Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer’s Disease-like Pathology
2017
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, III
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.
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