@article {pmid40838403,
year = {2025},
author = {Rodríguez Sarmiento, RM},
title = {A Career Long Effort to Discover a Drug to Treat Neurodegenerative Diseases. My Adventures with γ-Secretase for the Treatment of Alzheimer's.},
journal = {Chimia},
volume = {79},
number = {7-8},
pages = {509-515},
doi = {10.2533/chimia.2025.509},
pmid = {40838403},
issn = {0009-4293},
mesh = {*Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy ; Humans ; *Drug Discovery ; *Neurodegenerative Diseases/drug therapy ; Amyloid beta-Peptides/metabolism ; },
abstract = {Neurodegenerative diseases encompass a range of chronic diseases marked by the progressive loss of structure or function of the nervous system, particularly within areas of the brain such as the neurons (or nerve cells). This degeneration leads to a decline in cognitive abilities, motor skills, and other neurological functions. The progression can be gradual, occurring over years or even decades, and often leads to significant disability and, ultimately, death. Alzheimer's disease (AD) is the most prevalent degenerative disease that affects cognition and that rises dramatically with age. It is a progressive, chronic disease that occurs when nerve cells in the brain die. Current treatments largely address symptoms without altering or reversing disease progression. However, recent advancements with amyloid-β (Aβ) antibodies validate Aβ as a therapeutic target for AD. This article details my long-term experience as a medicinal chemist and project leader working on γ-secretase, a key target in AD drug discovery. I will share initial insights from a multi-disciplinary effort to discover a disease modifying treatment for Alzheimer's disease.},
}

*Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors
*Alzheimer Disease/drug therapy
Humans
*Drug Discovery
*Neurodegenerative Diseases/drug therapy
Amyloid beta-Peptides/metabolism

@article {pmid40836982,
year = {2024},
author = {Grados, M and Salehi, M and Lotfi, A and Dua, S and Xie, I},
title = {A selective review of inhibitors of protein kinase C gamma: a neuroplasticity-related common pathway for psychiatric illness.},
journal = {Frontiers in drug delivery},
volume = {4},
number = {},
pages = {1364037},
pmid = {40836982},
issn = {2674-0850},
abstract = {Psychotropics are currently developed and marketed with a limited understanding of their mechanism of action. The notion that protein kinase C (PKC) activity is highly relevant to learning and memory function stems from experiments in the 1980s, which associated protein kinase alpha (pka) and pkc to animal models of associative learning, opening an area of exploration for psychotropic development. The PKC family consists of several isoforms, including PKC alpha, beta1, beta1, gamma, delta and epsilon among others. In particular, PKC gamma (PRKCG) is highly brain-expressed and is singled out as a candidate for modulation in psychiatric illness. With hundreds of identified substrates, PRKCG affects multiple pathways relevant for regulation of neuronal health. In this review, converging lines of evidence are presented in the context of psychotropic drug action, which point to downregulation of PKC activity as a potential common mechanism across several psychiatric disorders. Using this mechanism through more targeted psychotropic action may then be used to develop agents that further ameliorate psychiatric symptom expression. Psychotropics including fluoxetine, tricyclics, lithium, valproate, ketamine and others are explored in relation to their effect of PKC, finding that across all drugs examined, a downregulation with chronic-but not acute-use constitutes their putative effect in ameliorating symptoms. This effect is compounded by findings that suggest that PKCs, and PRKCG in particular, promote neuroplastic effects by their downregulation. This effect is in contrast to PKC activators, which have been used in neurodegenerative disorders such as Alzheimer's disease. Cross-disorder mechanisms need to continue to be explored in neuropsychiatric illness and targeted treatments developed in turn to address treatment-resistant conditions.},
}

@article {pmid40836645,
year = {2025},
author = {Liu, T and Li, X},
title = {The Crosstalk Between Protective and Detrimental Interleukin (IL)-1 Family of Cytokines in Alzheimer's Disease.},
journal = {Journal of biochemical and molecular toxicology},
volume = {39},
number = {9},
pages = {e70460},
doi = {10.1002/jbt.70460},
pmid = {40836645},
issn = {1099-0461},
support = {//Project no. (2024 Foshan self-funded science and technology innovation project (2420001004404), Education and Department of Guangdong Province (2024GCZX011))./ ; },
mesh = {*Alzheimer Disease/metabolism/pathology/immunology ; Humans ; *Interleukin-1/metabolism/immunology ; Animals ; },
abstract = {Alzheimer's disease (AD) is a long-term, progressive, degenerative disorder. One of the most important pathological characteristics of AD is the deposition of β-amyliod (Aβ) peptide, which initiates a spectrum of cerebral neuroinflammation. Vascular changes also play an important role in the pathophysiology of the disease. Cytokines, secreted by immune cells, can facilitate cell-to-cell signaling and influence the functions of the central nervous system (CNS). These important mediators of the immune system, which are known to orchestrate various molecular and cellular mechanisms in both physiological and pathological situations, can be upregulated or downregulated, leading to a complex crosstalk with numerous receptors mediating pro-inflammatory and/or anti-inflammatory actions. In particular, the interleukin (IL)-1 family of cytokines has been implicated to significantly correlate with AD pathogenesis among other cytokines in the CNS. The IL-1 family of cytokines is essential in both the innate and adaptive immune responses. This pleiotropic family of cytokines includes IL-1α, IL-1β, IL-1 receptor antagonist (RA), IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36RA, IL-37, and IL-38. Recent studies have demonstrated that the upregulation of pro-inflammatory cytokines, such as IL-1α and IL-1β, or the downregulation of anti-inflammatory mediators, exerts multifaceted influences on both neurodegeneration and neuroprotection. The lack of effective treatment for AD necessitates the search for new drugs that target several processes in the disease's pathology. This review aims to give a comprehensive overview of the emerging roles of the IL-1 family of cytokines in AD pathology and to explain their perspectives on introducing novel strategies for effective therapeutic/neuropsychiatric management of AD in clinical settings by discussing both the pathogenic and protective roles of these cytokines.},
}

*Alzheimer Disease/metabolism/pathology/immunology
Humans
*Interleukin-1/metabolism/immunology
Animals

@article {pmid40836165,
year = {2025},
author = {Bayat, A and Mirmomeni, G and Aiken, S and Jafari, Z},
title = {Meta-Analyses of Auditory Evoked Potentials as Alzheimer Biomarkers.},
journal = {Ear and hearing},
volume = {},
number = {},
pages = {},
doi = {10.1097/AUD.0000000000001718},
pmid = {40836165},
issn = {1538-4667},
abstract = {OBJECTIVES: Alterations in auditory evoked potential (AEP) parameters have been associated with sensory memory deficits and may serve as biomarkers for cognitive decline. This systematic review and meta-analysis aimed to evaluate the effectiveness of AEPs in the early detection of Alzheimer disease (AD).

DESIGN: The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. A comprehensive search was performed across five electronic databases (EMBASE, Scopus, Cochrane Library, Web of Science, PubMed, and CINAHL) from their inception until August 2024, without restrictions on date or language. The methodological quality of evidence was assessed using the Crew Critical Appraisal Tool. Data were extracted on the latency and amplitude of five AEP components, including auditory P50 gating, mismatch negativity, and late-latency responses (N100, N200, P300), comparing patients with AD to age-matched control peers.

RESULTS: Out of 437 publications, 54 articles were selected for review, with most rated as having high methodological quality. The analysis revealed a significantly larger P50 gating amplitude (p < 0.001) in patients with AD. Furthermore, patients with AD demonstrated significantly prolonged latencies and reduced amplitudes for N100, N200, and P300 components (p ≤ 0.001) compared with controls. Among all AEPs, P300 latency exhibited the largest effect size. Funnel plot analysis and Egger's regression test showed no evidence of publication bias.

CONCLUSIONS: Our findings support the clinical utility of AEPs in early AD detection, with the P300 response identified as the most accurate electrophysiological measure for distinguishing patients with AD from the control group. These results highlight the value of incorporating AEPs into clinical assessment protocols to enhance early-stage AD diagnosis and monitoring, thereby facilitating timely interventions and the development of personalized treatment strategies.},
}

@article {pmid40835596,
year = {2025},
author = {Molokanova, E and Zhou, T and Vasupal, P and Cherkas, VP and Narute, P and Ferraz, MSA and Reiss, M and Almenar-Queralt, A and Chaldaiopoulou, G and de Souza, JS and Hemati, H and Downey, F and Olajide, OO and Thörn Perez, C and Puppo, F and Mesci, P and Pfaff, SL and Kireev, D and Muotri, AR and Savchenko, A},
title = {Non-genetic neuromodulation with graphene optoelectronic actuators for disease models, stem cell maturation, and biohybrid robotics.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {7499},
pmid = {40835596},
issn = {2041-1723},
support = {1R43MH124563//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; 1R01MH128365//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; MH123828//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; DISC2-13866//California Institute for Regenerative Medicine (CIRM)/ ; 1R43AG076088//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 5R44DA050393//U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/ ; 1R43NS122666//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS123642//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 1R01ES033636//U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)/ ; },
mesh = {*Graphite/chemistry ; *Robotics/methods/instrumentation ; Induced Pluripotent Stem Cells/cytology ; Humans ; Organoids/cytology ; Neurons/cytology ; Brain/cytology ; Alzheimer Disease/pathology/therapy ; Optogenetics/methods ; Cell Differentiation ; Animals ; },
abstract = {Light can serve as a tunable trigger for neurobioengineering technologies, enabling probing, control, and enhancement of brain function with unmatched spatiotemporal precision. Yet, these technologies often require genetic or structural alterations of neurons, disrupting their natural activity. Here, we introduce the Graphene-Mediated Optical Stimulation (GraMOS) platform, which leverages graphene's optoelectronic properties and its ability to efficiently convert light into electricity. Using GraMOS in longitudinal studies, we found that repeated optical stimulation enhances the maturation of hiPSC-derived neurons and brain organoids, underscoring GraMOS's potential for regenerative medicine and neurodevelopmental studies. To explore its potential for disease modeling, we applied short-term GraMOS to Alzheimer's stem cell models, uncovering disease-associated alterations in neuronal activity. Finally, we demonstrated a proof-of-concept for neuroengineering applications by directing robotic movements with GraMOS-triggered signals from graphene-interfaced brain organoids. By enabling precise, non-invasive neural control across timescales from milliseconds to months, GraMOS opens new avenues in neurodevelopment, disease treatment, and robotics.},
}

*Graphite/chemistry
*Robotics/methods/instrumentation
Induced Pluripotent Stem Cells/cytology
Humans
Organoids/cytology
Neurons/cytology
Brain/cytology
Alzheimer Disease/pathology/therapy
Optogenetics/methods
Cell Differentiation
Animals

@article {pmid40835473,
year = {2025},
author = {Naeshiro, Y and Kitani-Morii, F and Kasai, T and Tanaka, E and Kobayashi, F and Ohara, T},
title = {Amyloid Clearance and Transient CSF Aβ40 Reduction in a Case of ARIA-E/H Following Lecanemab Treatment.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {},
number = {},
pages = {},
doi = {10.2169/internalmedicine.6070-25},
pmid = {40835473},
issn = {1349-7235},
abstract = {We herein report a case of amyloid-related imaging abnormality (ARIA)-E/H following lecanemab treatment in a 70-year-old man with mild cognitive impairment due to Alzheimer's disease. Generalized seizures occurred after the third infusion and were accompanied by FLAIR hyperintensity, microbleeds, and a minor acute infarct. Amyloid PET revealed focal clearance of amyloid plaques in the ARIA-affected regions. CSF Aβ40 levels transiently decreased by ~30% during the ARIA episode, whereas Aβ42 remained stable, thereby increasing the Aβ42/40 ratio. These findings suggest that ARIA may facilitate focal amyloid clearance and that CSF Aβ40 reduction may serve as a potential biomarker for ARIA onset and resolution.},
}

@article {pmid40833911,
year = {2025},
author = {Wei, Y and Abrol, A and Lah, J and Levey, AI and Calhoun, VD},
title = {From Symptomatic to Pre-symptomatic: Adaptive Knowledge Distillation for Early Alzheimer's Detection Using Functional MRI.},
journal = {IEEE transactions on bio-medical engineering},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TBME.2025.3597261},
pmid = {40833911},
issn = {1558-2531},
abstract = {Alzheimer's disease (AD) progresses from asymptomatic changes to clinical symptoms, underscoring the critical need for early detection to facilitate timely treatment. Functional magnetic resonance imaging (fMRI) offers non-invasive biomarkers for detection, but current methods fail to reliably identify pre-symptomatic individuals due to two key challenges: (1) Subtle, anatomically distinct fMRI patterns in pre-symptomatic cases that resemble healthy controls more than symptomatic patients, and (2) Severe class imbalance in real-world data, where healthy controls vastly outnumber pre-symptomatic subjects. To address this, we reconceptualize AD diagnosis as a multi-stage distillation task, where insights from easier-to-detect symptomatic cases guide pre-symptomatic detection. We propose a novel margin-aware knowledge distillation (KD) framework with two innovations: (1) We leverage Unbalanced Optimal Transport (UOT) for Feature Distillation to flexibly adapt to anatomical differences in brain patterns caused by neurodegeneration and ensure effective distillation from later to earlier disease stages. (2) We propose Self-Distillation with Dynamic Margins to combat class imbalance by adaptively refining the classification boundary. We evaluate our proposed framework across four distinct base models and demonstrate its superiority over state-of-the-art KD methods. Additionally, we show the significance of various brain regions in identifying pre-symptomatic subjects, as well as how features are transferred during distillation. These contributions advance the development of more precise diagnostic tools and foster a deeper understanding of early disease manifestations, marking a significant stride towards more reliable and earlier AD diagnosis.},
}

@article {pmid40833319,
year = {2025},
author = {Agarwal, U and Verma, S and Gandhi, V and Patil, VM and Tonk, RK},
title = {Multitarget 8-methoxypsoralens against Alzheimer's disease: extraction, synthesis, in vitro and in silico studies.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/17568919.2025.2546776},
pmid = {40833319},
issn = {1756-8927},
abstract = {AIM: Alzheimer's disease poses a serious global health challenge, and there is an urgent need for novel therapeutic agents, as existing drugs have limited efficacy and notable adverse effects. Chromenones, known for their diverse biological activities, have emerged as promising drug candidates for AD treatment due to their capacity to target multiple enzymes. In this study, investigated the chromenone derivative 8-methoxypsoralen (8-MOP) as a potential multi-target inhibitor of key AD targets, highlighting the importance of the scaffold in target-based drug design.

MATERIAL AND METHODS: 8-MOP, a phytochemical extracted and isolated from parsley leaves, was utilized to synthesize new derivatives, which were then screened against enzymes involved in AD progression (BACE1, AChE, BuChE) and targets involved in oxidative pathways (DPPH, NO). In support of the in vitro activity, in silico ADMET predictions and docking experiments were performed.

RESULTS AND CONCLUSIONS: Among the synthesized compounds, 3d and 3e demonstrated significant inhibitory effects against the chosen targets, exhibiting IC50 values between 5.8 ± 0.13 μM and 13 ± 0.12 μM. Furthermore, the docking experiments showed important binding interactions of these compounds with BACE1, AChE, and BuChE. The study demonstrates the potential of 8-MOP derivatives for targeting AD drug targets.},
}

@article {pmid40832968,
year = {2025},
author = {Zhang, X and Chu, S and Huang, Y and Li, Z and Song, J and Wang, P and Su, Y and Zhang, Z and Xie, Z},
title = {Atractylenolide III Mitigates Alzheimer's Disease by Enhancing Autophagy via the YY1-TFEB Pathway.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70069},
pmid = {40832968},
issn = {1099-1573},
support = {2024ZY1027//Special Research Project of Henan Province on Traditional Chinese Medicine/ ; 82274612//National Natural Science Foundation of China/ ; 23HASTIT044//Program for Science & Technology Innovation Talents in Universities of Henan Province/ ; 231111312900//Key Research and Development Program of Henan Province/ ; 232301420085//Henan Provincial Science and Technology Research and Development Program Joint Fund/ ; 232301420093//Henan Provincial Science and Technology Research and Development Program Joint Fund/ ; 242301420019//Henan Provincial Science and Technology Research and Development Program Joint Fund/ ; },
abstract = {Autophagy dysregulation serves as a significant pathogenic factor in Alzheimer's disease (AD), with transcription factor EB (TFEB) acting as a pivotal transcription factor that governs the process of autophagy. Atractylenolide III (AT-III), a terpenoid compound found in medicinal Atractylodes macrocephala Koidz, is well-known for its role in antioxidant and anti-inflammatory activities. The purpose of this study is to explore the beneficial impact of AT-III on AD pathology and identify the mechanisms involved. C. elegans CL4176, SH-SY5Y APPSWE, and APP/PS1 mice were used to investigate the efficacy and possible mechanism of AT-III on the treatment of AD. AT-III reduced amyloid protein (Aβ) deposition in C. elegans CL4176 heads, prolonged the paralysis time, and reduced Aβ levels in SH-SY5Y APPSWE cells. AT-III improved the learning and memory ability of APP/PS1 mice and decreased the deposition of Aβ plaques. Transcriptomics and experimental validation showed that AT-III stimulated transcription and translation of autolysosome-associated genes. AT-III enhanced co-localization of LC3 and LAMP2 with Aβ in APP/PS1 mice. Meanwhile, AT-III increased TFEB transcriptional activity, mRNA, and protein levels in the nucleus. Furthermore, AT-III enhanced the expression of Yin Yang 1 (YY1) protein, an upstream regulator of TFEB, and led to the stimulation of autophagy and lysosome biogenesis both in vivo and in vitro. The observed effects were reversed upon silencing YY1. AT-III may regulate the YY1-TFEB pathway, thereby restoring autophagy flux disturbances and ameliorating AD-related pathological changes and cognitive decline. This study provides a promising lead compound for intervention in AD.},
}

@article {pmid40832697,
year = {2025},
author = {Kang, S and Kafetsouli, D and Ford, J and Wong, J and Bracoud, L and Suhy, J and Giannakopoulou, P and Udeh-Momoh, C and Russ, TC and Ritchie, C and Alexopoulou, Z and Salinas, C and Saad, ZS and Novak, G and Robinson, O and Middleton, LT},
title = {Prevalence and risk factors of cerebral microhemorrhages and superficial siderosis in cognitively unimpaired older adults: analysis from the CHARIOT-PRO SubStudy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70594},
doi = {10.1002/alz.70594},
pmid = {40832697},
issn = {1552-5279},
support = {//Janssen Research & Development, LLC, a Johnson & Johnson company/ ; NIHR200180//NIHR ARC Dementia Fellowship/ ; MR/S03532X/1//UKRI Future Leaders Fellowship/ ; MR/Y02012X/1//UKRI Future Leaders Fellowship/ ; //Takeda/ ; //Merck/ ; //Gates Ventures/ ; },
mesh = {Humans ; Aged ; Female ; Male ; Risk Factors ; Cross-Sectional Studies ; Aged, 80 and over ; *Cerebral Hemorrhage/epidemiology/diagnostic imaging ; Prevalence ; Middle Aged ; Apolipoprotein E4/genetics ; *Siderosis/epidemiology ; Magnetic Resonance Imaging ; Amyloid beta-Peptides/metabolism ; Prospective Studies ; },
abstract = {INTRODUCTION: Cerebral microhemorrhages (CMHs) and superficial siderosis (SS) are relatively common side effects of anti-amyloid immunotherapies, termed amyloid-related imaging abnormalities (ARIA-H). They are also observed in treatment-naïve older adults. This study explored relationships with modifiable and non-modifiable risk factors.

METHODS: This cross-sectional study included 1414 cognitively unimpaired, treatment-naïve individuals aged 60 to 85 years from the Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy. Relationships between CMHs/SS and cardiovascular risk factors, amyloid beta (Aβ) load, apolipoprotein E (APOE) ε4 status, educational attainment, and white matter hyperintensities were investigated using regression analyses and structural equation modeling.

RESULTS: CMHs were observed in 8.3% of participants and SS in 1.3%. Significant risk factors for CMHs included age and hypertension. Higher education attainment appeared to have a protective effect. Elevated amyloid is a risk factor, particularly when adjusting for APOE ε4 status in individuals aged 70 or younger.

DISCUSSION: Increasing age and hypertension are significant risk factors of CMHs. Higher educational attainment may offer a protective effect.

HIGHLIGHTS: Of the 1414 participants from the CHARIOT-PRO SubStudy (CPSS), CMHs were present in 118 (8.3%), and SS was present in 18 (1.3%). Age and hypertension were identified as significant risk factors for CMHs, and the latter had a stronger association with the presence of CMHs among female participants. Having a bachelor's degree or higher was found to be protective. Elevated brain amyloid burden, particularly when adjusted for APOE ε4 carrier status, was identified as a risk factor in individuals aged 70 years and below.},
}

Humans
Aged
Female
Male
Risk Factors
Cross-Sectional Studies
Aged, 80 and over
*Cerebral Hemorrhage/epidemiology/diagnostic imaging
Prevalence
Middle Aged
Apolipoprotein E4/genetics
*Siderosis/epidemiology
Magnetic Resonance Imaging
Amyloid beta-Peptides/metabolism
Prospective Studies

@article {pmid40832432,
year = {2025},
author = {, and Boquet-Pujadas, A and Anagnostakis, F and Yang, Z and Tian, YE and Duggan, MR and Erus, G and Srinivasan, D and Joynes, CM and Bai, W and Patel, PJ and Walker, KA and Zalesky, A and Davatzikos, C and Wen, J},
title = {Multi-organ AI Endophenotypes Chart the Heterogeneity of Pan-disease in the Brain, Eye, and Heart.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.09.25333350},
pmid = {40832432},
abstract = {Disease heterogeneity and commonality pose significant challenges to precision medicine, as traditional approaches frequently focus on single disease entities and overlook shared mechanisms across conditions [1] . Inspired by pan-cancer [2] and multi-organ research [3] , we introduce the concept of "pan-disease" to investigate the heterogeneity and shared etiology in brain, eye, and heart diseases. Leveraging individual-level data from 129,340 participants, as well as summary-level data from the MULTI consortium, we applied a weakly-supervised deep learning model (Surreal-GAN [4,5]) to multi-organ imaging, genetic, proteomic, and RNA-seq data, identifying 11 AI-derived biomarkers - called Multi-organ AI Endophenotypes (MAEs) - for the brain (Brain 1-6), eye (Eye 1-3), and heart (Heart 1-2), respectively. We found Brain 3 to be a risk factor for Alzheimer's disease (AD) progression and mortality, whereas Brain 5 was protective against AD progression. Crucially, in data from an anti-amyloid AD drug (solanezumab [6]), heterogeneity in cognitive decline trajectories was observed across treatment groups. At week 240, patients with lower brain 1-3 expression had slower cognitive decline, whereas patients with higher expression had faster cognitive decline. A multi-layer causal pathway pinpointed Brain 1 as a mediational endophenotype [7] linking the FLRT2 protein to migraine, exemplifying novel therapeutic targets and pathways. Additionally, genes associated with Eye 1 and Eye 3 were enriched in cancer drug-related gene sets with causal links to specific cancer types and proteins. Finally, Heart 1 and Heart 2 had the highest mortality risk and unique medication history profiles, with Heart 1 showing favorable responses to antihypertensive medications and Heart 2 to digoxin treatment. The 11 MAEs provide novel AI dimensional representations for precision medicine and highlight the potential of AI-driven patient stratification for disease risk monitoring, clinical trials, and drug discovery.},
}

@article {pmid40832393,
year = {2025},
author = {Cohen, BM and Koh, E and Levental, KR and Levental, I and Sonntag, KC},
title = {Specific Lipid Abnormalities Are Inherently Associated with Late-Onset Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.08.25333304},
pmid = {40832393},
abstract = {INTRODUCTION: Lipid abnormalities have been observed in brain, CSF, and blood in association with late-onset Alzheimer's disease (LOAD). It is unknown which abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived neural lines.

METHODS: iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Lipidomics analyses were performed on whole cell and mitochondrial extracts.

RESULTS: Large reductions in cholesterol esters (CE) and imbalances in fatty acids (FA) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids.

DISCUSSION: The findings identify abnormalities in CE and FA as likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD.},
}

@article {pmid40832216,
year = {2025},
author = {Bartlett, MJ and Erickson, RP and Frye, J and Doyle, KP and Pires, PW and Witte, MH},
title = {Manual lymph drainage massage of the head and neck improves cognition and reduces pathological biomarkers in the 5x-FAD mouse model of Alzheimers disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.08.669361},
pmid = {40832216},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) affects 6.9 million people over the age of 65 in the US and is expected to double by 2060. While FDA approved immunotherapies slow cognitive decline in some individuals with AD, they do not improve cognition, are costly, and have significant side-effects. Therefore, new targets, approaches, and treatments for AD are a necessity. There are no FDA approved therapies for AD that target the brain's lymphatic system. It is well established that the toxic protein, amyloid-beta (Aβ), accumulates in the AD brain. Recent studies have shown that Aβ is cleared via interstitial fluid and cerebrospinal fluid through a pathway involving the glymphatic system-meningeal lymphatic vessels-leading to deep and superficial cervical lymphatic vessels and nodes. Therefore, any blockage along this route can cause inefficient drainage and result in pathological buildup of Aβ, which can lead to AD. Here, we propose a new approach to treating AD by manual lymph drainage (MLD), which is a light skin massage traditionally used to reduce fluid accumulation in lymphedema. This therapy has also been demonstrated to be safe in individuals with AD, but its effects on cognition and biomarkers of AD has never been investigated. In this study we demonstrate that repeated MLD of the head and neck, including the superficial cervical lymphatic vessels (scLVs), improves cognitive function in AD as measured in both the Y-maze and nest-building tests. We also show that this coincides with a reduction in plasma levels of neurofilament light chain (NfL), a non-specific biomarker for neuronal cell death and axonal damage. MLD was also shown to reduce Aβ in the hippocampus of these mice. Combined, this data provides compelling proof-of-principle evidence for the potential of MLD as a standalone or adjunct therapy in the treatment of AD.},
}

@article {pmid40832110,
year = {2025},
author = {Androni, X and Boyd, RJ and Rosenberg, PB and Mahairaki, V},
title = {Psychedelics meet human brain organoids: insights into proteomics and potential for Alzheimer's disease treatment.},
journal = {Frontiers in dementia},
volume = {4},
number = {},
pages = {1605051},
pmid = {40832110},
issn = {2813-3919},
abstract = {Alzheimer's disease (AD) is characterized by a long preclinical phase lasting more than a decade before the onset of its clinical phase of mild cognitive impairment (MCI) or dementia. Recent advances in psychedelic research underscore numerous neuroplastogenic and anti-inflammatory alterations induced by these compounds, making them promising therapeutic candidates for AD. In this mini review, we will briefly summarize the existing literature using human cerebral organoids to study the molecular and metabolic changes caused by various psychedelic compounds, focusing on their potential therapeutic applications for AD.},
}

@article {pmid40831271,
year = {2025},
author = {Takakuwa, M and Izuo, N and Chino, K and Yano, Y and Yokose, J and Shigetsura, Y and Nitta, A},
title = {Construction of Shati/Nat8l Plasmid Vectors, and Analysis of Mitochondrial Function Mediated by Shati/Nat8l Against Amyloid β Toxicity.},
journal = {Neuropsychopharmacology reports},
volume = {45},
number = {3},
pages = {e70041},
doi = {10.1002/npr2.70041},
pmid = {40831271},
issn = {2574-173X},
support = {AdAMS JP22H04922//Japan Society for the Promotion of Science/ ; JP21H02632//Japan Society for the Promotion of Science/ ; JPMJSP2145//Japan Science and Technology SPRING/ ; //Tamura Science and Technology Foundation/ ; //Smoking Research Foundation/ ; //Kobayashi Foundation/ ; },
mesh = {*Amyloid beta-Peptides/toxicity ; Animals ; *Mitochondria/metabolism/drug effects ; Mice ; Plasmids/genetics ; Genetic Vectors ; Humans ; Cell Line, Tumor ; Membrane Potential, Mitochondrial/drug effects ; Peptide Fragments/toxicity ; },
abstract = {In Alzheimer's disease (AD), the accumulation of senile plaques composed of neurotoxic amyloid β (Aβ) is known to be one of the causes. Shati/Nat8l, a gene related to neuropsychiatric disorders, encodes an enzyme that biosynthesizes N-acetyl aspartate (NAA) from aspartate and acetyl CoA. Studies on AD patients and model mice show that NAA and Shati/Nat8l are associated with AD pathology. We previously demonstrated that hippocampal overexpression of Shati/Nat8l in 5xFAD mice, an AD model, improved cognitive suppress without altering the number or size of Aβ plaques. To investigate the cellular mechanisms underlying the neuroprotective effects of Shati/Nat8l on Aβ neurotoxicity, we constructed a vector containing the full-length Shati/Nat8l sequence and transfected it into Neuro-2a cells to produce a stably Shati/Nat8l-overexpressing cell line (N2A-Shati). N2A-Shati cells expressed threefold higher Shati/Nat8l mRNA levels compared with a control cell line (N2A-Control). Treatment with Aβ for 48 h reduced the viability of N2A-Shati and N2A-Control cells at concentrations ≧ 0.03 μM compared to their own vehicle. Exposure to 0.03 μM Aβ for 24 h did not induce any detectable changes in mitochondrial mass or mitochondrial membrane potential in either N2A-Control or N2A-Shati cells. However, N2A-Shati cells demonstrated reduced pyruvate dehydrogenase kinase 1 (Pdk1) mRNA expression and enhanced nuclear respiratory factor 1 (Nrf1) and mitochondrial transcription factor A (Tfam) mRNA expression levels. These results suggest that, although Shati/Nat8l does not significantly affect cell viability, mitochondrial mass, or membrane potential, it could modulate specific intracellular pathways.},
}

*Amyloid beta-Peptides/toxicity
Animals
*Mitochondria/metabolism/drug effects
Mice
Plasmids/genetics
Genetic Vectors
Humans
Cell Line, Tumor
Membrane Potential, Mitochondrial/drug effects
Peptide Fragments/toxicity

@article {pmid40831183,
year = {2025},
author = {Sampath, R and Baskar, M},
title = {Biomarker extraction-based Alzheimer's disease stage detection using optimized deep learning approach.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251360394},
doi = {10.1177/13872877251360394},
pmid = {40831183},
issn = {1875-8908},
abstract = {BackgroundCognitive decline and memory loss in Alzheimer's disease (AD) progresses over time. Early diagnosis is crucial for initiating treatment that can slow progression and preserve daily functioning. However, challenges such as overfitting in prediction models, underutilized biomarker features, and noisy imaging data hinder the accuracy of current detection methods.ObjectiveThis study proposes a novel deep learning-based framework aimed at improving the identification of AD stages while addressing the limitations of existing diagnostic techniques.MethodsStructural MRI scans are employed as the primary diagnostic tool. To enhance image quality, contrast-limited adaptive histogram equalization and wavelet soft thresholding are applied for noise reduction. Biomarker segmentation focuses on ventricular and hippocampal abnormalities, optimized using a firefly algorithm. Dimensionality reduction is performed via Linear Discriminant Analysis to minimize overfitting. Finally, a Deep Belief Network optimized using the Cuckoo Search algorithm is employed for classification and feature learning.ResultsThe proposed framework demonstrates improved performance over existing methods, achieving a 0.66% increase in accuracy and a 0.0345% decrease in error rate for AD stage detection.ConclusionsThis deep learning strategy shows promise as an effective tool for early and accurate AD stage identification. Enhanced segmentation, dimensionality reduction, and classification contribute to its improved performance, offering a meaningful advancement in AD diagnostics.},
}

@article {pmid40830489,
year = {2025},
author = {de Weerd, L and Hummel, S and Müller, SA and Paris, I and Sandmann, T and Eichholtz, M and Gröger, R and Englert, AL and Wagner, S and Ha, C and Davis, SS and Warkins, V and Xia, D and Nuscher, B and Berghofer, A and Reich, M and Feiten, AF and Schlepckow, K and Willem, M and Lichtenthaler, SF and Lewcock, JW and Monroe, KM and Brendel, M and Haass, C},
title = {Early intervention anti-Aβ immunotherapy attenuates microglial activation without inducing exhaustion at residual plaques.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {92},
pmid = {40830489},
issn = {1750-1326},
mesh = {Animals ; *Microglia/metabolism/drug effects/immunology ; Mice ; *Plaque, Amyloid/pathology/metabolism/immunology ; *Amyloid beta-Peptides/immunology/metabolism/antagonists & inhibitors ; *Immunotherapy/methods ; *Alzheimer Disease/pathology/metabolism/immunology ; Mice, Transgenic ; Disease Models, Animal ; },
abstract = {Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer's disease. Efficient amyloid clearance has been proven in clinical trials testing anti-Aβ antibodies, by their impact on cognitive endpoints correlating with the extent of amyloid removal. However, treatment is associated with adverse side effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-Aβ antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-Aβ treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model with an intervention paradigm early during amyloidogenesis. Long-term treatment with anti-Aβ results in a robust and dose-dependent lowering of amyloid plaque pathology, with a higher efficiency for reducing diffuse over dense-core plaque deposition. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and α-Synuclein, as well as immune-cell-related proteins. Bulk RNA-seq revealed a dose-dependent attenuation of disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around residual plaques remains high, regardless of treatment dose. In addition, microglia surrounding residual plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen-presenting and immune signalling proteins. These findings demonstrate that chronic early intervention by an anti-amyloid immunotherapy leads to a dose-dependent decrease in plaque formation, which is associated with lower brain-wide microglial DAM activation and neurodegeneration. Microglia at residual plaques still display a combined DAM and antigen-presenting phenotype that suggests a continued treatment response.},
}

Animals
*Microglia/metabolism/drug effects/immunology
Mice
*Plaque, Amyloid/pathology/metabolism/immunology
*Amyloid beta-Peptides/immunology/metabolism/antagonists & inhibitors
*Immunotherapy/methods
*Alzheimer Disease/pathology/metabolism/immunology
Mice, Transgenic
Disease Models, Animal

@article {pmid40829311,
year = {2025},
author = {Park, S and Park, M and Lee, HJ},
title = {Ginkgolide A enhances cognition and reduces amyloid-β by activating autophagy in the murine 5xFAD Alzheimer's disease model.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {191},
number = {},
pages = {118472},
doi = {10.1016/j.biopha.2025.118472},
pmid = {40829311},
issn = {1950-6007},
abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder closely associated with impaired autophagy. Ginkgolide A (GA), a principal bioactive constituent of Ginkgo biloba, has garnered attention for its antioxidant, anti-inflammatory, and autophagy-modulating properties.

MAIN TEXT: To evaluate the therapeutic potential of GA, we administered oral GA (20 mg/kg/day) for four weeks to 5xFAD transgenic mice. GA treatment significantly reduced soluble and insoluble forms of amyloid-β (Aβ) in the cortex and hippocampus, and markedly decreased Aβ plaque deposition. Cognitive performance was improved, as evidenced by increased spontaneous alternation in the Y-maze test. GA enhanced synaptic plasticity, indicated by increased expression of the synaptic markers synaptophysin 11 (SP11) and postsynaptic density 95 (PSD95). At the molecular level, GA activated autophagy by modulating PI3K-Akt signaling, relieving endoplasmic reticulum (ER) stress, and enhancing energy stress responses, ultimately leading to mTOR pathway suppression.

CONCLUSION: These findings demonstrate that GA is a promising multifunctional therapeutic candidate for AD. Its ability to regulate autophagy and related signaling pathways provides new insights into disease mitigation and cognitive improvement.},
}

@article {pmid40829243,
year = {2025},
author = {Liu, Z and Huang, X and Zhang, M and Quan, YS and Wang, YL and Liu, JY and Nie, WZ and Zhao, YQ and Guo, HY and Quan, ZS and Li, G and Shen, QK},
title = {Discovery of oleanolic acid derivatives that inhibit tau protein phosphorylation and neuroinflammation induced by Aβ25-35 in vitro and in vivo.},
journal = {Bioorganic chemistry},
volume = {164},
number = {},
pages = {108866},
doi = {10.1016/j.bioorg.2025.108866},
pmid = {40829243},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder. The primary pathological features of AD are the abnormal deposition of extracellular β-amyloid (Aβ) protein and hyperphosphorylated microtubule-associated protein tau. Excessive Aβ aggregation triggers neuroinflammation. Oleanolic acid (OA) has significant neuroprotective and anti-inflammatory effects. In this study, we designed and synthesized 35 OA derivatives for the treatment of AD, targeting Aβ and hyperphosphorylated tau. The results showed that compound B1, an OA derivative with a tetrazole, had the strongest activity against Aβ25-35-induced cytotoxicity (EC50 = 1.93 ± 0.76 μM), approximately 14.75-fold more potent than OA and could penetrate the BBB. Intracerebroventricular injection of Aβ25-35 to establish an AD-like mouse model, the histopathological results showed that B1 relieved nerve damage, and Morris water maze results showed that B1 improved learning and memory. Mechanistically, B1 reversed the hyperphosphorylation of tau, significantly inhibited the expression of certain immune-related cytotoxic factors, suppressed the MAPK and NF-κB signaling pathways, and significantly inhibited the expression of RAGE and the apoptosis factors Bax/Bcl-2, both in vitro and in vivo. In conclusion, B1 regulates neuroinflammatory mediators in response to Aβ and reverses the hyperphosphorylation of tau, and is a promising multifunctional compound for treating AD.},
}

@article {pmid40827126,
year = {2025},
author = {Price, BR and Walker, KA and Eissman, JM and Suryadevara, V and Sime, LN and Hohman, TJ and Gordon, MN},
title = {Sex differences and the role of estrogens in the immunological underpinnings of Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {3},
pages = {e70139},
pmid = {40827126},
issn = {2352-8737},
abstract = {UNLABELLED: Alzheimer's disease (AD) affects women more frequently and more severely than men, but the biological mechanisms underlying these sex differences remain poorly understood. This review integrates recent findings from neuroscience, immunology, endocrinology, and genetics to explore how sex steroid hormones, particularly estrogen, shape neuroimmune responses and influence AD risk. We highlight the pivotal roles of microglia and astrocytes, whose inflammatory and neuroprotective actions are modulated by hormonal fluctuations across the female lifespan, including pregnancy, menopause, and menopausal hormone replacement therapy. Key genetic risk factors, such as apolipoprotein E ε4, show sex-specific effects on glial activation, tau pathology, and cognitive decline. Furthermore, life-stage transitions, especially menopause, intersect with changes in brain metabolism, immune signaling, and epigenetic regulation, increasing susceptibility to neurodegeneration in women. We propose a framework for sex-aware, personalized approaches to AD prevention and treatment. By integrating hormone-immune interactions with genetic and glial biology, this review emphasizes the critical need for sex-specific models in AD research.

HIGHLIGHTS: Women develop greater tauopathy, with more cognitive and clinical consequences in Alzheimer's disease (AD).Glial activation is adapted by estrogens to shape vulnerability or resilience to AD.Sex differences in innate and adaptive immunity could contribute to AD progression.Effects of menopausal hormone therapy on immunity in AD remain understudied.Future studies to explore sex differences in immune function during AD are needed.},
}

@article {pmid40826719,
year = {2025},
author = {Ma, W and Yuan, X and Liu, Y and Wang, Q and Zhang, Y and Dong, P and Zhou, C},
title = {Immune regulatory mechanisms of different exercise methods promoting Parkinson's rehabilitation: A narrative review.},
journal = {Medicine},
volume = {104},
number = {33},
pages = {e44035},
doi = {10.1097/MD.0000000000044035},
pmid = {40826719},
issn = {1536-5964},
support = {YDZX2022091//the central government guides local Sci-tech development funds/ ; ZR2021QH070//the Natural Scientific Foundation of Shandong Province, China/ ; },
abstract = {Parkinson disease (PD) is the second largest and most common neurodegenerative disease globally, following Alzheimer disease. Its pathological features include the deformation and loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, as well as the aggregation of α-synuclein in the form of Lewy bodies. This leads to motor symptoms such as resting tremors, muscle rigidity, bradykinesia, and postural instability, as well as non-motor symptoms including cognitive, emotional, and sleep disorders. Currently, PD is mainly treated by medication and surgery. Medication, though widely used, has limited efficacy and causes adverse reactions. With the intensification of global aging and the annual increase in the incidence of PD, the limitations of existing treatment approaches have become increasingly prominent, and there is an urgent need to explore safer and more effective treatment strategies. Numerous clinical studies have demonstrated that exercise rehabilitation training can not only effectively ameliorate the motor and non-motor symptoms of PD patients, but also promote the generation of neurotrophic factors, neurotransmitters, and hormones, and regulate the dopaminergic system. Therefore, an in-depth exploration of the mechanisms and effects of different exercise rehabilitation training methods in the treatment of PD holds great significance for refining the comprehensive treatment plan for PD and enhancing the quality of life of patients. This article will conduct a comprehensive review of the mechanisms and effects of various exercise rehabilitation training methods in treating PD.},
}

@article {pmid40810748,
year = {2025},
author = {Nabizadeh, A and Rafati, A and Karbalaei, N and Namavar, MR and Hosseinzadeh, S and Moatamed Jahromi, H and Rahimi, A and Naseh, M},
title = {Probiotic effects on cognitive performance, hippocampal oxidative stress, and structural damage induced by icv STZ in Alzheimer-like rat model.},
journal = {Brain structure & function},
volume = {230},
number = {7},
pages = {135},
pmid = {40810748},
issn = {1863-2661},
abstract = {Alzheimer's disease (AD) is a deteriorating neurodegenerative disorder defined by cognitive decline and neuronal damage, with oxidative stress and neuroinflammation as central pathological features. Emerging evidence suggests the gut-brain axis is a key modulator in neurodegeneration, highlighting probiotics' potential in mitigating AD progression. This study investigates the effects of Lactobacillus acidophilus ATCC4356, Lactobacillus reuteri DSM 17938, and their combination on cognitive performance, oxidative stress, and hippocampal structure in a streptozotocin (STZ)-induced AD-like rat model. Thirty-Five male Sprague-Dawley rats were randomly assigned to five groups: Sham, AD-like model (STZ), STZ + Ac, STZ + Re, and STZ + Comb. The AD-like model was induced via intracerebroventricular (icv) injection of STZ. Probiotics were administered by gavage for 35 days. Behavioral assessments, including the open field test and Morris water maze, were conducted to evaluate cognitive and anxiety-like behaviors. Hippocampal oxidative stress markers, including malondialdehyde (MDA), glutathione, superoxide dismutase, and catalase , were analyzed biochemically. Additionally, stereological techniques were used to assess hippocampal volume and cellular densities. Behavioral results demonstrated significant improvement in anxiety-like behavior and spatial memory in probiotic-treated groups compared to the STZ group. Biochemical analysis revealed reduced MDA levels and enhanced antioxidant markers following probiotic intervention. Histological and stereological analyses indicated increased neuronal density and reduced glial cell activation in hippocampal subregions (CA1, CA3, DG), though hippocampal volume loss remained unaltered. These findings underscore the neuroprotective potential of probiotics in alleviating AD-related neurodegeneration, possibly through antioxidative and anti-inflammatory mechanisms. Further pre-clinical studies are warranted to optimize probiotic regimens for AD prevention and treatment.},
}

@article {pmid40807232,
year = {2025},
author = {Chávez-Castillo, M and Gotera, MP and Duran, P and Díaz, MP and Nava, M and Cano, C and Díaz-Camargo, E and Cano, G and Cano, R and Rivera-Porras, D and Bermúdez, V},
title = {Neuroprotective Role of Omega-3 Fatty Acids: Fighting Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {15},
pages = {},
pmid = {40807232},
issn = {1420-3049},
abstract = {Alzheimer's disease (AD) is one of the main causes of dementia, with an exponential increment in its incidence as years go by. However, since pathophysiological mechanisms are complex and multifactorial, therapeutic strategies remain inconclusive and only provide symptomatic relief to patients. In order to solve this problem, new strategies have been investigated over recent years for AD treatment. This field has been reborn due to epidemiological and preclinical findings that demonstrate the fact that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) can be promising therapeutic agents because of their anti-inflammatory, antioxidant, and neurogenic-promoting activities, thus allowing us to classify these molecules as neuroprotectors. Similarly, ω-3 PUFAs perform important actions in the formation of characteristic AD lesions, amyloid-β plaques (Aβ) and neurofibrillary tangles, reducing the development of these structures. Altogether, the aforementioned actions hinder cognitive decline and possibly reduce AD development. In addition, ω-3 PUFAs modulate the inflammatory response by inhibiting the production of pro-inflammatory molecules and promoting the synthesis of specialised pro-resolving mediators. Consequently, the present review assesses the mechanisms by which ω-3 PUFAs can act as therapeutic molecules and the effectiveness of their use in patients. Clinical evidence so far has shown promising results on ω-3 PUFA effects, both in animal and epidemiological studies, but remains contradictory in clinical trials. More research on these molecules and their neuroprotective effects in AD is needed, as well as the establishment of future guidelines to obtain more reproducible results on this matter.},
}

@article {pmid40794901,
year = {2025},
author = {Tavakoli, E and Niciforos, E and Amid, P and Cuperfain, AB and Burhan, AM and Colman, S and Chu, L and Davies, SJC and Derkach, P and Gerretsen, P and Graff-Guerrero, A and Hussain, M and Ismail, Z and Kim, D and Krisman, L and Mulsant, BH and Pollock, BG and Rej, S and Rostas, A and Rajji, TK and Van Bussel, L and Kumar, S and Elmi, S},
title = {The impact of lifetime excessive alcohol use on behavioural and psychological symptoms of dementia.},
journal = {Alcohol and alcoholism (Oxford, Oxfordshire)},
volume = {60},
number = {5},
pages = {},
doi = {10.1093/alcalc/agaf048},
pmid = {40794901},
issn = {1464-3502},
support = {//The Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN)/ ; //Brain Canada Foundation/ ; //Centre for Aging and Brain Health Innovation/ ; },
mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Alcoholism/psychology/epidemiology/complications ; Alzheimer Disease/psychology ; Cross-Sectional Studies ; *Dementia/psychology/epidemiology ; Randomized Controlled Trials as Topic ; },
abstract = {INTRODUCTION: Excessive alcohol use (EAU) elevates the risk of dementia through various mechanisms, yet its impact on the behavioural and psychological symptoms of dementia (BPSDs) remains uncertain.

METHODS: In this exploratory cross-sectional analysis of baseline data from the Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov/NCT03672201), we included individuals with Alzheimer's disease and related dementias requiring BPSD treatment. We compared demographic characteristics and presentation of BPSDs (using the total and domain scores on the Neuropsychiatric Inventory-Clinician) in those with and without a lifetime history of EAU.

RESULTS: Among 193 participants [mean (SD) age: 80.6 (9.7) years, male: 48.4%], those in the EAU group (n = 17) and in the comparator group (n = 176) had severe and comparable cognitive impairment, with a median Functional Assessment Staging Tool for Dementia score of 6e. Participants with EAU were significantly younger than comparators [mean age (SD): 72.9 (7.1) years vs. 81.4 (9.5) years] (t = -3.678, df = 181, P < .001), and were more frequently male (76.5% [13 of 17] vs. 46.6% [82 of 176]; P = .036). In a sensitivity analysis, there were no differences in the Neuropsychiatric Inventory-Clinician total or individual domain scores between those with EAU and a subsample of those without EAU matched for age, sex, and recruitment site.

CONCLUSION: This exploratory study found that among individuals with Alzheimer's disease and related dementias and BPSDs, lifetime history of EAU is more frequent in younger males. Future studies may further examine the impact of EAU in individuals with BPSDs.},
}

Aged
Aged, 80 and over
Female
Humans
Male
*Alcoholism/psychology/epidemiology/complications
Alzheimer Disease/psychology
Cross-Sectional Studies
*Dementia/psychology/epidemiology
Randomized Controlled Trials as Topic

@article {pmid40786362,
year = {2025},
author = {Chowdhury, A and Bhasin, G and Ganti, L},
title = {Bibliometric Analysis of the Epidemiological Research on Alzheimer's Disease Treatment.},
journal = {Cureus},
volume = {17},
number = {7},
pages = {e87484},
pmid = {40786362},
issn = {2168-8184},
abstract = {Alzheimer's disease presents a complex global health issue. It is characterized by a decline in cognitive function, starting with memory impairment, and extending to impact reasoning, language abilities, and spatial awareness. Despite decades of research, Alzheimer's disease remains a global challenge lacking long-term treatments. Institutions like the Karolinska Institutet, Columbia University, the University of California San Francisco (UCSF), and the University of Pittsburgh contribute significantly to Alzheimer's research, with a growth in publications in 2022 post-COVID-19. While current treatments offer symptomatic relief, there's a need for disease-modifying therapies targeting its mechanisms. This analysis aims to provide a comprehensive overview of the available research and medical literature on Alzheimer's disease by employing bibliometric methods to identify publication trends, leading research institutions, and the evolving focus from symptomatic treatments to disease-modifying therapies. This paper seeks to analyze the research papers on Alzheimer's disease and catalog the metadata associated with each paper.},
}

@article {pmid40784411,
year = {2025},
author = {Yang, J and Chen, Y and Dong, G and Ma, Y and Lin, R and Yuan, Y},
title = {Immune-metabolic perspective on the association of seven psychiatric disorders and five common auditory diseases: a bidirectional two-sample Mendelian randomization study and mediation analysis.},
journal = {Journal of affective disorders},
volume = {391},
number = {},
pages = {120044},
doi = {10.1016/j.jad.2025.120044},
pmid = {40784411},
issn = {1573-2517},
abstract = {INTRODUCTION: Although the relationship between psychiatric disorders and common auditory diseases has been discovered in observational studies, the causal linkage between them remains inconclusive.

METHODS: The bidirectional two-sample Mendelian randomization (MR) analysis was performed, drawing on the most recent and expansive genome-wide association studies (GWAS) data for seven psychiatric disorders and five common auditory diseases. Additionally, a mediation analysis was conducted using data on 731 immune cell phenotypes and 1400 metabolite levels to explore potential mediating factors influencing the causal pathways.

RESULTS: Autism Spectrum Disorder (ASD) could increase the risk of presbycusis (odds ratio [OR] = 1.161 [95 % confidence interval (CI), 1.042-1.295], P-value = 0.007) through CD25 on CD45RA- CD4 not regulatory T cell (Mediation effect β = 0.017), and Major Depressive Disorder (MDD) could increase the risk of vertigo (OR = 1.215 [95 % CI, 1.043-1.415], P-value = 0.012) through CD33+ HLA DR+ CD14dim Absolute Count (Mediation effect β = 0.007). Alzheimer's Disease (AD) could reduce the risk of presbycusis through four metabolite levels related to lipid metabolism. And Bipolar Disorder I (BD I) could reduce the risk of vertigo, as well as sudden sensorineural hearing loss (SSNHL) could reduce the risk of Post Traumatic Stress Disorder (PTSD).

CONCLUSION: This study underscores the intricate causal links between psychiatric disorders and auditory diseases. Mediation analyses indicate that immune cells are facilitators of positive effects, while metabolite levels play a protective role. These insights offer potential pathways for more effective clinical diagnosis and treatment.},
}

@article {pmid40709598,
year = {2025},
author = {Kaur, G and Mankoo, OK and Kaur, A and Mann, S and Priyadarshi, N and Singh, PP and Goyal, B and Singhal, NK and Goyal, D},
title = {The Synergistic Potential of Rationally Designed Phenol-Triazole Derivatives to Attenuate Aβ/Cu[2+]-Aβ Aggregation and Reactive Oxygen Species.},
journal = {ACS chemical neuroscience},
volume = {16},
number = {15},
pages = {3020-3037},
doi = {10.1021/acschemneuro.5c00386},
pmid = {40709598},
issn = {1948-7193},
mesh = {*Amyloid beta-Peptides/metabolism ; *Reactive Oxygen Species/metabolism ; Animals ; *Copper/metabolism ; Rats ; PC12 Cells ; *Peptide Fragments/metabolism ; *Triazoles/pharmacology/chemistry ; Chelating Agents/pharmacology ; Clioquinol/pharmacology/chemistry ; Protein Aggregates/drug effects ; Phenols/pharmacology/chemistry ; Protein Aggregation, Pathological/metabolism/drug therapy ; },
abstract = {Alzheimer's disease (AD) is a neurological disorder characterized by a spectrum of symptoms such as memory loss and cognitive decline. AD is a multifaceted disease, and designing multipotent ligands is an effective strategy for AD treatment. In this regard, the pharmacophore moiety of clioquinol (CQ, metal chelator) was employed to design the multifunctional phenol-triazole derivatives 4(a-p). In particular, 4k with an o-I group on the phenyl ring displayed a noteworthy higher inhibition (inhibition efficiency 4k = 90.5%, IC50 = 6.51 ± 0.01 μM) against Aβ42 aggregation as compared to 38.1% noted for CQ. Furthermore, 4k significantly disassembled the preformed Aβ42 fibrils (Aβf, 92.5%), chelated Cu[2+] ions, and inhibited Cu[2+]-mediated Aβ42 aggregation. Compound 4k ceases the production of reactive oxygen species (ROS) as it acts as an antioxidant due to the presence of a phenolic hydroxyl group. Compound 4k has a sufficient safety-efficacy profile and alleviates the cytotoxicity by Aβ42 aggregates in PC-12 cells. For studying the modulation in the fibrillary architecture, hydrodynamic size, and structural transition of Aβ42 in the presence of 4k, we resorted to transmission electron microscopy (TEM), dynamic light scattering (DLS), and circular dichroism (CD), respectively. The molecular dynamics (MD) simulations depicted a notable reduction in the conformational transformations in the Aβ42 monomer (Aβm) and Aβf on the incorporation of 4k. Compound 4k modulates Aβ42 fibrillation by maintaining a helix conformation and simultaneously reduces the sampling of β-sheet structures in Aβm, consistent with the CD results. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis depicted a favorable binding of 4k to Aβm (-42.12 ± 7.14 kcal/mol) and Aβf (-74.42 ± 4.98 kcal/mol) with a significant contribution of van der Waals interactions to the binding free energy. The 4k-induced deformation in Aβf chains noted in the conformational snapshots depicts its destabilization potential against Aβf. Finally, our results uncovered the potential of phenol-triazole derivatives as a promiscuous ligand for targeting various pathological conditions in AD. The key insights into the prevention of conformational transitions in Aβm and destabilization of Aβf by 4k illuminated by experimental and computational studies are central to unraveling the molecular understanding of amyloid aggregation as well as designing future therapeutic candidates against multifaceted AD.},
}

*Amyloid beta-Peptides/metabolism
*Reactive Oxygen Species/metabolism
Animals
*Copper/metabolism
Rats
PC12 Cells
*Peptide Fragments/metabolism
*Triazoles/pharmacology/chemistry
Chelating Agents/pharmacology
Clioquinol/pharmacology/chemistry
Protein Aggregates/drug effects
Phenols/pharmacology/chemistry
Protein Aggregation, Pathological/metabolism/drug therapy

@article {pmid40614949,
year = {2025},
author = {Sarkar, SK and Gubert, C and Hannan, AJ},
title = {The microbiota-inflammasome-brain axis as a pathogenic mediator of neurodegenerative disorders.},
journal = {Neuroscience and biobehavioral reviews},
volume = {176},
number = {},
pages = {106276},
doi = {10.1016/j.neubiorev.2025.106276},
pmid = {40614949},
issn = {1873-7528},
abstract = {In various neurodegenerative disorders, inflammation and associated inflammasome activation play an important role. The most prevalent and extensively researched inflammasomes are NLRP3 inflammasomes, which are triggered by pathogens or danger signals mediating inflammatory reaction. Extracellular ATP also activates NLRP3 by stimulating the purinergic receptor P2X7 (P2X7R). Central and peripheral cells, including those in the gut, have been shown to have activated inflammasomes during pathological changes co-occurring with inflammation in various neurodegenerative disorders. Gut injury or dysfunction is increasingly recognised as one of the peripheral pathogenic characteristics of many neurodegenerative disorders, and has been found to associate with changes in gut microbes. In this article, we review data from preclinical and clinical studies regarding the involvement of the NLRP3 inflammasome and the purinergic receptor P2X7R in the pathophysiology of major CNS disorders involving neurodegeneration, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), and the most common form of motor neuron disease, amyotrophic lateral sclerosis (ALS). We also scrutinise the relationship of the NLRP3 inflammasome to intestinal microbiota alterations in these diseases. Both the NLRP3 inflammasome and P2X7R have been shown to play important roles in the pathogenesis and progression of these neurodegenerative diseases. However, most studies have focused on central nervous system (CNS) pathology, particularly within the brain, with comparatively less attention given to their contribution to gut pathology. Additionally, changes in the microbial ecosystems of the intestine have also been implicated in these disorders. However, the association between gut microbiota alterations and inflammasome activity in the pathology of these neurodegenerative disorders remains poorly understood. Therefore, further investigation is urgently needed to explore the microbiota-inflammasome-brain axis in these neurodegenerative conditions, in order to better understand their contribution to disease pathogenesis and progression, and identify novel therapeutic targets and new approaches to prevention and treatment.},
}

@article {pmid40614596,
year = {2025},
author = {Xiong, L and Yu, Q and Chen, L and Deng, Y and Ai, Q and Xu, X and Meng, Z and Chen, F and Zhao, X and Wei, J and Yu, H},
title = {Curcumin analogue C66 ameliorates the pathology of Alzheimer's disease through suppression of JNK signaling pathway.},
journal = {International immunopharmacology},
volume = {162},
number = {},
pages = {115156},
doi = {10.1016/j.intimp.2025.115156},
pmid = {40614596},
issn = {1878-1705},
abstract = {Oxidative stress and neuroinflammation are two key pathological features in the early stage of Alzheimer's disease (AD), and they promote each other to further drive the progression of AD. Therefore, the development of therapeutic agents with dual anti-inflammatory and antioxidant properties represents a promising strategy for AD treatment. C66, a synthetic derivative of curcumin, protected PC12 cells and primary neurons from oxidative damage caused by Aβ. In addition, C66 alleviated Aβ-induced excessive inflammatory response in BV2 cells. Further results showed that C66 reduced neuroinflammation and neuronal apoptosis, ultimately improved cognitive decline in APPswe/PSEN1dE9 (APP/PS1) double transgenic AD mice. Importantly, C66 exhibited superior improved properties in APP/PS1 mice compared with the clinical control drug donepezil. Mechanistically, we indicated that C66 conferred its neuroprotective effects by inhibiting c-Jun N-terminal kinase (JNK) pathway. The result was further confirmed by using SP600125, a specific JNK inhibitor. Together, our findings suggest that C66 is expected to be further developed as a drug candidate for AD therapy.},
}

@article {pmid40498572,
year = {2025},
author = {Goins, RT and Shi, Y and Corrada, MM and Manson, SM and O'Connell, J and Jiang, L},
title = {Longitudinal associations of depression and diabetes with Alzheimer's disease and related dementias risk among American Indian and Alaska Native peoples.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {80},
number = {8},
pages = {},
pmid = {40498572},
issn = {1758-535X},
support = {/NH/NIH HHS/United States ; R01AG061189/AG/NIA NIH HHS/United States ; NIA P30 AG15297/AG/NIA NIH HHS/United States ; P30DK092923/DK/NIDDK NIH HHS/United States ; U54 MD000507/MD/NIMHD NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) research worldwide indicate that it is more common in Indigenous than in non-Indigenous populations. We examined the relationship of depression and diabetes, alone and together, with incident ADRD in a large sample of American Indian and Alaska Native (AIAN) peoples.

METHODS: We examined a sample of 65,801 AIAN peoples aged ≥ 45 years in fiscal year 2007 who were ADRD-free between FY2007-09. Cox proportional hazard models were employed to estimate associations between ADRD risk and baseline depression and diabetes, adjusting for potential confounding variables.

RESULTS: We found 2.3% received an ADRD diagnosis during FY2010-13. Compared to persons with neither depression nor diabetes, the fully adjusted hazard ratio (HR) for those aged ≥ 45 years with depression and diabetes was 1.82 (95% CI 1.53-2.16) for ADRD and those with depression only had a hazard ratio of 1.70 (95% CI 1.44-2.00). A significant relationship was not found between diabetes only and ADRD risk. Compared with women without depression, the adjusted risk of ADRD was 50% higher (HR = 1.50, 95% CI 1.30-1.73) for women with depression, while 115% higher (HR = 2.15, 95% CI 1.76-2.61) for men with depression.

CONCLUSIONS: Depression is associated with a substantially higher risk of ADRD among adult AIAN peoples. This association varies by sex and age, with the strongest association observed among relatively young men. Helpful future efforts include ensuring clinical and behavioral services for AIAN peoples provide regular mental health screening and any needed treatment.},
}

@article {pmid40420219,
year = {2025},
author = {Talaat, AN and Elnaggar, MS and Ibrahim, N and Ayoub, IM and Abbas, H and El Sayed, N and Labib, RM and Singab, ANB},
title = {Targeted Neuroprotection in Sporadic Alzheimer's Disease: UPLC-ESI-MS/MS Profiling and Bilosome-Mediated Delivery of Crateva magna and Its Endophytic Fungal Extracts.},
journal = {Phytochemical analysis : PCA},
volume = {36},
number = {6},
pages = {1719-1746},
doi = {10.1002/pca.3540},
pmid = {40420219},
issn = {1099-1565},
abstract = {INTRODUCTION: Crateva magna (Cm) was utilized as a folkloric medicine against neurological disorders.

OBJECTIVES: This study aimed to investigate the phytochemical profile of Cm leaf extract and its endophytic fungus, Nigrospora oryzae (No) extract. Additionally, the neuroprotective potential of their optimized bilosomes (BLs) will be assessed as an approach to Alzheimer's disease (AD) treatment.

MATERIALS AND METHODS: UPLC-ESI-MS/MS chemical profiling was performed. In vitro anti-Alzheimer activity of Cm and No extracts was evaluated against AChE and BACE1 enzymes. Cm-BLs and No-BLs were prepared using the thin-film hydration technique. In vivo anti-Alzheimer potential was assessed in a streptozotocin (STZ)-induced sporadic AD mouse model. Behavioral assays, neurochemical assays, RT-PCR analysis, histopathological examination, and immunohistochemical analysis were performed.

RESULTS: Chemical profiling revealed diverse metabolites from various chemical classes. The major class identified in Cm extract was flavonoids, e.g., kaempferol-O-hexoside, whereas in No extract, it was alkaloids, e.g., phenazine carboxamide. The neuropathological markers (Aβ1-42, IL-6, and p-Tau protein) were reduced by ≈50% and 60% in mice receiving Cm-BLs and No-BLs, respectively, relative to the STZ group. Also, the BLs exhibited the greatest ability to downregulate the expression of p-JNK, p-P38, and p-ERK in the brain. Histopathological examination revealed that No-BLs showed the highest protection for the hippocampus and cerebral cortex regions. Also, it revealed a significantly decreased reaction for NFκB in cerebral cortex neurons.

CONCLUSION: Cm-BLs and No-BLs exhibit considerable potential as novel adjuvant therapies for AD, utilizing natural bioactive compounds to improve the efficiency of targeted drug delivery and enhance therapeutic outcomes.},
}

@article {pmid40380033,
year = {2025},
author = {Alqahtani, SM and Al-Kuraishy, HM and Al Gareeb, AI and Albuhadily, AK and Alexiou, A and Papadakis, M and Hemeda, LR and Faheem, SA and El-Saber Batiha, G},
title = {Unlocking Alzheimer's Disease: The Role of BDNF Signaling in Neuropathology and Treatment.},
journal = {Neuromolecular medicine},
volume = {27},
number = {1},
pages = {36},
pmid = {40380033},
issn = {1559-1174},
mesh = {*Alzheimer Disease/drug therapy/pathology/metabolism/physiopathology ; Humans ; *Brain-Derived Neurotrophic Factor/physiology/agonists ; *Signal Transduction/drug effects/physiology ; Receptor, trkB/agonists/physiology ; Animals ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use/pharmacology ; Blood-Brain Barrier/metabolism ; Metformin/therapeutic use/pharmacology ; Neuronal Plasticity/drug effects ; Neurogenesis/drug effects ; Amyloid beta-Peptides ; Molecular Targeted Therapy ; },
abstract = {Alzheimer's disease (AD) remains one of the most debilitating neurodegenerative disorders, with its pathological hallmark being progressive cognitive decline and memory loss. Recent research has illuminated the crucial role of the brain-derived neurotrophic factor (BDNF) in the central nervous system (CNS), highlighting its impact on neurogenesis, synaptic plasticity, and neuronal survival. Dysregulation of the BDNF signaling axis, particularly the imbalance between its precursor form and mature BDNF, is strongly implicated in the pathophysiology of AD. This review explores the molecular mechanisms through which BDNF modulates AD neuropathology and presents novel therapeutic strategies to activate BDNF signaling. We focus on the potential of BDNF activators, such as TrkB agonists and mimetic molecules, to restore synaptic function and ameliorate cognitive deficits in AD. Furthermore, we examine the challenges in translating these findings into clinical practice, including issues with blood-brain barrier penetration and the need for precise receptor targeting. The review emphasizes the therapeutic potential of repurposed drugs, including statins and metformin, in enhancing BDNF signaling and offers new insights into the future of AD treatment. Ultimately, this work provides a compelling argument for BDNF-based therapies as a promising avenue for mitigating the cognitive decline associated with Alzheimer's disease, signaling a hopeful direction for future research and clinical trials.},
}

*Alzheimer Disease/drug therapy/pathology/metabolism/physiopathology
Humans
*Brain-Derived Neurotrophic Factor/physiology/agonists
*Signal Transduction/drug effects/physiology
Receptor, trkB/agonists/physiology
Animals
Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use/pharmacology
Blood-Brain Barrier/metabolism
Metformin/therapeutic use/pharmacology
Neuronal Plasticity/drug effects
Neurogenesis/drug effects
Amyloid beta-Peptides
Molecular Targeted Therapy

@article {pmid40320783,
year = {2025},
author = {Blostein, F and Bakulski, KM and Fu, M and Wang, H and Zawistowski, M and Ware, EB},
title = {DNA methylation age acceleration is associated with incident cognitive impairment in the health and retirement study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {105},
number = {3},
pages = {966-976},
doi = {10.1177/13872877251333707},
pmid = {40320783},
issn = {1875-8908},
support = {R01 AG067592/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *DNA Methylation ; Female ; Male ; Aged ; *Cognitive Dysfunction/genetics/epidemiology ; Longitudinal Studies ; Middle Aged ; *Aging/genetics ; Aged, 80 and over ; United States/epidemiology ; Incidence ; },
abstract = {BackgroundDNA methylation clocks have emerged as promising biomarkers for cognitive impairment and dementia. Longitudinal studies exploring the association between DNA methylation clocks and cognitive decline have been constrained by limited sample sizes and a lack of diversity.ObjectiveOur study aimed to investigate associations between DNA methylation clocks and incident cognitive impairment using a larger and US nationally-representative sample from the Health and Retirement Study.MethodsWe measured DNA methylation age acceleration in 2016 by regressing the DNA methylation clocks, including GrimAge, against chronological age. Cognitive change over time was determined by Langa-Weir cognition status from 2016 to 2018. Multivariable logistic regression evaluated the association between DNA methylation age acceleration and cognitive change, adjusting for cell-type proportions, demographic, and health factors. We also applied inverse probability weighting to address potential selection bias from varying loss-to-follow-up rates.ResultsThe analytic sample (N = 2713) was 54% female, 8.4% Black/African American, 86% White, 7.5% Hispanic, and 68 years old at baseline. During the two years of follow-up, 12% experienced cognitive change and had higher baseline GrimAge (mean = 1.2 years) acceleration compared to those maintaining normal cognition (mean = -0.8 years). A one-year increase in GrimAge acceleration was associated with 1.05 times higher adjusted and survey-weighted odds of cognitive change during follow-up (95% CI: 1.01-1.10). This association was consistent after accounting for loss-to-follow-up (OR = 1.07, 95% CI: 1.04-1.11).ConclusionsOur study offers insights into DNA methylation age acceleration associated with cognitive change over time, suggesting avenues for improved prevention, diagnosis, and treatment.},
}

Humans
*DNA Methylation
Female
Male
Aged
*Cognitive Dysfunction/genetics/epidemiology
Longitudinal Studies
Middle Aged
*Aging/genetics
Aged, 80 and over
United States/epidemiology
Incidence

@article {pmid40289967,
year = {2025},
author = {Zhong, J and Sun, J and Zhou, B},
title = {Metabolic Regulation as a Potential Therapeutic Approach for Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {22},
number = {3},
pages = {174-178},
pmid = {40289967},
issn = {1875-5828},
support = {2019YFA0508603//Chinese Ministry of Science and Technology, China/ ; 82271513, 81971198//National Natural Science Foundation of China/ ; L222080, 7192103//Beijing Natural Science Foundation/ ; },
mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; Animals ; Lipid Metabolism/drug effects/physiology ; Glucose/metabolism ; },
abstract = {Lecanemab, a therapeutic antibody designed to target amyloid-beta (Aβ) clearance, has recently been approved by the FDA and introduced in multiple countries, representing a significant milestone in advancing Alzheimer's disease (AD) treatment. However, its limited clinical efficacy underscores the need for further investigation of disease pathogenesis. Emerging evidence suggests that glucose and lipid metabolism dysfunction plays a critical role in AD, with metabolic changes emerging as one of the most significantly altered pathways in the early stage of pathology. These findings highlight the therapeutic potential of targeting metabolic regulation as a strategy to address AD.},
}

*Alzheimer Disease/metabolism/drug therapy
Humans
Animals
Lipid Metabolism/drug effects/physiology
Glucose/metabolism

@article {pmid40144670,
year = {2025},
author = {Évora, A and Garcia, G and Rubi, A and De Vitis, E and Matos, AT and Vaz, AR and Gervaso, F and Gigli, G and Polini, A and Brites, D},
title = {Exosomes enriched with miR-124-3p show therapeutic potential in a new microfluidic triculture model that recapitulates neuron-glia crosstalk in Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1474012},
pmid = {40144670},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD), a complex neurodegenerative disease associated with ageing, is the leading cause of dementia. Few people with early AD are eligible for the novel Food and Drug Administration (FDA)-approved drug treatments. Accordingly, new tools and early diagnosis markers are required to predict subtypes, individual stages, and the most suitable personalized treatment. We previously demonstrated that the regulation of microRNA (miR)-124 is crucial for proper neuronal function and microglia reshaping in human AD cell models.

OBJECTIVE: The aim of this study was to develop an efficient miR-124-3p-loaded exosome strategy and validate its therapeutic potential in using a multi-compartment microfluidic device of neuron-glia that recapitulates age-AD pathological features.

METHODS AND RESULTS: Using cortical microglia from mouse pups, separated from glial mixed cultures and maintained for 2 days in vitro (stressed microglia), we tested the effects of SH-SY5Y-derived exosomes loaded with miR-124-3p mimic either by their direct transfection with Exo-Fect™ (ET124) or by their isolation from the secretome of miR-124 transfected cells (CT124). ET124 revealed better delivery effciency and higher potent effects in improving the stressed microglia status than CT124. Tricultures of human SH-SY5Y neuroblastoma cells (SH-WT) were established in the presence of the human microglia cell line (HMC3) and immortalized human astrocytes (IM-HA) in tricompartmentalized microfluidic devices. Replacement of SH-WT cells with those transfected with APP695 (SH-SWE) in the tricultures and addition of low doses of hydrogen peroxide were used to simulate late-onset AD. The system mimicked AD-associated neurodegeneration and neuroinflammation processes. Notably, ET124 exhibited neuroprotective properties across the three cell types in the AD model by preventing neuronal apoptosis and neurite deficits, redirecting microglial profiles towards a steady state, and attenuating the inflammatory and miRNA fingerprints associated with astrocyte reactivity.

CONCLUSION: To the best of our knowledge, this is the first study supporting the neuro- and immunoprotective properties of miR-124-engineered exosomes in a microfluidic triculture platform, recapitulating age-related susceptibility to AD. Our system offers potential to develop personalized medicines in AD patient subtypes.},
}

@article {pmid40073978,
year = {2025},
author = {Mukherjee, AG and Mishra, S and Gopalakrishnan, AV and Kannampuzha, S and Murali, R and Wanjari, UR and B, S and Vellingiri, B and Madhyastha, H and Kanagavel, D and Vijayan, M},
title = {Unraveling the mystery of citrate transporters in Alzheimer's disease: An updated review.},
journal = {Ageing research reviews},
volume = {107},
number = {},
pages = {102726},
doi = {10.1016/j.arr.2025.102726},
pmid = {40073978},
issn = {1872-9649},
mesh = {*Alzheimer Disease/metabolism ; Humans ; Animals ; *Carrier Proteins/metabolism ; *Citric Acid/metabolism ; Mitochondria/metabolism ; *Brain/metabolism ; },
abstract = {A key molecule in cellular metabolism, citrate is essential for lipid biosynthesis, energy production, and epigenetic control. The etiology of Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive decline, may be linked to dysregulated citrate transport, according to recent research. Citrate transporters, which help citrate flow both inside and outside of cells, are becoming more and more recognized as possible participants in the molecular processes underlying AD. Citrate synthase (CS), a key enzyme in the tricarboxylic acid (TCA) cycle, supports mitochondrial function and neurotransmitter synthesis, particularly acetylcholine (ACh), essential for cognition. Changes in CS activity affect citrate availability, influencing energy metabolism and neurotransmitter production. Choline, a precursor for ACh, is crucial for neuronal function. Lipid metabolism, oxidative stress reactions, and mitochondrial function can all be affected by aberrant citrate transport, and these changes are linked to dementia. Furthermore, the two main pathogenic characteristics of AD, tau hyperphosphorylation and amyloid-beta (Aβ) aggregation, may be impacted by disturbances in citrate homeostasis. The goal of this review is to clarify the complex function of citrate transporters in AD and provide insight into how they contribute to the development and course of the illness. We aim to provide an in-depth idea of which particular transporters are dysregulated in AD and clarify the functional implications of these dysregulated transporters in brain cells. To reduce neurodegenerative processes and restore metabolic equilibrium, we have also discussed the therapeutic potential of regulating citrate transport. Gaining insight into the relationship between citrate transporters and the pathogenesis of AD may help identify new indicators for early detection and creative targets for treatment. This study offers hope for more potent ways to fight this debilitating illness and is a crucial step in understanding the metabolic foundations of AD.},
}

*Alzheimer Disease/metabolism
Humans
Animals
*Carrier Proteins/metabolism
*Citric Acid/metabolism
Mitochondria/metabolism
*Brain/metabolism

@article {pmid40055203,
year = {2025},
author = {Soni, S and Kaur, G},
title = {Emerging therapeutic application of clemastine: a review of recent patents updates.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {398},
number = {8},
pages = {9609-9622},
pmid = {40055203},
issn = {1432-1912},
abstract = {Clemastine, a first-generation antihistamine traditionally used for treating allergic rhinitis and urticaria, has recently gathered interest due to its potential therapeutic applications beyond its antihistaminergic properties. This review examines recent patent filings (2015-2024) to elucidate the emerging therapeutic landscape for this compound. The analysis reveals various potential applications, including neurodegenerative disorders, cardiovascular diseases, and cancer treatment. Specifically, several studies focus on its ability to promote remyelination in multiple sclerosis and other demyelinating disorders, highlighting its potential neuroprotective effects. Recent findings suggest its efficacy in treating heart failure and arrhythmias, possibly through its action on cardiac ion channels. In oncology, patents propose this compound as an adjuvant therapy to enhance the efficacy of existing treatments and potentially overcome drug resistance. This review also explores combination therapies involving this drug, which aim to synergize its effects with other active compounds. The patent literature indicates a significant change in the therapeutic potential of ethanolamine derivatives, from a simple antihistamine to a multifaceted drug candidate with far-reaching implications across various medical fields. These developments emphasize the importance of repurposing existing drugs and highlight Clemastine as a promising candidate for further clinical investigation in multiple therapeutic areas.},
}

@article {pmid40034321,
year = {2025},
author = {Uthaman, SK and Kang, WS and Park, JY and Kim, S and Le, DD and Oh, SJ and Murugesh, K and Oh, LM and Lee, M and Park, JW},
title = {Endogenous extraction yielded high quality sulforaphane from broccoli sprouts unveils potent antioxidant and anti-Alzheimer's activities.},
journal = {Heliyon},
volume = {11},
number = {4},
pages = {e42673},
pmid = {40034321},
issn = {2405-8440},
abstract = {The extraction of sulforaphane (SFN) is challenging due to its instability and low water solubility, with existing methods often involving toxic solvents or yielding low SFN. We optimized an endogenous extraction protocol for high SFN content, characterized by HPLC and LC-MS analyses. SFN remained stable in refrigerated broccoli sprout extract powder (BSEP) for over a month. BSEP showed four times higher oxygen radical absorbance capacity (ORAC) than the SFN standard, indicating high antioxidant capacity. It also reduced inflammatory responses by down-regulating COX-2, IL-6, and TNF-α gene expression in LPS-induced RAW 264.7 macrophages. Additionally, BSEP exhibited neuroprotective properties in amyloid-beta (1-42) (Aβ1-42)-induced Alzheimer's disease (AD) mice, enhancing memory and learning retention in water maze and passive avoidance tests. BSEP mitigated spatial cognitive impairment and improved memory function in Aβ1-42-induced memory-deficient mice. While BSEP did not alter acetylcholine (ACh) concentration, it improved memory and learning by inhibiting acetylcholinesterase (AChE) activity. BSEP with SFN content exceeding 200 mg/kg ameliorated neurobehavioral deficits and protected the brain from amyloid deposition, suggesting its therapeutic potential in AD treatment. We propose an eco-friendly form of SFN-rich BSEP for daily intake and commercial therapeutics.},
}

@article {pmid39925461,
year = {2024},
author = {Ouyang, Z and Wang, L and , },
title = {Imputation-Based Variable Selection Method for Block-Wise Missing Data When Integrating Multiple Longitudinal Studies.},
journal = {Mathematics (Basel, Switzerland)},
volume = {12},
number = {7},
pages = {},
pmid = {39925461},
issn = {2227-7390},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; P50 DA054039/DA/NIDA NIH HHS/United States ; R01 CE003497/CE/NCIPC CDC HHS/United States ; R01 ES033515/ES/NIEHS NIH HHS/United States ; },
abstract = {When integrating data from multiple sources, a common challenge is block-wise missing. Most existing methods address this issue only in cross-sectional studies. In this paper, we propose a method for variable selection when combining datasets from multiple sources in longitudinal studies. To account for block-wise missing in covariates, we impute the missing values multiple times based on combinations of samples from different missing pattern and predictors from different data sources. We then use these imputed data to construct estimating equations, and aggregate the information across subjects and sources with the generalized method of moments. We employ the smoothly clipped absolute deviation penalty in variable selection and use the extended Bayesian Information Criterion criteria for tuning parameter selection. We establish the asymptotic properties of the proposed estimator, and demonstrate the superior performance of the proposed method through numerical experiments. Furthermore, we apply the proposed method in the Alzheimer's Disease Neuroimaging Initiative study to identify sensitive early-stage biomarkers of Alzheimer's Disease, which is crucial for early disease detection and personalized treatment.},
}

@article {pmid39832031,
year = {2025},
author = {Padti, AC and Bhavi, SM and Thokchom, B and Singh, SR and Bhat, SS and Harini, BP and Sillanpää, M and Yarajarla, RB},
title = {Nanoparticle Interactions with the Blood Brain Barrier: Insights from Drosophila and Implications for Human Astrocyte Targeted Therapies.},
journal = {Neurochemical research},
volume = {50},
number = {1},
pages = {80},
pmid = {39832031},
issn = {1573-6903},
mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Astrocytes/metabolism/drug effects ; *Nanoparticles/metabolism/administration & dosage ; Drug Delivery Systems/methods ; Drosophila ; Neurodegenerative Diseases/drug therapy/metabolism ; },
abstract = {This review explores the intricate connections between Drosophila models and the human blood-brain barrier (BBB) with nanoparticle-based approaches for neurological treatment. Drosophila serves as a powerful model organism due to its evolutionary conservation of key biological processes, particularly in the context of the BBB, which is formed by glial cells that share structural and functional similarities with mammalian endothelial cells. Recent advancements in nanoparticle technology have highlighted their potential for effective drug delivery across the BBB, utilizing mechanisms such as passive diffusion, receptor-mediated transcytosis, and carrier-mediated transport. The ability to engineer nanoparticles with specific physicochemical properties-such as size, surface charge, and functionalization-enhances their targeting capabilities, particularly towards astrocytes, which play a crucial role in maintaining BBB integrity and responding to neuroinflammation. Insights gained from Drosophila studies have informed the design of personalized nanomedicine strategies aimed at treating neurodegenerative diseases, including Alzheimer's, Parkinson's disease etc. As research progresses, the integration of findings from Drosophila models with emerging humanized BBB systems will pave the way for innovative therapeutic approaches that improve drug delivery and patient outcomes in neurological disorders.},
}

Animals
*Blood-Brain Barrier/metabolism/drug effects
Humans
*Astrocytes/metabolism/drug effects
*Nanoparticles/metabolism/administration & dosage
Drug Delivery Systems/methods
Drosophila
Neurodegenerative Diseases/drug therapy/metabolism

@article {pmid39769398,
year = {2024},
author = {Testa, G and Giannelli, S and Staurenghi, E and Cecci, R and Floro, L and Gamba, P and Sottero, B and Leonarduzzi, G},
title = {The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer's Disease: A Possible Target for the Disease Treatment.},
journal = {International journal of molecular sciences},
volume = {25},
number = {24},
pages = {},
pmid = {39769398},
issn = {1422-0067},
support = {LEOG_RILO_23_01; GAMP_RILO_23_01; SOTB_RILO_23_01; LEOG_RF_CLINIC_23_01//University of Turin/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/etiology/pathology/drug therapy ; *Proprotein Convertase 9/metabolism ; Animals ; Brain/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; PCSK9 Inhibitors ; Cholesterol/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease mainly caused by β-amyloid (Aβ) accumulation in the brain. Among the several factors that may concur to AD development, elevated cholesterol levels and brain cholesterol dyshomeostasis have been recognized to play a relevant role. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein primarily known to regulate plasma low-density lipoproteins (LDLs) rich in cholesterol and to be one of the main causes of familial hypercholesterolemia. In addition to that, PCSK9 is also recognized to carry out diverse important activities in the brain, including control of neuronal differentiation, apoptosis, and, importantly, LDL receptors functionality. Moreover, PCSK9 appeared to be directly involved in some of the principal processes responsible for AD development, such as inflammation, oxidative stress, and Aβ deposition. On these bases, PCSK9 management might represent a promising approach for AD treatment. The purpose of this review is to elucidate the role of PCSK9, whether or not cholesterol-related, in AD pathogenesis and to give an updated overview of the most innovative therapeutic strategies developed so far to counteract the pleiotropic activities of both humoral and brain PCSK9, focusing in particular on their potentiality for AD management.},
}

Humans
*Alzheimer Disease/metabolism/etiology/pathology/drug therapy
*Proprotein Convertase 9/metabolism
Animals
Brain/metabolism/pathology
Amyloid beta-Peptides/metabolism
PCSK9 Inhibitors
Cholesterol/metabolism

@article {pmid39683070,
year = {2024},
author = {Rodrigues, T and Lima, A and Wortham, T and Arruda, F and Janeiro, A and Baptista, J and Lima, E},
title = {Essential Oil Composition and Anti-Cholinesterase Properties of Cryptomeria japonica Foliage Harvested in São Miguel Island (Azores) in Two Different Seasons.},
journal = {Plants (Basel, Switzerland)},
volume = {13},
number = {23},
pages = {},
pmid = {39683070},
issn = {2223-7747},
support = {M1.1.C/PROJ.EXPLORATÓRIOS/003/2022 - PotBioCJap//Direção Regional da Ciência e Tecnologia (DRCT)/ ; },
abstract = {The Azorean Cryptomeria japonica forest operations and wood industry generate considerable foliage biomass residues that are used for local essential oil (EO) production. However, research on seasonal variation of C. japonica EO remains scarce. In this study, the EOs from fresh Azorean C. japonica foliage (Az-CJF) collected in autumn (Aut) and spring (Spr) were obtained via hydrodistillation and investigated for their physical properties, yield, chemical composition, and bioactivities. Both EOs presented a strong odor, a yellowish color, a density around 0.9 g·mL[-1], and similar yields (approximately 1% v/w, dry matter). Nevertheless, the GC-MS analyses showed a decrease in monoterpene hydrocarbons (MH) and an increase in oxygenated sesquiterpenes (OS) contents in Spr-EO compared with Aut-EO (16% vs. 35% for MH and 45% vs. 31% for OS, respectively). In addition, the predominant components were kaur-16-ene (23%) for Spr-EO and phyllocladene (19%) for Aut-EO, revealing that both EOs were rich in diterpene hydrocarbons (29% vs. 26%). Concerning its toxicity against brine shrimp, a low mortality (0-38%) was observed at a concentration range of 100-180 μg·mL[-1]. Regarding the anti-cholinesterase properties, both EOs were inactive against acetylcholinesterase but showed anti-butyrylcholinesterase activity superior to (-)-α-pinene, a major compound of Az-CJF EO (IC50 values: 84, 148, and 648 μg·mL[-1] for Spr-EO, Aut-EO, and α-pinene, respectively). Overall, the results indicate the potential benefit of both seasonal EOs in Alzheimer's disease treatment. In conclusion, this study demonstrated that season strongly influences the Az-CJF EO quantitative composition and thus its bioactivity, aiding in the selection of the most high-quality raw materials for use in Azorean C. japonica EO aromatherapy industry.},
}

@article {pmid39571156,
year = {2024},
author = {Wang, Z and Zhou, L and Zhao, N and Zhang, Z and Zhang, J and Ren, QG},
title = {Bidirectional Crosstalk between the Heart and Brain in Alzheimer's Disease.},
journal = {Aging and disease},
volume = {16},
number = {5},
pages = {2979-2998},
pmid = {39571156},
issn = {2152-5250},
mesh = {Humans ; *Alzheimer Disease/physiopathology/metabolism ; *Brain/physiopathology/metabolism ; *Heart/physiopathology ; Autonomic Nervous System/physiopathology ; *Cardiovascular Diseases/physiopathology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder condition linked to various systemic comorbidities. Numerous studies have shown bidirectional crosstalk between the heart and the brain, but the specifics of how these interactions occur in AD are poorly understood. This narrative review summarizes the clinical evidence for a firm link between AD and cardiovascular health and discusses the bidirectional roles of AD and the cardiovascular system. AD pathogenic proteins, AD risk genes, neurohormones, the autonomic nervous system, and neurotransmitters may affect cardiovascular health, and cardiac-derived proteins, neurohormones, vascular function, inflammation, and other potential specific molecules or neural pathways may also influence AD pathology and cognitive function. Additionally, we propose potential AD intervention strategies based on the heart-brain axis to provide novel insights into AD prevention and treatment.},
}

Humans
*Alzheimer Disease/physiopathology/metabolism
*Brain/physiopathology/metabolism
*Heart/physiopathology
Autonomic Nervous System/physiopathology
*Cardiovascular Diseases/physiopathology

@article {pmid39403908,
year = {2024},
author = {Xu, Y and Li, D and Xue, A and Gu, J and Ren, Y and Zhu, S and Lei, X and Liu, J and Zhao, J and Geng, F and Zhang, N},
title = {Calycosin-7-O-β-D-Glucoside Ameliorates Palmitate-Induced Lipid Accumulation in HT22 Cells.},
journal = {Actas espanolas de psiquiatria},
volume = {52},
number = {5},
pages = {641-652},
pmid = {39403908},
issn = {1578-2735},
mesh = {*Isoflavones/pharmacology ; *Glucosides/pharmacology ; *Lipid Metabolism/drug effects ; Palmitates/pharmacology ; Alzheimer Disease/metabolism/drug therapy ; Mice ; Cells, Cultured ; Animals ; },
abstract = {BACKGROUND: The pathogenesis of Alzheimer's disease (AD) is complex. Recent research suggests that AD patients have early disorders in brain cholesterol metabolism. Cholesterol and its derivatives accumulate in neurons, leading to p-Tau overproduction and synaptic dysfunction, initiating AD progression. Calycosin-7-O-β-D-glucoside (CG), a distinctive constituent of Astragali Radix, holds a representative position. Many clinical trials have demonstrated that CG can attenuate cerebral ischemia/reperfusion injury and preserve the structural integrity of the blood-brain barrier. However, whether CG alleviates tau-mediated neurodegeneration by increasing cholesterol efflux after lipid accumulation remains unexplored.

METHODS: Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) and multivariate data analysis were employed to investigate metabolic changes in HT22 cells induced by sodium palmitate following 24 hours of CG treatment. The potential therapeutic mechanisms of CG on AD were further examined through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis.

RESULTS: Metabolomic analysis characterized 24 potential biomarkers, revealing that CG could ameliorate cholesterol metabolic pathways. The results of cell experiments revealed that CG can increase the expression of enzyme cholesterol 24-hydroxylase (CYP46A1) (p < 0.05) and the level of 24 hydroxycholesterol (24-OHC) (p < 0.05), reduce the expression of p-Tau (Thr231)/Tau (p < 0.01), inhibit the formation of lipid droplets.

CONCLUSION: CG may inhibit the accumulation of cholesterol and its derivatives in neurons by affecting the CYP46A1-CE-Tau axis, offering a potential therapeutic strategy for AD.},
}

*Isoflavones/pharmacology
*Glucosides/pharmacology
*Lipid Metabolism/drug effects
Palmitates/pharmacology
Alzheimer Disease/metabolism/drug therapy
Mice
Cells, Cultured
Animals

@article {pmid39263555,
year = {2024},
author = {Hainsworth, AH and Blackburn, TP and Bradshaw, EM and Elahi, FM and Gorelick, PB and Isaacs, JD and Wallin, A and Williams, SC},
title = {The promise of molecular science in brain health. What breakthroughs are anticipated in the next 20 years?.},
journal = {Cerebral circulation - cognition and behavior},
volume = {7},
number = {},
pages = {100364},
pmid = {39263555},
issn = {2666-2450},
support = {IK2 CX002180/CX/CSRD VA/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; PG/20/10397/BHF_/British Heart Foundation/United Kingdom ; SP/F/22/150042/BHF_/British Heart Foundation/United Kingdom ; },
abstract = {Brain health means optimal physiological brain function across the normal life-course. It encompasses not only healthy brain aging but also brain diseases, their diagnosis and treatment. In all these areas, molecular science has advanced our understanding. This multi-disciplinary review combines viewpoints from laboratory science, clinical medicine and the bioscience industry. First, we review the advances that molecular science has brought to brain health in the past twenty years. These include therapeutic antibodies for CNS diseases (multiple sclerosis, Alzheimer disease) and the dramatic introduction of RNA-targeted therapeutics. Second, we highlight areas where greater molecular understanding is needed. Salient examples are the relation of brain structure to cognitive symptoms, and molecular biomarkers for diagnosis, target discovery and testing of interventions. Finally, we speculate on aspects of molecular science that are likely to advance brain health in the next twenty years. These include: cell senescence and chronobiology; gene editing (notably, CRISPR) and RNA targeting (RNA interference, miRNA manipulation); brain-immune interactions; novel drug targets (AQP4, HIF1, Toll-like receptors); and novel chemistry to make new drugs (molecular machines, quantum molecular modelling and "click" chemistry). Early testing of the relationships between molecular pathways and clinical manifestations will drive much-needed breakthroughs in neurology and psychiatry.},
}

@article {pmid39194762,
year = {2024},
author = {Zaigham, SB and Paeng, DG},
title = {Effects of Mucuna pruriens (L.) DC. and Levodopa in Improving Parkinson's Disease in Rotenone Intoxicated Mice.},
journal = {Current issues in molecular biology},
volume = {46},
number = {8},
pages = {9234-9244},
pmid = {39194762},
issn = {1467-3045},
support = {2023//Jeju National University Education fund 2023/ ; },
abstract = {Parkinson's disease (PD) is the second leading neurodegenerative disease after Alzheimer's disease. Mucuna pruriens (L.) DC. (MP) is a plant that contains Levodopa (L-DOPA) and has been known to improve the symptoms of PD. In this preliminary study, we investigated the anti-parkinsonian potential of MP to compare the effects of L-DOPA. We first developed an in vivo model of the PD in C57BL/6 male mice using rotenone. A total of twelve mice were used for this experiment. Nine mice were injected with rotenone (28 mg/kg) daily for 28 days. The mice experiments were performed to validate the effectiveness of MP to treat PD. Synthetic L-DOPA in a ratio of 1:20 with MP was used as MP contains 5% L-DOPA by weight in it. MP and L-DOPA were injected for 19 days on a daily basis. Cognitive function was evaluated using beam balance and olfactory tests. Serum analysis was performed using serum enzyme-linked immunosorbent assay (ELISA) analysis test. IL-12, IL-6, and TGF-β 1 were evaluated to validate the PD inducement and treatment. The levels of IL-12, IL-6, and TGF-β1 (p < 0.0001) in the PD mice group were significantly higher than those in the control group. The PD mice also showed higher latencies in beam balance and olfactory tests (p < 0.0001) compared to the control group. Both MP and L-DOPA-treated groups showed alleviation in latencies in beam balance and olfactory tests and decreased neuroinflammation in ELISA analysis (p < 0.001). The results treated by MP and L-DOPA showed insignificant differences in their values (p > 0.05). This proved that the MP and L-DOPA had similar effects in improving the symptoms of PD when used in the ratio of 1:20. Furthermore, both MP and L-DOPA reduced the level of IL-6 and TGF-β1 in this study. It may be inferred that a reduction in the level of IL-6 and TGF-β1 eventually leads to a reduction in the Th17 cells. The pathogenic Th17 is thought to be present in virtually all chronic inflammatory disorders. This can be an interesting area of research in further understanding the immunological effect of MP in ameliorating PD symptoms.},
}

@article {pmid38965489,
year = {2024},
author = {Wu, S and Zhan, P and Wang, G and Yu, X and Liu, H and Wang, W},
title = {Changes of brain functional network in Alzheimer's disease and frontotemporal dementia: a graph-theoretic analysis.},
journal = {BMC neuroscience},
volume = {25},
number = {1},
pages = {30},
pmid = {38965489},
issn = {1471-2202},
support = {2022YFC2402202//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Frontotemporal Dementia/physiopathology ; *Alzheimer Disease/physiopathology ; Female ; Male ; Aged ; *Electroencephalography/methods ; *Brain/physiopathology ; Middle Aged ; Nerve Net/physiopathology/diagnostic imaging ; Neural Pathways/physiopathology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias, presenting with similar clinical features that challenge accurate diagnosis. Despite extensive research, the underlying pathophysiological mechanisms remain unclear, and effective treatments are limited. This study aims to investigate the alterations in brain network connectivity associated with AD and FTD to enhance our understanding of their pathophysiology and establish a scientific foundation for their diagnosis and treatment.

METHODS: We analyzed preprocessed electroencephalogram (EEG) data from the OpenNeuro public dataset, comprising 36 patients with AD, 23 patients with FTD, and 29 healthy controls (HC). Participants were in a resting state with eyes closed. We estimated the average functional connectivity using the Phase Lag Index (PLI) for lower frequencies (delta and theta) and the Amplitude Envelope Correlation with leakage correction (AEC-c) for higher frequencies (alpha, beta, and gamma). Graph theory was applied to calculate topological parameters, including mean node degree, clustering coefficient, characteristic path length, global and local efficiency. A permutation test was then utilized to assess changes in brain network connectivity in AD and FTD based on these parameters.

RESULTS: Both AD and FTD patients showed increased mean PLI values in the theta frequency band, along with increases in average node degree, clustering coefficient, global efficiency, and local efficiency. Conversely, mean AEC-c values in the alpha frequency band were notably diminished, which was accompanied by decreases average node degree, clustering coefficient, global efficiency, and local efficiency. Furthermore, AD patients in the occipital region showed an increase in theta band node degree and decreased alpha band clustering coefficient and local efficiency, a pattern not observed in FTD.

CONCLUSIONS: Our findings reveal distinct abnormalities in the functional network topology and connectivity in AD and FTD, which may contribute to a better understanding of the pathophysiological mechanisms of these diseases. Specifically, patients with AD demonstrated a more widespread change in functional connectivity, while those with FTD retained connectivity in the occipital lobe. These observations could provide valuable insights for developing electrophysiological markers to differentiate between the two diseases.},
}

Humans
*Frontotemporal Dementia/physiopathology
*Alzheimer Disease/physiopathology
Female
Male
Aged
*Electroencephalography/methods
*Brain/physiopathology
Middle Aged
Nerve Net/physiopathology/diagnostic imaging
Neural Pathways/physiopathology

@article {pmid38842122,
year = {2024},
author = {Ha, W and Ma, R and Kang, JY and Iradukunda, Y and Shi, YP},
title = {Green and shape-tunable synthesis of ellagic acid crystalline particles by tannic acid for neuroprotection against oxidative stress.},
journal = {Biomaterials science},
volume = {12},
number = {14},
pages = {3610-3621},
doi = {10.1039/d4bm00380b},
pmid = {38842122},
issn = {2047-4849},
mesh = {*Ellagic Acid/pharmacology/chemistry ; *Tannins/pharmacology/chemistry ; *Oxidative Stress/drug effects ; PC12 Cells ; Animals ; Rats ; *Reactive Oxygen Species/metabolism ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Antioxidants/pharmacology/chemistry/chemical synthesis ; Blood-Brain Barrier/metabolism/drug effects ; Hydrogen Peroxide/pharmacology/chemistry ; Neuroprotection/drug effects ; Green Chemistry Technology ; Polyphenols ; },
abstract = {Oxidative stress (OS) plays an important role in the emergence and prevention of neurodegenerative diseases, such as Alzheimer's disease (AD). Excess reactive oxygen species (ROS) accumulated in a neuronal cell can lead to OS, producing cell injury and death. Seeking nanoantioxidants against AD-related oxidative stress has attracted a lot of attention, especially those potential antioxidant agents derived from natural polyphenols. However, the transformation of abundant plant polyphenols to antioxidative biomaterials against OS is still challenging. In this work, we report a new method to transform amorphous tannic acid (TA) into tailorable shaped ellagic acid (EA) crystalline particles without using an organic solvent. EA crystalline particles were generated from TA, which underwent a chemical transformation, in situ metal phenolic coordination and acid-induced assembly process, and the size and shape could be controlled by varying the amount of acid. As-prepared EA crystalline particles showed excellent stability in water and lysosomal mimicking fluid and possess unique fluorescence properties and a strong response in mass spectrometry, which is beneficial for their imaging analysis in cells and tissues. More importantly, EA particles have shown significant H2O2-related ROS scavenging ability, a high cellular uptake capacity, an excellent neuroprotective effect in PC12 cells, a high drug loading capacity and BBB permeability to enter the brain. Our study suggested that the EA crystalline particles show great potential for OS-mediated AD treatment.},
}

*Ellagic Acid/pharmacology/chemistry
*Tannins/pharmacology/chemistry
*Oxidative Stress/drug effects
PC12 Cells
Animals
Rats
*Reactive Oxygen Species/metabolism
*Neuroprotective Agents/pharmacology/chemistry/chemical synthesis
Antioxidants/pharmacology/chemistry/chemical synthesis
Blood-Brain Barrier/metabolism/drug effects
Hydrogen Peroxide/pharmacology/chemistry
Neuroprotection/drug effects
Green Chemistry Technology
Polyphenols

@article {pmid38362508,
year = {2023},
author = {Yu, X and Zhang, L and Lyu, Y and Liu, T and Zhu, D},
title = {SUPERVISED DEEP TREE IN ALZHEIMER'S DISEASE.},
journal = {Proceedings. IEEE International Symposium on Biomedical Imaging},
volume = {2023},
number = {},
pages = {},
pmid = {38362508},
issn = {1945-7928},
support = {R01 AG075582/AG/NIA NIH HHS/United States ; RF1 NS128534/NS/NINDS NIH HHS/United States ; },
abstract = {As a progressive neurodegenerative disorder, the pathological changes of Alzheimer's disease (AD) might begin as much as two decades before the manifestation of clinical symptoms. Since the nature of the irreversible pathology of AD, early diagnosis provides a more tractable way for disease intervention and treatment. Therefore, numerous approaches have been developed for early diagnostic purposes. Although several important biomarkers have been established, most of the existing methods show limitations in describing the continuum of AD progression. However, understanding this continuous development is essential to understand the intrinsic progression mechanism of AD. In this work, we proposed a supervised deep tree model (SDTree) to integrate AD progression and individual prediction. The proposed SDTree method models the progression of AD as a tree embedded in a latent space using nonlinear reversed graph embedding. In this way, the continuum of AD progression is encoded into the locations on the tree structure. The learned tree structure can not only represent the continuum of AD but make predictions for new subjects. We evaluated our method on the classification task and achieved promising results on Alzheimer's Disease Neuroimaging Initiative dataset.},
}

@article {pmid38337696,
year = {2024},
author = {Dissanayaka, DMS and Jayasena, V and Rainey-Smith, SR and Martins, RN and Fernando, WMADB},
title = {The Role of Diet and Gut Microbiota in Alzheimer's Disease.},
journal = {Nutrients},
volume = {16},
number = {3},
pages = {},
pmid = {38337696},
issn = {2072-6643},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Gastrointestinal Microbiome ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Diet ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by the accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated tau tangles. Currently, Alzheimer's disease (AD) impacts 50 million individuals, with projections anticipating an increase to 152 million by the year 2050. Despite the increasing global prevalence of AD, its underlying pathology remains poorly understood, posing challenges for early diagnosis and treatment. Recent research suggests a link between gut dysbiosis and the aggregation of Aβ, the development of tau proteins, and the occurrence of neuroinflammation and oxidative stress are associated with AD. However, investigations into the gut-brain axis (GBA) in the context of AD progression and pathology have yielded inconsistent findings. This review aims to enhance our understanding of microbial diversity at the species level and the role of these species in AD pathology. Additionally, this review addresses the influence of confounding elements, including diet, probiotics, and prebiotics, on AD throughout different stages (preclinical, mild cognitive impairment (MCI), and AD) of its progression.},
}

Humans
*Alzheimer Disease/metabolism
*Gastrointestinal Microbiome
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Diet
Brain/metabolism

@article {pmid38306042,
year = {2024},
author = {Sible, IJ and Nation, DA},
title = {Blood Pressure Variability and Plasma Alzheimer's Disease Biomarkers in the SPRINT Trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {97},
number = {4},
pages = {1851-1860},
pmid = {38306042},
issn = {1875-8908},
support = {R01 AG064228/AG/NIA NIH HHS/United States ; R01 AG060049/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; R01 AG082073/AG/NIA NIH HHS/United States ; P01 AG052350/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease ; Blood Pressure ; tau Proteins ; Amyloid beta-Peptides ; Biomarkers ; },
abstract = {BACKGROUND: Recent observational studies suggest higher blood pressure (BP) variability (BPV) is associated with Alzheimer's disease (AD) biomarkers amyloid-beta (Aβ) and tau. Less is known about relationships in interventional cohorts with strictly controlled mean BP levels.

OBJECTIVE: Investigate the longitudinal relationship between BPV and change in plasma AD biomarkers under standard versus intensive BP treatment.

METHODS: In this post hoc analysis of the SPRINT trial, 457 participants (n = 206 in standard group, n = 251 in intensive group) underwent repeated BP measurement between baseline and 12-months follow-up, and venipuncture at baseline and median (IQR) 3.5 (3.0-4.0) years later to determine plasma AD biomarkers total tau and Aβ1-42:Aβ1-40 ratio. BPV was calculated as tertiles of variability independent of mean. Linear mixed models investigated the effect of BPV×time on AD biomarker levels.

RESULTS: Higher BPV was associated with increased levels of total tau in the standard group (β [95% CI] 1st versus 3rd tertiles of BPV: 0.21 [0.02, 0.41], p = 0.035), but not in the intensive group (β [95% CI] 1st versus 3rd tertiles of BPV: -0.02 [-0.19, 0.16], p = 0.843). BPV was not associated with Aβ 1-42:Aβ 1-40 ratio in either group. Mean BP was not associated with biomarkers.

CONCLUSIONS: Higher BPV was associated with increased plasma total tau under standard BP treatment. Findings add new evidence to prior observational work linking BPV to AD pathophysiology and suggest that, despite strict control of mean BP, BPV remains a risk for pathophysiological change underlying risk for AD.},
}

Humans
*Alzheimer Disease
Blood Pressure
tau Proteins
Amyloid beta-Peptides
Biomarkers

@article {pmid37891608,
year = {2023},
author = {Wang, Q and Wang, Y and Li, S and Shi, J},
title = {PACAP-Sirtuin3 alleviates cognitive impairment through autophagy in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {15},
number = {1},
pages = {184},
pmid = {37891608},
issn = {1758-9193},
support = {XDB39000000//Strategic Priority Research Program of the Chinese Academy of Sciences/ ; XDB39000000//Strategic Priority Research Program of the Chinese Academy of Sciences/ ; },
mesh = {Humans ; Mice ; Animals ; *Alzheimer Disease/complications/drug therapy/genetics ; Pituitary Adenylate Cyclase-Activating Polypeptide/genetics/metabolism/pharmacology ; Amyloid beta-Peptides/metabolism ; Phosphatidylinositol 3-Kinases ; *Sirtuin 3/therapeutic use ; *Cognitive Dysfunction/drug therapy ; Autophagy ; Mice, Transgenic ; },
abstract = {BACKGROUND: Autophagy is vital in the pathogenesis of neurodegeneration. Thus far, no studies have specifically investigated the relationship between pituitary adenylate cyclase-activating polypeptide (PACAP) and autophagy, particularly in the context of Alzheimer's disease (AD). This study used in vitro and in vivo models, along with clinical samples, to explore interactions between PACAP and autophagy in AD.

METHODS: AD model mice were administered 6 μl of 0.1 mg/ml PACAP liquid intranasally for 4 weeks, then subjected to behavioral analyses to assess the benefits of PACAP treatment. The underlying mechanisms of PACAP-induced effects were investigated by methods including real-time quantitative polymerase chain reaction, RNA sequencing, immunofluorescence, and western blotting. Exosomes were extracted from human serum and subjected to enzyme-linked immunosorbent assays to examine autophagy pathways. The clinical and therapeutic implications of PACAP and autophagy were extensively investigated throughout the experiment.

RESULTS: Impaired autophagy was a critical step in amyloid β (Aβ) and Tau deposition; PACAP enhanced autophagy and attenuated cognitive impairment. RNA sequencing revealed three pathways that may be involved in AD progression: PI3K-AKT, mTOR, and AMPK. In vivo and in vitro studies showed that sirtuin3 knockdown diminished the ability of PACAP to restore normal autophagy function, resulting in phagocytosis dysregulation and the accumulation of pTau, Tau, and Aβ. Additionally, the autophagic biomarker MAP1LC3 demonstrated a positive association with PACAP in human serum.

CONCLUSIONS: PACAP reverses AD-induced cognitive impairment through autophagy, using sirtuin3 as a key mediator. MAP1LC3 has a positive relationship with PACAP in humans. These findings provide insights regarding potential uses of intranasal PACAP and sirtuin3 agonists in AD treatment.

TRIAL REGISTRATION: NCT04320368.},
}

Humans
Mice
Animals
*Alzheimer Disease/complications/drug therapy/genetics
Pituitary Adenylate Cyclase-Activating Polypeptide/genetics/metabolism/pharmacology
Amyloid beta-Peptides/metabolism
Phosphatidylinositol 3-Kinases
*Sirtuin 3/therapeutic use
*Cognitive Dysfunction/drug therapy
Autophagy
Mice, Transgenic

@article {pmid36775895,
year = {2023},
author = {Jeanneteau, F},
title = {Stress and the risk of Alzheimer dementia: Can deconstructed engrams be rebuilt?.},
journal = {Journal of neuroendocrinology},
volume = {35},
number = {9},
pages = {e13235},
doi = {10.1111/jne.13235},
pmid = {36775895},
issn = {1365-2826},
mesh = {Humans ; *Alzheimer Disease/pathology ; Learning ; Synapses/metabolism ; Neurons/pathology ; Neural Pathways ; },
abstract = {The exact neuropathological mechanism by which the dementia process unfolds is under intense scrutiny. The disease affects about 38 million people worldwide, 70% of which are clinically diagnosed with Alzheimer's disease (AD). If the destruction of synapses essential for learning, planning and decision-making is part of the problem, must the restoration of previously lost synapses be part of the solution? It is plausible that neuronal capacity to restitute information corresponds with the adaptive capacity of its connectivity reserve. A challenge will be to promote the functional connectivity that can compensate for the lost one. This will require better clarification of the remodeling of functional connectivity during the progression of AD dementia and its reversal upon experimental treatment. A major difficulty is to promote the neural pathways that are atrophied in AD dementia while suppressing others that are bolstered. Therapeutic strategies should aim at scaling functional connectivity to a just balance between the atrophic and hypertrophic systems. However, the exact factors that can help reach this objective are still unclear. Similarities between the effects of chronic stress and some neuropathological mechanisms underlying AD dementia support the idea that common components deserve prime attention as therapeutic targets.},
}

Humans
*Alzheimer Disease/pathology
Learning
Synapses/metabolism
Neurons/pathology
Neural Pathways

@article {pmid36594931,
year = {2023},
author = {Yılmaz, ŞG and Almasri, S and Karabulut, YY and Korkmaz, M and Bucak, Ö and Balcı, SO},
title = {Okadaic Acid-Induced Alzheimer's in Rat Brain: Phytochemical Cucurbitacin E Contributes to Memory Gain by Reducing TAU Protein Accumulation.},
journal = {Omics : a journal of integrative biology},
volume = {27},
number = {1},
pages = {34-44},
doi = {10.1089/omi.2022.0175},
pmid = {36594931},
issn = {1557-8100},
mesh = {Rats ; Female ; Animals ; tau Proteins/metabolism ; Okadaic Acid/pharmacology ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; Rats, Sprague-Dawley ; Amyloid beta-Peptides/metabolism/pharmacology ; *Neurodegenerative Diseases/metabolism ; Brain/metabolism ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive decline, with hallmark pathologies related to amyloid beta (Aβ) and TAU. Natural phytochemicals show promise for drug discovery to fill the current therapeutic innovation gap in AD. This study investigated the effect of cucurbitacin E (CuE), one of the bioactive components of Ecballium elaterium, on TAU fibril formation in okadaic acid-induced AD in rats. In a randomized design, we assigned 30 female Sprague Dawley rats to one of five experimental groups: (1) control, (2) stereotaxic surgery, (3) stereotaxic surgery + artificial cerebrospinal fluid, (4) stereotaxic surgery + okadaic acid (AD model), and (5) stereotaxic surgery + okadaic acid + CuE treatment. For experimental groups 4 and 5, rats were administered OKA-ICV (200 ng/kg) followed by CuE (4 mg/[kg·day], intraperitoneally) for 20 days. Expression of the MAPK1/3 and MAPK14 genes associated with TAU metabolism, hippocampal protein levels of these genes, cognitive functions of the rats, and histological accumulation of TAU in the brain were evaluated. Our findings in this preclinical model collectively suggest that phytochemical CuE contributes to memory gain by reducing TAU protein accumulation, which warrants further evaluation in future in vitro and in vivo studies.},
}

Rats
Female
Animals
tau Proteins/metabolism
Okadaic Acid/pharmacology
*Alzheimer Disease/chemically induced/drug therapy/metabolism
Rats, Sprague-Dawley
Amyloid beta-Peptides/metabolism/pharmacology
*Neurodegenerative Diseases/metabolism
Brain/metabolism
Disease Models, Animal

@article {pmid36069168,
year = {2022},
author = {Dai, W and Yao, RM and Mi, TY and Zhang, LM and Wu, HL and Cheng, JB and Li, YF},
title = {Cognition-enhancing effect of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in the 5 × FAD transgenic mouse model of Alzheimer's pathology.},
journal = {Journal of psychopharmacology (Oxford, England)},
volume = {36},
number = {10},
pages = {1176-1187},
doi = {10.1177/02698811221122008},
pmid = {36069168},
issn = {1461-7285},
mesh = {Animals ; Mice ; *Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Cognition ; Disease Models, Animal ; Imidazoles ; Interleukin-6/metabolism ; Ligands ; Mice, Transgenic ; Microglia ; Pyridines ; Tumor Necrosis Factor-alpha/metabolism ; },
abstract = {BACKGROUND: Intracerebral translocator protein 18 kDa (TSPO) mediates the transport of cholesterol from cytoplasm to mitochondria and activation of microglia. The change of TSPO and the dysfunction of microglia are closely related to the pathogenesis of Alzheimer's disease (AD).

AIMS: This study aimed to investigate the effects of microglial TSPO and its selective ligand YL-IPA08 on the cognitive function of transgenic mice in 5 × familial Alzheimer's disease (FAD) mouse model of AD.

METHODS: The TSPO knockout 5 × FAD transgenic mice were bred, and tested by Morris water maze. The effects of YL-IPA08 on cognitive abilities and expression of Aβ in 5 × FAD mice were also explored into.

RESULTS: The latency of escape by TSPO knockout 5 × FAD mice was significantly prolonged compared with the 5 × FAD group, indicating that the cognitive impairment of mice aggravated. With the attenuated phagocytic ability of microglia, the deposition of Aβ in prefrontal cortex of TSPO knockout 5 × FAD mice increased, and the expression of proinflammatory factors (IL-1β, TNF-α, IL-6) were upregulated. In addition, YL-IPA08 significantly reduced the latency of escape by 5 × FAD mice, increased the number of times of crossing over the platform by mice, and inhibited the deposition of Aβ in the prefrontal cortex of 5 × FAD mice without affecting the cleavage of APP.

CONCLUSION: Our findings suggested that TSPO knockout in 5 × FAD mice inhibited microglial phagocytosis, promoted Aβ deposition and neuroinflammation, and aggravated cognitive dysfunction in AD mice. YL-IPA08 had a significant cognition-enhancing effect in 5 × FAD transgenic mice, which might provide a new basis for potential drug candidates in AD treatment.},
}

Animals
Mice
*Alzheimer Disease/drug therapy/metabolism
Amyloid beta-Peptides/metabolism
Cognition
Disease Models, Animal
Imidazoles
Interleukin-6/metabolism
Ligands
Mice, Transgenic
Microglia
Pyridines
Tumor Necrosis Factor-alpha/metabolism

@article {pmid35745834,
year = {2022},
author = {Lo Presti, E and D'Orsi, L and De Gaetano, A},
title = {A Mathematical Model of In Vitro Cellular Uptake of Zoledronic Acid and Isopentenyl Pyrophosphate Accumulation.},
journal = {Pharmaceutics},
volume = {14},
number = {6},
pages = {},
pmid = {35745834},
issn = {1999-4923},
abstract = {The mevalonate pathway is an attractive target for many areas of research, such as autoimmune disorders, atherosclerosis, Alzheimer's disease and cancer. Indeed, manipulating this pathway results in the alteration of malignant cell growth with promising therapeutic potential. There are several pharmacological options to block the mevalonate pathway in cancer cells, one of which is zoledronic acid (ZA) (an N-bisphosphonate (N-BP)), which inhibits the farnesyl pyrophosphate (FPP) synthase enzyme, inducing cell cycle arrest, apoptosis, inhibition of protein prenylation, and cholesterol reduction, as well as leading to the accumulation of isopentenyl pyrophosphate (IPP). We extrapolated the data based on two independently published papers that provide numerical data on the uptake of zoledronic acid (ZA) and the accumulation of IPP (Ag) and its isomer over time by using in vitro human cell line models. Two different mathematical models for IPP kinetics are proposed. The first model (Model 1) is a simpler ordinary differential equation (ODE) compartmental system composed of 3 equations with 10 parameters; the second model (Model 2) is a differential algebraic equation (DAE) system with 4 differential equations, 1 algebraic equation and 13 parameters incorporating the formation of the ZA+enzyme+Ag complex. Each of the two models aims to describe two different experimental situations (continuous and pulse experiments) with the same ZA kinetics. Both models fit the collected data very well. With Model 1, we obtained a prevision accumulation of IPP after 24 h of 169.6 pmol/mgprot/h with an IPP decreasing rate per (pmol/mgprot) of ZA (kXGZ) equal to 13.24/h. With Model 2, we have comprehensive kinetics of IPP upon ZA treatment. We calculate that the IPP concentration was equal to 141.6 pmol/mgprot/h with a decreasing rate/percentage of 0.051 (kXGU). The present study is the first to quantify the influence of ZA on the pharmacodynamics of IPP. While still incorporating a small number of parameters, Model 2 better represents the complexity of the biological behaviour for calculating the IPP produced in different situations, such as studies on γδ T cell-based immunotherapy. In the future, additional clinical studies are warranted to further evaluate and fine-tune dosing approaches.},
}

@article {pmid34960353,
year = {2021},
author = {Breasail, MÓ and Biswas, B and Smith, MD and Mazhar, MKA and Tenison, E and Cullen, A and Lithander, FE and Roudaut, A and Henderson, EJ},
title = {Wearable GPS and Accelerometer Technologies for Monitoring Mobility and Physical Activity in Neurodegenerative Disorders: A Systematic Review.},
journal = {Sensors (Basel, Switzerland)},
volume = {21},
number = {24},
pages = {},
pmid = {34960353},
issn = {1424-8220},
support = {GAT3676//The Gatsby Foundation/ ; },
mesh = {Accelerometry ; Exercise ; Geographic Information Systems ; Humans ; *Neurodegenerative Diseases ; Technology ; *Wearable Electronic Devices ; },
abstract = {Neurodegenerative disorders (NDDs) constitute an increasing global burden and can significantly impair an individual's mobility, physical activity (PA), and independence. Remote monitoring has been difficult without relying on diaries/questionnaires which are more challenging for people with dementia to complete. Wearable global positioning system (GPS) sensors and accelerometers present a cost-effective and noninvasive way to passively monitor mobility and PA. In addition, changes in sensor-derived outcomes (such as walking behaviour, sedentary, and active activity) may serve as potential biomarkers of disease onset, progression, and response to treatment. We performed a systematic search across four databases to identify papers published within the past 5 years, in which wearable GPS or accelerometers were used to monitor mobility or PA in patients with common NDDs (Parkinson's disease, Alzheimer's disease, motor neuron diseases/amyotrophic lateral sclerosis, vascular parkinsonism, and vascular dementia). Disease and technology-specific vocabulary were searched singly, and then in combination, identifying 4985 papers. Following deduplication, we screened 3115 papers and retained 28 studies following a full text review. One study used wearable GPS and accelerometers, while 27 studies used solely accelerometers in NDDs. GPS-derived measures had been validated against current gold standard measures in one Parkinson's cohort, suggesting that the technology may be applicable to other NDDs. In contrast, accelerometers are widely utilised in NDDs and have been operationalised in well-designed clinical trials.},
}

Accelerometry
Exercise
Geographic Information Systems
Humans
*Neurodegenerative Diseases
Technology
*Wearable Electronic Devices

@article {pmid34521461,
year = {2021},
author = {Kim, HJ and Cho, KR and Jang, H and Lee, NK and Jung, YH and Kim, JP and Lee, JI and Chang, JW and Park, S and Kim, ST and Moon, SW and Seo, SW and Choi, SJ and Na, DL},
title = {Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer's disease dementia: a phase I clinical trial.},
journal = {Alzheimer's research & therapy},
volume = {13},
number = {1},
pages = {154},
pmid = {34521461},
issn = {1758-9193},
mesh = {*Alzheimer Disease/therapy ; Animals ; Fetal Blood ; Follow-Up Studies ; Humans ; *Mesenchymal Stem Cell Transplantation ; *Mesenchymal Stem Cells ; },
abstract = {BACKGROUNDS: Alzheimer's disease is the most common cause of dementia, and currently, there is no disease-modifying treatment. Favorable functional outcomes and reduction of amyloid levels were observed following transplantation of mesenchymal stem cells (MSCs) in animal studies.

OBJECTIVES: We conducted a phase I clinical trial in nine patients with mild-to-moderate Alzheimer's disease dementia to evaluate the safety and dose-limiting toxicity of three repeated intracerebroventricular injections of human umbilical cord blood-derived MSCs (hUCB-MSCs).

METHODS: We recruited nine mild-to-moderate Alzheimer's disease dementia patients from Samsung Medical Center, Seoul, Republic of Korea. Four weeks prior to MSC administration, the Ommaya reservoir was implanted into the right lateral ventricle of the patients. Three patients received a low dose (1.0 × 10[7] cells/2 mL), and six patients received a high dose (3.0 × 10[7] cells/2 mL) of hUCB-MSCs. Three repeated injections of MSCs were performed (4-week intervals) in all nine patients. These patients were followed up to 12 weeks after the first hUCB-MSC injection and an additional 36 months in the extended observation study.

RESULTS: After hUCB-MSC injection, the most common adverse event was fever (n = 9) followed by headache (n = 7), nausea (n = 5), and vomiting (n = 4), which all subsided within 36 h. There were three serious adverse events in two participants that were considered to have arisen from the investigational product. Fever in a low dose participant and nausea with vomiting in another low dose participant each required extended hospitalization by a day. There were no dose-limiting toxicities. Five participants completed the 36-month extended observation study, and no further serious adverse events were observed.

CONCLUSIONS: Three repeated administrations of hUCB-MSCs into the lateral ventricle via an Ommaya reservoir were feasible, relatively and sufficiently safe, and well-tolerated. Currently, we are undergoing an extended follow-up study for those who participated in a phase IIa trial where upon completion, we hope to gain a deeper understanding of the clinical efficacy of MSC AD therapy.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02054208. Registered on 4 February 2014. ClinicalTrials.gov NCT03172117. Registered on 1 June 2017.},
}

*Alzheimer Disease/therapy
Animals
Fetal Blood
Follow-Up Studies
Humans
*Mesenchymal Stem Cell Transplantation
*Mesenchymal Stem Cells

@article {pmid33352990,
year = {2020},
author = {Herrero-Labrador, R and Trueba-Saiz, A and Martinez-Rachadell, L and Fernandez de Sevilla, ME and Zegarra-Valdivia, JA and Pignatelli, J and Diaz-Pacheco, S and Fernandez, AM and Torres Aleman, I},
title = {Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance.},
journal = {International journal of molecular sciences},
volume = {21},
number = {24},
pages = {},
pmid = {33352990},
issn = {1422-0067},
support = {PIE14/00061//Ciberned/ ; SAF2013-40710-R (AEI/FEDER, UE)//Mineco/ ; },
mesh = {Alzheimer Disease/etiology/metabolism/pathology ; Amyloid beta-Peptides/*metabolism ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Biomarkers ; Brain/metabolism/pathology ; *Diet, High-Fat ; Disease Models, Animal ; Hepatocytes/metabolism ; Insulin-Like Growth Factor I/*metabolism ; Mice ; Mice, Transgenic ; Overweight ; },
abstract = {Obesity is a risk factor for Alzheimer's disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact brain Aβ load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain Aβ clearance and is increased in the serum of overweight mice. Overweight mice showed increased Aβ accumulation by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. We also found that Aβ accumulation by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced liver Aβ accumulation-ameliorated by IGF-I administration, and unchanged brain Aβ levels. In the brain, IGF-I favored the association of its receptor (IGF-IR) with the Aβ precursor protein (APP), and at the same time, stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPβ ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly reduced brain IGF-IR phosphorylation and APP/IGF-IR association were found in overweight mice as compared to lean controls. Collectively, these results indicate that a high-fat diet influences peripheral clearance of Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ load probably because its brain entrance is reduced.},
}

Alzheimer Disease/etiology/metabolism/pathology
Amyloid beta-Peptides/*metabolism
Amyloid beta-Protein Precursor/metabolism
Animals
Biomarkers
Brain/metabolism/pathology
*Diet, High-Fat
Disease Models, Animal
Hepatocytes/metabolism
Insulin-Like Growth Factor I/*metabolism
Mice
Mice, Transgenic
Overweight

@article {pmid32171792,
year = {2020},
author = {Hu, S and Xian, Y and Fan, Y and Mak, S and Wang, J and Tang, J and Pang, Y and Pi, R and Tsim, KW and Liu, F and Lin, Z and Han, Y},
title = {Significant combination of Aβ aggregation inhibitory and neuroprotective properties in silico, in vitro and in vivo by bis(propyl)-cognitin, a multifunctional anti-Alzheimer's agent.},
journal = {European journal of pharmacology},
volume = {876},
number = {},
pages = {173065},
doi = {10.1016/j.ejphar.2020.173065},
pmid = {32171792},
issn = {1879-0712},
mesh = {Alzheimer Disease/*drug therapy/metabolism ; Amyloid/metabolism/toxicity ; Amyloid beta-Peptides/*metabolism/toxicity ; Animals ; Computer Simulation ; Disease Models, Animal ; Glycogen Synthase Kinase 3 beta/metabolism ; Male ; Maze Learning/drug effects ; Molecular Dynamics Simulation ; Neuroprotective Agents/*pharmacology ; PC12 Cells ; Peptide Fragments/*metabolism/toxicity ; Protein Aggregation, Pathological/metabolism/*prevention & control ; Protein Binding ; Rats ; Rats, Sprague-Dawley ; Tacrine/*analogs & derivatives/pharmacology ; },
abstract = {Inhibition of Aβ aggregation and neurotoxicity has been developed as an attractive therapeutic strategy to combat Alzheimer's disease (AD). Bis(propyl)-cognitin (B3C) is a multifunctional dimer derived from tacrine. Herein, the anti-aggregation and disassembly effects of B3C on Aβ, together with the neuroprotective effects and underlying mechanisms of B3C against Aβ-induced neurotoxicity were investigated in silico, in vitro and in vivo. Data from Thioflavin-T fluorescence and atomic force microscopy assays indicated that B3C (1-10 μM), but not its monomer tacrine, greatly inhibited the formation of Aβ fibrils and disaggregated pre-formed mature Aβ fibrils. Comparative molecular dynamics simulation results revealed a possible binding mode that prevented Aβ fibrils formation, showing that B3C favorably bound to Aβ via hydrophobic interactions. Additionally, B3C was able to block the neurotoxicity caused by Aβ fibrils in cultured PC12 cells. Very encouragingly, B3C (0.3 and 0.45 mg/kg) markedly alleviated the cognitive impairments in rats insulted by intra-hippocampal injection of Aβ1-42 fibrils, more potently than tacrine (1 and 2 mg/kg). Furthermore, mechanistic studies demonstrated that B3C reversed the inhibition of phospho-GSK3β at Ser[9] site in vitro and in vivo caused by Aβ, suggesting the neuroprotection of B3C was achieved through the inhibition of GSK3β pathway. These findings indicate that B3C could serve as an effective inhibitor of Aβ aggregation and neurotoxicity, and provide novel molecular insights into the potential application of B3C in AD prevention and treatment.},
}

Alzheimer Disease/*drug therapy/metabolism
Amyloid/metabolism/toxicity
Amyloid beta-Peptides/*metabolism/toxicity
Animals
Computer Simulation
Disease Models, Animal
Glycogen Synthase Kinase 3 beta/metabolism
Male
Maze Learning/drug effects
Molecular Dynamics Simulation
Neuroprotective Agents/*pharmacology
PC12 Cells
Peptide Fragments/*metabolism/toxicity
Protein Aggregation, Pathological/metabolism/*prevention & control
Protein Binding
Rats
Rats, Sprague-Dawley
Tacrine/*analogs & derivatives/pharmacology

@article {pmid27597412,
year = {2016},
author = {Ramshini, H and Mannini, B and Khodayari, K and Ebrahim-Habibi, A and Moghaddasi, AS and Tayebee, R and Chiti, F},
title = {Bis(indolyl)phenylmethane derivatives are effective small molecules for inhibition of amyloid fibril formation by hen lysozyme.},
journal = {European journal of medicinal chemistry},
volume = {124},
number = {},
pages = {361-371},
doi = {10.1016/j.ejmech.2016.08.056},
pmid = {27597412},
issn = {1768-3254},
mesh = {Amyloid/*chemistry ; Dose-Response Relationship, Drug ; Humans ; Indoles/*chemistry/*pharmacology/toxicity ; Kinetics ; MCF-7 Cells ; Muramidase/*chemistry ; Protein Aggregates/*drug effects ; },
abstract = {Amyloid or similar protein aggregates are the hallmarks of many disorders, including Alzheimer's, Parkinson's, Huntington's diseases and amyloidoses. The inhibition of the formation of these aberrant species by small molecules is a promising strategy for disease treatment. However, at present, all such diseases lack an appropriate therapeutic approach based on small molecules. In this work we have evaluated five bis(indolyl)phenylmethane derivatives to reduce amyloid fibril formation by hen egg white lysozyme (HEWL) and its associated cytotoxicity. HEWL is a widely used model system to study the fundamentals of amyloid fibril formation and is heterologous to human lysozyme, which forms amyloid fibrils in a familial form of systemic amyloidosis. HEWL aggregation was tested in the presence and absence of the five compounds, under conditions in which the protein is partially unfolded. To this purpose, various techniques were used, including Congo red and Thioflavin T binding assays, atomic force microscopy, Fourier-Transform Infrared spectroscopy and cell-based cytotoxicity assays, such as the MTT reduction test and the trypan blue test. It was found that all compounds inhibited the formation of amyloid fibrils and their associated toxicity, diverging the aggregation process towards the formation of large, morphologically amorphous, unstructured, nontoxic aggregates, thus resembling class I molecules defined previously. In addition, the five compounds also appeared to disaggregate pre-formed fibrils of HEWL, which categorizes them into class IA. The half maximal inhibitory concentration (IC50) was found to be ca 12.3 ± 1.0 μM for the forefather compound.},
}

Amyloid/*chemistry
Dose-Response Relationship, Drug
Humans
Indoles/*chemistry/*pharmacology/toxicity
Kinetics
MCF-7 Cells
Muramidase/*chemistry
Protein Aggregates/*drug effects

@article {pmid25407821,
year = {2015},
author = {Hu, S and Wang, R and Cui, W and Zhang, Z and Mak, S and Xu, D and Choi, C and Tsim, KW and Carlier, PR and Lee, M and Han, Y},
title = {Inhibiting β-amyloid-associated Alzheimer's pathogenesis in vitro and in vivo by a multifunctional dimeric bis(12)-hupyridone derived from its natural analogue.},
journal = {Journal of molecular neuroscience : MN},
volume = {55},
number = {4},
pages = {1014-1021},
pmid = {25407821},
issn = {1559-1166},
mesh = {Alzheimer Disease/*drug therapy ; Animals ; Apoptosis ; Cell Line, Tumor ; Humans ; Male ; Maze Learning ; Memory ; Neuroprotective Agents/*therapeutic use ; Protein Aggregation, Pathological/*drug therapy ; Quinolones/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; },
abstract = {Fibrillar aggregates of β-amyloid protein (Aβ) is the main constituent of senile plaques and considered to be one of the causative events in the pathogenesis of Alzheimer's disease (AD). Compounds that could inhibit the formation of Aβ fibrils and block Aβ fibrils-associated toxicity may have therapeutic potential to combat AD. Bis(12)-hupyridone (B12H) is a multifunctional homodimer derived from huperzine A, which is an anti-AD drug in China. In the current study, the inhibitory effect of B12H on the formation of Aβ fibrils and their associated toxicity was investigated both in vitro and in vivo. By using Thioflavin T fluorescence assay, we found that B12H (0.3-3 μM) directly inhibited Aβ fibrils formation following co-incubation of B12H and Aβ1-40 at 37 °C for 6 days in vitro. However, huperzine A, at the same concentrations, did not show significant inhibitory effect on Aβ1-40 fibrils formation. Moreover, B12H markedly reduced Aβ1-40-induced cytotoxicity in cultured SH-SY5Y cells, as evidenced by the increase in cell viability, the decrease in lactate dehydrogenase release, and the reduction of apoptotic nuclei. Most importantly, B12H (0.2 and 0.4 mg/kg) reduced intracerebroventricular Aβ1-40 infusion-induced cognitive and memory impairments in rats, as evidenced by the decrease in escape latency and the increase in the spatial bias in Morris water maze test along with increasing choline acetyltransferase activity and decreasing acetylcholinesterase activity. Collectively, our study provided novel sights into the potential application of B12H in AD treatment.},
}

Alzheimer Disease/*drug therapy
Animals
Apoptosis
Cell Line, Tumor
Humans
Male
Maze Learning
Memory
Neuroprotective Agents/*therapeutic use
Protein Aggregation, Pathological/*drug therapy
Quinolones/*therapeutic use
Rats
Rats, Sprague-Dawley

@article {pmid23436051,
year = {2014},
author = {Degnan, AJ and Levy, LM},
title = {Neuroimaging of rapidly progressive dementias, part 1: neurodegenerative etiologies.},
journal = {AJNR. American journal of neuroradiology},
volume = {35},
number = {3},
pages = {418-423},
pmid = {23436051},
issn = {1936-959X},
mesh = {Dementia/*diagnosis/etiology ; Disease Progression ; Humans ; Neurodegenerative Diseases/complications ; *Neuroimaging ; Time Factors ; },
abstract = {Most dementias begin insidiously, developing slowly and generally occurring in the elderly age group. The so-called rapidly progressive dementias constitute a different, diverse collection of conditions, many of which are reversible or treatable. For this reason, prompt identification and assessment of acute and subacute forms of dementia are critical to effective treatment. Numerous other entities within this category of presenile rapid-onset dementias are untreatable such as the prion-related diseases. Neuroimaging aids in the diagnosis and evaluation of many of these rapidly progressive dementias, which include myriad conditions ranging from variations of more common neurodegenerative dementias, such as Alzheimer disease, dementia with Lewy bodies, and frontotemporal dementia; infectious-related dementias such as acquired immune deficiency syndrome dementia; autoimmune and malignancy-related conditions; to toxic and metabolic forms of encephalopathy. This first of a 2-part review will specifically address the ability of MR imaging and ancillary neuroimaging strategies to support the diagnostic evaluation of rapidly progressive dementias due to neurodegenerative causes.},
}

Dementia/*diagnosis/etiology
Disease Progression
Humans
Neurodegenerative Diseases/complications
*Neuroimaging
Time Factors

@article {pmid21660200,
year = {2011},
author = {Cosentino, S and Metcalfe, J and Cary, MS and De Leon, J and Karlawish, J},
title = {Memory Awareness Influences Everyday Decision Making Capacity about Medication Management in Alzheimer's Disease.},
journal = {International journal of Alzheimer's disease},
volume = {2011},
number = {},
pages = {483897},
pmid = {21660200},
issn = {2090-0252},
support = {K23 AG032899/AG/NIA NIH HHS/United States ; L30 AG026603/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; R01 MH060637/MH/NIMH NIH HHS/United States ; },
abstract = {Memory awareness in early Alzheimer's disease (AD) influences capacity to provide informed consent for a memory treatment. This study investigated the extent to which aspects of memory awareness influence everyday decision-making capacity about medication management in AD. 42 participants with mild AD and 50 healthy elders underwent clinical ratings of memory awareness, metamemory testing, and an interview of everyday decision-making capacity regarding medication management. 45% of AD subjects were classified as aware (AAD) and 55% as unaware (UAD) based on clinical ratings and supported by metamemory testing (P = .015). Capacity was impaired in each of the AD groups as compared to the healthy elders F(2, 67) = 17.63, UAD, P < .01; AAD, P = .01). Within the AD group, capacity correlated selectively with awareness as measured with clinical ratings (r = -.41, P = .007) but not objective metamemory testing (r = -.10, P = .60). Appreciation scores were lower in UAD as compared with AAD F(1,35) = 8.36, P = .007. Unawareness of memory loss should heighten clinicians' concern about everyday decision-making capacity in AD.},
}

@article {pmid15296846,
year = {2004},
author = {Ricceri, L and Minghetti, L and Moles, A and Popoli, P and Confaloni, A and De Simone, R and Piscopo, P and Scattoni, ML and di Luca, M and Calamandrei, G},
title = {Cognitive and neurological deficits induced by early and prolonged basal forebrain cholinergic hypofunction in rats.},
journal = {Experimental neurology},
volume = {189},
number = {1},
pages = {162-172},
doi = {10.1016/j.expneurol.2004.05.025},
pmid = {15296846},
issn = {0014-4886},
mesh = {Acetylcholine/*metabolism ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Animals, Newborn ; Antibodies, Monoclonal/toxicity ; Behavior, Animal ; Blotting, Western/methods ; Brain Chemistry/drug effects ; Choline O-Acetyltransferase/metabolism ; Cognition Disorders/*etiology/metabolism ; Conditioning, Operant/drug effects/physiology ; Cues ; Cyclooxygenase 2 ; Electroencephalography/drug effects ; Female ; Gene Expression Regulation, Developmental/drug effects ; Hippocampus/drug effects/metabolism/physiopathology ; Immunotoxins/toxicity ; Isoenzymes/metabolism ; Male ; Membrane Proteins/metabolism ; N-Glycosyl Hydrolases ; Nervous System Diseases/*etiology/metabolism ; Phobic Disorders/metabolism/physiopathology ; Presenilin-1 ; Presenilin-2 ; Prosencephalon/metabolism/*physiopathology ; Prostaglandin-Endoperoxide Synthases/metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Ribosome Inactivating Proteins, Type 1 ; Saporins ; Social Behavior ; Time Factors ; },
abstract = {In the present study we examined the long-term effects of neonatal lesion of basal forebrain cholinergic neurons induced by intracerebroventricular injections of the immunotoxin 192 IgG saporin. Animals were then characterised behaviourally, electrophysiologically and molecularly. Cognitive effects were evaluated in the social transmission of food preferences, a non-spatial associative memory task. Electrophysiological effects were assessed by recording of cortical electroencephalographic (EEG) patterns. In addition, we measured the levels of proteins whose abnormal expression has been associated with neurodegeneration such as amyloid precursor protein (APP), presenilin 1 and 2 (PS-1, PS-2), and cyclooxygenases (COX-1 and COX-2). In animals lesioned on postnatal day 7 and tested 6 months thereafter, memory impairment in the social transmission of food preferences was evident, as well as a significant reduction of choline acetyltransferase activity in hippocampus and neocortex. Furthermore, similar to what observed in Alzheimer-like dementia, EEG cortical patterns in lesioned rats presented changes in alpha, beta and delta activities. Levels of APP protein and mRNA were not affected by the treatment. Levels of hippocampal COX-2 protein and mRNA were significantly decreased whereas COX-1 remained unaltered. PS-1 and PS-2 transcripts were reduced in hippocampus and neocortex. These findings indicate that neonatal and permanent basal forebrain cholinergic hypofunction is sufficient to induce behavioural and neuropathological abnormalities. This animal model could represent a valid tool to evaluate the role played by abnormal cholinergic maturation in later vulnerability to neuropathological processes associated with cognitive decline and, possibly, to Alzheimer-like dementia.},
}

Acetylcholine/*metabolism
Amyloid beta-Protein Precursor/metabolism
Animals
Animals, Newborn
Antibodies, Monoclonal/toxicity
Behavior, Animal
Blotting, Western/methods
Brain Chemistry/drug effects
Choline O-Acetyltransferase/metabolism
Cognition Disorders/*etiology/metabolism
Conditioning, Operant/drug effects/physiology
Cues
Cyclooxygenase 2
Electroencephalography/drug effects
Female
Gene Expression Regulation, Developmental/drug effects
Hippocampus/drug effects/metabolism/physiopathology
Immunotoxins/toxicity
Isoenzymes/metabolism
Male
Membrane Proteins/metabolism
N-Glycosyl Hydrolases
Nervous System Diseases/*etiology/metabolism
Phobic Disorders/metabolism/physiopathology
Presenilin-1
Presenilin-2
Prosencephalon/metabolism/*physiopathology
Prostaglandin-Endoperoxide Synthases/metabolism
RNA, Messenger/metabolism
Rats
Rats, Wistar
Reverse Transcriptase Polymerase Chain Reaction/methods
Ribosome Inactivating Proteins, Type 1
Saporins
Social Behavior
Time Factors

@article {pmid11487523,
year = {2001},
author = {Law, A and Gauthier, S and Quirion, R},
title = {Neuroprotective and neurorescuing effects of isoform-specific nitric oxide synthase inhibitors, nitric oxide scavenger, and antioxidant against beta-amyloid toxicity.},
journal = {British journal of pharmacology},
volume = {133},
number = {7},
pages = {1114-1124},
pmid = {11487523},
issn = {0007-1188},
mesh = {Amyloid beta-Peptides/*toxicity ; Animals ; Antioxidants/*pharmacology ; Benzoates/pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Cerebral Cortex/cytology/drug effects/metabolism ; Chromans/pharmacology ; Citrulline/analogs & derivatives/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Imidazoles/pharmacology ; Isoenzymes/antagonists & inhibitors ; Lysine/analogs & derivatives/pharmacology ; Neuroprotective Agents/*pharmacology ; Nitrates/pharmacology ; Nitric Oxide/*antagonists & inhibitors/metabolism ; Nitric Oxide Synthase/*antagonists & inhibitors ; Nitroarginine/pharmacology ; Oxidants/pharmacology ; Peptide Fragments/toxicity ; Rats ; Rats, Sprague-Dawley ; Thiourea/analogs & derivatives/pharmacology ; Time Factors ; },
abstract = {Beta amyloid (Abeta) is implicated in Alzheimer's disease (AD). Abeta(1 - 42) (5, 10, or 20 microM) was able to increase NO release and decrease cellular viability in primary rat cortical mixed cultures. L-NOARG and SMTC (both at 10 or 100 microM) - type I NOS inhibitors - reduced cellular NO release in the absence of Abeta(1 - 42). At 100 microM, both drugs decreased cell viability. L-NIL (10 or 100 microM), and 1400W (1 or 5 microM) - type II NOS inhibitors - reduced NO release and improved viability when either drug was administered up to 4 h post Abeta(1 - 42) (10 microM) treatment. L-NOARG and SMTC (both at 10 or 100 microM) were only able to decrease NO release. Carboxy-PTIO or Trolox (both at 10 or 100 microM) - a NO scavenger and an antioxidant, respectively - increased viability when administered up to 1 h post Abeta(1 - 42) treatment. Either L-NIL (50 microM) or 1400W (3 microM) and Trolox (50 microM) showed synergistic actions. Peroxynitrite (100 or 200 microM) reduced cell viability. Viabilities were improved by L-NIL (100 microM), 1400W (5 microM), carboxy-PTIO (10 or 100 microM), and Trolox (10 or 100 microM). Hence, the data show that Abeta(1 - 42) induced NO release in neurons and glial cells, and that Abeta neurotoxicity is, at least in part, mediated by NO. NO concentration modulating compounds and antioxidant may have therapeutic importance in neurological disorders where oxidative stress is likely involved such as in AD.},
}

Amyloid beta-Peptides/*toxicity
Animals
Antioxidants/*pharmacology
Benzoates/pharmacology
Cell Survival/drug effects
Cells, Cultured
Cerebral Cortex/cytology/drug effects/metabolism
Chromans/pharmacology
Citrulline/analogs & derivatives/pharmacology
Dose-Response Relationship, Drug
Enzyme Inhibitors/pharmacology
Imidazoles/pharmacology
Isoenzymes/antagonists & inhibitors
Lysine/analogs & derivatives/pharmacology
Neuroprotective Agents/*pharmacology
Nitrates/pharmacology
Nitric Oxide/*antagonists & inhibitors/metabolism
Nitric Oxide Synthase/*antagonists & inhibitors
Nitroarginine/pharmacology
Oxidants/pharmacology
Peptide Fragments/toxicity
Rats
Rats, Sprague-Dawley
Thiourea/analogs & derivatives/pharmacology
Time Factors

@article {pmid8006353,
year = {1994},
author = {Tappen, RM},
title = {Development of the refined ADL Assessment Scale for patients with Alzheimer's and related disorders.},
journal = {Journal of gerontological nursing},
volume = {20},
number = {6},
pages = {36-42},
doi = {10.3928/0098-9134-19940601-09},
pmid = {8006353},
issn = {0098-9134},
mesh = {Activities of Daily Living ; Aged ; Aged, 80 and over ; Alzheimer Disease/*diagnosis ; Female ; *Geriatric Assessment ; Humans ; *Psychiatric Status Rating Scales ; },
abstract = {1. Most activities of daily living (ADL) scales currently available for assessment of the older person's functional level were developed for the physically (not cognitively) impaired individual. 2. The Refined ADL Assessment Scale (RADL) measures three dimensions of functional ability: the components of a given task in sequential order, degree of assistance needed to carry out the task, and the amount of time needed to complete the task. 3. Each of the 14 tasks on the RADL is broken down into its simpler component parts, a process called task analysis. 4. The RADL may be used as a guide to providing assistance with the basic ADLs and to evaluate an individual's improvement with treatment.},
}

Activities of Daily Living
Aged
Aged, 80 and over
Alzheimer Disease/*diagnosis
Female
*Geriatric Assessment
Humans
*Psychiatric Status Rating Scales

@article {pmid1487856,
year = {1992},
author = {Mitsuyama, Y and Hashiguchi, H and Murayama, T and Koono, M and Nishi, S},
title = {An autopsied case of interferon encephalopathy.},
journal = {The Japanese journal of psychiatry and neurology},
volume = {46},
number = {3},
pages = {741-748},
doi = {10.1111/j.1440-1819.1992.tb00550.x},
pmid = {1487856},
issn = {0912-2036},
mesh = {Aged ; Alzheimer Disease/pathology ; Brain/drug effects/pathology ; Carcinoma, Renal Cell/pathology/*therapy ; Diagnosis, Differential ; Encephalitis/*chemically induced/pathology ; Humans ; Interferon-alpha/administration & dosage/*adverse effects ; Intracranial Arteriosclerosis/pathology ; Kidney Neoplasms/pathology/*therapy ; Magnetic Resonance Imaging ; Male ; Myelin Sheath/pathology ; Neuropsychological Tests ; Psychoses, Substance-Induced/*pathology ; Tomography, X-Ray Computed ; },
abstract = {A 78-year-old male with renal carcinoma was treated with a high dose infusion of interferon-alpha (IFN-alpha) for eight months. The patient had evidence of organic brain syndrome such as dysfunction of memory, slowing of behavior, and development of mental confusion that appeared eight months after the treatment. MRI at the time of mental confusion revealed diffuse white matter lesions. Neuropathologic findings were compatible to Binswanger's disease and Senile Dementia of Alzheimer Type (SDAT), Preexisting neurologic abnormalities including intracerebral arteriosclerosis and cerebral atrophy may increase susceptibility to unacceptably severe IFN neurotoxicity.},
}

Aged
Alzheimer Disease/pathology
Brain/drug effects/pathology
Carcinoma, Renal Cell/pathology/*therapy
Diagnosis, Differential
Encephalitis/*chemically induced/pathology
Humans
Interferon-alpha/administration & dosage/*adverse effects
Intracranial Arteriosclerosis/pathology
Kidney Neoplasms/pathology/*therapy
Magnetic Resonance Imaging
Male
Myelin Sheath/pathology
Neuropsychological Tests
Psychoses, Substance-Induced/*pathology
Tomography, X-Ray Computed

@article {pmid2163437,
year = {1990},
author = {Norenberg, MD and Neary, JT and Norenberg, LO and McCarthy, M},
title = {Ammonia induced decrease in glial fibrillary acidic protein in cultured astrocytes.},
journal = {Journal of neuropathology and experimental neurology},
volume = {49},
number = {4},
pages = {399-405},
doi = {10.1097/00005072-199007000-00004},
pmid = {2163437},
issn = {0022-3069},
mesh = {Ammonia/*pharmacology ; Ammonium Chloride/pharmacology ; Animals ; Astrocytes/*metabolism ; Bucladesine/pharmacology ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; Fluorescent Antibody Technique ; Glial Fibrillary Acidic Protein/*metabolism ; Rats ; },
abstract = {Previous studies of human hepatic encephalopathy (HE) have shown decreased levels of glial fibrillary acidic protein (GFAP) in Alzheimer type II astrocytes. In view of the important role of ammonia in the pathogenesis of HE, we carried out immunocytochemical and enzyme-linked immunosorbent assay (ELISA) studies on the effect of ammonium chloride (10 mM) on GFAP content in primary astrocyte cultures. There was a 39% loss of GFAP after a four day treatment. There was no fall in total cell protein. Potential mechanisms for this apparent selective loss of GFAP are discussed.},
}

Ammonia/*pharmacology
Ammonium Chloride/pharmacology
Animals
Astrocytes/*metabolism
Bucladesine/pharmacology
Cells, Cultured
Enzyme-Linked Immunosorbent Assay
Fluorescent Antibody Technique
Glial Fibrillary Acidic Protein/*metabolism
Rats

@article {pmid40826256,
year = {2025},
author = {Langness, VF and Simmons, DA and McHugh, TLM and Butler, RR and Zhou, J and Liu, H and Yang, T and Ellerby, LM and Longo, FM},
title = {Twenty years of therapeutic development in tauopathy mouse models: a scoping review.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70578},
doi = {10.1002/alz.70578},
pmid = {40826256},
issn = {1552-5279},
support = {//Jean Perkins Foundation/ ; //Taube Philanthropies/ ; T32 AG052374/AG/NIA NIH HHS/United States ; PO1 AG066591/AG/NIA NIH HHS/United States ; },
abstract = {Tauopathies are neurodegenerative diseases characterized by pathological tau protein inclusions and dementia. Tauopathy mouse models with MAPT mutations replicate tau-related pathologies and are widely used for therapeutic research. This scoping review examines 409 treatment evaluations in MAPT mouse models. We identify trends in therapeutic strategies and frequently used mouse models, treatment routes, and endpoints. We also document treatment effects and when treatment is initiated relative to tau pathology emergence. Many treatments produced positive effects in multiple MAPT mouse models across many endpoints but showed limited success in clinical trials. Potential barriers to mouse-to-human translation include differences between mouse and human studies in the timing of treatment initiation relative to tau pathology onset, predominant testing of a limited number of endpoints, lack of translatable treatment response biomarkers, and the limited ability of individual mouse models to represent the diversity of tauopathies. Addressing these obstacles could improve mouse-to-human translation for tauopathy therapeutics. HIGHLIGHTS: Two decades of therapeutic research in tauopathy mouse models were reviewed. Treatments often began before or at tau pathology onset in tauopathy mouse models. Key endpoints (e.g., cognition and synaptic degeneration) were underassessed. Well-characterized preclinical treatments often had limited success in humans. Single-sex mouse studies and a lack of biomarkers hinder clinical translation.},
}

@article {pmid40826098,
year = {2025},
author = {Chia, SY and Li, M and Li, Z and Tu, H and Lee, JWL and Qiu, L and Ling, J and Reynolds, R and Albani, S and Tan, EK and Ng, ASL and Chen, J and Zeng, L},
title = {Single-nucleus transcriptomics reveals a distinct microglial state and increased MSR1-mediated phagocytosis as common features across dementia subtypes.},
journal = {Genome medicine},
volume = {17},
number = {1},
pages = {92},
pmid = {40826098},
issn = {1756-994X},
support = {LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; NMRC/OFLCG/002/2018//National Medical Research Council Open Fund-Large Collaborative Grant/ ; LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; MOH-CIRG21nov-0001//Clinician Scientist Individual Research Grant/ ; MOH-CIRG21nov-0001//Clinician Scientist Individual Research Grant/ ; MOH-CIRG21nov-0001//Clinician Scientist Individual Research Grant/ ; CIRG19may0052//Clinician Scientist Individual Research Grant/ ; MOH-CIRG21nov-0001//Clinician Scientist Individual Research Grant/ ; OFIRG23jul-0075//Open Fund-Individual Research Grant/ ; OFIRG23jul-0075//Open Fund-Individual Research Grant/ ; OFIRG23jul-0075//Open Fund-Individual Research Grant/ ; OFIRG23jul-0075//Open Fund-Individual Research Grant/ ; MOH-STaR19nov-0002//NMRC Awarded Projects Talent Development/ ; MOH-000988//Duke-NUS and SingHealth AMC core funding as well as Singapore Ministry of Health's NMRC under its Centre Grant Program/ ; A*STAR PEC21-H22P0M0003//A*STAR/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD) collectively represent the majority of dementia cases worldwide. While these subtypes share clinical, genetic, and pathological features, their transcriptomic similarities and differences remain poorly understood.

METHODS: We applied single-nucleus RNA-sequencing (snRNA-seq) to prefrontal cortex samples from individuals with non-cognitive impairment control (NCI), and dementia subtypes (AD, DLB, and PDD) to investigate cell type-specific gene expression patterns and pathways underlying pathological similarities and differences across dementia subtypes. SnRNA-seq findings were validated through RNAscope, immunohistochemistry, and additional biochemical analyses in human tissues and cellular models.

RESULTS: SnRNA-seq analysis revealed elevated microglial proportions across all dementia subtypes compared to NCI. Further analysis of cell type-specific transcriptomes identified overlapping differentially expressed genes (DEGs) between microglia and oligodendrocytes across all dementia subtypes. While AD showed molecular similarities to NCI, PDD and DLB were clustered more closely together, sharing a greater number of DEGs and related pathways, predominantly associated with microglia. Investigation of interactions between microglia and oligodendrocytes revealed a distinct microglial state in all dementia subtypes. MSR1, a gene encoding a scavenger receptor, was upregulated in microglia across all dementia subtypes, along with its associated gene HSPA1A in oligodendrocytes. RNAscope supported the potential interaction between microglia and oligodendrocytes, where these cells were in closer proximity to each other in human cortical tissues of PDD compared to NCI. MSR1 expression was significantly increased in cortical primary microglia from PD mice compared with non-transgenic (NTg) mice. Additionally, the expression of myelin-associated genes (MBP, MOBP, and PLP1) was significantly upregulated in PD microglia compared to NTg, supporting the presence of the distinct microglia. Furthermore, MSR1-positive microglia colocalised with MBP in cortical tissue of PDD patients, suggesting a functional role of MSR1 in myelin debris clearance. Overexpression of MSR1 in microglial cells enhanced their phagocytic activity toward myelin, and reciprocally, myelin treatment upregulated MSR1 protein levels, indicating enhanced MSR1-mediated myelin phagocytosis.

CONCLUSIONS: Our findings provide novel insights into the cell type-specific role of microglial MSR1 in AD, DLB, and PDD, linking its increased phagocytic capacity to myelin defects as a common feature of neurodegenerative dementias.},
}

@article {pmid40825623,
year = {2025},
author = {Ma, W and Tang, B and Zhang, H and Qu, Y and Luan, J and Wang, K and Chen, W and Wang, X and Liu, X and Zhao, H and Li, H and Luo, M and Luo, Z and Shen, L and Chen, M},
title = {Small-molecule fluorescent probes for imaging intracellular amyloid toxicity induces ferroptosis via HClO fluctuation in Alzheimer's disease.},
journal = {Analytica chimica acta},
volume = {1371},
number = {},
pages = {344485},
doi = {10.1016/j.aca.2025.344485},
pmid = {40825623},
issn = {1873-4324},
abstract = {BACKGROUND: Amyloid toxicity induces ferroptosis play a crucial role in the pathological dysfunction of brains affected by Alzheimer's disease (AD). Despite this, brain probing implements for looking into the relationship between ferroptosis and ROS in the brains of AD victims are currently scarce. Herein, a HClO activated ESIPT fluorescent probe HCC-Br was engineered to investigate the complicated correlations between HClO and AD, achieving in vivo diagnosing and evaluating of AD progression.

RESULTS: With this probe, we could also utilize HCC-Br for the visualization and tracking of endogenous HClO production in live cells during Aβ42-induced ferroptosis. More crucially, our findings suggest that tannic acid (TA) shows promise as an effective neuroprotective agent to control MPO-mediated oxidative stress in this stimulated condition. The small molecular structure and suitable lipophilicity endowed HCC-Br with remarkable blood-brain barrier (BBB) permeability, making it enormously applicable to the in vivo detection of HClO variations in AD brains.

SIGNIFICANCE AND NOVELTY: Overall, this study presents a versatile fluorescence tool that can help clarify the contributions of HClO production by MPO in the pathogenic mechanisms of AD. Furthermore, it holds tremendous prospects in exploring the function of HClO in ferroptosis-related pathogenesis and treatment of AD.},
}

@article {pmid40825553,
year = {2025},
author = {Sato, S and Iwata, A and Ishii, K and Kamiki, E and Nishimoto, T},
title = {[Donanemab, an Amyloid β-targeting Antibody for Early Symptomatic Alzheimer's Disease: Summary of Clinical Study Results].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {8},
pages = {907-920},
doi = {10.11477/mf.188160960770080907},
pmid = {40825553},
issn = {1881-6096},
abstract = {Alzheimer's disease is an age-related neurodegenerative disorder, and is considered to contribute to dementia in 60%-70% of individuals with dementia. In recent years, a series of amyloid β protein (Aβ)-targeting antibodies that act directly on Aβ aggregates in the brain, one of the factors which contributes to the onset of Alzheimer's disease, have been approved to suppress the clinical progression, and Alzheimer's disease treatment in Japan is changing. This review article focuses on one of these Aβ-targeting antibodies, donanemab, and summarizes its clinical study results. (Received November 1, 2024; Accepted May 7, 2025; Published August 1, 2025).},
}

@article {pmid40825453,
year = {2025},
author = {Cozza, M and Fimognari, FL and Castagna, A and Boccardi, V},
title = {Antidepressant use in dementia: Assessing effective strategies for a vulnerable population.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106340},
doi = {10.1016/j.neubiorev.2025.106340},
pmid = {40825453},
issn = {1873-7528},
abstract = {Depression is closely associated with dementia and may serve as a risk factor, an early symptom, or a prodromal feature, particularly in Alzheimer's disease, the most common form of dementia. It can also emerge during disease progression, not only in Alzheimer's but in other dementias such as vascular dementia, Lewy body dementia, and frontotemporal dementia. Recognizing the timing and context of depressive symptoms is crucial for accurate diagnosis and management. While non-pharmacological interventions and psychosocial approaches are generally recommended as the first line of treatment, clinical practice often sees widespread use of antidepressants in this vulnerable population. However, such usage is not always supported by robust evidence, particularly given the heightened risk of side effects in older adults with cognitive decline. This narrative review seeks to critically examine the role of antidepressants in managing depression among patients with dementia. Rather than dismissing their use outright, we aim to provide a nuanced perspective on their application, emphasizing the importance of a thorough multidimensional geriatric assessment. The attempt is to help the clinicians in making more individualized, evidence-based decisions that balance the potential benefits and risks, ensuring that treatment is tailored to the unique needs of each patient.},
}

@article {pmid40825161,
year = {2025},
author = {Kapasi, A and James, BD and Yu, L and Sood, A and Arvanitakis, Z and Bennett, DA and Boyle, P and Schneider, JA},
title = {Mixed Pathologies and Cognitive Outcomes in Persons Considered for Anti-Amyloid Treatment Eligibility Assessment: A Community-Based Study.},
journal = {Neurology},
volume = {105},
number = {5},
pages = {e214004},
doi = {10.1212/WNL.0000000000214004},
pmid = {40825161},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Despite the capability of anti-amyloid monoclonal antibodies to lower β-amyloid (Aβ) brain levels, there is thus far limited clinical efficacy on cognitive outcomes. Among individuals with mild cognitive impairment (MCI) or mild-stage dementia, the cognitive impact of other brain pathologies may limit efficacy of anti-amyloid drugs. This study examined the burden and cognitive associations of mixed brain pathologies among autopsied persons who would have been considered as patients to undergo anti-amyloid treatment eligibility assessment.

METHODS: Eligibility was defined based on a Mini-Mental State Examination score ≥20, a clinical diagnosis of MCI or mild-stage Alzheimer dementia, and a level of Aβ pathology at autopsy indicative of having a positive amyloid PET scan (Consortium to Establish a Registry for Alzheimer's Disease score ≥moderate). The number and types of copathologies were examined. Mixed-effects models were used to examine the association of Aβ, tangles, limbic predominant age-related transactive response DNA-binding protein 43 encephalopathy neuropathologic changes (LATE-NC), infarcts, Lewy bodies (LBs), and vessel diseases, with the rate of cognitive decline.

RESULTS: Among 428 older autopsied persons (mean age at death = 91 years, 70% women) considered for anti-amyloid treatment eligibility assessment, 58% had MCI and 42% had mild-stage Alzheimer dementia. Although the majority (94%) had a pathologic diagnosis of Alzheimer disease neuropathologic changes (ADNC), only 26% had ADNC without LATE-NC, LB, or infarcts. The majority (68%) had ADNC with ≥1 copathology with ADNC + infarcts and ADNC + LATE-NC being equally common. In mixed-effects models, tangles and arteriolosclerosis were both associated with a faster rate of global cognitive decline. Separately, tangles and LATE-NC were associated with a faster decline in episodic memory, ADNC was associated with faster decline in semantic memory with Aβ being further associated with decline in working memory, and atherosclerosis was associated with a faster decline in perceptual speed. Infarcts and LBs were not associated with decline in global cognition or any cognitive domain.

DISCUSSION: Mixed pathologies are common among community-dwelling older persons considered for anti-amyloid treatment eligibility assessment. Beyond Aβ, tangles, LATE-NC, and vessel pathologies drive cognitive decline in this group of individuals, especially episodic memory decline. These findings suggest that, even among those eligible for anti-amyloid therapies, substantial cognitive decline may occur because of the presence of coexisting pathologies.},
}

@article {pmid40824894,
year = {2025},
author = {Almarri, B},
title = {Deep learning-based Alzheimer's disease detection using magnetic resonance imaging and gene expression data.},
journal = {PloS one},
volume = {20},
number = {8},
pages = {e0330085},
doi = {10.1371/journal.pone.0330085},
pmid = {40824894},
issn = {1932-6203},
abstract = {Alzheimer's disease (AD) poses significant challenges to healthcare systems across the globe. Early and accurate AD diagnosis is crucial for effective management and treatment. Recent advances in neuroimaging and genomics provide an opportunity for developing multi-modality-based AD diagnosis models using artificial intelligence (AI) techniques. However, the data complexities cause challenges in developing interpretable AI-based AD identification models. In this study, the author built a comprehensive AD diagnostic model using magnetic resonance imaging (MRI) and gene expression data. MobileNet V3 and EfficientNet B7 model was employed to extract AD features from gene expression data. The author introduced a hybrid TWIN-Performer-based feature extraction model to derive features from MRI. The attention-based feature fusion was used to fuse the crucial features. An ensemble learning-based classification model integrating CatBoost, XGBoost, and extremely randomized tree (ERT) was developed to identify cognitively normal (CN) and AD features. The proposed model was validated on diverse datasets. It achieved a superior performance on MRI and gene expression datasets. The area under the receiver operating characteristic (AUROC) scores were consistently above 0.85, indicating excellent model performance. The use of Shapley Additive exPlanations (SHAP) values improved the model's interpretability, leading to earlier interventions and personalized treatment strategies.},
}

@article {pmid40824589,
year = {2025},
author = {Borioni, MS and Morano, A and De Matteis, AL and Mazzeo, A and Moro, P and Di Bonaventura, C and Irelli, EC},
title = {Neuroglial biomarkers in autoimmune encephalitis: advances in diagnosis, prognosis, and pathophysiological insights.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40824589},
issn = {1590-3478},
abstract = {Autoimmune encephalitis (AE) presents with a diverse spectrum of neuropsychiatric symptoms, often leading to diagnostic challenges and delays in treatment. Neuroglial biomarkers may improve AE diagnosis, disease monitoring, and prognostication. This review examines the diagnostic and prognostic value of fluid biomarkers in AE, focusing on markers of neuroaxonal damage, synaptic dysfunction, astroglial activation, and amyloid metabolism. A systematic search of PubMed, Cochrane, and Scopus databases (from inception until November 26, 2024) was performed. Of the 1,270 articles screened, 31 studies met the inclusion criteria. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was the most frequently investigated subtype (70% of studies). Neurofilament light chain (NfL) was the most widely analyzed biomarker, with elevated levels in both cerebrospinal fluid and serum, aiding in the differentiation of AE from primary psychiatric disorders and in the early identification of checkpoint inhibitor-related neurotoxicity. NfL and total tau (t-Tau) were consistently higher in paraneoplastic than non-paraneoplastic AE. Despite some variability across studies, amyloid-beta (Aβ) 42 and Aβ40, as well as phosphorylated tau (p-Tau), were altered in AE compared to controls, although generally to a lesser extent than in Alzheimer's disease. Higher baseline NfL and YKL-40 correlated with disease severity, and NfL reductions post-immunotherapy were linked to treatment response. Despite consistent heterogeneities in sampling timing, these findings highlight the potential of neuroglial biomarkers as diagnostic and prognostic tools in AE. Future studies should explore longitudinal biomarker dynamics and refine their clinical applications.},
}

@article {pmid40823879,
year = {2025},
author = {Lee, J and Sim, S and Jin, Y and Park, H and Byeon, EY and Kim, SJ and Yun, S and Lee, HE and Jeong, DU and Suh, JM and Lee, IH and Lee, HY and Choi, Y and Bae, YS},
title = {NADPH Oxidase Inhibition Promotes Brain Resilience by Attenuating Tauopathy and Neuroinflammation in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e05495},
doi = {10.1002/advs.202505495},
pmid = {40823879},
issn = {2198-3844},
support = {20165925//Starting Growth Technological R&D Program/ ; RS-2024-00398295//Korean National Reseach Foundation (NRF)/ ; },
abstract = {Alzheimer's disease (AD) associates closely associated with the activation of NADPH oxidase (Nox) isozymes. CRB-2131, a novel oxadiazole derivative, is identified as a potently suppresses Nox isozymes. It inhibits reactive oxygen species production (ROS) by hippocampal neuronal and microglial cells and reduces microglial activation. Prophylactic (starting at 3.5 months of age) and therapeutic (starting at 6 months of age) oral administration with CRB-2131 for 10 weeks in 5XFAD mice reduced hippocampal superoxide levels, lipid peroxidation, Tau phosphorylation, and neuroinflammation. Prophylactic and therapeutic CRB-2131 treatment of 5XFAD mice restored their impaired cognition as shown by the novel-object recognition, Y-maze, and Morris water-maze tests. CRB-2131 treatment increased mature neurons, reduced apoptotic mature neurons, and elevated immature neurons in the hippocampus. Positron-emission tomography/computed-tomography imaging confirmed that CRB-2131 stimulated neuronal regeneration. CRB-2131 suppresses brain oxidation, tauopathy, and neuroinflammation, thereby preventing mature neuron death and promoting neuron regeneration. Ultimately, this fosters a resilient brain and protects cognition.},
}

@article {pmid40823789,
year = {2025},
author = {Shwab, EK and Pathak, GA and Harvey, J and Belloy, ME and Fischer, CE and Lutz, MW and Scholz, SW and Cook, N and Reid, DM and Chen, J and Guan, DX and Oliveira, F and Sinclair, LI and Imo, U and Creese, B and Chiba-Falek, O and , },
title = {Leveraging multiomic approaches to elucidate mechanisms of heterogeneity in Alzheimer's disease: Neuropsychiatric symptoms, co-pathologies, and sex differences.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70549},
doi = {10.1002/alz.70549},
pmid = {40823789},
issn = {1552-5279},
support = {R01 AG057522/AG/NIA NIH HHS/United States ; RF1 AG077695/AG/NIA NIH HHS/United States ; R00AG078503//National Institutes of Health/National Institute on Aging/ ; R00AG075238//National Institutes of Health/National Institute on Aging/ ; R01AG067015//National Institutes of Health/National Institute on Aging/ ; RF1-NS113548-01A1//National Institute of Neurological Disorders & Stroke/ ; ZIANS003154//National Institute of Neurological Disorders & Stroke/ ; 2U10AA008401/AA/NIAAA NIH HHS/United States ; //Cure Alzheimer's Fund/ ; 2015/10109-5//The State of São Paulo Research Foundation/ ; AARG-24-1027303/ALZ/Alzheimer's Association/United States ; 22-AAIIA-953269/ALZ/Alzheimer's Association/United States ; AARF-22-967171/ALZ/Alzheimer's Association/United States ; },
abstract = {The heterogeneity of Alzheimer's disease (AD) is multi-dimensional, encompassing clinical features such as neuropsychiatric symptoms (NPS), rate of progression, age of onset, comorbidities, and neuropathological features such as co-pathologies, and represents the diverse outcomes of manifold genetic and environmental risk determinants. These diverse features of AD also vary significantly between sexes and across ancestral backgrounds, but the specific variations and causal mechanisms are not well understood. Recent technological advances, particularly single-cell and spatial omics, have provided new tools to dissect the molecular underpinnings of AD heterogeneity and its multifactorial nature. This perspective review highlights molecular differences, general and sex-specific, that contribute to the heterogeneity of AD in aspects such as NPS, co-pathology prevalence, and general disease trajectories. We further examined the potential for multiomic approaches to direct future translational studies aimed at the development of precision medicine strategies for the treatment of AD in all its diverse forms. HIGHLIGHTS: Alzheimer's disease (AD) represents diverse subtypes characterized by comorbid clinical symptoms and co-pathologies. Integration of bulk, single-cell, spatial multiomics reveals factors underlying AD variation. Multiomics studies indicate shared and distinct mechanisms between major psychiatric disorders and AD. Multiomics data have transformative implications for sex- and population-specific AD therapies. New tailored precision medicine strategies are needed to address the full range of complexity in AD.},
}

@article {pmid40823654,
year = {2025},
author = {Dougnon, G and Matsui, H},
title = {Lipofuscin autofluorescence confounds intracellular amyloid β detection in the aged mouse brain.},
journal = {Aging brain},
volume = {8},
number = {},
pages = {100148},
pmid = {40823654},
issn = {2589-9589},
abstract = {Intracellular amyloid β (Aβ) accumulation is a contentious feature of Alzheimer's disease (AD), increasingly reported in young adults and aged animal models of AD. However, autofluorescent lipofuscin granules which consist of a mixture of highly oxidized lipids, misfolded proteins, and metals, accumulates with aging in neurons and microglia and renders difficult the interpretation of immunofluorescence-based studies. Here, we show that lipofuscin accumulation in aged wild-type (WT) mouse brains exhibits significant spectral overlap with commonly used antibodies for Aβ detection, leading to potential misinterpretation of intracellular Aβ signals. Through a combination of dye staining, immunohistochemistry (IHC), and confocal microscopy, we show that fluorescence signals resembling intracellular Aβ and commonly reported in aged animal models of AD, may reflect the presence of lipofuscin granules. Importantly, these signals persisted in control sections where primary Aβ antibodies were omitted, but disappeared following TrueBlack autofluorescence quencher. We also performed Aβ immunofluorescence staining using 5xFAD mice as model for AD, revealing that intracellular Aβ in these models can be diminished by TrueBlack treatment, thus confounding the interpretation of true intracellular Aβ signals. Our findings underscore the need for caution in interpreting intracellular Aβ signals in young adults and aged models of Aβ pathology inside neurons or microglia.},
}

@article {pmid40822853,
year = {2025},
author = {Tiunova, AA and Diffine, EA and Anokhin, KV},
title = {Memory reconsolidation impairment by amyloid beta (1-42) and its prevention by non-competitive antagonists of NMDA receptors.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1629492},
pmid = {40822853},
issn = {1662-5102},
abstract = {In a healthy brain, the reactivation of memories under conditions of novelty leads to their labilization and subsequent reconsolidation. However, if plasticity of the nervous system is reduced reconsolidation mechanisms may be disrupted, leading to weakening and loss of existing memory. We hypothesize that such self-degradation of old memory due to its reactivation in the compromised brain may lead to progressive memory loss in Alzheimer's disease. Preventing memory lability when accessing it, may slow down such engram degradation. To test these hypotheses, we first examined whether beta-amyloid peptide Aβ1-42 can impair reconsolidation of memory in one-trial passive avoidance task in young chicks. Next, we examined the possibility to prevent such reminder-associated amnesia by administering a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 prior to memory reactivation. Finally, we compared the memory protecting effects of two non-competitive NMDA antagonists, MK-801 and memantine which is a clinically used medication for treatment of Alzheimer's disease. We found that administration of Aβ1-42 prior to memory reactivation in passive avoidance task in chicks impaired its subsequent reconsolidation. Concurrent systemic injection of MK-801 or memantine prevented this impairment. Our data thus support the hypothesis about the possible role of impaired reconsolidation in the progressive deterioration of old memories in neurodegenerative diseases, particularly in Alzheimer's disease. This hypothesis offers a new explanation for the protective effects of memantine and suggests the possibility of similar effects with other NMDA receptor antagonists.},
}

@article {pmid40822397,
year = {2025},
author = {Liu, X and Sun, C and Dai, Y and Duan, F and He, T and Zhen, M and Liang, E and Zhang, S and Xia, Y and Hu, N and Zhan, R and Deng, D and Liu, S},
title = {Study on the improvement of cognitive deficits in APP/PS1 mice by danggui shaoyao san and its disassembled prescriptions through modulation of the gut microbiota.},
journal = {Frontiers in microbiology},
volume = {16},
number = {},
pages = {1620784},
pmid = {40822397},
issn = {1664-302X},
abstract = {BACKGROUND: Alzheimer's disease (AD), a neurodegenerative disorders linked to gut microbiota dysbiosis, may benefit from Traditional Chinese Medicine (TCM) interventions.

OBJECTIVES: Danggui Shaoyao San (DSS), a classic traditional Chinese Medicine (TCM) formula. This study investigated whether Danggui Shaoyao San and its disassembled prescriptions could improve cognitive deficits in APP/PS1 mice by modulating the structure of the gut microbiota, thereby providing a theoretical basis for AD treatment and the further development and application of Danggui Shaoyao San.

METHODS: Forty APP/PS1 and eight C57BL/6 mice were divided into six groups: DSS (6.4 g/kg/d), QDW (4.6 g/kg/d), DW (1.8 g/kg/d), GV971 (positive control, 40 mg/kg/d), model (saline), and control (saline). After 60 days of treatment, the mice underwent behavioral testing in the open field, novel object recognition, and water maze. Gut microbiota composition, diversity, and function were then analyzed by 16S rRNA sequencing.

RESULTS: The results of Behavioral experiment indicate that Danggui Shaoyao San and its disassembled prescriptions can ameliorate spatial memory deficits (Morris water maze), enhance recognition memory (novel object recognition), and reduce anxiety-like behaviors (open field test), with the DSS group demonstrating the most pronounced effects. In addition, through 16S sequencing analysis we predicted DSS and its disassembled prescriptions reduced harmful bacteria (Firmicutes, Akkermansia) while increasing beneficial bacteria (Bacteroidetes, Bifidobacterium, Lactobacillus). DSS restored microbial diversity closest to healthy controls, evidenced by elevated Chao1/Shannon indices and reduced Simpson index. Beta diversity revealed structural divergence between treatment and model groups. Functional predictions highlighted enriched pathways (D-glutamine metabolism, bile acid biosynthesis) and suppressed antibiotic biosynthesis.

CONCLUSION: Danggui Shaoyao San and its disassembled prescriptions ameliorate AD-related cognitive impairment and gut dysbiosis, enhance microbial diversity, and modulate metabolic pathways, supporting their therapeutic potential via gut-brain axis regulation. This study elucidates the multi-target mechanisms of DSS in AD treatment, advancing TCM rationalization for neurodegenerative disorders.},
}

@article {pmid40822322,
year = {2025},
author = {Diniz, JRG and de Almondes, KM and Godeiro, C and Silva, RAE},
title = {Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy: report of two cases.},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {},
pages = {e20240198},
pmid = {40822322},
issn = {1980-5764},
abstract = {UNLABELLED: The polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy-Nasu-Hakola disease-is a hereditary and progressive pathology, which is mainly associated with pre-senile dementia and changes in bone architecture.

OBJECTIVE: To report two rare cases of sibling patients treated with early-onset dementia syndrome with genetic etiology, and to review the literature on the topic.

METHODS: Review of medical records, interviews and recording of the diagnostic methods to which patients were subjected. From this, a report was prepared of two cases who began behavioral changes in the third decade of life, who developed, at different times, symptoms of similar cognitive impairment. Bibliographic research carried out in the United States National Library of Medicine (PubMed), Medical Literature Analysis and Retrieval System Online (MEDLINE), Latin American and Caribbean Health Sciences Literature (LILACS), UpToDate and Scientific Electronic Library Online (SciELO) databases for bibliographic review.

RESULTS: Two clinical cases with genetic confirmation of Nasu-Hakola disease and a brief literature review were described.

CONCLUSION: These cases illustrate a presentation of pre-senile dementia syndrome and reinforce the importance of adequate diagnosis for timely treatment, humanized multidisciplinary follow-up aiming to improve quality of life, as well as genetic and family counseling.},
}

@article {pmid40822124,
year = {2025},
author = {Wang, H and Qiu, M and Wang, C and Zhang, L and Fan, N and Chen, Z and Liu, Y and Li, T and Wang, Z and Zhu, Y and Zhang, Y and Tian, X and Wang, Y and Yang, M and Fan, D and Luo, Q and Jiang, K and Luo, H and Zhang, H},
title = {Light-Triggered Graphene/Black Phosphorus Heterostructure FET Platform for Ultrasensitive Detection of Alzheimer's Disease Biomarkers at the Zeptomole Level.},
journal = {Research (Washington, D.C.)},
volume = {8},
number = {},
pages = {0772},
pmid = {40822124},
issn = {2639-5274},
abstract = {Due to the low concentration of amyloid-beta (Aβ) in plasma and the high content of interfering factors, the conventional detection method for the quantification of Aβ still faces the problem of insufficient limit of detection (LOD). In this work, we propose a new light-triggered graphene-black phosphorus heterostructure (G-BP) field-effect transistor (FET) biosensing platform that achieves a marked reduction in the LOD. The LOD for Alzheimer's disease (AD) biomarker Aβ42 detection using the G-BP FET is as low as 235.1 zM (2.351 × 10[-19] M), which is the lowest value reported to date and is approximately 2 to 3 orders of magnitude lower than other reported biosensing platforms. The G-BP FET platform provides precise, real-time guidance for non-invasive early diagnosis, disease monitoring, and personalized treatment plans for AD. Moreover, this method has good scalability and potential applications in other areas, including early detection of cancer and other major chronic diseases.},
}

@article {pmid40821309,
year = {2025},
author = {Matsuura, K and Mayahara, T and Katayama, T and Arai, H},
title = {Recurrent Cholinergic Crisis Caused by Therapeutic-Dose Rivastigmine Patch in an Elderly Patient With Alzheimer's Disease: A Case Report.},
journal = {Cureus},
volume = {17},
number = {7},
pages = {e87868},
pmid = {40821309},
issn = {2168-8184},
abstract = {Cholinesterase inhibitors (ChEIs) are widely used for the treatment of dementia and other conditions, but may rarely cause cholinergic crisis, a potentially life-threatening complication. We report an elderly female patient with Alzheimer's disease who experienced three episodes of cholinergic crisis over 32 months while receiving a therapeutic dose of transdermal rivastigmine (18 mg/day). Each episode involved vomiting, diarrhea, diaphoresis, and neurological symptoms, with marked reductions in serum cholinesterase levels (53-63 U/L at presentation). During the first two episodes, alternative diagnoses such as acute gastroenteritis and possible pesticide exposure were initially suspected, and cholinergic crisis secondary to rivastigmine was not recognized. After the third episode, rivastigmine was permanently discontinued, resulting in the complete resolution of both acute and chronic mild gastrointestinal and autonomic symptoms. This case highlights the diagnostic challenges of cholinergic crisis in elderly patients receiving ChEIs and underscores the importance of considering this condition when unexplained gastrointestinal or autonomic symptoms occur even during standard therapeutic dosing.},
}

@article {pmid40820453,
year = {2025},
author = {Sharma, H and Chandra, P},
title = {Development of Ergosterol Nanoliposome-based Delivery System Pertaining Toxicity Evaluation and Therapeutic Potential for Alzheimer's Disease.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273388820250724174247},
pmid = {40820453},
issn = {1996-3181},
abstract = {INTRODUCTION: Alzheimer's disease (AD), a debilitating neurodegenerative disorder, presents a growing global health challenge due to limited therapeutic options. Ergosterol, known for its neuroprotective and antioxidant properties, suffers from poor bioavailability. This study aimed to develop ergosterol-loaded nanoliposomes (ER-NL-2) and evaluate their safety, antioxidant potential, and therapeutic efficacy in animal models of AD.

METHODS: ER-NL-2 was formulated using the ultrasonic thin-film dispersion method and characterized via dynamic light scattering (DLS), zeta potential, and TEM. Acute oral toxicity was assessed in Wistar rats and Swiss mice (2000 mg/kg). Two AD models were employed: Streptozotocin (STZ)- induced in Swiss albino mice and AlCl₃-induced in Wistar albino rats. Behavioral studies included actophotometer and elevated plus maze tests. Antioxidant assays measured SOD, CAT, GSH, and LPO levels. Histopathological analysis of brain tissue was conducted.

RESULTS: ER-NL-2 exhibited a mean droplet size of ~180 nm, PDI <0.3, and zeta potential of -27.9 mV. TEM confirmed spherical morphology. Toxicity studies showed no abnormalities. In both AD models, ER-NL-2 improved locomotor activity and reduced transfer latency. Biochemical analyses revealed elevated SOD, CAT, GSH and reduced LPO levels. Histopathology showed preserved neuronal integrity and reduced neurofibrillary tangles in treated groups.

DISCUSSION: ER-NL-2 demonstrated neuroprotective efficacy through behavioral, biochemical, and histological endpoints, confirming its antioxidative mechanism and brain safety profile. It was comparable to standard therapy (donepezil).

CONCLUSION: ER-NL-2 is a safe and promising nanocarrier for Alzheimer's treatment with significant neuroprotective and antioxidant properties. Further studies are warranted to explore its pharmacokinetics and clinical applicability.},
}

@article {pmid40819956,
year = {2025},
author = {Wang, J and Wang, ZY and Chen, SF and Wang, RZ and Chen, KL and Lu, JY and Xin, JW and Huang, YY and Wang, MY and Xie, F and Cheng, W and Yen, TC and Wischik, CM and Cui, M and Zuo, CT and Zhao, QH and Wang, YJ and Yu, JT},
title = {Role of [18]F-florzolotau PET in diagnostic and therapeutic decision-making for cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70563},
doi = {10.1002/alz.70563},
pmid = {40819956},
issn = {1552-5279},
support = {2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; 82371188//National Natural Science Foundation of China/ ; 2023YFC3605400//National Key Research and Development Program of China/ ; },
abstract = {INTRODUCTION: The novel positron emission tomography (PET) tracer, [18]F-florzolotau, enables in vivo visualization of tau pathology.

METHODS: We evaluated the diagnostic performance of disease-specific spatial patterns of [18]F-florzolotau PET imaging by visual read for tauopathies and its added value in diagnostic and therapeutic decision-making in 1277 participants with cognitive complaints.

RESULTS: The disease-specific spatial patterns of [18]F-florzolotau PET imaging demonstrated high diagnostic accuracy in differentiating various tauopathies, with 96.0% for Alzheimer's disease, 94.4% for frontotemporal lobe degeneration, 93.7% for progressive supranuclear palsy, and 97.5% for corticobasal degeneration. Added to a standard diagnostic workup, [18]F-florzolotau PET reading led to diagnostic revisions for 247 participants (19.3%), increased diagnostic confidence from 68.6% to 81.3%, and resulted in medication changes for 284 participants (22.2%).

DISCUSSION: Our data advocate for the strategic implementation of [18]F-florzolotau PET in memory clinics, offering transformative potential for patient care and management.

HIGHLIGHTS: [18]F-Florzolotau PET imaging presented disease-specific spatial patterns for different tauopathies. The disease-specific spatial patterns of [18]F-florzolotau positron emission tomography (PET) imaging exhibited high diagnostic accuracy in differentiating various tauopathies. Integration of [18]F-florzolotau PET imaging modality to a standard diagnostic workup significantly enhanced diagnostic confidence, enabled diagnostic revisions, and informed adjustments to treatment strategies.},
}

@article {pmid40819191,
year = {2025},
author = {Ismail, Z and Wilson, M and Khalifa, H and Belovich, D and Shaw, E and Pham, T and McMullen, S and Chen, Y and Sadman, N and Cai, J and Zulkernine, F and Barber, D},
title = {Diagnosis and Management of Alzheimer's Disease in Primary Care: A Real-World Study in Ontario, Canada.},
journal = {Journal of primary care & community health},
volume = {16},
number = {},
pages = {21501319251363156},
pmid = {40819191},
issn = {2150-1327},
abstract = {OBJECTIVE: To understand the real-world clinical practice patterns and variation in Alzheimer's disease (AD) diagnostic and screening tool utilization by primary care physicians (PCPs), including tools used for assessing dementia/AD severity and subsequent treatment patterns.

METHODS: This retrospective observational study used de-identified primary care data from electronic medical records (EMR) data provided by the researchers from Queen's University, Ontario, Canada from August 2011 to August 2021. Individuals ≥50 years old with dementia or AD were identified using AD and dementia-related diagnostic codes, medications, and keywords searched using natural language processing (NLP) and Artificial Intelligence (AI) algorithms from EMR chart notes. Diagnostic and screening tools included scales, neuroimaging, and laboratory tests. Medications examined were cholinesterase inhibitors, memantine, antidepressants, and antipsychotics.

RESULTS: The study cohort included 417 individuals with all-cause dementia (mean [standard deviation: SD] age: 78.86 [0.19] years), and 71 individuals with AD (mean [SD] age: 76.13 [1.07]). The most-used scale was the Montreal Cognitive Assessment (MoCA; dementia: 53.2%, AD: 84.5%). The mean [SD] frequency of MoCA administration doubled in the year following AD index date compared to the year prior (0.29 [0.82] to 0.67 [1.19] times per patient-year). Severity scores, often unspecified, suggested various stages of cognitive impairment. Among the medications examined, cholinesterase inhibitors were prescribed in 27.8% (n = 116) and 57.8% (n = 41) of people with dementia and AD, respectively. Antidepressants were the most frequently prescribed medication examined (dementia: 49.6%; AD: 71.8%).

CONCLUSION: PCPs play an important role in the early detection and management of dementia/AD. As new biomarkers and therapies emerge for early AD, there is a need for connected health system data to guide PCPs through the early diagnostic process.},
}

@article {pmid40818921,
year = {2025},
author = {Moorthy, DK and Chinnasamy, P and Nagaraj, P},
title = {Optimization enabled ResNet features with transfer learning for Alzheimer's disease detection.},
journal = {Computational biology and chemistry},
volume = {},
number = {},
pages = {108613},
doi = {10.1016/j.compbiolchem.2025.108613},
pmid = {40818921},
issn = {1476-928X},
abstract = {Millions of individuals worldwide suffer from Alzheimer's Disease (AD), a debilitating degenerative condition. Early detection of Alzheimer's disease is critical to ensure effective treatment and better patient outcomes. In the past few years, advanced medical imaging techniques, particularly MRI, have shown potential for diagnosing Alzheimer's disease. However, developing accurate and efficient techniques for Alzheimer's disease detection offcuts a demanding duty suitable to the complication of medical images and the limited availability of labelled data. The early detection of Alzheimer's disease is critical for effective treatment and management of this debilitating neurodegenerative condition. The research proposes a novel method for Alzheimer's disease detection using an optimization-enabled ResNet feature extraction technique with transfer learning that is proposed by combining LeNet and VGG networks. The pre-processing was done using image resizing and median filter and the featureextraction was conducted using the proposed Walrus Optimization Algorithm-Residual neural network (WOA-ResNet), where WOA is employed for training ResNet. The conducted experiments with the Alzheimer's dataset achieved a higher accuracy using the proposed LeNet-VGG method. The findings suggest that optimization-enabled ResNet feature extraction with LeNet-VGG networks can significantly improve the accuracy of Alzheimer's disease detection. The presented method achieved maximum accuracy value of 95.37 %, sensitivity value of 97.24 % and specificity value of 93.73 %.},
}

@article {pmid40817880,
year = {2025},
author = {da Silva, AWR and da Silva, LB and Rambo, DF and Biegelmeyer, R},
title = {Application of zebrafish (Danio rerio) as a model organism for central nervous system disorders screening of natural products.},
journal = {The Journal of pharmacy and pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jpp/rgaf067},
pmid = {40817880},
issn = {2042-7158},
support = {PIE0001/2024//Bahia State Research Support Foundation/ ; //National Council for Scientific and Technological Development/ ; //Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES)/ ; },
abstract = {OBJECTIVES: Natural products (NP) play a crucial role in the development of new compounds, due to their complex chemical structure and pharmacological diversity. Neurodegenerative diseases and other disorders in the central nervous system (CNS) have become a significant problem in the world due to the increase in life expectancy of the elderly population. This increases the risk of developing diseases, such as Parkinson's disease, Huntington's disease, Alzheimer's disease. Therefore, this exploratory review aims to show the applications of zebrafish for NP research and how they can be used in CNS's in vivo studies.

METHODS: The present review covers the literature survey until 2023, including the descriptors for zebrafish, natural product and neurodegenerative diseases. The databases used were PubMed, Scopus, Cochrane and Lilacs.

KEY FINDINGS: For the development of new medicines, an efficient animal model is required, and the zebrafish has stood out as a promising model due to its small size, low cost of maintenance, ease of handling, and transparency of embryos, which allows real-time observation of development and pathological processes. They possess conserved neurotransmission systems such as glutamatergic, cholinergic, dopaminergic, serotonergic, histaminergic, GABAergic, and purinergic pathways, making them especially relevant for modelling CNS disorders. From literature survey, flavonoids, alkaloids, and phenolic compounds were the most frequently studied, indicating that its influence the pathophysiological mechanisms associated with neurodegenerative diseases.

CONCLUSIONS: This current review offers data for further research work with natural products aiming treatment for CNS disorders.},
}

@article {pmid40817783,
year = {2025},
author = {Torres, VO and Pizzo, ME and Chan, D and Dugas, JC and Huynh, D and Joy, D and Liang, EK and Sarrafha, L and Becerra, I and Chau, R and Chew, KS and Chow, J and Discenza, CB and Earr, TK and Furaso, L and Khoury, N and Lechtenberg, KJ and Leung, AW and Nguyen, HN and Ojo, ES and Roche, E and Simon, MJ and Solanoy, H and Tong, M and Tong, RK and Henne, K and Lewcock, JW and Watts, RJ and Calvert, ME and Thorne, RG and Zuchero, YJY},
title = {Transferrin receptor-mediated transport at the blood-brain barrier is elevated during early development and maintained across aging and in an Alzheimer's mouse model.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X251361997},
pmid = {40817783},
issn = {1559-7016},
abstract = {Transferrin receptor (TfR)-targeting of biologics has emerged as a promising strategy to improve drug delivery across the blood-brain barrier (BBB). However, most preclinical studies evaluating TfR-enabled drugs have been conducted in young adult animals. It remains unclear whether age and aging-related diseases impact TfR protein levels and/or BBB transport capacity. Here, we utilized a previously described TfR-targeting antibody transport vehicle (ATV[TfR]) to investigate how healthy aging and disease progression in the 5xFAD mouse model of Alzheimer's disease (AD) impact TfR protein and TfR-mediated brain delivery. ATV[TfR] transport capacity remained stable across 3- to 24-month-old healthy mice and 5xFAD progression did not impair ATV[TfR] brain transport up to 10.5 months, despite significant amyloid burden. Interestingly, neonates exhibited significantly elevated levels of vascular TfR protein and ATV[TfR] brain exposure compared to adult mice. Furthermore, vascular TfR in AD patient brains was similar to age-matched controls, suggesting conserved TfR transport is also likely in human AD. Overall, our data demonstrates broad functional utility for TfR-based brain delivery in both healthy aging and in an AD mouse model. Additionally, elevated TfR-mediated brain delivery during early mouse development highlights the potential of added efficacy in utilizing such platforms in disease treatment of infants and children.},
}

@article {pmid40817729,
year = {2025},
author = {Xia, S and He, C and Li, Y and Li, H and Wang, B and Xu, L and Zhao, X},
title = {Low-intensity transcranial ultrasound neuromodulation promotes neuronal regeneration: A new hope for noninvasive treatment of neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00113},
pmid = {40817729},
issn = {1673-5374},
abstract = {Neurodegenerative diseases, which are characterized by progressive neuronal loss and the lack of disease-modifying therapies, are becoming a major global health challenge. The existing neuromodulation techniques, such as deep brain stimulation and transcranial magnetic stimulation, show limitations such as invasiveness, restricted cortical targeting, and irreversible tissue effects. In this context, low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity. This review comprehensively assesses the therapeutic mechanisms, efficacy, and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases, with emphasis on its role in promoting neuronal regeneration, modulating neuroinflammation, and enhancing functional recovery. We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms, enhancing neural repair and regeneration, and alleviating symptoms associated with neurodegenerative diseases. Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors (e.g., brain-derived neurotrophic factor), promote autophagy to clear protein aggregates, modulate microglial activation, and temporarily open the blood-brain barrier to facilitate targeted drug delivery. Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-? plaques, improve motor and cognitive deficits, and promote remyelination in various disease models. Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer's disease and alleviate motor symptoms in Parkinson's disease, all while demonstrating a favorable safety profile. Past studies support the notion that by integrating safety, precision, and reversibility, low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease. However, more advancements are necessary for future clinical application of low-intensity transcranial ultrasound, including optimizing parameters such as frequency, intensity, and duty cycle; considering individual anatomical differences; and confirming long-term efficacy. We believe establishing standardized protocols, conducting larger trials, and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard. Future research should focus on translating preclinical findings into clinical practice, addressing technical challenges, and exploring combination therapies with pharmacological or gene interventions.},
}

@article {pmid40817268,
year = {2025},
author = {Ibrar, W and Khan, MA and Hamza, A and Rubab, S and Alqahtani, O and Alouane, MT and Teng, S and Nam, Y},
title = {A novel interpreted deep network for Alzheimer's disease prediction based on inverted self attention and vision transformer.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {29974},
pmid = {40817268},
issn = {2045-2322},
abstract = {In the world, Alzheimer's disease (AD) is the utmost public reason for dementia. AD causes memory loss and disturbing mental function impairment in aging people. The loss of memory and disturbing mental function brings a significant load on patients as well as on society. So far, there is no actual treatment that can cure AD; however, early diagnosis can slow down this disease. Deep learning has shown substantial success in diagnosing AZ disease. However, challenges remain due to limited data, improper model selection, and extraction of irrelevant features. In this work, we proposed a fully automated framework based on the fusion of a vision transformer and a novel inverted residual bottleneck with self-attention (IRBwSA) for AD diagnosis. In the first step, data augmentation was performed to balance the selected dataset. After that, the vision model is designed and modified according to the dataset. Similarly, a new inverted bottleneck self-attention model is developed. The designed models are trained on the augmented dataset, and extracted features are fused using a novel search-based approach. Moreover, the designed models are interpreted using an explainable artificial intelligence technique named LIME. The fused features are finally classified using a shallow wide neural network and other classifiers. The experimental process was conducted on an augmented MRI dataset, and 96.1% accuracy and 96.05% precision rate were obtained. Comparison with a few recent techniques shows the proposed framework's better performance.},
}

@article {pmid40816573,
year = {2025},
author = {Škorić, I and Sviben, M and Mlakić, M and Čadež, T and Hrvat, NM and Kovarik, Z},
title = {Photochemistry-Driven Design of Small Molecule Cholinesterase Ligands.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111703},
doi = {10.1016/j.cbi.2025.111703},
pmid = {40816573},
issn = {1872-7786},
abstract = {The development of small-molecule ligands targeting cholinesterases remains a central focus in neuropharmacology, particularly for the treatment of neurodegenerative disorders and organophosphate poisoning. This review highlights the rational design, synthesis, and biological profiling of diverse classes of heterocyclic compounds - including oxazoles, heterostilbenes, triazoles, and bicyclo[3.2.1]octane/octadiene derivatives - as reversible inhibitors and reactivators of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Novel amino-oxazolostilbenes and their photoproducts exhibited selective BChE inhibition, while naphtoxazole and triazole-containing scaffolds demonstrated promising dual-target or BChE-selective profiles. Several uncharged oximes, such as thienostilbene and heterostilbene oximes, showed potential for reactivating cyclosarin-inhibited BChE, supporting their further development as CNS-permeable antidotes. Additionally, resveratrol-based triazoles and carbamates revealed enhanced BChE inhibition, antioxidant activity, and favorable selectivity. Collectively, these findings underscore the therapeutic potential of structurally diverse cholinesterase ligands and provide a framework for the discovery of multifunctional agents for Alzheimer's disease and chemical threat countermeasures.},
}

@article {pmid40816274,
year = {2025},
author = {Zeng, PM and Sun, XY and Li, Y and Wu, WD and Huang, J and Cao, DD and Qian, PJ and Ju, XC and Luo, ZG},
title = {Thymosin beta 4 as an Alzheimer disease intervention target identified using human brain organoids.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102601},
doi = {10.1016/j.stemcr.2025.102601},
pmid = {40816274},
issn = {2213-6711},
abstract = {The developmental origin of Alzheimer disease (AD) has been proposed but is arguably debated. Here, we developed cerebral organoids from induced pluripotent stem cells (iPSCs) with mutations in amyloid precursor protein (APP) associated with familial AD (fAD) and analyzed the dynamic changes of cellular states. We found that mature neurons induced in fAD organoids markedly decreased compared to that of health control, accompanied with increased cell senescence and β-amyloid (Aβ) production. Interestingly, the expression level of the gene TMSB4X that encodes thymosin beta 4 (Tβ4) significantly decreased both in fAD organoids' neurons and AD patients' excitatory neurons. Remarkably, the neurodevelopmental deficits and Aβ formation in fAD organoids were rescued by treatment with Tβ4. The beneficial effects of Tβ4 were also revealed in 5xfAD model mice. Thus, this study has identified Tβ4 as a neuroprotective factor that may mitigate altered neurogenesis and AD pathology, highlighting a potential for disease intervention.},
}

@article {pmid40815967,
year = {2025},
author = {Scuteri, D and Adornetto, C and Greco, G and Nicotera, P and Bagetta, G and Corasaniti, MT},
title = {Pharmacoutilization data-driven artificial intelligence-assisted diagnosis algorithm to improve the pharmacological treatment of pain and agitation in patients suffering from severe dementia.},
journal = {Current opinion in pharmacology},
volume = {84},
number = {},
pages = {102563},
doi = {10.1016/j.coph.2025.102563},
pmid = {40815967},
issn = {1471-4973},
abstract = {The number of diagnoses and drug prescriptions for dementia patients is poorly available. Delay in the diagnosis of Alzheimer's disease (AD), for which missed diagnoses amount to over half cases, and undertreatment of chronic and neuropathic pain mirroring excessive use of harmful antipsychotics and antidepressants is reported. Our study aimed at diagnosing AD through the most advanced artificial intelligence (AI) methodologies even in patients who escaped clinical observation. To this end, pharmacoepidemiology data collected as part of the first retrospective community study in a wide sample of 298,000 individuals, 84,235 aged over 60 years, were used to set up an AI algorithm for the rescue of missed diagnoses of AD. The core of the algorithm consisted in the management of time series represented by pharmacological therapies through a distance matrix and in the use of autoencoders. Patients without a diagnosis of AD based on pharmacotherapy were 114.920, while diagnosed patients were 1.150, mainly aged between 75 and 84 years, pointing at late start of treatment. Increased use of antidepressants, neuroleptics, and mood stabilizers is found in patients treated with acetylcholinesterase inhibitors (AChEIs) and memantine, while nonsteroidal anti-inflammatory drugs, paracetamol-codeine and opioids are mostly prescribed to patients not receiving AChEIs and memantine. The classification model demonstrated good global accuracy at the end of training, equal to 79.12%. Further studies and longitudinal monitoring of patients are needed to improve disease detection and management. The deep learning-based pharmacoutilization algorithm generated in the present study will aid the diagnosis of AD and the understanding of neuropsychiatric symptoms treatment.},
}

@article {pmid40815522,
year = {2025},
author = {Yun, H and Unruh, MA and Qian, Y and Zhang, Y and Jung, HY},
title = {Clinicians Who Practice Primarily in Nursing Homes and the Quality of Care for Residents With Alzheimer Disease and Related Dementias.},
journal = {JAMA health forum},
volume = {6},
number = {8},
pages = {e252465},
pmid = {40815522},
issn = {2689-0186},
abstract = {IMPORTANCE: The number of physicians and advanced practitioners (APs) whose care is concentrated in nursing homes (often referred to as nursing home or skilled nursing facility specialists [SNFists]) has increased rapidly. Therefore, whether these clinicians provide better care is important.

OBJECTIVE: To examine the association between SNFist care and outcomes of long-stay nursing home (NH) residents with Alzheimer disease and related dementias (ADRD).

In this retrospective cohort study of 417 378 residents with ADRD in US NHs, claims for a 20% national sample of Medicare fee-for-service beneficiaries between 2013 and 2019 were analyzed. Adjusted estimates were based on a machine learning approach that incorporated a doubly robust procedure using a generalized estimating equation with inverse probability treatment weighting. Three secondary analyses were conducted: (1) stratified analyses for physicians and APs, (2) inclusion of physicians of any specialty and APs, and (3) use of proxy outcomes for in-place deaths. Data were analyzed from June 1, 2024, to May 3, 2025.

INTERVENTION: Receipt of care from a SNFist; SNFists included generalist physicians and APs.

MAIN OUTCOMES AND MEASURES: Hospitalizations and emergency department (ED) visits for ambulatory care-sensitive (ACS) conditions. Death without an ACS hospitalization and death without any hospitalization were used in secondary analyses.

RESULTS: Of the total 417 378 residents, 242 540 received care from SNFists (mean [SD] age, 83.5 [8.7] years), and 174 838 never received care from SNFists (mean [SD] age, 84.8 [8.5] years). Compared with the residents who never received care from SNFists, the residents who received care from SNFists were more likely to be Black (12.6% vs 9.4%; P < .001), dually eligible (77.5% vs 73.1%; P < .001), and have more chronic conditions (eg, anemia, 60.9% vs 57.6%). Compared with non-SNFist clinicians, the SNFist clinicians were more likely to be female (physicians, 37.1% vs 23.3%; APs, 88.1% vs 85.1%), practice at more facilities (mean [SD] number of facilities, 9.4 [8.7] for SNFist physicians vs 6.4 [6.1] for non-SNFist physicians; 8.6 [8.1] for SNFist APs vs 7.1 [6.8] for non-SNFist APs), and less likely to practice in rural areas (physicians, 9.3% vs 25.4%; APs, 8.1% vs 20.2%). In adjusted analyses, receiving care from a SNFist vs non-SNFist was associated with 7% lower odds of an ACS hospitalization (odds ratio [OR], 0.93; 95% CI, 0.90-0.96) and 7% lower odds of an ACS ED visit (OR, 0.93; 95% CI, 0.90-0.96). In stratified analyses, receiving care from a SNFist physician vs a non-SNFist physician was associated with 13% lower odds (OR, 0.87; 95% CI, 0.83-0.90) of an ACS hospitalization and 7% lowers odds of an ACS ED visit (OR, 0.93, 95% CI, 0.88-0.97); comparisons of SNFist APs vs non-SNFist APs were not statistically significant. Estimates from the analysis including physicians of any specialty and APs were consistent with the primary results. SNFist care was associated with increased odds of in-place death.

CONCLUSIONS AND RELEVANCE: Findings of this cohort study suggest that the use of SNFists by NHs may enhance the quality of care for residents with ADRD.},
}

@article {pmid40814948,
year = {2025},
author = {Bujalance-Fernández, J and Carro, E and Antequera, D and Jurado-Sánchez, B and Escarpa, A},
title = {ZIF-8 Microswimmers Self-Fast Dynamic Destruction in Microliter Volumes of Cerebrospinal Fluid Samples: Toward a Selective Assessment of Amyloidosis.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c03467},
pmid = {40814948},
issn = {1520-6882},
abstract = {Herein, we describe the synthesis of magnetic zeolitic imidazole framework (ZIF-8) microswimmers for detecting and quantifying the amyloid beta (Aβ1-42) peptide in cerebrospinal fluid (CSF) samples, which are used as a biomarker of amyloidosis for diagnosing Alzheimer's disease (AD). The microswimmers are prepared by external decoration of the ZIF-8 with magnetic Fe3O4 nanoparticles, followed by post internal encapsulation of quinine as fluorescent probe. The magnetic and surface properties of the microswimmers are fine-tuned to obtain tailored structures with an inner porous structure with the loaded fluorescent probe and outer magnetic engines. A macroporous structure was preferred over a microporous structure for quinine encapsulation, increasing the loading efficiency by about 50%, allowing also external decoration of the ferrite to impart the desired magnetic properties to the microswimmer. The principle for detection relies on the specific affinity of target sequence of amino acids in the Aβ1-42 peptide structure toward the Zn units in the ZIF-8, resulting in the self-destruction of the microswimmers and subsequent release of quinine in a concentration-dependent manner. The use of the bioreceptor-free magnetic assisted microswimmers allows for direct assessment of Aβ1-42 peptide in only 10 μL of CSF samples in just 10 min. Excellent analytical performance with a limit of detection of 40 pg/mL and a linear range ranging from 140 to 1200 pg/mL (r = 0.9990), covering the range in the clinical practice, is obtained. An excellent selectivity was also obtained toward the Aβ1-42 peptide which approaches an excellent assessment of amyloidosis in the human brain, as demonstrated by the good correlation obtained (r = 0.97) between the quantitative levels obtained in our microswimmers approach in comparison with the enzyme-linked immunosorbent assay method in diagnosed CSF samples from patients where Tau protein was also determined due to its coexistence with Aβ1-42 peptides. Since CSF biomarkers are currently the only clinically validated biofluid diagnostic test for AD, our approach will drastically reduce the volume required to determine Aβ levels, reducing the impact of the side effects of lumbar puncture in clinical practice. It became a novel bioreceptor-free approach to more easily, less invasively measure Aβ1-42 peptide in CSF, becoming a valuable tool for indirect amyloidosis prediction in brain tissues in the patient's lifetime, opening the possibility for early treatment of the AD.},
}

@article {pmid40814010,
year = {2025},
author = {Li, Z and Yang, J and Li, J and Zhao, S and Jiang, S and Liu, W and Li, X and Zhang, S and Du, H and Ni, J and Huang, Y and Qing, H and Ruan, S},
title = {Targeted delivery of BACE1 siRNA for synergistic treatment of Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {41},
pmid = {40814010},
issn = {2047-9158},
support = {82302387//Innovative Research Group Project of the National Natural Science Foundation of China/ ; L222128//Beijing Natural Science Foundation grant/ ; XSQD-202121010//Beijing Institute of Technology Research Fund Program for Young Scholars grant/ ; JCYJ20241202130511015//Fundamental Research Project funding from Shenzhen Science and Technology Innovation Committee/ ; JCYJ20230807142704008//Fundamental Research Project funding from Shenzhen Science and Technology Innovation Committee/ ; 2024KCXTD016//Alzheimer's Disease Pathogenesis and Drug Development Innovation Team, Innovation Team Project of Guangdong General Colleges and Universities (Natural Science)/ ; },
abstract = {BACKGROUND: The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD.

METHODS: We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1).

RESULTS: PPR@siBACE1 crossed the blood-brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice.

CONCLUSIONS: This study provides a reliable delivery platform for gene therapies for AD.},
}

@article {pmid40812721,
year = {2025},
author = {Barroso de Sousa, D and Zucato, MCR and Ribeiro, HM and Alexandre-Silva, V and Cominetti, MR},
title = {Interplay between depressive symptoms and Alzheimer's disease dementia: unraveling the potential roles of ADAM10 and Negr1.},
journal = {Neuroscience},
volume = {584},
number = {},
pages = {60-64},
doi = {10.1016/j.neuroscience.2025.08.012},
pmid = {40812721},
issn = {1873-7544},
abstract = {Late-onset depression (LOD) is closely linked to Alzheimer's disease (AD), marked by shared biological pathways and common risk factors. The neurobiological alterations associated with depression, particularly the dysregulation of amyloid-β (Aβ), play a critical role in the acceleration of disease progression. In individuals suffering from LOD, Aβ peptides - specifically Aβ40 and Aβ42 - exhibit distinct profiles in plasma, cerebrospinal fluid (CSF), and brain tissue, highlighting the substantial influence of AD pathology. Central to this relationship is A Disintegrin and Metalloprotease 10 (ADAM10), an essential α-secretase that exerts a protective effect by decreasing Aβ formation through the non-amyloidogenic processing of the amyloid precursor protein (APP). Furthermore, ADAM10 regulates the shedding of Neuronal Growth Regulator 1 (Negr1), a protein intricately linked to both LOD and AD, thereby enhancing synaptic plasticity and neuronal development - two critical processes in addressing these challenging disorders. Given the rapidly rising prevalence of both depression and dementia in aging populations, understanding these molecular interactions is more urgent than ever. Despite growing evidence, the interplay among LOD, AD, ADAM10, and Negr1 remains insufficiently explored, particularly in diverse populations. This review synthesizes recent advancements that illuminate the complex interactions among LOD, AD, and the regulatory function of ADAM10, particularly concerning one of its substrates, Negr1. By elucidating these fundamental interactions, the study paves the way for innovative treatment approaches aimed at both LOD and AD, advocating for a synergistic strategy to address these multifaceted conditions effectively, meeting a critical and time-sensitive challenge in global brain health.},
}