Proteomic changes in the human cerebrovasculature in Alzheimer's disease and related tauopathies linked to peripheral biomarkers in plasma and cerebrospinal fluid

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(6), P. 4043 - 4065

Published: May 7, 2024

Cerebrovascular dysfunction is a pathological hallmark of Alzheimer's disease (AD). Nevertheless, detecting cerebrovascular changes within bulk tissues has limited our ability to characterize proteomic alterations from less abundant cell types.

Language: Английский

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

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(8), P. 101669 - 101669

Published: Aug. 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.

Language: Английский

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Large‐scale deep proteomic analysis in Alzheimer's disease brain regions across race and ethnicity

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 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.

Language: Английский

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Large-scale Deep Proteomic Analysis in Alzheimer’s Disease Brain Regions Across Race and Ethnicity

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 26, 2024

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into proteomic landscape of AD across diverse racial and ethnic groups.

Language: Английский

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Differences in the cerebral amyloid angiopathy proteome in Alzheimer’s disease and mild cognitive impairment

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: July 22, 2024

Abstract Cerebral amyloid angiopathy (CAA) is characterized by beta (Aβ) deposition in cerebrovasculature. It prevalent with aging and Alzheimer’s disease (AD), associated intracerebral hemorrhage, contributes to cognitive deficits. To better understand molecular mechanisms, CAA(+) CAA(−) vessels were microdissected from paraffin-embedded autopsy temporal cortex of age-matched Control ( n = 10), mild impairment (MCI; 4), sporadic AD 6) cases, followed label-free quantitative mass spectrometry. 257 proteins differentially abundant compared neighboring MCI, 289 p < 0.05, fold-change > 1.5). 84 changed the same direction both groups, many among significant at least one group 0.0001, R 2 0.62). In vessels, significantly increased MCI particularly collagen-containing extracellular matrix, while ribonucleoprotein complex decreased MCI. 61 112 when cases. Increased external encapsulating structure, matrix MCI; collagen trimer AD. Twenty two Comparison CAA proteome published amyloid-plaque proteomic datasets identified similarly enriched plaques, as well a protein subset hypothesized preferentially plaques. SEMA3G emerged specific marker, validated immunohistochemically correlation pathology levels 0.0001; 0.90). Overall, vessel proteomes indicated changes integrity absence Aβ, was similar AD, which vascular reorganization, translation deficits, blood brain barrier breakdown.

Language: Английский

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Proximity labeling of the Tau repeat domain enriches RNA-binding proteins that are altered in Alzheimer's disease and related tauopathies

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

In Alzheimer's disease (AD) and other tauopathies, tau dissociates from microtubules forms toxic aggregates that contribute to neurodegeneration. Although some of the pathological interactions have been identified postmortem brain tissue, these studies are limited by their inability capture transient interactions. To investigate interactome aggregate-prone fragments tau, we applied an in vitro proximity labeling technique using split TurboID biotin ligase (sTurbo) fused with microtubule repeat domain (TauRD), a core region implicated aggregation. We characterized sTurbo TauRD co-expression, robust enzyme activity nuclear cytoplasmic localization human cell line. Following enrichment biotinylated proteins mass spectrometry, over 700 interactors. Gene ontology analysis enriched interactors highlighted processes often dysregulated including spliceosome complexes, RNA-binding (RBPs), speckles. The relevance was supported integrating recombinant data AD datasets protein co-expression networks individuals related tauopathies. This revealed overlap several modules RBPs increased Progressive Supranuclear Palsy (PSP). These findings emphasize importance pathways pathology, such as RNA splicing nuclear-cytoplasmic transport establish system valuable tool for exploring interactome.

Language: Английский

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Alzheimer’s, Parkinson’s, Frontotemporal Lobar Degeneration, and Amyotrophic Lateral Sclerosis Start in Pediatric Ages: Ultrafine Particulate Matter and Industrial Nanoparticles Are Key in the Early-Onset Neurodegeneration: Time to Invest in Preventive Medicine

Toxics, Journal Year: 2025, Volume and Issue: 13(3), P. 178 - 178

Published: Feb. 28, 2025

Billions of people are exposed to fine particulate matter (PM2.5) levels above the USEPA’s annual standard 9 μg/m3. Common emission sources anthropogenic, producing complex aerosolized toxins. Ultrafine (UFPM) and industrial nanoparticles (NPs) have major detrimental effects on brain, but USA does not measure UFPM a routine basis. This review focuses development progression common neurodegenerative diseases, as diagnosed through neuropathology, among young residents in Metropolitan Mexico City (MMC). MMC is one most polluted megacities world, with population 22 million residents, many whom unaware brain caused by their atmosphere. Fatal diseases (such Alzheimer’s Parkinson’s) that begin childhood populations living air environments preventable. We conclude UFPM/NPs capable disrupting neural homeostasis give rise relentless processes throughout entire life highly MMC. The paradigm reaching old age neurodegeneration no longer supported. Neurodegenerative changes start early pediatric ages irreversible. It time invest preventive medicine.

Language: Английский

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SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment

Cell Reports, Journal Year: 2025, Volume and Issue: 44(4), P. 115535 - 115535

Published: April 1, 2025

Impaired neuronal and synaptic function are hallmarks of early Alzheimer's disease (AD), preceding other neuropathological traits cognitive decline. We previously showed that SFRP1, a glial-derived protein elevated in AD brains from preclinical stages, contributes to progression, implicating glial factors pathogenesis. Here, we generate analyze transgenic mice overexpressing astrocytic SFRP1. SFRP1 accumulation causes dendritic defects adult mice, followed by impaired long-term potentiation decline, evident only when the animals age, thereby mimicking AD's structural-functional temporal distinction. This phenotype correlates with proteomic changes, including increased structural proteins like neurexin, which localizes close proximity cultured hippocampal neurons. conclude excessive hinders turnover, reducing plasticity-a mechanism may underlie synaptopathy observed prodromal patients.

Language: Английский

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Proteomics approach identifies aqueous humor biomarkers in retinal diseases

Communications Medicine, Journal Year: 2025, Volume and Issue: 5(1)

Published: April 24, 2025

Language: Английский

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Data-independent acquisition proteomic analysis of the brain microvasculature in Alzheimer’s disease identifies major pathways of dysfunction and upregulation of cytoprotective responses

Fluids and Barriers of the CNS, Journal Year: 2024, Volume and Issue: 21(1)

Published: Oct. 21, 2024

Abstract Brain microvascular dysfunction is an important feature of Alzheimer’s disease (AD). To better understand the brain molecular signatures AD, we processed and analyzed isolated human microvessels by data-independent acquisition liquid chromatography with tandem mass spectrometry (DIA LC–MS/MS) to generate a quantitative dataset at peptide protein level. were from parietal cortex grey matter using protocols that preserve viability for downstream functional studies. Our cohort included 23 subjects clinical neuropathologic concordance disease, 21 age-matched controls. In our analysis, identified 168 proteins whose abundance was significantly increased, no decreased in AD. The most highly increased amyloid beta, tau, midkine, SPARC related modular calcium binding 1 (SMOC1), fatty acid 7 (FABP7). Additionally, Gene Ontology (GO) enrichment analysis involved cellular detoxification antioxidative responses. A systematic evaluation functions UniProt database groupings into common themes including regulation proliferation, differentiation survival, inflammation, extracellular matrix, cell stress responses, metabolism, coagulation heme breakdown, degradation, cytoskeleton, subcellular trafficking, motility, signaling. This suggests AD exist stressed state energy demand, mount compensatory response ongoing oxidative damage associated We also used public RNAseq databases identify cell-type enriched genes detected level found changes these between control groups, indicating composition minimal no-AD groups. Using data, additionally under half had concordant mRNA, implying substantial discordance gene levels. Together, results offer novel insights underpinnings

Language: Английский

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