Mild traumatic brain injury induces microvascular injury and accelerates Alzheimer-like pathogenesis in mice

Abstract

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.

A Quantum Dot Biomimetic for SARS-CoV-2 to Interrogate Dysregulation of the Neurovascular Unit Relevant to Brain Inflammation

“…Thus, TJDP exposure may disrupt normal glial limitans architecture with a compensatory response in GFAP expression. This extensive barrier breakdown and resultant leakage in our modular model NVU system in turn may explain why the TJDP reagent can induce astrogliosis, similar to observations in pathologies with extensive BBB breakdown, without upregulating VCAM-1 (60, 63).…”

“…Of interest for our future studies is to delineate cellular and molecular constituents that participate in inflammatory signaling pathways from the endothelium to CNS resident immune cells, as well as peripheral immune cell recruitment. This may help better explain the comparable levels of neuronal injury in all three treatment groups, with the caveat that TJDP treatment may artifactually induce astrogliosis because of the magnitude of BBB injury and subsequent exposure of neuroglia to endothelial cell media (60,63). Notably, our results do not include the likely involvement of peripheral immune cell mediated dysregulation of the NVU; as with sepsis associated encephalopathy, peripheral immune contributions such as granulocytes and monocyte-derived macrophages are likely to result in lasting immune activation in the CNS (7-9, 73, 79).…”

“…Of interest for our future studies is to delineate cellular and molecular constituents that participate in inflammatory signaling pathways from the endothelium to CNS resident immune cells, as well as peripheral immune cell recruitment. This may help better explain the comparable levels of neuronal injury in all three treatment groups, with the caveat that TJDP treatment may artifactually induce astrogliosis because of the magnitude of BBB injury and subsequent exposure of neuroglia to endothelial cell media (60, 63).…”

Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study

“…In the light of our data showing continuous complement dysregulation at 2 years after TBI (and with aging), it will be important to extend single cell profiling of complement gene expression to chronic time points. Specifically, understanding the cellular source of the upregulated central complement genes C2, C3, and C4a, as well as C1qa-c and C3ar1, will help elucidate the role of complement in delayed-onset neurocognitive deficits after TBI and in TBI-induced tauopathies implicated in Alzheimer-like pathology [ 55 ].…”

Chronic effects of blast injury on the microvasculature in a transgenic mouse model of Alzheimer’s disease related Aβ amyloidosis

“…These data indicate that different models of bTBI and use of different markers of pericytes can result in different and even opposite observations when pericyte numbers are assessed acutely after bTBI in rodents. In other models of TBI, loss of pericytes, a disrupted (permeable) BBB, and gliosis within days after TBI (i.e., acutely) were reported in wild type C57Bl/6 mice exposed to closed head mild controlled cortical impact (CCI) [ 133 ] and in rats with fluid percussion injury to the exposed brain dura [ 12 ]. Another study, using the model of CCI injury over the exposed brain dura of wild type C57Bl/6 mice, reported loss of pericytes within 6–12 h after injury followed by a recovery and proliferation of pericytes by 5 days after injury [ 135 ].…”