ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells

Jiyeon Lee, Haeryung Lee, Hyein Lee, Miram Shin, Min-Gi Shin, Jinsoo Seo, Eun Jeong Lee, Sun Ah Park and Soochul Park ()
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Jiyeon Lee: Sookmyung Women’s University
Haeryung Lee: Sookmyung Women’s University
Hyein Lee: Daegu Gyeongbuk Institute of Science & Technology (DGIST)
Miram Shin: Sookmyung Women’s University
Min-Gi Shin: Ajou University School of Medicine
Jinsoo Seo: Daegu Gyeongbuk Institute of Science & Technology (DGIST)
Eun Jeong Lee: Ajou University School of Medicine
Sun Ah Park: Ajou University School of Medicine
Soochul Park: Sookmyung Women’s University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Brain endothelial LDL receptor-related protein 1 (LRP1) is involved in the clearance of Aβ peptides across the blood-brain barrier (BBB). Here we show that endothelial deficiency of ankyrin repeat and SAM domain containing 1 A (ANKS1A) reduces both the cell surface levels of LRP1 and the Aβ clearance across the BBB. Association of ANKS1A with the NPXY motifs of LRP1 facilitates the transport of LRP1 from the endoplasmic reticulum toward the cell surface. ANKS1A deficiency in an Alzheimer’s disease mouse model results in exacerbated Aβ pathology followed by cognitive impairments. These deficits are reversible by gene therapy with brain endothelial-specific ANKS1A. In addition, human induced pluripotent stem cell-derived BBBs (iBBBs) were generated from endothelial cells lacking ANKS1A or carrying the rs6930932 variant. Those iBBBs exhibit both reduced cell surface LRP1 and impaired Aβ clearance. Thus, our findings demonstrate that ANKS1A regulates LRP1-mediated Aβ clearance across the BBB.

Date: 2023
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DOI: 10.1038/s41467-023-44319-3

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