A recent hypothesis in Alzheimer's disease (AD) is that beta amyloid, the toxic peptide implicated in AD, disrupts synaptic function. Disruption in synaptic function is thought to lead to the cognitive deficits that are so prevalent in this illness.My laboratory studies the function of STriatal Enriched protein tyrosine Phosphatase (STEP). STEP is a brain-specific protein responsible for removing glutamate receptors (specifically, AMPARs and NMDARs) from neuronal surfaces. These receptors are critical for the conversion of short-term memories into long-term memories. STEP therefore plays an important role by regulating glutamate receptor trafficking to and away from neuronal membranes. We recently showed that beta amyloid disrupts the normal degradation of STEP. As a result, STEP protein accumulates in neurons. Not only does beta amyloid increase STEP levels in cortical cultures, but elevated STEP levels are also observed in the cortex of a mouse model of AD. Most importantly, we found elevated STEP levels in human postmortem AD cortex. The increased STEP levels exhibited greater activity. Consequently, there was a decrease in the number of AMPARs and NMDARs on neuronal membranes.The aim of this proposal is to find small molecule inhibitors of STEP. In a collaborative project with the Laboratory for Drug Discovery for Neurodegeneration at Harvard Medical School, we have screened a library of 160,000 compounds. We have rescreened these hits in an independent assay, and have now selected several of our most promising hits as the starting point for this application. We will chemically modify these initial hits to produce libraries of related compounds, with the purpose of increase their activity, potency, and selectivity. We will test these hits and analogs in several biological assays relevant to AD as well as in animal models. The significance of this work is that it uncovers a novel pathway that leads to the disruption of synaptic function. The implication is that blocking STEP activity with small molecule inhibitors may show therapeutic benefits in this devastating disease.