Alzheimer disease pathology and the cerebrospinal fluid proteome

Abstract

BackgroundAltered proteome profiles have been reported in both postmortem brain tissues and body fluids of subjects with Alzheimer disease (AD), but their broad relationships with AD pathology, amyloid pathology, and tau-related neurodegeneration have not yet been fully explored. Using a robust automated MS-based proteomic biomarker discovery workflow, we measured cerebrospinal fluid (CSF) proteomes to explore their association with well-established markers of core AD pathology.MethodsCross-sectional analysis was performed on CSF collected from 120 older community-dwelling adults with normal (n = 48) or impaired cognition (n = 72). LC-MS quantified hundreds of proteins in the CSF. CSF concentrations of β-amyloid 1–42 (Aβ1–42), tau, and tau phosphorylated at threonine 181 (P-tau181) were determined with immunoassays. First, we explored proteins relevant to biomarker-defined AD. Then, correlation analysis of CSF proteins with CSF markers of amyloid pathology, neuronal injury, and tau hyperphosphorylation (i.e., Aβ1–42, tau, P-tau181) was performed using Pearson’s correlation coefficient and Bonferroni correction for multiple comparisons.ResultsWe quantified 790 proteins in CSF samples with MS. Four CSF proteins showed an association with CSF Aβ1–42 levels (p value ≤ 0.05 with correlation coefficient (R) ≥ 0.38). We identified 50 additional CSF proteins associated with CSF tau and 46 proteins associated with CSF P-tau181 (p value ≤ 0.05 with R ≥ 0.37). The majority of those proteins that showed such associations were brain-enriched proteins. Gene Ontology annotation revealed an enrichment for synaptic proteins and proteins originating from reelin-producing cells and the myelin sheath.ConclusionsWe used an MS-based proteomic workflow to profile the CSF proteome in relation to cerebral AD pathology. We report strong evidence of previously reported CSF proteins and several novel CSF proteins specifically associated with amyloid pathology or neuronal injury and tau hyperphosphorylation.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0397-4) contains supplementary material, which is available to authorized users.

Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease

“…We detected more than two-thirds of our 60 prioritized markers in each of these datasets. Although the Swiss study used a different MS platform and TMT quantification approach ( 45 , 46 ), we strongly reproduced our panel trends across both replication analyses ( Fig. 5, C and D , and table S2, I and J).…”

“…In CSF replication 2, we used single-shot TMT-MS to analyze an independent cohort of 297 control and AD samples from the Emory Goizueta ADRC ( 17 ). CSF replication 3 comprised a reanalysis of available TMT-MS data from 120 control and patients with AD in Lausanne, Switzerland ( 45 ). We detected more than two-thirds of our 60 prioritized markers in each of these datasets.…”

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease

“…The increasing recognition that a broad spectrum of pathologies contribute to AD and the repeated failures of amyloid-targeting drugs have highlighted the urgent need for biomarkers that more comprehensively reflect the complex mechanisms underlying this disease [4][5][6]68]. While others have embarked on large-scale discovery-driven investigations of AD CSF, the context of emerging targets within the intricate landscape of brain-based pathophysiology has remained largely unexplored [61,69]. To address this challenge, we applied an unbiased, integrative proteomics approach to the brain and CSF of AD subjects to identify fluid markers linked to a variety of processes in the diseased brain.…”

A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation

“…Elevations in PRDX1, DDAH, and protein/nucleic acid deglycase DJ-1 (PARK7) were also observed, all of which are important anti-oxidant effector proteins [101][102][103] and are likely elevated in concert with increased glycolytic flux. LDHB, PKM, and DDAH1 have recently been reported as promising AD CSF biomarkers 104,105 . Separate from the metabolic pathway, we observed increased levels of M4 proteins osteopontin (SPP1), dickkopf-related protein 3 (DKK3), and CD44.…”