Hypoxia suppresses astrocyte glutamate transport independently of amyloid formation.
Sustained hypoxia alters the expression of numerous proteins and predisposes individuals to Alzheimer's disease (AD). We have previously shown that hypoxia in vitro alters Ca2+ homeostasis in astrocytes and promotes increased production of amyloid beta peptides (Abeta) of AD. Indeed, alteration of Ca2+ homeostasis requires amyloid formation. Here, we show that electrogenic glutamate uptake by astrocytes is suppressed by hypoxia (1% O2, 24h) in a manner that is independent of amyloid beta peptide formation. Thus, hypoxic suppression of glutamate uptake and expression levels of glutamate transporter proteins EAAT1 and EAAT2 were not mimicked by exogenous application of amyloid beta peptide, or by prevention of endogenous amyloid peptide formation (using inhibitors of either beta or gamma secretase). Thus, dysfunction in glutamate homeostasis in hypoxic conditions is independent of Abeta production, but will likely contribute to neuronal damage and death associated with AD following hypoxic events.
Boycott
Hannah E
HE
School of Medicine, University of Leeds, Worsley Building, Leeds LS2 9JT, UK.
Dallas
Mark
M
Boyle
John P
JP
Pearson
Hugh A
HA
Peers
Chris
C
D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D005071:Evoked Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D000860:Hypoxia / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar
D000682:Amyloid; D016229:Amyloid beta-Peptides; D018698:Glutamic Acid