LRP (low-density lipoprotein receptor-related protein) is linked to Alzheimer's disease (AD). Here, we report amyloid β-peptide Aβ40 binds to immobilized LRP clusters II and IV with high affinity (Kd = 0.6–1.2 nM) compared to Aβ42 and mutant Aβ, and LRP-mediated Aβ brain capillary binding, endocytosis, and transcytosis across the mouse blood-brain barrier are substantially reduced by the high β sheet content in Aβ and deletion of the receptor-associated protein gene. Despite low Aβ production in the brain, transgenic mice expressing low LRP-clearance mutant Aβ develop robust Aβ cerebral accumulations much earlier than Tg-2576 Aβ-overproducing mice. While Aβ does not affect LRP internalization and synthesis, it promotes proteasome-dependent LRP degradation in endothelium at concentrations >1 μM, consistent with reduced brain capillary LRP levels in Aβ-accumulating transgenic mice, AD, and patients with cerebrovascular β-amyloidosis. Thus, low-affinity LRP/Aβ interaction and/or Aβ-induced LRP loss at the BBB mediate brain accumulation of neurotoxic Aβ.
