Compilation of reported protein changes in the brain in Alzheimer’s disease

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 25, 2023

Abstract Proteomic studies of human Alzheimer’s disease brain tissue have potential to identify protein changes that drive disease, and new drug targets. Here, we analyse 38 published proteomic studies, generating a map in across thirteen regions, three stages (preclinical mild cognitive impairment, advanced disease), proteins enriched amyloid plaques, neurofibrillary tangles, cerebral angiopathy. Our dataset is compiled into searchable database (NeuroPro). We found 848 were consistently altered 5 or more studies. Comparison early-stage revealed associated with synapse, vesicle, lysosomal pathways show change early but widespread mitochondrial expression are only seen disease. Protein similar for regions considered vulnerable resistant. This resource provides insight highlights interest further study.

Язык: Английский

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Cryo-EM structures of amyloid-β and tau filaments in Down syndrome

Nature Structural & Molecular Biology, Год журнала: 2024, Номер 31(6), С. 903 - 909

Опубликована: Март 29, 2024

Abstract Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and regarding the structure of amyloid-β (Aβ) tau filaments unknown. Here we report Aβ from two brains. We found 40 (types IIIa IIIb) that differ those previously reported sporadic types 42 (I II) identical to familial AD. Tau (paired helical straight filaments) were AD, supporting notion common mechanism through which amyloids trigger aggregation tau. This knowledge important for understanding assessing whether adults could be included clinical trials.

Язык: Английский

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Proteomic changes in Alzheimer disease associated with progressive Aβ plaque and tau tangle pathologies

Nature Neuroscience, Год журнала: 2024, Номер 27(10), С. 1880 - 1891

Опубликована: Авг. 26, 2024

Abstract Proteomics can shed light on the dynamic and multifaceted alterations in neurodegenerative disorders like Alzheimer’s disease (AD). Combining radioligands measuring β-amyloid (Aβ) plaques tau tangles with cerebrospinal fluid proteomics, we uncover molecular events mirroring different stages of AD pathology living humans. We found 127 differentially abundant proteins (DAPs) across spectrum. The strongest Aβ-related were mainly expressed glial cells included SMOC1 ITGAM. A dozen linked to ATP metabolism preferentially neurons independently associated tangle load accumulation. Only 20% DAPs also altered other diseases, underscoring AD’s distinct proteome. Two co-expression modules related, respectively, protein microglial immune response encompassed most DAPs, opposing, staggered trajectories along continuum. unveil signatures Aβ proteinopathy vivo, offering insights into complex neural responses potential biomarkers therapeutics targeting stages.

Язык: Английский

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A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer’s disease

Nature Medicine, Год журнала: 2025, Номер unknown

Опубликована: Март 31, 2025

Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% variance AD-related impairment (CI). To discover novel CI AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective case-control cohorts. Synapse proteins emerged as strongest correlates CI, independent Aβ tau. Using machine learning, derived CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% beyond pTau181:Aβ42, 11% positron emission tomography, 28% neurofilament, growth-associated 43 neurogranin Aβ+ phosphorylated tau+ (A+T1+) individuals. also increased with normal aging 20 years before estimated symptom onset carriers autosomal dominant mutations. Regarding prognosis, predicted conversion A+T1+ cognitively to mild (standard deviation increase hazard ratio = 3.0, P 7.0 × 10-4) dementia 2.2, 8.2 10-16) over a 15-year follow-up, adjusting neurogranin, 43, age, APOE4 sex. We developed plasma proteomic signature evaluated 13,401 samples, partly recapitulated YWHAG:NPTX2. Overall, our findings underscore robust prognostic biomarker resilience versus progression, highlight potential replacing measurement further implicate dysfunction core driver dementia.

Язык: Английский

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Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer’s disease, and late-onset Alzheimer’s disease

Acta Neuropathologica, Год журнала: 2025, Номер 149(1)

Опубликована: Янв. 18, 2025

Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar early-onset (EOAD) late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 4.07 (82.1 6.37 controls (66.4 13.04). identified differentially abundant proteins when comparing plaques neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in 132), 192), 128), 43 plaque-associated shared across all groups. Positive correlations were observed between (R2 .77), .73), .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p 1.29 × 10−5) for immune system regulation 4.33 lysosome organization 0.029) LOAD. Protein networks revealed a protein signature involving metabolism, response, functions. In vs. control tissue, we 263, 269, 301 proteins, 65 altered cohorts. Non-plaque showed modest .59) .33) compared correlation .79). GOBP term groups was chromatin remodeling 0.001), additional terms including extracellular matrix, protein–DNA complexes expression Our study reveals key functional characteristics amyloid LOAD, highlighting pathways endo/lysosomal functions responses. The distinct alterations ECM structure, underscoring unique differences subtypes. findings enhance our understanding pathogenesis identify potential biomarkers therapeutic targets.

Язык: Английский

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Glymphatic system clearance and Alzheimer’s disease risk: a CSF proteome-wide study

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

Опубликована: Янв. 31, 2025

The emerging evidence of the role glymphatic system (GS) in Alzheimer's disease (AD) provides new opportunities for intervention from earliest stages disease. aim study is to evaluate efficacy GS AD identify biomarkers. We performed a two-stage proteomic health using intravenous gadolinium-based contrast agent (GBCA) with serial T1 3T magnetic resonance imaging (MRI) individuals amnestic mild cognitive impairment (aMCI). In Stage 1 (evaluated Cohort aMCI participants (n = 11)), we correlated levels 7K cerebrospinal fluid (CSF) proteins (estimated by SOMAscan) 78 Freesurfer-segmented brain regions interest (ROIs). A total seven different were significantly associated (p-value < 6.4 × 10-4). stronger correlations identified NSUN6, GRAAK, OLFML3, ACTN2, RUXF, SHPS1 and TIM-4. pathway enrichment analysis revealed that mainly implicated neurodegenerative processes, immunity inflammation. 2, validated these results cohort (with without pathology CSF (aMCI(-) aMCI/AD( +); n 22 7, respectively) healthy controls 10). Proteomic prediction models generated each ROI. These compared demographic-only identifying aMCI(-) +) vs controls. This was repeated determine if could those both found outperform models. Our identifies linked involved immune participants.

Язык: Английский

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CSF proteomics in autosomal dominant Alzheimer’s disease highlights parallels with sporadic disease

Brain, Год журнала: 2023, Номер 146(11), С. 4495 - 4507

Опубликована: Июнь 22, 2023

Autosomal dominant Alzheimer's disease (ADAD) offers a unique opportunity to study pathophysiological changes in relatively young population with few comorbidities. A comprehensive investigation of proteome occurring ADAD could provide valuable insights into AD-related biological mechanisms and uncover novel biomarkers therapeutic targets. Furthermore, might serve as model for sporadic AD, but in-depth comparisons are lacking. We aimed identify dysregulated CSF proteins determine the degree overlap AD. measured 1472 PSEN1 or APP mutation carriers (n = 22) age- sex-matched controls 20) from Amsterdam Dementia Cohort using proximity extension-based immunoassays (PEA). compared protein abundance between groups two-sided t-tests identified enriched pathways. Using same panels paired plasma samples, we investigated correlations their counterparts. Finally, our results recently published PEA data an international cohort AD 230) non-AD dementias 301). All statistical analyses were false discovery rate-corrected. detected 66 differentially abundant (65 increased, 1 decreased) (q < 0.05). The most strongly upregulated (fold change >1.8) related immunity (CHIT1, ITGB2, SMOC2), cytoskeletal structure (MAPT, NEFL) tissue remodelling (TMSB10, MMP-10). Significant CSF-plasma found SMOC2 LILR1B. Of expressed proteins, 36 had been previously cohort, 34 which (94%) also significantly strong correlation fold these both cohorts (rs 0.730, P 0.001). Twenty-nine (81%) among patients suspected co-pathology. This proteomics demonstrates substantial biochemical similarities suggesting involvement processes. Besides known several such TMSB10, MMP-10 SMOC2, have potential biomarkers. With shared changes, findings be translatable greatly expedite therapy development.

Язык: Английский

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Alzheimer's disease: The role of proteins in formation, mechanisms, and new therapeutic approaches

Neuroscience Letters, Год журнала: 2023, Номер 817, С. 137532 - 137532

Опубликована: Окт. 20, 2023

Язык: Английский

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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, Год журнала: 2024, Номер 20(6), С. 4043 - 4065

Опубликована: Май 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.

Язык: Английский

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Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer’s disease

Nature Aging, Год журнала: 2024, Номер 4(10), С. 1446 - 1464

Опубликована: Авг. 21, 2024

A deeper understanding of the molecular processes underlying late-onset Alzheimer's disease (LOAD) could aid in biomarker and drug target discovery. Using high-throughput serum proteomics prospective population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES) cohort 5,127 older Icelandic adults (mean age, 76.6 ± 5.6 years), we identified 303 proteins associated with incident LOAD over a median follow-up 12.8 years. Over 40% these were independently APOE-ε4 carrier status, implicated neuronal overlapped protein signatures brain cerebrospinal fluid. We 17 whose associations strongly dependent on mostly consistent Remarkably, four (TBCA, ARL2, S100A13 IRF6) downregulated by yet upregulated due to LOAD, finding replicated external cohorts possibly reflecting response onset. These findings highlight dysregulated pathways at preclinical stages including those both independent status.

Язык: Английский

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