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 ß-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).