Sarm1 loss reduces axonal damage and improves cognitive outcome after repetitive mild closed head injury

Abstract

One of the consistent pathologies associated with both clinical and experimental traumatic brain injury is axonal injury, especially following mild traumatic brain injury (or concussive injury). Several lines of experimental evidence have demonstrated a role for NAD+ metabolism in axonal degeneration. One of the enzymes that metabolizes NAD+ in axons is Sarm1 (Sterile Alpha and TIR Motif Containing 1), and its activity is thought to play a key role in axonal degeneration. Using a Sarm1 knock-out mouse, we examined if loss of Sarm1 offers axonal injury protection and improves cognitive outcome after repeated mild closed head injury (rmCHI). Our results indicate that rmCHI caused white matter damage that can be observed in the corpus callosum, cingulum bundle, alveus of the hippocampus, and fimbria of the fornix of wild-type mice. These pathological changes were markedly reduced in injured Sarm1−/− mice. Interestingly, the activation of astrocytes and microglia was also attenuated in the areas with white matter damage, suggesting reduced inflammation. Associated with these improved pathological outcomes, injured Sarm1−/− mice performed significantly better in both motor and cognitive tasks. Taken together, our results suggest that strategies aimed at inhibiting Sarm1 and/or restoring NAD+ levels in injured axons may have therapeutic utility.