@article {pmid41264165,
year = {2025},
author = {Gao, H and Cheng, F and Zhang, Z and Yan, B and Liao, P and Zhang, S and Li, D and Chen, F and Lei, P},
title = {Breaking the Alzheimer's Treatment Stalemate: Synergistic Application Strategies of Nanomaterials and Pharmaceutical Agents.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {107},
pmid = {41264165},
issn = {1559-1182},
support = {grant no. 82271401//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/drug therapy/diagnosis ; Humans ; *Nanostructures/therapeutic use ; Animals ; Drug Delivery Systems/methods ; Nanomedicine/methods ; },
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid beta accumulation and tau pathology propagation. Nanomedicine, a discipline enabling targeted drug delivery with precision, holds significant promise in the treatment of neurodegenerative diseases. This review explores the diagnostic and therapeutic applications of nanomaterials in neurodegenerative diseases, particularly AD, emphasizing their properties and their role in modulating pathogenic proteins. Advances in the development of novel anti-AD nanomedicines and their clinical progress are also highlighted. Despite the growing potential of nanotechnology in AD therapy, a definitive cure remains elusive. The review further addresses the current challenges in the field of AD nanomedicines and outlines future research directions to propel their development.},
}

*Alzheimer Disease/drug therapy/diagnosis
Humans
*Nanostructures/therapeutic use
Animals
Drug Delivery Systems/methods
Nanomedicine/methods

@article {pmid41262573,
year = {2025},
author = {Demsey, LL and Burch, D and Lin, E and Quach, D and Podvin, S and Boyarko, B and Levey, AI and Weinshenker, D and Edland, S and Galasko, D and Jacobs, H and Bang, A and Neil, A and Silverman, J and Feldman, HH and Hook, V},
title = {Atomoxetine Drug Properties for Repurposing as a Candidate Alzheimer's Disease Therapeutic Agent.},
journal = {ACS pharmacology & translational science},
volume = {8},
number = {11},
pages = {3757-3772},
pmid = {41262573},
issn = {2575-9108},
abstract = {Ongoing Alzheimer's disease (AD) drug development research addresses the need for therapeutic agents that can ameliorate cognitive symptoms and attenuate the course of AD synaptic deficits and neurodegeneration. There is growing interest in evaluating FDA-approved drugs for repurposing as candidate AD therapeutics. Such drugs have the advantage that data are available about their pharmaceutical properties, including doses, pharmacokinetics, pharmacodynamics, biomarkers, metabolism, and safety, to inform the design of clinical drug trials. Importantly, the suitability of such drugs with properties needed for AD requires evaluation. In the early stage of AD, degeneration of the locus coeruleus (LC) brain region results in the reduction of noradrenergic neurons and the loss of the neurotransmitter norepinephrine (NE) that regulates cognition and degeneration. Elevation of extracellular NE through inhibition of the NE transporter (NET) is hypothesized to ameliorate AD deficits. Notably, the NET reuptake inhibitor atomoxetine, an FDA-approved drug for the treatment of attention deficit hyperactivity disorder (ADHD), provides an attractive candidate as an AD therapeutic agent because it may attenuate cognitive decline in AD patients, positively impact AD biomarkers, and reduce neuropathology. The goal of this review is to assess atomoxetine for repurposing in AD based on its ability to improve cognition, regulate NE, impact AD biomarkers, and preserve LC neuronal function, with suitable pharmacokinetics, drug metabolism, and safety based on analysis of clinical and preclinical studies. Evidence for neuroprotective effects of atomoxetine in the early stage of AD at clinically safe doses with suitable pharmaceutical properties supports its candidacy as a repurposed drug for AD therapeutics.},
}

@article {pmid41262391,
year = {2025},
author = {Latella, D and Calderone, A and Casella, C and De Luca, R and Gangemi, A and Impellizzeri, F and Caliri, S and Quartarone, A and Calabrò, RS},
title = {Cognitive behavioral therapy for insomnia in neurodegenerative disorders-targeting sleep disturbances in Alzheimer's and Parkinson's disease: a scoping review.},
journal = {Frontiers in psychology},
volume = {16},
number = {},
pages = {1700496},
pmid = {41262391},
issn = {1664-1078},
abstract = {INTRODUCTION: Insomnia is highly prevalent in neurodegenerative disorders, yet pharmacological options carry safety and tolerability concerns. This scoping review mapped contemporary evidence for cognitive behavioral therapy for insomnia (CBT-I) across Alzheimer's disease (AD), mild cognitive impairment (MCI), and Parkinson's disease (PD).

METHODS: Following a preregistered protocol (OSF DOI: 10.17605/OSF.IO/8VP3F), we searched PubMed, Cochrane Library, Web of Science, and Scopus for studies published 2015-2025. We screened English-language studies in adults and applied dual independent review with consensus resolution. Of 105 records, 70 were screened after de-duplication, and 8 met eligibility criteria.

RESULTS: Across randomized trials, pilot and feasibility studies, and single-case experimental designs, CBT-I-delivered in person or via telehealth-consistently reduced insomnia severity and improved sleep quality, with frequent ancillary gains in mood, anxiety, and daytime functioning. Remote and digitally augmented delivery appeared feasible and acceptable for cognitively vulnerable adults and caregivers. Early signals suggested potential cognitive benefits in prodromal populations (AD/MCI), and exploratory observations linked improved sleep with plausible neurobiological mechanisms such as amyloid-beta dynamics. In PD, findings aligned with a mechanistic pathway in which presleep cognitive arousal, safety behaviors, and dysfunctional sleep beliefs are modifiable targets. Non-pharmacological comparators (e.g., mindfulness, therapeutic exercise, neuromodulation) also showed benefits, helping contextualize where CBT-I may offer disorder-relevant leverage on insomnia outcomes.

DISCUSSION: The overall strength of evidence is tempered by small samples, heterogeneity in comparators and dosing, short follow-up, and inconsistent reporting of clinically meaningful change. Priorities include multicenter randomized trials with standardized sleep and cognitive endpoints, longer observation, head-to-head comparative effectiveness with economic evaluation, adaptive protocols tailored to PD-specific disruptors, and mechanistic studies integrating digital phenotyping and biomarkers to test durability and downstream clinical impact.},
}

@article {pmid41262225,
year = {2025},
author = {Bayram, E},
title = {Sex and gender differences in Lewy body dementia: a narrative review.},
journal = {Equity neuroscience},
volume = {1},
number = {2},
pages = {},
pmid = {41262225},
issn = {3050-8401},
abstract = {Lewy body dementia (LBD), including Parkinson's disease dementia and dementia with Lewy bodies, is one of the most prevalent and burdensome type of dementias. Clinical diagnostic accuracy during life remains limited and there are currently only symptomatic therapy options without disease modification. However, recent advances in biomarkers and clinical trials are promising. Literature so far showed sex and gender differences in older adults without cognitive changes, people with all-cause dementia, Alzheimer's disease, and Parkinson's disease. While the number of studies in LBD are lower, understanding sex and gender differences and the underlying reasons can improve both diagnosis and treatment for LBD. Accordingly, the aim of this narrative review is to provide a summary of the literature for sex and gender differences in LBD. Majority of the studies for LBD investigating sex/gender differences so far focused on sex, with sex and gender terms being misused at times. Experiences of people in non-binary categories for sex or gender have yet to be investigated. While more research is needed, findings so far outline sex differences in prevalence, risk factors, biomarkers, symptoms, progression, treatment, daily life, and pathology for LBD. Sex-specific risk factors have also been reported, emphasizing the value of sex-stratified analyses and investigating female/male-specific factors such as sex hormones, menopause, and sex chromosomes. Lack of adequate research representation for females and women, as well as people from non-binary categories, is an important limitation that should be addressed to obtain more applicable findings in LBD.},
}

@article {pmid41261421,
year = {2025},
author = {Etani, H and Takatori, S and Wang, W and Omi, J and Amiya, Y and Akahori, A and Watanabe, H and Sonn, I and Okano, H and Hara, N and Hasegawa, M and Miyashita, A and Kikuchi, M and Ikeuchi, T and Morishima, M and Saito, Y and Murayama, S and Saito, T and Saido, TC and Takai, T and Ohwada, T and Aoki, J and Tomita, T},
title = {Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {248},
pmid = {41261421},
issn = {1758-9193},
mesh = {*Microglia/metabolism/drug effects ; Animals ; *Amyloid beta-Peptides/metabolism ; Humans ; Mice ; *Receptors, G-Protein-Coupled/agonists/metabolism ; Alzheimer Disease/metabolism/pathology ; Phagocytosis/drug effects ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; Cells, Cultured ; },
abstract = {BACKGROUND: Microglia play a crucial role in brain homeostasis through phagocytosis of amyloid-β (Aβ) fibrils, a hallmark of Alzheimer disease (AD) pathology. The balance between Aβ production and clearance is critical for AD pathogenesis, with impaired clearance mechanisms potentially contributing to disease progression. G-protein coupled receptor 34 (GPR34), a microglia-enriched Gi/o-coupled receptor, is highly expressed in homeostatic microglia and may regulate phagocytic functions, yet its role in Aβ clearance remains poorly understood.

METHODS: Using flow cytometry-based assays, we investigated the effect of a selective GPR34 agonist (M1) on Aβ uptake in mouse primary microglia and human induced pluripotent stem cell-derived microglia. We evaluated uptake specificity across different Aβ species and phagocytic substrates, and measured intracellular cyclic adenosine monophosphate (cAMP) levels to determine the signaling mechanism. We performed in vivo studies using human amyloid precursor protein knock-in mice with intrahippocampal M1 injections. Additionally, we analyzed GPR34 expression in Japanese AD patient brain samples using single-nucleus RNA sequencing and examined age-dependent expression changes across multiple datasets.

RESULTS: M1 specifically enhanced uptake of Aβ fibrils through reduction of intracellular cAMP levels, without affecting monomeric or oligomeric Aβ internalization. Gpr34 knockdown experiments confirmed GPR34 as the molecular target of M1. An intrahippocampal injection of M1 significantly increased microglial Aβ uptake in vivo, an effect that required functional TREM2 signaling. GPR34 expression was significantly reduced in microglia from AD patients and showed age-dependent decline in both humans and mice.

CONCLUSIONS: Our findings identify GPR34 as a promising therapeutic target for enhancing microglial Aβ clearance and highlight the potential of GPR34 agonists for AD treatment. The age-dependent decline in GPR34 expression may contribute to reduced Aβ clearance efficiency in aging brains, exacerbating amyloid accumulation. Pharmacological activation of GPR34 represents a novel strategy to counteract impaired Aβ clearance in both aging and AD brains, potentially modifying disease progression through enhancement of microglial phagocytic function.},
}

*Microglia/metabolism/drug effects
Animals
*Amyloid beta-Peptides/metabolism
Humans
Mice
*Receptors, G-Protein-Coupled/agonists/metabolism
Alzheimer Disease/metabolism/pathology
Phagocytosis/drug effects
Mice, Transgenic
Male
Mice, Inbred C57BL
Cells, Cultured

@article {pmid41261317,
year = {2025},
author = {Zhou, R and Tian, G and Yu, J and Wang, R and Peng, N and Guo, X and Li, R},
title = {Echinacoside Improves Memory Function and Bone Mineral Density in the Aged SAMP8 Mouse Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {102},
pmid = {41261317},
issn = {1559-1182},
mesh = {Animals ; Male ; Mice ; *Bone Density/drug effects ; *Aging/drug effects/pathology ; Disease Models, Animal ; *Memory/drug effects ; *Glycosides/pharmacology/therapeutic use ; Osteoporosis/drug therapy ; },
abstract = {Alzheimer's disease (AD) and osteoporosis (OP) are prevalent age-related degenerative diseases that often coexist. Echinacoside (ECH) has been extensively studied for its potential to mitigate AD and bone mineral density (BMD) loss. This study aimed to evaluate the simultaneous therapeutic effects of ECH on AD-OP comorbidity using the senescence-accelerated mouse-prone 8 (SAMP8) model, which exhibits both age-related memory deficits and bone metabolism abnormalities. Six-month-old male SAMP8 mice (n = 8-9) were used as the model group, while age-matched senescence-accelerated mouse resistant 1 (SAMR1) mice served as normal controls. SAMP8 mice were administered ECH intragastrically (100 mg/kg/day) for 10 weeks, while control groups received saline. Behavioral tests, including the open field test (OFT), novel object recognition test (NORT), and Morris Water Maze (MWM), assessed locomotor ability, emotionality, and cognitive functions. Bone microstructure was evaluated using micro-computed tomography (micro-CT), and pathological changes in the brain were analyzed via Western blotting and immunofluorescence. As compared to SAMR1 mice, SAMP8 mice exhibited significant locomotor activity issues, impaired memory (P < 0.05), glial activation (P < 0.01), reduced trabecular bone number (P = 0.007), and altered trabecular separation (P = 0.040). ECH treatment improved memory function and inhibited glial activation (P < 0.05). Bone-related parameters showed that ECH intervention had a trend of improvement in bone health, but this did not reach statistical significance. The SAMP8 model exhibits key features of both AD and OP, making it a valuable tool for investigating their comorbidity and underlying mechanisms. ECH improves cognitive functions and alleviates bone loss, indicating its potential as a therapeutic candidate for AD-OP comorbidity.},
}

Animals
Male
Mice
*Bone Density/drug effects
*Aging/drug effects/pathology
Disease Models, Animal
*Memory/drug effects
*Glycosides/pharmacology/therapeutic use
Osteoporosis/drug therapy

@article {pmid41261299,
year = {2025},
author = {Zhang, R and Wu, K and Yang, Q and Kong, M and Guo, L and You, Q},
title = {Hyperprolactinemia and Brain Health: Exploring the Gut-Brain Axis and Therapeutic Strategies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {101},
pmid = {41261299},
issn = {1559-1182},
mesh = {Humans ; *Hyperprolactinemia/therapy/metabolism ; *Brain/pathology/metabolism ; Animals ; *Gastrointestinal Tract ; Gastrointestinal Microbiome/physiology ; Prolactin/metabolism ; *Brain-Gut Axis/physiology ; },
abstract = {Prolactin is a pituitary anterior lobe hormone that plays a crucial role in milk secretion from the mammary glands. Hyperprolactinemia is a common endocrine disorder characterized by abnormally elevated levels of prolactin in the serum. Recent research findings indicate that prolactin also exerts important physiological effects beyond lactation, including effects on brain health and the central nervous system. The gut-brain axis has become an important area of neuroscience research, providing insights into the complex interactions between the gastrointestinal system and the central nervous system. Future research may involve developing new probiotic therapies or optimizing the gut microbiota through dietary and lifestyle interventions. In addition, understanding the mechanisms by which hyperprolactinemia contributes to various neurological disorders and targeting prolactin for treatment are crucial areas of research. Therefore, this study aimed to investigate the correlation between hyperprolactinemia and brain health from the perspective of the gut-brain axis, with the goal of discovering new approaches for preventing and treating neurodegenerative and mental health conditions. This synthesis highlights potential strategies for future therapeutic interventions.},
}

Humans
*Hyperprolactinemia/therapy/metabolism
*Brain/pathology/metabolism
Animals
*Gastrointestinal Tract
Gastrointestinal Microbiome/physiology
Prolactin/metabolism
*Brain-Gut Axis/physiology

@article {pmid41261295,
year = {2025},
author = {Kritika, and Sood, R and Sanjay, and Lee, HJ},
title = {Nobiletin Reduces LPS-Induced Neuroinflammation through TLR4/MyD88/NF-κB and Oxidative Stress via Nrf2/HO-1 Signaling in Human Microglial HMC3 Cells.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {103},
pmid = {41261295},
issn = {1559-1182},
support = {GCU-202401020001//Gachon University research fund of 2023 (GCU-202401020001)/ ; (project No. RS-2022-RD010230)//Cooperative Research Program for Agriculture Science and Technology Development (project No. RS-2022-RD010230), Rural Development Administration, Republic of Korea./ ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *Myeloid Differentiation Factor 88/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Toll-Like Receptor 4/metabolism ; *Signal Transduction/drug effects ; Lipopolysaccharides ; *NF-kappa B/metabolism ; *Microglia/drug effects/metabolism/pathology ; *Heme Oxygenase-1/metabolism ; *Flavonols/pharmacology ; *Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced/pathology ; *Flavones/pharmacology ; Cell Line ; Inflammation/metabolism/drug therapy ; Reactive Oxygen Species/metabolism ; },
abstract = {Neuroinflammation and oxidative stress (OS) are the major contributors to the onset and progression of neurodegenerative diseases (NDs), where microglial activation and dysregulated inflammatory signaling exacerbate neuronal injury. Nobiletin (NOB), a polymethoxylated flavonoid abundant in citrus fruits, has been reported to possess excellent bioactivities; however, its effects in combating inflammation and OS in human microglial cells (HMC3) have not been comprehensively examined. In this study, we investigated the effects of NOB on lipopolysaccharide (LPS)-induced inflammatory and oxidative responses in HMC3 cells. The HMC3 cells exposed to LPS (1 µg/mL) in the presence/absence of NOB (5, 10, 20, and 40 µM) for 24 h showed that NOB could attenuate LPS-induced cytotoxicity. NOB treatment attenuated LPS-induced upregulation of pro-inflammatory cytokines including interleukin (IL)-1β, and IL-6, and suppressed activation of the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa-light-chain-enhancer of activated B (TLR4/MyD88/NF-κB) pathway. NOB enhanced the protein expression levels of TLR10, a negative regulator of TLR4-mediated inflammatory signaling. In addition, NOB increased the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression, along with other antioxidants including catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), leading to reduced intracellular reactive oxygen species (ROS). These findings suggest that NOB has promising anti-inflammatory and antioxidant effects in an in vitro model of LPS-induced neuroinflammation, potentially through modulation of TLR4/MyD88/NF-κB and Nrf2/HO-1 signaling pathways. However, further in vivo studies are needed to validate these effects and explore NOB's potential as a candidate for therapeutic development in NDs.},
}

Humans
*Oxidative Stress/drug effects
*Myeloid Differentiation Factor 88/metabolism
*NF-E2-Related Factor 2/metabolism
*Toll-Like Receptor 4/metabolism
*Signal Transduction/drug effects
Lipopolysaccharides
*NF-kappa B/metabolism
*Microglia/drug effects/metabolism/pathology
*Heme Oxygenase-1/metabolism
*Flavonols/pharmacology
*Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced/pathology
*Flavones/pharmacology
Cell Line
Inflammation/metabolism/drug therapy
Reactive Oxygen Species/metabolism

@article {pmid41260559,
year = {2025},
author = {Peng, D and Wu, L and Zhang, L and Chen, H and Hu, B and Zhang, Q and Huang, Y},
title = {haFGF14-154 attenuates Aβ1-42-induced neurotoxicity by facilitating BDNF maturation in a neuron-astrocyte co-culture system.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104056},
doi = {10.1016/j.mcn.2025.104056},
pmid = {41260559},
issn = {1095-9327},
abstract = {haFGF14-154 improves cognitive impairment in animal models of Alzheimer's disease (AD), but the effects and mechanisms of astrocytes on the neuroprotection mediated by haFGF14-154 remain unclear. Here, a neuron-astrocyte co-culture system was established to investigate the functions of astrocytes. The results showed that astrocytes strengthened the protective effect of haFGF14-154 on Aβ1-42-treated neurons. This enhanced protective function of haFGF14-154 correlates with phenotypic transition in astrocytes, as demonstrated by the suppression of Aβ1-42-induced A1-like genes and the elevation of A2-like markers in vitro. These observations are consistent with the reduction of GFAP and C3 levels in the hippocampus and prefrontal cortex of APP/PS1 mice treated with haFGF14-154. haFGF14-154 modified the function of astrocytes by activating the AKT/CREB/BDNF pathway, thereby promoting neurite growth. Moreover, haFGF14-154 up-regulated the expression of Furin and MMP9 in astrocytes, leading to the processing of pro-BDNF. This effect was replicated in APP/PS1 mice administered with haFGF14-154. Compared to the Aβ group, the BDNF level in the co-culture system supernatant was increased, while the IL-1β level was decreased following haFGF14-154 treatment. Additionally, haFGF14-154 inhibited neuronal apoptosis in the co-culture system, as evidenced by a decrease in pro-BDNF/P75[NTR], an increase in Bcl-2, and a reduction of Bad and Cleaved-caspase-3. In conclusion, current results demonstrate that astrocytes are crucial for mediating the protective effect of haFGF14-154 against neuronal damage, and underline the importance of the AKT/CREB/BDNF pathway in promoting neurite growth and attenuating neuronal apoptosis.},
}

@article {pmid41260370,
year = {2025},
author = {Xiao, K and Sayed, H and Xing, J and Zhang, XY and Ai, J and Kirichek, E and Le, GH and Wong, S and Valentino, K and Teopiz, KM and Vinberg, M and Rosenblat, JD and Lo, HKY and Zhang, MC and McIntyre, RS},
title = {The effects of Lithium on Beta-amyloid deposition and tau phosphorylation: A systematic review.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {120721},
doi = {10.1016/j.jad.2025.120721},
pmid = {41260370},
issn = {1573-2517},
abstract = {BACKGROUND: Current anti-amyloid treatments often cause amyloid-related imaging abnormalities in the treatment of Alzheimer's disease (AD). Lithium demonstrates neuroprotective and neurotrophic effects, and preclinical studies indicate it reduces intracerebral amyloid deposition and tau phosphorylation. This systematic review evaluates lithium's effects on beta-amyloid, tau, and cognitive deficits in major neurocognitive disorders.

METHODS: A systematic review of primary research was conducted using Embase, PsycInfo, MEDLINE, and PubMed databases from inception to September 2024, following PRISMA criteria. Animal and adult human studies evaluating lithium monotherapy's effects on AD were included.

RESULTS: Long-term low-dose lithium treatment demonstrates inconsistent efficacy in lowering intracerebral amyloid deposition and reversing AD-related cognitive deficits in preclinical and clinical trials. Lithium potentially slows amyloid plaque formation in pre-plaque stages through increasing heat shock proteins and suppressing protein synthesis in preclinical trials. Intracerebral lithium concentrations above 1 mM reduced phosphorylated tau through promoting tau ubiquitination and inhibiting CDK5 signalling in preclinical trials.

LIMITATIONS: AD currently needs a comprehensive animal model accurately representing human AD symptoms and progression, and more clinical trials are needed. Several included studies utilize peripheral lithium administration, which complicates assessment of effective intracerebral concentrations.

CONCLUSIONS: Lithium potentially reduces intracerebral amyloid deposition and tau phosphorylation in AD animal models and may reverse associated cognitive deficits. Further research should seek to replicate similar findings in larger samples and explore lithium's optimal dosage range in promoting intracerebral amyloid clearance.},
}

@article {pmid41260286,
year = {2025},
author = {Altındağ, F and Bayır, MH and Alhalboosi, JKI and Yıldızhan, K},
title = {Syringic acid mitigates scopolamine-induced cognitive impairment by regulating PSD-95 and GSK-3β and by preventing neurodegeneration in an Alzheimer-like rat model.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115556},
doi = {10.1016/j.expneurol.2025.115556},
pmid = {41260286},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a disorder characterized by progressive cognitive impairment. Syringic acid (SA) is a phenolic compound with many beneficial effects, such as antioxidant, anti-inflammatory, anti-diabetic, anti-carcinogenic, and neuroprotective. Our study aimed to investigate the effects of SA (50 mg/kg/day) on scopolamine (SCO)-induced AD-like condition in rats. Immunohistochemical evaluation was performed using antibodies to postsynaptic density protein 95 (PSD-95), Glycogen synthase kinase-3β (GSK-3β), TNF-α, and caspase-3. The hippocampus was stained with Hematoxylin-Eosin, and the total number of hippocampal neurons and hippocampal volume were calculated using the stereological method. The Y-maze task behavioral test was performed. SCO decreased PSD-95 expression while increasing GSK-3β, TNF-α, and caspase-3 expression. SA treatment increased PSD-95 expression while decreasing GSK-3β, TNF-α, and caspase-3 expression. Compared to the control group, the number of hippocampal neurons was significantly decreased in the Alzheimer's group, but the number of neurons in the SA group was significantly higher than in the Alzheimer's group. Hippocampal volume was lower in the Alzheimer's group, although there was no statistical difference between the groups. SA also improved SCO-induced cognitive impairment. Our study findings suggest that SA may mitigate SCO-induced cognitive impairment in the AD rat model, modulating PSD-95 and GSK-3β and decreasing neuroinflammation and apoptosis.},
}

@article {pmid41259985,
year = {2025},
author = {Lin, C and Li, Q and Liu, G and Xi, Z and Yan, X and Li, S and He, L and Bai, P},
title = {Fe3O4@MoS2@Au-Ag microsphere-based ultrasensitive immunobiosensor for the early diagnosis of Alzheimer's disease.},
journal = {Talanta},
volume = {299},
number = {},
pages = {129127},
doi = {10.1016/j.talanta.2025.129127},
pmid = {41259985},
issn = {1873-3573},
abstract = {Alzheimer's Disease (AD), a most common neurodegenerative disease, has aroused people's great attention. Amyloid-β 1-42 (Aβ42) from serum/plasma has been listed as Core 1 biomarker in diagnostic guide and explore an ultrasensitive detection method of Aβ42 is of great significance for early AD diagnosis and treatment. Herein, an ultrasensitive fluorescent biosensor for Aβ42 detection is designed, which is composed of Fe3O4@MoS2 microsphere and Au-Ag alloy. Compared with typical single gold nanoparticles in traditional fluorescent biosensor, alloy nanoparticles can generate a stronger electromagnetic field to enhance the fluorescence of quantum dots via surface plasmon resonance, achieve the effect of signal amplification. Importantly, our design significantly improved the limit of detection to 11 ag/mL, with a linear response ranging from 0.1 to 10[4] fg/mL. Moreover, by replacing the detection antibody in the biosensor, it can also be applied to other common AD biomarkers, such as Aβ40 (linear range: 0.1 to 10[5] fg/mL, LOD: 61 ag/mL) and total Tau protein (linear range: 0.1 to 10[5] fg/mL, LOD: 40 ag/mL). The biosensor exhibited excellent performance in both spiked and real serum samples. This fluorescent biosensor based on Au-Ag alloy strategy with ultra-sensitivity and good selectivity, provides a reliable solution for AD's early diagnosis.},
}

@article {pmid41261258,
year = {2025},
author = {Rahmani, D and Chodari, L and Kakallahpour, M and Niknam, Z},
title = {Therapeutic Potential of Sodium Butyrate in Neurological and Psychiatric Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {90},
pmid = {41261258},
issn = {1559-1182},
mesh = {Humans ; *Mental Disorders/drug therapy ; Animals ; *Butyric Acid/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Histone Deacetylase Inhibitors/therapeutic use/pharmacology ; },
abstract = {Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are characterized by progressive neuronal loss associated with neuroinflammation, oxidative stress, and epigenetic dysregulation. Emerging evidence suggests that histone deacetylases (HDACs) are overexpressed in these conditions, making HDAC inhibitors (HDACIs) like sodium butyrate (NaB) promising candidates for therapeutic intervention. In addition, NaB has shown beneficial effects in various psychiatric disorders, including depression, anxiety, and schizophrenia, suggesting a broader neurotherapeutic potential. This review synthesizes findings from various in vitro and in vivo studies investigating the mechanisms and therapeutic applications of NaB, in both neurological and psychiatric disorders. We focus on its role as an HDACI, its impact on histone acetylation and gene expression, its ability to modulate gut microbiota, and its capacity to cross the blood-brain barrier (BBB) to exert neuroprotective effects. NaB demonstrates anti-inflammatory, antioxidant, anti-apoptotic, and neurotrophic properties, contributing to improved cognitive, motor, and behavioral outcomes in multiple models of central nervous system (CNS) dysfunction. Accumulating evidence supports its efficacy not only in NDDs but also in mental health disorders, highlighting its potential as a complementary treatment alongside conventional therapies. Given its multifaceted mechanisms and favorable safety profile, NaB holds promise as a novel therapeutic agent across a spectrum of neurological and psychiatric conditions. Further clinical investigation is warranted to fully establish its translational value.},
}

Humans
*Mental Disorders/drug therapy
Animals
*Butyric Acid/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy
Histone Deacetylase Inhibitors/therapeutic use/pharmacology

@article {pmid41261002,
year = {2025},
author = {Canney, M and Bouchoux, G and Carpentier, A and De Rossi, P},
title = {Repeated blood-brain barrier opening using low-intensity pulsed ultrasound mitigates amyloid pathology.},
journal = {Ultrasound in medicine & biology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ultrasmedbio.2025.10.008},
pmid = {41261002},
issn = {1879-291X},
abstract = {OBJECTIVE: The delivery of large molecules to the pathological brain is one of the main obstacles in the development of disease-modifying drugs. This is partly due to the presence of the blood-brain barrier (BBB), which blocks the free passage of lipophobic molecules and those larger than 400 Da. One strategy to bypass this natural barrier is to use low-intensity pulsed ultrasound to oscillate circulating micro-sized microbubbles, which then exert mechanical stress on the vessel walls. This procedure allows for temporary disruption of the BBB and enhanced local delivery of therapeutics from the blood to the brain parenchyma. In this study, the effect of repeated BBB opening on neuroinflammation in a healthy mouse model was first explored, followed by the effect of repeated opening on amyloid-beta (Aβ) pathology in an Alzheimer's disease model.

METHODS: A cohort of wild-type mice was used to determine the effect of a single BBB opening session mediated by ultrasound/microbubbles (US/MBs) on the inflammatory profile via real-time quantitative polymerase chain reaction on brain extracts at 2, 4, 8 and 15 d post-opening. A second cohort of ARTE10 mice, a mouse model for Aβ pathology, was treated with a different sequence of repeated US/MB-mediated BBB opening to explore the effect on Aβ pathology. Tissues were also analyzed for immune cell infiltration, microglia and astrocyte activation, as well as inflammatory response.

RESULTS: Our results demonstrate that opening the BBB leads to a mild inflammatory response in wild-type animals. However, repeated opening of the BBB in the ARTE10 model resulted in a mild decrease in Aβ pathology, along with a mild increase in growth factor.

CONCLUSION: Altogether, this study suggests that sonication is not only a safe method to deliver therapeutics to the brain but could also have synergistic effects in the treatment of neurodegenerative disease.},
}

@article {pmid41260522,
year = {2025},
author = {Park, JK and Kim, HG and Lee, JS and Joo, JH and Yoo, HR},
title = {Traditional Herbal Medicine Ga-Mi Gongjindan Improves Muscarinic Cholinergic Dysfunction through Regulation of BDNF/CREB Signaling Pathway Using a Scopolamine-Induced Cognitive Impairment of Mouse Model.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111644},
doi = {10.1016/j.brainresbull.2025.111644},
pmid = {41260522},
issn = {1873-2747},
abstract = {BACKGROUND: Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by progressive memory loss and cognitive dysfunction, often linked to cholinergic system deterioration and hippocampal oxidative stress. Current pharmacological treatments offer only modest symptomatic relief and are often accompanied by adverse effects. In traditional Korean medicine, Ga-Mi Gongjindan (GJD), a modified formulation of Gongjindan, has long been used for enhancing cognitive function, but its neuropharmacological basis remains largely unexplored.

OBJECTIVE: This study aimed to investigate the neuroprotective potential and underlying mechanisms of GJD in a murine model of scopolamine-induced cognitive impairment, which mimics aspects of muscarinic cholinergic dysfunction observed in Alzheimer's disease (AD).

METHODS: C57BL/6J mice were administered GJD or tacrine (positive control) for 14 days. Cognitive impairment was induced by a single intraperitoneal injection of scopolamine (2mg/kg), and behavioral analysis was assessed using the Morris Water Maze. Hippocampal tissues were analyzed for markers of oxidative stress, inflammation, cholinergic function, and neurotrophic signaling by focusing on the BDNF/CREB signaling pathway.

RESULTS: GJD treatment significantly improved spatial learning and memory performance. It restored cholinergic function by reducing acetylcholinesterase (AChE) activity and increasing choline acetyltransferase (ChAT) levels. GJD also suppressed oxidative stress and neuroinflammation and markedly enhanced hippocampal expression of brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and their receptors (TrkA, TrkB, and M1 mAChR).

CONCLUSION: GJD exerted significant neuroprotective effects in a scopolamine-induced model of cognitive dysfunction, potentially via modulation of cholinergic and BDNF/CREB signaling pathways. These findings provide a scientific rationale for the traditional use of GJD in cognitive disorders and support its further development as a candidate for treating neurodegenerative diseases such as AD.},
}

@article {pmid41260167,
year = {2025},
author = {Wang, X and Li, W and Liu, X and Liang, J and Wang, L and Liu, G and Liu, Y and Song, M and Li, Z and Guo, Y and Li, S and Fu, N and Zhang, B},
title = {Celastrol as a neuroprotective drug: current status and challenges.},
journal = {International immunopharmacology},
volume = {168},
number = {Pt 2},
pages = {115846},
doi = {10.1016/j.intimp.2025.115846},
pmid = {41260167},
issn = {1878-1705},
abstract = {Neurological disorders are increasing worldwide, imposing a major social and economic burden. Therefore, there is an urgent need to explore effective treatment methods to alleviate neurological disorders. Celastrol, derived from the traditional Chinese medicine Tripterygium wilfordii Hook. f., has been shown in multiple studies to exhibit promising neuroprotective effects in neurodegenerative, including Parkinson's disease, Alzheimer's disease, and spinal cord injury. The targets or pathways through which celastrol exerts its neuroprotective effects are diverse. This paper primarily focuses on in vivo animal models (such as Parkinson's disease mouse models, Alzheimer's disease mouse models) and in vitro cell models (such as neuronal cell lines, primary cultured neurons) experiments to comprehensively summarize the molecular mechanisms underlying celastrol's neuroprotective effects. Celastrol exerts its neuroprotective effects through pathways such as reducing inflammation, activating the autophagy-lysosome pathway, and inhibiting ferroptosis. Additionally, we discuss the current challenges faced by celastrol and potential strategies to address them. Collectively, these findings highlight celastrol as a promising therapeutic candidate, although further pharmacokinetic optimization and clinical validation are essential.},
}

@article {pmid41258757,
year = {2025},
author = {Saini, TC and Randhawa, S and Bathla, M and Nisha, A and Teji, N and Acharya, A},
title = {Nanoengineered Polyphenol-Quantum Dot Conjugates Inhibit Biofilm Protein-Aβ42 Heterotypic Fibrillogenesis, Restore Synaptic Transmission, and Suppress Apoptosis in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00467},
pmid = {41258757},
issn = {1948-7193},
abstract = {The gut microbiota influences neurodegenerative disease progression, including Alzheimer's disease (AD), through microbial metabolites like amyloids in bacterial biofilms, such as the curli protein in Eshcherichia coli biofilm. In this context, the study focuses on two key aspects, namely, (i) how cross-kingdom bacterial biofilm proteins accelerate Aβ42 aggregation and induce neurotoxicity and (ii) whether a nanochaperone with hydrophobic sheets and hydrophilic polyphenolic moieties could inhibit cross-seeded aggregation. Considering this, we chemically synthesized and further characterized gallic acid-conjugated molybdenum disulfide quantum dots (GA@MoS2 QDs, ∼9.6 ± 4.2 nm) using spectroscopy and microscopy techniques, which showed ∼1.84-fold reduction in E. coli biofilm thickness, indicating interaction with biofilm components. The presence of the curli protein in E. coli was confirmed by dot blot and MALDI-TOF studies. Subsequent biophysical studies showed that isolated E. coli biofilm protein accelerated Aβ42 aggregation (heterotypic) by ∼6.76-fold, while GA@MoS2 QDs reduced this heterotypic aggregation by ∼9.49-fold reduction in Aβ42+ECBFP fluorescence relative to Aβ42 aggregates. In vitro studies with SH-SY5Y cells showed that heterotypic protein aggregation led to increased ROS production, intracellular calcium influx, and apoptosis induction, which were mitigated by GA@MoS2 QDs. The neuroprotective effect of GA@MoS2 QDs was also studied on Caenorhabditis elegans. Overall, the present studies suggested that the bacterial amyloid proteins may play a crucial role in Aβ42 aggregation, suggesting that targeting coaggregation could provide a novel therapeutic approach for the treatment of early onset AD.},
}

@article {pmid41258645,
year = {2025},
author = {Katsuse, K and Kakinuma, K and Niimi, Y and Iseki, C and Kawakami, N and Ota, S and Kawamura, A and Ogawa, N and Yano, S and Kakumoto, T and Takao, H and Hamada, M and Kanno, S and Toda, T and Suzuki, K},
title = {Lecanemab for posterior cortical atrophy: Two contrasting cases.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/13854046.2025.2590527},
pmid = {41258645},
issn = {1744-4144},
abstract = {OBJECTIVE: This study aimed to evaluate the clinical implications, limitations, and potential risks of lecanemab treatment for posterior cortical atrophy (PCA) by conducting a comparative analysis of two cases.

METHOD: We retrospectively analyzed two patients with biomarker-confirmed PCA-pure who met the eligibility criteria for lecanemab. Clinical history, neuropsychological profiles, imaging findings, and treatment outcomes for more than 1 year were comprehensively reviewed.

RESULTS: At treatment initiation, Patients 1 and 2 were one year post-onset and five years post-onset, respectively, with comparable baseline Mini-Mental State Examination (25-26) and Clinical Dementia Rating (0.5) scores. Patient 1, who exhibited prominent agraphia with left-dominant parieto-occipital atrophy, began lecanemab early and maintained stable daily functioning despite a gradual decline in reading, figure copying, and visual cancelation tasks. Patient 2, with right-dominant posterior atrophy and more severe visuospatial deficits, including simultanagnosia and prosopagnosia, developed parkinsonism and hallucinations after treatment initiation, followed by rapid functional decline, possibly due to mixed pathology, ultimately leading to treatment discontinuation. Patient 1 reported high treatment satisfaction, whereas Patient 2 expressed regret.

CONCLUSION: These cases raise concerns regarding the direct application of treatment eligibility criteria developed for typical Alzheimer's disease to PCA. Clinical decision-making in PCA requires visual cognition-specific assessments that are less vulnerable to floor effects and tailored to phenotypic heterogeneity and hemispheric lateralization. Coexisting pathologies may influence the treatment response and complicate the interpretation of outcomes. A tailored, multimodal approach that integrates longitudinal neuropsychological assessments with advanced imaging is essential to ensure appropriate use of disease-modifying therapies for PCA.},
}

@article {pmid41258002,
year = {2025},
author = {Yang, C and Wang, P and Zhu, Z and Wu, H and Su, Q and Zhu, S and Shao, Y and Lin, H and Biswal, BB},
title = {Individualized functional connectome biomarkers predict clinical symptoms after rTMS treatment in Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-025-03726-4},
pmid = {41258002},
issn = {2158-3188},
abstract = {Pharmacological treatments for Alzheimer's disease (AD) often show limited effectiveness, prompting growing interest in non-drug approaches such as repetitive transcranial magnetic stimulation (rTMS). However, the effects of rTMS can vary widely between individuals with AD, highlighting the need to better understand brain characteristics that may influence treatment response. In this study, we applied a personalized method to divide each participant's brain cortex into functionally meaningful regions based on their brain activity patterns, rather than relying on a standard brain template. Using this individualized brain mapping approach, we examined how rTMS changes functional connectivity (FC) across the brain. We further used support vector regression to estimate whether these individualized FC patterns could predict the severity of clinical symptoms. The results showed that rTMS significantly increased whole-brain individualized FC strength during resting state, with the most prominent effects observed in the default mode and visual networks (Cohen's d > 0.27, corrected p < 0.05). Importantly, the personalized FC features served as predictive biomarkers, demonstrating greater accuracy in forecasting clinical outcomes compared to the conventional group-based approach. These findings suggest that individualized brain connectivity holds significant potential for guiding personalized therapeutic strategies and improving treatment efficacy in AD.},
}

@article {pmid41257439,
year = {2025},
author = {Vázquez-Oliver, A and Pérez-García, S and Romero-Pérez, R and Pizarro, N and Galarraga-Shinin, D and Molina-Porcel, L and de la Torre, R and Maldonado, R and Ozaita, A},
title = {Targeting dysregulated CB1 receptors in a Down syndrome mouse model improves neurological outcomes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70874},
doi = {10.1002/alz.70874},
pmid = {41257439},
issn = {1552-5279},
support = {RTI2018-099282-B-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2021-123482OB-I00-/MICIN/AEI/10.13039/501100011033/FEDER//Ministerio de Ciencia, Innovación y Universidades/ ; PID2020- 120029GB-I00/MICIN/AEI/10.13039/501100011033//Ministerio de Ciencia, Innovación y Universidades/ ; 1896_GRT-2019B//Fondation Jérôme Lejeune/ ; #2416_GRT-2024B//Fondation Jérôme Lejeune/ ; CA2018010//Bright Focus foundation/ ; RD16/0017/0020//Ministerio de Sanidad, Servicios Sociales e Igualdad/ ; 2017SGR-669//Departament de Recerca i Universitats, Generalitat de Catalunya/ ; 2017SGR-138//Departament d'Economia i Coneixement, Generalitat de Catalunya/ ; //Institució Catalana de Recerca i Estudis Avançats, ICREA-Acadèmia 2021/ ; },
mesh = {Animals ; *Down Syndrome/metabolism/drug therapy ; *Receptor, Cannabinoid, CB1/metabolism/antagonists & inhibitors ; Mice ; Disease Models, Animal ; *Hippocampus/metabolism/drug effects ; *Rimonabant/pharmacology ; Humans ; Male ; Female ; Alzheimer Disease/metabolism ; *Cannabinoid Receptor Antagonists/pharmacology ; Mice, Transgenic ; Middle Aged ; },
abstract = {INTRODUCTION: Down syndrome (DS) is the most common genetic cause of intellectual disability, affecting cognitive function and increasing the risk of early-onset Alzheimer's disease (AD). The endocannabinoid system may serve as a therapeutic target for cognitive deficits by inhibiting cannabinoid type-1 receptor (CB1R) function.

METHODS: CB1R expression was analyzed in the hippocampi of aged DS-associated AD (DSAD) individuals and middle-aged Ts65Dn mice. Long-term oral treatment with the CB1R antagonist rimonabant was used to assess its effects on memory and neuroinflammation in the Ts65Dn mouse model of DS.

RESULTS: CB1R expression was significantly increased in both aged DSAD subjects (specifically in the dentate gyrus and CA2 posterior hippocampal subregions) and Ts65Dn mice. Long-term rimonabant treatment improved memory performance, normalized microglial morphology, and reduced plasma inflammatory markers in trisomic mice without preventing neuron decline.

DISCUSSION: These findings suggest that sustained CB1R inhibition may enhance cognitive function by modulating neuroinflammation, highlighting its therapeutic potential for cognitive impairments in DS.

HIGHLIGHTS: Cannabinoid type-1 receptor (CB1R) expression is increased in the posterior hippocampus of aged Down syndrome (DS) subjects and Ts65Dn mice. Long-term rimonabant treatment enhances memory in middle-aged Ts65Dn mice. CB1R inhibition shifts neuroinflammatory features in Ts65Dn mice. CB1R inhibition does not halt noradrenergic/cholinergic neurodegeneration in Ts65Dn. CB1R inhibition presents potential for memory improvement in DS-related deficits.},
}

Animals
*Down Syndrome/metabolism/drug therapy
*Receptor, Cannabinoid, CB1/metabolism/antagonists & inhibitors
Mice
Disease Models, Animal
*Hippocampus/metabolism/drug effects
*Rimonabant/pharmacology
Humans
Male
Female
Alzheimer Disease/metabolism
*Cannabinoid Receptor Antagonists/pharmacology
Mice, Transgenic
Middle Aged

@article {pmid41257084,
year = {2025},
author = {Elshahary, A and Safwan, H and Abdelwaly, A and Arafa, RK and Helal, MA},
title = {Discovery of indole- and quinolone-based inhibitors of the mTOR/Akt/Pi3K pathway for the potential treatment of autism and certain types of cancer.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41257084},
issn = {2632-8682},
abstract = {Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the PI3K-related protein kinase family. It is an integral part of two functionally distinct protein complexes: mTOR complex 1 and mTOR complex 2. Its signaling pathway is linked to cell survival, growth, proliferation, and motility. Deregulation of the mTOR pathway has been reported in many types of cancer. Hence, mTOR is an attractive target for the treatment of certain cancers such as renal cell carcinoma and pancreatic tumors. In addition, hyperactivity in mTOR-mediated signaling is associated with the pathogenesis of autism spectrum disorder (ASD) and Alzheimer's disease. Recently, mTOR inhibitors have been considered as emerging pharmacotherapy for these disorders. In this research, we have used molecular modeling techniques to design three series of compounds, indoles, β-carbolines, and 4-aminoquinolines, targeting the ATP site of the mTOR kinase. Based on insights from molecular docking, we developed twenty eight derivatives of these scaffolds to explore the SAR and optimize their affinities. The prepared compounds were evaluated for their inhibitory activity against mTOR as well as other closely related kinases such as PI3K and AKt. To our delight, twenty compounds have shown sub-micromolar activities towards the mTOR kinase. Compounds HA-2l and HA-2c showed a superior IC50 of 66 and 75 nM, respectively, for mTOR, while being selective against AKt and Pi3K. Upon optimization, these selective inhibitors could be useful for the management of ASD due to their relatively higher safety and, hence, suitability for long-term use. On the other hand, derivatives HA-1e, HA-2g, and HA-3d exhibited high affinities for the three enzymes, suggesting their potential utility as anticancer agents. Also, the cytotoxicity of the most active compounds was assessed using different cell-lines. Compounds HA-2g, HA-2l, and HA-3d showed sub-micromolar inhibition, in the range of 0.610-0.780 μM, against the tested cancer cell lines MDA-MB231 and HCT-116. The discovery of a clinically useful mTOR inhibitor would represent a new hope for patients of two important non-communicable diseases, cancer and ASD.},
}

@article {pmid41257022,
year = {2025},
author = {Abdel-Magid, AF},
title = {Inhibitors of Stearoyl-Coenzyme A Desaturase 1 and 5 May Provide a Novel Therapeutic Strategy for the Treatment of Neurological Disorders and Brain Cancer.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {11},
pages = {2191-2193},
pmid = {41257022},
issn = {1948-5875},
abstract = {The invention in this patent application relates to heterocyclic compounds represented herein generally by formula 1. These compounds are inhibitors of stearoyl-coenzyme A desaturases (SCD1 and/or SCD5) and may provide a useful treatment for neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) as well as primary brain cancer such as glioblastoma (GBM).},
}

@article {pmid41257016,
year = {2025},
author = {Song, Z and Liang, SH},
title = {Novel 2H‑Pyrazolo[3,4‑d]thiazole Compounds Targeting NLRP3 for the Treatment of Neurodegenerative Diseases.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {11},
pages = {2200-2201},
pmid = {41257016},
issn = {1948-5875},
abstract = {The invention discloses novel NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inhibitors featuring a 2H-pyrazolo-[3,4-d]-thiazole scaffold. These NLRP3 inhibitors exhibit significant potential as therapeutic candidates for neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.},
}

@article {pmid41256885,
year = {2025},
author = {Cottrell, S and Yoon, S and Wei, X and Dickson, A and Wei, GW},
title = {Computational Drug Repurposing for Alzheimer's Disease via Sheaf Theoretic Population-Scale Analysis of snRNA-seq Data.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41256885},
issn = {2331-8422},
abstract = {Single-cell and single-nucleus RNA sequencing (scRNA-seq /snRNA-seq) are widely used to reveal heterogeneity in cells, showing a growing potential for precision and personalized medicine. Nonetheless, sustainable drug discovery must be based on a population-level understanding of molecular mechanisms, which calls for the population-scale analysis of scRNA-seq/snRNA-seq data. This work introduces a sequential target-drug selection model for drug repurposing against Alzheimer's Disease (AD) targets inferred from population-level snRNA-seq studies of AD progression in microglia cells as well as different cell types taken from an AD affected brain vascular tissue atlas, involving hundreds of thousands of nuclei from multi-patient and multi-regional studies. We utilize Persistent Sheaf Laplacians (PSL) to facilitate a Protein-Protein Interaction (PPI) analysis of AD targets inferred from differential gene expression (DEG), and then use machine learning models to predict repurpose-able DrugBank compounds for molecular targeting. We screen the efficacy of different DrugBank small compounds and further examine their central nervous system (CNS)-relevant ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity), resulting in a list of lead candidates for AD treatment. The list of significant genes establishes a target domain for effective machine learning based AD drug repurposing analysis of DrugBank small compounds to treat AD related molecular targets.},
}

@article {pmid41256774,
year = {2025},
author = {Yu, J and Bao, X and Shan, C and Yu, Z and Yu, Y and Wang, H and Zhang, Y},
title = {Traditional Chinese medicine's holistic approach: regulating microglia-driven neuroinflammation for the resolution of Alzheimer's disease.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1691253},
pmid = {41256774},
issn = {1662-5102},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive dysfunction, motor abnormalities, and memory disorders, with a persistently high and rising incidence. The pathological features of AD include the extracellular deposition of the amyloid beta peptide (Aβ), the accumulation of neurofibrillary tangles (NFTs), and neuroinflammation. Microglia (MG), the main immune cells in the central nervous system (CNS), can transform into different phenotypes. An imbalance in their phenotypic transformation may induce neuroinflammation and lead to neurological diseases, playing a central role in the onset and progression of AD.

PURPOSE: This article aims to briefly review the key role of microglia-mediated neuroinflammation in the pathogenesis of AD and to summarize and analyze the strategies of traditional Chinese medicine (TCM) for targeting microglia in AD treatment.

METHODS: Literature review and analysis were conducted to summarize the role of microglia-mediated neuroinflammation in AD pathogenesis and to collate TCM therapeutic strategies aimed at modulating microglia.

RESULTS AND CONCLUSION: Microglia-mediated neuroinflammation plays a central role in the pathological progression of AD. TCM demonstrates potential in intervening in AD neuroinflammation by regulating the microglial phenotype and function. These related therapeutic strategies warrant further summary and analysis.},
}

@article {pmid41256155,
year = {2025},
author = {Su, CW and Chen, K and Wu, T and Reiman, EM and Wang, Q and , },
title = {TAS2R38-Linked MGAM Expression in Alzheimer's Disease: A Novel Target for Precision Drug Repurposing.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.09.25334938},
pmid = {41256155},
abstract = {OBJECTIVE: TAS2R38 is a taste receptor implicated in innate immunity. Identifying its genetic connection with Alzheimer's disease (AD) could aid in developing new drugs or repurposing existing ones for treatment.

METHODS: We examined the relationship between TAS2R38 taster variants and AD risk using linear mixed-effects models, utilizing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 2,342). We investigated molecular mechanisms of the association by identifying expression quantitative trait loci (eQTLs) using RNA-seq data from postmortem tissues from the Religious Orders Study/Memory and Aging Project (ROSMAP) (n = 947). We evaluated whether FDA-approved drugs targeting the identified gene could reduce dementia risk using 1:1 propensity score-matched groups in the National Alzheimer's Coordinating Center (NACC) study, comparing cognitive performance between drug-taking and non-taking patients with linear mixed-effects models (n = 76).

RESULTS: TAS2R38 supertasters were linked to reduced AD risk with advancing age in various AD biomarkers (P < 0.001). eQTL analysis connected the nontaster allele to increased expression of the gene MGAM in AD-affected brain regions (P < 0.001). Elevated MGAM expression was also associated with more severe Tau burdens (P < 0.05). A significant group difference was observed in clinical dementia rating (CDR) progression (P < 0.001) in various domains for individuals taking MGAM-inhibiting diabetes drugs (Acarbose and Miglitol) compared to the non-taking group.

INTERPRETATION: The genetic association between TAS2R38 and AD biomarkers implicates MGAM as a novel drug target with existing FDA-approved inhibitors. This supports the potential of TAS2R38 haplotypes in guiding precision drug repurposing strategies for AD, warranting clinical trials.},
}

@article {pmid41256144,
year = {2025},
author = {Yakoub, Y and Qiu, T and Peyrot, C and Salvadó, G and Villeneuve, S and Binette, AP and , },
title = {Trajectories of plasma biomarkers, amyloid-beta burden and cognitive decline in Alzheimer's disease: A Longitudinal ADNI Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.30.25337003},
pmid = {41256144},
abstract = {As novel amyloid-β targeted therapies emerge, plasma biomarkers have promising potential to serve as screening tools and as surrogate measures for treatment outcomes. Understanding longitudinal trajectories of these biomarkers and how their changes relate to changes in AD pathology and cognition is needed to help track treatment response and guide patient care. We analyzed data from 394 individuals in the ADNI-FNIH dataset who had plasma biomarkers available across 14 assays, Aβ-PET scans and cognitive assessments over a 10-year period. Plasma p-tau217, regardless of the assay used, had the greatest rate of change over time. This increase was related to concurrent increase in Aβ-PET burden only in individuals with low levels of Aβ. The rate of p-tau217 change, rather than its baseline level, was the strongest predictor of future Aβ-PET positivity. On the other hand, in individuals with elevated levels of Aβ, higher rate of change in p-tau217 was associated with faster cognitive decline. These findings highlight a "dual" role of plasma p-tau217 rate of change, being either predictive of accumulating Aβ pathology at early stages and of cognitive decline at later stages of the AD continuum.},
}

@article {pmid41256136,
year = {2025},
author = {Tang, AS and Zeng, BZD and Rankin, KP and Miller, B and Gorno-Tempini, ML and Seeley, WW and Rosen, HJ and Rabinovici, GD and Oskotsky, TT and Sirota, M and Pinheiro-Chagas, P},
title = {Characterizing Dementia Phenotypes from Unstructured EHR Notes with Generative AI and Interpretable Machine Learning.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.01.25336815},
pmid = {41256136},
abstract = {Dementia encompasses diverse clinical syndromes where diseases of the brain can manifest as impaired cognitive abilities, such as in Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). The diversity of symptom presentations often results in challenges in diagnosis. Crucial clinical information remains in unstructured narrative notes within electronic health records (EHRs). We leverage large language models (LLMs) for symptom phenotyping from notes in UCSF Information Commons, focusing on patients with expert dementia syndrome diagnosed from a multidisciplinary team of specialists from the UCSF Memory and Aging Center. We developed a pipeline to extract findings in a validated structured output, clustered into symptom groups, and then classified patients into syndromes with traditional machine learning paradigms. From over 9,000 cross-referenced patients and over 350,000 specialty-related notes, matched cohorts of bvFTD (122 patients) and AD (170) syndromes were identified. From notes, 12,637 distinct symptom phrases were extracted, with clustering analysis revealing 51 symptom groups. A logistic regression model separated AD and bvFTD with an AUC of 0.83. Disinhibition and obsessive-compulsive behaviors favored bvFTD, while anxiety and visuospatial abnormalities favored AD. This novel approach, combining LLM-based structured information extraction with traditional interpretable prediction paradigms, demonstrates a promising approach for enhanced symptom characterization in dementia. Our findings suggest potential future applications in improving diagnostic accuracy, developing prediction models, and optimizing treatment strategies in dementia care.},
}

@article {pmid41255958,
year = {2025},
author = {Biswas, P and Rahman, MH and Tabassum, A and Shoyshob, TZ and Jalouli, M and Islam Tareq, MM and Imtiaz, M and Dona, HA and Harrath, AH and Rahman, MA},
title = {Novel Drug Targets for Neurodegenerative Diseases of Elderly People to Develop Effective Therapeutics: A Comprehensive Analysis.},
journal = {Advances in pharmacological and pharmaceutical sciences},
volume = {2025},
number = {},
pages = {8847508},
pmid = {41255958},
issn = {2633-4690},
abstract = {Neurodegenerative diseases (NDs) represent an increasingly important burden of disease, particularly in the aging population. The etiology of NDs like Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) is associated with progressive neuronal degeneration and a paucity of effective therapies. Accumulating evidence suggests that common and intersecting genetic and pathological pathways play a critical role in disease onset and progression, revealing new opportunities for target discovery. Here, we review promising therapeutic targets based on the convergence of genetics, molecular pathology, and cellular signaling in neurodegeneration. This narrative will focus on key proteins (amyloid-beta [Aβ], tau, and α-synuclein) and enzymes (acetylcholinesterase and asparagine endopeptidase [AEP]), including their pathological significance and therapeutic implications. N-Methyl-D-aspartate receptors (NMDARs) and cholinergic receptor subtypes are highlighted as important regulators of neurotoxicity, synaptic transmission, and inflammation. Emerging advances in genomics, neuroimaging, and drug delivery are poised to advance precision medicine strategies for early diagnosis and intervention. Important challenges remain, including the complexity of the blood-brain barrier (BBB), pathology heterogeneity, and the need for new biomarkers. We propose that a shift from phenotype-driven diagnoses to mechanistic, genetically informed approaches may improve treatment efficacy. Target identification, validation, and targeted delivery are critical considerations for the success of future therapeutic development. This integrated view will help to inform and improve drug discovery and personalized medicine approaches in the field of neurodegeneration.},
}

@article {pmid41255128,
year = {2025},
author = {Nilsson, P and Sörgjerd, K and Kakiya, N and Sasaguri, H and Watamura, N and Johansson, L and Shimozawa, M and Tsubuki, S and Zhou, Z and Loera-Valencia, R and Takamura, R and Sekiguchi, M and Pegel, A and Schulz, S and Saito, T and Iwata, N and Winblad, B and Saido, TC},
title = {Somatostatin receptor subtypes 1 and 4 regulate neprilysin, the major amyloid-β degrading enzyme in brain.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392782},
doi = {10.1177/13872877251392782},
pmid = {41255128},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) brains are characterized by increased levels of the pathogenic amyloid-β (Aβ) peptide, which accumulates into extracellular plaques. Finding a way to lower Aβ levels is fundamental for the prevention and treatment of AD. Neprilysin is the major Aβ degrading enzyme which is regulated by the neuropeptide somatostatin.ObjectiveWe here aimed at identifying the subtype specificity of the five somatostatin receptors (SSTs) expressed in the brain, involved in the regulation of neprilysin.MethodsWe used a combination of in vitro and in vivo approaches using a battery of generated Sst double knockout (dKO) mice. We investigated SST specificity of neprilysin regulation using primary neuronal cultures in combination with SST agonist treatments and neprilysin activity measurements. Brains from Sst dKO mice were analyzed for neprilysin and Aβ by biochemical and immunohistological means. Amyloid-beta precursor protein (App) knock-in mice were treated with SST1,4 agonist and its effects on neprilysin and Aβ were assessed by immunostaining and ELISA.ResultsWe show that neprilysin is regulated by SST1 and SST4 in a redundant manner. Sst1 and Sst4 dKO mice exhibit a specific decrease of presynaptic neprilysin in the Lacunosum molecular layer. Moreover, a genetic deficiency of Sst1 and Sst4 in App knock-in mice aggravates the Aβ pathology in hippocampus. As a first proof of concept towards an Aβ-lowering strategy involving neprilysin, we demonstrate that treatment with an SST1,4 agonist ameliorates the Aβ pathology.ConclusionsSST1 and SST4 redundantly regulate neprilysin in the hippocampus where it controls Aβ metabolism.},
}

@article {pmid41254914,
year = {2025},
author = {Mackey-Alfonso, SE and Barrientos, RM},
title = {Neuroinflammatory mechanisms linking high-fat diets to Alzheimer's disease vulnerability: Beyond the amyloid hypothesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70911},
doi = {10.1002/alz.70911},
pmid = {41254914},
issn = {1552-5279},
support = {RFAG028271/AG/NIA NIH HHS/United States ; R03AG067061/AG/NIA NIH HHS/United States ; R21AG071133/AG/NIA NIH HHS/United States ; //Ohio State University Presidential Fellowship/ ; },
mesh = {*Alzheimer Disease/metabolism/etiology/pathology ; Humans ; *Diet, High-Fat/adverse effects ; *Neuroinflammatory Diseases/metabolism ; Amyloid beta-Peptides/metabolism ; Toll-Like Receptor 4/metabolism ; Animals ; Brain/metabolism/pathology ; },
abstract = {As global life expectancy increases, Alzheimer's disease (AD) incidence is rising rapidly. While research has long focused on amyloid beta (Aβ) and tau pathology, recent controversies and limited clinical success of Aβ-targeting therapies have challenged their centrality in AD. Emerging evidence highlights neuroinflammation as an earlier and potentially more critical driver of disease, particularly in response to environmental and lifestyle factors. High saturated fat diets (HFD) are strongly associated with increased AD risk in both clinical and preclinical studies. This review examines how HFD promotes AD vulnerability via neuroinflammatory mechanisms, including toll-like receptor 4 activation and complement system overactivation, which contribute to synaptic loss and cognitive decline-often independent of Aβ burden and metabolic dysfunction. Short-term HFD exposure can rapidly induce neuroinflammation and impair memory, underscoring the direct impact of diet on brain health. These insights support a shift toward targeting immune pathways and synaptic preservation in AD prevention and treatment. HIGHLIGHTS: High saturated fat diets (HFDs) increases Alzheimer's disease risk independently of obesity or insulin resistance. Neuroinflammation is a key driver of HFD-induced cognitive decline. Toll-like receptor 4 (TLR4) activation links saturated fats to synaptic loss and memory deficits. HFDs promote complement-mediated microglial synaptic engulfment. Short-term HFD exposure rapidly impairs memory and increases brain inflammation.},
}

*Alzheimer Disease/metabolism/etiology/pathology
Humans
*Diet, High-Fat/adverse effects
*Neuroinflammatory Diseases/metabolism
Amyloid beta-Peptides/metabolism
Toll-Like Receptor 4/metabolism
Animals
Brain/metabolism/pathology

@article {pmid41254870,
year = {2025},
author = {Rathod, SS and Agrawal, YO},
title = {β-Caryophyllene Ameliorates STZ-Induced Alzheimer's Disease-Like Conditions in Rats via Modulation of Brain-Derived Neurotrophic Factor, Synaptic Plasticity, and Neuroinflammation.},
journal = {The European journal of neuroscience},
volume = {62},
number = {10},
pages = {e70317},
doi = {10.1111/ejn.70317},
pmid = {41254870},
issn = {1460-9568},
mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; *Neuronal Plasticity/drug effects ; Male ; *Polycyclic Sesquiterpenes/pharmacology ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; Rats ; Rats, Sprague-Dawley ; Streptozocin/toxicity ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Hippocampus/drug effects/metabolism ; *Neuroprotective Agents/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and neuroinflammation. Synaptic plasticity and neuroinflammation are hallmarks of AD, with their dysregulation forming a self-reinforcing cycle that aggravates neurodegeneration. Proinflammatory cytokines impair synaptic signaling by suppressing brain-derived neurotrophic factor (BDNF) expression and neuroplasticity markers, further compromising synaptic plasticity. β-Caryophyllene (BCP), a natural bicyclic sesquiterpene with anti-inflammatory and neuroprotective properties, may counteract these pathological processes. This study evaluated the effect of BCP in mitigating streptozotocin (STZ)-induced AD-like conditions in male Sprague-Dawley rats. Two doses of STZ (3 mg/kg) on Days 1 and 3 were administered intracerebroventricularly to induce AD-like pathology. Rats received BCP (10, 20 mg/kg, i.p.) or rivastigmine (2.5 mg/kg) for 28 days. Cognitive performance was assessed using the Barnes maze and novel object recognition tests. Hippocampal tissues were analyzed for BDNF expression, synaptic plasticity markers (e.g., synaptophysin, neural cell adhesion molecule [NCAM], and ciliary neurotrophic factor [CNTF]), neuroinflammatory markers (e.g., IL-1β, TNF-α, IL-6, COX2, and NF-κB), and oxidative stress markers. Histological (hematoxylin and eosin) and Golgi-Cox staining techniques were employed to evaluate neuronal integrity and synaptic organization. STZ-induced rats exhibited significant cognitive deficits, synaptic loss, and increased neuroinflammation. BCP treatment improved spatial learning and memory retention, increased BDNF expression, and restored synaptic plasticity markers. Furthermore, BCP attenuated neuroinflammation by reducing proinflammatory cytokine levels. Histopathology confirms normal hippocampal neuronal architecture in BCP-treated groups. These findings highlight the ability of BCP to modulate BDNF signaling, synaptic plasticity, and neuroinflammatory pathways, underscoring its potential as a multitarget therapeutic candidate for AD.},
}

Animals
*Brain-Derived Neurotrophic Factor/metabolism
*Neuronal Plasticity/drug effects
Male
*Polycyclic Sesquiterpenes/pharmacology
*Alzheimer Disease/drug therapy/chemically induced/metabolism
Rats
Rats, Sprague-Dawley
Streptozocin/toxicity
*Neuroinflammatory Diseases/drug therapy/metabolism
Hippocampus/drug effects/metabolism
*Neuroprotective Agents/pharmacology

@article {pmid41254247,
year = {2025},
author = {Kochman, U and Sitka, H and Kuźniar, J and Czaja, M and Kozubek, P and Beszłej, JA and Leszek, J},
title = {Targeted Nanoparticles for Drug Delivery Across the Blood-Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {75},
pmid = {41254247},
issn = {1559-1182},
mesh = {*Blood-Brain Barrier/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; *Nanoparticles/metabolism/chemistry ; Animals ; *Drug Delivery Systems/methods ; Drug Carriers ; },
abstract = {Alzheimer's disease (AD) presents important challenges for treatment. One significant factor that may reduce the effectiveness of therapy is the limited drug delivery to the brain due to the blood-brain barrier (BBB). Advancements in nanotechnology are offering innovative solutions to bypass this obstacle. This review highlights the role of targeted nanoparticles (NPs) as effective drug carriers across the BBB for both early and late stages of AD. The distinct pathophysiological traits of these stages-such as amyloid aggregation, abnormal accumulation of tau protein, neuroinflammation, and oxidative stress-are examined for their impact on therapy. The analysis includes lipid-based, polymeric, and inorganic NPs, exploring their unique properties for drug delivery. Strategies to target NPs to brain tissues affected by AD are discussed, emphasizing surface modifications to enhance BBB permeability. Uptake mechanisms like receptor-mediated and adsorptive-mediated transcytosis are detailed alongside safety, toxicity, and biocompatibility evaluations to assess clinical feasibility. Key findings indicate that targeted NPs significantly improve brain drug bioavailability and enable stage-specific therapeutic interventions, addressing challenges unique to early and late AD. Future research should focus on optimizing NP design for enhanced targeting specificity and minimizing long-term toxicity, ultimately paving the way for personalized nanomedicine approaches in AD treatment.},
}

*Blood-Brain Barrier/metabolism/drug effects
*Alzheimer Disease/drug therapy/metabolism/pathology
Humans
*Nanoparticles/metabolism/chemistry
Animals
*Drug Delivery Systems/methods
Drug Carriers

@article {pmid41252538,
year = {2025},
author = {Depp, C and Holden, J and Granholm, E},
title = {Digital Measurement of Subjective Experiences in Alzheimer Disease and Related Dementias (AD/ADRD).},
journal = {JMIR aging},
volume = {8},
number = {},
pages = {e71920},
doi = {10.2196/71920},
pmid = {41252538},
issn = {2561-7605},
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis ; Caregivers/psychology ; Quality of Life ; Wearable Electronic Devices ; *Dementia/psychology ; },
abstract = {Symptoms such as loss of pleasure, agitation, and sadness are subjective experiences that contribute significantly to caregiver burden and health care costs in Alzheimer disease and related dementias (AD/ADRD). However, traditional self-report measures of subjective experiences are limited in AD/ADRD due to cognitive impairments and awareness. Passive sensing, which collects data without active participant input, has emerged as a promising approach to quantify aspects of subjective experiences. Smartphones, wearables, and in-home sensors can quantify mobility, physiology, speech, and social interaction markers of constructs relevant to AD/ADRD. Available research indicates potential but is largely at the proof-of-concept stage. In this Commentary, we discuss several roadblocks to future translation of passive sensing in measuring subjective experiences in AD/ADRD, including technical implementation, data harmonization, validation, ethical and privacy principles. Addressing these challenges could lead to transformative applications to care for AD/ADRD, enabling precise monitoring of behavioral symptoms and related treatment targets, ultimately improving quality of life for persons with AD/ADRD and their caregivers.},
}

Humans
*Alzheimer Disease/psychology/diagnosis
Caregivers/psychology
Quality of Life
Wearable Electronic Devices
*Dementia/psychology

@article {pmid41251074,
year = {2025},
author = {Joshi, S and Chutia, P and Tripathi, SM},
title = {Paratonia in dementia: diagnosis and management strategies.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/17582024.2025.2591413},
pmid = {41251074},
issn = {1758-2032},
abstract = {Paratonia is a type of hypertonia with involuntary resistance to passive movement depending on the pace and force being applied. People with paratonia may find it challenging to modify their movements and posture. Limited awareness among healthcare professionals can lead to a delay in diagnosis and inadequate treatment. Here, we present two cases diagnosed with dementia due to Alzheimer's disease. The two patients developed stiffness in their bodies as the dementia progressed. Paratonia was diagnosed using the Paratonia Assessment Inventory. Severity of paratonia was assessed using the Modified Ashworth scale for paratonia (MAS-P). The caregiver's primary concern was the stiffness of the body, which created difficulties in routine care. Amantadine was initiated in both patients. Both patients demonstrated improvement in paratonia following amantadine treatment, with reduced stiffness and greater ease in caregiving tasks. The present case series highlights the role of amantadine in the management of paratonia and can contribute to the development of more treatment options.},
}

@article {pmid41250246,
year = {2025},
author = {Shang, J and Zhong, S and Shang, L and Zeng, Q and Zhao, S and Luo, X and Li, K and Zhang, X and Huang, P and Yan, Y and Liu, Z and Zhang, B and Chen, Y},
title = {Real-world application of lecanemab in early-stage alzheimer's disease: a single-center prospective cohort analysis.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {249},
pmid = {41250246},
issn = {1758-9193},
support = {82402209//National Natural Science Foundation of China/ ; 82271936//National Natural Science Foundation of China/ ; 82202090//National Natural Science Foundation of China/ ; 82271268//National Natural Science Foundation of China/ ; 82371190//National Natural Science Foundation of China/ ; LQ24H180002//Natural Science Foundation of Zhejiang Province/ ; LY24H090007//Natural Science Foundation of Zhejiang Province/ ; 2025C02113//Key Research and Development Program of Zhejiang Province/ ; },
abstract = {BACKGROUND AND OBJECTIVES: Lecanemab (Leqembi®) has been approved for the treatment of early Alzheimer’s disease (AD) patients. However, the safety and efficacy of lecanemab in clinical practice in Asia population remain unclear.

This prospective cohort study was conducted in a single center in Eastern China, including 76 early-stage AD participants treated with lecanemab. All participants underwent at least 1 lecanemab infusion.

RESULTS: The mean age was 66 years (65.53 ± 9.31), and 51 (67.1%) participants being female. A total of 49 (64.5%) participants were ApoE-ε4 carriers, including 34 (44.7%) heterozygotes and 15 (19.7%) homozygotes. Infusion-related side effects (IRSE), primarily occurred after the first infusion, were observed in 14 participants (18.4%). The most common IRSE were fever and fatigue. Until 9 Aug 2025, 58 participants had received treatment for more than 3 months, 44 for more than 6 months and 12 for more than 12 months. Amyloid-related imaging abnormalities (ARIA) were observed in 11 participants. Specifically, solitary ARIA-H (hemorrhage) was detected in 7 participants, while ARIA-E (edema) with or without cerebral micro-hemorrhage was identified in 4. Notably, all the 11 participants with ARIA were asymptomatic. Participants with isolated ARIA-H exhibited higher baseline Fazekas scores of PVWMHs (p = 0.008). Participants with a Clinical Dementia Rating Scale Global Score (CDR-GS) of 1 had a more rapid decline in Mini-Mental State Global Score (MMSE) scores as compared to those with a CDR-GS of 0.5. Following 12 months of lecanemab therapy, amyloid PET exhibited a significant reduction in brain amyloid burden.

CONCLUSION: These data support that lecanemab appears to be generally tolerated in Asian population. The IRSE and ARIA-E events were less common than the Clarity AD study.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01886-5.},
}

@article {pmid41251026,
year = {2025},
author = {Ahmad, N and Ambreen, N and Ayaz, M and Zainab, and Alam, A and Ahmad, I and Elhenawy, AA and Zghab, I and Shah, SAA and Ahmad, M},
title = {Synthesis, In Vitro Cholinesterase Inhibition, Molecular Docking, Density Functional Theory Analysis of Benzimidazole Based Hydrazone Schiff Bases.},
journal = {Journal of molecular recognition : JMR},
volume = {38},
number = {6},
pages = {e70012},
doi = {10.1002/jmr.70012},
pmid = {41251026},
issn = {1099-1352},
mesh = {*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology ; Schiff Bases/chemistry/chemical synthesis/pharmacology ; Molecular Docking Simulation ; *Hydrazones/chemistry/chemical synthesis/pharmacology ; *Benzimidazoles/chemistry/chemical synthesis/pharmacology ; Butyrylcholinesterase/chemistry/metabolism ; Acetylcholinesterase/chemistry/metabolism ; Molecular Dynamics Simulation ; Density Functional Theory ; Humans ; },
abstract = {Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are the main therapeutic targets for the treatment of neurodegenerative diseases, predominantly Alzheimer's disease. This work reports the synthesis, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of synthesized hydrazone Schiff base derivatives of benzimidazole. The compounds have been structurally deduced by means of HR-ESI-MS, [1]H-NMR and [13]C-NMR techniques and finally assessed for their in vitro AChE and BuChE inhibitory activities. All the compounds attributed notable inhibitory potential with IC50 values ranging from 34.7 ± 0.02 to 185.2 ± 2.47 μM for AChE and 40.8 ± 0.32 to 188.8 ± 2.47 μM for BuChE enzymes. The molecular docking and TD-DFT studies attributed that the compound with methoxy groups, specifically compound (7) displays increased electronic properties and strong dual binding to AChE and BuChE enzymes. Molecular dynamics (MD) simulations for the most active compound (7) were performed, which showed that compound (7) exploits the integral flexibility of AChE and BuChE to encourage conformational variations that lock both enzymes into a two-site inhibitory state. These compounds presented orbitals and favorable electrostatic profiles that improve the inhibitory potential. The results authenticate the SAR trends and highlight the significance of methoxy groups in planning potent cholinesterase inhibitors.},
}

*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology
Schiff Bases/chemistry/chemical synthesis/pharmacology
Molecular Docking Simulation
*Hydrazones/chemistry/chemical synthesis/pharmacology
*Benzimidazoles/chemistry/chemical synthesis/pharmacology
Butyrylcholinesterase/chemistry/metabolism
Acetylcholinesterase/chemistry/metabolism
Molecular Dynamics Simulation
Density Functional Theory
Humans

@article {pmid41250235,
year = {2025},
author = {Corbett, A and Sultana, J and Stych, K and Mills, R and Cummings, JL and Williams, G and Ismail, Z and Soto-Martin, M and Mintzer, J and Gauthier, S and Greig, NH and Noble, W and Killick, R and Lai, MKP and Routledge, C and Walsh, F and Fillit, H and Aarsland, D and Lane, R and Mills, K and Ballard, C},
title = {Drug repurposing for Alzheimer's disease: a Delphi consensus and stakeholder consultation.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {237},
pmid = {41250235},
issn = {1758-9193},
mesh = {*Drug Repositioning/methods ; *Alzheimer Disease/drug therapy ; Humans ; Delphi Technique ; Consensus ; Stakeholder Participation ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is an escalating global challenge, with more than 40 million people affected, and this number is projected to increase to more than 100 million by 2050. While amyloid-targeting antibody treatments (lecanemab and donanemab) are a significant step forward, the benefits of these therapies remain limited. This highlights the necessity for safe and effective compounds that offer greater therapeutic benefits to the majority of individuals with or at risk of AD. Drug repurposing allows for a cost-effective, time-efficient strategy to accelerate the availability of treatments, owing to the availability of safety information.

METHOD: This study focuses on the third iteration of the Delphi consensus programme aimed at identifying new high-priority drug candidates for repurposing in AD. An international expert panel comprising academics, clinicians and industry representatives was convened. Through a combination of anonymized drug nominations, systemic evidence reviews, iterative consensus rankings, and lay advisory inputs, drug candidates were evaluated and ranked based on rational, non-clinical, and clinical evidence and overall safety profiles.

RESULTS: Among the 80 candidates that were nominated by the expert panel, seven underwent review, with only three candidates meeting the following consensus criteria of relevant mechanisms for targeting neurodegenerative pathways, non-clinical efficacy, and tolerability in older individuals. The three agents were: [1] the live attenuated herpes zoster (HZ) vaccine (Zostavax) [2], sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, and [3] riluzole, a glutamate antagonist. The HZ vaccine additionally offers potential for population-level dementia risk reduction.

CONCLUSION: This Delphi consensus identified three high-priority drug repurposing candidates for AD with favourable safety profiles and mechanistic plausibility, which are considered suitable for pragmatic clinical trials, including remote or hybrid designs. The PROTECT platform, which supports international cohorts in the UK, Norway, and Canada, offers a well-established means to conduct such trials effectively, thus helping to accelerate the evaluation and potential deployment of these drug candidates to benefit individuals with or at risk for AD.},
}

*Drug Repositioning/methods
*Alzheimer Disease/drug therapy
Humans
Delphi Technique
Consensus
Stakeholder Participation

@article {pmid41249122,
year = {2025},
author = {Diamandis, N and van den Anker, JN and Denisova, K},
title = {Effect of Alzheimer's disease medications on neurocognitive outcomes in children and adolescents with autism spectrum disorder and low IQ: a scoping review.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {475},
pmid = {41249122},
issn = {2158-3188},
support = {R01MH121605//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; 614242//Simons Foundation/ ; },
mesh = {Humans ; Child ; Adolescent ; *Autism Spectrum Disorder/drug therapy/complications/psychology ; *Alzheimer Disease/drug therapy/complications ; *Intellectual Disability/complications ; Young Adult ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; Child, Preschool ; },
abstract = {BACKGROUND: Individuals with autism spectrum disorder (ASD) and comorbid intellectual disability (ID) are particularly vulnerable to poor developmental trajectories. These individuals are at increased risk of Alzheimer's disease (AD) relative to those without comorbid ID and the general population. Considering that there could be an important mechanistic link underlying ASD and AD, individuals with these conditions may stand to benefit from similar psychopharmacological treatments.

METHODS: This scoping review aimed to evaluate and synthesize the evidence on the effect of AD medications on neurocognitive outcomes in children and adolescents with ASD and low intelligence quotient (IQ). We performed the search according to PRISMA guidelines from inception to May 21[st], 2025 in four databases: PubMed, PsycInfo, Scopus, and Web of Science. We included studies of children and adolescents (2 - 21 years) with ASD and low IQ (<85) treated with at least one Food and Drug Administration (FDA)-approved AD medication (donepezil, galantamine, rivastigmine, benzgalantamine, memantine, aducanumab, lecanemab or donanemab) and investigating neurocognitive outcomes.

RESULTS: Twelve studies met the eligibility criteria. Six studies reported on neurocognitive outcomes from N-methyl-D-aspartate (NMDA) receptor antagonist treatment and six studies from cholinesterase inhibitor treatment. Among studies reporting on cholinesterase inhibitors, significant improvement was detected in language (60% of five reporting studies), executive function (100% of two reporting studies), complex attention (100% of one reporting study), and general cognitive ability (50% of two reporting studies). Among the NMDA receptor antagonist studies, evidence of improvement was detected in language (60% of five reporting studies), executive function (75% of four reporting studies), learning and memory (100% of two reporting studies), perceptual-motor functioning (66.6% of three reporting studies), complex attention (100% of one reporting study), and general cognitive ability (50% of two reporting studies). Across studies, treatment with either a cholinesterase inhibitor or an NMDA receptor antagonist was associated with improvements in language, executive function, complex attention, and general cognitive ability. A pattern of significance was detected with age, in that younger children may benefit more from these medications than adolescents.

CONCLUSION: This scoping review identified promising evidence of neurocognitive improvement in children and adolescents with ASD and low IQ following treatment with either a cholinesterase inhibitor or an NMDA receptor antagonist. Considering the lack of FDA-approved treatments for the cognitive deficits associated with ASD and an absence of medications approved to treat core features of ASD, our findings highlight an opportunity for innovative directions in autism research and treatment.},
}

Humans
Child
Adolescent
*Autism Spectrum Disorder/drug therapy/complications/psychology
*Alzheimer Disease/drug therapy/complications
*Intellectual Disability/complications
Young Adult
*Cholinesterase Inhibitors/therapeutic use/pharmacology
Child, Preschool

@article {pmid41249052,
year = {2025},
author = {Szatmari, EM and Moran, C and Cohen, SJ and Bashtovyy, D and Jacob, A and Bunner, W and Phipps, M and Lora, JC and Stackman, RW and Yasuda, R},
title = {Lack of ADAP1/Centaurin-α1 Ameliorates Cognitive Impairment and Neuropathological Hallmarks in a Mouse Model of Alzheimer's Disease.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0063-25.2025},
pmid = {41249052},
issn = {2373-2822},
abstract = {ArfGAP, with dual PH domain-containing protein 1/Centaurin-α1 (ADAP1/CentA1), is a brain-enriched and highly conserved Arf6 GTPase-activating and Ras-anchoring protein. CentA1 is involved in dendritic outgrowth and arborization, synaptogenesis, and axonal polarization by regulating the actin cytoskeleton dynamics. CentA1 upregulation and association with amyloid plaques in the human Alzheimer's disease (AD) brain suggest a role for this protein in AD progression. To understand the role of CentA1 in neurodegeneration, we crossbred CentA1 KO mice with the J20 mouse model of AD. We evaluated AD-associated behavioral and neuropathological hallmarks and gene expression profiles in J20 and J20 crossed with CentA1 KO (J20xKO) male mice to determine the impact of eliminating CentA1 expression on AD-related phenotypes. Spatial memory assessed by the Morris Water Maze test showed significant impairment in J20 mice, which was rescued in J20xKO mice. Moreover, neuropathological hallmarks of AD, such as amyloid plaque deposits and neuroinflammation, were significantly reduced in J20xKO mice. To identify potential mediators of AD phenotype rescue, we analyzed differentially expressed genes (DEGs) between genotypes. We found that changes in the gene profile by deletion of CentA1 from J20 (J20xKO vs J20) were anti-correlated with changes caused by APP overexpression (J20 vs WT), consistent with rescue of J20 phenotypes by CentA1 KO. In summary, our data indicate that CentA1 is required for the progression of AD phenotypes in this model and that targeting CentA1 signaling might have therapeutic potential for AD prevention or treatment.Significance statement ADAP1/Centaurin-α1 (CentA1) is highly enriched in the brain, and increased CentA1 level has been linked to Alzheimer's disease (AD). However, the precise role of CentA1 in the pathogenesis of AD is poorly understood. We found that genetic deletion of CentA1 in the AD model mice rescues the pathological hallmarks of AD, including loss of dendritic spines in the hippocampus, amyloid plaque deposition, neuroinflammation, and spatial memory deficits. Transcriptome analysis of the forebrain demonstrated that gene expression changes caused by APP overexpression were restored in J20 mice lacking CentA1. These findings support the role of CentA1 in AD progression.},
}

@article {pmid41249005,
year = {2026},
author = {Shepard, CD and Chang, X and Seidler, PM and Curran, SP},
title = {Polyphyletic screen defines distinct classes of plant-derived natural products that oppose tauopathy.},
journal = {Life science alliance},
volume = {9},
number = {2},
pages = {},
doi = {10.26508/lsa.202503393},
pmid = {41249005},
issn = {2575-1077},
mesh = {Caenorhabditis elegans/metabolism ; Animals ; tau Proteins/metabolism ; *Biological Products/pharmacology ; *Tauopathies/drug therapy/metabolism ; Humans ; Alzheimer Disease/drug therapy/metabolism ; Disease Models, Animal ; Protein Aggregation, Pathological/drug therapy ; Naphthoquinones/pharmacology ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Protein Aggregates/drug effects ; Animals, Genetically Modified ; },
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disease hallmarked by the presence of amyloid-β (Aβ) plaques and tau fibrils but with limited treatment options. Here, we describe two plant-derived natural products with distinct mechanisms of action on tau fibril disaggregation and prionogenic seeding. We first characterized the effects of oolonghomobisflavan A (OFA) and oolonghomobisflavan B (OFB) treatments, which alter the transcriptional landscape toward enhanced proteostasis and reverse the shortened lifespan in a Caenorhabditis elegans model expressing pathogenic human tau ("hTau-expressing"), but increase healthspan. Mechanistically, OFA treatment reduced the burden of tau protein aggregation and promoted tau disaggregation in hTau-expressing C. elegans and also inhibited seeding in assays using ex vivo brain-derived paired helical filament tau protein fibrils from Alzheimer's disease brain donors. We leveraged this finding to develop a facile screening approach for compounds, like OFA, that could mitigate tau aggregation, which revealed plumbagin (PB) as a potent inhibitor of tau monomer aggregation which is mechanistically distinct from the tau fibril disaggregase activity associated with OFA. Collectively, this study reveals a new strategy for identifying therapeutic compounds that target tauopathy and provides mechanistic insight supporting the neuroprotective effects of plant-derived natural products.},
}

Caenorhabditis elegans/metabolism
Animals
tau Proteins/metabolism
*Biological Products/pharmacology
*Tauopathies/drug therapy/metabolism
Humans
Alzheimer Disease/drug therapy/metabolism
Disease Models, Animal
Protein Aggregation, Pathological/drug therapy
Naphthoquinones/pharmacology
Amyloid beta-Peptides/metabolism
Brain/metabolism
Protein Aggregates/drug effects
Animals, Genetically Modified

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

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

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

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

PROSPERO REGISTRATION NUMBER: CRD42023434024.},
}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Humans
*Lewy Body Disease/therapy/diagnosis

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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