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

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 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.

Language: Английский

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

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(6), P. 903 - 909

Published: March 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.

Language: Английский

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

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(10), P. 1880 - 1891

Published: Aug. 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.

Language: 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, Journal Year: 2025, Volume and Issue: 149(1)

Published: Jan. 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.

Language: Английский

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Human and mouse proteomics reveals the shared pathways in Alzheimer’s disease and delayed protein turnover in the amyloidome

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 11, 2025

Murine models of Alzheimer's disease (AD) are crucial for elucidating mechanisms but have limitations in fully representing AD molecular complexities. Here we present the comprehensive, age-dependent brain proteome and phosphoproteome across multiple mouse amyloidosis. We identified shared pathways by integrating with human metadata prioritized components multi-omics analysis. Collectively, two commonly used (5xFAD APP-KI) replicate 30% protein alterations; additional genetic incorporation tau splicing pathologies increases this similarity to 42%. dissected proteome-transcriptome inconsistency 5xFAD brains, revealing that inconsistent proteins enriched within amyloid plaque microenvironment (amyloidome). Our analysis turnover demonstrates formation delays degradation amyloidome components, including Aβ-binding autophagy/lysosomal proteins. proteomic strategy defines pathways, identifies potential targets, underscores contributes discrepancies during progression. This study maps changes models, identifying humans, amyloid-driven turnover, differences, offering insights into targets.

Language: Английский

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

Brain, Journal Year: 2023, Volume and Issue: 146(11), P. 4495 - 4507

Published: June 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.

Language: 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, 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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Alterations in Alzheimer's disease microglia transcriptome might be involved in bone pathophysiology

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 191, P. 106404 - 106404

Published: Jan. 4, 2024

Aging is a major risk factor for multiple chronic disorders in the elderly population, including Alzheimer's disease (AD) and Osteoporosis. AD progressive neurodegenerative characterized by memory loss. In addition to dementia, several studies have shown that patients experience an increased rate of musculoskeletal co-morbidities, such as osteoporosis. Since tissue-specific macrophages contribute both diseases, this study analyzed microglia transcriptome mice determine common gene signature involved osteoclast biology. After comparing differentially regulated genes from GEO data sets (GSE93824 GSE212277), there were 35 upregulated 89 downregulated genes. Of these genes, seven are known play important role bone homeostasis. CSF1, SPP1, FAM20C, Cst7 associated with osteoclastogenesis inflammation. Among LILRA6, MMP9, COL18A1 formation regulation. We further validated some (CSF1, Cst7, SPP1) cortex models. The dysregulation microglial might provide insights into co-occurrence osteoporosis offer potential therapeutic targets combat progression.

Language: Английский

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Human brain glycoform coregulation network and glycan modification alterations in Alzheimer’s disease

Science Advances, Journal Year: 2024, Volume and Issue: 10(14)

Published: April 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

Language: Английский

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