Search Results (12,117)

Synaptic failure is the most accurate pathological correlate of cognitive and motor decline in neurodegenerative diseases. However, the molecular logic governing selective synaptic vulnerability in Alzheimer’s (AD) and Parkinson’s (PD) remains a fundamental enigma. This review dissects the hierarchical organization of the synaptome, arguing that synaptic decay is not a generic process of attrition but a specific collapse of subsynaptic domains (SSDs) and trans-synaptic nanocolumns, considered here within the framework of the tetrapartite synapse, which comprises the presynaptic and postsynaptic compartments together with glia and the perisynaptic extracellular matrix. We use the term pathological convergence in a restricted sense, to denote that, although the primary aggregates differ, the two diseases converge on the same postsynaptic scaffolding hubs and on a comparable loss of condensate fluidity. We propose a biophysical model where the Post-Synaptic Density (PSD) matrix, governed by liquid–liquid phase separation (LLPS), may undergo a pathological liquid-to-solid transition—characterized by condensate maturation and the formation of insoluble protein aggregates—driven by proteotoxic species. Specifically, we analyze how Aβ-mediated zinc sequestration disrupts the Shank-SAM scaffold hierarchy in AD, while α-synuclein aggregates arrest presynaptic vesicle dynamics and mitochondrial homeostasis in PD. Furthermore, we explore the emerging frontier of "Precision Synaptopharmacology," highlighting how targeted modulation of protein–protein interaction (PPIs), synthetic synaptic organizers (e.g., CPTX), and phase-stabilizing chaperones can restore nanocolumn alignment and synaptic fluidity. We also set out the principal limitations of these strategies, including blood–brain barrier delivery, off-target effects, the immaturity of condensate-directed pharmacology and the incomplete translation of rodent findings to human disease, and we consider the vascular and peripheral contributions that modify the synaptic environment. By integrating recent advances in super-resolution microscopy, systems biology, and activity-based neurorehabilitation, we provide a comprehensive framework for shifting neuroprotective strategies toward the precision engineering and functional recovery of synaptic nano-architecture. Full article

Background/Objectives: Brain pericytes are contractile mural cells of the neurovascular unit whose responses to endothelin-1 (ET-1) are mediated primarily by endothelin type A (ETA) receptors. ET-1/ETA signaling has been implicated in pathological pericyte contraction in neurovascular disorders such as Alzheimer’s disease and in cerebrovascular dysfunction after subarachnoid hemorrhage, motivating pharmacological evaluation of selective ETA receptor antagonists at the pericyte level. Clazosentan is a selective ETA receptor antagonist used clinically for cerebral vasospasm; however, its pharmacodynamic effects on brain pericytes remain insufficiently characterized. Methods: Pericyte impedance-based contractile and recovery responses to ET-1 were evaluated by xCELLigence real-time cell index analysis. Pericyte viability, morphology, and ETA protein abundance were examined using Cell Counting Kit-8 assay, immunocytochemistry, and Western blotting. As a secondary barrier-related assessment, transendothelial electrical resistance (TEER) was measured in primary rat brain endothelial cell-based in vitro blood–brain barrier models. Results: ET-1 induced impedance-based contractile responses with a concentration-related trend, followed by recovery responses, and increased ETA protein abundance in a time- and concentration-related manner; clazosentan significantly attenuated ET-1-induced ETA upregulation. Repeated ET-1 exposure was associated with an enhanced subsequent ET-1-induced impedance-based contractile response and a more sustained response, suggesting contractile sensitization; both effects were significantly attenuated by clazosentan. Clazosentan did not overtly disrupt TEER-assessed barrier properties. Conclusions: These findings suggest that ET-1/ETA signaling may shift brain pericytes toward a sensitized contractile response state and that selective ETA blockade by clazosentan attenuates this process without overtly disrupting TEER-assessed barrier properties under the present in vitro conditions. These observations support further pharmacological characterization of clazosentan as a modulator of pericyte ET-1 responses. Full article

Background: Preventive strategies, including adherence to specific dietary patterns, have received increasing attention as approaches to reduce cognitive decline and dementia risk. However, findings remain inconsistent, partly due to differences in dietary assessment methods, cognitive outcomes, and THE consideration of genetic susceptibility factors such as apolipoprotein E (APOE) genotype. Methods: This study examined associations between dietary patterns and longitudinal cognitive change in 185 older adults without dementia from the Western Australia Memory Study. Participants completed a food frequency questionnaire at baseline and underwent comprehensive neuropsychological assessments at baseline and up to five follow-up visits at 18-month intervals. Composite scores were generated for six cognitive domains and the Preclinical Alzheimer’s Cognitive Composite (PACC). Results: Western and Prudent dietary pattern scores were analysed using linear mixed-effects models stratified by APOE ε4 carrier status. Among APOE ε4 carriers, greater adherence to a Western dietary pattern was associated with a faster decline in attention (p = 0.016), whereas no significant associations were observed for the Prudent dietary pattern or among APOE ε4 non-carriers. This association was attenuated after excluding participants with possible baseline cognitive impairment (MoCA < 23). Conclusion: These findings suggest that adherence to a Western dietary pattern may accelerate cognitive decline in individuals genetically at risk for Alzheimer’s disease, highlighting the importance of considering gene–diet interactions when developing dietary strategies for dementia prevention. Full article

Canonical signal peptides (SPs) are short N-terminal sequences that direct nascent proteins into the secretory pathway, but their role extends far beyond protein targeting. Advances in sequencing and computational tools have enabled their systematic identification across proteomes, highlighting SPs as critical regulators of protein biogenesis, including endoplasmic reticulum (ER) targeting, translocation, folding, and proteostasis. Clinically, mutations affecting SP function underlie a distinct group of human disorders, while SP-derived fragments are emerging as diagnostic biomarkers and therapeutic targets. In biotechnology, SPs are engineered to enhance recombinant protein production and serve as molecular tags for intracellular delivery. Together, these developments position SPs at the intersection of fundamental cell biology, medicine, and biotechnology. While this review primarily focuses on canonical SPs, it also considers selected non-canonical targeting and topogenic sequences whose dysfunction contributes to protein misfolding, impaired ER translocation, disrupted degradation pathways, and altered intracellular trafficking in neurodegenerative diseases. Aberrations involving both conventional SPs and alternative targeting/topogenic elements contribute to pathological protein aggregation, a hallmark of major neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington Disease (HD), prion diseases, and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); in multiple sclerosis (MS) is primarily an inflammatory demyelinating disease, where abnormal protein exposure, potentially linked to misprocessed SPs, can activate immune responses. By synthesizing current knowledge, the review explores how alterations in targeting determinants influence key proteostasis pathways, acting as upstream modulators of disease-relevant molecular cascades. It further discusses the emerging concept that SP-derived fragments may participate in intercellular communication, adding an additional layer of regulatory complexity. Full article

Alzheimer’s disease (AD) involves not only amyloid-β and tau pathology but also extensive disturbances in lipid metabolism, membrane organization, neuroinflammatory signaling, and tissue homeostasis. Conventional lipidomics has identified changes in phospholipids, sphingolipids, sulfatides, ceramides, gangliosides, and cholesterol-related pathways, but tissue homogenization removes their anatomical context. The aim of this review is to critically assess how matrix selection, sample preparation, ionization polarity, and emerging analytical strategies influence the detection and interpretation of spatial lipid alterations specifically associated with AD neuropathology. Current evidence shows that AD-related lipid remodeling is region- and lesion-specific, with recurrent findings including ganglioside accumulation, sulfatide depletion, ceramide-related alterations, phospholipid remodeling, lysosomal lipid changes, and disturbed cholesterol homeostasis within or around amyloid plaques. Matrix chemistry strongly influences lipid-class coverage, ionization efficiency, spectral background, adduct formation, spatial resolution, and biological interpretation. Matrix-Assisted Laser Desorption/Ionization with Laser-Induced Post-Ionization (MALDI-2), ion mobility, reactive matrices, on-tissue derivatization, structural lipidomics, single-cell imaging, and spatial multiomics are expanding molecular coverage and annotation confidence. However, broader translation requires standardized workflows, structurally validated assignments, quantitative quality control, larger human cohorts, and improved interlaboratory reproducibility. Collectively, the available evidence indicates that the principal value of Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) in AD lies not merely in detecting altered lipid abundance, but in resolving lesion-specific lipid microenvironments whose interpretation depends directly on matrix chemistry, spatial resolution, and structural validation. Full article

Background/Objectives: Alzheimer’s disease (AD) is associated with amyloid-β (Aβ)-induced neuronal injury, oxidative stress, inflammatory activation, and cellular senescence. Phycocyanobilin (PCB), an algae nutritive compound, has shown neuroprotective potential, but whether it attenuates Aβ-induced neuronal senescence remains unclear. This study investigated the protective effects of PCB against Aβ_1–42 oligomer-induced senescence-like alterations in SH-SY5Y cells and examined the involvement of sirtuin 1 (SIRT1) signaling. Methods: Differentiated SH-SY5Y cells were pretreated with PCB (50 μmol/L) in the presence or absence of EX527 (10 μmol/L) for 24 h, followed by exposure to Aβ_1–42 oligomers (20 μmol/L) for an additional 24 h. Cell viability, lactate dehydrogenase (LDH) release, senescence-associated β-galactosidase (SA-β-gal) staining, senescence-associated heterochromatin foci (SAHF)-associated di-/tri-methylated histone H3 lysine 9 (H3K9me2/3) fluorescence, senescence-associated secretory phenotype (SASP)-related cytokines, phosphorylated histone H2AX (γ-H2AX) accumulation, Ki67 expression, p53/p21/p16 signaling, and silent information regulator 1 (SIRT1) expression and activity were assessed using cell counting kit-8 assay, LDH assay, enzyme-linked immunosorbent assay, immunofluorescence staining, quantitative real-time PCR analysis, Western blotting, and fluorometric enzymatic activity assay. Results: Aβ_1–42 oligomers reduced cell viability, increased LDH release, promoted SA-β-gal positivity, enhanced H3K9me2/3 and γ-H2AX signals, elevated IL-1β, IL-6, and IL-8 levels, suppressed Ki67 expression, and upregulated p53, p21, and p16. PCB pretreatment markedly attenuated these cytotoxic, senescence-associated inflammatory, and DNA damage-related responses while restoring SIRT1 mRNA, protein expression, and enzymatic activity. EX527 partially reversed these protective effects. Conclusions: PCB attenuates Aβ_1–42 oligomer-induced neuronal senescence-like alterations, at least partly through SIRT1-associated regulation, supporting its potential as a naturally derived anti-senescent neuroprotective compound for AD-related neuronal aging. Full article

Background/Objectives: Mental and neurological disorders contribute substantially to the global burden of disease, affecting people of all ages and backgrounds. As their prevalence increases with age, their overall impact is expected to grow in the coming decades. Although psychological and pharmacological treatments are available, many patients fail to achieve satisfactory outcomes, underscoring the need for improved therapeutic strategies. Cannabis sativa L. has been used for medicinal purposes for centuries, and cannabidiol (CBD) has attracted increasing attention because of its broad therapeutic potential. Scientific studies indicate that CBD may be beneficial in several mental and neurological disorders. Methods: A comprehensive literature search was conducted to identify articles investigating the therapeutic potential of CBD and cannabis in selected disorders. Results: Evidence from preclinical and clinical studies, together with findings from the broader cannabis literature, indicates that CBD may offer therapeutic benefits in a range of conditions, including Alzheimer’s and Parkinson’s disease, anxiety disorders, and epilepsy. Emerging data also support its potential use as an adjunctive therapy for COVID-19. Current research has improved understanding of the neurobiological mechanisms underlying these disorders and the molecular pathways through which CBD may exert its effects. CBD has demonstrated good tolerability, with predominantly mild adverse effects and a favorable safety profile. Conclusions: Despite promising findings, many available studies are preclinical or involve small patient cohorts, and the mechanisms underlying the therapeutic effects of CBD remain incompletely understood. Further well-designed, randomized, controlled, multicenter trials are needed to establish the efficacy and safety of CBD and support its integration into clinical practice. Full article

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Early diagnosis of AD is crucial for delaying disease progression and improving patients’ quality of life. Blood biomarkers, particularly amyloid-beta (Aβ) and Tau proteins along with their phosphorylated isoforms, show advantages such as convenient sampling, minimal invasiveness, and excellent repeatability. However, the extremely low concentrations of AD biomarkers in blood impose stringent requirements on the sensitivity, specificity, and anti-interference capability of detection methods. Optical methods provide promising analytical platforms to address these challenges in view of their intrinsic merits of high sensitivity and selectivity; rapid response; and potential for miniaturization. This review systematically summarizes the latest advances in optical methods for the detection of the two core AD blood biomarkers (Aβ and Tau), covering techniques such as colorimetry, fluorescence, chemiluminescence, surface plasmon resonance (SPR), and surface-enhanced Raman scattering (SERS). The sensing principles, design strategies, and analytical performances of these methods are discussed, with special emphasis on different signal amplification strategies. In addition, several challenges and future prospects are provided with a primary focus on single-molecule detection, insufficient sensitivity and stability, lack of validation with large clinical cohorts, and absence of standardization. This review aims to provide researchers with guidance for the rational development of high-performance optical methods to achieve early diagnosis of AD. Full article

Early diagnosis of Alzheimer’s disease (AD) can facilitate the establishment and implementation of therapeutic interventions. The currently used diagnosis methods for AD mainly include cerebrospinal fluid analysis and positron emission tomography imaging. Due to their high invasiveness, high cost, and limited accessibility, these technologies are difficult to meet the needs of large-scale population screening, grading diagnosis, and treatment, thereby limiting the popularization of early diagnosis of AD. The detection of blood biomarkers has become an important breakthrough in early screening and diagnosis of different diseases due to its non-invasive, low-cost, and easy-to-operation advantages. Recently, blood proteins such as amyloid-beta (Aβ), total and phosphorylated Tau, light chain neurofilaments (NFL), and glial fibrillary acidic protein (GFAP) have been considered promising biomarkers for the diagnosis of AD. However, there is currently no effective, minimally invasive, and easily accessible detection method for clinical diagnosis and risk prediction of AD. Electrochemical and electrical biosensors are highly sensitive, simple, fast, and cost-effective analytical tools for disease monitoring, drug development, and target detection. In this work, we comprehensively and systematically overview the progress of various electrochemical and electrical techniques for determining AD-related blood protein biomarkers, mainly including electrochemistry, electrochemiluminescence, photoelectrochemistry, quartz crystal microbalance, field-effect transistor, and organic electrochemical transistor. This work can provide guidance for researchers to develop novel electrochemical and electrical biosensors for early and accurate diagnosis of AD. Full article

Background: Dementia develops through the combined influence of genetic vulnerability, biological processes, and environmental exposures. The apolipoprotein E (APOE) ε4 allele is a well-known genetic contributor to dementia risk, and growing evidence links gut microbial alterations to cognitive decline and cerebrovascular-related pathology. Nevertheless, studies jointly evaluating genetic, microbiome, and clinical information remain relatively scarce. This study examined an integrated framework combining APOE genotype and gut microbiome data for cross-sectional dementia classification. Methods: We analyzed 292 participants representing three cognitive stages: subjective memory impairment (SMI), mild cognitive impairment, and dementia. Clinical variables, APOE genotype, and gut microbial metagenomic profiles were examined. Associations among genetic risk, Alzheimer’s disease pathology, and brain structural changes were assessed, and multivariable models were used to distinguish participants with dementia from those with SMI or MCI. Results: APOE ε4 carriage was most frequent among participants with dementia, while no ε4 carriers were observed in the SMI group. Gut microbial profiles differed according to the dementia-related genetic-risk category (mild vs. moderate-to-high). The fully integrated model showed a numerically higher cross-validated AUC than models constructed from fewer data domains. Streptococcus, Akkermansia, and Fusicatenibacter were more abundant in the moderate-to-high genetic-risk group; these taxon-level findings were exploratory and based on nominal p-values. Conclusions: The findings support an exploratory integrated framework for cross-sectional dementia classification based on genetic and gut microbiome information. Independent longitudinal and multicenter validation is required before the framework can be interpreted as predicting future dementia risk or supporting personalized clinical decisions. Full article

Alzheimer’s disease (AD) is characterized by the excessive production and aggregation of β-amyloid (Aβ), which serves as key pathological features of disease progression. Although Humulus japonicus Siebold & Zucc. is a traditional medicinal plant rich in flavonoids and phenolic compounds, its specific anti-amyloidogenic constituents remain to be fully elucidated. This study evaluated the effects of the aerial parts of H. japonicus on Aβ production and aggregation, and identified its active constituents through bioassay-guided isolation. The 80% ethanolic extract of H. japonicus aerial parts significantly reduced soluble amyloid precursor protein β (sAPPβ) levels and BACE1 protein expression in Chinese Hamster Ovary cells stably expressing amyloid precursor protein (APP-CHO cells). Furthermore, it inhibited Aβ aggregation and promoted fibril disaggregation in Thioflavin T assays. Among the solvent-partitioned fractions, the ethyl acetate fraction exhibited the most potent anti-amyloidogenic activity and was subjected to chromatographic isolation, leading to the characterization of fourteen compounds (7 flavonoids, 2 phenolic acids, 2 sesquiterpenoids, and 3 phenylpropanoids). Specifically, luteolin 7-O-β-d-glucopyranoside (2), orientin (3), vitexin (5), vomifoliol (8), abscisic acid (9), and p-hydroxyphenylethyl-p-coumarate (12) significantly decreased sAPPβ levels, as well as BACE1 and Presenilin-1 protein expression. Meanwhile, luteolin 7-O-β-d-glucopyranoside (2), orientin (3), vitexin (5), and quercetin 7-O-β-d-glucopyranoside trimer (7) effectively reduced Aβ aggregation and enhanced the disaggregation of pre-formed Aβ aggregates. Collectively, luteolin 7-O-β-d-glucopyranoside (2), orientin (3), and vitexin (5) exhibited the most consistent dual inhibitory effects on both Aβ production and aggregation, supporting their selection as key marker compounds. Among the extracts prepared with varying ethanol concentrations, the 100% ethanol extract yielded the highest levels of these flavonoid glycosides and exhibited the strongest anti-amyloidogenic activity. These findings suggest that the aerial parts of H. japonicus and its constituent flavonoid glycosides represent promising natural resources for modulating amyloidogenic APP processing and Aβ aggregation in AD. Full article

Background: The interaction between sex, APOE ε4 status, and clinical progression in Alzheimer’s Disease (AD) remains a subject of debate. While females are often considered at higher risk for AD, the underlying structural neuroanatomical trajectories and how they are modulated by genotype are not fully elucidated. This study aims to evaluate how sex and the APOE ε4 genotype interact to influence longitudinal brain atrophy across three clinical groups. Methods: We analyzed longitudinal data from 2400 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), stratified by clinical group (i.e., cognitively normal, mild cognitive impairment, and AD), sex, and APOE ε4 carrier status. Using Type III Sum of Squares ANCOVA, we modeled the longitudinal variation in brain volume, controlling for baseline brain volume, and baseline severity of neurocognitive impairment and age at entry. Results: While main effects of sex and APOE genotype were not significant, the triple interaction (APOE * Sex * Clinical Group) was marginally significant (p = 0.051). Post hoc analysis revealed a distinct pattern of structural dimorphism within the AD cohort among APOE ε4-negative individuals with females exhibiting significantly greater structural preservation compared to males (Mean difference = 11.32, p = 0.051). Among APOE ε4 carriers, atrophy trajectories for males and females were statistically indistinguishable (p = 0.922), potentially suggesting that the ε4 allele exerts a dominant neurodegenerative influence that overrides sex-specific physiological differences. Conclusions: These emerging findings highlight the importance of jointly considering biological sex and APOE ε4 status to improve the characterization of Alzheimer’s disease heterogeneity and support precision medicine approaches. Full article

Bisphenol A (BPA) is a ubiquitous environmental endocrine-disrupting compound whose potential neurotoxicity is attracting increasing interest. A growing body of evidence suggests a possible link between BPA exposure and neurodegenerative processes; however, comprehensive analyses of its role in Alzheimer’s disease (AD) are lacking. The aim of this systematic review was to evaluate the available scientific evidence regarding the association between BPA exposure and Alzheimer’s disease. A systematic literature review was conducted in accordance with the PRISMA 2020 guidelines. The PubMed/MEDLINE, Scopus, and Web of Science databases were searched up to 23 July 2026. Original research articles and meta-analyses published in English were included, covering studies in humans and animal models that analyzed the effects of BPA on Alzheimer’s disease or related mechanisms. Study selection and data extraction were performed independently by two reviewers. The risk of bias was assessed using the ROBINS-E and SYRCLE tools. Of the 70 publications identified, 12 studies were included in the analysis. Most data came from in vivo and in vitro studies, and one study was clinical in nature (autopsy-based). The findings indicate that BPA exposure is associated with cognitive dysfunction, increased oxidative stress and neuroinflammation, amyloid-β accumulation, and tau protein hyperphosphorylation. Identified mechanisms included, among others, disturbances in insulin signaling, activation of the NF-κB and STAT3 pathways, and mitochondrial dysfunction. Eighty percent of the studies were rated as having good methodological quality. The analysis was limited by study heterogeneity, the small number of clinical studies, and the inability to perform a meta-analysis. The predominance of animal models and the use of high BPA doses hinder the direct extrapolation of the results to the human population. The available evidence suggests a possible association between BPA exposure and neuropathological processes characteristic of Alzheimer’s disease. However, further well-designed epidemiological studies are needed to assess the impact of long-term, low-dose BPA exposure on the risk of developing AD. Full article

Background: Dysregulated brain aging leads to dementia in some older adults. South Asia is one of the most populous regions of the world with a rapidly growing older adult population. Yet, very few studies have focused on quantifying the status and risk factors driving aging-related conditions such as dementia in this part of the world. Objectives: We explored multiple sources of global health data to quantify and compare all-cause dementia indices in South Asian countries. Design: Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka were considered. Population statistics and dementia as a priority area were examined using US Census Bureau and World Health Organization Global Dementia Observatory data. Crude and age-standardized rates (ASR) of dementia incidence, deaths and disability-adjusted life years (DALYs) were extracted and analyzed from the Global Burden of Disease (GBD) 2019 Study. Results: Our analysis reiterated that there are limited resources dedicated to dementia in this region. Sri Lanka and Afghanistan had the highest dementia crude rates and age-standardized rates, respectively [Crude DALYs, Sri Lanka = 321.52 (132.12–736.58); ASR DALYs, Afghanistan = 432.72 (179.01–1001.95)]. The burden of dementia in some South Asian countries was comparable to estimated global averages, and was largely driven by population aging. Analyses of available data on known biological, behavioral, environmental and disease risk factors in the region highlighted the role of metabolic dysregulation in dementia. Conclusions: Our preliminary analysis of available global health data highlights an emerging need for resources for dementia prevention and care in South Asia. There is also a critical need for future longitudinal follow-up studies focusing on dementia that are well-designed and can be harmonized with other dementia-related studies. We describe a roadmap for designing them—taking into account cultural, economic, public health and population aging dynamics that may be uniquely applicable to South Asian countries. Full article