Zhang Haokang, Fan Jie, Zhao Zhen, Wang Chunyu, Wan Leo Q
Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180 USA.
Center for Biotechnology & Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180 USA.
Cell Mol Bioeng. 2021 Mar 22;14(3):231-240. doi: 10.1007/s12195-021-00669-w. eCollection 2021 Jun.
Cell chirality is an intrinsic cellular property that determines the directionality of cellular polarization along the left-right axis. We recently show that endothelial cell chirality can influence intercellular junction formation and alter trans-endothelial permeability, depending on the uniformity of the chirality of adjacent cells, which suggests a potential role for cell chirality in neurodegenerative diseases with blood-brain barrier (BBB) dysfunctions, such as Alzheimer's disease (AD). In this study, we determined the effects of AD-related proteins amyloid-β (Aβ), tau, and apolipoprotein E4 (ApoE4) on the chiral bias of the endothelial cell component in BBB.
We first examined the chiral bias and effects of protein kinase C (PKC)-mediated chiral alterations of human brain microvascular endothelial cells (hBMECs) using the ring micropattern chirality assay. We then investigated the effects of Aβ, tau, and ApoE4 on hBMEC chirality using chirality assay and biased organelle positions.
The hBMECs have a strong clockwise chiral bias, which can be reversed by protein kinase C (PKC) activation. Treatment with tau significantly disrupted the chiral bias of hBMECs with altered cellular polarization. In contrast, neither ApoE4 nor Aβ-42 caused significant changes in cell chirality.
We conclude that tau might cause BBB dysfunction by disrupting cell polarization and chiral morphogenesis, while the effects of ApoE4 and Aβ-42 on BBB integrity might be chirality-independent. The potential involvement of chiral morphogenesis in tau-mediated BBB dysfunction in AD provides a novel perspective in vascular dysfunction in tauopathies such as AD, chronic traumatic encephalopathy, progressive supranuclear palsy, and frontotemporal dementia.
The online version contains supplementary material available at 10.1007/s12195-021-00669-w.
细胞手性是一种内在的细胞特性，它决定了细胞沿左右轴极化的方向性。我们最近发现，内皮细胞手性可影响细胞间连接的形成，并改变跨内皮通透性，这取决于相邻细胞手性的一致性，这表明细胞手性在伴有血脑屏障（BBB）功能障碍的神经退行性疾病（如阿尔茨海默病（AD））中可能发挥潜在作用。在本研究中，我们确定了AD相关蛋白β-淀粉样蛋白（Aβ）、tau蛋白和载脂蛋白E4（ApoE4）对BBB中内皮细胞成分手性偏倚的影响。
我们首先使用环形微图案手性测定法检测了蛋白激酶C（PKC）介导的人脑微血管内皮细胞（hBMECs）手性改变的手性偏倚和影响。然后，我们使用手性测定法和偏向性细胞器位置研究了Aβ、tau蛋白和ApoE4对hBMECs手性的影响。
hBMECs具有强烈的顺时针手性偏倚，蛋白激酶C（PKC）激活可将其逆转。tau蛋白处理显著破坏了hBMECs的手性偏倚，并改变了细胞极化。相比之下，ApoE4和Aβ-42均未引起细胞手性的显著变化。
我们得出结论，tau蛋白可能通过破坏细胞极化和手性形态发生导致BBB功能障碍，而ApoE4和Aβ-42对BBB完整性的影响可能与手性无关。手性形态发生在AD中tau蛋白介导的BBB功能障碍中的潜在作用，为tau蛋白病（如AD、慢性创伤性脑病、进行性核上性麻痹和额颞叶痴呆）中的血管功能障碍提供了一个新的视角。
在线版本包含可在10.1007/s12195-021-00669-w获取的补充材料。
