Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance

PICALM is a highly validated genetic risk factor for Alzheimer's disease (AD). We found that reduced expression of PICALM in AD and murine brain endothelium correlated with amyloid-beta (A beta) pathology and cognitive impairment. Moreover, Picalm deficiency diminished A beta clearance across the murine blood-brain barrier (BBB) and accelerated A beta pathology in a manner that was reversible by endothelial PICALM re-expression. Using human brain endothelial monolayers, we found that PICALM regulated PICALM/clathrin-dependent internalization of A beta bound to the low density lipoprotein receptor related protein-1, a key A beta clearance receptor, and guided A beta trafficking to Rab5 and Rab11, leading to A beta endothelial transcytosis and clearance. PICALM levels and A beta clearance were reduced in AD-derived endothelial monolayers, which was reversible by adenoviral-mediated PICALM transfer. Inducible pluripotent stem cell-derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced A beta clearance. Thus, PICALM regulates A beta BBB transcytosis and clearance, which has implications for A beta brain homeostasis and clearance therapy.