Abstract Body: Background: Ischemic stroke triggers a chronic B-lymphocyte response in the stroke core that is required for delayed post-stroke cognitive decline in mice. Because immune cells primarily infiltrate into connected subcortical axonal tracts after stroke, we hypothesized that degenerating axons promulgate a persistent neuroinflammation that is critical for late cognitive decline. To test this, we utilized mice deficient in Sarm1 (Sarm1-/-), a molecular trigger of axon degeneration and the loss of which leads to axonal protection after injury.
Methods: Wildtype and Sarm1-/- male mice (N=9 per condition) underwent distal MCA stroke followed by transient hypoxia, which reliably leads to infarct-induced neurodegeneration 7 weeks after injury. Innate (monocytes) and adaptive (T, B lymphocytes) immune cell infiltration were evaluated via immunohistochemistry 1 & 7 weeks after stroke. Cognition was assessed using the Barnes maze at both time points after stroke.
Results: Absence of Sarm1 resulted in robust axonal protection after ischemic stroke. In connected thalamic region, mean immunostained intensity of axons was 166 in wildtype vs. 267 in Sarm1-/- (p < 0.005) 1 week, and 106 vs. 201 (p < 0.005) 7 weeks after stroke. Compared to wildtype mice, Sarm1-/- mice had an attenuated innate immune response in connected subcortical white matter 1 week after stroke (% area of CD68+ reactivity was 35 ± 5% in WT vs. 19 ± 4% in Sarm1-/- (p < 0.01), while peri-infarct CD68 was not different. Moreover, loss of Sarm1 reduced B220+ B-cell infiltration into the infarct 7 weeks after stroke. Percent area of B220+ reactivity was 30 ± 8% in WT vs 15 ± 7% in Sarm1-/- (p <0.05). Compared to wildtype littermates, Sarm1-/- mice were resistant to chronic post-stroke cognitive decline on the Barnes maze. There was no difference in cognition between cohorts 1 week after stroke but there was at 7 weeks. The mean escape latency was 97 ± 11 sec in wildtype vs 57 ± 9 sec in Sarm1-/- mice (P<0.05).
Conclusion: We report that Sarm1-mediated axonal degeneration is critical for chronic neuroinflammation and delayed cognitive decline after ischemic stroke. Directly targeting axon degeneration by modulating Sarm1 activity provides a novel therapeutic approach to ameliorate infarct-induced neurodegeneration.