Neuronal tau pathology worsens late-phase white matter degeneration after traumatic brain injury in transgenic mice

Abstract

Traumatic brain injury (TBI) causes diffuse axonal injury which can produce chronic white matter pathology and subsequent post-traumatic neurodegeneration with poor patient outcomes. Tau modulates axon cytoskeletal functions and undergoes phosphorylation and mis-localization in neurodegenerative disorders. The effects of tau pathology on neurodegeneration after TBI are unclear. We used mice with neuronal expression of human mutant tau to examine effects of pathological tau on white matter pathology after TBI. Adult male and female hTau.P301S (Tg2541) transgenic and wild-type (Wt) mice received either moderate single TBI (s-TBI) or repetitive mild TBI (r-mTBI; once daily × 5), or sham procedures. Acutely, s-TBI produced more extensive axon damage in the corpus callosum (CC) as compared to r-mTBI. After s-TBI, significant CC thinning was present at 6 weeks and 4 months post-injury in Wt and transgenic mice, with homozygous tau expression producing additional pathology of late demyelination. In contrast, r-mTBI did not produce significant CC thinning except at the chronic time point of 4 months in homozygous mice, which exhibited significant CC atrophy (− 29.7%) with increased microgliosis. Serum neurofilament light quantification detected traumatic axonal injury at 1 day post-TBI in Wt and homozygous mice. At 4 months, high tau and neurofilament in homozygous mice implicated tau in chronic axon pathology. These findings did not have sex differences detected. Conclusions: Neuronal tau pathology differentially exacerbated CC pathology based on injury severity and chronicity. Ongoing CC atrophy from s-TBI became accompanied by late demyelination. Pathological tau significantly worsened CC atrophy during the chronic phase after r-mTBI.

Identifying the Phenotypes of Diffuse Axonal Injury Following Traumatic Brain Injury

“…Similarly, in a pig model of rotational TBI, N52, which recognizes both phosphorylated and non-phosphorylated forms of NF-H, still detected swollen axonal bulbs at 6 months post-injury, although this was considerably reduced compared to that observed acutely at 3-7 days post-injury [98]. This may be injury dependent, with Iliff et al [125] only detecting sparse SMI-34 immunoreactive varicosities in the cortex and corpus callosum 28 days postmild closed head impact and Yu et al [126] finding no SMI-34 axonal pathology 4 months post-mild TBI. Nonetheless, like axonal transport defects, it appears that neurofilament pathology continues into the chronic post-injury phase in at least some types of TBI.…”

A strike to the head: Parallels between the pediatric and adult human and the rodent in traumatic brain injury

“…A variety of modalities can measure axonal damage of the CC. Using a closed‐head model of CCI performed on a mutant human tau transgenic mouse, a single moderate TBI produced more extensive axonal damage and CC thinning than mild repeated TBI at 1 day, 6 weeks, and 4 months post‐injury (Yu et al., 2023). This group also investigated the contribution of SARM1 to axonal integrity by producing a closed‐head CCI in both wildtype and SARM1 null mice (Marion et al., 2019).…”