Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures

Abstract

Traumatic brain injury (TBI) causes chronic symptoms and increased risk of neurodegeneration. Axons in white matter tracts, such as the corpus callosum (CC), are critical components of neural circuits and particularly vulnerable to TBI. Treatments are needed to protect axons from traumatic injury and mitigate post-traumatic neurodegeneration. SARM1 protein is a central driver of axon degeneration through a conserved molecular pathway. Sarm1−/− mice with knockout (KO) of the Sarm1 gene enable genetic proof-of-concept testing of the SARM1 pathway as a therapeutic target. We evaluated Sarm1 deletion effects after TBI using a concussive model that causes traumatic axonal injury and progresses to CC atrophy at 10 weeks, indicating post-traumatic neurodegeneration. Sarm1 wild-type (WT) mice developed significant CC atrophy that was reduced in Sarm1 KO mice. Ultrastructural classification of pathology of individual axons, using electron microscopy, demonstrated that Sarm1 KO preserved more intact axons and reduced damaged or demyelinated axons. Longitudinal MRI studies in live mice identified significantly reduced CC volume after TBI in Sarm1 WT mice that was attenuated in Sarm1 KO mice. MR diffusion tensor imaging detected reduced fractional anisotropy in both genotypes while axial diffusivity remained higher in Sarm1 KO mice. Immunohistochemistry revealed significant attenuation of CC atrophy, myelin loss, and neuroinflammation in Sarm1 KO mice after TBI. Functionally, Sarm1 KO mice exhibited beneficial effects in motor learning and sleep behavior. Based on these findings, Sarm1 inactivation can protect axons and white matter tracts to improve translational outcomes associated with CC atrophy and post-traumatic neurodegeneration.

Acute axon damage and demyelination are mitigated by 4-aminopyridine (4-AP) therapy after experimental traumatic brain injury

“…A single impact closed head TBI model was used to produce traumatic axonal injury in the CC that models traumatic axonal injury in human TBI pathophysiology [ 7 , 50 , 54 , 55 , 72 , 84 ]. An Impact One Stereotaxic Impactor (Leica Biosystems, Buffalo Grove, IL) attached to a steel impactor with a 3-mm flat tip with rounded edges (Cat# 2520-3S, Neuroscience Tools, Aurora, IL) was zeroed on the surface of the skull centered at bregma (0 ML, 0 AP, 0 DV).…”

“…Isoflurane administration was terminated immediately prior to impact. Our prior studies have shown that these parameters induce mild-moderate closed skull TBI with CC pathology that progresses to late stage CC atrophy without gross tissue damage or microhemorrhages, detected by neuropathology or magnetic resonance imaging [ 7 , 50 , 54 , 84 ]. Sham mice followed identical procedures but did not receive the impact.…”

“…Transmission EM was performed to assay the efficacy of 4-AP treatment by detecting ultrastructural pathology, including myelin integrity, of individual axons as in prior studies [ 7 , 49 , 54 ]. C57BL/6J male mice were perfused with fixative containing 2.5% glutaraldehyde and 4% PFA in 0.1 M phosphate buffer pH 7.4.…”

“…A single impact closed head TBI in adult mice produced traumatic axonal injury in the corpus callosum (CC). This injury models human TBI pathology and neuroimaging features from acute injury through chronic neurodegeneration [ 7 , 50 , 54 , 72 ]. The current study design demonstrates reproducible CC pathology and functional deficits to rigorously evaluate acute effects of 4-AP treatment.…”

The SARM1 TIR NADase: Mechanistic Similarities to Bacterial Phage Defense and Toxin-Antitoxin Systems

“…Injured or diseased axons initiate a self-destruction program known as Wallerian degeneration. SARM1 triggers this pathological axon degeneration (1), and is a key driver of pathology in models of chemotherapy-induced peripheral neuropathy (2)(3)(4)(5), traumatic brain injury (6)(7)(8)(9)(10), glaucoma (11), and retinal degeneration (12,13). SARM1 also participates in antiviral defense.…”