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

Erik C.B. Johnson, Eric B. Dammer, Duc M. Duong, Lingyan Ping, Maotian Zhou, Luming Yin, Lenora A. Higginbotham, Andrew Guajardo, Bartholomew White, Juan C. Troncoso, Madhav Thambisetty, Thomas J. Montine, Edward B. Lee, John Q. Trojanowski, Thomas G. Beach, Eric M. Reiman, Vahram Haroutunian, Minghui Wang, Eric Schadt, Bin ZhangDennis W. Dickson, Nilüfer Ertekin-Taner, Todd E. Golde, Vladislav A. Petyuk, Philip L. De Jager, David A. Bennett, Thomas S. Wingo, Srikant Rangaraju, Ihab Hajjar, Joshua M. Shulman, James J. Lah, Allan I. Levey, Nicholas T. Seyfried

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)769-780
Number of pages12
JournalNature Medicine
Volume26
Issue number5
DOIs
StatePublished - May 1 2020

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Johnson, E. C. B., Dammer, E. B., Duong, D. M., Ping, L., Zhou, M., Yin, L., Higginbotham, L. A., Guajardo, A., White, B., Troncoso, J. C., Thambisetty, M., Montine, T. J., Lee, E. B., Trojanowski, J. Q., Beach, T. G., Reiman, E. M., Haroutunian, V., Wang, M., Schadt, E., ... Seyfried, N. T. (2020). Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nature Medicine, 26(5), 769-780. https://doi.org/10.1038/s41591-020-0815-6