avoidance memory model was induced in rats via electrical destruction of the nucleus basalis of Meynert. Molecular analysis showed that resveratrol increased HSP70 expression by 3.1-fold and significantly decreased IL-1β levels. SLN treatment had no notable effect on these genes, but the SLN/resveratrol increased HSP70 expression by fourfold and significantly reduced IL-1β. Resveratrol significantly upregulated the antioxidant enzymes CAT and GPX, whereas SLNs alone had no effect. The SLN/resveratrol also markedly enhanced CAT and GPX levels. Behavioral tests demonstrated that the SLN/resveratrol treatment improved passive avoidance memory in the Alzheimer's model. Collectively, these results indicate that SLN/resveratrol robustly enhances neuroprotection by modulating signaling pathways, reducing oxidative stress, and improving memory, with the SLN delivery system potentially increasing bioavailability and neural exposure.},
}

*Resveratrol/pharmacology/administration & dosage/chemistry
Animals
*Nanoparticles/chemistry/ultrastructure
*Neuroprotective Agents/pharmacology/administration & dosage/chemistry
Male
Rats
Oxidative Stress/drug effects
*Lipids/chemistry
Antioxidants/pharmacology
Neural Stem Cells/drug effects/metabolism
*Behavior, Animal/drug effects
Rats, Sprague-Dawley
Interleukin-1beta/metabolism
Memory/drug effects

@article {pmid41493675,
year = {2026},
author = {Usman, AS and Manoharan, SD and Che Mohd Nassir, CMN and Abdul Hamid, H and Hein, ZM and Norazit, A and Murthy, J and Zainol, M and Kamaruzzaman, MA and Chiroma, SM and Mustapha, M and Mohd Moklas, MA and Mehat, MZ},
title = {Neuroprotective Effects of Ficus deltoidea in Alzheimer's Disease-Like Rat Model: Insights from Behavior, Histology, and Amyloid Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {345},
pmid = {41493675},
issn = {1559-1182},
support = {(FRGS/1/2021/SKK0/UPM/02/15)//the Ministry of Higher Education under the Fundamental Research Grant Scheme/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism ; *Ficus/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Rats, Wistar ; Disease Models, Animal ; *Plant Extracts/pharmacology/therapeutic use ; Plaque, Amyloid/pathology/drug therapy ; Amyloid beta-Peptides/metabolism ; Hippocampus/pathology/drug effects/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Maze Learning/drug effects ; Rats ; *Behavior, Animal/drug effects ; Spatial Memory/drug effects ; Aspartic Acid Endopeptidases/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and accumulation of amyloid-β (Aβ) plaques. While current treatments offer limited efficacy, medicinal plants such as Ficus deltoidea (FD), a traditional remedy, have shown promise due to their neuroprotective and anti-inflammatory properties. An AD-like phenotype was induced in male Wistar rats using D-galactose and aluminum chloride over 70 days. FD extract was administered orally at 50, 100, and 200 mg/kg. Spatial memory was evaluated using the T-maze test. Histological analyses of the hippocampi's Cornu Ammonis 1 and 3 (CA1 and CA3) regions were conducted via hematoxylin and eosin (H&E) staining, and Aβ plaques deposition was assessed with Congo red. Enzyme-linked immunosorbent assay (ELISA) was used to quantify hippocampal levels of Aβ (1-42) and β-secretase-1 (BACE-1). FD treatment significantly enhanced spatial memory, preserved pyramidal neuron integrity in CA1 and CA3, and reduced amyloid plaque formation. Biochemically, FD markedly decreased hippocampal Aβ (1-42) and BACE-1 concentrations in a dose-dependent manner. Thus, FD exhibits multi-target neuroprotective effects in an AD-like model, potentially via modulation of amyloidogenic pathways. Further studies are warranted to explore its mechanisms and therapeutic potential in other brain regions implicated in AD.},
}

Animals
*Alzheimer Disease/pathology/drug therapy/metabolism
*Ficus/chemistry
*Neuroprotective Agents/pharmacology/therapeutic use
Male
Rats, Wistar
Disease Models, Animal
*Plant Extracts/pharmacology/therapeutic use
Plaque, Amyloid/pathology/drug therapy
Amyloid beta-Peptides/metabolism
Hippocampus/pathology/drug effects/metabolism
Amyloid Precursor Protein Secretases/metabolism
Maze Learning/drug effects
Rats
*Behavior, Animal/drug effects
Spatial Memory/drug effects
Aspartic Acid Endopeptidases/metabolism

@article {pmid41493656,
year = {2026},
author = {Cicero, CE and Angelini, L and Abbadessa, G and Bruno, M and Fiume, G and Nucera, B and Ornello, R and Arabia, G and Giuliano, L and Guarnieri, B and Lugaresi, A and Perani, D and Sacco, S and Tassorelli, C and Nicoletti, A and Pellecchia, MT and , },
title = {Sex and gender-related differences in neurological diseases: current challenges and recommendations for clinical practice.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {1},
pages = {108},
pmid = {41493656},
issn = {1590-3478},
mesh = {Humans ; *Nervous System Diseases/therapy/epidemiology ; Female ; *Sex Characteristics ; Male ; Pregnancy ; },
abstract = {Neurological diseases include a large variety of conditions ranging from inflammatory, vascular and neurodegenerative disorders to epilepsy and headache. The impact of sex and gender on various aspects of these conditions (epidemiology, risk factors, pathophysiology, clinical features, treatment, and management of pregnancy and breastfeeding) is still not entirely taken into consideration, despite a rapidly increasing body of evidence. This position paper covers six neurological conditions (Alzheimer's Disease, Cerebrovascular disease, Parkinson's disease, Epilepsy, Headache disorders, Multiple Sclerosis) providing an overview of available evidence on sex and gender differences, identifying knowledge gaps and providing recommendations for clinical practice and future studies. We recommend taking into consideration modifiable sex and gender specific risk factors, the role of hormones across women's lifespan and a personalized treatment approach based on gender. We also recommend that future efforts should be devoted to increase the representation of women in clinical studies, to promote sex and gender-based guideline production and to better characterize the safety profile in pregnancy of newer drugs.},
}

Humans
*Nervous System Diseases/therapy/epidemiology
Female
*Sex Characteristics
Male
Pregnancy

@article {pmid41491579,
year = {2026},
author = {Kamali, M and Ansari, M and Nooraee, P and Tajadini, H and Kamali, H and Dehesh, T and Ashrafzadeh, A and Sharififar, F},
title = {Preliminary clinical evaluation of capsules containing standard hydroalcoholic extract of Myrtus communis L. in patients with mild to moderate Alzheimer' disease: a randomized, double-blind parallel-group clinical trial.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-025-04994-9},
pmid = {41491579},
issn = {2662-7671},
abstract = {BACKGROUND: This study evaluated the effectiveness of Myrtus communis L. extract, known for its antioxidant and anticholinesterase properties, to enhance cognitive function and mitigate disease progression in individuals with mild to moderate Alzheimer's disease (AD).

METHODS: Fifty elderly patients with mild to moderate AD residing in a Kerman nursing home were enrolled in a randomized, placebo-controlled trial conducted between November 2019 to February 2020. Participants were randomly assigned to either an intervention group (n = 25), receiving M. communis L. capsules (500 mg each capsule), or a control group (n = 25), receiving placebo capsules. Cognitive function was assessed at baseline and after four weeks using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scales. Statistical analyses, performed using SPSS version 22, considered a significance level of p < 0.05.

RESULTS: All fifty patients completed the four-week trial. Baseline characteristics-including sex, mean age, and education level-were well-matched between the intervention and control groups. After four weeks of treatment, the intervention group demonstrated a statistically significant improvement in cognitive function, as evidenced by significantly higher MMSE scores compared to the placebo group (23.4 ± 0.25 vs. 19.6 ± 0.25; p < 0.0001). Concurrently, the intervention group exhibited a significant reduction in dementia severity, indicated by lower CDR scores compared to the control group (0.8 ± 0.04 vs. 1.5 ± 0.04; p < 0.0001).

CONCLUSIONS: These findings suggest that M. communis L. holds promise as a potential complementary therapy for AD, capable of improving cognitive function and potentially slowing disease progression. However, further research is necessary to corroborate these results, elucidate the underlying mechanisms of action, and optimize treatment parameters before definitive conclusions can be drawn.

TRIAL REGISTRATION: irct.ir, ID: 20170702034861N8. Registered on 26/08/2019.},
}

@article {pmid41491073,
year = {2026},
author = {Wasim, R and Azmi, S and Ahmad, A and Srivastava, A},
title = {NLRP3 inflammasome and Alzheimer's disease: bridging inflammation and neurodegeneration.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41491073},
issn = {1568-5608},
abstract = {The progressive neurodegenerative disease known as Alzheimer's disease (AD) is characterized by widespread neuronal death, memory loss, and cognitive decline. The NLRP3 inflammasome has emerged as a key modulator of neuroinflammation, which is increasingly implicated in the pathophysiology of AD. In response to endogenous and pathogenic danger signals, the innate immune system's multiprotein complex known as the NLRP3 inflammasome is activated. Pyroptosis and neuroinflammatory cascades are eventually triggered by its activation, which causes caspase-1 to be cleaved and pro-inflammatory cytokines like interleukin-1β and interleukin-18 to be released. NLRP3 activation is strongly stimulated by tau aggregation and β-amyloid plaques in AD, which accelerates neuronal damage and prolongs chronic inflammation. The control and activation of inflammasomes are involved in both canonical and non-canonical pathways as well as mitochondrial dysfunction. Significantly, animal models indicate that NLRP3's therapeutic potential is highlighted by the reduction of amyloid burden and amelioration of cognitive decline that results from its inhibition or genetic deletion. Small-molecule inhibitors and natural substances that can alter NLRP3 activity have been discovered recently, providing intriguing approaches to AD treatment. Despite tremendous advancements, issues with medication selectivity and blood-brain barrier penetration still need to be resolved before these discoveries can be used in clinical settings. Comprehending the complex relationship between NLRP3 activation and Alzheimer's pathology may open the door to new, focused treatments meant to slow or stop the progression of the illness.},
}

@article {pmid41490490,
year = {2026},
author = {Wang, W and Huang, R and Lv, L and Ma, X and Li, Z and Zhang, Y and Wu, J and Wu, S and Xu, J and Hu, Y and Turck, CW and Li, H and Hu, X},
title = {Long-term effects of forty-hertz auditory stimulation as a treatment of Alzheimer's disease: Insights from an aged monkey model study.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {2},
pages = {e2529565123},
doi = {10.1073/pnas.2529565123},
pmid = {41490490},
issn = {1091-6490},
mesh = {Animals ; *Alzheimer Disease/therapy/pathology/cerebrospinal fluid ; Macaca mulatta ; tau Proteins/cerebrospinal fluid ; Disease Models, Animal ; Amyloid beta-Peptides/cerebrospinal fluid ; *Acoustic Stimulation/methods ; Male ; Female ; *Aging ; Humans ; Brain/pathology ; },
abstract = {Based mainly on rodents studies, forty-hertz (40-Hz) physical stimulation has been regarded as a potential noninvasive treatment for Alzheimer's disease (AD). Considering the brain differences between rodents and humans, the effects of 40-Hz physical stimulation need to be further validated using nonhuman primates before its clinical application. Here, we took advantage of a rare opportunity to expose nine aged rhesus monkeys (26 to 31 y old) to 40-Hz auditory stimulation. Given the strong correlation between cerebrospinal fluid (CSF) Aβ and Tau concentrations and corresponding AD pathology in brain parenchyma in clinical practice, we investigated the effects of 40-Hz stimulation on AD pathology by monitoring changes in CSF Aβ and Tau concentrations. Our results revealed that 7 consecutive days of 40-Hz auditory stimulation triggered a rapid and significant increase of Aβ levels by more than 200%, but no effect on Tau levels in the CSF. Additionally, we observed that the elevation of CSF Aβ levels persisted for more than 5 wk after cessation, which had not been reported in any previous studies. After this, a pathological examination of the temporal cortices of 4 of the experimental monkeys was carried out and the data demonstrated that all of them had prevalent extracellular Aβ senile plaque pathology, whereas Tau pathology was negative or very weak. These results provide a good explanation for the differences between the CSF Aβ and Tau protein levels. Together, these first-time results from monkeys suggest that 40-Hz auditory stimulation has strong potential of a noninvasive AD treatment method.},
}

Animals
*Alzheimer Disease/therapy/pathology/cerebrospinal fluid
Macaca mulatta
tau Proteins/cerebrospinal fluid
Disease Models, Animal
Amyloid beta-Peptides/cerebrospinal fluid
*Acoustic Stimulation/methods
Male
Female
*Aging
Humans
Brain/pathology

@article {pmid41490210,
year = {2026},
author = {Giuffrè, GM and Battisti, F and Tudor, AM and Lenkowicz, J and Avitabile, A and Rosati, AM and Martellacci, N and Patarnello, S and Torelli, F and Cesario, A and Marra, C},
title = {Redefining management of mild cognitive impairment and Alzheimer's disease through the shift from clinical to clinical-biological diagnosis: Insights from a single-center experience.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411461},
doi = {10.1177/13872877251411461},
pmid = {41490210},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) diagnosis has shifted from a purely clinical framework to a clinical-biological paradigm, driven by biomarker integration. This evolution is motivated by the wider availability of reliable biomarkers and the advent of disease-modifying treatments.ObjectiveTo assess changes over time in clinical characteristics, diagnostic pathways, and healthcare resource utilization in a real-world cohort of individuals with cognitive impairment attending a Memory Clinic.MethodsThis secondary data retrospective observational study analyzed two patient cohorts with newly diagnosed cognitive impairment: one from 2017-2019 and another from 2021-2023. Anonymized medical records and structured hospital data were examined using natural language processing to extract demographic and clinical information, diagnostic pathways, treatment patterns and comorbidities.ResultsThe 2021-2023 cohort was significantly younger, exhibited higher baseline Mini-Mental State Examination scores, and underwent more instrumental assessments than the 2017-2019 cohort. These findings likely reflect a shift in public awareness and attitudes toward cognitive health. AD diagnoses increased in both cohorts over time, while mild cognitive impairment diagnoses declined. The use of diagnostic combinations was more frequent in the recent cohort, in which clinical-biological diagnoses were significantly more prevalent.ConclusionsThis study provides real-world insights into the evolving landscape of cognitive impairment diagnostics and care, underscoring a shift toward earlier, biologically grounded diagnosis, supporting precision medicine in AD care. The expanded use of biomarkers reflects evolving practice standards and prepares the ground for disease-modifying therapies in AD.},
}

@article {pmid41490207,
year = {2026},
author = {Liu, Y and Su, H and Guan, T and Li, X and Dong, C and Hu, Z and Zhang, Y},
title = {Risk prediction of progression from normal cognitive function to Alzheimer's disease in elderly aged 65 and above based on deep learning methods.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410937},
doi = {10.1177/13872877251410937},
pmid = {41490207},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a severe neurological disorder for which a complete cure is not currently available. Therefore, predicting the risk of AD in elderly individuals with normal cognitive function is crucial for early prevention, treatment, and family-provided daily care preparation.ObjectiveThis study aimed to establish a risk prediction model for the progression from normal cognitive function to AD in elderly via deep learning (DL) methods to provide a reference for clinical decision-making and the development of screening tools for the early diagnosis of AD.MethodsDeepSurv, DeepHit, and Cox models were constructed, and the consistency index (C-index), integrated Brier score (IBS), and area under the ROC curve (AUC) were used to evaluate the accuracy, calibration and discriminative power of the three prediction models.ResultsThe overall predictive ability of the model was relatively stable, with concordance indices of 0.82 (DeepSurv), 0.83 (DeepHit), and 0.81 (Cox) and IBSs of 0.08, 0.07, and 0.05, respectively. From the perspective of the C-index indicator, the consistency of the deep learning model was better than that of the Cox model.ConclusionsRisk prediction models for the progression from normal cognitive function to AD can be established using easily obtainable early-stage predictors, which are expected to be used for rapid screening of the risk of developing AD in elderly after clinical validation.},
}

@article {pmid41490027,
year = {2026},
author = {Yang, JW and Jiang, J},
title = {Association between varicella-zoster virus and Alzheimer's disease: A systematic review and meta-analysis of comprehensive evidence from infection, treatment to prevention.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411573},
doi = {10.1177/13872877251411573},
pmid = {41490027},
issn = {1875-8908},
abstract = {BackgroundThe association between varicella-zoster virus (VZV) infection and Alzheimer's disease (AD) risk has shown inconsistent results. Given difficulties in early diagnosis and limited therapeutic options for AD, identifying modifiable risk factors is significant for prevention.ObjectiveTo systematically evaluate the impact of VZV infection on AD risk and explore protective effects of antiviral treatment and vaccination.MethodsWe searched PubMed and Web of Science databases up to April 2025. The Newcastle-Ottawa Scale assessed study quality. Random-effects models were used for meta-analysis using risk ratios (RR) as the primary effect measure, with sensitivity and subgroup analyses conducted.ResultsTwenty-one studies were included. Meta-analysis showed: (1) herpes zoster patients had significantly higher AD risk (RR = 1.12, 95% CI: 1.01-1.24, p = 0.04); (2) patients receiving antiviral treatment had lower AD risk (RR = 0.55, 95% CI: 0.37-0.82, p = 0.003); (3) vaccinated individuals had lower AD risk (RR = 0.72, 95% CI: 0.68-0.78, p < 0.0001). The strongest association occurred in the >70 years age group, demonstrating age as an important effect modifier.ConclusionsThis meta-analysis provides systematic evidence supporting that VZV infection increases AD risk while confirming protective effects of antiviral treatment and vaccination. These findings support including herpes zoster vaccination in preventive healthcare for elderly populations.},
}

@article {pmid41488982,
year = {2025},
author = {Ressa, R and Ettinger, J and Chowdhury, E and Graham, L and Ndirangu, K and Mancebo, JZ and Bodnar, C},
title = {A value assessment of patient-level outcomes and productivity loss for intravenous and subcutaneous lecanemab for patients with early Alzheimer's disease.},
journal = {Journal of medical economics},
volume = {29},
number = {1},
pages = {118-134},
doi = {10.1080/13696998.2025.2609499},
pmid = {41488982},
issn = {1941-837X},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Injections, Subcutaneous ; Markov Chains ; Patient Preference ; Administration, Intravenous ; Cost-Benefit Analysis ; Caregivers ; Efficiency ; Decision Support Techniques ; },
abstract = {AIMS: Intravenous (IV) lecanemab is approved for the treatment of patients with early Alzheimer's disease (AD); a subcutaneous (SC) option may offer additional benefits. We assessed the overall value of SC treatments, and direct/indirect outcomes associated with IV and SC lecanemab.

METHODS AND MATERIALS: For the narrative review, PubMed was searched (February 2025) for studies comparing patient preferences for IV/SC treatment administration published between 2015-2025. Study eligibility was determined using patient, intervention, comparator, outcomes, and study criteria. For the decision-analytic model, a Markov model was developed with four lecanemab treatment scenarios. Scenarios one to three included IV initiation (10 mg/kg biweekly) to month 18, followed by either IV initiation continued (10 mg/kg biweekly), SC maintenance (250 mg weekly) or IV maintenance (10 mg/kg every 4 weeks). Scenario four included SC initiation (500 mg weekly) for an 18-month period, followed by SC maintenance (250 mg weekly). Outcomes were administration time/frequency; patient, caregiver, and healthcare professional time; and caregiver productivity loss.

RESULTS: Forty-three publications reported patient treatment preferences. Most (88.4%) reported that patients preferred SC over IV. Key reasons for this were time savings (n = 13/43 studies; 30.2%), convenience (n = 11/43; 25.6%), treatment frequency (n = 12/43; 27.9%). Two studies (n = 2/43; 4.7%) reported an IV preference over SC; for three studies (n = 3/43; 7.0%), treatment preference was driven by administration frequency. Decision-analytic modeling of lecanemab treatment scenarios revealed that IV initiation to IV maintenance had the lowest number of administrations, whereas SC initiation to SC maintenance had the lowest number of treatment hours and caregiver productivity losses.

LIMITATIONS: Caution must be taken when generalizing these results for all AD patients.

CONCLUSIONS: SC treatments show value as a therapeutic option. IV and SC lecanemab availability may offer benefits to patients, caregivers, and society, and improve shared decision making.},
}

Humans
*Alzheimer Disease/drug therapy
Injections, Subcutaneous
Markov Chains
Patient Preference
Administration, Intravenous
Cost-Benefit Analysis
Caregivers
Efficiency
Decision Support Techniques

@article {pmid41488470,
year = {2026},
author = {Cho, Y and Lee, J and Choi, BY and Yun, JH and Han, S and Baek, SH and Park, J and Cho, Y and Kim, HK and Kim, E and Palomera, LF and Lim, J and Jeon, Y and Im, J and Hong, JM and Kim, TK and Kim, SH and Yim, JH and Jo, DG},
title = {Ramalin Ameliorates Alzheimer's Disease Pathology by Targeting BACE1, HDAC6, and MAPK Pathways.},
journal = {MedComm},
volume = {7},
number = {1},
pages = {e70518},
pmid = {41488470},
issn = {2688-2663},
abstract = {Aberrant deposition of β-amyloid (Aβ) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating β-site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen-activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, Aβ plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed Aβ oligomer-induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease-modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease-modifying candidate with the potential to drive a breakthrough approach targeting AD pathology.},
}

@article {pmid41488323,
year = {2025},
author = {Lotlikar, MS and Zellmer, JC and Bhattacharyya, R},
title = {Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1733659},
pmid = {41488323},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.},
}

@article {pmid41487944,
year = {2026},
author = {Rus Prelog, P and Zupan, M and Gregorič Kramberger, M and Frol, S},
title = {The Concomitant Use of Selective Serotonin Reuptake Inhibitors and Anti-Amyloid Treatment in Alzheimer's Disease: Balancing Benefits and Risks.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {16},
number = {1},
pages = {1-3},
pmid = {41487944},
issn = {1664-5464},
}

@article {pmid41487496,
year = {2025},
author = {Cheng, R and Kim, J},
title = {Intranasal delivery of iron chelators and management of central nervous system disease.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1709259},
pmid = {41487496},
issn = {1663-9812},
abstract = {Brain iron dyshomeostasis plays a critical role in the pathology of multiple central nervous system (CNS) disorders, including neurodegenerative and neuropsychiatric diseases. Iron chelators such as deferoxamine (DFO) and deferiprone (DFP) have demonstrated therapeutic potential in mitigating disease progression in these conditions. However, systemic administration is hindered by poor blood-brain barrier (BBB) permeability, dose-limiting toxicity, and poor patient compliance due to frequent dosing regimens. In recent years, intranasal (IN) drug delivery has emerged as a promising strategy to bypass the BBB, providing a direct nose-to-brain delivery route via olfactory and trigeminal pathways while minimizing systemic exposure. This review provides a comprehensive summary of the current status of iron chelation therapy for CNS disorders with a focus on pharmacokinetics, efficacy, and translational potential of IN administration. While IN DFO has been extensively studied in preclinical models of Alzheimer's disease and stroke, recent developments have expanded the scope to other chelators such as DFP. We compare traditional systemic routes, including oral and intravenous, with intranasal administration, highlighting their respective advantages and limitations for CNS delivery. With ongoing advances in formulation and delivery technologies, IN iron chelators provide a promising alternative for the treatment of CNS disorders characterized by impaired iron homeostasis in the brain.},
}

@article {pmid41487012,
year = {2026},
author = {Verma, R and Bahadur, S},
title = {A Comprehensive Review of Naringin Loaded Nano Drug Delivery System in Treatment of CNS Disorders.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128407188251116030341},
pmid = {41487012},
issn = {1873-4286},
abstract = {Citrus fruits are an abundant source of the polyphenolic phytoconstituent naringenin, which belongs to the class of flavanones. NRG shows a lot of potential as a drug for treating a number of CNS disorders, such as neuroprotective activity, antiamyloidosis, antiparkinson, antialzheimer activity, and more. However, naringenin's hydrophobic nature, which results in limited absorption, limits its therapeutic potential. In this article, we provide an outline of the variety of nanocarriers employed for delivering naringenin as carriers. Some of them include solid lipid nanoparticles, liposomes, micelles, polymeric nanoparticles, nanostructured lipid carriers, nanosuspensions, and nanoemulsions, among others. These formulations of naringenin nanomedicine have been used for the potential treatment of a series of CNS disorders. Based on various research reports, it can be said that with the right nanocarriers, naringenin proves to be a promising therapeutic alternative for the treatment of several CNS ailments, including neurological diseases, Alzheimer's, Parkinson's disease, cerebral ischemia, etc. Therefore, the present manuscript highlights the various aspects of naringenin and its pharmacological activities. Further, naringenin-loaded nanocarriers have been enlisted and discussed in detail.},
}

@article {pmid41486993,
year = {2026},
author = {Cai, M and Yan, S and Sun, Y and Huo, Q and Dai, X},
title = {miRNAs: Promising Biomarkers for Alzheimer's Diagnosis and Treatment.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050427877251118111643},
pmid = {41486993},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, and chronic neuroinflammation, leading to synaptic dysfunction and cognitive decline. Current diagnostic methods rely on clinical symptoms and limited biomarkers, while available treatments only provide symptomatic relief without halting disease progression. MicroRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have emerged as crucial regulators of gene expression through post-transcriptional mechanisms and show distinct dysregulation patterns in AD patients' blood, cerebrospinal fluid (CSF), and brain tissues. Key miRNAs such as miR-132, miR-146a, miR-34a, and miR-125b demonstrate consistent alterations in expression levels, correlating with disease progression and offering potential as non-invasive diagnostic tools. This review comprehensively examines the dual role of miRNAs as diagnostic biomarkers and therapeutic targets for AD. We also provide an analysis of specific miRNA signatures in different biofluids (plasma, serum, CSF) and brain regions that correlate with disease stages, highlighting their potential for early and non-invasive diagnosis. Therapeutically, miRNAs modulate multiple AD-related pathways, including neuroinflammation via NF-κB signaling, Aβ production through BACE1 inhibition, and tau phosphorylation via GSK3β regulation. miRNAs also influence synaptic plasticity, mitochondrial function, and autophagy, presenting multifaceted opportunities for intervention. However, challenges, including miRNA heterogeneity, stability, and targeted delivery, remain critical impediments. Advances in nanocarriers, exosomal miRNAs, and viral vectors show promise in overcoming these obstacles, enabling precise miRNA modulation. In addition, we underscore the need for standardized protocols, further validation in clinical cohorts, and the development of cost-effective detection methods to translate miRNA-based approaches into practical diagnostics and therapies. By integrating miRNA biomarkers with existing diagnostic tools and exploring combinatorial therapeutic strategies, researchers can harness the potential of miRNAs to revolutionize AD intervention, paving the way for early detection and effective treatment of this devastating disease.},
}

@article {pmid41486988,
year = {2026},
author = {Ranjbari, F and Dadkhah, M and Pirdel, Z and Fathi, F},
title = {Margatoxin Peptide: Preparation and the Potential Use for Biological Applications in Cancer and Neurological Disorders.},
journal = {Protein and peptide letters},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298665415268251024053300},
pmid = {41486988},
issn = {1875-5305},
abstract = {Scorpion venom compounds are known to contain nucleotides, polypeptides, mucoproteins, lipids, biogenic amines, and other unidentified macromolecules. Several peptides in scorpion fluids have demonstrated a wide range of biological activities with strong specificity for their targeted sites. Margatoxin, isolated from the venom of the scorpion, exhibits desirable properties, including high selectivity, good permeability, and stability in cancer cells, which can be achieved at picomolar doses, thereby blocking voltage-gated K+ channels. This narrative review consolidates results from an extensive literature search conducted in major electronic databases up to September 2024. Important studies were identified using keywords associated with scorpion venom peptides, Kv1.3 channels, cancer treatment, and neurodegenerative disorders. The amino acids that make up Margatoxin have an effective molecular function in blocking voltage-gated K+ channels 1.3. Due to the abnormally high expression of voltage-gated K[7] channel 1.3 in various types of cancers, blockers of this channel can inhibit apoptosis, metabolic changes, tumor angiogenesis, invasion, and migration. On the other hand, these channel blockers have emerged as a promising therapeutic approach for neurological disorders, such as Alzheimer's and Parkinson's diseases. The strong efficacy and targeted action of margatoxin further position it as a promising drug candidate. As the number of individuals affected by cancer and neurological conditions continues to rise, research into scorpion venom peptides like margatoxin may lead to innovative therapeutic options for future treatments.},
}

@article {pmid41486697,
year = {2026},
author = {Pan, H and Cheng, X and Zhang, J and Hou, K and Murray, KA and Manglani, K and Zhu, C and Hsu, HK and Mekkittikul, M and Halladay, T and Mirbaha, H and Elezi, G and Abskharon, R and Sawaya, MR and Bombino, A and Williams, CK and DeTure, M and Dickson, DW and Vinters, HV and Whitelegge, JP and Harran, PG and Cole, GM and Frautschy, SA and Eisenberg, DS},
title = {In Vitro and In Vivo Evaluation of Small-Molecule Disassemblers of Pathological Tau Fibrils.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00940},
pmid = {41486697},
issn = {1948-7193},
abstract = {Aggregation of the microtubule-binding protein tau is the histopathological hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, which are collectively known as tauopathies. Tau aggregation in AD patients is correlated with neuron loss, brain atrophy, and cognitive decline, and pro-aggregation tau mutations are sufficient to cause neurodegeneration and dementia in humans and tauopathy model mice. Thus, reversing tau aggregation is a potential therapeutic avenue for AD. In a previous study, we discovered CNS-11, a small molecule that disaggregates AD patient brain-extracted tau fibrils in vitro. In this study, we identify two chemical analogs of CNS-11, named CNS-11D and CNS-11G, that disaggregate AD patient brain-extracted tau fibrils and prevent seeding in a tau aggregation cell culture model. We also demonstrate that 8 weeks of treatment with either CNS-11D or CNS-11G reduces levels of insoluble tau in a mouse model of tauopathy. Our work defines the properties of two small molecules that diminish aggregation of tau in vivo and provides further support for structure-based methods to target tau for treatment of AD.},
}

@article {pmid41486173,
year = {2026},
author = {Silva-Llanes, I and Smith, LA and Abdelkader-Guillén, A and Jiménez-Villegas, J and Sarrió, D and Moreno-Bueno, G and Lastres-Becker, I},
title = {GASDERMIN D-mediated pyroptosis as a therapeutic target in TAU-dependent frontotemporal dementia mouse model.},
journal = {Journal of biomedical science},
volume = {33},
number = {1},
pages = {6},
pmid = {41486173},
issn = {1423-0127},
support = {PID2022-136854OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2022-137065OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; CB16/12/00295//Centro de Investigación Biomédica en Red de Cáncer/ ; CB06/05/0089//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; },
mesh = {Animals ; *Pyroptosis/genetics ; Mice ; *tau Proteins/metabolism/genetics ; Disease Models, Animal ; Humans ; *Phosphate-Binding Proteins/metabolism/genetics ; Mice, Transgenic ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism/drug therapy/pathology ; Male ; Female ; Alzheimer Disease/genetics ; Mice, Inbred C57BL ; Aged ; Hippocampus/metabolism ; Gasdermins ; },
abstract = {BACKGROUND: Recent research has revealed a strong connection between neuroinflammation and TAU protein-related neurodegeneration. A key discovery shows that the NLRP3 inflammasome, when activated, can significantly impact TAU pathology and subsequent neuronal death. This process involves pyroptosis, a lytic form of programmed cell death driven by inflammasome activation, leading to GASDERMIN D (GSDMD) cleavage and the subsequent release of inflammatory molecules IL-1β and IL-18. In this study, we explore the role of pyroptosis and GSDMD in Alzheimer's disease (AD) and tauopathy models, focusing on the TAU-induced neuroinflammatory process and its correlation with synaptic plasticity loss.

METHODS: Hippocampal tissue from AD patients at Braak stage II-III has been analyzed using qPCR to assess pyroptosis-related gene expression. To determine the role of TAU in pyroptosis and neuroinflammation, we used two different models: one based on intracerebral injection of an adeno-associated virus that specifically overexpresses TAU in the neurons of the hippocampus (AAV-TAU[P301L]), and a transgenic mouse model Tg-TAU[P301S] at 8 and 10 months of age. Gene expression, protein levels, and neuroinflammation markers were evaluated using qPCR and immunofluorescence. Additionally, both genetic (GSDMD-deficient mice) and pharmacological (dimethyl fumarate, DMF) interventions targeting pyroptosis have been explored to assess their impact on neuroinflammation and synaptic plasticity.

RESULTS: AD patients exhibited increased expression of pyroptosis-related genes, supporting the involvement of pyroptosis in neurodegeneration. Furthermore, TAU overexpression induced pyroptosis in both mouse models, and GSDMD protein levels increased alongside reactive microglial morphology. Our data supports that TAU-induced neuroinflammation correlated with synaptic plasticity impairment. GSDMD deficiency significantly reduced pyroptosis-related markers associated to TAU, but unexpectedly worsened synaptic plasticity deficits, suggesting GSDMD may play a dual role in inflammation and synaptic function. Finally, we showed that DMF treatment suppressed pyroptosis gene expression, reduced GSDMD levels, and alleviated neuroinflammation, correlating with improved synaptic marker expression.

CONCLUSION: Our findings demonstrate that TAU-induced pyroptosis contributes to neuroinflammation and synaptic dysfunction. While GSDMD inhibition mitigates inflammation, its absence exacerbates synaptic impairment, highlighting its complex role in tauopathies. Our results indicate that DMF treatment could offer a promising therapeutic avenue to modulate pyroptosis and neuroinflammation, and restore synaptic integrity in tauopathies.},
}

Animals
*Pyroptosis/genetics
Mice
*tau Proteins/metabolism/genetics
Disease Models, Animal
Humans
*Phosphate-Binding Proteins/metabolism/genetics
Mice, Transgenic
*Intracellular Signaling Peptides and Proteins/metabolism/genetics
*Frontotemporal Dementia/genetics/metabolism/drug therapy/pathology
Male
Female
Alzheimer Disease/genetics
Mice, Inbred C57BL
Aged
Hippocampus/metabolism
Gasdermins