Apolipoprotein E genotype regulates amyloid-beta cytotoxicity.
The epsilon4 allele of apolipoprotein E (ApoE) is a risk factor for Alzheimer's disease (AD), whereas the epsilon2 allele may be relatively protective. Both alleles are risk factors for cerebral amyloid angiopathy (CAA)-related hemorrhages. CAA is associated with degeneration of smooth muscle cells and pericytes. Previously, we described that synthetic amyloid-beta1-40 peptide (Abeta1-40) with the 22Glu--> Gln "Dutch" mutation caused pericyte death in vitro by a mechanism that involves Abeta fibril-like assembly at the cell surface. It is known that ApoE binds to Abeta and may modify its biological activities. In the present study, we evaluated the effect of ApoE on Abeta-mediated toxicity of cerebrovascular cells. We observed that cultured cells with an epsilon4/epsilon4 genotype were more vulnerable to Abeta than cultures with an epsilon3/epsilon3 or epsilon3/epsilon4 genotype. The one cell culture with the epsilon2/epsilon3 genotype was relatively resistant to Abeta compared with other cultures. Furthermore, we observed a dose-dependent protective effect of native ApoE against Abeta-mediated toxicity of cerebrovascular cells and, in addition, ApoE epsilon2/epsilon3 cells secreted more ApoE protein compared with cells with other ApoE genotypes, in particular, compared with epsilon4/epsilon4 cells. Thus, the disparity between ApoE genotype and Abeta-mediated toxicity might be related to differences in the cellular capacity to secrete ApoE. The present data suggest that one mechanism by which ApoE may alter the risk for AD is a genotype-dependent regulation of Abeta cytotoxicity, possibly via variations in its secretion levels, whereby extracellular ApoE may bind to Abeta and thereby modify Abeta-mediated cell death.
Wilhelmus
Micha M M
MM
Department of Neurology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands. m.wilhelmus@pathol.umcn.nl
Otte-Höller
Irene
I
Davis
Judianne
J
Van Nostrand
William E
WE
de Waal
Robert M W
RM
Verbeek
Marcel M
MM
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005838:Genotype; D006801:Humans; D008297:Male; D016253:Microscopy, Immunoelectron / Q000379:methods; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010446:Peptide Fragments / Q000633:toxicity*; D020286:Pericytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection / Q000379:methods
D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D017077:Culture Media, Conditioned; D010446:Peptide Fragments; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40)