Lipoprotein receptor-related protein-1 mediates amyloid-β-mediated cell death of cerebrovascular cells

Inefficient clearance of Aβ, caused by impaired blood-brain barrier crossing into the circulation, seems to be a major cause of Aβ accumulation in the brain of late-onset Alzheimer's disease patients and hereditary cerebral hemorrhage with amyloidosis Dutch type. We observed association of receptor for advanced glycation end products, CD36, and low-density lipoprotein receptor (LDLR) with cerebral amyloid angiopathy in both Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis Dutch type brains and increased low-density lipoprotein receptor-related protein-1 (LRP-1) expression by perivascular cells in cerebral amyloid angiopathy. We investigated if these Aβ receptors are involved in Aβ internalization and in Aβ-mediated cell death of human cerebrovascular cells and astrocytes. Expression of both the LRP-1 and LDLR by human brain pericytes and leptomeningeal smooth muscle cells, but not by astrocytes, increased on incubation with Aβ. Receptor-associated protein specifically inhibited Aβ-mediated up-regulation of LRP-1, but not of LDLR, and receptor-associated protein also decreased Aβ internalization and Aβ-mediated cell death. We conclude that especially LRP-1 and, to a minor extent, LDLR are involved in Aβ internalization by and Aβ-mediated cell death of cerebral perivascular cells. Although perivascular cells may adapt their Aβ internalization capacity to the levels of Aβ present, saturated LRP-1/LDLR-mediated uptake of Aβ results in degeneration of perivascular cells.