Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells.
Inefficient clearance of A beta, caused by impaired blood-brain barrier crossing into the circulation, seems to be a major cause of A beta 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 beta receptors are involved in A beta internalization and in A beta-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 beta. Receptor-associated protein specifically inhibited A beta-mediated up-regulation of LRP-1, but not of LDLR, and receptor-associated protein also decreased A beta internalization and A beta-mediated cell death. We conclude that especially LRP-1 and, to a minor extent, LDLR are involved in A beta internalization by and A beta-mediated cell death of cerebral perivascular cells. Although perivascular cells may adapt their A beta internalization capacity to the levels of A beta present, saturated LRP-1/LDLR-mediated uptake of A beta results in degeneration of perivascular cells.
Department of Neurology and Alzheimer Center, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Micha M M
MM
Wilhelmus
Irene
I
Otte-Höller
Jos J J
JJ
van Triel
Robert
R
Veerhuis
Marion L C
ML
Maat-Schieman
Guojun
G
Bu
Robert M W
RM
de Waal
Marcel M
MM
Verbeek
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D017209:Apoptosis; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D018955:CD36 Antigens / Q000378:metabolism; D028243:Cerebral Amyloid Angiopathy, Familial / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000032:analysis / Q000378:metabolism*; D008297:Male; D020286:Pericytes / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D011973:Receptors, LDL / Q000032:analysis / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018955:CD36 Antigens; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011973:Receptors, LDL