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Nakagawa Lab

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

AUTHORS

Savas JNJeffrey N , Wang YZ Yi-Zhi , DeNardo LA Laura A , Martinez-Bartolome S Salvador , McClatchy DB Daniel B , Hark TJ Timothy J , Shanks NF Natalie F , Cozzolino KA Kira A , Lavallée-Adam M Mathieu , Smukowski SN Samuel N , Park SK Sung Kyu , Kelly JW Jeffery W , Koo EH Edward H , Nakagawa T Terunaga , Masliah E Eliezer , Ghosh A Anirvan , Yates JR John R . Cell reports. 2017 11 28; 21(9). 2614-2627

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.