Integrative proteomics identifies a conserved Aβ amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer’s disease

Cell Reports Medicine, Год журнала: 2024, Номер 5(8), С. 101669 - 101669

Опубликована: Авг. 1, 2024

Alzheimer's disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare proteome network changes with the proteomes of amyloid β (Aβ)-depositing mice to identify conserved divergent networks identifying an Aβ responsome. Proteins most (M42) accumulate plaques, cerebrovascular (CAA), and/or dystrophic neuronal processes, overexpression two M42 proteins, midkine (Mdk) pleiotrophin (PTN), increases accumulation plaques CAA. proteins bind fibrils vitro, MDK PTN co-accumulate cardiac transthyretin amyloid. appear intimately linked deposition can regulate deposition, suggesting they are pathology modifiers thus putative therapeutic targets. We posit amyloid-scaffolded M42+ central mechanism mediating downstream pathophysiology AD.

Язык: Английский

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Structural variants linked to Alzheimer’s disease and other common age-related clinical and neuropathologic traits

Genome Medicine, Год журнала: 2025, Номер 17(1)

Опубликована: Март 4, 2025

Alzheimer's disease (AD) is a complex neurodegenerative disorder with substantial genetic influence. While genome-wide association studies (GWAS) have identified numerous risk loci for late-onset AD (LOAD), the functional mechanisms underlying most of these associations remain unresolved. Large genomic rearrangements, known as structural variants (SVs), represent promising avenue elucidating such within some loci. By leveraging data from two ongoing cohort aging and dementia, Religious Orders Study Rush Memory Aging Project (ROS/MAP), we performed analysis testing 20,205 common SVs 1088 participants whole genome sequencing (WGS) data. A range other age-related clinical neuropathologic traits were examined. First, mapped across 81 discovered 22 in linkage disequilibrium (LD) GWAS lead directly associated phenotypes tested. The strongest was deletion an Alu element 3'UTR TMEM106B gene, high LD respective locus multiple AD-related disorders (ADRD) phenotypes, including tangles density, TDP-43, cognitive resilience. this also linked to lower protein abundance. We found 22-kb depression ROS/MAP bearing similar patterns SNPs at IQCK locus. In addition, leveraged our catalog SV-GWAS replicate characterize independent findings SV-based five diseases. Among findings, highlight replication significant progressive supranuclear palsy (PSP), markers 17q21.31 MAPT inversion 1483-bp CYP2A13 locus, along suggestive associations, 994-bp duplication LMNTD1 suggestively 3958-bp DOCK5 Lewy body (LBD) (P = 3.36 × 10-4). still limited sample size, study highlights utility provides valuable resource characterization effects pathogenesis.

Язык: Английский

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Integrative Analysis of Metabolome and Proteome in the Cerebrospinal Fluid of Patients with Multiple System Atrophy

Cells, Год журнала: 2025, Номер 14(4), С. 265 - 265

Опубликована: Фев. 12, 2025

Multiple system atrophy (MSA) is a progressive neurodegenerative synucleinopathy. Differentiating MSA from other synucleinopathies, especially in the early stages, challenging because of its overlapping symptoms with forms Parkinsonism. Thus, there pressing need to clarify underlying biological mechanisms and identify specific biomarkers for MSA. The metabolic profile cerebrospinal fluid (CSF) known be altered To further investigate behind changes, we created network CSF metabolites patients analysed these changes using bioinformatic software. Acknowledging limitations metabolomics, incorporated proteomic data improve overall comprehensiveness study. Our silico predictions showed elevated ROS, cytoplasmic inclusions, white matter demyelination, ataxia, neurodegeneration, ATP concentration, neurotransmitter release, oligodendrocyte count predicted suppressed samples. Machine learning dimension reduction are important multi-omics approaches as they handle large amounts data, patterns, make while reducing variance without information loss generating easily visualised plots that help clusters, or outliers. integrated multiomics machine essential elucidating identifying potential diagnostic

Язык: Английский

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Proteomic Subtyping of Alzheimer's Disease CSF links Blood-Brain Barrier Dysfunction to Reduced levels of Tau and Synaptic Biomarkers

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 15, 2025

Abstract Alzheimer’s disease (AD) is characterized by significant clinical and molecular heterogeneity, influenced genetic demographic factors. Using an unbiased, network-driven approach, we analyzed the cerebrospinal fluid (CSF) proteome from 431 individuals (483 samples), including 111 African American participants, to identify core protein modules associated with AD, race, sex, age. Our analysis revealed ten co-expression linked distinct biological pathways cell types, many of which correlated established AD biomarkers such as β-amyloid, tau, phosphorylated tau. To further resolve applied a proteomic subtyping identifying six CSF subtypes spanning pathological spectrum. These were validated across independent cohorts, aligning previously defined subtypes, those neuronal hyperplasticity, immune activation, blood-brain barrier (BBB) integrity. Notably, BBB subtype, enriched Americans men, was low high CSF/serum albumin ratios, reduced synaptic levels. This subtype also exhibited increased levels proteolytic enzymes, thrombin matrix metalloproteases, that cleave Plasma dilution into hyperplastic led tau module levels, indicating plasma protease activity contributes depletion underlying brain pathology. findings highlight impact integrity on particularly in men Americans, underscore need for diversity-informed biomarker strategies improve diagnostics therapeutic targeting populations.

Язык: Английский

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Translating the Post-Mortem Brain Multi-Omics Molecular Taxonomy of Alzheimer's Dementia to Living Humans

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 24, 2025

ABSTRACT Alzheimer’s disease (AD) dementia is characterized by significant molecular and phenotypic heterogeneity, which confounds its mechanistic understanding, diagnosis, effective treatment. In this study, we harness the most comprehensive dataset of paired ante-mortem blood omics, clinical, psychological, post-mortem brain multi-omics data neuroimaging to extensively characterize translate taxonomy AD living individuals. First, utilizing a integration eight complementary layers from (N = 1,189), identified three distinct subtypes exhibiting strong associations with cognitive decline, sex, psychological traits, morphology, specific cellular drivers involving immune, vascular, oligodendrocyte precursor cells. Next, in translational effort, developed predictive models convert these advanced brain-derived profiles (AD pseudotimes subtypes) into blood-, MRI- traits-based markers. The translation results underscore both promise opportunities for further enhancement. Our findings enhance understanding value multi-scale approaches elucidating causal mechanisms, lay groundwork development novel therapies persons that target multi-level dementia.

Язык: Английский

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CLU alleviates Alzheimer’s disease-relevant processes by modulating astrocyte reactivity and microglia-dependent synaptic density

Neuron, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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CNS muscarinic receptors and muscarinic receptor agonists in Alzheimer disease treatment

Handbook of clinical neurology, Год журнала: 2025, Номер unknown, С. 161 - 184

Опубликована: Янв. 1, 2025

Язык: Английский

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Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(5)

Опубликована: Май 1, 2025

Abstract INTRODUCTION Sex differences exist in Alzheimer's disease (AD), but the underlying mechanisms remain unclear. METHODS We examined brain proteomes profiled from dorsolateral prefrontal cortex of 770 donors (66.2% female). RESULTS Proteome‐wide differential expression analysis males and females jointly identified many significant proteins for AD dementia ( n = 1228), amyloid beta 1183), tangles 1309), global cognitive trajectory 2325) at a false discovery rate <0.05. Sex‐stratified analyses also associated with or its endophenotypes. Finally, we found 10 sex‐by‐trait interactions, including one clinical diagnosis (MARCKS), seven trajectories (TOGARAM1, PLCD3, SLC22A5, MTFR1L, DCUN1D5, S100A12, TRIM46), two cerebral pathologies (PANK4 SOS1). DISCUSSION The sex interaction cover range functions likely relevant pathogenesis, estrogen response, inflammation, mitochondrial biology, their specific roles ought to be studied. Future work should test potential as sex‐specific biomarkers. Highlights At phenotypic level, baseline performance, trajectories, hallmark pathologies. endophenotypes either alone when considered together. interactions endophenotypes, which could investigated biomarkers AD.

Язык: Английский

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A primer on copper biology in the brain

Neurobiology of Disease, Год журнала: 2025, Номер unknown, С. 106974 - 106974

Опубликована: Май 1, 2025

This primer aims to expose scientists who study the brain field of copper biology. We briefly discuss key homeostasis mechanisms and proteins place these functions in context neurodevelopment. A small number genes are explored as representative examples importance this metal brain. show that expressed throughout their defects linked a diverse array neurological phenotypes, which we further several neurodegenerative diseases associated with dysregulation copper. review interested fundamental roles for brain, primary responsible maintaining classic metal.

Язык: Английский

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Protein co-aggregates of dense core amyloid plaques and CSF differ in rapidly progressive Alzheimer’s disease and slower sporadic Alzheimer’s disease

Alzheimer s Research & Therapy, Год журнала: 2025, Номер 17(1)

Опубликована: Май 27, 2025

The rapidly progressive phenotype of Alzheimer's disease (rpAD) remains a rare and less-studied entity. Therefore, the replication key results from rpAD brain cerebrospinal fluid (CSF) is lacking. A label-free quantitative LC-MS/MS analysis proteins co-aggregating with core-amyloid β plaques in fresh frozen tissue (FFT) medial temporal regions ( n=8 ) neuropathologically characterized at National Prion Disease Pathology Surveillance Center (NPDPSC), compared microdissected amyloid formalin-fixed, paraffin-embedded (FFPE) blocks patients n=22 previously published NPDPSC cohort, was performed. Matched CSF FFT cases were to proteomic evaluation AD subtype rapid progression. total 1841 study, which 463 consistently identified every patient analyzed. One thousand two hundred eighty-three shared between prior FFPE study. offered more comprehensive profile than study prominently included immune system pathways. Thirty-five tissue, matched same subjects, biological processes related response again notable. These validated against data faster rate progression identify top 5 potential protein biomarkers CSF. support distinct immune-related both that can be explored as future for clinical diagnosis rpAD.

Язык: Английский

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