Alzheimer’s disease (AD) is an incurable brain disorder that currently debilitates millions of people world-wide. Historically, the etiological model has been that early alterations at synapses cause changes in the activity of neuronal circuits, which occur many years prior to the presentation of clinically impaired cognition. Consistently, synapse loss represents an important and early feature of AD that correlates with the severity of dementia. The mechanisms leading to synaptic dysfunction and loss are not fully understood and both direct and indirect effects of Abeta peptides and Tau pathology are recognized as key drivers. <br/>Our team recently applied a systems biology approach using dynamic metabolic isotopic labeling with 15N and mass-spectrometry-based proteomics to investigate changes to protein turnover in the App knockin (APP KI) mice. In these preclinical Alzheimer’s disease mouse models, we found that proteostasis in the presynaptic terminal is specifically altered. Notably, synaptic vesicle (SV)-associated proteins functioning in exo- and endocytosis have impaired degradation and elevated levels in the cortex and hippocampus. Finally, we found that the readily releasable SV pool and presynaptic potentiation is enhanced at the earliest stages of amyloid beta accumulation.<br/>Due to numerous failed clinical AD trials focused on reducing Abeta levels, the importance of the amyloid cascade has been brought into question. Intriguingly, we observe a relationship between these observations and the effects of the atypical antiepileptic drug levetiracetam that is currently the subject of several Phase II clinical trials for AD. Our preliminary studies demonstrated that levetiracetam selectively normalizes SV endocytosis machinery abundance and restores non-amyloidogenic processing of APP which is anti-correlated to our disease progression observations in APP KI mice. Thus we have uncovered a potential mechanism that may explain the therapeutic benefits of levetiracetam as well as targets for future therapeutic intervention.

Pulse-chase proteomics of the APP knock-in mouse models of Alzheimer’s disease reveals synaptic dysfunction originates in presynaptic terminals

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.