Multi-platform proteomic analysis of Alzheimer’s disease cerebrospinal fluid and plasma reveals network biomarkers associated with proteostasis and the matrisome

Alzheimer s Research & Therapy, Journal Year: 2022, Volume and Issue: 14(1)

Published: Nov. 17, 2022

Abstract Robust and accessible biomarkers that can capture the heterogeneity of Alzheimer’s disease its diverse pathological processes are urgently needed. Here, we undertook an investigation cerebrospinal fluid (CSF) plasma from same subjects ( n= 18 control , AD) using three different proteomic platforms—SomaLogic SomaScan, Olink proximity extension assay, tandem mass tag-based spectrometry—to assess which protein markers in these two biofluids may serve as reliable AD pathophysiology observed unbiased brain proteomics studies. Median correlation overlapping measurements across platforms CSF r ~0.7) ~0.6) was good, with more variability plasma. The SomaScan technology provided most Surprisingly, many proteins altered were found to be opposite direction plasma, including important members co-expression modules. An exception SMOC1, a key member matrisome module associated amyloid-β deposition AD, elevated both Protein analysis on greater than 7000 9500 all revealed strong changes modules related autophagy, ubiquitination, sugar metabolism CSF, endocytosis Cross-platform cross-biofluid represents promising approach for biomarker development.

Language: Английский

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Proteomic analysis of Alzheimer’s disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(753)

Published: June 26, 2024

Alzheimer’s disease (AD) is currently defined by the aggregation of amyloid-β (Aβ) and tau proteins in brain. Although biofluid biomarkers are available to measure Aβ pathology, few markers complex pathophysiology that associated with these two cardinal neuropathologies. Here, we characterized proteomic landscape cerebrospinal fluid (CSF) changes pathology 300 individuals using different technologies—tandem mass tag spectrometry SomaScan. Integration both data types allowed for generation a robust protein coexpression network consisting 34 modules derived from 5242 measurements, including disease-relevant autophagy, ubiquitination, endocytosis, glycolysis. Three strongly apolipoprotein E ε4 ( APOE ε4) AD risk genotype mapped oxidant detoxification, mitogen-associated kinase signaling, neddylation, mitochondrial biology overlapped previously described lipoprotein module serum. Alterations all three blood were dementia more than 20 years before diagnosis. Analysis CSF samples an phase 2 clinical trial atomoxetine (ATX) demonstrated abnormal elevations glycolysis module—the most correlated cognitive function—were reduced ATX treatment. Clustering based on their profiles revealed heterogeneity pathological not fully reflected tau.

Language: Английский

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Batch correction and harmonization of –Omics datasets with a tunable median polish of ratio

Frontiers in Systems Biology, Journal Year: 2023, Volume and Issue: 3

Published: April 12, 2023

Large scale -omics datasets can provide new insights into normal and disease-related biology when analyzed through a systems framework. However, technical artefacts present in most due to variations sample preparation, batching, platform settings, personnel, other experimental procedures prevent useful analyses of such data without prior adjustment for these factors. Here, we demonstrate tunable median polish ratio (TAMPOR) approach batch effect correction agglomeration multiple, multi-batch, site-specific cohorts single analyte abundance matrix that is suitable analyses. We illustrate the utility versatility TAMPOR four distinct use cases where method has been applied different proteomic datasets, some which contain specific defect must be addressed analysis. compare quality control metrics sources variance before after application show effective at removing effects unwanted data. also how used harmonize even are acquired using analytical approaches. powerful flexible cleaning harmonization downstream

Language: Английский

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The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Feb. 21, 2023

Abstract Background The protease BACE1 is a major drug target for Alzheimer’s disease, but chronic inhibition associated with non-progressive cognitive worsening that may be caused by modulation of unknown physiological substrates. Methods To identify in vivo-relevant substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment BACE inhibitors. Results Besides SEZ6, the strongest, dose-dependent reduction was observed pro-inflammatory cytokine receptor gp130/IL6ST, which establish as an vivo substrate. Gp130 also reduced human CSF from clinical trial inhibitor and plasma BACE1-deficient mice. Mechanistically, demonstrate directly cleaves gp130, thereby attenuating membrane-bound gp130 increasing soluble abundance controlling function neuronal IL-6 signaling survival upon growth-factor withdrawal. Conclusion new modulator function. BACE1-cleaved, serve pharmacodynamic activity marker reduce occurrence side effects humans. Graphical abstract

Language: Английский

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Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes

Science Translational Medicine, Journal Year: 2025, Volume and Issue: 17(784)

Published: Feb. 5, 2025

We used an untargeted mass spectrometric approach, tandem tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total 238 cerebrospinal fluid (CSF) samples from Genetic FTD Initiative were analyzed, including 107 presymptomatic (44 C9orf72 , 38 GRN and 25 MAPT ) 55 symptomatic (27 17 11 mutation carriers as well 76 mutation-negative controls (“noncarriers”). found shared distinct alterations each form FTD. Among proteins significantly altered compared with noncarriers, we that a set neuronal pentraxin 2 fatty acid binding protein 3 changed across all three forms patients Alzheimer’s disease previously published datasets. observed differential changes lysosomal among marked abundance decreases but not other carriers. Further, identified mutation-associated already evident Weighted gene coexpression network analysis combined ontology annotation revealed clusters enriched neurodegeneration glial responses synapse- or lysosome-related indicating these are central biological processes affected These correlated measures severity associated cognitive decline. This study CSF FTD, providing insights into pathological involved disease. In addition, warrant further exploration diagnostic prognostic biomarker candidates.

Language: Английский

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

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: March 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.

Language: Английский

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A microglial activity state biomarker panel differentiates FTD-granulin and Alzheimer’s disease patients from controls

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Sept. 29, 2023

With the emergence of microglia-modulating therapies there is an urgent need for reliable biomarkers to evaluate microglial activation states.Using mouse models and human induced pluripotent stem cell-derived microglia (hiMGL), genetically modified yield most opposite homeostatic (TREM2-knockout) disease-associated (GRN-knockout) states, we identified activity-dependent markers. Non-targeted mass spectrometry was used identify proteomic changes in cerebrospinal fluid (CSF) Grn- Trem2-knockout mice. Additionally, analyzed proteome GRN- TREM2-knockout hiMGL their conditioned media. Candidate marker proteins were tested two independent patient cohorts, ALLFTD cohort (GRN mutation carriers versus non-carriers), as well data set available from EMIF-AD MBD study.We between states CSF, cell lysates For further verification, CSF heterozygous GRN suffering frontotemporal dementia (FTD). We a panel six (FABP3, MDH1, GDI1, CAPG, CD44, GPNMB) potential indicators activation. Moreover, confirmed three these MDH1) be significantly elevated Alzheimer's (AD) patients. Remarkably, each markers differentiated amyloid-positive cases with mild cognitive impairment (MCI) amyloid-negative individuals.The candidate reflect activity may relevant monitoring response clinical practice trials modulating amyloid deposition. finding that differentiate MCI AD suggests associate very early immune seeded amyloid. This consistent our previous findings Dominantly Inherited Disease Network (DIAN) cohort, where soluble TREM2 increases 21 years before symptom onset. amyloidogenesis, seeding limited by physiologically active supporting protective role. The biological functions some main candidates also emphasize lipid dysmetabolism common feature neurodegenerative disorders.

Language: Английский

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Proteomic Network Analysis of Alzheimer’s Disease Cerebrospinal Fluid Reveals Alterations Associated withAPOEε4 Genotype and Atomoxetine Treatment

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 30, 2023

Abstract Alzheimer’s disease (AD) is currently defined at the research level by aggregation of amyloid-β (Aβ) and tau proteins in brain. While biofluid biomarkers are available to measure Aβ pathology, few complex pathophysiology that associated with these two cardinal neuropathologies. Here we describe proteomic landscape cerebrospinal fluid (CSF) changes pathology 300 individuals as assessed different technologies—tandem mass tag (TMT) spectrometry SomaScan. Harmonization integration both data types allowed for generation a robust protein co-expression network consisting 34 modules derived from 5242 measurements, including disease-relevant autophagy, ubiquitination, endocytosis, glycolysis. Three strongly apolipoprotein E ε4 ( APOE ε4) AD risk genotype mapped oxidant detoxification, mitogen kinase (MAPK) signaling, neddylation, mitochondrial biology, overlapped previously described lipoprotein module serum. Neddylation detoxification/MAPK signaling had negative association whereas mitochondrion positive ε4. The directions were consistent between CSF blood independent longitudinal cohorts, altered levels all three dementia over 20 years prior diagnosis. Dual-proteomic platform analysis samples an phase 2 clinical trial atomoxetine (ATX) demonstrated abnormal elevations glycolysis module—the most correlated cognitive function—were reduced ATX treatment. Individuals who more severe glycolytic baseline responded better ATX. Clustering based on their profiles revealed ten groups did not cleanly stratify status, underscoring heterogeneity pathological fully reflected tau. proteomics holds promise development reflect diverse pathologies use trials precision medicine.

Language: Английский

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Effects of dietary arginine supplementation on muscle structure, meat characteristics and lipid oxidation products in lambs and its potential mechanisms of action

Meat Science, Journal Year: 2024, Volume and Issue: 216, P. 109581 - 109581

Published: June 26, 2024

Language: Английский

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MAPPING THE CEREBROSPINAL FLUID PROTEOME IN BIPOLAR DISORDER

Biological Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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