The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM

The accumulation of neurotoxic amyloid-beta (A beta) in the brain is a characteristic hallmark of Alzheimer's disease (AD). The blood-brain barrier (BBB) provides a large surface area and has been shown to be an important mediator for removal of brain A beta. Both, the ABC transporter P-glycoprotein (ABCB1/P-gp) and the receptor low density lipoprotein receptor-related protein 1 (LRP1) have been implicated to play crucial roles in A beta efflux from brain. Here, with immunoprecipitation experiments, co-immunostainings and dual inhibition of ABCB1/P-gp and LRP1, we show that both proteins are functionally linked, mediating a concerted transcytosis of A beta through endothelial cells. Late-onset AD risk factor Phosphatidylinositol binding clathrin assembly protein (PICALM) is associated with both ABCB1/P-gp and LRP1 representing a functional link and guiding both proteins through the brain endothelium. Together, our results give more mechanistic insight on A beta transport across the BBB and show that the functional interplay of different clearance proteins is needed for the rapid removal of A beta from the brain.