Heme oxygenase-1 protects against Alzheimer’s amyloid-β1-42-induced toxicity via carbon monoxide production

Heme oxygenase-1 (HO-1), an inducible enzyme up-regulated in Alzheimer’s disease, catabolises heme to biliverdin, Fe 2+ 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 (A β ) toxicity in AD, we investigated the protective effects of HO-1 and CO against A β 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 β 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 β 1-42 toxicity. Pharmacological induction or genetic over-expression of HO-1 significantly ameliorated the effects of A β 1-42 . The CO-donor CORM-2 protected cells against A β 1-42 toxicity in a concentration-dependent manner. Electrophysiological studies revealed no differences in the outward current pre- and post-A β 1-42 treatment suggesting that K + channel activity is unaffected in these cells. Instead, A β toxicity was reduced by the L-type Ca 2+ channel blocker nifedipine, and by the CaMKKII inhibitor, STO-609. A β 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 β 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 β . These data provide a novel, beneficial effect of CO which adds to its growing potential as a therapeutic agent.