Department of Neurology, University of Pittsburgh School of Medicine, 3471 Fifth Ave, Pittsburgh, PA, 15213, USA.
Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, University Drive C, Pittsburgh, PA, 15240, USA.
Fluids Barriers CNS. 2022 Jan 10;19(1):5. doi: 10.1186/s12987-021-00301-z.
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). 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.
We 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.
The 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.
In 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.
颅脑创伤（TBI）后脑血管功能改变和淀粉样蛋白-β（Aβ）的积累可导致慢性神经病理学，并增加阿尔茨海默病（AD）的风险。爆炸引起的冲击波（bTBI）导致的 TBI 在损伤后急性期对神经血管单元（NVU）产生不利影响。然而，bTBI 和 Aβ对 NVU 和毛细血管网络的细胞成分的慢性影响尚不清楚。
我们使年轻成年（年龄范围：76-106 天）的转基因（Tg）APP/PS1 小鼠，一种 AD 样 Aβ淀粉样变性模型，和野生型（Wt）小鼠暴露于单次 bTBI（约 138 kPa 或约 20 psi）或假手术。在暴露后 3 个月或 12 个月存活期时，我们量化了 Tg 小鼠的新皮质 Aβ负荷，以及水通道蛋白-4（AQP4）免疫反应性星形胶质细胞终足与脑毛细血管之间的接触面积百分比、血小板衍生生长因子受体β（PDGFRβ）免疫反应性周细胞的数量，以及两种基因型的毛细血管密度。
Tg-bTBI 组在 3 个月存活期时，星形胶质细胞 AQP4-毛细血管接触面积明显低于 Tg-Sham 组。在 12 个月存活期或 Wt 组中，Tg-bTBI 组的 AQP4-毛细血管接触面积没有明显变化。在 12 个月存活期时，Tg-bTBI 组的毛细血管密度明显高于 Tg-Sham 对照组和 Tg-bTBI 3 个月存活组。与 3 个月存活期相比，Wt-bTBI 组在 12 个月存活期时的毛细血管密度和周细胞数量明显较低。当周细胞相对于毛细血管密度进行定量时，两种基因型的实验各组之间没有发现显著差异。
在大脑中 Aβ 浓度较高的情况下，bTBI 暴露导致星形胶质细胞-微血管界面处的 AQP4 表达减少，并导致慢性毛细血管增殖，类似于 AD 中报道的情况。bTBI 后的长期微血管变化可能会增加晚年发生慢性神经退行性疾病的风险。
