@article {pmid40962722,
year = {2025},
author = {Wu, M and Hao, X and Li, T and Tian, JJ and Gao, XM and Li, ZG},
title = {[Effect of "Tongdu Qishen" acupuncture on pyroptosis in hippocampus and cortex of SAMP8 mice].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {50},
number = {9},
pages = {995-1004},
doi = {10.13702/j.1000-0607.20240754},
pmid = {40962722},
issn = {1000-0607},
mesh = {Animals ; *Pyroptosis ; Male ; Mice ; *Hippocampus/metabolism/cytology ; *Acupuncture Therapy ; Humans ; Acupuncture Points ; *Cerebral Cortex/metabolism/cytology ; Interleukin-1beta/genetics/metabolism ; Caspase 1/genetics/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; *Alzheimer Disease/therapy/genetics/physiopathology ; },
abstract = {OBJECTIVES: To explore the underlying mechanism of "Tongdu Qishen" acupuncture (dredging the Govern Vessel and normalizing mental activities) in treating SAMP8 mice from the perspective of pyroptosis.

METHODS: Six-month-old male SAMP8 mice were randomly divided into model and "Tongdu Qishen" acupuncture (EA) groups, with 12 mice in each group. SAMR1 mice of the same age (n=12) were used as the normal group. In the EA group, EA (2 Hz/50 Hz, 20 min) was applied to "Baihui" (GV20) and "Yintang" (GV24[+]), and pricking bleeding was applied to "Shuigou" (GV26). The treatment was performed once a day, for a total of 28 days. Morris water maze test was used to evaluate the learning and memory ability of mice, and HE staining was used to observe the morphology of cells in the hippocampus and cortex. Nissl staining was used to observe the number of neurons in the hippocampus and cortex. Immunohistochemistry was used to observe the expressions of Aβ1-40, interleukin (IL)-1β and IL-18 in the hippocampus and cortex. The co-staining of TUNEL and Caspase-1 was detected by immunofluorescence. Western blot and real-time quantitative PCR were used to observe the protein and mRNA expression levels of Nod-like receptor 3 (NLRP3), Caspase-1 and Gasdermin D (GSDMD) in the hippocampus and cortex, respectively.

RESULTS: Behavioral results showed that compared with the normal group, the escape latency was prolonged (P<0.001), the dwell time in the original platform quadrant and the times of crossing the original platform were considerably decreased (P<0.001) in the model group. In comparison with the model group, the escape latency was shortened (P<0.05, P<0.001, P<0.01), and the dwell time in the original platform quadrant was significantly increased (P<0.01) in the EA group. Following modeling, the number of neurons was decreased (P<0.001), the positive expression of Aβ1-40, IL-1β and IL-18 in the hippocampus and cortex, the co-expression of TUNEL and Caspase-1, and the protein and mRNA expression levels of NLRP3, Caspase-1, GSDMD were all increased (P<0.001) in the model group relevant to the normal group. After EA intervention, modeling induced increase and decrease of indexes mentioned above were completely reversed (P<0.01, P<0.05, P<0.001).

CONCLUSIONS: "Tongdu Qishen" acupuncture may improve the cognitive function of SAMP8 mice by regulating the NLRP3/Caspase-1/GSDMD pathway, relieving the release of inflammatory factors and reducing the content of Aβ1-40.},
}

Animals
*Pyroptosis
Male
Mice
*Hippocampus/metabolism/cytology
*Acupuncture Therapy
Humans
Acupuncture Points
*Cerebral Cortex/metabolism/cytology
Interleukin-1beta/genetics/metabolism
Caspase 1/genetics/metabolism
NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism
*Alzheimer Disease/therapy/genetics/physiopathology

@article {pmid40962125,
year = {2025},
author = {Lian, W and Yuan, X and Zhou, F and Tong, Z and Cheng, Y and Zhang, W and He, J and Xu, J},
title = {Cornuside ameliorates LPS induced cognitive dysfunction and microglial NLRP3 inflammasome activation by enhancing Sirt1-mediated autophagy.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120615},
doi = {10.1016/j.jep.2025.120615},
pmid = {40962125},
issn = {1872-7573},
abstract = {Corni fructus are the fruits of Cornus officinalis Sieb. et Zucc. and is widely used in traditional Chinese Medicine for the treatment of dementia. Cornuside, derived from Corni fructus, has been shown to be effective in improving cognition of AD mouse.

AIM: In the present study, we investigated the effect of cornuside on cognitive dysfunction and microglial NLRP3 inflammasome activation, as well as explored the underlying mechanism with respect to Sirt1 and autophagy.

METHODS: AD mice were established and then treated with cornuside (3, 10, and 30 mg/kg) for 2 weeks. A series of behavioral tests were performed to assess cognition, including the Morris water maze, Y maze, nest building, step-down and step-through tests. Nissl staining was used to evaluate neuronal structural damage. LPS-stimulated BV2 cells were used for in vitro experiments. The anti-inflammatory effects of cornuside on cytokines and NLRP3 inflammasome activation were assessed using ELISA, RT-PCR, immunohistochemistry, western blotting, and immunofluorescence assays. To further elucidate the relationship between Sirt1, autophagy, and NLRP3 inflammasome activation, EX527 and 3-MA were used to inhibit Sirt1 and block autophagy flux in vitro, respectively.

RESULTS: Cornuside significantly improved various behavioral performance and inhibited NLRP3 inflammasome activation in LPS-induced mice, as evidenced by decreased levels of NLRP3, ASC, pro-caspase1, caspase1, pro-IL-1β, IL-1β, GSDMD, GSDMD-NT and IL-18. Similar inhibitory effects of cornuside on NLRP3 inflammasome activation was also detected in LPS stimulated BV2 cells. The involvement of Sirt1 and autophagy were further explored in-vivo and in-vitro, revealing that cornuside increased the expression of Sirt1 and enhanced autophagy, with decreased SQSTM1/p62 and increased LC3B II. However, the inhibitory effect of cornuside on NLRP3 inflammasome activation was abrogated by 3-MA, and the effects of cornuside on promoting autophagy and inhibiting NLRP3 inflammasome activation was abolished by EX527.

CONCLUSION: Cornuside exerts therapeutic effects on LPS induce AD mice by inhibiting microglial activation and NLRP3 inflammasome overactivation. And Sirt1 mediated autophagy activation is a vital mechanism by which cornuside degrades NLRP3 inflammasome, thereby alleviating neuroinflammation and improving cognitive function.},
}

@article {pmid40959937,
year = {2025},
author = {Navakkode, S and Kennedy, BK},
title = {Alpha-Ketoglutarate Ameliorates Synaptic Plasticity Deficits in APP/PS1 Mice Model of Alzheimer's Disease.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70235},
doi = {10.1111/acel.70235},
pmid = {40959937},
issn = {1474-9726},
support = {//NUS Medicine/ ; },
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders, characterized by a progressive decline in cognitive function. Increasing evidence indicates that alpha-ketoglutarate (AKG), a key metabolite in the tricarboxylic acid (TCA) cycle, can extend lifespan and healthspan across various animal models, raising interest in its potential neuroprotective effects in age-related disorders such as AD. Our previous research found that dietary supplementation with calcium alpha-ketoglutarate (CaAKG), a calcium derivative of AKG, enhances both lifespan and healthspan in mice. However, little is known about the neuroprotective role of AKG/CaAKG in AD. Here, we show that CaAKG could rescue synaptic deficits that are associated with AD. Treatment with AKG or CaAKG ameliorates long-term potentiation (LTP) at hippocampal CA1 synapses in APP/PS1 mice, with a more profound effect in female AD mice than in males. The effects of CaAKG were mediated through an NMDA receptor-independent mechanism involving L-type calcium channels (LTCC) and calcium-permeable AMPA receptors (CP-AMPARs). Analysis of protein expression showed that AD hippocampal slices treated with CaAKG exhibited increased LC3-II levels, indicating enhanced autophagy. Similarly, rapamycin, an mTOR inhibitor, also rescued LTP deficits in AD mice, suggesting that the observed increase in autophagy may contribute to neuroprotection. Interestingly, rapamycin showed differential effects, as it rescued LTP in AD mice but blocked LTP in WT mice. We also observed that CaAKG facilitated synaptic tagging and capture (STC), a widely studied cellular model for associative memory, indicating its potential to facilitate associative memory. Overall, our findings suggest that CaAKG has neuroprotective effects in APP/PS1 mice. We propose CaAKG as a promising therapeutic target not only for aging but also for AD and potentially other age-associated neurodegenerative diseases, highlighting geroprotective strategies as viable alternatives for the prevention and treatment of AD.},
}

@article {pmid40959879,
year = {2025},
author = {Miller, ZA and Ossenkoppele, R and Graff-Radford, NR and Allen, IE and Shwe, W and Rosenberg, L and Olguin, DJ and Erkkinen, MG and Butler, PM and Spina, S and Yokoyama, JS and Desikan, RS and Scheltens, P and van der Flier, W and Pijnenburg, Y and Wolters, E and Rademakers, R and Geschwind, DH and Kramer, JH and Rosen, HJ and Rankin, KP and Grinberg, LT and Seeley, WW and Sturm, V and Perry, DC and Miller, BL and Rabinovici, GD and Gorno-Tempini, ML},
title = {Neurodevelopment and neural environment inform Alzheimer's disease age at onset and phenotype.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70668},
doi = {10.1002/alz.70668},
pmid = {40959879},
issn = {1552-5279},
support = {AG048291//National Institutes of Health/ ; AG053435/NH/NIH HHS/United States ; AG019724/NH/NIH HHS/United States ; AG062422/NH/NIH HHS/United States ; AG045611/NH/NIH HHS/United States ; AG062588/NH/NIH HHS/United States ; DC015544/NH/NIH HHS/United States ; NS050915/NH/NIH HHS/United States ; //Hellman Research Scientist Award/ ; //Arking Foundation for Frontotemporal Dementia/ ; //Jon and Gale Love fund/ ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology ; Age of Onset ; Female ; Phenotype ; Male ; Aged ; Risk Factors ; Middle Aged ; Cohort Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Risk factors associated with sporadic non-amnestic and early-onset Alzheimer's disease (AD) remain underexamined.

METHODS: We investigated a large, clinically heterogeneous, AD cohort for frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus) alongside novel factors (non-right-handedness, learning disability, seizures, autoimmune disease).

RESULTS: Early-onset AD possessed lower frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus, all p < 0.001) and higher frequencies of novel factors (non-right-handedness, learning disability, active seizure, all p < 0.001; remote seizure, p = 0.002; and autoimmune disease, p = 0.007). An age at onset < 70 maximally distinguished novel from typical factors. Principal component analysis loaded novel factors into two components, non-right-handedness and learning disability versus seizure and autoimmune disease, which combined, resulted in an exponential decrease in age at onset from one factor alone.

DISCUSSION: Identifying novel factors enriched in early-onset and non-amnestic AD introduces new theories of AD susceptibility and phenotypic heterogeneity, with significant implications for disease prediction and treatment.

HIGHLIGHTS: We identified a suite of novel factors overrepresented in early-onset and non-amnestic AD. These factors can be broadly conceptualized as neurodevelopmental (non-right-handedness and learning disability) and neural environmental (seizure and autoimmunity). The combination of these factors produced exponential decreases in AD age at onset, compared to each alone, supporting a new theoretical framework for understanding AD risk with implications for disease prediction, prevention, and therapeutic intervention.},
}

Humans
*Alzheimer Disease/epidemiology
Age of Onset
Female
Phenotype
Male
Aged
Risk Factors
Middle Aged
Cohort Studies
Aged, 80 and over

@article {pmid40959450,
year = {2025},
author = {Shi, G and Ni, L and Kong, X and Ren, R and Shi, X and Xu, Y and Qu, Z and Zhou, H and Zhang, X},
title = {Unveiling the therapeutic potential of caudatin: Structural optimization, pharmacological mechanisms, and therapeutic implications.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1640365},
pmid = {40959450},
issn = {1663-9812},
abstract = {Caudatin is a C21 steroidal glycoside isolated from many species of the genus Cynanchum, has been utilized by traditional medicine to treat cancer and inflammation which is increasingly being considered a drug candidate because of the pharmacological activity it displays. This review provides a discussion of caudatin's structure-activity relationship (SAR), pharmacology, and therapeutic uses along with a synthesis of future challenges. Caudatin is a potent anti-cancer therapeutic that has been shown to modulate several important signaling pathways, which include but are not limited to: Wnt/β-catenin, NF-κB, and PI3K/AKT pathway, induce apoptosis through ROS mediated mitochondrial dysfunction, reduce metastatic spread through inhibition of epithelial-mesenchymal transition (EMT), and have an anti-inflammatory effect through inhibition of JNK/AP-1/NF-κB signaling. Caudatin has also displayed neuroprotection in models of Alzheimer's disease by activating TFEB and the autophagosome-lysosomal pathway mechanism of action, while also modulating PPARα. Furthermore, pharmacokinetic studies indicate that caudatin is rapidly absorbed and is able to selectively tail hepatic tissue while having little to no toxicity or significant adverse events in pre- clinical animal studies. Structure-activity studies suggest that modifications on the C-3 hydroxyl position, primarily with nitrogen heterocycles and/or sugars greatly enhance the bioactivity and solubility. With caudatin being such a great scaffold for medicinal chemistry, there is great opportunity to take advantage of caudatin as a building block to generate novel therapies which bridge traditional medicine with modern drug discovery. The future is aimed primarily at a combination strategy of synthetic derivatives, translational studies, and formulations. In further exploring caudatin as a treatment for cancer and neurodegenerative diseases, and inflammation.},
}

@article {pmid40959086,
year = {2025},
author = {Chen, R and Tang, X and Wang, Y and Wang, B and Mao, F},
title = {Protein palmitoylation: an emerging regulator of inflammatory signaling and diseases.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1652741},
pmid = {40959086},
issn = {1664-3224},
mesh = {Humans ; *Lipoylation ; *Signal Transduction ; *Inflammation/metabolism/immunology ; Animals ; *Protein Processing, Post-Translational ; Thiolester Hydrolases ; },
abstract = {Protein palmitoylation is a reversible lipid modification in which palmitoyl esters are covalently attached to cysteine residues of proteins. It controls various cellular physiological processes and alters protein stability, conformation, localization, membrane binding, and interaction with other effector proteins. Palmitoylation is catalyzed by a group of zinc finger DHHC-containing proteins (ZDHHCs), while the acyl-protein thioesterase family mediates depalmitoylation. Emerging evidence suggests that palmitoylation is critical for inflammatory signaling pathways, where palmitoylation is particularly important in the membrane localization of inflammation-associated proteins. Notably, dysregulation of palmitoylation has been associated with a variety of inflammatory diseases. Here, we provide an overview of the regulatory mechanisms of palmitoylation, explore the emerging role of palmitoylation in inflammatory signaling pathways, and examine the link between dysregulated palmitoylation and the pathogenesis of inflammatory diseases, including inflammatory bowel disease, autoimmune diseases, metabolic dysfunction-associated steatohepatitis, sepsis, Alzheimer's disease, Parkinson's disease, and diabetes. Finally, we discuss some of the challenges and opportunities facing the field. Targeting palmitoylation or its associated enzymes serves as a novel therapeutic approach for the treatment of inflammatory diseases.},
}

Humans
*Lipoylation
*Signal Transduction
*Inflammation/metabolism/immunology
Animals
*Protein Processing, Post-Translational
Thiolester Hydrolases

@article {pmid40958782,
year = {2025},
author = {Sun, LC and Li, WS and Chen, W and Zhao, DQ and Zhang, X and Li, CX and Ren, Z},
title = {Frontiers and Emerging Trends in Edaravone Research: A Bibliometric Analysis of Molecular Basis and Clinical Studies Using CiteSpace and VOSviewer.},
journal = {Journal of multidisciplinary healthcare},
volume = {18},
number = {},
pages = {5743-5758},
pmid = {40958782},
issn = {1178-2390},
abstract = {PURPOSE: Edaravone is a potent free-radical scavenger and antioxidant that has been widely investigated for its therapeutic potential in neurodegenerative diseases and oxidative stress-related conditions. Although previous studies have explored its molecular structure, pharmacological effects, and clinical applications, a comprehensive bibliometric analysis of its research trends and future directions remains lacking.

METHODS: This study employed bibliometric methods to analyze edaravone-related publications from 2000 to 2024, using the Web of Science Core Collection database. The analysis examined publication trends; contributions by countries, institutions, and authors; and keyword clustering. Data visualization tools, such as CiteSpace and VOSviewer, were utilized to identify research clusters and emerging trends in edaravone research.

RESULTS: The findings revealed a significant increase in edaravone-related publications, with China, Japan, and the United States as the leading contributors. Notable researchers, including Abe K and Yoshino H, have made substantial contributions to this field. Four major research clusters were identified: free radical scavenging, cerebral infarction, amyotrophic lateral sclerosis, and oxidative stress. Emerging trends suggest a growing interest in edaravone dexbornel for acute ischemic stroke treatment, as well as its potential applications in blood-brain barrier interactions and Alzheimer's disease.

CONCLUSION: This bibliometric analysis highlights the growing interest in edaravone and its potential clinical application, particularly in neuroprotection. While this study provides valuable insights into current research trends, future studies should incorporate a broader range of sources and languages to obtain a more comprehensive understanding of the impact and scope of edaravone.},
}

@article {pmid40957902,
year = {2025},
author = {Ekins, TG and Rybicki-Kler, C and Deng, T and Brooks, IAW and Jedrasiak-Cape, I and Donoho, E and Ahmed, OJ},
title = {Psychedelic neuroplasticity of cortical neurons lacking 5-HT2A receptors.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {40957902},
issn = {1476-5578},
support = {R01MH129282//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R34NS127101//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P50NS123067//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; AARG-NTF-21-846572//Alzheimer's Association/ ; T32DA007268//U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/ ; T32DC000011//U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD)/ ; T32DC000011//U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD)/ ; },
abstract = {Classical psychedelic drugs show promise as a treatment for major depressive disorder and related psychiatric disorders. This therapeutic efficacy stems from long-lasting psychedelic-induced neuroplasticity onto prefrontal cortical neurons and is thought to require the postsynaptic expression of serotonin 2A receptors (5-HT2AR). However, other cortical regions such as the granular retrosplenial cortex (RSG) - important for memory, spatial orientation, fear extinction, and imagining oneself in the future, but impaired in Alzheimer's disease - lack 5-HT2AR and are thus considered unlikely to benefit from psychedelic therapy. Here, we show that RSG pyramidal cells lacking postsynaptic 5-HT2A receptors still undergo long-lasting psychedelic-induced synaptic enhancement. A newly engineered CRISPR-Cas-based conditional knockout mouse line reveals that this form of psychedelic-induced retrosplenial plasticity requires presynaptic 5-HT2A receptors expressed on anterior thalamic axonal inputs to RSG. These results highlight a broader psychedelic therapeutic utility than currently appreciated, suggesting potential for augmenting RSG circuit function in Alzheimer's disease, post-traumatic stress disorder, and other neuropsychiatric conditions, despite the lack of postsynaptic 5-HT2A receptors.},
}

@article {pmid40956653,
year = {2025},
author = {Shaker, A and Ljunggren, G and Vossen, LE and Religa, D and Raaschou, P},
title = {Impact of socio-economic and patient-centered characteristics on access to Alzheimer's disease medication in primary care: A population-based study in the Stockholm county, Sweden.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375900},
doi = {10.1177/13872877251375900},
pmid = {40956653},
issn = {1875-8908},
abstract = {BackgroundDespite treatment guidelines for Alzheimer's disease (AD), access to AD medications varies significantly within the same health care setting.ObjectivePredictors influencing access to AD medication were assessed in a retrospective cohort study comprising most individuals diagnosed with AD in Stockholm 2013-2021.Methods14,884 individuals were included, with an incident AD diagnosis between 2013-2021 in Stockholm, Sweden. The primary outcome was the dispensation of AD-specific drugs (cholinesterase inhibitors or memantine) within 90 days before to 180 days after AD diagnosis. We used a generalized linear mixed-effects model (GLMM). Variables included patient-centered characteristics such as age and comorbidities, and characteristics of the primary care centers (PCC) where the individuals were listed, including Care Need Index (CNI).ResultsOverall, 77% of diagnosed patients were dispensed AD medications. Individuals listed at PCCs with high CNI score, indicative of lower socio-economic resources of the area, were less likely to receive a dispensation of any AD medication compared with low CNI score (76.2% versus 84.8%; OR 0.65, 95% CI 0.50-0.86). The association between CNI score and likelihood of receiving AD medication was attenuated in subgroup analysis of individuals living in nursing homes. Also associated with lower likelihood of receiving AD medications were age ≥85 years (OR 0.25, 95% CI 0.21-0.28), nursing home residency (OR 0.37, 95% CI 0.34-0.41), and comorbidity (OR 0.63, 95% CI 0.57-0.70).ConclusionsSocio-economic factors strongly influenced the likelihood of receiving AD medication, in addition to more established factors such as age and comorbidities. Interventions are needed to eliminate barriers to equal drug treatment in AD, particularly those related to socio-economic disadvantages.},
}

@article {pmid40956407,
year = {2025},
author = {Guo, S and Wei, F and Chang, Y and Wu, S and Lou, Z and Ma, Y and Huang, Q and He, K and Fu, C and Cao, X and Liang, S and Cheng, W and Yin, Y},
title = {Early astrocyte-targeted intervention guided by [18]F-SMBT-1 imaging attenuates disease progression in 3xTg-AD mice.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {40956407},
issn = {1619-7089},
support = {82472014//National Natural Science Foundation of China/ ; 81974270//National Natural Science Foundation of China/ ; 24ZR1450000//Natural Science Foundation of Shanghai Municipality/ ; 23ZR1441200//Natural Science Foundation of Shanghai Municipality/ ; },
abstract = {PURPOSE: Astrocyte reactivity is a key pathological feature and potential therapeutic target of Alzheimer's disease (AD), however, the optimal timing of its modulation remains unexplored. This study aims to combine [18]F-SMBT-1 based molecular imaging with astrocyte-targeted intervention in 3xTg-AD mice to address this challenge.

METHODS: PET imaging with [18]F-SMBT-1 was conducted in 3xTg-AD mice at 4, 6, 10, and 12 months of age, with age-matched wild-type (WT) mice as controls. The standardized uptake value ratio was calculated using cerebellum as the reference region by PMOD software. Immunofluorescence (IF) analysis was used to assess astrocyte reactivity ex vivo. Astrocyte-targeted intervention via Nrf2 overexpression was performed in 4-month-old 3xTg-AD mice using adeno-associated virus vectors. Following intervention, PET imaging with [18]F-SMBT-1 was performed to assess astrocyte reactivity, open field test and Morris water maze test were performed to evaluate cognitive function, and IF analysis was used to assess pathological feature of AD.

RESULTS: In 3xTg-AD mice of different ages, higher uptake of [18]F-SMBT-1 was observed in the cortex and hippocampus compared to age-matched WT controls. IF analysis further confirmed the presence of reactive astrocytes activation in 3xTg-AD mice. Both in vivo [18]F-SMBT-1 imaging and ex vivo IF analysis identified early-onset astrocyte activation in 3xTg-AD mice. Based on these observations, we implemented early astrocyte-targeted intervention via Nrf2 overexpression at 4 months of age in 3xTg-AD mice. Subsequent in vivo [18]F-SMBT-1 PET imaging demonstrated a significant reduction in astrocyte reactivity following this intervention. Our findings also demonstrated that early astrocyte-targeted intervention might delay AD pathological progression in 3xTg-AD mice, as supported by attenuated anxiety-like behavior and ameliorated neuropathological features.

CONCLUSION: [18]F-SMBT-1 PET imaging served as a diagnostic biomarker for monitoring astrocyte reactivity to guide therapeutic timing decisions, and as a therapeutic response indicator for evaluating treatment efficacy. Early astrocyte-targeted intervention demonstrated significant therapeutic potential. These findings highlighted the translational potential of molecular imaging-guided strategies and astrocyte-targeted therapies in AD.},
}

@article {pmid40956219,
year = {2025},
author = {Landhuis, E and Christiansen, J and Studios, NM},
title = {A Multipronged Assault: A new understanding of Alzheimer's is leading to a variety of new treatment approaches.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {89},
doi = {10.1038/scientificamerican102025-5T8bP0cW0x69LnvyUGc4td},
pmid = {40956219},
issn = {0036-8733},
}

@article {pmid40955908,
year = {2025},
author = {Atewogboye, O and Taylor, JP and Harrison, JR},
title = {Pharmacological strategies for managing dementia with Lewy Bodies: an expert review of symptom-targeted care.},
journal = {Expert review of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17512433.2025.2562151},
pmid = {40955908},
issn = {1751-2441},
abstract = {INTRODUCTION: Dementia with Lewy Bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease, characterized by a complex combination of cognitive, neuropsychiatric, motor, autonomic, and sleep-related symptoms. Symptom fluctuation, polypharmacy risks, and high sensitivity to commonly used drugs present unique challenges in its management.

AREAS COVERED: This review provides a comprehensive overview of the symptomatic management of DLB, organized by clinical domains. It critically evaluates current pharmacological and non-pharmacological treatment strategies for cognitive impairment, hallucinations, parkinsonism, autonomic dysfunction, and sleep disturbances. Evidence is drawn from clinical trials, meta-analyses, and extrapolated findings from related disorders such as Alzheimer's disease and Parkinson's disease.

EXPERT OPINION: Effective DLB management requires an individualized, symptom-prioritized approach that carefully balances therapeutic benefit with potential adverse effects, particularly given the high risk of antipsychotic sensitivity and treatment-induced worsening of symptoms. Despite recent progress, evidence remains sparse for many symptom domains. Greater investment in DLB-specific clinical trials and development of targeted therapies is urgently needed to improve patient outcomes.},
}

@article {pmid40955711,
year = {2025},
author = {Tan, A and Wang, Z and Aumont, E and Li, A and Qin, X and Yang, X and Feng, W and Yang, J and Li, X and Xiao, J and Zhou, B and Xing, Y and Yi, Y and Li, J},
title = {Determinants of Treatment Willingness and Willingness-to-Pay for Lecanemab in China: A Network Analysis.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000689},
pmid = {40955711},
issn = {1546-4156},
abstract = {BACKGROUND: Lecanemab is the first disease-modifying therapy for Alzheimer's disease (AD) approved in China. However, the factors affecting patient and caregiver willingness to adopt this novel treatment have not been assessed yet.

OBJECTIVE: To investigate the factors influencing both treatment willingness and willingness-to-pay for lecanemab among Chinese AD patients and their caregivers.

METHODS: We surveyed 195 AD patients and their caregivers using structured questionnaires assessing key factors influencing treatment willingness, including efficacy (Wefficacy), adverse effects (Wadverse), inconvenience (Winconvenience), cost (Wcost), overall willingness to treat (Wtreat), and amount willing to pay (Wamount). Additional variables included income, cognitive and functional assessments, caregiver burden (ZBI), health status (HS), education levels (patient/caregiver: edu, edu.c), psychiatric symptoms (PSY), and satisfaction with conventional treatments (effect). Network analysis mapped variable inter-relationships.

RESULTS: Wtreat showed a strong direct association with Wcost (0.99). Wefficacy and Winconvenience indirectly influenced Wtreat through Wcost (Wefficacy-Winconvenience: 1.5, Winconvenience-Wcost: 1.12, Wcost-Wtreat: 0.99). Income (0.48) and effect (0.51) directly impacted Wtreat. Edu, edu.c, CDR, PSY, ZBI, and HS were indirectly correlated with Wtreat. Wamount was directly associated with Wtreat (0.31), Wcost (0.68), and Wadverse (0.16). Wefficacy and Winconvenience indirectly influenced Wamount through Wcost (Wefficacy- Winconvenience: 1.5, Winconvenience-Wcost: 1.12, Wcost-Wamount: 0.68). Network stability tests (CS >0.50) confirmed robustness.

CONCLUSION: This study demonstrates that reducing payment barriers has a greater impact on real-world adoption of innovative therapies than clinical efficacy alone. Addressing financial constraints also enhances patients' willingness to pay. These findings provide evidence-based insights for developing patient-centered clinical decision pathways.},
}

@article {pmid40955309,
year = {2025},
author = {Wang, L and Feng, L and Ning, B and Wang, Z and Dai, C and Li, M},
title = {Natural Products from Chinese Medicine Targeting NF-κB Signaling: Emerging Therapeutic Avenues for Neurodegenerative Diseases.},
journal = {Drug design, development and therapy},
volume = {19},
number = {},
pages = {8135-8159},
pmid = {40955309},
issn = {1177-8881},
mesh = {Humans ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Biological Products/pharmacology/chemistry ; *Medicine, Chinese Traditional ; Signal Transduction/drug effects ; Animals ; *Drugs, Chinese Herbal/pharmacology/chemistry ; },
abstract = {This review summarizes recent advances in leveraging natural products from Chinese medicine to modulate the nuclear factor kappa B (NF-κB) signaling pathway for the prevention and treatment of neurodegenerative diseases (NDDs), focusing specifically on Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). NF-κB proteins regulate cellular biological activity by binding to promoter regions in the nucleus and transcribing various protein-coding genes. Emerging evidence indicates that NF-κB plays a pivotal role in driving key hallmarks of NDD progression, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and dysregulation of the cell cycle. Natural products from Chinese medicine exert modulatory effects on NF-κB signaling through diverse pharmacological mechanisms, ultimately improving cognitive and motor impairments in preclinical NDDs models. The pleiotropic nature of natural products derived from traditional Chinese medicine (TCM)-which operate through subunit-specific modulation of NF-κB-underscores their potential as next-generation therapeutics. Investigating the intricate regulation of NF-κB by natural products from Chinese medicine will not only enrich our understanding of the pathogenesis of NDDs but also establish a theoretical foundation for the development of new therapeutic drugs for NDDs, providing innovative strategies for prevention and treatment.},
}

Humans
*NF-kappa B/metabolism/antagonists & inhibitors
*Neurodegenerative Diseases/drug therapy/metabolism
*Biological Products/pharmacology/chemistry
*Medicine, Chinese Traditional
Signal Transduction/drug effects
Animals
*Drugs, Chinese Herbal/pharmacology/chemistry

@article {pmid40954136,
year = {2025},
author = {Martínez-García, J and Fernández, B and Artime, E and Álvarez, L and González-Iglesias, H and Clases, D and Pereiro, R},
title = {ICP-MS for Multiplexed Protein Determination in Extracellular Vesicles from APP/PS1 Mice Blood Serum-Application to a Zn Supplementation Pilot Study.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c03630},
pmid = {40954136},
issn = {1520-6882},
abstract = {Neurodegenerative diseases represent a significant challenge due to their complex etiology, late diagnosis, and lack of effective treatments. Extracellular vesicles (EVs) have emerged as promising carriers of disease biomarkers, especially proteins, but their low abundance in biological fluids complicates their detection. Here, we present a novel strategy for the multiplexed quantitative determination of EV-associated proteins in blood serum from APP/PS1 transgenic mice, a model of Alzheimer's disease. The method combines inductively coupled plasma-time-of-flight mass spectrometry (ICP-ToFMS) with competitive immunoassays using metal nanocluster-labeled (AuNCs, PtNCs, IrNCs) antibodies targeting Alpha-Actinin 1 (ACTN), Galectin-3-binding protein (LG3BP), and Moesin (MSN). EVs were isolated using an optimized ultracentrifugation protocol to reduce the level of serum protein contamination. Proteomic screening identified target proteins with a known relevance to neurodegeneration, and the developed assay achieved detection limits in the low femtomolar range. The approach was applied to a pilot study on Zn supplementation in 16-month-old APP/PS1 mice, revealing sex-dependent and genotype-specific differences in protein expression but sex-independent patterns in regulatory mechanisms (especially for MSN and LG3BP). Among the studied markers, MSN levels showed statistically significant differences with Zn treatment in male homozygous mice. This work demonstrates the potential of ICP-MS for sensitive and multiplexed biomarker quantification in EVs, supporting its use in neurodegenerative research and supplementation studies.},
}

@article {pmid40953123,
year = {2025},
author = {Haaland, B and Dickson, SP and Santana, AF and Tanzi, RE and Dubois, B and Peters, O and Grimmer, T and Christensen, J and Mallinckrodt, C and Schneeberger, A and Hendrix, SB},
title = {Efficacy of AD04, an aluminum-based vaccine adjuvant, in patients with early Alzheimer's disease: Post hoc analysis of AFF006 (NCT01117818), a proof-of-concept, phase 2 randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375985},
doi = {10.1177/13872877251375985},
pmid = {40953123},
issn = {1875-8908},
abstract = {BackgroundThe AFF006 trial (NCT01117818) provided unexpected evidence of benefits of the vaccine adjuvant AD04 (aluminum oxyhydroxide) in patients with early Alzheimer's disease (AD), compared with AD02, a vaccine consisting of a peptide that mimics the N-terminal region of human amyloid-β (Aβ) conjugated with keyhole limpet hemocyanin.ObjectiveThe objective of this post hoc analysis was to assess whether this unexpected benefit of AD04 was an artifact of multiple testing (i.e., type I error inflation) or a robust result.MethodsIn this post hoc assessment, we used permutation testing to estimate type I error inflation due to the evaluation of multiple outcomes in AFF006. Efficacy was assessed using a patient-level global statistical test combining composite endpoints of cognition, function, and global AD. In addition, we examined the observed treatment benefits of AD04 in the context of effects observed in trials of aducanumab, donanemab, and lecanemab, monoclonal anti-Aβ antibodies that received regulatory approval for AD.ResultsThe global statistical test suggested a treatment benefit of AD04 versus ineffective AD02 arms, even after accounting for multiplicity (primary methodology p-value, 0.03; permutation test p-value, 0.02). The observed effect estimates for AD04 compared favorably with approved monoclonal antibodies.ConclusionsPost-hoc analyses are hypothesis generating rather than confirmatory. Adjusting for multiplicity using permutation testing can determine whether post-hoc effects are worth pursuing, or unlikely to be confirmed. These analyses have motivated a follow-up prospective randomized controlled trial, ADVANCE (EudraCT 2022-003532-73), in which optimized AD04 dosing will be compared to placebo in early AD.},
}

@article {pmid40953121,
year = {2025},
author = {Gao, M and Chen, J and Zhang, B and Li, J and Lang, J and Zhao, X and Zhang, Q},
title = {Melatonin alleviates cognitive impairment via modulating NLRP3/Caspase 1 pathway in db/db mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375479},
doi = {10.1177/13872877251375479},
pmid = {40953121},
issn = {1875-8908},
abstract = {BackgroundActivation of NLRP3 inflammasome has been implicated in cognitive impairment. Melatonin, known for its anti-inflammatory properties and traditional use in regulating circadian rhythms, is the focus of this study. This study intended to investigate the role of melatonin in diabetic cognitive impairment model.ObjectiveThe present study aimed to investigate the underlying mechanism of melatonin in alleviating diabetic cognitive impairment by suppressing NLRP3/Caspase 1 signaling pathway.MethodsCognitive function was assessed using Morris water maze test and Novel Object Recognition test. Apoptosis rate of hippocampal neurons was evaluated by TUNEL staining. Western blot was used to evaluate NLRP3/Caspase 1 pathway expression. Double immunofluorescence labelling of GFAP, Iba-1 or NeuN with NLRP3 respectively showed the localization of NLRP3 in hippocampus of db/db mice. In vitro, HT-22 cells treated with high glucose as cellular model were transfected with pc-DNA3.1-mNLRP3 or co-cultured with NLRP3 inhibitor MCC950 to elucidate NLRP3/Caspase 1 pathway in neuronal apoptosis regulation.ResultsMelatonin treatment improved cognitive function and morphologic abnormalities of hippocampal neurons. The double immunofluorescence labelling revealed melatonin inhibited NLRP3 inflammasome activation in hippocampal neurons rather than microglia or astrocytes. TUNEL staining and western blot showed melatonin markedly reversed the upregulation of NLRP3/Caspase 1 signaling pathway against neuronal apoptosis.ConclusionsMelatonin attenuates diabetic cognitive impairment in db/db mice with down-regulation of NLRP3/Caspase 1 signaling pathway. In vivo and vitro studies supported that NLRP3 activation in hippocampal neurons was associated with diabetic cognitive impairment progression.},
}

@article {pmid40953107,
year = {2025},
author = {Li, H and Wu, Y and Huang, T and Sun, Y and Lu, Z and Li, M and Wo, H and Shao, F and Tang, S and Zhao, Y and Dai, J and Yi, H},
title = {Development of a risk prediction model for Alzheimer's disease based on the UK Biobank prospective study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375473},
doi = {10.1177/13872877251375473},
pmid = {40953107},
issn = {1875-8908},
abstract = {BackgroundEarly prevention and intervention for Alzheimer's disease (AD) are critical due to the absence of effective therapeutic treatment. However, a widely accepted risk prediction model for AD has yet to be established.ObjectiveTo develop a novel risk prediction model for AD by leveraging recent advances in identifying risk factors, focusing on multi-omics data.MethodsGenetic data from the UK Biobank were employed to calculate the polygenic risk score (PRS) using the clumping and thresholding (C + T) method. Univariate Cox regression and Elastic Net Cox models were utilized to identify significant predictors in the training cohort. Subsequently, a multivariate Cox regression model was developed to construct the prediction model, which was visualized using a nomogram. The performance of the model was evaluated through calibration curves, receiver operating characteristic (ROC) curves, and the Hosmer-Lemeshow test.ResultsTen risk factors, including age, education, family history of dementia, diabetes, depression, hypertension, anemia, coronary heart disease (CAD), falls and PRS, were identified as significant predictors through Cox regression and Elastic Net Cox model. The model demonstrated strong predictive performance, with area under the curves (AUCs) of 0.864 [95% CI: (0.814, 0.911)], 0.860 [95% CI: (0.842, 0.876)], and 0.842 [95% CI: (0.819, 0.863)] at 5, 10, and 14 years, respectively, in the validation cohort.ConclusionsIncorporating colocalized single nucleotide polymorphisms (SNPs) into the PRS derived using the C + T method significantly enhances predictive accuracy. This study highlights the importance of integrating multimodal patient data, including colocalized genetic information, to refine AD risk prediction.},
}

@article {pmid40952625,
year = {2025},
author = {Kocanci, FG and Sarban, HE and Yildiz, F},
title = {Evaluating the Neuroprotective and Acetylcholinesterase Inhibitory Properties of Four Calcineurin Inhibitor Drugs: Tacrolimus, Pimecrolimus, Cyclosporin A, and Voclosporin.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40952625},
issn = {1559-1182},
support = {32126//President of the Turkish Health Institutes (TUSEB)/ ; 32126//President of the Turkish Health Institutes (TUSEB)/ ; 32126//President of the Turkish Health Institutes (TUSEB)/ ; },
abstract = {Neurodegenerative diseases (ND), marked by progressive neuronal degeneration, often involve dysregulation of acetylcholinesterase (AChE), a key enzyme in cholinergic neurotransmission. AChE inhibition is a well-established therapeutic strategy for Alzheimer's disease (AD), the most prevalent ND, as it aims to restore impaired cholinergic function. However, the effects of calcineurin inhibitors (CNIs), primarily used as immunosuppressants, on AChE activity remain largely unexplored. Recent evidence suggests CNIs possess neuroprotective properties, highlighting their potential for ND treatment. This study evaluated the binding affinities of FDA-approved CNIs-Tacrolimus (Tac), Pimecrolimus (Pim), Cyclosporine A (Csa), and Voclosporin (Voc)-to AChE via molecular docking and molecular dynamic simulation. AChE inhibition was assessed in vitro using the Ellman method and in H2O2-induced degenerative neuron-like SH-SY5Y cells via ELISA and qRT-PCR. Neuroprotection was examined through MTT assays and neurite analysis. Additionally, the antiapoptotic effect was examined by ELISA analysis measuring caspase-3. Docking studies confirmed strong AChE binding for all CNIs, with Voc exhibiting the highest affinity. Voc demonstrated superior in vitro AChE inhibition, surpassing galantamine at low concentrations. Cellular assays showed that CNIs, particularly Voc, significantly inhibited AChE expression at the gene level. Moreover, Voc markedly restored cell viability and reduced neuronal degeneration in H2O2-treated cells. These findings suggest CNIs, especially Voc, as promising candidates for ND treatment, targeting AChE overactivity and oxidative stress.},
}

@article {pmid40952411,
year = {2025},
author = {Kanda, A and Rani, A and Mazumder, A},
title = {Exploring precision medicine by utilizing individual genetic information for the management of Alzheimer's disease.},
journal = {Pharmacogenomics},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/14622416.2025.2560296},
pmid = {40952411},
issn = {1744-8042},
abstract = {Alzheimer's Disease (AD) represents a formidable challenge in neurology, characterized by progressive neurodegeneration and cognitive decline. Traditional therapeutic approaches have failed to deliver significant outcomes, underscoring the need for innovative paradigms such as precision medicine. The review explores integrating genomic, biomarker-driven, and individualized therapeutic strategies to tackle AD. It examines the role of key genetic factors, including APOE and MTHFR polymorphisms, in influencing disease susceptibility and treatment responses. Advances in biomarker technologies, such as blood-based and imaging biomarkers, are highlighted for their potential in early diagnosis and patient stratification. Additionally, the review underscores the importance of tailoring interventions across different stages of AD, incorporating lifestyle modifications and emerging tools like artificial intelligence & recent patented technologies. Precision medicine offers a transformative pathway, aiming to deliver personalized, effective care that addresses the complex and multifactorial nature of AD. The paradigm shift promises improved clinical outcomes and enhanced patient quality of life.},
}

@article {pmid40952136,
year = {2025},
author = {Frykman, H},
title = {Analytical considerations and clinical utility of plasma phosphorylated Tau217.},
journal = {Critical reviews in clinical laboratory sciences},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/10408363.2025.2551648},
pmid = {40952136},
issn = {1549-781X},
abstract = {Blood-based biomarkers are an easily available and practical tool for Alzheimer's disease (AD) screening and diagnosis. Plasma phosphorylated Tau217 (p-tau217) is the front-runner candidate for AD diagnosis due to its strong correlation with core AD pathology determined either by cerebrospinal fluid biomarker (CSF) and positron emission tomography (PET) or postmortem examination. While plasma p-tau217 is firmly associated with AD pathology, it is crucial to evaluate its performance in distinguishing AD from mixed pathologies, as brain autopsies have shown the coexisting of AD pathology with other related types of dementia. Moreover, the measurement of AD biomarkers will be a crucial element in defining eligibility for disease-modifying treatment in clinical practice. Moreover, plasma p-tau217 is a highly efficacious biomarker in the early detection of Aβ pathology, making it a feasible test for AD screening in clinical practice. Several assays, including the ALZpath p-tau217 assay and the Fujirebio plasma p-tau217 assay, have been made commercially available for research use. A few studies analytically and clinically have validated these immunoassays as laboratory diagnostic tests for AD diagnosis and differentiating from non-AD neurodegenerative disorders in clinical practice.},
}

@article {pmid40951935,
year = {2025},
author = {Wei, Y and Li, H},
title = {The Efficacy and Safety of Amyloid Beta-Directed Monoclonal Antibodies for Alzheimer's Disease: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials.},
journal = {Human psychopharmacology},
volume = {40},
number = {5},
pages = {e70017},
doi = {10.1002/hup.70017},
pmid = {40951935},
issn = {1099-1077},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of mortality worldwide. One of the newer treatments for AD is amyloid beta (Aβ) directed monoclonal antibodies (mAbs). This systematic review and meta-analysis aimed to assess the efficacy and safety of this class of drugs.

METHODS: A comprehensive literature search was conducted across Scopus, Web of Science, PubMed, and the Cochrane Library until January 30, 2025, focusing on phase III randomized controlled trials (RCTs) evaluating anti-Aβ mAbs.

RESULTS: Twelve RCTs with 24 arms were included. Anti-Aβ mAbs significantly reduced the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score (mean difference (MD): -0.16, 95% confidence interval (CI) (-0.29, -0.04)), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score (MD: -0.87, 95% CI (-1.13, -0.60)), and amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR) (MD: -0.11, 95% CI (-0.19, -0.02)). They also significantly increased the Mini-Mental State Examination (MMSE) score (MD: 0.31, 95% CI (0.15, 0.46)) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score (MD: 1.21, 95% CI (0.89, 1.53)). However, they were associated with a significant increase in complications, including amyloid-related imaging abnormalities-edema/effusion (ARIA-E) (odds ratio (OR): 10.20, 95% CI (7.17, 14.50)), ARIA-hemosiderosis or microhemorrhage (ARIA-H) (OR: 1.75, 95% CI (1.22, 2.50)), and any adverse events (OR: 1.22, 95% CI (1.08, 1.38), I[2]: 48.59%)). The subgroup analysis showed that treatment administered in the early/preclinical stages of AD resulted in a greater reduction in CDR-SB and ADAS-Cog scores, as well as in amyloid burden.

CONCLUSIONS: Anti-Aβ mAbs offer modest clinical benefits, and pose some serious complications, necessitating a cautious approach to their prescription.},
}

@article {pmid40951730,
year = {2025},
author = {Besin, V and Humardani, FM and Yudiarto, FL and Ong, PA and Putra, SED and Ningrum, RA},
title = {Amyloid-Related Imaging Abnormality (ARIA) Beyond the APOE-ε4 Allele.},
journal = {Chronic diseases and translational medicine},
volume = {11},
number = {3},
pages = {186-196},
pmid = {40951730},
issn = {2589-0514},
abstract = {Monoclonal antibodies (mAbs) have made significant progress in the treatment of Alzheimer's disease (AD). However, mAbs are associated with adverse effects, including Amyloid-Related Imaging Abnormality (ARIA), which manifests as edema or effusion (ARIA-E) and hemorrhage (ARIA-H). The mechanisms behind these effects are not yet fully understood. Moreover, spontaneous ARIA has been insufficiently explored, and mAb therapies, particularly lecanemab, have mainly focused on patients with the APOE-ε4 allele carrier. This review aims to address this gap by examining the mechanisms of spontaneous ARIA, ARIA induced by mAbs, and the influence of genetic variants on ARIA development. The autoantibody-Aβ-mediated immune response targets excessive Aβ deposits, increasing immune activity through microglial reactivity. The heightened immune response, driven by Aβ accumulation in blood vessels, promotes angiopathy and inflammation, potentially contributing to spontaneous ARIA. The APOE-ε4 allele carrier is more strongly associated with ARIA-E because it redistributes Aβ deposition from the brain to blood vessels, influencing microglial reactivity. The redistribution enhances vascular integrity and reduces the risk of ARIA-H. However, it also increases the likelihood of ARIA-E due to Aβ accumulation in the vasculature, triggering inflammation. In contrast, the development of ARIA-H is linked to increased TREM2 expression and microglial reactivity, leading to impaired vascular integrity and disrupted matrix remodeling, which worsens the condition. Additionally, the adverse effects of mAbs may extend beyond the APOE-ε4 allele, possibly impacting other genetic variants involved in microglial reactivity, Aβ redistribution, and vascular integrity.},
}

@article {pmid40951709,
year = {2025},
author = {Cui, CX and Shao, XN and Li, YY and Qiao, L and Lin, JT and Guan, LH},
title = {Therapeutic potential of mesenchymal stem cells in neurodegenerative diseases.},
journal = {World journal of stem cells},
volume = {17},
number = {8},
pages = {107717},
pmid = {40951709},
issn = {1948-0210},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, are characterized by the progressive loss of neuronal function and structure, leading to severe morbidity and mortality. Current therapeutic approaches are ineffective at stopping or reversing disease progression. Stem cell therapy has emerged as a promising candidate in research and treatment. Mesenchymal stem cells (MSCs) are considered ideal candidates for regenerative medicine because of their high proliferation rate and multi-differentiation potential. MSCs can differentiate into neurons and glial cells, modulate immune responses, and reduce inflammation, and their exosomes can promote neural repair and regulate neuronal function; thus, MSCs offer unique advantages for treating neurodegenerative diseases. However, challenges remain in optimizing cell delivery methods, ensuring the long-term survival and integration of transplanted cells, and fully understanding their therapeutic effects. This article primarily outlines the functions of MSCs in neurodegenerative diseases, with the intention that further research will fully harness their potential and translate these findings into clinical applications, offering new hope for patients suffering from neurodegenerative diseases.},
}

@article {pmid40951706,
year = {2025},
author = {Shan, XQ and He, MH and Gao, WL and Li, YJ and Liu, SZ and Liu, Y and Wang, CL and Zhao, L and Xu, SX},
title = {Mesenchymal stem cell-derived exosomes: Shaping the next era of Alzheimer's disease treatment.},
journal = {World journal of stem cells},
volume = {17},
number = {8},
pages = {109006},
pmid = {40951706},
issn = {1948-0210},
abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disease for which effective disease-modifying therapies are lacking. Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as a promising therapeutic approach due to their unique biological functions and favorable biocompatibility. This review systematically explores the mechanism of action of MSC-Exos in AD therapy, including the removal of β-amyloid via the delivery of degradative enzymes, modulation of neuroinflammation, and promotion of neural regeneration. Meanwhile, this paper summarizes recent advances in preclinical and clinical studies, and analyzes the challenges in production standardization, safety assessment, and long-term efficacy validation of exosome therapies. Finally, several innovative strategies are proposed to enhance the therapeutic potential of MSC-Exos, including exosome functionalization and targeting optimization, gene editing techniques. This aims to promote the translation of exosomes from basic research to clinical application.},
}

@article {pmid40951469,
year = {2025},
author = {Widaja, E and Pawitan, JA and Ramli, Y},
title = {Therapeutic potential of hUC-MSC secretome preconditioned with IFN-γ and/or TNF-α: An in vitro study on Alzheimer's neuronal cell models.},
journal = {Narra J},
volume = {5},
number = {2},
pages = {e2281},
pmid = {40951469},
issn = {2807-2618},
abstract = {Alzheimer's disease is a progressive neurodegenerative disease that is characterized by toxic Amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). Treatment options include the use of human umbilical cord mesenchymal stem cell (hUC-MSC)-based therapy. Its secretome contains healing substances such as neprilysin (CD10), which breaks down Aβ42; anti-inflammatory cytokines, which lower inflammation; and growth factors, which promote neuronal regeneration. The aim of this study was to produce hUC-MSC secretomes preconditioned with tumor necrosis factor-alpha (TNF-α) and/or interferon-gamma (IFN-γ) to enhance the secretion of these healing substances. hUC-MSCs were sub-cultured in T-25 flasks at a seeding density of 5×103 cells/cm[2] in 10 mL xeno-free medium. hUC-MSCs were preconditioned with TNF-α only, IFN-γ only, and a combination of TNF-α and IFN-γ. This study used 10 ng/mL TNF-α and 20 ng/mL IFN- γ. The secretome was harvested after 48 hours of preconditioning and then filtered through a 0.22 µm filter. In vitro tests were conducted to assess the effects of the secretome on neuronal survival using the neuroblastoma SH-SY5Y cell line. These cells were differentiated with retinoic acid (RA) and then exposed to Aβ42 to mimic Alzheimer's disease neurons. Secretome therapy was applied at concentrations of 5%, 10%, and 20% to evaluate neuroprotective effects. Four types of secretome were tested: unpreconditioned, TNF-α preconditioned, IFN-γ preconditioned, and a combination of TNF-α and IFN-γ. High levels of CD10 (neprilysin) expression were observed in hUC-MSCs treated with IFN-γ and TNF-α, although they did not release sufficient soluble neprilysin (sNEP). Viability results indicated that secretomes preconditioned with IFN-γ at 10% and 20% concentrations provided the highest increase in cell viability after 72 hours post-therapy. The combination of TNF-α and IFN-γ preconditioned secretome exhibited synergistic effects, particularly at 5% and 10% doses at 24- and 72-hours post- therapy. In conclusion, preconditioned hUC-MSC secretome represents a promising therapeutic approach for Alzheimer's disease, as it enhances neuronal cell viability and promotes neuronal regeneration. However, further studies are required to optimize sNEP release and maximize therapeutic efficacy in in vivo models.},
}

@article {pmid40950425,
year = {2025},
author = {Brown, CA and Cousins, KAQ and Korecka, M and McGrew, E and Chen-Plotkin, A and Detre, JA and McMillan, CT and Lee, EB and Das, SR and Mechanic-Hamilton, D and Yushkevich, PA and Nasrallah, IM and Shaw, LM and , and Wolk, DA},
title = {Temporal Modeling of Amyloid and Tau Trajectories in Alzheimer's Disease using PET and Plasma Biomarkers.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.04.25334935},
pmid = {40950425},
abstract = {OBJECTIVE: To compare PET and plasma-based temporal modeling of amyloid and tau biomarkers in Alzheimer's disease.

METHODS: Longitudinal amyloid PET, [18] F-flortaucipir tau-PET, and Fujirebio Lumipulse plasma p-tau 217 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and University of Pennsylvania Alzheimer's Disease Research Center (Penn ADRC) were used to generate biomarker trajectory models using Sampled Iterative Local Approximation (SILA). SILA models using plasma p-tau 217 were compared to amyloid and tau PET-based models to estimate tau onset age (ETOA) and estimate amyloid onset age (EAOA), and factors influencing ETOA and time from ETOA to dementia were evaluated for PET and plasma-based models.

RESULTS: Plasma-based models generated similar results to PET for EAOA and ETOA, with stronger model agreement for ETOA than EAOA. Accuracy of estimated onset age compared to actual onset age was high within modality with slightly greater error when comparing across modalities (i.e. plasma to PET). For both plasma and PET models, earlier ETOA was associated with younger EAOA, female sex, and ≥1 ApoE ε4 allele. Earlier dementia onset after ETOA was associated with later ETOA for both plasma and PET models, while male sex was associated with shorter tau to dementia gap in plasma models.

INTERPRETATION: Temporal modeling of plasma biomarkers provides comparable information to PET-based models, particularly for tau onset age. Plasma-based temporal modeling can serve as a widely accessible tool for clinical assessment of biological disease duration that places the patient on the disease timeline, which may allow for improved discussion of prognosis and treatment decisions.},
}

@article {pmid40950166,
year = {2025},
author = {Wang, Y and Anchipolovsky, S and Bhuiyan, P and Sato, L and Liang, G and Chuang, DM and Wei, H},
title = {Lithium Chloride Inhibits Iron Dysregulation and Ferroptosis in Induced Pluripotent Stem Cells with ApoE4/E4 from a sporadic Alzheimer's disease patient.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.28.672956},
pmid = {40950166},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD), particularly its sporadic form (SAD, 95% AD patients), is strongly associated with the apolipoprotein E4 ApoE4 genotype and characterized by oxidative stress, iron dysregulation, and increased susceptibility to ferroptosis. Lithium, a well-established neuroprotective agent, has shown potential to mitigate several pathological mechanisms in AD, including ferroptosis. This study investigates the therapeutic potential of lithium chloride in human induced pluripotent stem cells (iPSCs) derived from a SAD patient with ApoE4/E4 genotype, and compared effects with those of isogenic gene-edited ApoE3/E3 control. Lithium treatment significantly improved cell viability in ApoE4/E4 iPSCs. It also reversed key ferroptosis phenotypes, including elevated cytosolic Fe [2+] , increased expression of divalent metal transporter 1, reduced level of glutathione peroxidase 4, enhanced lipid peroxidation, and excessive ROS production. Moreover, lithium normalized mitochondrial respiration and reduced proton leak, indicating preservation of mitochondrial function and protection against mitochondrial damage and cell death. Lithium also reduced the expression of type 1 InsP3 receptor (InsP3R-1) protein, a Ca [2+] channel located on the endoplasmic reticulum (ER) membrane. Together, these findings highlight lithium's inhibition of ferroptosis through modulation of iron metabolism, antioxidant defenses, and inhibition of disrupted Ca [2+] signaling. Given its demonstrated efficacy in reversing ApoE4-driven cellular vulnerabilities, lithium salt warrants further investigation for the treatment of AD.},
}

@article {pmid40950069,
year = {2025},
author = {Simpson, D and Morrone, CD and Wear, D and Khani, A and Liu, F and Gutierrez, J and Yu, WH},
title = {Brain large artery dilatation increases the risk for Alzheimer's disease pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.29.672901},
pmid = {40950069},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) and related dementia cases are increasing globally, emphasizing the urgent need to clarify disease mechanisms for translational application in diagnoses and treatment. Vascular alterations represent a major pathological feature of AD, and beyond the well-established roles of small vessel disease and large artery atherosclerosis, our group has previously demonstrated that brain large artery dilatation is associated with elevated risk of dementia and Alzheimer pathology. The most severe manifestation of this non-atherosclerotic arterial phenotype is dolichoectasia, an enlargement of large blood vessels (Gutierrez et al., 2019; Melgarejo et al., 2024). Despite consistent epidemiological evidence across populations, the mechanistic link between arterial dilatation and AD remains poorly understood. To address this gap, we induced dolichoectasia in App [NL-G-F] mice, a model of amyloid pathology, by injecting elastase into the cisterna magna. After three months, brains were examined using biochemical and immunohistochemical methods. Elastase-treated mice exhibited a significant increase in amyloid plaques in the hippocampus (p = 0.021) and cortex (p = 0.029) compared with vehicle-treated controls. Neuronal loss was evident in the CA1 region of the hippocampus (p = 0.036), with a trend towards neurodegeneration in CA3 (p = 0.055). We also observed elevated p62 in the hippocampus and cortex (p = 0.009 and p = 0.001 , respectively), suggesting impaired protein or autophagic-lysosomal clearance. Although no overt increase in neuroinflammation or astrogliosis was detected at this time point, matrix metalloproteinase-9 (MMP-9) levels were trending towards elevated levels (p = 0.058). Combined, these findings indicate successful elastase-induced brain arterial dilatation accelerates AD-related pathology in App [NL-G-F] mice, providing mechanistic evidence that large artery dilatation may contribute directly to Alzheimer's disease progression.},
}

@article {pmid40949788,
year = {2025},
author = {Alzenaidi, F and Aldoweesh, O and Alghofaili, S and Fadel, A and Ali Awad Lasloom, R and Alharbi, D and Almalki, F and Ahmad Alkhairi, A and Alharbi, M and Ahmed Alhamdan, N and Azzam, AY},
title = {Selective serotonin reuptake inhibitors and glucose metabolism in Alzheimer's disease and related dementias: A systematic review and meta-analysis of brain metabolic and adverse event data.},
journal = {Metabolism open},
volume = {27},
number = {},
pages = {100389},
pmid = {40949788},
issn = {2589-9368},
abstract = {INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression in Alzheimer's disease (AD), however their effects on glucose metabolism remain poorly understood. We conducted a systematic review and meta-analysis to evaluate SSRI effects on brain glucose metabolism and metabolic adverse events in AD patients.

METHODS: Following PRISMA 2020 guidelines, we searched multiple databases up to July 11, 2025 for studies investigating SSRI effects on glucose-related outcomes in AD patients. Despite significant heterogeneity in study designs and populations, we performed meta-analyses for adverse events and coordinate-based meta-analysis for neuroimaging data. We performed meta-analyses for adverse events and coordinate-based meta-analysis for neuroimaging data. Advanced Bayesian hierarchical modeling and Markov simulations projected long-term metabolic outcomes.

RESULTS: Twelve studies with total included 7143 participants met our inclusion criteria, including nine randomized controlled trials and three observational studies. Brain FDG-PET revealed SSRI use restored dorsal raphe nucleus hypometabolism (standardized mean difference 0.87, 95 % CI: 0.52-1.22, P-value = 0.001). Meta-analysis demonstrated increased gastrointestinal adverse events (risk ratio 2.15, 95 % CI: 1.68-2.76, P-value<0.001, with moderate between-study heterogeneity), with sertraline showing highest rates. Citalopram 30 mg provided significant weight loss protection (risk ratio 0.13, 95 % CI: 0.02-0.98, P-value = 0.02), though this exceeds the recommended 20 mg maximum dose for elderly patients due to cardiac safety considerations. Long-term diabetes incidence showed no increased risk (hazard ratio 0.75, 95 % CI: 0.50-1.12, P-value = 0.15). Bayesian modeling revealed 85 % probability of beneficial brain metabolic effects and 89 % probability of citalopram superiority for weight protection.

CONCLUSIONS: SSRIs restore brain glucose metabolism in AD patients while causing manageable peripheral metabolic effects. Citalopram appears the best for weight-sensitive patients, while sertraline requires gastrointestinal monitoring. These findings support SSRI safety for metabolic outcomes in AD treatment, however longer-term studies with controlled metabolic outcomes are needed to confirm our findings. The observed citalopram weight protection benefit was documented at 30 mg daily, which exceeds recommended dosing limits for elderly patients due to cardiac safety concerns.},
}

@article {pmid40949676,
year = {2025},
author = {Cai, H and Hu, J and Zhao, C and Lin, J},
title = {Wearable devices in neurological disorders: a narrative review of status quo and perspectives.},
journal = {Annals of translational medicine},
volume = {13},
number = {4},
pages = {46},
pmid = {40949676},
issn = {2305-5839},
abstract = {BACKGROUND AND OBJECTIVE: Neurological disorders are a group of diseases involving motor, sensory, cognitive, and autonomic functions, among which stroke, Alzheimer's disease (AD), and Parkinson's disease (PD) are prevalent. Their management, especially in conditions with chronic courses or long-term sequelae, remains a substantial unmet need. With the growing comprehension of neuroscience, the development of digital technology, and the rising demand for quality of life, wearable devices offer a promising solution for disease management. The review aimed to evaluate the application and prospect of wearable devices in neurological disorders.

METHODS: We conducted the review by searching papers on the application of wearable devices and wearable technology in neurology and neurological disorders using multiple databases. We summarized the present development status of wearable devices, and outlined the potential value and future direction for further research.

KEY CONTENT AND FINDINGS: Existing wearable devices for neurological diseases can be applied to diagnosis and follow-up, as an electronic biomarker detector capturing subtle and objective changes in motor, sensory, and cognitive function. The devices can also be utilized for treatment and rehabilitation, mainly through exoskeletons and brain-computer interface. The application of wearable devices in neurology currently faces several critical limitations, including technical bottlenecks in the detection of fine motor and sensory functions, a lack of industry standards, and a limited sample size.

CONCLUSIONS: This review demonstrates the potential of wearable technology in people with neurological disorders, enabling disease management and clinical trials outside clinical settings in the future. Nevertheless, further research is required to develop lighter, more user-friendly devices with various functions. It is believed that with increasing demand and technical support, wearable devices would have a promising range of applications.},
}

@article {pmid40949612,
year = {2025},
author = {Gao, L and Wang, J and Bi, Y},
title = {Nanotechnology for Neurodegenerative Diseases: Recent Progress in Brain-Targeted Delivery, Stimuli-Responsive Platforms, and Organelle-Specific Therapeutics.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {11015-11044},
pmid = {40949612},
issn = {1178-2013},
abstract = {Neurodegenerative diseases-including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis-are characterized by progressive neuronal loss and complex pathological mechanisms such as protein aggregation, mitochondrial dysfunction, and neuroinflammation. Conventional therapies offer limited efficacy due to the blood-brain barrier (BBB) and lack of targeted delivery. Nanotechnology has emerged as a transformative strategy for precise brain-targeted treatment. This review summarizes recent advances in nanoparticle-based drug delivery systems, including polymeric nanoparticles, liposomes, inorganic nanomaterials, and biomimetic carriers, highlighting their design features, BBB-penetration mechanisms, and disease-specific applications. Emphasis is placed on stimuli-responsive nanocarriers that react to pH, reactive oxygen species, or enzyme activity, enabling site-specific drug release. Additionally, organelle-targeting strategies-particularly those directed at mitochondria and lysosomes-are explored for their role in subcellular precision therapy. The integration of diagnostic and therapeutic modalities in theranostic nanoplatforms is also discussed. By consolidating preclinical progress and emerging technologies, this review offers insights into the future of nanomedicine in treating neurodegenerative diseases and lays the groundwork for clinical translation.},
}

@article {pmid40949219,
year = {2025},
author = {Van, DTT and Hoang, TLH and Tran, TVT and Le, TH and Le, LS and Nguyen, QM and Nguyen, THH and Bich, TTN and Nguyen, THC and Phan, CU and Nguyen, CC},
title = {Structural Characterizations and In Vitro Bioactivities of a d‑Fructose-Rich Polysaccharide from Gymnopetalum cochinchinense as a Potential Candidate for Alleviating Alzheimer's Disease.},
journal = {ACS omega},
volume = {10},
number = {35},
pages = {40342-40353},
pmid = {40949219},
issn = {2470-1343},
abstract = {The presented investigation attempts to unveil the structural characteristics, bioactivities, and potential application of Gymnopetalum cochinchinense-derived d-fructose-rich heteropolysaccharide (denoted as PS-HB5) for the treatment of Alzheimer's disease (AD). Structural analyses of the PS-HB5 evaluated by FT-IR, GC-MS, and NMR techniques reveal a novel repeating unit composed of d-glucose and d-fructose linked through (1 → 6)-glucosyl, (2 → 6)-fructosyl, and (2 → 4)-fructosyl bonds, and possesses a molecular weight of 1.217 × 10[5] Da. The PS-HB5 exhibits strong antioxidant activity, as evidenced by its DPPH and ABTS radical scavenging rates of 84.12% and 74.14%, associated with the IC50 values of 0.80 and 3.06 mg.mL[-1], respectively. In addition, the PS-HB5 shows an inhibition rate of 78.37% (IC50 = 221.96 μg.mL[-1]) toward nitric oxide (NO) production in LPS-stimulated macrophages. Cytotoxicity assays indicate selective inhibition of the PS-HB5 against HepG2 and KB cancer cell lines (IC50 = 449.95 and 408.34 μg/mL), with minimal impact on MCF-7 and SK-LU-1. Interestingly, PS-HB5 demonstrates an outstanding AChE inhibitory effect, achieving 41.01% inhibition at 500 μg.mL[-1], placing it among the most active AChE-inhibitory polysaccharides. These findings unveil the PS-HB5 potential as a candidate for the treatment of Alzheimer's Disease.},
}

@article {pmid40949132,
year = {2025},
author = {Han, X and Meng, X and Wu, Y and Xia, W and Xue, S and Liu, X and Lyu, C and Li, Z and Yan, X and Won Jung, H and Zhang, S},
title = {Systems pharmacology identifies ajugol-mediated NF-κB/caspase-3 inhibition and isoacteoside-driven p62/mTOR-mediated autophagy as key mechanisms of Rehmanniae Radix and its processed form in Alzheimer's treatment.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1644847},
pmid = {40949132},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the deposition of senile plaques, neurofibrillary tangles, and neuronal dysfunction, resulting in severe cognitive and memory decline. The root of the Scrophulariaceae plant Rehmannia glutinosa (Gaertn.) DC. (Rehmanniae radix; RR) and its product Rehmanniae radix praeparata (RRP) possess high nutritional and medicinal value. Both show therapeutic potential for AD in traditional medical settings. However, the differences in their bioactive components and the mechanisms of action underlying their anti-AD effects remain unclear.

METHODS: In this study, APP/PS1 mice were used as the animal model of AD. Ultra-high-performance liquid chromatography coupled with Q-Exactive tandem mass spectrometry (MS/MS) (UPLC-QE-MS/MS), network pharmacology, proteomics, molecular docking, and 16S rRNA sequencing were used to investigate the differences in the medicinal components of RR and RRP and their mechanisms of action in the treatment of AD. The mechanisms of action of two identified critical components, ajugol and isoacteoside, were further verified in the D-galactose/AlCl3-induced Institute of Cancer Research (ICR) mouse model of AD-with cognitive function evaluated using the Morris water maze and open-field tests-and the amyloid-beta (Aβ)-induced BV2 cell model of inflammation.

RESULTS: Ajugol and isoacteoside were identified as the key anti-AD bioactive compounds in RR and RRP, respectively, through UPLC-QE-MS/MS. Integrated network pharmacology, proteomics, and 16S rRNA sequencing implicated neuroinflammation, apoptosis, and autophagy as critical pathways for their anti-AD effects. Subsequently, in vivo and in vitro experiments demonstrated that ajugol exerted its effects mainly by modulating the TLR/NF-κB/NLRP3 and BCL-2/BAX/cytochrome C/caspase-3 pathways, while isoacteoside primarily acted via the LC3-Ⅱ/P62/p-mTOR/mTOR pathway. Ajugol and isoacteoside mitigated cognitive impairment in AD models, decreased Aβ plaque accumulation in hippocampal tissues, and attenuated inflammatory injury-induced cytotoxicity in BV2 microglia, thereby suppressing AD progression.

CONCLUSION: In this work, we systematically elucidated the differential mechanisms underlying the anti-AD effects of ajugol and isoacteoside. We found that ajugol primarily acts via the TLR/NF-κB/NLRP3 and BCL-2/BAX/cytochrome C/caspase-3 pathways, while isoacteoside acts via the LC3-II/P62/p-mTOR/mTOR pathway. These findings establish a foundation for developing RRP-based complementary medicines and functional foods.},
}

@article {pmid40948811,
year = {2025},
author = {Imiruaye, OE and Perez, IG and Carson, BC and Crouzet, C and Garcia, J and Han, D and Bhattacharya, S},
title = {Spatiotemporal differential regulation of extrasynaptic GluN2B receptor subunits and PSA-NCAM in brain aging and Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1649625},
pmid = {40948811},
issn = {1662-4548},
abstract = {INTRODUCTION: Extrasynaptic GluN2B N-methyl-D-aspartate receptors (ES-GluN2B) are localized outside synapses and promote excitotoxic signaling, apoptosis, and long-term depression (LTD) in Alzheimer's disease (AD). Polysialylated neural cell adhesion molecule (PSA-NCAM) physiologically inhibits ES-GluN2B activity, and its downregulation is associated with impaired synaptic plasticity. However, the spatiotemporal changes of ES-GluN2B and PSA-NCAM during brain aging versus AD remain poorly understood.

METHODS: We investigated GluN2A, GluN2B, ES-GluN2B, and PSA-NCAM expression across brain regions in young and old Tg2576 AD and wild-type (WT) mice. Additional experiments included PSD-95 pulldown assays, analysis of GluN2B phosphorylation at Ser1480, CRISPRa-driven ST8Sia4 upregulation in IMR-32 neuroblastoma cells, and Aβ treatment to assess effects on PSA-NCAM biosynthetic enzymes.

RESULTS: Normal aging was associated with decreased GluN2B, increased GluN2A, stable ES-GluN2B, and elevated PSA-NCAM levels. In contrast, AD aging showed elevated ES-GluN2B and reduced PSA-NCAM, particularly in the hippocampus and cortex, with no change in total NCAM expression. PSD-95 pulldown revealed increased extrasynaptic GluN2B in aged AD brains. AD aging was associated with elevated phosphorylation of GluN2B at Ser1480 by casein kinase 2 (CK2), promoting GluN2B redistribution to extrasynaptic sites. CRISPRa-driven ST8Sia4 upregulation increased PSA-NCAM and reduced pGluN2B expression supporting a direct regulatory role for PSA-NCAM in GluN2B trafficking. Additionally, Aβ suppressed PSA-NCAM biosynthetic enzymes ST8Sia4 and UDP-E linking Aβ to impaired polysialylation.

DISCUSSION: These findings highlight distinct regulatory patterns of ES-GluN2B and PSA-NCAM in AD versus normal aging and support a model in which impaired PSA-NCAM buffering facilitates pathological ES-GluN2B signaling and plasticity loss in AD progression.},
}

@article {pmid40948809,
year = {2025},
author = {Kynigopoulos, D and Fella, E and Shahabian, L and Christodoulou, CC and Papacharalampous, R and Diskos, K and Vagiaki, LE and Sidiropoulou, K and Pipis, M and Kleopa, KA and Panayiotou, E},
title = {Systemic lipid and glucose modulation differentially affects cognitive function and neuroinflammation in a mouse model of Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1636624},
pmid = {40948809},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and cognitive decline. Increasing evidence implicates systemic metabolic dysregulation in AD pathogenesis, yet it remains unclear whether modulation of peripheral lipid and glucose metabolism can alter disease progression.

METHODS: We investigated the effects of two FDA-approved metabolic agents-Alirocumab, a PCSK9 inhibitor that lowers LDL cholesterol, and Gliclazide, a sulfonylurea that enhances insulin secretion-in male 5xFAD mice, a transgenic model of AD. Animals received chronic treatment for five months. Behavioral testing, hippocampal electrophysiology, ELISA, lipidomics, and adipokine profiling were performed to assess cognitive, synaptic, and molecular outcomes.

RESULTS: Alirocumab significantly improved spatial working memory, restored hippocampal long-term potentiation, and normalized synaptophysin expression. Gliclazide reduced neuroinflammation and partially preserved glial and neuronal markers. Both treatments decreased amyloid burden and modulated adipokine levels, with Alirocumab elevating leptin and omentin in brain and serum. Lipidomic profiling of visceral adipose tissue revealed distinct lipid remodeling and highlighted candidate pathways linking systemic metabolism to central nervous system outcomes.

DISCUSSION: These findings demonstrate that systemic modulation of lipid and glucose metabolism can influence neurodegenerative and synaptic processes in AD. The results support metabolic interventions as a potential strategy to modify AD progression through peripheral-central metabolic crosstalk.},
}

@article {pmid40948808,
year = {2025},
author = {Cansiz, B and Ilhan, HO and Aydin, N and Serbes, G},
title = {Olfactory EEG based Alzheimer disease classification through transformer based feature fusion with tunable Q-factor wavelet coefficient mapping.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1638922},
pmid = {40948808},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease has been considered one of the most dangerous neurodegenerative health problems. This disease, which is characterized by memory loss, leads to conditions that adversely affect daily life. Early diagnosis is crucial for effective treatment and is achieved through various imaging technologies. However, these methods are quite costly and their results depend on the expertise of the specialist physician. Therefore, deep learning techniques have recently been utilized as decision support tools for Alzheimer's disease.

METHODS: In this research, the detection of Alzheimer's disease was investigated using a deep learning model applied to electroencephalography signals, taking advantage of olfactory memory. The dataset comprises three categories: healthy individuals, those with amnestic mild cognitive impairment, and Alzheimer's disease patients. The proposed model integrates three distinct feature types through a transformer-based fusion approach for classification. These feature vectors are derived from the Common Spatial Pattern, Covariance matrix-Tangent Space and a Tunable Q-Factor wavelet coefficient mapping.

RESULTS: The results demonstrated that subject-based classification of rose aroma attained a 93.14% accuracy using EEG-recorded olfactory memory responses.

CONCLUSION: This output has demonstrated superiority over EEG-based results reported in the literature.},
}

@article {pmid40948654,
year = {2025},
author = {Cui, S and Zhao, Y and Wang, X and Huang, Y and Ye, J and Deng, Z and Li, Y and Qin, H and Wang, L and Li, Y and Wang, K and Zheng, G and Qin, Q},
title = {Evaluating the clinical evidence of TCM in Alzheimer's disease: an evidence map perspective.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1571361},
pmid = {40948654},
issn = {1664-2295},
abstract = {OBJECTIVE: This systematic review aimed to synthesize current clinical evidence from randomized controlled trial (RCT) and meta-analyses on the efficacy and safety of TCM in the treatment of Alzheimer's Disease (AD).

METHODS: Systematic searches across eight biomedical databases (PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang, VIP, SinoMed) through October 26, 2024 yielded an evidence matrix, which was analyzed through integrated narrative-graphic synthesis.

RESULTS: Our analysis encompassed 187 studies (141 RCTs and 46 systematic reviews/meta-analyses), demonstrating cyclical publication growth with recent contraction. Study characteristics included sample sizes of 50-100 participants and intervention durations of 4-24 weeks. Interventions included acupuncture, herbal decoctions, and proprietary medicines. Outcomes focused on clinical efficacy, scale scores, TCM syndrome scores, and safety. While TCM demonstrated therapeutic potential, prescription heterogeneity and diagnostic ambiguity constrained specificity. Methodological quality was generally low, with few high-quality systematic reviews or meta-analyses.

CONCLUSION: While TCM shows therapeutic potential in Alzheimer's disease, methodological limitations persist. Subsequent research requires enhanced trial designs with standardized outcome metrics and rigorous bias control protocols.},
}

@article {pmid40947745,
year = {2025},
author = {Ogunsuyi, OB and Oluokun, OO and Ademiluyi, AO and Oboh, G and Akeeb, RA and Umar, HI and Olagoke, OC},
title = {Synergistic effects of curcumin-donepezil therapy in a Drosophila Alzheimer's disease model.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/17582024.2025.2558428},
pmid = {40947745},
issn = {1758-2032},
abstract = {BACKGROUND: Despite emerging therapeutic options, Alzheimer´s disease (AD) management remains suboptimal due to multimodal pathogenesis. We investigated curcumin-donepezil combination therapy, as curcumin demonstrates antioxidant, anti-inflammatory, and anti-amyloidogenic properties that may complement donepezil's cholinesterase inhibition.

RESEARCH DESIGN AND METHODS: We employed the elav-Gal4/UAS-hAPP-BACE-1 Drosophila melanogaster model alongside molecular docking simulation and ADMET prediction to evaluate curcumin-donepezil combination versus monotherapy. Fruit flies received the treatment regimen, and were tested for survival, memory performance, and biochemical markers, including BACE-1 activity and oxidative stress parameters.

RESULTS: Combination therapy significantly improved survival rates and memory performance compared to individual treatment. The combination effectively modulated multiple AD-related pathways, demonstrating reduced BACE-1 activity and decreased oxidative stress markers. Molecular docking confirmed favorable drug interactions, and ADMET profiles supported therapeutic viability.

CONCLUSIONS: Curcumin-donepezil combination therapy shows promise as a multi-target approach for AD management. However, translation to clinical applications requires validation in higher-order models and human trials.},
}

@article {pmid40947724,
year = {2025},
author = {Aljabali, AAA and Alkaraki, A and Obeid, MA},
title = {MAPT Haplotype Variation and Alzheimer's Disease Risk: A Narrative Review with Focus on the Jordanian Population.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X371971250818110608},
pmid = {40947724},
issn = {1875-6190},
abstract = {INTRODUCTION: Genetic variations in the microtubule-associated protein tau (MAPT) gene play a central role in Alzheimer's disease (AD) pathogenesis. Two major MAPT haplotypes, H1 and H2, show differential associations with tau expression and AD risk. However, data from Middle Eastern populations remain limited, restricting our understanding of population-specific disease susceptibility patterns and therapeutic responses.

METHODS: We conducted a comprehensive literature review using PubMed, Scopus, and Web of Science databases. Search terms included "MAPT haplotype," "Alzheimer's disease," "H1 H2," "tau pathology," and "pharmacogenetics." We analyzed peer-reviewed articles published between 2000 and 2024, focusing on studies reporting haplotype frequencies, MAPT expression levels, APOE interactions, and clinical outcomes. This review synthesizes published data without generating new experimental results.

RESULTS: The H1 haplotype consistently associates with increased MAPT expression, tau accumulation, and elevated AD risk, particularly in APOE ε4 noncarriers. Conversely, the H2 haplotype appears protective, correlating with reduced tau burden and slower cognitive decline. Notably, recent reports reveal significant overrepresentation of the H2 haplotype in the Jordanian population compared to European and East Asian cohorts, where H2 frequency is substantially lower or absent. This distinct genetic architecture suggests altered regional AD risk profiles.

DISCUSSIONS: The elevated H2 frequency in Jordan represents a unique population-specific genetic signature that may influence regional AD susceptibility patterns. These findings challenge current risk models predominantly based on European populations and suggest the need for populationtailored approaches in neurodegenerative disease research. The naturally H2-enriched Jordanian cohort provides an exceptional opportunity to investigate protective mechanisms against tau pathology.

CONCLUSION: MAPT haplotype distributions show significant population variation with important implications for AD risk assessment and therapeutic targeting. The high H2 frequency in Jordan warrants integration into personalized medicine frameworks and population-specific disease models, potentially informing more effective regional prevention and treatment strategies.},
}

@article {pmid40947692,
year = {2025},
author = {Manubolu, K and Peeriga, R},
title = {Revolutionizing Neurodegenerative Disease Management: The Synergy of AI and Pharmacy.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098375978250820220024},
pmid = {40947692},
issn = {1874-6128},
abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS), represent major healthcare challenges worldwide. Despite advances in diagnosis and treatment, these conditions remain incurable, and there is a need for more effective management strategies. The integration of artificial intelligence (AI) in healthcare has emerged as a promising solution, offering new approaches to diagnosis, personalized treatment, and patient care. This paper explores the potential of AI to revolutionize the management of neurodegenerative diseases, with a focus on its synergistic role in pharmacy. By leveraging AI in drug discovery, personalized treatment plans, and clinical decision-making, AI can enhance therapeutic outcomes and improve patient quality of life. The study reviews the current landscape of AI applications in neurodegenerative disease management, with a focus on pharmacy-related interventions. The review includes AI-driven approaches in genomics, biomarkers, drug repurposing, and clinical trials. It also examines AI's role in optimizing pharmaceutical care, improving medication adherence, and tailoring treatments based on individual genetic profiles. AI has demonstrated its capability to analyze vast datasets, from genetic information to clinical records, to identify novel drug targets and predict patient responses to specific therapies. The use of AI in precision medicine has enabled more accurate diagnosis and has facilitated the development of personalized treatments for neurodegenerative diseases. Additionally, AI tools are enhancing medication management by providing personalized therapy adjustments and improving adherence. AI offers transformative potential for the future of neurodegenerative disease management. Its integration into pharmacy practice promises more effective, individualized treatments, accelerating drug discovery, and optimizing patient care. As AI technologies continue to advance, their role in managing complex neurological disorders will become increasingly vital.},
}

@article {pmid40947660,
year = {2025},
author = {Noguchi, Y and Masuda, R and Yoshimura, T},
title = {Sequence Symmetry Analysis of the Interrelationships Between Ramelteon and Parkinson's Disease.},
journal = {Journal of pineal research},
volume = {77},
number = {5},
pages = {e70080},
doi = {10.1111/jpi.70080},
pmid = {40947660},
issn = {1600-079X},
support = {//This study was supported by JSPS KAKENHI, 22K12890./ ; },
abstract = {Parkinson's disease is the second most frequent neurodegenerative disease after Alzheimer's disease, and the most common neurodegenerative disease that causes movement dysfunction. Without innovations in prevention and treatment, the incidence and prevalence of Parkinson's disease is projected to increase by > 30% by 2030, making the development of new treatments an urgent priority. We previously investigated the association between melatonin receptor agonists and Parkinson's disease using the US Food and Drug Administration's Adverse Event Reporting System (FAERS). The results showed that ramelteon may reduce the incidence of Parkinson's disease. However, since the US FAERS relies on spontaneous reports, which are susceptible to reporting bias, further validation using real-world data is required. This study investigated the association between ramelteon use and risk of developing Parkinson's disease using the DeSC database, a Japanese claims database reported to be representative of the general Japanese population. The association was evaluated using sequence symmetry analysis, with the adjusted sequence ratio (ASR) serving as the evaluation index. Our DeSC database analysis showed a negative association between ramelteon use and Parkinson's disease (ASR: 0.959, 95% confidence interval: 0.955-0.964). Our results support previous reports suggesting that ramelteon may help suppress the onset of Parkinson's disease. However, even though this study used real-world data, these results should be interpreted with caution, as a sequence symmetry analysis cannot be adjusted for covariates. Therefore, additional pharmacoepidemiological studies are needed to further verify the potential risk of Parkinson's disease associated with ramelteon use.},
}

@article {pmid40947402,
year = {2025},
author = {Ghosh, D and Xu, X and Luo, S and , },
title = {Power and Sample Size Calculation for Multivariate Longitudinal Trials Using the Longitudinal Rank Sum Test.},
journal = {Statistics in medicine},
volume = {44},
number = {20-22},
pages = {e70261},
doi = {10.1002/sim.70261},
pmid = {40947402},
issn = {1097-0258},
support = {R01AG064803/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; },
abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's often exhibit complex, multivariate longitudinal outcomes that require advanced statistical methods to comprehensively evaluate treatment efficacy. The Longitudinal Rank Sum Test (LRST) offers a nonparametric framework to assess global treatment effects across multiple longitudinal endpoints without requiring multiplicity corrections. This study develops a robust methodology for power and sample size estimation specific to the LRST, integrating theoretical derivations, asymptotic properties, and practical estimation techniques under large sample conditions. Validation through numerical simulations demonstrates the accuracy of the proposed methods, while real-world applications to clinical trials in Alzheimer's disease (AD) and Parkinson's disease (PD) highlight their practical significance. This framework facilitates the design of efficient, well-powered trials, advancing the evaluation of treatments for complex diseases with multivariate longitudinal outcomes.},
}

@article {pmid40946953,
year = {2025},
author = {Sun, C and Cai, X and Jiang, X and Wen, F and Wan, L},
title = {Neuroprotective alpha-linolenic acid derived from black pepper targets PGK1 and activates the Nrf2 pathway in PC12 cells and mice.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178154},
doi = {10.1016/j.ejphar.2025.178154},
pmid = {40946953},
issn = {1879-0712},
abstract = {BACKGROUND: Oxidative stress is a significant contributor to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Nuclear factor E2-related factor 2 (Nrf2), a pivotal regulator of antioxidant responses, is an emerging therapeutic target for these conditions. Our study assessed the neuroprotective effects of monomeric compounds derived from black pepper against hydrogen peroxide (H2O2)-induced damage in neuron-like PC12 cells. Alpha-linolenic acid (ALA) demonstrated superior protective effects.

PURPOSE: The aim of this study was to investigate the mechanism underlying the neuroprotective activity of ALA derived from black pepper.

METHODS: H2O2 induces oxidative stress in vitro, and MPTP induces Parkinson's syndrome in vivo. Proliferation and apoptosis assays, fluorescent dye staining, Western blotting, real-time PCR, immunofluorescence, luciferase reporter assays, behavioural experiments, and immunohistochemistry were performed to investigate the effects of ALA and the underlying mechanism in vitro and in vivo.

RESULTS: Our findings indicate that the ROS-scavenging and cytoprotective properties of ALA are likely mediated through Nrf2 activation and the upregulation of phase II antioxidant enzymes, including HO-1 and NQO1. Drug affinity responsive target stability (DARTS) assays revealed that ALA interacts with the PGK1 protein, potentially inhibiting its activity to promote Nrf2 activation. In vivo, the oral administration of ALA (60 and 120 mg/kg) significantly mitigated the behavioural deficits associated with Parkinson's disease, preserved dopaminergic neurons in an MPTP-induced mouse model of PD, and relieved nerve inflammation.

CONCLUSION: Our data suggest that ALA may be a candidate neuroprotective agent for the treatment of neurodegenerative diseases, offering novel insights and potential therapeutic targets for future interventions.},
}

@article {pmid40945030,
year = {2025},
author = {Tang, P and Zhao, D and Lin, H and Li, X and Shi, C and Li, P and Chen, H},
title = {Potential modulation of microglial ferroptosis by Linggui Zhugan decoction in Alzheimer's disease through IL-17 and TNF pathways.},
journal = {International immunopharmacology},
volume = {165},
number = {},
pages = {115489},
doi = {10.1016/j.intimp.2025.115489},
pmid = {40945030},
issn = {1878-1705},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative condition marked by cognitive decline and memory loss, with ferroptosis, an iron-dependent form of regulated cell death, emerging as a contributing factor. This study explored the potential modulatory effects of key components of the traditional Chinese medicine (TCM) formula Linggui Zhugan Decoction (LZD) on microglial ferroptosis in AD, focusing on IL-17 and TNF signaling pathways. Using single-cell RNA sequencing, we observed alterations in microglial populations and ferroptosis-related gene expression in AD mice. Network pharmacology and in vitro experiments indicated that LZD components might influence ferroptosis-related pathways, coinciding with reduced IL-17 and TNF levels in Aβ1-42-treated microglia. In vivo, LZD administration was associated with improved behavioral outcomes and modulation of ferroptosis markers. Although our findings suggest a correlation between LZD treatment and attenuation of ferroptosis-associated pathology, further mechanistic validation is necessary to establish causal links. This study provides preliminary evidence supporting the therapeutic potential of TCM in AD via inflammatory pathway modulation.},
}

@article {pmid40944899,
year = {2025},
author = {Sharma, DK},
title = {Nanotechnology-driven approaches for the early detection and targeted treatment of Alzheimer's disease.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-32},
doi = {10.1080/1061186X.2025.2561788},
pmid = {40944899},
issn = {1029-2330},
abstract = {A neurodegenerative condition called Alzheimer's disease (AD) is brought on by the buildup of beta-amyloid plaques in the brain. As of right now, AD has no known cure. The only thing the medications on the market can do is slow their development. Nonetheless, nanotechnology has demonstrated its superiority in its application in medicine. It has great promise for AD therapy, mostly in diagnosing the ailment and offering a different treatment method. Penetrating and bypassing the blood-brain barrier (BBB) increases the effectiveness of drug delivery. The most recent advancements in AD diagnosis using nanotechnology based on nanoparticles with optical sensing, electrochemical sensing, and imaging approaches are summarised in this study. When treating AD, nanocarriers help deliver the targeted medication. Since one of the newest and most active treatments for AD is nanomedicines, the main goal of this review is to comprehend the sophisticated application of nanocarriers for targeted drug delivery in AD treatment.},
}

@article {pmid40943807,
year = {2025},
author = {Rajič Bumber, J and Rački, V and Mežnarić, S and Pelčić, G and Mršić-Pelčić, J},
title = {Clinical Significance of APOE4 Genotyping: Potential for Personalized Therapy and Early Diagnosis of Alzheimer's Disease.},
journal = {Journal of clinical medicine},
volume = {14},
number = {17},
pages = {},
doi = {10.3390/jcm14176047},
pmid = {40943807},
issn = {2077-0383},
support = {uniri-iskusni-biomed-23-82//University of Rijeka/ ; },
abstract = {Apolipoprotein E (APOE) remains the most robust and widely replicated genetic risk factor for late-onset Alzheimer's disease (AD) susceptibility, with the ε4 allele (APOE4) demonstrating profound associations with accelerated symptom manifestation, enhanced disease trajectory, and modified therapeutic responsiveness. This comprehensive review synthesizes contemporary evidence regarding the clinical utility of APOE4 genotyping, emphasizing its integration into personalized therapeutic frameworks and early diagnostic paradigms. The APOE4 variant exerts pathogenic influence through impaired amyloid-β clearance, enhanced tau pathology, and compromised neuronal repair mechanisms that alter disease phenotype. We systematically examine available genotyping methodologies, encompassing polymerase chain reaction (PCR) and next-generation sequencing (NGS) platforms, and evaluate their practical implementation within clinical environments. Recent investigations demonstrate that APOE4 status profoundly influences therapeutic efficacy, particularly with anti-amyloid interventions such as lecanemab, where carriers exhibit enhanced treatment response alongside increased adverse event susceptibility. Emerging gene therapeutic approaches show promise in mitigating APOE4-associated risks through targeted molecular interventions. The integration of APOE4 genotyping with fluid biomarkers and neuroimaging techniques enables refined patient stratification and enhanced diagnostic precision, facilitating earlier intervention windows that optimize therapeutic outcomes before irreversible neuronal damage occurs. This review underscores APOE4 testing as a transformative component of precision medicine in AD management, emphasizing its contribution to diagnostic refinement, clinical decision support, and targeted therapeutic interventions.},
}

@article {pmid40943686,
year = {2025},
author = {Bishara, H and Cohen, H and Hadar, D and Specktor, P},
title = {Ethnic Differences in Dementia Diagnosis and Treatment in Israel.},
journal = {Journal of clinical medicine},
volume = {14},
number = {17},
pages = {},
doi = {10.3390/jcm14175926},
pmid = {40943686},
issn = {2077-0383},
abstract = {Background/Objectives: Lifestyle and socioeconomic disparities influence dementia prevalence and treatment across ethnic groups worldwide. Our study aimed to examine differences in the diagnosis, work-up, and treatment of mild cognitive impairment (MCI) as well as various types of dementia provided to Arab and Jewish participants in Israel. Methods: Data were collected retrospectively and anonymously between 1 January 2010 and 12 September 2021, by Clalit Health Services' research department. Ethnicity was determined based on residence, including only cities with a 99% majority of either Jewish or Arab participants, according to the Central Bureau of Statistics (CBS). Subjects over the age of 60 with an MCI or dementia diagnosis were analyzed. Results: Of 212,091 diagnosed individuals, 14,742 were of a definite ethnicity as defined. The mean age at diagnosis was significantly younger for Arab participants (75.78 ± 10.28) compared to Jewish participants (80.14 ± 9.45) (p < 0.001). The gender distribution was similar (42.5% male). The most common diagnosis was Alzheimer's disease (AD), affecting 2495 (29.8%) of Jewish participants and 2387 (38%) of Arab participants (p < 0.001). Vascular dementia (VD) was also more prevalent in Arab participants, 12.6%, vs. 6.42% in Jewish participants (p < 0.001). MCI was more common in Jewish participants, 26.2%, compared to 10.3% in Arab participants (p < 0.001). Conclusions: Arab participants were diagnosed with dementia at a younger age and showed higher rates of AD and VD diagnosis compared to Jewish participants, but were significantly less likely to be diagnosed with MCI. Efforts to understand and address these underlying causes are warranted to promote health equity.},
}

@article {pmid40943548,
year = {2025},
author = {Yudaev, P and Aleksandrova, Y and Neganova, M},
title = {Recent Insights into the Creation of Histone Deacetylase Inhibitors for the Treatment of Human Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
doi = {10.3390/ijms26178629},
pmid = {40943548},
issn = {1422-0067},
support = {25-73-20033//Russian Science Foundation/ ; },
abstract = {This review examines publications over the past two years devoted to histone deacetylase inhibitors for the treatment of cancer, diseases of the nervous, cardiovascular, digestive, and respiratory systems, and autoimmune diseases. The review covers various classes of histone deacetylase inhibitors depending on the zinc-binding group, in particular hydroxamic acids, benzamides, hydrazides, carboxylic acids, and cyclic peptides. The review pays special attention to the mechanisms of development of pathologies involving various isoforms of histone deacetylases. The review shows that, for the treatment of cancer, nervous, cardiovascular, respiratory systems, and autoimmune diseases, the most promising compounds are hydroxamic acids, and for the treatment of diseases of the digestive system, they are hydrazides and cyclic peptides. Variation in the linker and cap group of hydroxamic acids will allow the creation of an inhibitor selective for a specific histone deacetylase isoform. The review may be useful for molecular biologists, medical workers, and pharmacologists involved in the design of new drugs.},
}

@article {pmid40943460,
year = {2025},
author = {Del Rio, EA and Valenzano, MC and DiGuilio, KM and Rybakovsky, E and Kjelstrom, S and Montone, G and Mercogliano, G and Newman, G and Wong, P and Albert, N and Burris, V and Szymanski, K and Rodriguez, A and Hollis, E and Kossenkov, A and Mullin, JM},
title = {Orally Administered Zinc Gluconate Induces Tight Junctional Remodeling and Reduces Passive Transmucosal Permeability Across Human Intestine in a Patient-Based Study.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
doi = {10.3390/ijms26178540},
pmid = {40943460},
issn = {1422-0067},
support = {2023-02//Sharpe-Strumia Research Foundation of the Bryn Mawr Hospital/ ; },
abstract = {This study focuses on the issue of whether orally administered zinc (gluconate) (26 mg BID) can induce the remodeling of gastrointestinal barrier function and reduce passive leak across the human intestinal mucosal barrier in situ. Increased transmucosal leak has been implicated in diseases as diverse and seemingly unconnected as Inflammatory Bowel Disease (IBD), Celiac Disease, Autism Spectrum Disorders and Alzheimer's Dementia. Our current investigation represents the first patient-based study to examine the effect of zinc on gastrointestinal epithelial tight junctions and gastrointestinal barrier leak in otherwise healthy test subjects. Using independent test subject groups for each endpoint, three separate molecular analyses indicated that zinc treatment can achieve a positive outcome: (1) RNA-seq analyses of intestinal biopsies showed salutary patterns of gene transcription changes dealing with not only transcripts of junctional proteins but also transcripts mitigating the proinflammatory state, as well as dedifferentiation (both modulators of tight junction permeability); (2) Western immunoblot analyses of intestinal tissue indicated that tight junctional protein expression was being modified by the administered zinc, most notably Claudin-2 and Tricellulin; (3) zinc treatment induced a reduction in serum levels of a functional marker of passive intestinal leak, namely the GI microbiome metabolite D-Lactate. The data collectively suggest that orally administered zinc can induce remodeling of the intestinal epithelial barrier, resulting in the reduction in GI barrier leak. The overall safety and economy of supplement levels of zinc suggest that this micronutrient could be efficacious as an adjuvant therapy to reduce the condition known as leaky gut, and possibly therefore be protective regarding diseases postulated to involve leaky gut.},
}

@article {pmid40943200,
year = {2025},
author = {Zhao, D and Ma, L and Brownlie, J and Tonissen, K and Pan, Y and Feng, Y},
title = {Neuroprotective Potential of Major Alkaloids from Nelumbo nucifera (Lotus): Mechanisms and Therapeutic Implications.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
doi = {10.3390/ijms26178280},
pmid = {40943200},
issn = {1422-0067},
abstract = {Nelumbo nucifera (lotus) has long been used in traditional medicine across Asia, and its bioactive alkaloids have recently garnered attention for their neuroprotective properties. This review summarizes the current research on the mechanisms by which lotus-derived alkaloids, particularly neferine, nuciferine, liensinine, and isoliensinine, protect neural tissues. These compounds exhibit a wide range of pharmacological activities, including antioxidant and anti-inflammatory effects, regulation of calcium signaling and ion channels, promotion of neurogenesis, and modulation of key neurotransmitter systems, such as dopaminergic, cholinergic, and GABAergic pathways. Notably, they attenuate tau hyperphosphorylation, reduce oxidative stress-induced neuronal apoptosis, and enhance neurotrophic signaling via BDNF-related pathways. While antioxidant and anti-inflammatory actions are the most extensively studied, emerging evidence also highlights their roles in autophagy modulation and mitochondrial protection. Together, these findings suggest that lotus alkaloids are promising candidates for the prevention and treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Further investigation is warranted to explore the synergistic mechanisms and potential clinical applications of these compounds.},
}

@article {pmid40943177,
year = {2025},
author = {Bowirrat, A and Pinhasov, A and Bowirrat, A and Badgaiyan, R},
title = {Navigation Between Alzheimer's Disease (AD) and Its Various Pathophysiological Trajectories: The Pathogenic Link to Neuroimmunology-Genetics and Neuroinflammation.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
doi = {10.3390/ijms26178253},
pmid = {40943177},
issn = {1422-0067},
abstract = {One hundred and eighteen years have passed since Alzheimer's disease (AD) was first diagnosed by Alois Alzheimer as a multifactorial and complex neurodegenerative disorder with psychiatric components. It is inaugurated by a cascade of events initiating from amnesic-type memory impairment leading to the gradual loss of cognitive and executive capacities. Pathologically, there is overwhelming evidence that clumps of misfolded amyloid-β (Aβ) and hyperphosphorylated tau protein aggregate in the brain. These pathological processes lead to neuronal loss, brain atrophy, and gliosis culminating in neurodegeneration and fueling AD. Thus, at a basic level, abnormality in the brain's protein function is observed, causing disruption in the brain network and loss of neural connectivity. Nevertheless, AD is an aging disorder caused by a combination of age-related changes and genetic and environmental factors that affect the brain over time. Its mysterious pathology seems not to be limited to senile plaques (Aβ) and neurofibrillary tangles (tau), but to a plethora of substantial and biological processes, which have also emerged in its pathogenesis, such as a breakdown of the blood-brain barrier (BBB), patients carrying the gene variant APOE4, and the immuno-senescence of the immune system. Furthermore, type 2 diabetes (T2DM) and metabolic syndrome (MS) have also been observed to be early markers that may provoke pathogenic pathways that lead to or aggravate AD progression and pathology. There are numerous substantial AD features that require more understanding, such as chronic neuroinflammation, decreased glucose utilization and energy metabolism, as well as brain insulin resistance (IR). Herein, we aim to broaden our understanding and to connect the dots of the multiple comorbidities and their cumulative synergistic effects on BBB dysfunction and AD pathology. We shed light on the path-physiological modifications in the cerebral vasculature that may contribute to AD pathology and cognitive decline prior to clinically detectable changes in amyloid-beta (Aβ) and tau pathology, diagnostic biomarkers of AD, neuroimmune involvement, and the role of APOE4 allele and AD-IR pathogenic link-the shared genetics and metabolomic biomarkers between AD and IR disorders. Investment in future research brings us closer to knowing the pathogenesis of AD and paves the way to building prevention and treatment strategies.},
}

@article {pmid40943145,
year = {2025},
author = {Öztan, G and İşsever, H and İşsever, T},
title = {The Role of miRNAs in the Differential Diagnosis of Alzheimer's Disease and Major Depression: A Bioinformatics-Based Approach.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
doi = {10.3390/ijms26178218},
pmid = {40943145},
issn = {1422-0067},
abstract = {Alzheimer's disease (AD) and major depressive disorder (MDD) are prevalent central nervous system (CNS) disorders that share overlapping symptoms but differ in underlying molecular mechanisms. Distinguishing these mechanisms is essential for developing targeted diagnostic and therapeutic strategies. In this study, we integrated multi-tissue transcriptomic datasets from brain and peripheral samples to identify differentially expressed microRNAs (miRNAs) in AD and MDD. Functional enrichment analyses (KEGG, GO) revealed that dysregulated miRNAs in AD were associated with MAPK, PI3K-Akt, Ras, and PD-1/PD-L1 signaling, pathways linked to synaptic plasticity, neuroinflammation, and immune regulation. In contrast, MDD-associated miRNAs showed enrichment in Hippo signaling and ubiquitin-mediated proteolysis, implicating altered neurogenesis and protein homeostasis. Network analysis highlighted key disease- and tissue-specific miRNAs, notably hsa-miR-1202 and hsa-miR-24-3p, with potential roles in neuronal survival and molecular network regulation. These findings suggest that miRNAs may serve as non-invasive biomarkers for diagnosis, prognosis, and treatment monitoring in both disorders. While therapeutic targeting of miRNAs offers promise, challenges such as blood-brain barrier penetration and tissue-specific delivery remain. This integrative approach provides a translational framework for advancing miRNA-based strategies in CNS disease research.},
}

@article {pmid40943059,
year = {2025},
author = {Nojima, H and Yamamoto, M and Kamada, J and Hamanaka, T and Aoyagi, K},
title = {Fully Automated Measurement of GFAP in CSF Using the LUMIPULSE[®] System: Implications for Alzheimer's Disease Diagnosis and Staging.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
doi = {10.3390/ijms26178134},
pmid = {40943059},
issn = {1422-0067},
abstract = {Glial fibrillary acidic protein (GFAP) has been shown to be a reliable biomarker for detecting neurological disorders. Recently, we developed the Lumipulse G GFAP plasma assay, which is a commercially available tool. Compared to existing assays, the LUMIPLSE G platform offers the high-throughput, rapid, and fully automated quantification of biomarkers, enabling more standardized and accessible clinical study. In this study, we evaluated this assay using cerebrospinal fluid (CSF) samples. Assessing GFAP in CSF may provide more direct insights into central nervous system pathology than plasma and could improve the characterization of Alzheimer's disease (AD) stages and support treatment monitoring. The LUMIPULSE G system is a chemiluminescent enzyme immunoassay (CLEIA) platform equipped with full automation, utilizing specialized cartridges to process samples within 30 min. The assay, which employs a pair of proprietary monoclonal antibodies targeting GFAP, was evaluated for clinical performance using 30 CSF samples from patients diagnosed with AD, patients with mild cognitive impairment (MCI), and cognitively unimpaired (CU) individuals, with 10 samples from each group. In addition, levels of β-amyloid 1-40 (Aβ40), β-amyloid 1-42 (Aβ42), and pTau181 were simultaneously measured. The Lumipulse G GFAP assay significantly differentiated (p < 0.05) between the amyloid accumulation and non-amyloid accumulation groups, as classified based on the CSF Aβ test. Furthermore, GFAP showed a moderate correlation with pTau181 (r = 0.588), as determined based on Spearman's rank correlation coefficient. Moreover, receiver operating characteristic (ROC) analysis was performed to determine the performance of GFAP in distinguishing amyloid-positive and amyloid-negative subjects, with an area under the curve (AUC) of 0.72 (0.50-0.93). When stratified by CSF pTau181 positivity, GFAP demonstrated an improved diagnostic accuracy, achieving an AUC of 0.86 (95% CI: 0.68-1.00). This study demonstrates that the Lumipulse G GFAP assay, when applied to CSF samples, has the potential to differentiate AD from non-AD cases, particularly suggesting its utility in detecting tau-related pathology. While GFAP has previously been established as a biomarker for AD, our findings highlight that combining GFAP with other biomarkers such as Aβ40, Aβ42, and pTau181 may enhance the understanding of AD pathogenesis, disease staging, and possibly treatment responses. These findings suggest that GFAP may serve as a complementary biomarker reflecting astroglial reactivity associated with tau positivity, alongside established biomarkers such as Aβ40, Aβ42, and pTau181. However, since GFAP levels may also be elevated in other neurological disorders beyond AD, further investigation into these conditions is required.},
}

@article {pmid40942908,
year = {2025},
author = {Mbue, ND and Tabei, F and Williams, K and Olanrewaju, K},
title = {Innovative Sensor-Based Approaches for Assessing Neurodegenerative Diseases: A Brief State-of-the-Art Review.},
journal = {Sensors (Basel, Switzerland)},
volume = {25},
number = {17},
pages = {},
doi = {10.3390/s25175476},
pmid = {40942908},
issn = {1424-8220},
support = {2024 TARC Pitch//2024 Texas A&M Engineering Experiment Station Annual Research Conference (TARC)./ ; },
abstract = {Sensor-based approaches are transforming the diagnosis and treatment of neurodegenerative diseases by offering more sensitive, non-invasive tools and are capable of real-time monitoring. Integrating advanced materials, nanotechnology, and artificial intelligence presents promise for earlier detection, enhanced disease management, and improved patient outcomes. From a clinical perspective, these technologies facilitate the shift toward precision medicine by enabling early intervention strategies, real-time treatment monitoring, and more refined patient stratification in practice and research contexts. This review provides an overview of recent advancements in sensor-based technologies aimed at enhancing the diagnosis and monitoring of neurodegenerative diseases (NDDs) such as Alzheimer's and Parkinson's, among others. Sensor-based technologies are adjunct tools and integral components of a next-generation framework for diagnosing, monitoring, and understanding neurodegenerative disorders.},
}

@article {pmid40942040,
year = {2025},
author = {Charissopoulos, E and Pontiki, E},
title = {Targeting Metal Imbalance and Oxidative Stress in Alzheimer's Disease with Novel Multifunctional Compounds.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {17},
pages = {},
doi = {10.3390/molecules30173512},
pmid = {40942040},
issn = {1420-3049},
abstract = {Alzheimer's disease (AD) is considered to be one of the most common types of dementia, threatening the health of elderly individuals. Enhancing the brain's cholinergic activity is currently the primary therapeutic strategy for treating AD patients. Acetylcholine and butyrylcholine are key targets in this approach, as they function as neuromodulators within the cerebrum-particularly in its various cholinergic regions responsible for essential functions like memory, thought, inspiration, and excitement. Oxidative stress and free radicals are considered to play a crucial role in the pathogenesis of AD and may be key factors in its etiology. Additionally, oxidants and oxidative stress-induced products can upregulate amyloid precursor protein (APP) expression, promoting Aβ aggregation. Another major factor in the pathogenesis of AD is the imbalance of metal homeostasis in the brain. Notably, the mammalian brain contains significantly higher concentrations of Cu, Zn, and Fe ions compared to other tissues. The present review focuses on novel bifunctional metal chelators with potential antioxidant activity for the treatment of AD.},
}

@article {pmid40942007,
year = {2025},
author = {Li, H and Shen, X and Zhang, B and Zhu, Z},
title = {Biologics as Therapeutical Agents Under Perspective Clinical Studies for Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {17},
pages = {},
doi = {10.3390/molecules30173479},
pmid = {40942007},
issn = {1420-3049},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, synaptic loss, and multifaceted pathology involving amyloid-β (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, and impaired proteostasis. In recent years, biologic therapies, such as monoclonal antibodies, vaccines, antisense oligonucleotides (ASOs), and gene therapies, have gained prominence as promising disease-modifying strategies. In this review, we provide a comprehensive synthesis of current biologic approaches under clinical evaluation for AD. Drawing on data curated from ClinicalTrials.gov (as of 2025), we systematically summarise the molecular targets, therapeutic modalities, mechanisms of action, trial phases, and sponsors of over 60 biologic agents. These include Aβ-directed antibodies targeting distinct conformers such as protofibrils, pyroglutamate-modified species, and soluble oligomers; tau-targeted immunotherapies and RNA-based interventions; and emerging platforms focused on neuroimmune modulation, peptide hormones, and microbiota-based strategies. Gene and RNA therapeutics, particularly ASOs and small interfering RNAs (siRNAs) delivered intrathecally or via lipid nanoparticles, are also reviewed for their potential to modulate intracellular targets with high specificity. We also analyse the historical landscape of biologic candidates that failed to reach approval, discussing key reasons for trial discontinuation, including lack of clinical efficacy, safety concerns (e.g., amyloid-related imaging abnormalities), or inadequate biomarker responses. These cases offer crucial insights for refining future drug design. Looking ahead, we highlight major challenges and evolving perspectives in AD biologic therapy: expanding therapeutic targets beyond Aβ and tau, overcoming delivery barriers to the brain, designing prevention-oriented and genetically stratified trials, and navigating regulatory and ethical considerations. Together, these efforts signal a paradigm shift in AD drug development, from symptomatic treatment to mechanism-based precision biologics. By integrating real-time clinical trial data with mechanistic insight, this review aims to inform both translational research and therapeutic innovation in AD.},
}

@article {pmid40941958,
year = {2025},
author = {Rodríguez-Escobar, ML and Martínez-Francés, V and Ríos, S and Feresin, GE and Borges, WS and Bastida, J and Torras-Claveria, L and Tallini, LR},
title = {Alkaloid Profile of Fifteen Different Species of Narcissus L. (Amaryllidoideae) Collected in Spain.},
journal = {Plants (Basel, Switzerland)},
volume = {14},
number = {17},
pages = {},
doi = {10.3390/plants14172793},
pmid = {40941958},
issn = {2223-7747},
abstract = {Molecular diversity is a key component of overall biodiversity, playing a vital role in evolution. It results from the adaptation of organisms to various habitats, which impacts their survival. The Amaryllidoideae subfamily is a significant group of monocotyledonous plants known for producing an exclusive and still-expanding group of molecules with diverse biological activities. Galanthamine (Gal), the most renowned metabolite from Amaryllidoideae subfamily, has been marketed for the palliative treatment of Alzheimer's disease since 2001 due to its ability to inhibit the acetylcholinesterase enzyme. Due to the high cost and low yield of its synthesis, pharmaceutical companies extract this drug from Amaryllidoideae plants, such as Narcissus pseudonarcissus cv. Carlton in Europe and Lycoris radiata in China. The aim of this study was to describe the alkaloid profile of fifteen different species of Narcissus L. (commonly known as daffodils) collected in Spain using gas chromatography coupled with mass spectrometry. Fifty-one alkaloids were identified and quantified within these species through our private library of Amaryllidaceae alkaloids (AA) built over the last four decades, while thirty structures remained not identified in thirteen of these species. The highest concentration of these nitrogenate metabolites was quantified in N. confusus, 541 μg Gal·100 mg[-1] DW, which also exhibited a notably high concentration of Gal, 301 μg Gal·100 mg[-1] DW, which represents about 55% of the alkaloids identified in this species. The species N. bujei was also found to contain a significant quantity of this compound, amounting to 103.2 μg Gal·100 mg[-1] DW. The plant N. assoanus harbored a total of seven unidentified compounds, indicating that this species could be a potentially important source of novel alkaloids. In conclusion, this study facilitates a direct comparison of alkaloid profiles for fifteen Narcissus plant species. This serves as a valuable tool for identifying possible new sources of galanthamine, as well as other novel medicinal alkaloids. Finally, this work presents the first alkaloid profile of the species N. minor and N. nevadensis.},
}

@article {pmid40941620,
year = {2025},
author = {Altıntop, ÇG},
title = {Enhancing Diagnostic Accuracy of Neurological Disorders Through Feature-Driven Multi-Class Classification with Machine Learning.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {17},
pages = {},
doi = {10.3390/diagnostics15172132},
pmid = {40941620},
issn = {2075-4418},
abstract = {Background/Objectives: Neurological disorders (ND) are a global health challenge, affecting millions and greatly reducing quality of life. Disorders such as Alzheimer's disease, mild cognitive impairment (MCI), schizophrenia, and depression often share overlapping symptoms, complicating diagnosis and treatment. Early detection is crucial for timely intervention; however, traditional diagnostic methods rely on subjective assessments and costly imaging, which are not universally accessible. Addressing these challenges, this study investigates the classification of multiple ND using electroencephalography (EEG) signals. Methods: Various feature extraction methods were employed, and the Least Absolute Shrinkage and Selection Operator (Lasso) algorithm was utilized for effective feature selection. Two-class (disease-disease and healthy control-disease), three-class (healthy control and two ND, as well as three ND), and four-class (healthy control and three ND) classifications were conducted using different machine learning algorithms with the selected features. An EEG dataset comprising 40 Alzheimer's patients, 43 healthy controls, 42 schizophrenia patients, 28 MCI patients, and 28 depression patients served as the experimental benchmark. Results: The Linear Discriminant Analysis (LDA) classifier achieved the highest accuracy, distinguishing between healthy controls and Alzheimer's with 100% accuracy and demonstrating strong performance in other comparisons. Multi-class classification reached 84.67% accuracy for distinguishing depression, MCI, and schizophrenia, while four-class classification achieved 57.89%, highlighting the complexity of differentiating among multiple ND. The frequent selection of frontal lobe channels across ND indicates their critical role in classification. Conclusions: This study contributes to the literature by emphasizing disease-to-disease classification over the traditional control-versus-patient framework, highlighting the potential for more effective diagnostic tools in clinical settings.},
}

@article {pmid40941175,
year = {2025},
author = {Jeong, H and Choi, H and Park, YS},
title = {Neuroprotective Potential of Broccoli Sprout Extract in Scopolamine-Induced Memory-Impaired Mice.},
journal = {Foods (Basel, Switzerland)},
volume = {14},
number = {17},
pages = {},
doi = {10.3390/foods14173059},
pmid = {40941175},
issn = {2304-8158},
support = {P0025365//Ministry of Trade, Industry and Energy/ ; },
abstract = {Alzheimer's disease is characterized by progressive cognitive decline associated with oxidative stress, neuroinflammation, and impaired neurotrophic signaling. Sulforaphane, a bioactive compound found in broccoli, has demonstrated neuroprotective effects by activating NRF2 and inhibiting NF-κB. However, the efficacy of whole-food-derived sulforaphane remains unclear. This study evaluated the neuroprotective potential of broccoli sprout extract using a scopolamine-induced mouse model of memory impairment. Mice were orally administered broccoli sprout extract once daily at doses of 100 mg/kg or 200 mg/kg for four weeks prior to behavioral and biochemical assessments. Treatment with broccoli sprout extract significantly improved scopolamine-induced deficits in long-term memory, as determined by the passive avoidance test. The spatial working memory remained unaffected. High doses of broccoli sprout extract restored hippocampal brain-derived neurotrophic factor levels and reduced cortical lipid peroxidation, suggesting antioxidant and neurotrophic benefits. Additionally, the low dose preserved striatal choline acetyltransferase expression and reduced systemic tumor necrosis factor-alpha and hippocampal cyclooxygenase-2 levels, indicating its anti-inflammatory and cholinergic protective effects. No significant changes in acetylcholinesterase activity or glutathione levels were observed. Overall, these results imply that broccoli sprout extract has multi-targeted neuroprotective effects, possibly involving redox and inflammatory regulation. Therefore, it may be a safe dietary strategy to support cognition in neurodegenerative conditions.},
}

@article {pmid40940798,
year = {2025},
author = {Li, L and Zheng, X and Ma, H and Zhu, M and Li, X and Sun, X and Feng, X},
title = {TREM2 in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential.},
journal = {Cells},
volume = {14},
number = {17},
pages = {},
doi = {10.3390/cells14171387},
pmid = {40940798},
issn = {2073-4409},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), represent significant global health challenges, affecting millions and straining healthcare systems. These disorders involve progressive neuronal loss and cognitive decline, with incompletely elucidated underlying mechanisms. Chronic neuroinflammation is increasingly recognized as a critical contributor to disease progression. The brain's resident immune cells, microglia, are central to this inflammatory response. When overactivated, microglia and other immune cells, such as peripheral macrophages, can exacerbate inflammation and accelerate disease development. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily that demonstrates high expression on microglia in the central nervous system. TREM2 serves a vital role in regulating phagocytosis, synaptic pruning, and energy metabolism. This review examines the functions of TREM2 in neurodegenerative diseases and its potential as a therapeutic target, aiming to inform future treatment strategies.},
}

@article {pmid40940766,
year = {2025},
author = {Kochman, U and Sitka, H and Kuźniar, J and Czaja, M and Kozubek, P and Beszłej, JA and Leszek, J},
title = {Neuronal Death and Biomolecular Condensates: Are There Any New Treatment Options for Alzheimer's Disease?.},
journal = {Cells},
volume = {14},
number = {17},
pages = {},
doi = {10.3390/cells14171356},
pmid = {40940766},
issn = {2073-4409},
abstract = {Alzheimer's disease (AD) is marked by the pathological aggregation of amyloid β (Aβ) and tau proteins. Emerging research reveals that these proteins undergo liquid-liquid phase separation (LLPS), forming biomolecular condensates that promote aggregation and neurotoxicity. These phase-separated structures reshape the intracellular environment, facilitating protein misfolding and spreading. This review highlights recent advances in understanding the role of condensates in AD pathogenesis and explores novel therapeutic strategies targeting condensate dynamics. Promising approaches include small molecules that disrupt LLPS, epigenetic drugs influencing nuclear condensates, and compounds like DDL 920 and RI AG03 that modulate tau phase separation and neuroinflammation, respectively. Additionally, anti-inflammatory agents, such as nucleotide reverse transcriptase inhibitors (NRTIs), offer potential for upstream intervention. Targeting biomolecular condensates presents a next-generation strategy for AD treatment. Future research should focus on in vivo profiling of condensate composition, biomarker development, and the development of patient-specific therapies to enable early, disease-modifying interventions.},
}

@article {pmid40940699,
year = {2025},
author = {Fazio-Eynullayeva, E and Mystkowski, P and Lv, L and Aly, A and Cotton, S and Grant, N and Johnson, W and Mattke, S},
title = {A Real-World Analysis of the Clinical Journey, Diagnosis, and Monitoring Patterns of Patients With Alzheimer Disease by Stage in the United States.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {40},
number = {},
pages = {15333175251375378},
doi = {10.1177/15333175251375378},
pmid = {40940699},
issn = {1938-2731},
abstract = {This study aimed to describe the clinical journey of patients with different stages of Alzheimer disease (AD). This was a cross-sectional survey of US primary care physicians (PCPs)/specialists and patients using the Adelphi Real World AD Disease Specific Programme™ (December 2022 - September 2023). Patients were stratified by disease severity and data are presented as the mean (SD) or frequencies/percentages. In the overall sample (N = 990), mean time from symptom onset to first evaluation was 31.4 (40.6) weeks and mean time from evaluation to diagnosis was 14.2 (29.0) weeks (mild cognitive impairment due to AD, 12.0 [22.7] weeks; mild AD dementia, 15.7 [31.6] weeks; moderate AD dementia, 14.0 [29.9] weeks; severe AD dementia, 5.1 [9.6] weeks). 74.5% of the overall sample was initially evaluated by their PCP and 13.8% by a neurologist. Patients with AD experience many barriers during the diagnostic journey; however, PCPs and neurologists play key roles in early diagnosis.},
}

@article {pmid40940304,
year = {2025},
author = {Francis, E and Paylor, S and Van, C and Mathews, B and Sobhanian, MJ and Mansour, DZ and Hennawi, G and Brandt, NJ},
title = {Review of Anti-amyloid-Beta (Aβ) monoclonal antibodies for the treatment of Alzheimer's disease.},
journal = {Expert review of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17512433.2025.2556122},
pmid = {40940304},
issn = {1751-2441},
abstract = {INTRODUCTION: Alzheimer's disease (AD) remains a major public health challenge, with growing prevalence and limited treatment options that modify disease progression. Recent advances have led to the development and approval of Anti-amyloid-β (Aβ) monoclonal antibodies, which represent a paradigm shift from symptomatic management to targeted disease modification.

AREAS COVERED: Agents such as lecanemab and donanemab selectively bind aggregated forms of Aβ and have demonstrated modest but statistically significant slowing of cognitive and functional decline in early AD. However, these therapies are associated with amyloid-related imaging abnormalities (ARIA), particularly in individuals carrying the APOE ε4 allele, necessitating close monitoring and individualized risk assessment. Implementation challenges, including high treatment burden, cost, and real-world applicability, have limited broad clinical adoption. This review examines the mechanistic differences, clinical trial outcomes, and safety considerations of Aβ monoclonal antibodies, while also highlighting emerging therapies and the need for inclusive, precision-guided approaches.

EXPERT OPINION: As research continues to evolve, balancing clinical benefit with safety and accessibility will be critical in defining the role of anti-amyloid therapies within the broader landscape of AD care.},
}

@article {pmid40940223,
year = {2025},
author = {Liu, C and Zhao, Y and Dao, JJ and Zhang, W and Liu, J and Ma, YK and Qiao, CM and Cui, C and Chen, SX and Shen, YQ and Zhao, WJ},
title = {Targeted ErbB4 receptor activation ameliorates neuronal deficits via DOCK3 signaling in a transgenic mouse AD model.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00739},
doi = {10.1016/j.neurot.2025.e00739},
pmid = {40940223},
issn = {1878-7479},
abstract = {Accumulating evidence has highlighted the critical involvement of ErbB4 receptor in the onset and progression of Alzheimer's disease (AD). Utilizing a small molecule ErbB4 receptor agonist (E4A) identified through virtual screening, it was observed that activation of ErbB4 receptor significantly ameliorated the cognitive behavioral deficits in APP/PS1 mice. Additionally, E4A treatment enhanced the expression of DOCK3 and SIRT3, leading to improvements in synaptic and mitochondrial dysfunction within the hippocampus of these mice. E4A also attenuated the activation of the TLR4-NF-κB-NLRP3 pathway, thereby reducing neuroinflammation and the formation of β-amyloid (Aβ) plaques. In vitro studies revealed that E4A partially mitigated the impact of hippocampal neuronal damage on microglial inflammation, which was partly compromised by the silencing of DOCK3. Collectively, our data suggest that targeted activation of ErbB4 receptor may treat AD via DOCK3 signaling by inhibiting neuronal damage and subsequent neuroinflammation, thereby offering a viable strategy for this neurodegenerative disease.},
}

@article {pmid40939527,
year = {2025},
author = {Pagan, FL and Torres-Yaghi, Y and Hebron, ML and Wilmarth, B and Liu, X and Ahn, J and Moussa, C},
title = {Safety, tolerability and potential biomarkers of vodobatinib in patients with dementia with Lewy bodies.},
journal = {Parkinsonism & related disorders},
volume = {140},
number = {},
pages = {108020},
doi = {10.1016/j.parkreldis.2025.108020},
pmid = {40939527},
issn = {1873-5126},
abstract = {INTRODUCTION: Activation of the tyrosine kinase Abelson (Abl) was suggested in the pathogenesis of neurodegenerative diseases. We investigated the effects of a potent and highly specific Abl kinase inhibitor vodobatinib (K0706) in patients diagnosed with dementia with Lewy bodies (DLB). We determined safety, tolerability and potential biomarkers following oral administration of vodobatinib versus placebo in DLB patients.

METHODS: Participants were randomized 1:1:1 into vodobatinib 192 mg, or 384 mg or matching placebo in a single-center, double-blind study. Study drug was taken orally once daily for 3 months followed by one-month wash-out.

RESULTS: Twenty-nine individuals were enrolled, 3 were women (10.3 %), age 76.3 ± 6 years (mean ± SD). Vodobatinib was safe and well-tolerated and more adverse events were noted in the placebo (56) vs vodobatinib 192 mg (19) or 384 mg (6) groups. The number of falls were reduced in the vodobatinib 192 mg (6) and 384 mg (0) compared to placebo (28) groups. The only potential significant change in cerebrospinal fluid (CSF) biomarkers was Aβ42/Aβ40 in 192 mg vodobatinib (p = 0.0002) and 384 mg (0.0121) compared to placebo. There was no change in homovanillic acid, a biomarker of dopamine level, or other potential CSF and plasma biomarkers of DLB. Exploratory clinical outcomes were not different between baseline and 3 months in vodobatinib compared to placebo.

CONCLUSIONS: Vodobatinib appears to be safe and tolerated, but larger trials and longer treatment periods are needed to determine its effects on biomarkers and clinical outcomes.},
}

@article {pmid40939126,
year = {2025},
author = {Boccalini, C and Mathoux, G and Hristovska, I and Ribaldi, F and Peretti, DE and Arnone, A and Scheffler, M and Frisoni, GB and Hansson, O and Vogel, JW and Garibotto, V},
title = {Visual Classification of Tau-PET Detects 4 Subtypes With Different Long-Term Outcomes.},
journal = {Neurology},
volume = {105},
number = {7},
pages = {e213950},
doi = {10.1212/WNL.0000000000213950},
pmid = {40939126},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Tau accumulation pattern shows substantial variability in Alzheimer disease (AD), and 4 distinct spatiotemporal trajectories were distinguished using a data-driven approach called the Subtype and Stage Inference (SuStaIn). A visual method to validate and identify these subtypes is a requirement for their clinical translation. Our study aimed to provide a standardized topographic method for identifying tau patterns visually using tau-PET in a clinical setting.

METHODS: Participants in this prospective study were included from the memory clinic of Geneva University Hospital. Inclusion criteria required participants to have undergone at least 1 [18]F-Flortaucipir tau-PET scan and a Mini-Mental State Examination (MMSE) within a 1-year time frame. All scans were classified into different tau subtypes (limbic [S1], medial temporal lobe-sparing [S2], posterior [S3], and lateral temporal [S4]) using both visual rating and SuStain algorithm. A subgroup underwent amyloid-PET and clinical follow-up. Cohen's κ tested the agreement between raters and between visual and automated subtypes. Chi-squared and Kruskal-Wallis tests assessed differences in clinical and biomarker features between subtypes, whereas differences in cognitive trajectories were tested using linear mixed-effects models, controlling for age, sex, and clinical and tau stages.

RESULTS: A total of 245 tau-PET scans of individuals ranging from cognitively unimpaired to mild dementia (mean age: 68.25 years, 52% women) were included and classified into different tau pattern subtypes. A substantial agreement between raters was found in visually interpreting tau subtypes (κ > 0.65, p < 0.001) and a fair agreement between visual and automated subtypes (κ = 0.39, p < 0.001), with the automated approach more likely to classify a scan as tau negative and lower agreement between methods in more severe cases and AD clinical variants. Regarding the visual classification, individuals with S2 subtype were younger than S1 and S3, had lower MMSE and verbal fluency scores than S4 and S1, showed higher global tau burden than other subtypes, and a steeper cognitive decline.

DISCUSSION: Visual classification reliably identified 4 tau patterns that differ in global tau load, clinical features, and long-term outcomes, suggesting its clinical usefulness for the detection of higher-risk AD variants. A clinically implementable classification of subtypes with faster decline is paramount for personalized diagnosis, accurate prognosis, and treatment.},
}

@article {pmid40939031,
year = {2025},
author = {Chun, H and Yoon, ML and Lee, HW and Lee, JY and Hong, SB and Ha, SS and Yoon, KJ},
title = {The Efficacy and Safety of Transcranial Photobiomodulation for Mild Cognitive Impairment Due to Alzheimer's Disease: A Randomized, Double-Blind, Sham-Controlled Study.},
journal = {Photobiomodulation, photomedicine, and laser surgery},
volume = {43},
number = {9},
pages = {411-416},
doi = {10.1177/15578550251369575},
pmid = {40939031},
issn = {2578-5478},
abstract = {Background: Transcranial photobiomodulation (tPBM) is a promising noninvasive neuromodulation modality with potential therapeutic benefits for neurodegenerative diseases. Infrared light delivered by a tPBM device penetrates the cortex, stimulating neuronal activity by increasing mitochondrial adenosine triphosphate production and enhancing regional cerebral blood flow. Objective: This study investigated the efficacy and safety of a self-administered, at-home, wearable tPBM device for improving cognitive function in individuals with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Methods: Individuals with MCI due to AD, diagnosed according to the National Institute on Aging and Alzheimer's Association criteria, with a Korean version of Mini-Mental State Examination-2 (K-MMSE2) score of 23-27 and a global Clinical Dementia Rating (CDR) score of 0.5-1.0 were enrolled. Subjects self-administered tPBM six times per week for 12 weeks. Assessments were conducted at weeks 7 and 13 using the Korean version of the Montreal Cognitive Assessment (K-MoCA), K-MMSE2, the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease, and the Geriatric Depression Scale. Results: A total of 26 participants were enrolled. The treatment group showed a statistically significant improvement in K-MoCA scores at week 13 (p < 0.05) compared with the sham group. Although K-MMSE2 scores improved in the treatment group, the difference was not statistically significant. No serious adverse events were reported. Conclusion: Findings suggest that tPBM is an effective and safe home-use intervention for individuals with MCI, with promising therapeutic and preventative roles in Alzheimer's dementia.},
}

@article {pmid40938652,
year = {2025},
author = {Tho Chu, TQ and Morimoto, K and Kowa, H},
title = {Cognitive performance and blood biomarkers: Insights into their relationship and predicting high Amyloid Probability Score in cognitively impaired older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251372958},
doi = {10.1177/13872877251372958},
pmid = {40938652},
issn = {1875-8908},
abstract = {BackgroundUnderstanding associations between cognitive performance and blood biomarkers supports diagnosis and treatment of Alzheimer's disease (AD); however, this relationship remains unclear.ObjectiveExploring associations between the Amyloid Probability Score (APS; PrecivityAD® blood test) and cognitive performance, and between Mini-Mental State Examination (MMSE) and Cogstate Brief Battery (CBB) in cognitively impaired older adults.MethodsOlder adults aged ≥ 60 years with MMSE from 10 to 27, recruited from a cohort in Japan, were assessed with the CBB, and plasma biomarkers to calculate APS. We used Spearman correlation to explore relationships; receiver operating curves and cross-validation to identify the best model for predicting high APS.ResultsAmong 46 participants (mean age = 78.3 ± 5.9; mean MMSE = 20.3 ± 4.6), 39.1% did not complete at least one test in the CBB. Lower MMSE were observed in those who were non-completers. MMSE correlated with Detection (Psychomotor function), Identification (Attention), and their composite (r = 0.34-0.52; p < 0.05; 95%CI excluding null value). Higher APS was seen in those who did not complete the One Card Learning (OCL-visual learning and short-term memory). The best model for predicting High APS included OCL completion status, MMSE and Years of Education, achieving accuracy = 0.808 and kappa = 0.606 in participants with MMSE < 21.ConclusionsOur findings suggest a consideration of incompletion when using CBB in cognitively impaired older adults and a potential approach to differentiate High APS group among those with moderate to severe dementia based on visual learning and short-term memory, global cognition and education level.},
}

@article {pmid40938517,
year = {2025},
author = {Xie, F and Zhou, L and Yu, M},
title = {Dihuang Yinzi Ameliorates Cognitive Impairments and Inhibits Ferroptosis in APP/PS1 Mice.},
journal = {Biochemical genetics},
volume = {},
number = {},
pages = {},
pmid = {40938517},
issn = {1573-4927},
support = {2024CCCX259//Anhui Traditional Chinese Medicine Inheritance and Innovation Research Project/ ; 2021byzd058//Bengbu Medical University Key Project/ ; Chinese Medicine Education Letter (2022) No. 75//National Administration of Traditional Chinese Medicine National Famous Traditional Chinese Medicine Expert Inheritance Studio Construction Project/ ; Project No. 202204295107020034//Clinical Medical Research Translation Special Project of Anhui Provincial Science and Technology Department/ ; 81803984//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss. Ferroptosis, a form of regulated cell death driven by iron overload and lipid peroxidation, has been implicated in AD pathology. DiHuangYinZi (DHYZ), a traditional Chinese herbal remedy, has been suggested to ameliorate cognitive impairments and reduce ferroptosis in AD models. This study aimed to investigate the effects of DHYZ on learning, memory, ferroptosis markers, and neuronal integrity in APP/PS1 transgenic mice. Six-month-old APP/PS1 transgenic mice were treated with DHYZ or donepezil for four weeks. Learning and memory functions were evaluated using the Morris Water Maze (MWM) and open field test. Neuronal integrity was assessed through Hematoxylin and Eosin (H&E) and Nissl staining. Ferroptosis markers, including superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), and the GSH/GSSG ratio, were measured in hippocampal tissues. Ferroptosis-related protein expressions, such as ferritin, DMT1, FPN1, Nrf2, and GPX4, were analyzed using Western blot. DHYZ treatment significantly improved learning and memory deficits in APP/PS1 mice, as evidenced by reduced escape latency and increased platform crossings in the MWM. DHYZ also reversed anxiety-like behavior in the open field test. Histological analysis showed that DHYZ treatment restored neuronal integrity, as indicated by better cellular arrangement and staining compared to untreated APP/PS1 mice. DHYZ inhibited ferroptosis by reducing iron overload, increasing SOD and GSH levels, and normalizing the GSH/GSSG ratio. Moreover, DHYZ modulated the expression of ferroptosis-related proteins, restoring FPN1 levels while reducing ferritin and DMT1 expressions. Nrf2 and GPX4 levels, which were reduced in APP/PS1 mice, were significantly increased after DHYZ treatment. DHYZ effectively improved cognitive deficits, inhibited ferroptosis, and restored neuronal integrity in APP/PS1 mice. These findings suggest that DHYZ may have therapeutic potential for AD by targeting ferroptosis and regulating iron metabolism.},
}

@article {pmid40938483,
year = {2025},
author = {Comert Onder, F and Ural, K and Onder, A and Ozpolat, B and Ay, M},
title = {Boron Containing Curcumin-Like Compound as an Acetylcholinesterase Inhibitor and Anticancer Agent: Synthesis, Biological Evaluation, and Computational Insights.},
journal = {Cell biochemistry and biophysics},
volume = {},
number = {},
pages = {},
pmid = {40938483},
issn = {1559-0283},
abstract = {Alzheimer's disease (AD) and cancer are significant global health challenges that highlight the need for the development of new therapeutics. Targeting biological mechanisms involved in both AD and cancer could be an effective treatment strategy for developing novel inhibitors. In this study, we investigated the effect of a newly synthesized boron containing curcumin-like compound as a potential acetylcholinesterase (AChE) inhibitor along with its cytotoxic effects on breast and colorectal cancer cell lines. Compound A exhibited a potent AChE inhibitory activity (IC50 = 22.89 ± 2.32 nM), demonstrating that it was more effective than the known inhibitors donepezil (IC50 = 28.32 ± 3.27 nM) and tacrine. Compound A showed a moderate cytotoxic activity on MCF-7 and BT20 cells with the IC50 values 40.70 ± 2.31 μM and 41.71 ± 4.51 μM, respectively. Throughout molecular dynamics (MD) simulations, the RMSD value of the protein was calculated as 1.56 ± 0.20 Å and 1.65 ± 0.19 Å for the complexes of compound A and curcumin, respectively. The interactions with specific amino acid residues such as Tyr124, Tyr337, and Trp86 for AChE, and Trp82, His438, and Tyr332 for BChE were obtained. Additionally, MM/GBSA calculations demonstrated that Compound A had the highest binding free energies (-88.89 ± 8.34 kcal/mol for AChE and -73.25 ± 8.83 kcal/mol for BChE) compared to curcumin (-67.87 ± 5.48 kcal/mol for AChE and -51.68 ± 5.28 kcal/mol for BChE) and tacrine (-56.67 ± 2.22 kcal/mol for BChE) were calculated. Overall, these findings suggest that Compound A is a promising agent with its potent AChE inhibitory activity and anticancer potential, making it a valuable candidate for further research in neurodegenerative diseases and cancer therapy.},
}

@article {pmid40937962,
year = {2025},
author = {Hillerstrom, H and Das, A and Janicki, MP and Rozas, NS and Santoro, SL},
title = {Specialists' perceptions of clinical instruments, practices, and staging of DS-AD: Results from an international survey.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70356},
doi = {10.1002/alz.70356},
pmid = {40937962},
issn = {1552-5279},
support = {//LuMind IDSC Foundation/ ; /DP/NCCDPHP CDC HHS/United States ; 1NU58DP006782-01-00//Healthy Brain Initiative/ ; //Eli Lilly and Company/ ; //Rainwater Charitable Foundation/ ; },
abstract = {INTRODUCTION: Diagnosing and staging Down syndrome-associated Alzheimer's disease (DS-AD) is hindered by the lack of standardized criteria, complicating clinical decision making, trial participation, and access to advanced therapies. This study aimed to explore perceptions of these issues.

METHOD: An international survey of 42 clinicians and researchers specializing in DS-AD gathered perspectives on instruments, symptomatic staging, clinical practices, and research priorities.

RESULTS: Respondents noted that key domains of impairment in mild cognitive impairment in Down syndrome and DS-AD dementia included memory, executive functioning, personality, social behavior, attention, mood, and language. Among the 10 assessment tools evaluated, informant-based interviews were noted as critical for individuals with severe intellectual disability (ID), while direct assessments were noted as useful for those with mild to moderate ID. Common diagnostic confounders like hypothyroidism and sleep disorders were identified.

DISCUSSION: Behavioral assessments provide a valuable function; however, future efforts should integrate behavioral assessments with biomarkers and develop standardized staging frameworks to improve diagnostic reliability, care planning, and treatment strategies for DS-AD.

HIGHLIGHTS: Personality, social behavior, language, mood/affect, memory, executive functioning, and attention are recognized as key domains of impairment in both mild cognitive impairment in Down syndrome (MCI-DS) and Down syndrome-associated Alzheimer's disease (DS-AD). Ten prominent informant and direct assessment tools were noted as appropriate for individuals with DS and mild to moderate intellectual disability (ID) for identifying both MCI-DS and DS-AD; however, for individuals with severe/profound ID, there was less assurance of applicability. Harmonizing recommended tools in a standardized list was identified as a strategy to promote consistency across clinical and research contexts.},
}

@article {pmid40937948,
year = {2025},
author = {Zhao, J and Chen, J and Lu, J and Shi, Q and Wang, Q and Gao, Z and Zeng, L and Liu, Q},
title = {Nitration of Tyrosine Residue Y10 of Aβ1-42 Ameliorates Aβ1-42-Induced Neurotoxicity and Memory Impairment In Vitro and In Vivo.},
journal = {Journal of neurochemistry},
volume = {169},
number = {9},
pages = {e70218},
doi = {10.1111/jnc.70218},
pmid = {40937948},
issn = {1471-4159},
support = {22377027//National Natural Science Foundation of China/ ; 2022C03034//Key R&D Program Project of Zhejiang/ ; 2023SHIBS0003//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; LTGD23C050001//Zhejiang Provincial Natural Science Foundation of China/ ; },
abstract = {The abnormal generation and aggregation of Aβ has been considered the central pathogenic mechanism of Alzheimer's disease (AD). Soluble Aβ tends to aggregate into toxic oligomers, which initiate neuronal dysfunction. Therefore, attenuation of Aβ oligomer formation might be an effective therapeutic strategy for AD. It has been reported that Aβ can be nitrated at tyrosine 10. Our previous study found that nitration of Y10 in Aβ significantly inhibits its aggregation and reduces its toxicity. However, the effects of Aβ nitration on its neurotoxicity remain unclear. Here, we used SH-SY5Y cells and a mouse model of AD induced by intrahippocampal Aβ1-42 oligomer injection to investigate the effects of tyrosine nitration on the neurotoxicity of Aβ1-42. The results of dot blot, gel electrophoresis analysis, transmission electron microscopy, atomic force microscopy, and dynamic light scattering indicated that nitration of Y10 in Aβ1-42 inhibits its oligomerization. Aβ1-42 treatment perturbed the integrity of intracellular membranes, eventually leading to apoptosis of SH-SY5Y cells. In contrast, nitrated Aβ1-42 exhibited little neurotoxicity toward SH-SY5Y cells. Additionally, mice injected with Aβ1-42 oligomer developed cognitive impairment in behavioral tests. Aβ1-42 oligomer caused neurotoxicity in the hippocampus of the mice, possibly through triggering apoptosis and neuroinflammation and promoting aberrant amyloid processing. As expected, nitrated Aβ1-42 also had little effect on physiological and cognitive capacities. These results further confirm that nitration of Y10 in Aβ can significantly inhibit its neurotoxicity. Moreover, our findings contribute to the understanding of the role of Aβ in the development of AD.},
}

@article {pmid40937337,
year = {2025},
author = {Han, SH and Jeong, HB and Lee, SJ and Jeong, HT and Shin, HW and Park, CY and Ahn, SW and Park, KY and Kim, HR and Youn, YC},
title = {Therapeutic Potential of Porcine Brain-Derived Peptide Mixture (PBDP) in Alzheimer's Disease: An Exploratory Study on Quantitative Electroencephalography (qEEG) Changes.},
journal = {Neuropsychiatric disease and treatment},
volume = {21},
number = {},
pages = {1981-1992},
pmid = {40937337},
issn = {1176-6328},
abstract = {BACKGROUND: This exploratory study investigates the therapeutic potential of Porcine Brain-Derived Peptide Mixture (PBDP) in Alzheimer's Disease (AD) by examining changes in quantitative electroencephalography (qEEG) parameters following treatment.

METHODS: We analyzed qEEG data from 27 AD patients treated with 2-weeks of PBDP treatment and compared them to a control group of 20 patients at 2-month follow-up, all of whom were previously on donepezil therapy.

RESULTS: EEG modifications were noted within two weeks of PBDP administration, including improvements in EEG patterns such as reduced Theta/Beta (4.437 ± 3.979 to 3.859 ± 3.587, p = 0.442), Theta/Alpha ratio (1.815 ± 1.637 to 1.578 ± 1.304, p < 0.05), and Delta/Alpha ratio (2.365 ± 2.471 to 2.105 ± 2.402, p < 0.05) across various brain regions, suggesting enhanced cortical activity. Post-intervention, 55% of patients showed caregiver-reported improvements in mood and daily activities.

CONCLUSION: PBDP could serve as a viable therapeutic approach for managing AD, and qEEG could serve as a monitoring biomarker for acute drug effects, warranting further investigation into its long-term benefits and mechanistic pathways.},
}

@article {pmid40936998,
year = {2025},
author = {Duehring, JA and Jacobs, DM and Thomas, ML and Dodge, HH and Feldman, HH and Edland, SD},
title = {Implications of practice effects for the design of Alzheimer clinical trials.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {3},
pages = {e70154},
pmid = {40936998},
issn = {2352-8737},
abstract = {INTRODUCTION: Practice effects (PEs) are a well-known potential confound in natural history studies of longitudinal cognitive decline in aging and early-stage Alzheimer's disease. The implication of PEs on Alzheimer's disease clinical trials is less well understood, although we have previously speculated that a "run-in" period of repeated cognitive assessments prior to randomization may improve the efficiency of clinical trials [Jacobs et al. Alzheimer's & Dementia 2017;3(4):531-535]. We have also described how the performance of composite outcome measures depends on parameters that may be influenced by PEs.

METHODS: To investigate this, we used the cognitive battery within the National Alzheimer's Coordinating Center (NACC) Uniform Data Set to characterize the potential impact of PEs on clinical trial design and outcome measures. The analysis restricted to N = 1094 amnestic mild cognitively impaired participants with 3 years of follow-up data. Linear mixed effects models estimate the magnitude of PEs observed in aMCI participants. Power calculations informed by the pattern of progression in the NACC sample were used to describe the net impact of PEs on trials with and without a run-in phase. Weighting parameters of optimal composite measures constructed from the NACC battery were also compared.

RESULTS: PEs were large, often exceeding the magnitude of annual rate of change observed in later assessments. Annualized rate of change, and therefore target treatment effect sufficient to achieve a specified percentage reduction in rate of decline, was larger after run-in. Sample size projections for the run-in design were a fraction of those required for trials without run-in. Weighting parameters that optimize composite outcome performance were also different for the two designs, underscoring the importance of considering design in the construction of composite outcomes.

DISCUSSION: Clinical trials randomizing after a run-in period measure treatment efficacy relative to decline unbiased by PEs, and require smaller sample size.

HIGHLIGHTS: In the National Alzheimer's Coordinating Center (NACC), amnestic mild cognitive impairment (aMCI) cohort practice effects often exceed annualized rate of change.Run-in clinical trial designs can be used to extinguish practice effects.Rate of decline after run-in is faster and unbiased by practice effects.Run-in designs correctly target the most clinically relevant outcome signal.Practice effects also impact weighting of optimal composite measures.},
}

@article {pmid40936458,
year = {2025},
author = {Paul, I and Roy, A and Ray, S and Pyne, S and Saha, M and Ray, S},
title = {Exploring the novel protein drug target BAG33339.1 of Porphyromonas gingivalis: an integrative subtractive proteomics and structural dynamics study.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-45},
doi = {10.1080/07391102.2025.2553155},
pmid = {40936458},
issn = {1538-0254},
abstract = {Porphyromonas gingivalis, a gram-negative, bacterium interacts favourably with host subgingival biofilms to cause adult tooth decay and loss. Consequently, the host is infested with an uncontrollable microbial community and a compromised immune system, ultimately leading to tissue damage and bone resorption. P. gingivalis has also been known to cause cardiovascular and metabolic diseases, Alzheimer's disease, depression, prostate and digestive system cancer, rheumatoid arthritis, and adverse pregnancy outcomes with high detection frequencies. Rising concerns in the recent past, highlight the inefficiency of antibiotics and antiseptics in the treatment of P. gingivalis-related infections. Hence, the current scenario impels the discovery of an alternative therapeutic avenue against P. gingivalis-infections. To elucidate the unidentified bacterial mechanisms of infection, we screened a non-homolog of the host and gut microbiome as a novel druggable target from 173 essential hypothetical proteins of P.gingivalis (BAG33339.1). BAG33339.1 was an inner membrane protein with a hydrophobic N-terminal transmembrane helix and a primarily reconfiguring C-terminal helical region (Y36 to E52) while the residues (downstream of Lys45) lay in the disordered region. Frustration index coupled with the mutation matrix showed the steadiness of the transmembrane helix and dynamicity of the C-terminal residues finally yielding a 'U'-shaped protein conformation. The tendency of the disordered C-terminal residues was to generate P. gingivalis variants. The overall conformational stability was determined by equilibrating RMSD, Rg and SASA values corroborated by increasing H-bonds and helix settling. Targeting the ligand binding pockets of BAG33339.1 would guide future endeavours to tackle P. gingivalis interaction with host systems.},
}

@article {pmid40936007,
year = {2025},
author = {Tskhakaia, I and Lema, D and Tsibadze, N and Lam, JR and Subramanian, A and Lau, A},
title = {Proton pump inhibitors in systemic sclerosis: should we exercise caution? Insights from a large-scale data analysis.},
journal = {Clinical rheumatology},
volume = {},
number = {},
pages = {},
pmid = {40936007},
issn = {1434-9949},
abstract = {BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune disorder often accompanied by gastroesophageal reflux disease (GERD), necessitating frequent use of proton pump inhibitors (PPIs). While PPIs mitigate GERD symptoms and protect against lung injury, concerns about their long-term safety, particularly regarding chronic kidney disease (CKD), osteoporosis, and Alzheimer's disease, are growing. This study aimed to assess whether the adverse effects of PPI are amplified in patients with scleroderma.

METHODS: This was a retrospective observational analysis that utilized the TriNetX research network, including over 130 million patients globally. The study population comprised 6800 SSc patients on PPIs and 1,889,433 GERD patients on PPIs. Outcomes were evaluated pre- and post-propensity score matching for demographic and clinical factors. Risks of CKD (including stages 3, 4, 5, ESRD, hemodialysis dependence), osteoporosis, vascular dementia, and Alzheimer's disease were assessed.

RESULTS: The SSc cohort exhibited higher risks of developing CKD (attributable risk [AR] 2.8%, p < 0.01) and osteoporosis (AR 9%, p < 0.01) after matching, compared to the GERD cohort. Notably, CKD stages 4 and 5 showed minimal differences between groups. SSc patients on PPI had lower risks of Alzheimer's disease (AR - 0.7%, p < 0.01). While the findings highlight an amplified risk of CKD and osteoporosis in SSc patients, the differences in advanced renal disease were modest.

CONCLUSION: PPI therapy remains indispensable in SSc management. While potentially associated with a slight but significant increase in the risks of CKD and osteoporosis, these adverse effects do not negate the critical role of PPIs in mitigating GERD and its serious pulmonary complications. A strategy of targeted monitoring is recommended to maximize safety. Key Points • Identified Amplified Risks in SSc: This large-scale study reveals that SSc patients on PPIs face significantly higher risks of chronic kidney disease and osteoporosis compared to GERD patients on PPIs, suggesting SSc pathophysiology amplifies PPI-associated adverse effects. • Uncovered Neuroprotective Association: Contrary to general population trends, SSc patients on PPIs showed a reduced risk of Alzheimer's disease, potentially linked to immunosuppressant use, closer monitoring, or unique disease mechanisms-a finding warranting further investigation. • Provided Real-World Safety Evidence: Leveraging global data (> 130 million patients), this study offers robust real-world evidence on PPI safety in SSc, reinforcing PPIs' vital role in GERD/ILD management while advocating vigilant monitoring for CKD/osteoporosis. • Informed Risk-Benefit Clinical Strategy: The findings underscore the need to balance PPI benefits (reducing GERD/aspiration-related lung injury) against amplified renal/bone risks in SSc, guiding individualized treatment and monitoring protocols despite causal limitations of retrospective data.},
}

@article {pmid40935607,
year = {2025},
author = {Yoo, HB and Kang, SK and Shin, SA and Kim, D and Choi, H and Kim, YK and Yi, D and Byun, MS and Lee, DY and Lee, JS and , },
title = {Artificial Intelligence-Powered Quantification of Flortaucipir PET for Detecting Tau Pathology.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.269636},
pmid = {40935607},
issn = {1535-5667},
abstract = {We developed and evaluated an artificial intelligence (AI)-powered approach for easier quantification of tau PET uptake without requiring structural MR to aid earlier tracking of Alzheimer disease (AD). Methods: We implemented a deep neural network model that normalizes [18]F-AV1451 (tau) PET images to a standard template without requiring MR, using transfer learning from a model pretrained on amyloid PET. This model was integrated into an MR-free pipeline for tau PET quantification and validated on external dataset (Alzheimer Disease Neuroimaging Initiative). We examined correlations between model-derived tau uptake estimates and cognitive measures, including AD stage and episodic memory performance (n = 666). Longitudinal analyses were conducted to assess whether baseline tau deposition predicted future cognitive decline (n = 168). Results: The AI-powered pipeline achieved robust performance with intraclass correlation coefficients exceeding 0.97 for regional uptake estimation compared with MR-based ground truth. We also showed that the tau deposition in metatemporal regions was significantly correlated with Mini-Mental State Examination and Montreal Cognitive Assessment scores. Elevated tau PET uptake in the entorhinal cortex and inferior temporal gyrus predicted future cognitive decline. Conclusion: The proposed AI-powered pipeline enhances the clinical accessibility of tau PET by reducing scan costs and streamlining the uptake quantification, achieving high performance without requiring structural MR. We further demonstrated that the pipeline yields cognitively relevant outcome measures for early diagnosis and monitoring of AD progression to aid more personalized treatment strategies targeting AD biomarkers.},
}

@article {pmid40935215,
year = {2025},
author = {Huang, H and Lu, W and Huang, Y and Su, Y and Luo, R and Zeng, Y and Yuan, C and Jia, Z and Wang, X},
title = {Bazi Bushen improves cognitive dysfunction in 5×FAD mice by targeting amyloid pathology, neuroinflammation and cellular senescence.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120586},
doi = {10.1016/j.jep.2025.120586},
pmid = {40935215},
issn = {1872-7573},
abstract = {Bazi Bushen (BZBS), a Traditional Chinese Medicine (TCM) formula, is composed of fourteen herbal ingredients, including classic tonics such as Ginseng Radix et Rhizoma and Cistanches Herba. Traditionally used to combat fatigue and promote vitality in aging individuals, BZBS is rooted in TCM principles of kidney essence replenishment and brain function enhancement. Recent pharmacological studies have begun to validate its efficacy in age-related cognitive decline, but its effects and mechanisms in Alzheimer's disease (AD) remain unclear.

AIM OF THE STUDY: This study aimed to evaluate the potential therapeutic effects of BZBS in 5×FAD transgenic mice, a commonly used Alzheimer's disease model, and to shed light on its possible mechanisms of action.

METHODS: Four- and six-month-old 5×FAD mice were treated with BZBS to examine how it might influence cognitive performance. Behavioral assessments were carried out using Y-Maze and the Morris Water Maze. To investigate the biological changes and uncover the mechanisms involved, we used a range of techniques-Thioflavin S staining, immunofluorescence, Western blotting, and qPCR-to look at Aβ plaque accumulation, Amyloid Precursor Protein C-terminal Fragments (APP-CTF) and β-secretase 1 (BACE1) expression levels, markers of inflammation, and indicators of cellular aging in hippocampus and motor cortex.

RESULTS: In the 4-month group, where treatment was started before severe pathology developed, BZBS improved learning and memory performance. It also reduced amyloid deposition in the cortex and hippocampus, and lowered the levels of APP-CTFs and BACE1. In addition, we observed decreased mRNA expression of IL-1α, IL-6, and NF-κB, along with reduced microglial activation in the hippocampus of BZBS-treated mice. Similarly BZBS downregulated key markers of cellular senescence, including p16, p21, and senescence-associated β galactosidase (SA-β-gal) activity. In the 6-month group, which already showed signs of amyloid pathology, BZBS still had beneficial effects-improving cognition, lowering Aβ load, and reducing microglial activity-suggesting that it may be effective even after disease onset.

CONCLUSION: These findings demonstrate that BZBS exerts significant therapeutic effects in 5×FAD mice, including improved cognitive improvement, reduced Aβ deposition, suppressed microglial activation, and attenuated hippocampal cellular senescence. Notably, BZBS was effective whether administered from the early stage of pathology (at four months of age) or after established amyloidosis (at six months of age), highlighting its dual potential as both a preventive and disease-modifying intervention for Alzheimer's disease (AD).},
}

@article {pmid40935202,
year = {2025},
author = {Yang, X and Hu, D and Zhao, S and Wan, J and Chen, L and Bao, Q and Zhang, Y and Wang, Q and Huang, Z},
title = {Neuroprotective Effects of Butyrolactone II from Aspergillus terreus via Nrf-2/SKN-1 Pathway Modulation in Caenorhabditis elegans.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110107},
doi = {10.1016/j.jnutbio.2025.110107},
pmid = {40935202},
issn = {1873-4847},
abstract = {Fourteen compounds were isolated from the fermentation broth of Aspergillus terreus, all of which were isolated from A. terreus for the first time. Among them, butyrolactone II (A9) had excellent DPPH radical scavenging activity, with an EC50 value of 42.05 μM superior to positive control drug BHT. Further neuroprotective activity evaluation of in Caenorhabditis elegans CL2355 revealed that butyrolactone II could alleviate Aβ, causing chemotaxis disorder, prolonging lifespan of C. elegans, and reducing 5-HT sensitivity. Butyrolactone Ⅱ treatment significantly elevated the chemotaxis index of genotyped nematode CL2355 by 15.06% (P<0.05), and reduced the sensitivity of nematodes to 5-HT, decreasing the paralysis rate by 9.8% (P<0.05). Moreover, it significantly increased median lifespan and maximum lifespan by 20% and 26% respectively. In the RNA transcriptome, Butyrolactone II caused upregulation of 277 differentially expressed genes and downregulation of 171 differentially expressed genes, inducing the entry of transcription factor SKN-1 into the nucleus and changes in its downstream genes. The annotation and enrichment of GO and KEGG pathways indicated that differentially expressed genes might be related to pathways such as metabolic detoxification, oxidative stress, and lysosomal autophagy. The qRT-PCR validation of gene expression was consistent with transcriptomics. Butyrolactone II could significantly increase the expression of mitochondrial fission factor (mff-2), downstream genes related to SKN-1 (dod-17, gst-38), heat shock protein genes (hsp-17, hsp-12.6), and oxidative stress related genes (cyp-14A5) in nematodes, while having no significant effect on the expression level of gst-33 gene. Taken conclusion, butyrolactone II exerts neuroprotective effects by modulating the Nrf-2/SKN-1 pathway and regulating metabolic pathways, underscoring its potential as a therapeutic strategy for Alzheimer's disease and other related neurodegenerative disorders.},
}

@article {pmid40934766,
year = {2025},
author = {Xin, X and Zong, T and Hu, Z and Jin, L and Zhou, W and Sun, J and Li, G},
title = {Discovery of natural compounds and their derivatives against neuroinflammation: Pharmacological mechanisms and structure-activity relationship.},
journal = {Bioorganic chemistry},
volume = {165},
number = {},
pages = {108934},
doi = {10.1016/j.bioorg.2025.108934},
pmid = {40934766},
issn = {1090-2120},
abstract = {Neuroinflammation refers to the inflammatory response within the central nervous system mediated by immune and glial cells, constitutes a pivotal mechanism in the pathological progression of neurodegenerative diseases. Alzheimer's disease (AD) serves as a paradigmatic example of neuroinflammation role in driving cytokine-mediated neuronal damage and perpetuating of disease progression. AD, which is characterized by memory decline and progressive cognitive impairment as its core clinical manifestations, currently has no effective treatment. Recent advances have underscored natural products as promising candidates for the development of safer and more effective anti-AD agents, particularly through the targeting of neuroinflammatory pathways that have emerged as central pathological mechanisms in the progression of AD. This review aims to elucidate the pathogenesis of neuroinflammation in AD and provides a comprehensive overview of anti-AD drugs currently in clinical research as well as those already available on the market. Additionally, this paper highlights natural compounds and their derivatives discovered over the past decade that exhibit anti-AD neuroinflammatory properties, analyzing the structure-activity relationships of selected compounds and their permeability across the blood-brain barrier. The goal is to offer valuable insights and references for drug developers.},
}

@article {pmid40934542,
year = {2025},
author = {Liu, T and Zhang, W and Bao, W and Wang, X and Zhang, F and Guo, J and Li, M},
title = {Aβ impairs bone vascular homeostasis in APP/PS1 mice via disrupting the mitochondrial fission-efferocytosis axis in macrophages.},
journal = {International immunopharmacology},
volume = {165},
number = {},
pages = {115526},
doi = {10.1016/j.intimp.2025.115526},
pmid = {40934542},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is associated with progressive bone loss, but the underlying mechanisms remain unclear. This study focused on how amyloid-β (Aβ) disrupted bone vascular homeostasis by impairing macrophage efferocytosis in APP/PS1 mice. We found that Aβ accumulation in bone tissue impaired MerTK-mediated macrophage efferocytosis and promoted excessive accumulation of apoptotic endothelial cells (ECs). Mechanistically, Aβ triggered excessive mitochondrial fission via GSK-3β-mediated DRP1 phosphorylation, resulting in elevated reactive oxygen species (ROS) and subsequent ADAM17 activation. ADAM17 cleaved MerTK, a critical efferocytosis receptor, impairing apoptotic cells (ACs) clearance. Pharmacological inhibition of GSK-3β (LiCl and TDZD-8) or mitochondrial fission (Mdivi-1) restored MerTK expression, improved efferocytosis, and reduced inflammatory cytokine release (such as TNF-α, IL-6), while enhancing vascular endothelial growth factors (VEGFs). In vivo, LiCl treatment ameliorated bone loss and vascular dysfunction in APP/PS1 mice. These findings revealed that Aβ disrupted the mitochondrial fission-efferocytosis axis in macrophages, contributing to AD-related bone pathology, and highlighted GSK-3β as a potential therapeutic target for preserving bone vascular homeostasis in AD.},
}

@article {pmid40933919,
year = {2025},
author = {Song, B and Yue, D and Yan, H and Feng, L and Li, M},
title = {Traditional Chinese Medicine Natural Products Targeting Shared Mechanisms of T2DM and AD: Potential Therapeutic Insights.},
journal = {Drug design, development and therapy},
volume = {19},
number = {},
pages = {7681-7705},
doi = {10.2147/DDDT.S531909},
pmid = {40933919},
issn = {1177-8881},
abstract = {As highly prevalent chronic diseases globally, AD (Alzheimer's disease) and T2DM (type 2 diabetes mellitus) not only severely affect the quality of life of patients but also impose a significant burden on their families. Numerous studies have gradually revealed that T2DM and AD are bidirectional risk factors, each capable of exacerbating the other. There is a notable correlation in their pathological mechanisms, primarily manifested in insulin resistance, OS (oxidative stress), and inflammatory responses. Currently, available drugs can only delay the progression of AD, such as Donepezil, Galantamine, and Carbamylcholine, making complete cures challenging to achieve. TCM (Traditional Chinese medicine) natural products exhibit characteristics such as multi-targeting, multi-pathway interactions, diverse biological activities, and relatively mild side effects, enabling synergistic intervention in both diseases. In recent years, TCM natural products have garnered increasing attention in research concentrated on the prevention and management of AD and T2DM. This article aims to comprehensively elucidate the collective pathogenic mechanism of AD and T2DM, and explore the progress of TCM natural products based on these mechanisms in the prevention and treatment of both diseases, thereby providing a theoretical foundation for the advancement of innovative treatment tactics.},
}

@article {pmid40933857,
year = {2025},
author = {Li, H and Zhu, J and Li, J and Wu, Y and Luo, C and Huang, Y and Wu, J and Liu, W and Wang, H and Mo, Z},
title = {Human brain organoids: an innovative model for neurological disorder research and therapy.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1658074},
doi = {10.3389/fncel.2025.1658074},
pmid = {40933857},
issn = {1662-5102},
abstract = {The emergence of human brain organoids (hBOs) has transformed how we study brain development, disease mechanisms, and therapy discovery. These 3D in vitro neural models closely mimic the cellular diversity, spatial structure, and functional connectivity of the human brain, providing a groundbreaking platform that outperforms traditional 2D cultures and animal models in studying neurodevelopment and neurological disorders. To further explore the potential of hBOs technology, we review current literature focusing particularly on its applications for diagnosing and treating major neurological diseases such as Alzheimer's disease, Parkinson's disease, and other related neurological disorders. Using patient-derived induced pluripotent stem cells combined with cutting-edge gene-editing technologies, hBOs enable highly precise mechanistic studies and scalable drug screening. Moreover, we further discuss the advantages and current limitations of hBOs. Despite these challenges, hBOs remain a transformative platform for the development of targeted neurotherapeutics. Collectively, this review offers a solid foundation for advancing neuroscience research and fostering innovative treatment strategies for neurological disorders.},
}

@article {pmid40933625,
year = {2025},
author = {Hean, AC and Jones, J and Arena, M and Kavanagh, K},
title = {Memantine leading to physical aggression in the treatment of chronic catatonia secondary to schizophrenia: A case report.},
journal = {The mental health clinician},
volume = {15},
number = {4},
pages = {218-221},
doi = {10.9740/mhc.2025.08.218},
pmid = {40933625},
issn = {2168-9709},
abstract = {INTRODUCTION: Memantine is a noncompetitive N-methyl-D-aspartate receptor antagonist approved by the FDA for moderate to severe Alzheimer's dementia. Memantine is also recommended as an off-label treatment in current catatonia clinical guidelines when benzodiazepines alone are inadequate.

CASE: A 37-year-old male with a history of schizophrenia on psychiatric conservatorship, stimulant use disorder, and traumatic brain injury was stabilized on risperidone 4 mg twice daily, diphenhydramine 50 mg twice daily, divalproex delayed release 500 mg twice daily, and lorazepam 1 mg twice daily for catatonia. Lorazepam was titrated for unresolved chronic catatonic symptoms but was not tolerated beyond 5 mg total per day due to hemodynamic instability. Owing to barriers in initiating clozapine or electroconvulsive therapy, the patient was started on memantine to address residual catatonia symptoms. After the addition of memantine, the patient began to spontaneously speak in multiple languages and engage in discharge planning, but shortly after a dose increase to 15 mg daily also displayed increased aggressive behaviors. The aggression improved after decreasing the dose to 10 mg daily, and the patient was discharged.

CONCLUSIONS: This case adds to the body of evidence for memantine in catatonia with underlying schizophrenia and, to our knowledge, is the first described case of memantine uncovering aggression during catatonia treatment.},
}

@article {pmid40933191,
year = {2025},
author = {Zhao, Y and Wang, X and Zhang, J and Zhao, Y and Li, Y and Shen, J and Yuan, Y and Li, J},
title = {Plasma FGF2 and YAP1 as novel biomarkers for MCI in the elderly: analysis via bioinformatics and clinical study.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1663276},
doi = {10.3389/fnins.2025.1663276},
pmid = {40933191},
issn = {1662-4548},
abstract = {The contemporary consensus firmly emphasizes the urgent need to reorient research efforts toward the early detection of preclinical Alzheimer's disease (AD) or mild cognitive impairment (MCI). However, there is still a notable absence of novel biomarkers that are both efficient, minimally invasive, and cost-effective in real-world clinical settings. To address this gap, datasets GSE29378 and GSE12685 were selected to screen differentially expressed genes (DEGs), and hub genes were identified by different algorithms. A total of 350 DEGs were identified in bioinformatics data mining. Functional enrichment analysis showed that fibroblast growth factor 2(FGF2) and yes-associated protein 1(YAP1) protein levels were highly expressed in AD samples, indicating their potential regulatory roles in AD. Between October and November 2024, a total of 146 elderly individuals diagnosed with MCI and 54 healthy elderly subjects were successfully recruited. Enzyme linked immunosorbent assay (ELISA) was used to detect plasma hub gene protein concentration. The results showed that the expression levels of plasma FGF2 and YAP1 proteins in the MCI group were significantly higher compared to the control group. Logistic regression analysis indicated that high plasma FGF2 and YAP1 expression levels were independently associated with MCI in the elderly. The Area under the curve (AUC) of FGF2 model and YAP1 model were 0.907 and 0.972, respectively. Therefore, the high expression of plasma FGF2 and YAP1 proteins may be independent predictive risk factors for MCI in the elderly. Our findings may provide targets for the development of early minimally invasive, efficient, and convenient screening tools, and even for the treatment of AD in the future.},
}

@article {pmid40933041,
year = {2025},
author = {He, C and Chen, B and Yan, C and Zhou, X},
title = {Stem cell and CRISPR/Cas9 gene editing technology in Alzheimer's disease therapy: from basic research to clinical innovation.},
journal = {Frontiers in genome editing},
volume = {7},
number = {},
pages = {1612868},
doi = {10.3389/fgeed.2025.1612868},
pmid = {40933041},
issn = {2673-3439},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by Aβ plaques, tau protein neuronal fiber tangles, and neuroinflammation, poses a significant global health problem, and current therapies focus on the symptoms rather than the cause. This paper gives a new multidimensional therapeutic form to AD treatment by exploring the integrated application of stem cell therapy and CRISPR/Cas9 gene editing technology. The study comprehensively dissected the roles of neural stem cells (NSCs), induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) in neural replacement, neuroinflammation modulation and neuroplasticity enhancement, and also explored the application of CRISPR/Cas9 in modifying the pathogenic variants of AD-related genes (APP, PSEN1 and PSEN2). The key findings suggest that gene-edited iPSCs can reduce abnormal Aβ and tau protein accumulation in AD models, improve cognitive function, and provide a platform for disease modeling and drug screening. Stem cell transplantation promotes neurogenesis and synaptic plasticity by secreting neurotrophic factors to improve the brain microenvironment. Despite the challenges of off-target effects, immune rejection, and long-term safety, the synergistic application of these two technologies offers a breakthrough solution for AD treatment. This paper highlights the translational potential of combining stem cells with gene editing technology, which is expected to drive clinical applications in the next 5-10 years. The integration of these advanced technologies not only addresses the limitations of current AD treatments, but also paves the way for a personalized medical approach that is expected to revolutionize the AD treatment landscape and bring new hope to patients worldwide.},
}

@article {pmid40932994,
year = {2025},
author = {Katel, S and Cicalo, J and Vasciaveo, V and Vecchio, LM and Carrion, J and Mahadeo, L and Huerta, PT and Choksi, JD and Aubert, I and Marambaud, P and Giliberto, L and d'Abramo, C},
title = {AAV-mediated peripheral scFv's administration to reduce cerebral tau in adult P301S transgenic mice: Mono-vs. combination therapy.},
journal = {Molecular therapy. Methods & clinical development},
volume = {33},
number = {3},
pages = {101563},
doi = {10.1016/j.omtm.2025.101563},
pmid = {40932994},
issn = {2329-0501},
abstract = {Tau is a primary target for immunotherapy in Alzheimer's disease (AD). Recent studies have shown the potential of anti-tau fragment antibodies in lowering pathological tau levels in vitro and in vivo. Here, we compared the effects of single-chain variable fragments (scFvs) derived from the well-characterized monoclonal antibodies PHF1 and MC1. We used adeno-associated virus 1 (AAV1) to deliver scFvs to skeletal muscle cells in 8-week-old P301S tau transgenic mice. We evaluated motor and behavioral functions at 16 and 23 weeks of age and measured misfolded, soluble, oligomeric, and insoluble brain tau species. Monotherapy with scFv-MC1 improved motor and behavioral functions more effectively than scFv-PHF1 or combination therapy. Brain glucose metabolism also benefited from scFv-MC1 treatment. Surprisingly, combining scFvs targeting early (MC1) and late (PHF1) tau modifications did not produce additive or synergistic effects. These results confirm that intramuscular AAV1-mediated scFv-MC1 gene therapy holds promise as a potential treatment for AD. Our findings also suggest that combining scFvs targeting different tau epitopes may not necessarily enhance efficacy if administered together in a prevention paradigm. Further research is needed to explore whether other antibodies' combinations and/or administration schedules could improve the efficacy of scFv-MC1 alone.},
}

@article {pmid40931963,
year = {2025},
author = {Nardi Cesarini, E and Falcicchio, G and Librizzi, L and Sciaccaluga, M and Assenza, G and Galimberti, CA and Giorgi, FS and DiFrancesco, JC and Costa, C and , },
title = {Etiological diagnosis of late-onset epilepsy: A key priority for Italian epileptologists - Insights from a LICE survey.},
journal = {Epilepsia open},
volume = {},
number = {},
pages = {},
doi = {10.1002/epi4.70131},
pmid = {40931963},
issn = {2470-9239},
abstract = {OBJECTIVE: The incidence of epilepsy rises markedly after age 50. While late-onset epilepsy (LOE) is often linked to structural brain abnormalities, non-structural factors, such as infections, autoimmune disorders, and neurodegenerative diseases, also contribute. Approximately 20% of LOE cases remain of unknown etiology (LOEU). This study evaluated the diagnostic and therapeutic strategies employed by Italian epileptologists in managing LOE and LOEU, with the ultimate goal of proposing a standardized diagnostic algorithm.

METHODS: Data were collected through a cross-sectional online survey administered to neurologists who are formal members of the Italian Chapter of the International League Against Epilepsy (LICE). Descriptive statistics were used to summarize responses, and inferential statistics were applied to derive meaningful conclusions.

RESULTS: Sixty-five epilepsy centers across 19 of the 20 Italian regions participated in the survey. EEG (100%; n = 65) and brain MRI (92.31%; n = 60) were routinely employed in the diagnostic evaluation of LOE. In over half of the centers (58.46%; n = 38), sleep-activated or sleep-influenced EEGs were also used. For LOEU cases, neuropsychological assessments were performed in 60% of centers. More than 30% of centers employed additional diagnostic tools, including lumbar puncture, FDG-PET, and serum antibody testing for neural autoantibodies. The most commonly prescribed anti-seizure medications (ASMs) for LOE were levetiracetam (86.15%; n = 56), lacosamide (81.54%; n = 53), and lamotrigine (61.54%; n = 40).

SIGNIFICANCE: These findings suggested that Italian epileptologists frequently evaluate patients with LOE during routine outpatient visits. LOEU is increasingly recognized as a distinct subtype of LOE that may warrant a targeted diagnostic approach due to the potential involvement of autoimmune and neurodegenerative mechanisms. There is a pressing need for focused cross-sectional or prospective multicenter studies to refine the diagnostic strategies for LOE, particularly for LOEU, and to enhance the characterization of its clinical and etiological features.

PLAIN LANGUAGE SUMMARY: After age 50, epilepsy rates rise, often linked to brain changes but sometimes with no clear cause (LOEU). We surveyed Italian epilepsy specialists and found that routine EEG and MRI are widely used, yet about 20% of cases require advanced tests to identify rare or autoimmune causes. Our findings will inform patient-focused diagnostic and treatment guidelines and underscore the need for standardized care pathways and further research in adult-onset epilepsy.},
}

@article {pmid40931717,
year = {2025},
author = {Rogers, EA and Diorio, TC and Beauclair, T and Martinez, J and Mufti, SJ and Kim, D and Krishnan, N and Rayz, V and Shi, R},
title = {Concussive injuries induce neuronal stress-dependent tau mislocalization to dendritic spines with acrolein and functional network alteration in TBI-on-a-chip.},
journal = {Lab on a chip},
volume = {},
number = {},
pages = {},
pmid = {40931717},
issn = {1473-0189},
abstract = {Traumatic brain injuries (TBIs) are a risk factor for Alzheimer's disease (AD), and share several important pathological features including the development of neurofibrillary tangles (NFT) of tau protein. While this association is well established, the underlying pathogenesis is poorly defined and current treatment options remain limited, necessitating novel methods and approaches. In response we developed "TBI-on-a-chip", an in vitro trauma model utilizing murine cortical networks on microelectrode arrays (MEAs), capable of reproducing clinically relevant impact injuries while providing simultaneous morphological and electrophysiological readout. Here, we incorporate a digital twin of the TBI-on-a-chip model to resolve cell-scale mechanical deformation via shear stresses and demonstrate direct connections between impact forces with aberrations in tau and synaptic deficits, and correlate these changes with elevations of oxidative stress, a suspected key contributor to both trauma and neurodegeneration. This multi-disciplinary investigation combines computational modeling, electrophysiology, and imaging, to explore tau mislocalization and functional deficits as a function of force, in the context of a potential mechanism via acrolein. We hope that this novel, integrative approach will help improve our mechanistic understanding of trauma and neurodegeneration, solo and in concert, and ultimately assist in generating more effective treatment options.},
}

@article {pmid40931680,
year = {2025},
author = {Stone, WJ and Pair, FS and Ekkatine, R and Gannon, M and Scholz, K and Pattanayak, R and Syed, R and Yacoubian, TA},
title = {14-3-3 Proteins Negatively Regulate Microglial Activation via Inhibition of the NF-κB Pathway.},
journal = {Journal of neurochemistry},
volume = {169},
number = {9},
pages = {e70228},
doi = {10.1111/jnc.70228},
pmid = {40931680},
issn = {1471-4159},
support = {//Parkinson Association of Alabama/ ; F31ES034985/NH/NIH HHS/United States ; R01NS112203/NH/NIH HHS/United States ; },
mesh = {*Microglia/metabolism/drug effects ; *14-3-3 Proteins/metabolism/antagonists & inhibitors ; Animals ; Mice ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Signal Transduction/physiology/drug effects ; Lipopolysaccharides/pharmacology ; Mice, Inbred C57BL ; Cells, Cultured ; },
abstract = {Microglia, the resident immune cells of the central nervous system (CNS), are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson's disease (PD). 14-3-3 proteins act as molecular hubs to regulate protein-protein interactions, which are involved in numerous cellular functions, including cellular signaling, protein folding, and apoptosis. We previously revealed decreased 14-3-3 levels in the brains of human subjects with neurodegenerative diseases. In this study, we examined the role of 14-3-3 proteins in the microglial proinflammatory response to lipopolysaccharide (LPS). We found that LPS treatment induced 14-3-3 protein levels within 6 hours. With the use of BV02 and dimeric fourteen-three-three peptide inhibitor (difopein), a small molecule and peptide inhibitor of 14-3-3 protein-protein interactions, respectively, we found a dramatic increase in microglial activation markers in both immortalized BV-2 microglial cells and in primary mouse microglia. Both 14-3-3 inhibitors also increased LPS-induced microglial phagocytosis, lysosomal proteolysis, and cytokine release in primary microglia. In contrast, chemotaxis toward the cellular damage stimulus, adenosine triphosphate (ATP), was diminished with 14-3-3 inhibition. Inhibition of 14-3-3's hastened LPS-induced activation of the nuclear factor-kB (NF-κB) signaling pathway, as measured by its nuclear translocation. 14-3-3's reduced activation of the NF-κB pathway by binding and inhibiting the release of IκB kinase beta (IKKβ). Disruption of 14-3-3's binding to IKKβ with BV02 or difopein increased the downstream phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα). Collectively, our findings suggest 14-3-3 proteins play a critical role in the regulation of inflammatory responses in microglia and may serve as potential targets for immunotherapy of CNS diseases.},
}

*Microglia/metabolism/drug effects
*14-3-3 Proteins/metabolism/antagonists & inhibitors
Animals
Mice
*NF-kappa B/metabolism/antagonists & inhibitors
*Signal Transduction/physiology/drug effects
Lipopolysaccharides/pharmacology
Mice, Inbred C57BL
Cells, Cultured

@article {pmid40931498,
year = {2025},
author = {Alemán-Villa, KM and Armienta-Rojas, DA and Camberos-Barraza, J and Rábago-Monzón, ÁR and Camacho-Zamora, A and Osuna-Ramos, JF and Magaña-Gómez, JA and Guadrón-Llanos, AM and Calderón-Zamora, L and Norzagaray-Valenzuela, CD and Valdez-Flores, MA and Picos-Cárdenas, VJ and De la Herrán-Arita, AK},
title = {Neuroinflammation across the spectrum of neurodegenerative diseases: mechanisms and therapeutic frontiers.},
journal = {Neuroimmunomodulation},
volume = {},
number = {},
pages = {1-33},
doi = {10.1159/000548021},
pmid = {40931498},
issn = {1423-0216},
abstract = {Neuroinflammation has emerged as a central and dynamic component of the pathophysiology underlying a wide range of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Far from being a secondary consequence of neuronal damage, inflammatory processes (mediated by microglia, astrocytes, peripheral immune cells, and associated molecular mediators) actively shape disease onset, progression, and symptomatology. This review synthesizes current knowledge on the cellular and molecular mechanisms that govern neuroinflammatory responses, emphasizing both shared and disease-specific pathways. We examine how innate and adaptive immune interactions contribute to neuronal vulnerability and neurodegenerative cascades, and explore the reciprocal communication between systemic and central immune compartments. Particular attention is given to emerging therapeutic strategies aimed at modulating neuroinflammation, including immunomodulatory drugs, glial-targeted interventions, and novel delivery platforms. By integrating findings across disciplines and disease models, we outline key translational challenges and propose future directions to harness neuroinflammation as a therapeutic target in the era of precision medicine. Ultimately, a deeper understanding of neuroimmune dynamics holds promise for redefining both the diagnosis and treatment of neurodegenerative disorders.},
}

@article {pmid40931359,
year = {2025},
author = {Ramonet, D and Daerr, A and Hallbeck, M},
title = {Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer's disease mouse model.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {190},
pmid = {40931359},
issn = {2051-5960},
support = {2019-01016//Swedish Research Council/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics/drug therapy ; Mice ; *Endosomes/metabolism/drug effects/pathology ; Disease Models, Animal ; *Synapses/metabolism/drug effects/pathology ; Mice, Transgenic ; *Vesicular Transport Proteins/metabolism/genetics ; Protein Transport/drug effects/physiology ; Humans ; },
abstract = {Disruptions in synaptic transmission and plasticity are early hallmarks of Alzheimer's disease (AD). Endosomal trafficking, mediated by the retromer complex, is essential for intracellular protein sorting, including the regulation of amyloid precursor protein (APP) processing. The VPS35 subunit, a key cargo-recognition component of the retromer, has been implicated in neurodegenerative diseases, with mutations such as L625P linked to early-onset AD. Despite growing evidence for retromer dysfunction in AD, its role in synaptic pathology and neuroinflammation remains incompletely understood. Here, we investigate the acute molecular effects of retromer stabilization in the 5xFAD mouse model of AD using the pharmacological chaperones R55 and R33, previously identified to enhance VPS35 stability. Following intracranial stereotaxic injections, we performed transcriptomic profiling, quantitative histology, and immunohistochemistry to assess synaptic function, neuroinflammation, and endosomal trafficking. Our findings reveal that retromer stabilization reverses multiple AD-associated molecular changes. R55 treatment significantly reduced Aβ-related pathology, normalized synaptic gene expression, and restored long-term potentiation (LTP)-associated pathways, including Gria1 (AMPA receptors), Grip1, and semaphorin/plexin signaling. Additionally, retromer stabilization counteracted dysregulated calcium signaling by modulating Ryr2 and L-type calcium channel expression. Beyond synaptic effects, we observed broad transcriptional and structural changes in the endosomal system. Notably, R55 treatment decreased VPS13 family gene expression, implicated in membrane contact site regulation, while increasing RAB7 levels, suggesting enhanced late-endosomal recycling. VPS35-positive vesicles were redistributed away from the nucleus, indicating restored intracellular trafficking dynamics. In the neuroinflammatory domain, retromer stabilization modulated microglial activation, shifting towards a profile characterized by balanced pro-inflammatory (Il1, Nfkb2) and anti-inflammatory (Il4r, Il13ra1, Stat6) markers, consistent with disease-associated microglia (DAM) phenotypes. Together, these findings demonstrate that retromer dysfunction contributes to key AD pathologies, including synaptic dysfunction and neuroinflammation, and that pharmacological retromer stabilization can restore cellular homeostasis. Given that 5xFAD mice lack direct VPS35 mutations, our results suggest that retromer-targeting strategies may be applicable to both familial and sporadic AD, offering a promising therapeutic avenue for modifying disease progression.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics/drug therapy
Mice
*Endosomes/metabolism/drug effects/pathology
Disease Models, Animal
*Synapses/metabolism/drug effects/pathology
Mice, Transgenic
*Vesicular Transport Proteins/metabolism/genetics
Protein Transport/drug effects/physiology
Humans

@article {pmid40931113,
year = {2025},
author = {Hu, M and Kang, X and Liu, Z and Wang, S and Liu, S and Li, C and Lu, D and Qin, Q and Liu, Y and Yi, H and Yuan, L and Liu, Q and Lu, Z and Cai, W},
title = {Senescent-like border-associated macrophages regulate cognitive aging via migrasome-mediated induction of paracrine senescence in microglia.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {40931113},
issn = {2662-8465},
support = {82271348//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Aging is a major risk factor for various neurological disorders, including Alzheimer's disease, and is associated with the accumulation of senescent cells, which can themselves propagate the senescence process through paracrine signaling. Migrasomes are organelles that form during cellular migration, detach from parent cells and mediate intercellular communication. Here we demonstrate that border-associated macrophages (BAMs) acquire senescence-associated properties during early brain aging, possibly due to prolonged exposure to amyloid beta. Senescent-like BAMs show elevated production of migrasomes, which convey senescence-associated signals including the apoptosis inhibitor of macrophage to neighboring cells. We show that microglia are prominent recipients of senescent-like BAM-derived migrasomes, and that through activation of CD16 in recipient cells, the apoptosis inhibitor of macrophage inhibits apoptosis and promotes senescence induction. Blocking migrasome induction in senescent-like BAMs through treatment with Tspan4-targeting siRNA-encapsulated liposomes ameliorates cognitive deficits in aged mice. Our findings suggest that migrasomes are potent vehicles of senescence-regulatory signals and represent a promising target for senomorphic therapy.},
}

@article {pmid40930236,
year = {2025},
author = {Zhang, F and Ding, K and Zhang, LM and Liu, DY and Dong, X and Wang, MN and Zhou, FL and Sun, YW and Zhang, WK and Yan, Y and He, J and Xu, JK},
title = {The role of the gut microbiota in neuropsychiatric disorders and therapy.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102894},
doi = {10.1016/j.arr.2025.102894},
pmid = {40930236},
issn = {1872-9649},
abstract = {The vast microbial community residing in the gut is known as the gut microbiota (GM). Alterations in the compositional equilibrium of the GM, a phenomenon termed GM dysbiosis, have been increasingly associated with the pathogenesis of various diseases, particularly neuropsychiatric disorders. The microbiota-gut-brain axis (MGBA) serves as a bidirectional communication system that connects the gut to the brain. Notably, several prevalent neuropsychiatric disorders, including depression, Alzheimer's disease (AD), and Parkinson's disease (PD), collectively affect over one billion individuals globally. Emerging scientific evidence has consistently demonstrated the presence of GM dysbiosis in various neuropsychiatric disorders, suggesting a potential etiological role of GM in these conditions through MGBA-mediated mechanisms. In this comprehensive review, we systematically discussed the GM and MGBA, and presented evidence from both animal and human studies that highlighted the significance of GM in the occurrence and development of neuropsychiatric disorders. Subsequently, we emphasized the potential impact of GM and its metabolites on neuropsychiatric disorders. Next, we summarized the drugs used to treat diseases by regulating the GM. Finally, we proposed strategies to ameliorate the malignant progression of neuropsychiatric disorders by manipulating the composition of the GM. These strategies encompass the application of probiotics, prebiotics and synbiotics, postbiotics, fecal microbiota transplantation (FMT), dietary interventions. Collectively, targeted GM therapy has the potential to be an effective treatment for neuropsychiatric disorders.},
}

@article {pmid40929163,
year = {2025},
author = {Schwertner, K and Basílio, J and Hoffmann-Sommergruber, K and Ellinger, I and Geiselhart, S},
title = {Global transcriptional analysis of human FHs 74 Int intestinal epithelial cells after exposure to advanced glycation end products.},
journal = {PloS one},
volume = {20},
number = {9},
pages = {e0331325},
doi = {10.1371/journal.pone.0331325},
pmid = {40929163},
issn = {1932-6203},
mesh = {Humans ; *Glycation End Products, Advanced/pharmacology ; *Intestinal Mucosa/metabolism/cytology/drug effects ; *Epithelial Cells/metabolism/drug effects ; S100A12 Protein/pharmacology ; *Transcriptome/drug effects ; Gene Expression Profiling ; Cell Line ; Gene Expression Regulation/drug effects ; Cell Proliferation/drug effects ; },
abstract = {Advanced glycation end products (AGEs) and reactive intermediates, such as methylglyoxal, are formed during thermal processing of foods and have been implicated in the pathogenesis of a series of chronic inflammatory diseases. AGEs are thought to directly interact with the intestinal epithelium upon ingestion of thermally processed foods, but their effects on intestinal epithelial cells are poorly understood. This study investigated transcriptomic changes in human intestinal epithelial FHs 74 Int cells after exposure to AGE-modified human serum proteins (AGE-HS), S100A12, a known RAGE ligand, and unmodified human serum proteins (HS). In contrast to previous studies employing cancer cell lines, RNA sequencing of FHs 74 Int cells treated with AGE-HS did not reveal transcriptional changes associated with increased proliferation, increased expression of tight junction proteins or proinflammatory responses. Surprisingly, neither AGE-HS nor S100A12 treatments resulted in significant differential gene expression at standard analysis thresholds, while unmodified HS induced minor transcriptional changes. Gene set enrichment analysis revealed that AGE-HS treatment induced downregulation of gene sets linked to MYC, interferon responses, and oxidative phosphorylation, as well as pathways related to neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, paralleling some effects observed with S100A12. This is the first global transcriptomic analysis of FHs 74 Int cells and the first unbiased investigation of signaling pathway alterations in intestinal epithelial cells exposed to AGEs. In contrast to previous studies, this analysis did not reveal any significantly differentially expressed genes, thus challenging previous reports of robust AGE-induced inflammatory and proliferative effects and emphasizing the importance of an isolated experimental setting and rigorous endotoxin testing.},
}

Humans
*Glycation End Products, Advanced/pharmacology
*Intestinal Mucosa/metabolism/cytology/drug effects
*Epithelial Cells/metabolism/drug effects
S100A12 Protein/pharmacology
*Transcriptome/drug effects
Gene Expression Profiling
Cell Line
Gene Expression Regulation/drug effects
Cell Proliferation/drug effects

@article {pmid40928812,
year = {2025},
author = {Taragano, F and Seinhart, D and Epstein, P and Sylvestre, V and Barañano, C and Otero Castro, V and Sánchez, V and Kilstein, A and González, R and Franco-Trecu, V and Costa-Urrutia, P},
title = {A real-world study on the safety and efficacy of therapeutic plasma exchange in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375430},
doi = {10.1177/13872877251375430},
pmid = {40928812},
issn = {1875-8908},
abstract = {BackgroundTherapeutic plasma exchange (TPE) with albumin replacement has emerged as a potential treatment for Alzheimer's disease (AD). The AMBAR trial showed that TPE could slow cognitive and functional decline, along with changes in core and inflammatory biomarkers in cerebrospinal fluid.ObjectiveTo evaluate the safety and effectiveness of TPE in a real-world setting in Argentina.MethodsFrom 2022 to 2024, 32 patients with mild-to-moderate AD received TPE and were compared to a historical control group (2008-2018, n = 194) matched for inclusion criteria and cognitive assessments. The protocol included six weekly intensive sessions followed by at least 10 monthly maintenance sessions. Outcomes were measured using the Mini-Mental State Examination (MMSE), and tests of memory, language, executive function, and attention. Linear models were used for analysis.ResultsPatients had a mean age of 72.1 years; 42.4% were female. Baseline MMSE scores ranged from 15 to 26. A total of 514 procedures were performed; 81.5% were uneventful. Mild-to-moderate adverse events occurred in 18.5% of sessions, mainly related to venipuncture; no severe events were reported. Mean plasma exchange volumes were 88.2% and 49.8% of estimated plasma volume during the intensive and maintenance phases, respectively. TPE significantly slowed MMSE decline (45% less than controls, p < 0.001) and reduced memory deterioration (88% less in immediate recall, p < 0.001; 74% in delayed recall, p = 0.04). Other domains were also better preserved.ConclusionsTPE appears to be a safe and effective intervention for slowing cognitive decline in AD, supporting the AMBAR findings.},
}

@article {pmid40928277,
year = {2025},
author = {Fu, JX and Wang, WP and Wang, YD and Wang, PC},
title = {Beams of Hope: Shedding New Light on Alzheimer's Treatment with Low-Dose Radiation Therapy.},
journal = {Biomedical and environmental sciences : BES},
volume = {38},
number = {8},
pages = {1001-1002},
doi = {10.3967/bes2025.100},
pmid = {40928277},
issn = {2214-0190},
}

@article {pmid40928009,
year = {2025},
author = {Weden, MM and Frank, L and Dick, AW and Wang, Z and Peschin, S and Bovenkamp, DE and Rossi, SL and Sciullo, D and Hillerstrom, H and Fisher, RA},
title = {Investment in Alzheimer's disease research for the next generation of adults with Down syndrome will yield health benefits for future generations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70348},
doi = {10.1002/alz.70348},
pmid = {40928009},
issn = {1552-5279},
support = {//LuMind IDSC Foundation/ ; //Alliance for Aging Research/ ; //BrightFocus® Foundation/ ; //National Down Syndrome Society/ ; },
mesh = {Humans ; *Down Syndrome/economics/complications/epidemiology/therapy ; *Alzheimer Disease/economics/therapy/epidemiology ; Life Expectancy ; Adult ; *Biomedical Research/economics ; Caregivers/economics ; },
abstract = {Recent innovations in Alzheimer's disease (AD) treatment highlight critical gaps in knowledge about how to support healthy aging of adults with Down syndrome (DS). RAND researchers updated demographic and epidemiological evidence about the DS population to assess the impact of increased investment in treatment innovations for DS-associated Alzheimer's disease (DS-AD). They estimated life expectancy at birth in 2020 to be 55 years, with ≈ 5 years of DS-AD. They found that the results of investment were dramatic. Between 2020 and 2070, adult years of life are expected to increase by 5 years without any increase in unhealthy years of life with DS-AD. Caregiving hours for individuals with DS-AD are expected to be reduced by 40%, which will generate large annual savings. The new evidence underscores the magnitude of the impact that investment in DS-AD treatments could have for individuals with DS, their families, and caregivers. HIGHLIGHTS: Evidence is sparse about treatment for Down syndrome (DS)-associated Alzheimer's disease (DS-AD) and healthy aging of DS adults. This population simulation model estimates DS-AD caregiving costs at ≈ $1 billion per year. DS-AD innovations could increase life expectancy by 5 years and reduce caregiving by 40% by 2070. This better forecasting can improve policy and service planning. DS-AD research investment could yield dramatic gains for individuals and families.},
}

Humans
*Down Syndrome/economics/complications/epidemiology/therapy
*Alzheimer Disease/economics/therapy/epidemiology
Life Expectancy
Adult
*Biomedical Research/economics
Caregivers/economics

@article {pmid40927759,
year = {2025},
author = {Aggarwal, A and Rajalekshmi, R and Aggarwal, A and Agrawal, DK},
title = {Plants, Pills, and the Brain: Exploring Phytochemicals and Neurological Medicines.},
journal = {International journal of plant, animal and environmental sciences},
volume = {15},
number = {3},
pages = {90-114},
pmid = {40927759},
issn = {2231-4490},
abstract = {Neurological disorders, such as Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injuries, and traumatic brain injuries, represent substantial global health challenges due to their chronic and often progressive nature. While allopathic medicine offers a range of pharmacological interventions aimed at managing symptoms and mitigating disease progression, it is accompanied by limitations, including adverse side effects, the development of drug resistance, and incomplete efficacy. In parallel, phytochemicals-bioactive compounds derived from plants-are receiving increased attention for their potential neuroprotective, antioxidant, and anti-inflammatory properties. This review will explore the therapeutic landscape of neurological diseases by providing a comprehensive overview of prevalent conditions and the current allopathic treatments available. Furthermore, this review will investigate specific phytochemicals, including flavonoids, alkaloids, and terpenoids, that exhibit promise in modulating various disease pathways. Emphasis will be placed on the interactions between plant-derived compounds and prescription medications, highlighting both potential synergistic effects and possible adverse interactions. A thorough understanding of these interactions is essential for the development of integrative treatment approaches that enhance therapeutic efficacy while minimizing harm. By bridging traditional herbal medicine with contemporary pharmacotherapy, this review aims to promote a more holistic perspective on the management of neurological diseases, while also encouraging further research into safe and effective combinatory therapies.},
}