Title: LRP1 mediates bidirectional transcytosis of amyloid-beta across the blood-brain-barrier
Authors: Pflanzner, Thorsten
Janko, Maren
André-Dohmen, Bettina
Reuss, Stefan
Weggen, Sascha
Roebroek, Anton
Kuhlmann, Christoph
Pietrzik, Claus # ×
Issue Date: Dec-2011
Publisher: Elsevier
Series Title: Neurobiology of aging vol:32 issue:12 pages:2323.e1-11
Abstract: 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.
ISSN: 0197-4580
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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