Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation
- 13 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 26 (5), 769-780
- https://doi.org/10.1038/s41591-020-0815-6
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.Keywords
This publication has 74 references indexed in Scilit:
- Genes and pathways underlying regional and cell type changes in Alzheimer's diseaseGenome Medicine, 2013
- MS3 eliminates ratio distortion in isobaric multiplexed quantitative proteomicsNature Methods, 2011
- Inferring causal genomic alterations in breast cancer using gene expression dataBMC Systems Biology, 2011
- Network medicine: a network-based approach to human diseaseNature Reviews Genetics, 2010
- Mapping protein abundance patterns in the brain using voxelation combined with liquid chromatography and mass spectrometryMethods, 2010
- Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjectsAnnals of Neurology, 2009
- Functional organization of the transcriptome in human brainNature Neuroscience, 2008
- Peroxiredoxin 6 in human brain: molecular forms, cellular distribution and association with Alzheimer’s disease pathologyActa Neuropathologica, 2008
- DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2Proceedings of the National Academy of Sciences of the United States of America, 2006
- Neuropathological stageing of Alzheimer-related changesActa Neuropathologica, 1991