LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms.
LRP (low-density lipoprotein receptor-related protein) is linked to Alzheimer's disease (AD). Here, we report amyloid beta-peptide Abeta40 binds to immobilized LRP clusters II and IV with high affinity (Kd = 0.6-1.2 nM) compared to Abeta42 and mutant Abeta, and LRP-mediated Abeta brain capillary binding, endocytosis, and transcytosis across the mouse blood-brain barrier are substantially reduced by the high beta sheet content in Abeta and deletion of the receptor-associated protein gene. Despite low Abeta production in the brain, transgenic mice expressing low LRP-clearance mutant Abeta develop robust Abeta cerebral accumulations much earlier than Tg-2576 Abeta-overproducing mice. While Abeta does not affect LRP internalization and synthesis, it promotes proteasome-dependent LRP degradation in endothelium at concentrations > 1 microM, consistent with reduced brain capillary LRP levels in Abeta-accumulating transgenic mice, AD, and patients with cerebrovascular beta-amyloidosis. Thus, low-affinity LRP/Abeta interaction and/or Abeta-induced LRP loss at the BBB mediate brain accumulation of neurotoxic Abeta.
Deane
Rashid
R
Frank P. Smith Laboratories for Neuroscience and Neurosurgical Research, Department of Neurosurgery, Arthur Kornberg Medical Research Building, University of Rochester Medical Center, Rochester, NY 14642, USA.
Wu
Zhenhua
Z
Sagare
Abhay
A
Davis
Judianne
J
Du Yan
Shi
S
Hamm
Katie
K
Xu
Feng
F
Parisi
Margaret
M
LaRue
Barbra
B
Hu
Hong Wei
HW
Spijkers
Patricia
P
Guo
Huang
H
Song
Xiaomei
X
Lenting
Peter J
PJ
Van Nostrand
William E
WE
Zlokovic
Berislav V
BV
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D026502:LDL-Receptor Related Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; C078592:amyloid beta-protein (1-40)