The Pluripotency Factor Nanog Protects against Neuronal Amyloid β-Induced Toxicity and Oxidative Stress through Insulin Sensitivity Restoration

Amyloid beta (A beta) is a peptide fragment of the amyloid precursor protein that triggers the progression of Alzheimer's Disease (AD). It is believed that A beta contributes to neurodegeneration in several ways, including mitochondria dysfunction, oxidative stress and brain insulin resistance. Therefore, protecting neurons from A beta-induced neurotoxicity is an effective strategy for attenuating AD pathogenesis. Recently, applications of stem cell-based therapies have demonstrated the ability to reduce the progression and outcome of neurodegenerative diseases. Particularly, Nanog is recognized as a stem cell-related pluripotency factor that enhances self-renewing capacities and helps reduce the senescent phenotypes of aged neuronal cells. However, whether the upregulation of Nanog can be an effective approach to alleviate A beta-induced neurotoxicity and senescence is not yet understood. In the present study, we transiently overexpressed Nanog-both in vitro and in vivo-and investigated the protective effects and underlying mechanisms against A beta. We found that overexpression of Nanog is responsible for attenuating A beta-triggered neuronal insulin resistance, which restores cell survival through reducing intracellular mitochondrial superoxide accumulation and cellular senescence. In addition, upregulation of Nanog expression appears to increase secretion of neurotrophic factors through activation of the Nrf2 antioxidant defense pathway. Furthermore, improvement of memory and learning were also observed in rat model of A beta neurotoxicity mediated by upregulation of Nanog in the brain. Taken together, our study suggests a potential role for Nanog in attenuating the neurotoxic effects of A beta, which in turn, suggests that strategies to enhance Nanog expression may be used as a novel intervention for reducing A beta neurotoxicity in the AD brain.