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Genetic Inactivation of SARM1 Axon Degeneration Pathway Improves

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Genetic Inactivation of SARM1 Axon Degeneration Pathway Improves Bradshaw Jr. et al. acta neuropathol commun (2021) 9:89 https://doi.org/10.1186/s40478-021-01193-8 RESEARCH Open Access Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures Donald V. Bradshaw Jr.1,2, Andrew K. Knutsen3,4, Alexandru Korotcov3,4, Genevieve M. Sullivan2, Kryslaine L. Radomski2,4, Bernard J. Dardzinski3,4,6, Xiaomei Zi2, Dennis P. McDaniel5 and Regina C. Armstrong1,2,4* Abstract Traumatic brain injury (TBI) causes chronic symptoms and increased risk of neurodegeneration. Axons in white mat- ter 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− therapeu- tic target. We evaluated Sarm1 deletion efects 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 signifcant CC atrophy that was reduced in Sarm1 KO mice. Ultrastructural classifcation 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 identifed signifcantly reduced CC volume after TBI in Sarm1 WT mice that was attenuated in Sarm1 KO mice. MR difusion tensor imaging detected reduced fractional anisotropy in both genotypes while axial difusivity remained higher in Sarm1 KO mice. Immunohistochem- istry revealed signifcant attenuation of CC atrophy, myelin loss, and neuroinfammation in Sarm1 KO mice after TBI. Functionally, Sarm1 KO mice exhibited benefcial efects in motor learning and sleep behavior. Based on these fnd- ings, Sarm1 inactivation can protect axons and white matter tracts to improve translational outcomes associated with CC atrophy and post-traumatic neurodegeneration. Keywords: Chronic traumatic brain injury, SARM1, Sterile alpha and Toll, interleukin-1 receptor containing motif 1, White matter, Corpus callosum atrophy, Magnetic resonance imaging Background Traumatic brain injury (TBI) results in long term dis- *Correspondence: [email protected] ability in more severe cases and can cause persistent 2 Department of Anatomy, Physiology and Genetics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, symptoms even in patients who receive a “mild” diag- 4301 Jones Bridge Rd., Bethesda, MD 20814, USA nosis [42, 67, 72]. TBI may also lead to post-traumatic Full list of author information is available at the end of the article neurodegeneration and increase the risk for co-morbid © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Bradshaw Jr. et al. acta neuropathol commun (2021) 9:89 Page 2 of 19 neurodegenerative diseases, such as Alzheimer’s dis- in cultured human sensory neurons and in live mice ease [16, 19, 31, 73]. In patients with moderate-severe reduced axon damage in models of peripheral neuropa- TBI, difuse axonal injury has been shown to predict thy induced by trauma or chemotherapy [14, 24, 26, 70]. the extent of post-traumatic neurodegeneration, based In multiple models of TBI, Sarm1 knockout (KO) mice on MRI volumetric and difusion tensor imaging (DTI) exhibited signifcantly reduced axon damage at acute and data [30]. Te strongest relationship was found in central late phase time points [35, 52, 58, 96]. Long-term studies white matter tracts, including the corpus callosum (CC). of TBI in mice can model post-traumatic neurodegenera- Te CC is one of the main structures exhibiting atrophy tion that includes atrophy of the CC [47, 53, 64]. Initial across patients with complicated mild to severe TBI [16, results from our prior studies provided the frst evidence 31]. Furthermore, DTI tractography demonstrated dis- that Sarm1 deletion may reduce both late stage axon rupted fber tract continuity in anterior CC regions after damage and CC atrophy [52]. concussions while broad areas of disrupted tracts were We now focus on CC atrophy as an important trans- found throughout the CC in patients with MRI fndings lational outcome measure of post-traumatic neurode- of difuse axonal injury [38]. Ex vivo MRI of a patient generation. We evaluate the efect of Sarm1 deletion who died 26 days after TBI demonstrated that white mat- on axon damage, demyelination, and neuroinfamma- ter tract disruptions detected by DTI correlated with tion on the progression of CC atrophy after closed head neuropathological identifcation of axonal injury [69]. TBI. We use longitudinal MRI to detect changes in CC Long axons in white matter tracts are particularly vul- volume and white matter integrity in live mice, which nerable to damage in all forms of closed head TBI [11, 40, provides a highly translational outcome measure of pro- 57, 78]. At an early stage of damage, axons can exhibit longed Sarm1 inactivation. To demonstrate whether the focal swellings yet longitudinal in vitro and in vivo imag- pathological efects of Sarm1 deletion have a meaning- ing has shown the potential to recover [32, 37, 68]. Once ful impact on complex functions, we assess motor skill mechanical or molecular processes fragment the axon, learning and sleep behavior. Tis experimental design then the distal axon irreversibly degrades by Wallerian provides a rigorous and translationally relevant screen to degeneration [32, 37, 54, 56, 68]. Te majority of axon evaluate the impact of Sarm1 deletion on long-term out- damage is due to secondary mechanisms of damage that come measures after TBI. can cause axons to initiate Wallerian degeneration for weeks or more after the initial TBI event [13, 54, 56]. Materials and methods Irreversible axonal injury leads to disconnection between Mice brain regions and disruption of neural circuits that may All mice were treated in accordance with guidelines of contribute to diverse TBI symptoms [33, 59]. To improve the Uniformed Services University of the Health Sci- outcomes for patients after TBI, research is needed to ences and the National Institutes of Health Guide for identify approaches to protect against axon degeneration the Care and Use of Laboratory Animals. Mice were and, further, to determine whether acute axon protection socially housed with 2–5 mice per 35 cm × 16.5 cm can reduce post-traumatic neurodegeneration. × 18 cm cages containing enrichment objects. Mice Wallerian degeneration is an “active program of axon were maintained on a standard 12 h cycle of daytime self-destruction” [76]. After injury or mitochondrial dys- light (6:00–18:00). Sarm1−/− knockout (KO) mice, function, the SARM1 (sterile alpha and Toll/interleukin-1 B6.129 × 1-Sarm1tm1Aidi/J (RRID:IMSR_JAX:018069) receptor motif-containing 1) protein executes a highly were originally obtained from Te Jackson Laboratory. conserved molecular axon degeneration pathway [27, 48, Sarm1 KO mice were generated by targeted mutation 70, 84]. Injury releases SARM1 from an auto-inhibited that replaced exons 3 through 6 with a neo cassette in state that is found in healthy axons [22, 76, 80]. Active the reverse orientation and absence of SARM1 protein in SARM1 is a glycohydrolase which depletes nicotinamide the brain was confrmed by western blot [43]. Sarm1 KO adenine dinucleotide (NAD +) that is critical for energy mice were backcrossed to C57BL/6 mice for 15 genera- stores in axons [18, 23, 26]. Loss of sufcient NAD + leads tions before arrival at Te Jackson Laboratory and then to a cascade of axon destruction in which ionic imbalance crossed at least once to C57BL/6 J mice. For our studies, leads to cytoskeletal and structural breakdown within the Sarm1 KO mice were crossed to C57BL/6 J mice and then axon [25, 26, 85]. heterozygotes were bred to generate littermates used in Deletion of the Sarm1 gene provides a genetic proof- experiments. Sarm1 is highly expressed in the brain; lack of-concept to examine the efects of long-term inac- of detectable SARM1 protein in Sarm1 KO mice does not tivation of this axon degeneration pathway in chronic produce gross or microscopic brain pathology [28, 43]. TBI and to evaluate the relationship of axonal injury to Te colony was maintained at Charles River Laboratories post-traumatic neurodegeneration. Knockout of Sarm1 (Wilmington, MA) where ear biopsies were genotyped Bradshaw Jr. et al. acta neuropathol commun (2021) 9:89 Page 3 of 19 using a 3-primer allele specifc PCR assay that targets the immersed in 2% osmium tetroxide (OsO4; Electron mutated Sarm1 region. Experimental mice were accli- Microscopy Sciences; Cat #19100) infltrated with Spurr mated for 3 days after shipment and prior to the start of epoxy resin (Electron Microscopy Sciences; Cat #14300), experiments.
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