LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms

Neuron. 2004 Aug 5;43(3):333-44. doi: 10.1016/j.neuron.2004.07.017.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism*
  • Cell Line
  • Cricetinae
  • Humans
  • LDL-Receptor Related Proteins / deficiency
  • LDL-Receptor Related Proteins / genetics
  • LDL-Receptor Related Proteins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Protein Binding
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism


  • Amyloid beta-Peptides
  • LDL-Receptor Related Proteins
  • Peptide Fragments
  • Protein Isoforms
  • amyloid beta-protein (1-40)