Heme oxygenase-1 protects against Alzheimer's amyloid-β(1-42)-induced toxicity via carbon monoxide production.
Heme oxygenase-1 protects against Alzheimer's amyloid-β(1-42)-induced toxicity via carbon monoxide production.
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DOI：
10.1038/cddis.2014.529
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发表时间：
2014-12-11
影响因子：
9
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血红素加氧酶-1（HO-1）是一种在阿尔茨海默病中上调的诱导酶，可将血红素分解代谢为胆绿素、Fe 2+和一氧化碳（CO）。CO可以通过抑制Kv2.1通道来保护神经元免受氧化应激诱导的凋亡，Kv2.1通道介导细胞K+流出作为凋亡级联反应的早期步骤。由于AD中与淀粉样β肽（Aβ）毒性相关的神经元损伤是由细胞凋亡引起的，因此我们采用空载体稳定转染或表达细胞朊蛋白PrPc的SH-SY 5 Y细胞和大鼠原代海马神经元，研究HO-1和CO对Aβ1-42毒性的保护作用。Aβ1-42（含原纤维）导致细胞活力浓度依赖性降低，至少部分归因于诱导细胞凋亡，PrPc表达细胞对Aβ1-42毒性的敏感性更高。药物诱导或HO-1基因过表达可显著改善Aβ1-42的作用。CO供体CORM-2以浓度依赖性方式保护细胞免受Aβ1-42毒性。电生理学研究显示，A β1-42处理前后外向电流无差异，表明这些细胞中K+通道活性不受影响。相反，Aβ毒性被L-型Ca 2+通道阻滞剂硝苯地平和CaMKKII抑制剂STO-609降低。Aβ还激活下游激酶，AMP依赖性蛋白激酶（AMPK）。CO阻止了AMPK的这种激活。我们的研究结果表明，HO-1通过产生CO来保护Aβ免受毒性。保护作用不是通过抑制阿尔茨海默病相关的K+流出，而是通过抑制AMPK激活，AMPK激活最近被认为与Aβ的毒性作用有关。这些数据提供了CO的一种新的有益作用，这增加了其作为治疗剂的增长潜力。
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.