Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 9, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40478-021-01178-7
Keywords
Traumatic brain injury; Alzheimer’ s disease; Microvascular injury; Blood– brain barrier; β -amyloid
Categories
Funding
- National Institutes of Health (NIH) [1R01NS112404, RF1NS122060]
- Alzheimer's Association [NIRG-15-363387]
- BrightFocus Foundation [A2019218S]
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This study demonstrates that microvascular injury plays a key role in the pathogenesis of Alzheimer's disease after mild traumatic brain injury. Restoring vascular functions may be beneficial for patients with mild TBI and potentially reduce the risk of developing AD.
Introduction Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer's disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored. Methods In a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, we examined the time courses of microvascular injury, blood-brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also evaluated the BBB integrity, amyloid pathology as well as cognitive functions after mTBI in the 5xFAD mouse model of AD. Results mTBI induced microvascular injury with BBB breakdown, pericyte loss, basement membrane alteration and cerebral blood flow reduction in mice, in which BBB breakdown preceded gliosis. More importantly, mTBI accelerated BBB leakage, amyloid pathology and cognitive impairment in the 5xFAD mice. Discussion Our data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD.
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