Influence of traumatic brain injury on extracellular tau elimination at the blood-brain barrier.
Influence of traumatic brain injury on extracellular tau elimination at the blood-brain barrier.
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DOI：
10.1186/s12987-021-00283-y
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发表时间：
2021-10-26
影响因子：
7.3
通讯作者：
Bachmeier C
中科院分区：
文献类型：
--
作者：
Eisenbaum M;Pearson A;Gratkowski A;Mouzon B;Mullan M;Crawford F;Ojo J;Bachmeier C
重复性头部创伤与大脑中tau物质的积累有关。我们先前的工作表明，脑血管壁细胞有助于脑中的tau蛋白加工，并且这些细胞在重复性轻度创伤性脑损伤（r-mTBI）后逐渐退化。目前的研究调查了脑血管系统在从脑中消除细胞外tau蛋白中的作用，以及r-mTBI对这些过程的影响。颅内注射生物素标记的tau后，与r-sham小鼠相比，在损伤后12个月时，r-mTBI小鼠模型中存在于脑中的外源性标记的tau水平升高，表明头部创伤后tau从脑中的消除减少。这可能是由于在血脑屏障（BBB）处小窝蛋白-1介导的tau流出减少，因为小窝蛋白抑制剂甲基-β-环糊精显著减少了分离的血管中的tau摄取，并且显著减少了tau穿过BBB的体外模型的基底侧向顶端转运。此外，我们发现，与r-sham相比，r-mTBI血管中内皮小窝蛋白-1的上游调节因子Mfsd 2a升高，这与r-mTBI后慢性期（损伤后> 3个月）脑血管小窝蛋白-1的表达降低一致。最后，血管生成素-1，壁细胞衍生的蛋白质管理内皮Mfsd 2a的表达，分泌从r-mTBI血管在更大程度上比r-sham动物。总之，在损伤后的慢性阶段，从退化的壁细胞释放血管生成素-1下调脑内皮细胞中的小窝蛋白-1表达，导致减少的tau消除穿过BBB，这可以描述头部创伤后tau种类在脑中的积累。
Repetitive head trauma has been associated with the accumulation of tau species in the brain. Our prior work showed brain vascular mural cells contribute to tau processing in the brain, and that these cells progressively degenerate following repetitive mild traumatic brain injury (r-mTBI). The current studies investigated the role of the cerebrovasculature in the elimination of extracellular tau from the brain, and the influence of r-mTBI on these processes. Following intracranial injection of biotin-labeled tau, the levels of exogenous labeled tau residing in the brain were elevated in a mouse model of r-mTBI at 12 months post-injury compared to r-sham mice, indicating reduced tau elimination from the brain following head trauma. This may be the result of decreased caveolin-1 mediated tau efflux at the blood–brain barrier (BBB), as the caveolin inhibitor, methyl-β-cyclodextrin, significantly reduced tau uptake in isolated cerebrovessels and significantly decreased the basolateral-to-apical transit of tau across an in vitro model of the BBB. Moreover, we found that the upstream regulator of endothelial caveolin-1, Mfsd2a, was elevated in r-mTBI cerebrovessels compared to r-sham, which coincided with a decreased expression of cerebrovascular caveolin-1 in the chronic phase following r-mTBI (> 3 months post-injury). Lastly, angiopoietin-1, a mural cell-derived protein governing endothelial Mfsd2a expression, was secreted from r-mTBI cerebrovessels to a greater extent than r-sham animals. Altogether, in the chronic phase post-injury, release of angiopoietin-1 from degenerating mural cells downregulates caveolin-1 expression in brain endothelia, resulting in decreased tau elimination across the BBB, which may describe the accumulation of tau species in the brain following head trauma.
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影响因子：
4.8
作者：
Hansen TM;Singh H;Tahir TA;Brindle NP
通讯作者：
Brindle NP
影响因子：
5.3
作者：
Bonds, Jacqueline A.;Shetti, Aashutosh;Lazarov, Orly
通讯作者：
Lazarov, Orly
影响因子：
5.3
作者：
Brickler, Thomas R.;Hazy, Amanda;Theus, Michelle H.
通讯作者：
Theus, Michelle H.
影响因子：
4
作者：
Banks, William A.;Kovac, Andrej;Zhang, Jing
通讯作者：
Zhang, Jing
DOI：
10.1038/jcbfm.2008.117
发表时间：
2009-01
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
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通讯作者：
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