Influence of LRP-1 and apolipoprotein E on amyloid-β uptake and toxicity to cerebrovascular smooth muscle cells.
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.
Dementia Research Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Frenchay Hospital, Bristol, UK.
Wan Adriyani W
WA
Ruzali
Patrick G
PG
Kehoe
Seth
S
Love
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D001057:Apolipoproteins E / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000502:physiology*; D005333:Fetus; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D018832:Molecular Chaperones / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity*; D020033:Protein Isoforms / Q000378:metabolism
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D018832:Molecular Chaperones; D010446:Peptide Fragments; D020033:Protein Isoforms; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)