Amyloid-beta-induced degeneration of human brain pericytes is dependent on the apolipoprotein E genotype.
Amyloid-beta (A beta) deposition in cerebral vessels (cerebral amyloid angiopathy, CAA) is accompanied by degeneration of vascular cells, including pericytes and smooth muscle cells. Previous studies indicated that specific A beta protein isoforms are toxic for cultured human brain pericytes and smooth muscle cells. In particular, A beta 1-40 carrying the E22Q mutation, as in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), is toxic. We investigated the effects of the A beta-binding protein apolipoprotein E (ApoE) on the toxicity of A beta for cultured human brain pericytes. We compared the toxicity of HCHWA-D A beta 1-40 for pericyte cultures with different ApoE genotypes, studied the accumulation of A beta and ApoE in these different cell cultures, and investigated the effects of exogenous ApoE. Pericyte cultures with an ApoE epsilon 2/epsilon 3 genotype were more resistant to HCHWA-D A beta 1-40 treatment than cultures with a epsilon 3/epsilon 3 or epsilon 3/epsilon 4 genotype. Cell death was highest in cultures homozygous for ApoE epsilon 4. The extent to which both A beta ApoE accumulated at the cell surface was parallel to the degree of toxicity. The addition of purified ApoE resulted in a decrease in cell death. These data suggest that ApoE4 may direct A beta more efficiently than other ApoE isoforms into a pathological interaction with the HBP cell surface. The results of this study are in line with the observations that inheritance of the ApoE epsilon 4 allele increases the risk of developing Alzheimer's disease, and that the ApoE epsilon 2 allele has a relatively protective effect.
Verbeek
M M
MM
Department of Pathology, University Hospital Nijmegen, The Netherlands. m.verbeek@CKSLKN.AZN.NL
Van Nostrand
W E
WE
Otte-Höller
I
I
Wesseling
P
P
De Waal
R M
RM
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000633:toxicity*; D000686:Amyloidosis / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000235:genetics; D002560:Cerebrovascular Circulation; D015161:Dementia, Multi-Infarct / Q000235:genetics / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000235:genetics / Q000633:toxicity*; D020286:Pericytes / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D017354:Point Mutation; D012016:Reference Values
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)