LRP1 mediates bidirectional transcytosis of amyloid-β across the blood-brain barrier

According to the amyloid hypothesis, the amyloid-beta (A beta) peptide is the toxic intermediate driving Alzheimer's disease (AD) pathogenesis. Recent evidence suggests that the low density lipoprotein receptor-related protein 1 (LRP1) transcytoses A beta out of the brain across the blood-brain barrier (BBB). To provide genetic evidence for LRP1-mediated transcytosis of A beta across the BBB we analyzed A beta transcytosis across primary mouse brain capillary endothelial cells (pMBCECs) derived from wild-type and LRP1 knock-in mice. Here, we show that pMBCECs in vitro express functionally active LRP1. Moreover, we demonstrate that LRP1 mediates transcytosis of [I-125]-A beta(1-40) across pMBCECs in both directions, whereas no role for LRP1-mediated A beta degradation was detected. Analysis of [I-125]-A beta(1-40) transport across pMBCECs generated from mice harboring a knock-in mutation in the NPxYxxL endocytosis/sorting domain of endogenous LRP1 revealed a reduced A beta clearance from brain-to-blood and blood-to-brain compared with wild-type derived pMBCECs. Therefore, for the first time, we present genetic evidence that LRP1 modulates the pathogenic actions of soluble A beta in the brain by clearing A beta across the BBB. (C) 2011 Elsevier Inc. All rights reserved.