Neuregulin1beta1 Antagonizes Apoptosis Via ErbB4-Dependent Activation of PI3-Kinase/Akt in APP/PS1 Transgenic Mice

Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid protein (A beta) and extensive neuronal cell death. Apoptosis plays a crucial role in loss of neurons in AD. Neuregulin1 (NRG1) has been found to protect neurons from oxygen glucose deprivation induced apoptosis and hypoxia ischemia induced apoptosis. However, the relationship between NRG1 and apoptosis related protein expression in AD and its mechanism remain uncertain. The present study explores the effects of NRG1 on A beta-induced apoptosis in AD. In this study, extracellular domain of NRG1beta1 (NRG1 beta 1-ECD) promoted the expression of p-ErbB4 receptor, p-Akt and increased the level of Bcl-2 both in APP/PS1 transgenic mice and in vitro. In primary culture of neurons, the level of Bcl-2 protein decreased significantly after A beta treatment. These changes were inhibited by pretreatment of neurons with NRG1 beta 1-ECD. A specific inhibitor of PI3-kinase/Akt pathway, wortmannin, significantly abrogated the effects of NRG1 beta 1-ECD on p-Akt and Bcl-2 levels. Furthermore, the expression of PI3-kinase/Akt by NRG1 beta 1-ECD was ErbB4-dependent. Our data demonstrated that NRG1 beta 1-ECD might serve as an obvious neuroprotection in AD, and the possible protective mechanism occurs most likely via ErbB4-dependent activation of PI3-kinase/Akt pathway.