Protective effects of [Gly14]-Humanin on β-amyloid-induced PC12 cell death by preventing mitochondrial dysfunction

Mitochondrial dysfunction is a hallmark of beta-amyloid (A beta)-induced neuronal toxicity in Alzheimer's disease (AD), and is considered as an early event in AD pathology. Humanin (HN) and its derivative, [Gly14]-Humanin (HNG), are known for their ability to suppress neuronal death induced by AD-related insults in vitro and in vivo. In the present study, we investigated the neuroprotective effects of HNG on A beta(25-35)-induced toxicity and its potential mechanisms in PC12 cells. Exposure of PC12 cells to 25 mu M A beta(25-35) caused significant viability loss and cell apoptosis. In addition, decreased mitochondrial membrane potential and increased cytochrome c releases from mitochondria were also observed after A beta(25-35) exposure. All these effects induced by A beta(25-35) were markedly reversed by HNG. Pretreatment with 100 nM HNG 6 h prior to A beta(25-35) exposure significantly elevated cell viability, reduced A beta(25-35)-induced cell apoptosis, stabilized mitochondrial membrane potential, and blocked cytochrome c release from mitochondria. Furthermore, HNG also ameliorated the A beta(25-35)-induced Bcl-2/Bax ratio reduction and decreased caspase-3 activity in PC12 cells. These results demonstrate that HNG could attenuate A beta(25-35)-induced PC1 2 cell injury and apoptosis by preventing mitochondrial dysfunction. Furthermore, these data suggest that mitochondria are involved in the protective effect of HNG against A beta(25-35), (C) 2009 Elsevier Ltd, All rights reserved.