Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation

Nat Med. 2020 May;26(5):769-780. doi: 10.1038/s41591-020-0815-6. Epub 2020 Apr 13.

Abstract

Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Animals
  • Astrocytes / metabolism*
  • Astrocytes / pathology
  • Astrocytes / physiology
  • Biomarkers / cerebrospinal fluid
  • Biomarkers / metabolism
  • Brain / metabolism*
  • Brain / pathology
  • Case-Control Studies
  • Cerebrospinal Fluid / chemistry
  • Cerebrospinal Fluid / metabolism*
  • Cohort Studies
  • Disease Progression
  • Energy Metabolism*
  • Female
  • Gene Regulatory Networks / physiology
  • Humans
  • Male
  • Mass Spectrometry
  • Metabolic Networks and Pathways
  • Mice
  • Microglia / metabolism*
  • Microglia / pathology
  • Microglia / physiology
  • Nerve Tissue Proteins / analysis
  • Nerve Tissue Proteins / cerebrospinal fluid
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis / physiology
  • Proteomics / methods
  • Sample Size
  • Time Factors

Substances

  • Biomarkers
  • Nerve Tissue Proteins