Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer's Disease-like Pathology

Jeffrey N. Savas, Yi Zhi Wang, Laura A. DeNardo, Salvador Martinez-Bartolome, Daniel B. McClatchy, Timothy J. Hark, Natalie F. Shanks, Kira A. Cozzolino, Mathieu Lavallée-Adam, Samuel N. Smukowski, Sung Kyu Park, Jeffery W. Kelly, Edward H. Koo, Terunaga Nakagawa, Eliezer Masliah, Anirvan Ghosh, John R. Yates*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Amyloid beta (Aβ) peptides impair multiple cellular pathways and play a causative role in Alzheimer's disease (AD) pathology, but how the brain proteome is remodeled by this process is unknown. To identify protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at young and old ages. Our analysis revealed a robust increase in Apolipoprotein E (ApoE) levels in nearly all brain regions with increased Aβ levels. Taken together with prior findings on ApoE driving Aβ accumulation, this analysis points to a pathological dysregulation of the ApoE-Aβ axis. We also found dysregulation of protein networks involved in excitatory synaptic transmission. Analysis of the AMPA receptor (AMPAR) complex revealed specific loss of TARPγ-2, a key AMPAR-trafficking protein. Expression of TARPγ-2 in hAPP transgenic mice restored AMPA currents. This proteomic database represents a resource for the identification of protein alterations responsible for AD. Savas et al. achieve proteome-wide measurements of protein abundance in brain extracts from three mouse models of AD-like pathology. These analyses revealed Aβ, brain region, and age-dependent alteration of protein levels of several functional categories. This resource provides a global protein expression atlas of AD mouse model brain proteomes.

Original languageEnglish (US)
Pages (from-to)2614-2627
Number of pages14
JournalCell reports
Volume21
Issue number9
DOIs
StatePublished - Nov 28 2017

Keywords

  • AD
  • AMPAR
  • ApoE
  • WGCNA
  • amyloid beta
  • mass spectrometry
  • proteomics
  • proteostasis
  • synapses

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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