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

Cell Rep. 2017 Nov 28;21(9):2614-2627. doi: 10.1016/j.celrep.2017.11.009.

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.

Keywords: AD; AMPAR; ApoE; WGCNA; amyloid beta; mass spectrometry; proteomics; proteostasis; synapses.

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Apolipoproteins E / metabolism
  • Brain / metabolism*
  • Calcium Channels / metabolism
  • Computational Biology
  • Female
  • Mass Spectrometry
  • Mice
  • Mice, Inbred C57BL
  • Proteome / analysis*

Substances

  • Amyloid beta-Peptides
  • Apolipoproteins E
  • Cacng2 protein, mouse
  • Calcium Channels
  • Proteome