Summary/Abstract Alzheimer's disease (AD) is characterized by Aβ plaques and Tau tangles, which negatively impact synaptic stability and synaptic plasticity and cause neuronal death and loss of memory. Apolipoprotein E4 (apoE4) is the major genetic risk factor for late-onset AD. Recent work suggests that apoE4 has profound effects on prominent AD pathologies, including amyloid-β, tau pathology, neuroinflammation, and neural network dysfunction, suggesting a common target for pathogenesis of AD. Work from our lab showed that planar cell polarity (PCP) plays an essential role in synapses formation in development. We also showed that oligomeric Aβ binds to Celsr3 and weakens the interaction between Celsr3 and Frizzled3 and assists Vangl2 in disassembling synapses. A regulator of PCP signaling, Ryk, is also required for Aβ-induced synapse loss functioning together with Vangl2. In the 5XFAD mouse model of Alzheimer’s disease, Ryk conditional knockout in neurons or intracerebroventricular infusion of a function-blocking monoclonal Ryk antibody protected synapses and preserved cognitive function. Our new preliminary results suggest a novel function of PCP in synapses. We found that PCP components, Dvl2 and Vangl2, which are not require for synapse maintenance, regulate synaptic plasticity. In addition, Dvl2 is down regulated in the synaptosome of the 5XFAD mice. To ask whether PCP pathway may also be the pathological target of ApoE, we tested the levels of PCP proteins in ApoE3 and ApoE4 knockin mice in collaboration with Yadong Huang of the Gladstone Institute at UC San Francisco. We found that in older animals (19-19.9 months old), there is a dramatic reduction of synapse numbers in ApoE4 animals compared to ApoE3 and a trend of reduction of some of the PCP proteins in the synapses. In younger animals (5.8-5.9 months old), there was no significant loss of synapses, while electrophysiological changes are already detectable. Our preliminary results show that there is a selective loss of synapses with specific compositions of PCP proteins. In this supplement, we propose a set of pilot experiments to ask whether the loss of Dvl2 is responsible for the loss of synaptic plasticity and eventually stability. We will test whether different compositions of PCP proteins in the synapses show different vulnerability in the ApoE model. The results from the proposed experiments will allow us to not only formulate hypothesis for future studies of synapse degeneration in Alzheimer’s disease but also obtain clues of how PCP proteins normally regulate the formation and function of synapses and how they regulate the regeneration of synapses for functional recovery after spinal cord injury, which is one of the aims of our parent grant.