Synapse loss represents an important and early feature of Alzheimer’s disease (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. Synapses in the entorhinal cortex and hippocampus are selectively affected in the early stages of AD but the underlying mechanism of this anatomical specificity remains a mystery. Further complicating this mystery, we still do not know if the initial stages of synaptic dysfunction are triggered by pre- or postsynaptic changes. Our team has recently discovered that there is impaired protein degradation selectively in axon terminals that results in elevated abundance of synaptic vesicle associated proteins in early stages of AD pathology. 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. Thus we have uncovered a potential mechanism that may explain the therapeutic benefits of levetiracetam as well as targets for future therapeutic intervention. To rigorously extend these findings, in Aim 1 we will confirm our preliminary findings in a larger study and characterize the effect of chronic levetiracetam treatment on Aβ42 production, the amyloid plaque load, and the axon terminal proteome in male and female App KI mice. The goal of Aim 2, is to determine if levetiracetam acts to slow the production or to enhance the clearance of existing amyloid associated pathology in App KI mice. The proposed research will advance our understanding of the critical protein networks that drive synaptic dysfunction in AD and advance our understanding of a promising therapeutic targets to prevent or treat cognitive impairment in AD.
|Effective start/end date||10/1/21 → 1/31/24|
- Alzheimer's Disease Research Foundation (Award Letter 1-20-23)
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