MassIVE MSV000085004

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Impaired presynaptic proteostasis in the initial stages of amyloid beta proteotoxicity

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Description

Compromised protein homeostasis underlies accumulation of plaques and tangles in Alzheimers disease (AD); however, little is known about the early mechanisms that contribute to this accumulation. To objectively assess the impaired protein turnover at early stages of amyloid beta (Abeta) proteotoxicity, we used dynamic 15N metabolic labeling followed by proteomic analysis of amyloid precursor protein knock in mouse brains. At initial stages of Abeta accumulation the turnover of proteins associated with presynaptic terminals is selectively impaired. Presynaptic proteins with impaired turnover, particularly synaptic vesicle (SV) associated proteins, have elevated levels, misfold in both a plaque dependent and independent manner, and interact with APP and Abeta. Concurrent with elevated levels of SV associated proteins, we found an enlargement of the SV pool as well as enhancement of presynaptic potentiation. Together, our findings reveal that the presynaptic terminal is particularly vulnerable and represents a critical site for manifestation of initial AD etiology. [doi:10.25345/C50D79] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Alzheimer's Disease

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Principal Investigators:
(in alphabetical order) 		Jeffrey N. Savas, PhD, Department of Neurology Northwestern University, USA
Submitting User: jeffsavas

Publications

Hark TJ, Rao NR, Castillon C, Basta T, Smukowski S, Bao H, Upadhyay A, Bomba-Warczak E, Nomura T, O'Toole ET, Morgan GP, Ali L, Saito T, Guillermier C, Saido TC, Steinhauser ML, Stowell MHB, Chapman ER, Contractor A, Savas JN.
Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals.
Cell Syst. Epub 2020 Dec 9.

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