Project Summary The loss of synaptic connectivity in the hippocampus is an early degenerative change that is highly associated with cognitive decline in Alzheimer’s Disease (AD) patients. Current FDA-approved treatments for AD are limited to targeting late-stage formation of amyloid beta plaques and do not address the earlier synaptopathy that contributes to cognitive decline. There is thus a significant unmet need for pharmacotherapeutics to maintain synaptic connectivity, or to stimulate synaptogenesis in aging brains, as an approach to ameliorate AD progression in patients. The actin cytoskeleton is the main structural scaffold determining post-synaptic spine architecture and formation of new spines. Based upon our preliminary data, we hypothesize that a myosin molecular motor is a critical component of the post-synaptic density that remodels the actin cytoskeleton to alter synaptic architecture. Our hypothesis is based upon multiple lines of preliminary evidence and builds upon the function of myosin motors controlling the actin cytoskeleton in other systems. The goal of this supplemental project is to perform a pilot study testing the hypothesis that manipulating myosin activity can control hippocampal synaptogenesis and plasticity in aging brains. In Aim 1, we will localize specific myosin proteins and their normal expression in hippocampal sub-regions, as well identify changes in synaptic structure resulting from their genetic ablation. In Aim 2, we will use electrophysiology and behavioral assays in mice to assess functional changes in response to loss of specific myosin proteins. If successful, this project will provide critical pre-clinical efficacy data for the development of myosin agonists / antagonists as potential pharmacotherapeutics for the treatment cognitive decline in AD.