LRP/Amyloid β-Peptide Interaction Mediates Differential Brain Efflux of Aβ Isoforms

Abstract

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.

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

“…77 Interestingly, LRP-1 expression in the endothelial cells of the BBB appears to decrease significantly with normal aging and in AD, and this may also be the case in aging rodents. 78 This may be one explanation for why the EV in the present study was ineffective in the older Tg2576 mice with substantial preexisting amyloid plaque deposition. This is not the first time that immunotherapy in APP transgenic mice with existing amyloid plaques did not reduce the amyloid load in the brain.…”

“…75 However, the "peripheral sink" pathway was dependent on Ab being exported from the CNS. The principle molecule involved in the transport of Ab out of the brain is the low-density lipoprotein receptor-protein-1 (LRP-1), [76][77][78] which, as suggested, binds to Ab at the abluminal side of the endothelium and transports this peptide across the BBB and into the bloodstream. 77 Interestingly, LRP-1 expression in the endothelial cells of the BBB appears to decrease significantly with normal aging and in AD, and this may also be the case in aging rodents.…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…Recombinant RAP and LRP1 antibody also reduce Ab efflux from mouse brain (Shibata et al 2000). In humans, a decreased LRP1 expression in the brain capillaries in AD brains may contribute to impaired Ab clearance (Deane et al 2004), whereas circulating soluble LRP1 (sLRP) might provide peripheral "sink" activity for Ab clearance through the BBB ).…”

“…LRP1 binds Ab directly (Deane et al 2004) or indirectly via its ligands, which include a2-macroglobulin (Narita et al 1997), RAP (Kanekiyo and Bu 2009), and apoE (Bu 2009;Kim et al 2009a). ApoE is the best-characterized Ab chaperone.…”

Ischemic brain injury in cerebral amyloid angiopathy

“…Impaired A clearance may be caused by alterations in perivascular drainage pathways [22][23][24] and deficits in endothelial-mediated active transport of A into the blood. 25 Factors such as age-related arterial stiffening may contribute to the failure of perivascular drainage of A . 23 Pathologic examination of blood vessels in both sporadic and familial CAA shows degeneration of smooth muscle cells, vessel wall thickening, luminal narrowing, concentric splitting of the vessel wall, microaneurysm formation, perivascular microhemorrhages, and perivascular leakage of blood products.…”