title: Heme oxygenase-1 protects against Alzheimer's amyloid-β(1-42)-induced toxicity via carbon monoxide production.
abstract: Heme oxygenase-1 (HO-1), an inducible enzyme up-regulated in Alzheimer's disease, catabolises heme to biliverdin, Fe2+ and carbon monoxide (CO). CO can protect neurones from oxidative stress-induced apoptosis by inhibiting Kv2.1 channels, which mediates cellular K+ efflux as an early step in the apoptotic cascade. Since apoptosis contributes to the neuronal loss associated with amyloid β peptide (Aβ) toxicity in AD, we investigated the protective effects of HO-1 and CO against Aβ(1-42) toxicity in SH-SY5Y cells, employing cells stably transfected with empty vector or expressing the cellular prion protein, PrP(c), and rat primary hippocampal neurons. Aβ(1-42) (containing protofibrils) caused a concentration-dependent decrease in cell viability, attributable at least in part to induction of apoptosis, with the PrP(c)-expressing cells showing greater susceptibility to Aβ(1-42) toxicity. Pharmacological induction or genetic over-expression of HO-1 significantly ameliorated the effects of Aβ(1-42). The CO-donor CORM-2 protected cells against Aβ(1-42) toxicity in a concentration-dependent manner. Electrophysiological studies revealed no differences in the outward current pre- and post-Aβ(1-42) treatment suggesting that K+ channel activity is unaffected in these cells. Instead, Aβ toxicity was reduced by the L-type Ca2+ channel blocker nifedipine, and by the CaMKKII inhibitor, STO-609. Aβ also activated the downstream kinase, AMP-dependent protein kinase (AMPK). CO prevented this activation of AMPK. Our findings indicate that HO-1 protects against Aβ toxicity via production of CO. Protection does not arise from inhibition of apoptosis-associated K+ efflux, but rather by inhibition of AMPK activation, which has been recently implicated in the toxic effects of Aβ. These data provide a novel, beneficial effect of CO which adds to its growing potential as a therapeutic agent.
authors.affiliation: Division of Cardiovascular and Diabetes Research, LICAMM Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: N
authors.initials: N
authors.lastname: Hettiarachchi
authors.affiliation: Division of Cardiovascular and Diabetes Research, LICAMM Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: M
authors.initials: M
authors.lastname: Dallas
authors.affiliation: Division of Cardiovascular and Diabetes Research, LICAMM Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: M
authors.initials: M
authors.lastname: Al-Owais
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: H
authors.initials: H
authors.lastname: Griffiths
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: N
authors.initials: N
authors.lastname: Hooper
authors.affiliation: Division of Cardiovascular and Diabetes Research, LICAMM Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: J
authors.initials: J
authors.lastname: Scragg
authors.affiliation: Division of Cardiovascular and Diabetes Research, LICAMM Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: J
authors.initials: J
authors.lastname: Boyle
authors.affiliation: Division of Cardiovascular and Diabetes Research, LICAMM Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: C
authors.initials: C
authors.lastname: Peers
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D002248:Carbon Monoxide / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D002248:Carbon Monoxide; D051547:Heme Oxygenase-1