PROJECT SUMMARY Approximately 1 in 10 people over the age of 65 have Alzheimer's disease (AD), a devastating illness that cannot be prevented, cured, or even slowed. Hence there is an urgent need to identify novel therapeutic targets and biomarkers for Alzheimer's Disease. Accumulating evidence suggests that in AD the brain is unable to process information properly due to faulty synaptic plasticity, the molecular driver of learning and memory. Homer1a is a protein expressed in response to neuronal activity that is essential for various forms of synaptic plasticity. Further, Homer1a expression is disrupted in mouse AD models as well as AD patient samples. Despite this information, the mechanism behind activity-induced Homer1a expression, as well as how this is disrupted in AD, remains unclear. We recently characterized a mouse model of persistent mTOR signaling, a characteristic often reported in AD, and generated data showing that Homer1a inducibility is lost in this model. The proposed research project combines molecular biology, gene expression techniques, and various in vivo and in vitro models of neuronal activity to elucidate the mechanisms of Homer1a expression and determine how these mechanisms are disrupted in persistent mTOR signaling and AD. Completion of the proposed study on this gene essential for plasticity and dysregulated in AD will shed light on its regulatory mechanisms, both physiologically and pathologically, which may lead to new therapeutic strategies and potential biomarkers for Alzheimer's Disease.