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.

Neurotoxic amyloid β peptide (Aβ) accumulates in the brains of individuals with Alzheimer disease (AD). The APOE4 allele is a major risk factor for sporadic AD and has been associated with increased brain parenchymal and vascular amyloid burden. How apoE isoforms influence Aβ accumulation in the brain has, however, remained unclear. Here, we have shown that apoE disrupts Aβ clearance across the mouse blood-brain barrier (BBB) in an isoform-specific manner (specifically, apoE4 had a greater disruptive effect than either apoE3 or apoE2). Aβ binding to apoE4 redirected the rapid clearance of free Aβ40/42 from the LDL receptor-related protein 1 (LRP1) to the VLDL receptor (VLDLR), which internalized apoE4 and Aβ-apoE4 complexes at the BBB more slowly than LRP1. In contrast, apoE2 and apoE3 as well as Aβ-apoE2 and Aβ-apoE3 complexes were cleared at the BBB via both VLDLR and LRP1 at a substantially faster rate than Aβ-apoE4 complexes. Astrocytesecreted lipo-apoE2, lipo-apoE3, and lipo-apoE4 as well as their complexes with Aβ were cleared at the BBB by mechanisms similar to those of their respective lipid-poor isoforms but at 2-to 3-fold slower rates. Thus, apoE isoforms differentially regulate Aβ clearance from the brain, and this might contribute to the effects of APOE genotype on the disease process in both individuals with AD and animal models of AD.

Low-density lipoprotein receptor-related protein-1 (LRP) on brain capillaries clears amyloid β-peptide (Aβ) from brain. Here, we show that soluble circulating LRP (sLRP) provides key endogenous peripheral 'sink' activity for Aβ in humans. Recombinant LRP cluster IV (LRP-IV) bound Aβ in plasma in mice and in Alzheimer's disease-affected humans with compromised sLRPmediated Aβ binding, and reduced Aβ-related pathology and dysfunction in a mouse model of Alzheimer mice, suggesting LRP-IV can effectively replace native sLRP and clear Aβ.LRP binds the Alzheimer's disease neurotoxin, Aβ, at the abluminal side of the blood-brain barrier (BBB), which initiates Aβ clearance from brain to blood via transcytosis across the BBB1 -4. In the liver, LRP mediates systemic clearance of Aβ5. β-secretase cleaves the Nterminus extracellular domain of LRP6, which releases soluble LRP (sLRP). sLRP normally circulates in plasma 7 .Two major binding domains of LRP, cluster II and cluster IV 8 , bind Aβ in vitro with high affinity: i.e., Aβ40 > Aβ42 (ref. 2). We hypothesized that LRP recombinant cluster IV (LRP-IV) retains its high-affinity binding for Aβ in vivo, and that this binding alters Aβ transport at the BBB, which is dominated by the cell-surface LRP1 -4 and the receptor for advanced glycation end-products (RAGE) 9 , resulting in Aβ efflux from the brain. We also hypothesized

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Objective To determine the role of Ptc-1 in mediating pulsatile flow-induced changes in VSMC growth and vascular remodeling. Approach and Results In vitro, HCASMC were exposed to “normal” or pathological “low” pulsatile flow conditions for 24 h utilizing a perfused transcapillary flow system. Low pulsatile flow increased VSMC proliferation when compared to normal flow conditions. Inhibition of Ptc-1 by cyclopamine attenuated low flow-induced increases in Notch expression while concomitantly decreasing HCASMC growth to that similar of normal flow conditions. In vivo, ligation injury-induced low flow increased vSMC growth and vascular remodeling while increasing Ptc-1/Notch expression. Perivascular delivery of Ptc-1 siRNA by pluronic gel inhibited the pathologic low flow-induced increases in Ptc-1/Notch expression and the subsequent increase in vascular remodeling. In addition, this pathologic low flow-induced remodeling and was returned to normal flow control levels following ptc-1 gene knockdown. Conclusions These results suggest that pathological low flow stimulates SMC growth in vitro and vascular remodeling in vivo via Ptc-1 regulation of Notch signaling.