Introduction

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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阿尔茨海默病相关蛋白对脑内皮细胞手性的影响

介绍

细胞手性是一种内在的细胞特性，它决定了细胞极化沿左右轴的方向性。我们最近表明，内皮细胞手性可以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均匀性，这表明细胞手性在具有血脑屏障 (BBB) 功能障碍的神经退行性疾病中具有潜在作用, 如阿尔茨海默病 (AD)。在这项研究中，我们确定了 AD 相关蛋白淀粉样蛋白-β (Aβ)、tau 和载脂蛋白 E4 (ApoE4) 对 BBB 中内皮细胞成分的手性偏向的影响。

方法

我们首先使用环形微模式手性测定法检查了蛋白激酶 C (PKC) 介导的人脑微血管内皮细胞 (hBMECs) 的手性改变的手性偏差和影响。然后，我们使用手性测定和偏向细胞器位置研究了 Aβ、tau 和 ApoE4 对 hBMEC 手性的影响。

结果

hBMECs 具有很强的顺时针手性偏向，可以通过蛋白激酶 C (PKC) 激活来逆转。tau 治疗显着破坏了 hBMECs 的手性偏向，并改变了细胞极化。相反，ApoE4 和 Aβ-42 都没有引起细胞手性的显着变化。

结论

我们得出结论，tau 可能通过破坏细胞极化和手性形态发生而导致 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。AD 中 tau 介导的 BBB 功能障碍可能涉及手性形态发生，这为研究 tau 病变（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新的视角。