| Summary: | Repeated mild traumatic brain injury (rmTBI) can lead to development of chronic traumatic encephalopathy (CTE), which is characterized by progressive neurodegeneration with presence of white matter damage, gliosis and hyper-phosphorylated tau. While animal models of rmTBI have been documented, few characterize the molecular pathogenesis and expression profiles of relevant injured brain regions. Additionally, while the usage of transgenic tau mice in rmTBI is prevalent, the effects of tau on pathological outcomes has not been well studied. Here we characterized a 42-impact closed-head rmTBI paradigm on 3–4 month old male C57BL/6 (WT) and Tau-overexpressing mice (Tau58.4). This injury paradigm resulted in chronic gliosis, T-cell infiltration, and demyelination of the optic nerve and associated white matter tracts at 1-month post-injury. At 3-months post-injury, Tau58.4 mice showed progressive neuroinflammation and neurodegeneration in multiple brain regions compared to WT mice. Corresponding to histopathology, RNAseq of the optic nerve tract at 1-month post-injury showed significant upregulation of inflammatory pathways and downregulation of myelin synthetic pathways in both genotypes. However, Tau58.4 mice showed additional changes in neurite development, protein processing, and cell stress. Comparisons with published transcriptomes of human Alzheimer's Disease and CTE revealed common signatures including neuroinflammation and downregulation of protein phosphatases. We next investigated the demyelination and T-cell infiltration phenotypes to determine whether these offer potential avenues for therapeutic intervention. Tau58.4 mice were treated with the histamine H3 receptor antagonist GSK239512 for 1-month post-injury to promote remyelination of white matter lesions. This restored myelin gene expression to sham levels but failed to repair the histopathologic lesions. Likewise, injured T-cell-deficient Rag2/Il2rg (R2G2) mice also showed evidence for inflammation and loss of myelin. However, unlike immune-competent mice, R2G2 mice had altered myeloid cell gene expression and fewer demyelinated lesions. Together this data shows that rmTBI leads to chronic white matter inflammatory demyelination and axonal loss exacerbated by human tau overexpression but suggests that immune-suppression and remyelination alone are insufficient to reverse damage.
|
|---|
