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

Synapse degeneration is a hallmark of neurodegenerative diseases1-3, including Parkinsons and Alzheimers disease (AD). Synapse loss has been known for decades as the strongest correlate with cognition and disease progression in AD patients4-8, 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 injuries9-12, as the key mediator of synaptic degeneration in AD brains. Sarm1 knockout largely reversed synapse loss, amyloid-{beta} (A{beta}) burden, and cognitive decline in 5XFAD mice. We found that Sarm1 is enriched in synaptic terminals and becomes activated in synaptic dystrophies adjacent to A{beta} 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-A{beta} 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. HighlightO_LISarm1 is enriched at presynaptic dystrophies and correlated with A{beta}. C_LIO_LIGenetic deletion of Sarm1 prevents synapse degeneration in AD. C_LIO_LISarm1 depletion is sufficient to reverse synaptic dysfunction and memory loss. C_LIO_LISarm1 depletion reduces A{beta} burden and neuroinflammation C_LIO_LIC1q--MERTK axis acts downstream of synaptic Sarm1 activation. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/695860v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@bd6b12org.highwire.dtl.DTLVardef@1c089e5org.highwire.dtl.DTLVardef@19d35fborg.highwire.dtl.DTLVardef@431364_HPS_FORMAT_FIGEXP M_FIG C_FIG