NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer’s disease

ABSTRACT Synapse degeneration is a hallmark of neurodegenerative diseases 1–3 , including Parkinson’s and Alzheimer’s disease (AD). Synapse loss has been known for decades as the strongest correlate with cognition and disease progression in AD patients 4–8 , but the molecular mechanisms that drive synapse degeneration remain elusive. Here, we identify Sarm1, a new class of NAD+ hydrolase required for Wallerian degeneration of periphery nerves after injuries 9–12 , as the key mediator of synaptic degeneration in AD brains. Sarm1 knockout largely reversed synapse loss, amyloid-β (Aβ) burden, and cognitive decline in 5XFAD mice. We found that Sarm1 is enriched in synaptic terminals and becomes activated in synaptic dystrophies adjacent to Aβ plaques, leading to synapse degeneration and subsequent neuroinflammation. Sarm1 deletion in the AD mice prevented synaptic dystrophies and rescued short-term and long-term synaptic plasticity. Further, Sarm1 deletion protected synapses from C1q tagging and phagocytosis, and C1q–MERTK signaling in complement cascades 7,13–15 was significantly reduced. The reduced synapse degeneration, in turn, broke the feed-forward loop of “glia activation–neuroinflammation–Aβ deposition”. These data suggest that Sarm1 plays a key role in driving synapse degeneration in AD before C1q-tagging and phagocytic clearance, and targeting Sarm1 may offer a novel intervention to attenuate synapse degeneration and memory loss in AD. Highlight Sarm1 is enriched at presynaptic dystrophies and correlated with Aβ. Genetic deletion of Sarm1 prevents synapse degeneration in AD. Sarm1 depletion is sufficient to reverse synaptic dysfunction and memory loss. Sarm1 depletion reduces Aβ burden and neuroinflammation C1q--MERTK axis acts downstream of synaptic Sarm1 activation.