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

Abstract

Brain endothelial LDL receptor-related protein 1 (LRP1) is involved in the clearance of A beta 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 A beta 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 A beta 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 A beta clearance. Thus, our findings demonstrate that ANKS1A regulates LRP1-mediated A beta clearance across the BBB. LRP1 plays a key role in the clearance of A beta peptides across the blood-brain barrier. Here, the authors report that ANKS1A promotes the LRP1-mediated A beta clearance in brain endothelium, providing insights into the pathology of Alzheimer's disease.