Frontiers in Neuroscience, Год журнала: 2017, Номер 11
Опубликована: Июнь 2, 2017
The "therapeutic chelation" approach to treating Alzheimer's disease (AD) evolved from the metals hypothesis, with premise that small molecules can be designed prevent transition metal-induced amyloid deposition and oxidative stress within AD brain. Over more than 20 years, countless
Язык: Английский
Alzheimer s & Dementia, Год журнала: 2024, Номер unknown
Опубликована: Ноя. 13, 2024
Abstract INTRODUCTION Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within non‐Hispanic White (NHW) populations. Here we provide an extensive survey of proteomic landscape AD across diverse racial/ethnic groups. METHODS Two cortical regions, from multiple centers, were harmonized by uniform neuropathological diagnosis. Among 998 unique donors, 273 donors self‐identified as African American, 229 Latino and 434 NHW. RESULTS While amyloid precursor protein microtubule‐associated tau demonstrated higher abundance in brains, no significant race‐related differences observed. Further proteome‐wide focused analyses (specific beta [Aβ] species domains) supported absence racial these pathologies brain proteome. DISCUSSION Our findings indicate that risk clinical presentation are not underpinned dramatically divergent patterns proteome, suggesting other determinants account for disparities. Highlights We present a large‐scale proteome (∼10,000 proteins) DLPFC (998) STG (244) cases. About 50% samples racially ethnically donors. Key proteins (amyloid tau) correlated with CERAD Braak stages. No levels observed brains. AD‐associated changes showed strong correlation between proteomes American individuals. This dataset advances understanding ethnoracial‐specific pathways potential therapies.
Язык: Английский
Процитировано
12
Molecular & Cellular Proteomics, Год журнала: 2024, Номер 23(2), С. 100721 - 100721
Опубликована: Янв. 20, 2024
Alzheimer's disease (AD) is characterised by several neuropathological changes, mainly extracellular amyloid aggregates (plaques), intraneuronal inclusions of phosphorylated tau (tangles), as well neuronal and synaptic degeneration, accompanied tissue reactions to these processes (astrocytosis microglial activation) that precede network disturbances in the symptomatic phase disease. A number biomarkers for brain changes have been developed, using immunoassays. In this review, we discuss how targeted mass spectrometry (TMS) can be used validate further characterize classes reflecting different AD pathologies, such tau- amyloid-beta dysfunction, lysosomal dysregulation, axonal damage, prospect TMS measure proteins clinical research diagnosis. advantages disadvantages relation immunoassays are discussed, complementary aspects technologies discussed.
Язык: Английский
Процитировано
10
Science Advances, Год журнала: 2024, Номер 10(14)
Опубликована: Апрель 5, 2024
Despite the importance of protein glycosylation to brain health, current knowledge glycosylated proteoforms or glycoforms in human and their alterations Alzheimer’s disease (AD) is limited. Here, we report a proteome-wide glycoform profiling study AD control brains using intact glycopeptide-based quantitative glycoproteomics coupled with systems biology. Our identified more than 10,000 N-glycoforms from nearly 1200 glycoproteins uncovered signatures altered glycan modifications, including reduced sialylation N-glycan branching elongation as well elevated mannosylation truncation AD. Network analyses revealed higher-order organization glycoproteome into networks coregulated glycans discovered modules associated clinical phenotype, amyloid-β accumulation, tau pathology. findings provide valuable insights pathogenesis rich resource changes pave way forward for developing glycosylation-based therapies biomarkers
Язык: Английский
Процитировано
10
Nature Aging, Год журнала: 2025, Номер unknown
Опубликована: Март 10, 2025
Dystrophic neurites (also termed axonal spheroids) are found around amyloid deposits in Alzheimer's disease (AD), where they impair electrical conduction, disrupt neural circuits and correlate with AD severity. Despite their importance, the mechanisms underlying spheroid formation remain incompletely understood. To address this, we developed a proximity labeling approach to uncover proteome of spheroids human postmortem mouse brains. Additionally, established induced pluripotent stem cell (iPSC)-derived model enabling mechanistic investigation optical electrophysiology. These complementary approaches revealed subcellular molecular architecture identified abnormalities key biological processes, including protein turnover, cytoskeleton dynamics lipid transport. Notably, PI3K/AKT/mTOR pathway, which regulates these was activated spheroids. Furthermore, phosphorylated mTOR levels correlated severity humans. inhibition iPSC-derived neurons mice ameliorated pathology. Altogether, our study provides multidisciplinary toolkit for investigating therapeutic targets pathology neurodegeneration. Axonal disease. In this study, using proteomics brain iPSC modeling, authors link dysregulated mTOR, cytoskeletal transport signaling.
Язык: Английский
Процитировано
1
Frontiers in Neuroscience, Год журнала: 2017, Номер 11
Опубликована: Июнь 2, 2017
The "therapeutic chelation" approach to treating Alzheimer's disease (AD) evolved from the metals hypothesis, with premise that small molecules can be designed prevent transition metal-induced amyloid deposition and oxidative stress within AD brain. Over more than 20 years, countless
Язык: Английский
Процитировано
83