Compromised protein homeostasis underlies accumulation of plaques and tangles in Alzheimer’s disease (AD); however, little is known about the early mechanisms that contribute to this process. To objectively assess protein turnover at early stages of amyloid beta (Aβ) proteotoxicity, we used dynamic metabolic labeling with stable isotopes followed by proteomic analysis in an in vitro model and an in vivo model, namely the amyloid precursor protein knock in mice. At initial stages of Aβ 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 Aβ. 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.

Creator

• Hark, Timothy

DOI

• https://doi.org/10.21985/n2-6efy-e308

Subject

• Neurosciences

Language

• en

Alternate Identifier

• http://dissertations.umi.com/northwestern:15385
• etdadmin_upload_780177

Keyword

• Synaptic Vesicles
• Alzheimer's Disease
• Presynapse
• Proteomics
• Protein Degradation

Date created

• 2020-01-01

Resource type

• Dissertation

Rights statement

• In Copyright