Heme oxygenase-1 protects against Alzheimer's amyloid-?(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 ? peptide (A?) toxicity in AD, we investigated the protective effects of HO-1 and CO against A?(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. A?(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 A?(1-42) toxicity. Pharmacological induction or genetic over-expression of HO-1 significantly ameliorated the effects of A?(1-42). The CO-donor CORM-2 protected cells against A?(1-42) toxicity in a concentration-dependent manner. Electrophysiological studies revealed no differences in the outward current pre- and post-A?(1-42) treatment suggesting that K+ channel activity is unaffected in these cells. Instead, A? toxicity was reduced by the L-type Ca2+ channel blocker nifedipine, and by the CaMKKII inhibitor, STO-609. A? also activated the downstream kinase, AMP-dependent protein kinase (AMPK). CO prevented this activation of AMPK. Our findings indicate that HO-1 protects against A? 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 A?. These data provide a novel, beneficial effect of CO which adds to its growing potential as a therapeutic agent.

SUBMITTER: Hettiarachchi N 

PROVIDER: S-EPMC4454163 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature