Project Summary
The major goal of this project is to characterize a novel mechanism for memory dysfunction in Alzheimer’s disease (AD). In Aim 1, we will determine how increasing or decreasing appoptosin expression levels can affect synaptic function through biochemical and high-resolution microscopy analysis. We will characterize changes in proteins required for synaptic function with the modulation of appoptosin expression levels in neurons, and quantify alterations in synaptic structures in these neurons. In Aim 2, we will determine whether reducing appoptosin levels can rescue synaptic and memory deficits in an AD mouse model. We will cross appoptosin knockout mice with Tg2576 AD lines and characterize synaptic activity, and memory formation/extinction in these mice through electrophysiological and behavioral analysis. We will also further characterize how reducing appoptosin levels can influence amyloid-beta (Aβ)-induced synaptic deficits in primary neuronal cultures. As appoptosin is a fundamental regulator of apoptosis and tau pathogenesis in AD, the key innovation of this project consists of exploring potential neuroprotective effects that may be associated with appoptosin downregulation. Moreover, our results implicate a novel role for appoptosin in memory formation/extinction; this implicates pleotropic neuroprotective effects through appoptosin modulation and attenuation of appoptosin function. Further, as previous studies in the AD field have focused exclusively on memory formation deficits, this may provide insight into memory extinction mechanisms that are dysregulated in AD. Successful completion of this study will help us understand how memory decay is regulated, and may bring insight into new therapeutic targets for AD.
