Project Summary The transmembrane protein β-amyloid precursor protein (APP) is central to the pathophysiology of Alzheimer’s disease (AD). The β-amyloid hypothesis posits that aberrant processing of APP leads to the formation of β- amyloid aggregates, which are neurotoxic leading to the cognitive impairments observed in AD. Despite the importance of APP in AD, little is known about its function or how neurons regulate its expression. We have found that Kismet (Kis), a chromatin remodeling protein in Drosophila, regulates expression of APP-like and neuronal processes that are dysregulated in AD. Kis is similar to the mammalian chromatin helicase binding domain (CHD) proteins CHD7 and CHD8, both of which are implicated in neurodevelopmental disorders including CHARGE Syndrome and autism spectrum disorders, respectively, and synaptic function. The goal of this proposal is to better understand how the epigenetic chromatin remodeling protein, Kis, regulates APP-like expression in animals. Mutations in kis lead to increased levels of APP-like in neurons and of cell adhesion molecules at the synapse. The latter are known to interact with APP and APP-like. We hypothesize that Kis promotes synaptic function and organization by suppressing synaptic levels of APP-like thereby affecting the recycling of synaptic vesicles. To test this hypothesis, we will first better characterize the functional interaction between Kis and APP-like. Then we will determine whether Kis and APP-like work cooperatively to influence synaptic vesicle endocytosis and localize cell adhesion molecules to the synapse. These data will help us better understand how chromatin remodeling proteins enable synapse function and provide mechanistic insight into the pathology of AD.