Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer’s Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals

Compromised protein homeostasis underlies accumulation of plaques and tangles in Alzheimer’s disease (AD). To observe protein turnover at early stages of amyloid beta (Aβ) proteotoxicity, we performed pulse-chase proteomics on mouse brains in three genetic models of AD that knock in alleles of amyloid precursor protein (APP) prior to the accumulation of plaques and during disease progression. 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. A record of this paper’s transparent peer review process is included in the Supplemental Information. [Display omitted] •Axon terminals are selective sites of impaired protein degradation in App KI brains•Presynaptic proteins have elevated levels at early stages of Aβ accumulation•Synaptic-vesicle-associated proteins accumulate with Aβ peptides and plaques•Aβ disrupts vesicle fusion and leads to a larger readily releasable vesicle pool Hark et al. use dynamic metabolic 15N labeling and mass-spectrometry-based proteomics to investigate changes to protein turnover in App knockin mice. In this preclinical Alzheimer’s disease mouse model, they find that proteostasis in the presynaptic terminal is specifically altered. Synaptic vesicle (SV)-associated proteins functioning in exo- and endocytosis have impaired degradation and elevated levels in the cortex and hippocampus. Finally, the readily releasable SV pool and presynaptic potentiation is enhanced at the earliest stages of amyloid beta accumulation.