Programmed axonal degeneration, also known as Wallerian degeneration, occurs in immune-mediated central nervous system (CNS) inflammatory disorders such as multiple sclerosis and the animal model experimental allergic encephalomyelitis (EAE). Sterile alpha and TIR domain containing protein 1 (SARM1) functions to promote programmed axonal degeneration. We previously showed that Sarm1 knockout mice showed less axonal degeneration early (14 days post-induction), but not late (42 days post-induction), in the course of EAE compared to wild type littermates (Viar, K, 2020). However, it was not clear whether this reflected less acute axonal injury or delayed Wallerian degeneration in the Sarm1 knockout mice.
To distinguish between acute axonal injury and Wallerian degeneration in the EAE-induced Sarm1 knockout mice compared to wild type littermates
Axonal injury and degeneration associated with EAE was compared in Sarm1 knockout mice and wild type littermates at 14, 21 and 42 days post-induction based on neuronal yellow fluorescent protein (YFP)-aided axonal morphology, axonal amyloid precursor protein (APP) accumulation, axonal neurofilament-H dephophsphorylation (SMI-32) and total phosphorylated neurofilament-H (SMI-31) density.
Clinical course of EAE was similar in Sarm1 knockout and wild type. Analysis of EAE in mice expressing neuronal YFP showed significantly less number of degenerating axons in Sarm1 knockout mice compared to wild type littermates at 14 days post-induction of EAE. However, axonal APP accumulation, a marker of acute axonal injury, did not differ significantly between Sarm1 knockout and wild type littermates at 14 days post-induction. At 21 days post-induction, differences in axonal degeneration were not significant based on YFP-aided morphologic analysis. At 42 days post-induction, Sarm1 knockout mice were indistinguishable from wild type with respect to markers of axonal injury (APP and SMI-32), and were similar with respect to reduced axonal density (SMI-31) in the lumbar cords.
Sarm1 deletion delayed axonal degeneration early in the course of EAE, but did not protect from early acute axonal injury. Sarm1 deletion did not confer long-term protection from axonal degeneration in an animal model of immune-mediated CNS inflammation.