Repetitive mild traumatic brain injuries (r-mTBI) sustained in the military or contact sports have been associated with the accumulation of extracellular tau in the brain, which may contribute to the pathogenesis of neurodegenerative tauopathies. The expression of the apolipoprotein E4 (apoE4) isoform has been associated with higher levels of tau in the brain, and worse clinical outcomes after r-mTBI, though the influence of apoE genotype on extracellular tau dynamics in the brain is poorly understood. We recently demonstrated that extracellular tau can be eliminated across blood-brain barrier (BBB), which is progressively impaired following r-mTBI. The current studies investigated the influence of repetitive mild TBI (r-mTBI) and apoE genotype on the elimination of extracellular solutes from the brain. Following intracortical injection of biotin-labeled tau into humanized apoE-Tr mice, the levels of exogenous tau residing in the brain of apoE4 mice were elevated compared to other isoforms, indicating reduced tau elimination. Additionally, we found exposure to r-mTBI increased tau residence in apoE2 mice, similar to our observations in E2FAD animals. Each of these findings may be the result of diminished tau efflux via LRP1 at the BBB, as LRP1 inhibition significantly reduced tau uptake in endothelial cells and decreased tau transit across an in vitro model of the BBB (basolateral-to-apical). Notably, we showed that injury and apoE status, (particularly apoE4) resulted in chronic alterations in BBB integrity, pericyte coverage, and AQP4 polarization. These aberrations coincided with an atypical reactive astrocytic gene signature indicative of diminished CSF-ISF exchange. Our work found that CSF movement was reduced in the chronic phase following r-mTBI (>18 months post injury) across all apoE genotypes. In summary, we show that apoE genotype strongly influences cerebrovascular homeostasis, which can lead to age-dependent deficiencies in the elimination of toxic proteins from the brain, like tau, particularly in the aftermath of head trauma.

在军事或接触性运动中遭受的重复性轻度创伤性脑损伤 (r-mTBI) 与大脑中细胞外 tau 蛋白的积累有关，这可能导致神经退行性tau 蛋白病的发病机制。载脂蛋白 E4 (apoE4) 亚型的表达与大脑中较高的 tau 水平以及 r-mTBI 后较差的临床结果相关，尽管 apoE 基因型对大脑中细胞外 tau 动力学的影响知之甚少。我们最近证明，细胞外 tau 蛋白可以穿过血脑屏障 (BBB) 被消除，血脑屏障在 r-mTBI 后逐渐受损。目前的研究调查了重复性轻度TBI（r-mTBI）和apoE基因型对脑内细胞外溶质清除的影响。将生物素标记的 tau 蛋白注射到人源化 apoE-Tr 小鼠的皮质内后，apoE4 小鼠大脑中的外源 tau 蛋白水平与其他亚型相比有所升高，表明 tau 蛋白消除减少。此外，我们发现暴露于 r-mTBI 会增加 apoE2 小鼠中 tau 蛋白的停留时间，这与我们在 E2FAD 动物中的观察结果相似。这些发现中的每一个都可能是 BBB 处通过 LRP1 的 tau 流出减少的结果，因为 LRP1 抑制显着减少了内皮细胞对 tau 的摄取，并减少了体外 BBB 模型（基底外侧到顶端）的 tau 转运。值得注意的是，我们发现损伤和 apoE 状态（特别是 apoE4）会导致 BBB 完整性、周细胞覆盖和 AQP4 极化的慢性改变。这些畸变与非典型反应性星形胶质细胞基因特征相一致，表明 CSF-ISF 交换减少。我们的工作发现，所有 apoE 基因型的 r-mTBI（伤后 >18 个月）后慢性期的脑脊液运动均减少。总之，我们发现 apoE 基因型强烈影响脑血管稳态，这可能导致大脑中有毒蛋白质（如 tau）的消除出现年龄依赖性缺陷，特别是在头部外伤后。