Staff Scientist Henry Jackson Foundation Bethesda, Maryland
Abstract Text: Traumatic brain injury (TBI) can lead to post-traumatic neurodegeneration and poor patient outcomes. Chronic atrophy of white matter, particularly the corpus callosum (CC), is a measure of post-traumatic neurodegeneration. Tau modulates axon cytoskeleton stability with unclear effects on TBI progression. We tested the effect of increasing levels of neuronal tau pathology on the progression of white matter atrophy after moderate single TBI (s-TBI) or repetitive mild TBI (r-mTBI; once daily x 5) in adult 8 week old male and female Tg(MAPT*P301S) mice. Beta APP immunohistochemistry confirmed more extensive CC axon damage at 24 hours after moderate s-TBI as compared to r-mTBI. Homogenates of cerebral cortex and CC, from under the TBI impact site at bregma, had increased soluble human tau protein and phosphorylation in hemizygous (Hemi) and homozygous (Hom) mice. Neuropathology demonstrated significant CC thinning at 6 weeks and 4 months after s-TBI in wildtype (Wt), Hemi, and Hom mice. After r-mTBI, CC width was not altered at 6 weeks, and then decreased 29.7% in Hom mice by 4 months, with contrasting increases in Hemi (4.3%) and Wt (13.2%) mice. Accordingly, at 4 months, a significant interaction of r-mTBI and Hom genotype increased CC microgliosis, but not astrogliosis. Simoa serum biomarker quantification detected human tau exposure in Hemi and Hom mice. Neurofilament light levels increased at 24 hours after s-TBI and r-mTBI, indicating axon damage, and increased in Hom mice through 4 months. These studies demonstrate significant interplay of pathological tau and r-mTBI in delayed progression to chronic phase CC atrophy.
