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Effects of Alzheimer’s Disease-Related Proteins on the Chirality of Brain Endothelial Cells

Abstract

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.

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Acknowledgments

This work was funded by the National Institutes of Health (OD/NICHD DP2HD083961). Leo Q. Wan is a Pew Scholar in Biomedical Sciences (PEW 00026185), supported by the Pew Charitable Trusts.

Conflict of interest

Haokang Zhang, Jie Fan, Zhen Zhao, Chunyu Wang and Leo Q. Wan declare that they have no conflicts of interest.

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No human studies or animal studies were carried out by the authors for this article.

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Zhang, H., Fan, J., Zhao, Z. et al. Effects of Alzheimer’s Disease-Related Proteins on the Chirality of Brain Endothelial Cells. Cel. Mol. Bioeng. 14, 231–240 (2021). https://doi.org/10.1007/s12195-021-00669-w

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  • DOI: https://doi.org/10.1007/s12195-021-00669-w

Keywords

  • Alzheimer’s disease
  • Cell chirality
  • Blood–brain barrier
  • Tau
  • Amyloid-β
  • Apolipoprotein E4