With the recent failure of clinical trials solely targeting the amyloid-beta pathway, there is an increasing need to develop novel therapeutic methods to treat Alzheimer's disease (AD). Mounting evidence has demonstrated that the presence of the APOE4 gene is the strongest genetic risk factor for late-onset AD. In the past several years, our laboratory has used cellular and animal models to address how apolipoprotein E (apoE) and its cell surface receptors regulate neuronal functions and how perturbation of this pathway disrupts synapses and memory. We found that apoE and apoE receptors regulate brain lipid metabolism and synaptic transmission. They also facilitate the clearance of Abeta, a toxic peptide that is central to the pathogenesis of AD. In this proposal, we plan to target the apoE and apoE receptor pathways to develop new strategies for AD therapy. First, in collaboration with Dr. Dennis Dickson, a renowned neuropathologist at Mayo Clinic, we plan to take advantage of the large collection of well characterized AD autopsy brains to address potential alterations in the expression and functions of apoE and apoE receptors during the development and progression of AD. Second, we plan to identify novel chemical compounds that regulate apoE and apoE receptor pathways by screening several compound libraries. We have optimized a neuron/glia co-culture system that resembles the physiological pathway of apoE and apoE receptor metabolism. This unique co-culture system allows us to efficiently and accurately quantify the levels of apoE, Abeta, and apoE receptors. Finally, we will analyze the effects of selected compounds in AD model mice to assess whether they can modulate apoE/Abeta metabolism, synaptic transmission and memory in vivo. Our innovative approach should allow us to identify compounds that target apoE and the apoE receptor pathway and lead to the development of AD therapies.