PROJECT SUMMARY A remarkable brain attribute is a lifelong ability to store and retrieve information for learning and memory. Alzheimer's disease (AD) destroys this function and generates enormous personal, familial, and societal impacts. This situation is further compounded by the lack of disease-modifying therapies and continuous failures of the related clinical trials. An incomplete understanding of the disease has severely limited the development of new treatments, calling for mechanistic research in AD. Synapse loss has been a hallmark of AD and shows the most robust correlation with the disease symptoms. This process occurs long before massive neuron death and AD diagnosis, indicating its central role in disease pathogenesis. However, molecular mechanisms underlying synapse degeneration remain incompletely understood. Our proposal aims to study this process by investigating a novel paradigm in which a sarm1-dependent mechanism contributes to AD synapse loss. Sarm1 is a newly identified NAD+ hydrolase enriched in axonal terminals, but its role in synapse degeneration in AD is entirely unknown. We hypothesize that sarm1 plays a crucial role in AD onset and progression by inducing axon and synapse degeneration. This hypothesis is formulated based on our preliminary data showing that sarm1 gene knockout significantly alleviates AD mice's synaptic disruptions and cognitive dysfunction. We will evaluate this hypothesis using new mouse models, cognitive assays, biochemistry, electrophysiology, and super-resolution imaging. To this end, we have assembled an outstanding, interactive team of investigators with substantial expertise in synapse biology, neurocircuitry, mouse genetics, and AD pathology. We propose three specific aims: 1) define the role of sarm1 in memory disruption and disease progression in AD mice; 2) evaluate sarm1 function in axon and synapse degeneration in AD brains; 3) illustrate molecular mechanisms of sarm1 action in the context of AD pathology and its impact on β-amyloid pathology. Through the proposed work, we will test a fundamentally new concept essential to a long-standing question of AD—synapse loss—and investigate sarm1-dependent signaling mechanisms in AD-associated neurodegeneration. The results will advance the current knowledge on AD pathogenesis and provide critical insights into its novel treatments by targeting the sarm1 signaling pathway. This proposal is submitted in accordance with the Grant Notice to Specify Interest (NOT-AG-21-041 of PAR-22-093).