Influence of LRP-1 and Apolipoprotein E on Amyloid-β Uptake and Toxicity to Cerebrovascular Smooth Muscle Cells

Abstract

Vascular deposition of amyloid-β (Aβ) leads to the death of cerebrovascular smooth muscle cells (CVSMCs) in cerebral amyloid angiopathy (CAA). Apolipoprotein E (APOE) genotype influences the severity of CAA and development of vasculopathic complications. We have studied the relationship between uptake of Aβ into human CVSMCs and cell death, and the influence of ApoE isoforms on this process. We found that both Aβ₄₂ and Aβ₄₀ were taken up by human CVSMCs, and that this uptake—particularly that of Aβ₄₂—caused disruption to smooth muscle actin and cell death. Uptake of Aβ₄₂ was partially blocked by the addition of receptor-associated protein (RAP), implicating low-density lipoprotein receptor-related protein-1 (LRP-1) as the cell surface receptor. RAP significantly reduced the death of CVSMCs exposed to Aβ₄₂. In further experiments, CVSMCs were exposed to Aβ₄₂ in the presence of the different isoforms of exogenous ApoE and high-density lipoprotein (HDL). All three isoforms of ApoE in the presence of HDL (HDL-ApoE) reduced the uptake of fluorescein-tagged Aβ₄₂ but only HDL-ApoE3 significantly decreased cell death. We conclude that HDL-ApoE3, acting as an Aβ chaperone molecule, significantly reduces the death of CVSMCs that result from LRP-1-mediated uptake of Aβ. This may contribute to the differential effects of APOE genotype on severity of CAA and the risk of rupture of Aβ-laden blood vessels.