Published online before print November 30, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070050

Accepted for publication August 28, 2007.

Article

Lipoprotein Receptor-Related Protein-1 Mediates Amyloid--Mediated Cell Death of Cerebrovascular Cells

Micha M.M. Wilhelmus^*, Irene Otte-Höller, Jos J.J. van Triel, Robert Veerhuis, Marion L.C. Maat-Schieman, Guojun Bu^¶, Robert M.W. de Waal, and Marcel M. Verbeek^*@

From the Departments of Neurology and Alzheimer Centre,* and Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; the Department of Pathology, Psychiatry, Clinical Chemistry, and Alzheimer Center, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands; the Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands; and the Department of Pediatrics,^¶ Washington University School of Medicine, St. Louis, Missouri

^@ To whom correspondence should be addressed. E-mail: m.verbeek{at}cukz.umcn.nl.

	Abstract

Inefficient clearance of A, caused by impaired blood-brain barrier crossing into the circulation, seems to be a major cause of A 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 A receptors are involved in A internalization and in A-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 A. Receptor-associated protein specifically inhibited A-mediated up-regulation of LRP-1, but not of LDLR, and receptor-associated protein also decreased A internalization and A-mediated cell death. We conclude that especially LRP-1 and, to a minor extent, LDLR are involved in A internalization by and A-mediated cell death of cerebral perivascular cells. Although perivascular cells may adapt their A internalization capacity to the levels of A present, saturated LRP-1/LDLR-mediated uptake of A results in degeneration of perivascular cells.