A microtubule stabilizer ameliorates protein pathogenesis and neurodegeneration in mouse models of repetitive traumatic brain injury.
Xinyi ZhaoWen ZengHong XuZihan SunYingxin HuBeibei PengJennifer D McBrideJiangtao DuanJuan DengBin ZhangSoo-Jung KimBryan ZollTakashi SaitoHiroki SasaguriTakaomi C SaidoCarlo BallatoreHaishan YaoZhaoyin WangJohn Q TrojanowskiKurt R BrundenVirginia M Y LeeZhuohao HePublished in: Science translational medicine (2023)
Tau pathogenesis is a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD). Although the events leading to initial tau misfolding and subsequent tau spreading in patient brains are largely unknown, traumatic brain injury (TBI) may be a risk factor for tau-mediated neurodegeneration. Using a repetitive TBI (rTBI) paradigm, we report that rTBI induced somatic accumulation of phosphorylated and misfolded tau, as well as neurodegeneration across multiple brain areas in 7-month-old tau transgenic PS19 mice but not wild-type (WT) mice. rTBI accelerated somatic tau pathology in younger PS19 mice and WT mice only after inoculation with tau preformed fibrils and AD brain-derived pathological tau (AD-tau), respectively, suggesting that tau seeds are needed for rTBI-induced somatic tau pathology. rTBI further disrupted axonal microtubules and induced punctate tau and TAR DNA binding protein 43 (TDP-43) pathology in the optic tracts of WT mice. These changes in the optic tract were associated with a decline of visual function. Treatment with a brain-penetrant microtubule-stabilizing molecule reduced rTBI-induced tau, TDP-43 pathogenesis, and neurodegeneration in the optic tract as well as visual dysfunction. Treatment with the microtubule stabilizer also alleviated rTBI-induced tau pathology in the cortices of AD-tau-inoculated WT mice. These results indicate that rTBI facilitates abnormal microtubule organization, pathological tau formation, and neurodegeneration and suggest microtubule stabilization as a potential therapeutic avenue for TBI-induced neurodegeneration.
Keyphrases
- cerebrospinal fluid
- traumatic brain injury
- diabetic rats
- wild type
- high fat diet induced
- oxidative stress
- mouse model
- spinal cord injury
- type diabetes
- multiple sclerosis
- metabolic syndrome
- white matter
- resting state
- gene expression
- brain injury
- high frequency
- insulin resistance
- optical coherence tomography
- cognitive decline
- circulating tumor cells
- single molecule
- circulating tumor
- mild cognitive impairment