Alzheimer’s disease is a devastating disease with few effective treatments. Understanding the molecular basis of this disease should lead the way to therapies. We are testing the hypothesis that a protein called STEP disrupts communication between neurons in Alzheimer's disease. We are proposing that finding inhibitors of STEP will prove beneficial. STEP is a brain-specific protein that regulates the activity of several proteins required for the stabilization of memories. Some of these proteins are members of the glutamate receptor family. These receptor complexes normally move from intracellular pools to the neuronal surface to receive neurotransmitter signals required for the formation of long-term memories. The trafficking to and from membranes is a tightly regulated process, and STEP participates in this process. We recently discovered that STEP is inappropriately activated by beta amyloid. Active STEP removes glutamate receptors from neuronal surfaces. This in turn leads to inappropriate loss of receptors from their sites of action on the neuronal membrane, resulting in disruption of synaptic function. We predict that reducing STEP activity will reduce the loss of receptors. Our preliminary data support this hypothesis. We have initiated a screen of a library of small molecules in the search for STEP inhibitors, and have developed and tested three assays for the screening. Success in this project may have important implications in the treatment of Alzheimer's disease.