Alzheimer disease pathology and the cerebrospinal fluid proteome

Loïc Dayon, Antonio Núñez Galindo, Jérôme Wojcik, Ornella Cominetti, John Corthésy, Aikaterini Oikonomidi, Hugues Henry, Martin Kussmann, Eugenia Migliavacca, India Severin, Gene L. Bowman, Julius Popp

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Background: Altered 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. Methods: Cross-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 (Aβ 1-42 ), 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., Aβ 1-42 , tau, P-tau181) was performed using Pearson's correlation coefficient and Bonferroni correction for multiple comparisons. Results: We quantified 790 proteins in CSF samples with MS. Four CSF proteins showed an association with CSF Aβ 1-42 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. Conclusions: We 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.

Original languageEnglish (US)
Article number66
JournalAlzheimer's Research and Therapy
Volume10
Issue number1
DOIs
StatePublished - Jul 18 2018

Keywords

  • Alzheimer disease
  • Amyloid
  • Biomarker
  • CSF
  • Cerebrospinal fluid
  • Mass spectrometry
  • Proteomics
  • Tandem mass tag
  • Tau

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience

Fingerprint Dive into the research topics of 'Alzheimer disease pathology and the cerebrospinal fluid proteome'. Together they form a unique fingerprint.

  • Cite this

    Dayon, L., Núñez Galindo, A., Wojcik, J., Cominetti, O., Corthésy, J., Oikonomidi, A., Henry, H., Kussmann, M., Migliavacca, E., Severin, I., Bowman, G. L., & Popp, J. (2018). Alzheimer disease pathology and the cerebrospinal fluid proteome. Alzheimer's Research and Therapy, 10(1), [66]. https://doi.org/10.1186/s13195-018-0397-4