Abstract
BackgroundAltered cerebrovascular function and accumulation of amyloid-β (Aβ) after traumatic brain injury (TBI) can contribute to chronic neuropathology and increase the risk for Alzheimer’s disease (AD). TBI due to a blast-induced shock wave (bTBI) adversely affects the neurovascular unit (NVU) during the acute period after injury. However, the chronic effects of bTBI and Aβ on cellular components of the NVU and capillary network are not well understood.MethodsWe exposed young adult (age range: 76–106 days) female transgenic (Tg) APP/PS1 mice, a model of AD-like Aβ amyloidosis, and wild type (Wt) mice to a single bTBI (~ 138 kPa or ~ 20 psi) or to a Sham procedure. At 3-months or 12-months survival after exposure, we quantified neocortical Aβ load in Tg mice, and percent contact area between aquaporin-4 (AQP4)-immunoreactive astrocytic end-feet and brain capillaries, numbers of PDGFRβ-immunoreactive pericytes, and capillary densities in both genotypes.ResultsThe astroglia AQP4-capillary contact area in the Tg-bTBI group was significantly lower than in the Tg-Sham group at 3-months survival. No significant changes in the AQP4-capillary contact area were observed in the Tg-bTBI group at 12-months survival or in the Wt groups. Capillary density in the Tg-bTBI group at 12-months survival was significantly higher compared to the Tg-Sham control and to the Tg-bTBI 3-months survival group. The Wt-bTBI group had significantly lower capillary density and pericyte numbers at 12-months survival compared to 3-months survival. When pericytes were quantified relative to capillary density, no significant differences were detected among the experimental groups, for both genotypes.ConclusionIn conditions of high brain concentrations of human Aβ, bTBI exposure results in reduced AQP4 expression at the astroglia-microvascular interface, and in chronic capillary proliferation like what has been reported in AD. Long term microvascular changes after bTBI may contribute to the risk for developing chronic neurodegenerative disease later in life.
Highlights
Altered cerebrovascular function and accumulation of amyloid-β (Aβ) after traumatic brain injury (TBI) can contribute to chronic neuropathology and increase the risk for Alzheimer’s disease (AD)
These results are in agreement with a recent report that Aβ plaque load is not significantly different in 5-months-old Amyloid precursor protein (APP)/Presenilin 1 (PS1) Tg mice exposed to repetitive low-level blast TBI (bTBI) compared to sham APP/PS1 Tg mice when assessed after 3–4 months survival [100]
Human and experimental studies of brain injury report changes in blood–brain barrier (BBB) permeability, induction of perivascular inflammation, altered endothelial-immune cell interactions, and dysfunction of endothelial cells and pericytes [4]. While most of these changes are reported within the acute and subacute period, the current study contributes to a better understanding of the chronic phase of bTBI in relation to a risk of developing sustained cerebral vascular dysfunction and AD-related Aβ pathology
Summary
Altered cerebrovascular function and accumulation of amyloid-β (Aβ) after traumatic brain injury (TBI) can contribute to chronic neuropathology and increase the risk for Alzheimer’s disease (AD). Traumatic brain injury (TBI) is considered a risk factor for chronic neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson disease (PD), and. Pertaining to the risk for AD following TBI, an injury-induced imbalance between Aβ production and clearance can promote accumulation of Aβ in the brain [20, 58, 109] which can contribute to, and be enhanced by, vascular changes involving impaired blood–brain barrier (BBB) function and dysregulation of cerebral blood flow [3, 53, 54, 57, 67, 118, 136]. Brain injury-induced dysfunction or loss of either cell type could impair these mechanisms and contribute to brain Aβ accumulation in conjunction with microvascular dysregulation
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