Inhibition of amyloid-beta-induced cell death in human brain pericytes in vitro.
Amyloid-beta protein (A beta) deposition in the cerebral vascular walls is one of the key features of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). A beta(1-40) carrying the 'Dutch' mutation (HCHWA-D A beta(1-40)) induces pronounced degeneration of cultured human brain pericytes. In this study, we aimed to identify inhibitors of A beta-induced toxicity in human brain pericytes. The toxic effect of HCHWA-D A beta(1-40) on human brain pericytes was inhibited by co-incubation with catalase, but not with superoxide dismutase, glutathione or vitamin E analogue Trolox. Catalase interacts with A beta, both in cell cultures and in cell-free assays, and has a prominent effect on the amount and conformational state of A beta binding to the cell surface of human brain pericytes. This activity of catalase is likely based on its ability to bind and slowly degrade A beta and not by its usual capacity to convert hydrogen peroxide. Our data confirm that assembly of A beta at the cell surface of human brain pericytes is a crucial step in A beta-induced cellular degeneration of human brain pericytes. Inhibition of fibril formation at the cell surface could be an important factor in therapy aimed at reducing cerebral amyloid angiopathy.
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000686:Amyloidosis / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000166:cytology; D002374:Catalase / Q000378:metabolism / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D016253:Microscopy, Immunoelectron; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D020286:Pericytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D013482:Superoxide Dismutase / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002839:Chromans; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid