TY - JOUR
T1 - Lipoprotein receptor-related protein-1 mediates amyloid-β-mediated cell death of cerebrovascular cells
AU - Wilhelmus, Micha M.M.
AU - Otte-Höller, Irene
AU - Van Triel, Jos J.J.
AU - Veerhuis, Robert
AU - Maat-Schieman, Marion L.C.
AU - Bu, Guojun
AU - De Waal, Robert M.W.
AU - Verbeek, Marcel M.
N1 - Funding Information:
Supported by the Internationale Stichting Alzheimer Onderzoek (grants 01506 and 03517 ), Zon-MW Innovational Research (grant 917.46.331 , Vidi program), the Hersenstichting Nederl and (grants 11F03(2)11 and 14F06.18 ), and the National Institutes of Health (grant AG027924 to G.B. ).
PY - 2007/12
Y1 - 2007/12
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2007.070050
DO - 10.2353/ajpath.2007.070050
M3 - Article
C2 - 18055545
AN - SCOPUS:38349026548
SN - 0002-9440
VL - 171
SP - 1989
EP - 1999
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -