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

作者：Fengshan Yu, Diego Iacono, Daniel P. Perl, Chen Lai, Jessica Gill, Tuan Q. Le, Patricia Lee, Gauthaman Sukumar, Regina C. Armstrong · 发表于：Acta Neuropathologica · 年份：2023 · DOI：10.1007/s00401-023-02622-9 · 被引用次数：15 · 研究领域：Alzheimer's disease research and treatments、Neurogenesis and neuroplasticity mechanisms、Neuroscience and Neuropharmacology Research

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: Neuron...