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

Mitochondrial dysfunction is a hallmark of beta-amyloid (Aβ)-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 Aβ25–35-induced toxicity and its potential mechanisms in PC12 cells. Exposure of PC12 cells to 25 μM Aβ25–35 caused significant viability loss and cell apoptosis. In addition, decreased mitochondrial membrane potential and increased cytochrome c releases from mitochondria were also observed after Aβ25–35 exposure. All these effects induced by Aβ25–35 were markedly reversed by HNG. Pretreatment with 100 nM HNG 6 h prior to Aβ25–35 exposure significantly elevated cell viability, reduced Aβ25–35-induced cell apoptosis, stabilized mitochondrial membrane potential, and blocked cytochrome c release from mitochondria. Furthermore, HNG also ameliorated the Aβ25–35-induced Bcl-2/Bax ratio reduction and decreased caspase-3 activity in PC12 cells. These results demonstrate that HNG could attenuate Aβ25–35-induced PC12 cell injury and apoptosis by preventing mitochondrial dysfunction. Furthermore, these data suggest that mitochondria are involved in the protective effect of HNG against Aβ25–35.