Hypoxic remodelling of Ca2+ mobilization in type I cortical astrocytes: involvement of ROS and pro-amyloidogenic APP processing.
Chronic hypoxia (CH) alters Ca2+ homeostasis in various cells and may contribute to disturbed Ca2+ homeostasis of Alzheimer's disease. Here, we have employed microfluorimetric measurements of [Ca2+]i to investigate the mechanism underlying augmentation of Ca2+ signalling by chronic hypoxia in type I cortical astrocytes. Application of bradykinin evoked significantly larger rises of [Ca2+]i in hypoxic cells as compared with control cells. This augmentation was prevented fully by either melatonin (150 micro m) or ascorbic acid (200 micro m), indicating the involvement of reactive oxygen species. Given the association between hypoxia and increased production of amyloid beta peptides (AbetaPs) of Alzheimer's disease, we performed immunofluorescence studies to show that hypoxia caused a marked and consistent increased staining for AbetaPs and presenilin-1 (PS-1). Western blot experiments also confirmed that hypoxia increased PS-1 protein levels. Hypoxic increases of AbetaP production was prevented with inhibitors of either gamma- or beta-secretase. These inhibitors also partially prevented the augmentation of Ca2+ signalling in astrocytes. Our results indicate that chronic hypoxia enhances agonist-evoked rises of [Ca2+]i in cortical astrocytes, and that this can be prevented by antioxidants and appears to be associated with increased AbetaP formation.
Smith
Ian F
IF
Institute for Cardiovascular Research School of Biomedical Sciences, University of Leeds, Leeds, UK.
Boyle
John P
JP
Green
Kim N
KN
Pearson
Hugh A
HA
Peers
Chris
C
D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001205:Ascorbic Acid / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D010450:Endopeptidases / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D008550:Melatonin / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D008959:Models, Neurological; D010100:Oxygen / Q000378:metabolism*; D053764:Presenilin-1; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016166:Free Radical Scavengers; D008565:Membrane Proteins; D053764:Presenilin-1; D017382:Reactive Oxygen Species; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D008550:Melatonin; D001205:Ascorbic Acid; D010100:Oxygen; D001920:Bradykinin; D002118:Calcium