PT  - JOURNAL ARTICLE
AU  - Jeffrey N. Savas
AU  - Yi-Zhi Wang
AU  - Laura A. DeNardo
AU  - Salvador Martinez-Bartolome
AU  - Daniel B. McClatchy
AU  - Timothy J. Hark
AU  - Natalie F. Shanks
AU  - Kira A. Cozzolino
AU  - Mathieu Lavallée-Adam
AU  - Samuel N. Smukowski
AU  - Sung Kyu Park
AU  - Jeffery W. Kelly
AU  - Edward H. Koo
AU  - Terunaga Nakagawa
AU  - Eliezer Masliah
AU  - Anirvan Ghosh
AU  - John R. Yates, 3rd
TI  - Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimer’s disease like pathology
AID  - 10.1101/150623
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 150623
4099  - http://biorxiv.org/content/early/2017/06/15/150623.short
4100  - http://biorxiv.org/content/early/2017/06/15/150623.full
AB  - Amyloid beta (Aβ) peptides impair multiple cellular pathways in the brain and play a causative role in Alzheimer’s disease (AD) pathology, but how the brain proteome is remodeled during this process is unknown. To identify new protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at pre- and post-symptomatic ages. Our analysis revealed a robust and consistent increase in Apolipoprotein E (ApoE) levels in nearly all transgenic 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 consistent with AD pathophysiology. Targeted analysis of the AMPA receptor complex revealed a specific loss of TARPγ-2, a key AMPA receptor trafficking protein. Expression of TARPγ-2 in vivo in hAPP transgenic mice led to a restoration of AMPA currents. This database of proteome alterations represents a unique resource for the identification of protein alterations responsible for AD.HighlightsProteomic analysis of mouse brains with AD-like pathology reveals stark remodelingProteomic evidence points to a dysregulation of ApoE levels associated with Aβ clearance rather than productionCo-expression analysis found distinctly impaired synapse and mitochondria modulesIn-depth analyses of AMPAR complex points to loss of TARPγ-2, which may compromise synapses in ADeTOC Blurb Proteome-wide profiling of brain tissue from three mouse models of AD-like pathology reveals Aβ, brain region, and age dependent alterations of protein levels. This resource provides a new global protein expression atlas for the Alzheimer’s disease research community.