Heme oxygenase-1 protects against Alzheimer’s amyloid-β1-42-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 Aβ1-42 toxicity in SH-SY5Y cells, employing cells stably transfected with empty vector or expressing the cellular prion protein, PrPc, and rat primary hippocampal neurons. Aβ1-42 (containing protofibrils) caused a concentration-dependent decrease in cell viability, attributable at least in part to induction of apoptosis, with the PrPc-expressing cells showing greater susceptibility to Aβ1-42 toxicity. Pharmacological induction or genetic over-expression of HO-1 significantly ameliorated the effects of Aβ1-42. The CO-donor CORM-2 protected cells against Aβ1-42 toxicity in a concentration-dependent manner. Electrophysiological studies revealed no differences in the outward current pre- and post-Aβ1-42 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.

Prenylated quinolinecarboxylic acid derivative prevents neuronal cell death through inhibition of MKK4

“…Human neuroblastoma SH-SY5Y cells (passage numbers 4-10, CRL-2266: American Type Culture Collection, Manassas, VA) were cultivated in growth medium consisting of a 1:1 mixture of MEM/Ham's F-12 supplemented with 10% (v/v) heat-inactivated fetal bovine serum (FBS, Sigma-Aldrich) in a humidified atmosphere of 5% CO2 and 95% air at 37°C. SH-SY5Y cells are widely used as a model in studies involving neuronal injury or death, as well as neurodegenerative diseases [27]. We confirmed that MPP + activates caspase-3 and JNK signaling in a dose-dependent manner in undifferentiated, intact SH-SY5Y cells.…”

“…Aβ1-42 was dissolved in growth medium without FBS to make up the 100 µM stock solution and kept at -80°C. When needed for experiments, an aliquot of Aβ1-42 solution was maintained at 37°C for 48 h to make aggregates prior to treating the cells [27]. For the assessment of cell death, SH-SY5Y cells were treated with or without MPP + at 3 mM for 24 h Aβ1-42 at 1 or 10 µMfor 48 h in the absence or presence of various concentrations of PQA-11 or SP600125 at 1 µM.…”

Modulation of antigen processing by haem‐oxygenase 1. Implications on inflammation and tolerance

“…Hence, the HO‐1–CO system can reduce inflammation in vivo by, for instance, promoting the secretion of IL‐10 . CO‐mediated protection has been observed in some inflammatory pathologies, such as acute pancreatitis, haemorragic shock, Alzheimer's amyloid‐β1‐42‐induced toxicity, ischaemia/reperfusion, autoimmunity and graft rejection . Because these pathologies are mainly mediated by innate or adaptive immune responses, it remains unknown whether CO can ameliorate disease progression by blocking the same or different inflammatory pathways in either innate or adaptive immune cells.…”

Role of Gasotransmitters in Oxidative Stresses, Neuroinflammation, and Neuronal Repair

“…One current study shows that, by selectively inhibiting of K v2.1 channel and promoting oxidant induced apoptosis, CO can work as a neuroprotective agent [170, 171]. …”