LRP1 mediates bidirectional transcytosis of amyloid-β across the blood-brain barrier.
According to the "amyloid hypothesis", the amyloid-β (Aβ) 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 Aβ out of the brain across the blood-brain barrier (BBB). To provide genetic evidence for LRP1-mediated transcytosis of Aβ across the BBB we analyzed Aβ 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]-Aβ(1-40) across pMBCECs in both directions, whereas no role for LRP1-mediated Aβ degradation was detected. Analysis of [(125)I]-Aβ(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 Aβ 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 Aβ in the brain by clearing Aβ across the BBB.
Pflanzner
Thorsten
T
Institute of Pathobiochemistry, University Medical Center of Johannes Gutenberg-University, Mainz, Germany.
Janko
Maren C
MC
André-Dohmen
Bettina
B
Reuss
Stefan
S
Weggen
Sascha
S
Roebroek
Anton J M
AJ
Kuhlmann
Christoph R W
CR
Pietrzik
Claus U
CU
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002478:Cells, Cultured; D055879:Gene Knock-In Techniques; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism*; D011973:Receptors, LDL / Q000502:physiology*; D057900:Transcytosis / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D016229:Amyloid beta-Peptides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D010446:Peptide Fragments; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C078592:amyloid beta-protein (1-40)