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.
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.
Rashid
R
Deane
Zhenhua
Z
Wu
Abhay
A
Sagare
Judianne
J
Davis
Shi
S
Du Yan
Katie
K
Hamm
Feng
F
Xu
Margaret
M
Parisi
Barbra
B
LaRue
Hong Wei
HW
Hu
Patricia
P
Spijkers
Huang
H
Guo
Xiaomei
X
Song
Peter J
PJ
Lenting
William E
WE
Van Nostrand
Berislav V
BV
Zlokovic
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)