Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma.
Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma.
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DOI：
10.1016/j.nbd.2020.105237
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发表时间：
2021-03
影响因子：
6.1
通讯作者：
Bachmeier C
中科院分区：
文献类型：
--
作者：
Ojo J;Eisenbaum M;Shackleton B;Lynch C;Joshi U;Saltiel N;Pearson A;Ringland C;Paris D;Mouzon B;Mullan M;Crawford F;Bachmeier C
重复性创伤性脑损伤（TBI）的病理学特征是脑中过度磷酸化和聚集的tau种类的沉积，并且细胞外单体tau的水平增加被认为在神经退行性tau蛋白病的发病机制中起作用。然而，细胞外tau从大脑中消除的途径仍然难以捉摸。本研究的目的是检查脑血管细胞对tau蛋白的摄取以及TBI对这些过程的影响。我们发现单体tau蛋白与脑血管壁细胞（周细胞和平滑肌细胞）的相互作用程度大于其他脑血管细胞，表明壁细胞可能有助于细胞外tau蛋白的消除，如前所述的其他溶质，如β-淀粉样蛋白。与其他神经退行性疾病一致，我们观察到与对照组相比，在重复性轻度TBI（r-mTBI）小鼠模型和人TBI脑标本中，脑血管壁细胞标志物在损伤后12个月内逐渐下降。这些变化似乎反映了壁细胞变性，而不是细胞损失，因为通过流式细胞术测定，在r-mTBI和r-sham动物之间未观察到壁细胞群的差异。此外，与r-sham动物相比，新鲜分离的r-mTBI血管在损伤后6个月和12个月显示出减少的tau摄取，这可能是脑血管内吞作用减少的结果，因为与其各自的对照相比，小鼠r-mTBI和人TBI血管中的小窝蛋白-1水平显著降低。进一步强调壁细胞和tau之间的相互作用，在转基因壁细胞耗尽动物的血管中观察到壁细胞标记物、tau摄取和小窝蛋白-1的类似减少。总之，我们的研究表明，大脑的重复损伤会导致慢性壁细胞变性，减少这些细胞对tau蛋白的小窝介导的摄取。血管壁细胞对tau蛋白摄取的改变可能有助于头部创伤后大脑中的tau蛋白沉积，并可能代表TBI或其他神经退行性疾病的新治疗靶点。
A pathological characteristic of repetitive traumatic brain injury (TBI) is the deposition of hyperphosphorylated and aggregated tau species in the brain and increased levels of extracellular monomeric tau are believed to play a role in the pathogenesis of neurodegenerative tauopathies. The pathways by which extracellular tau is eliminated from the brain, however, remains elusive. The purpose of this study was to examine tau uptake by cerebrovascular cells and the effect of TBI on these processes. We found monomeric tau interacts with brain vascular mural cells (pericytes and smooth muscle cells) to a greater extent than other cerebrovascular cells, indicating mural cells may contribute to the elimination of extracellular tau, as previously described for other solutes such as beta-amyloid. Consistent with other neurodegenerative disorders, we observed a progressive decline in cerebrovascular mural cell markers up to 12 months post-injury in a mouse model of repetitive mild TBI (r-mTBI) and human TBI brain specimens, when compared to control. These changes appear to reflect mural cell degeneration and not cellular loss as no difference in the mural cell population was observed between r-mTBI and r-sham animals as determined through flow cytometry. Moreover, freshly isolated r-mTBI cerebrovessels showed reduced tau uptake at 6 and 12 months post-injury compared to r-sham animals, which may be the result of diminished cerebrovascular endocytosis, as caveolin-1 levels were significantly decreased in mouse r-mTBI and human TBI cerebrovessels compared to their respective controls. Further emphasizing the interaction between mural cells and tau, similar reductions in mural cell markers, tau uptake, and caveolin-1 were observed in cerebrovessels from transgenic mural cell-depleted animals. In conclusion, our studies indicate repeated injuries to the brain causes chronic mural cell degeneration, reducing the caveolar-mediated uptake of tau by these cells. Alterations in tau uptake by vascular mural cells may contribute to tau deposition in the brain following head trauma and could represent a novel therapeutic target for TBI or other neurodegenerative disorders.
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影响因子：
5.6
作者：
ElAli A;Thériault P;Rivest S
通讯作者：
Rivest S
影响因子：
17.1
作者：
Goldstein LE;Fisher AM;Tagge CA;Zhang XL;Velisek L;Sullivan JA;Upreti C;Kracht JM;Ericsson M;Wojnarowicz MW;Goletiani CJ;Maglakelidze GM;Casey N;Moncaster JA;Minaeva O;Moir RD;Nowinski CJ;Stern RA;Cantu RC;Geiling J;Blusztajn JK;Wolozin BL;Ikezu T;Stein TD;Budson AE;Kowall NW;Chargin D;Sharon A;Saman S;Hall GF;Moss WC;Cleveland RO;Tanzi RE;Stanton PK;McKee AC
通讯作者：
McKee AC
影响因子：
6.3
作者：
Donovan, Virginia;Kim, Claudia;Obenaus, Andre
通讯作者：
Obenaus, Andre
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：
82.9
作者：
Holcomb, L;Gordon, MN;Duff, K
通讯作者：
Duff, K