LRP1 mediates bidirectional transcytosis of amyloid-beta across the blood-brain-barrier
Pflanzner, Thorsten Janko, Maren André-Dohmen, Bettina Reuss, Stefan Weggen, Sascha Roebroek, Anton Kuhlmann, Christoph Pietrzik, Claus # ×
Neurobiology of aging vol:32 issue:12 pages:2323.e1-11
According to the "amyloid hypothesis", the amyloid-beta (Abeta) 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 Abeta out of the brain across the blood-brain barrier (BBB). To provide genetic evidence for LRP1-mediated transcytosis of Abeta across the BBB we analyzed Abeta 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 [(125)I]-Abeta(1-40) across pMBCECs in both directions, whereas no role for LRP1-mediated Abeta degradation was detected. Analysis of [(125)I]-Abeta(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 Abeta 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 Abeta in the brain by clearing Abeta across the BBB.