Inhibition of Bax protects neuronal cells from oligomeric Aβ neurotoxicity

Although oligomeric beta-amyloid (A beta) has been suggested to have an important role in Alzheimer disease (AD), the mechanism(s) of how A beta induces neuronal cell death has not been fully identified. The balance of pro- and anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2 and Bcl-w versus Bad, Bim and Bax) has been known to have a role in neuronal cell death and, importantly, expression levels of these proteins are reportedly altered in the vulnerable neurons in AD. However, the roles of apoptotic proteins in oligomeric A beta-induced cell death remain unclear in vivo or in more physiologically relevant models. In addition, no study to date has examined whether Bax is required for the toxicity of oligomeric A beta. Here, we found that treatment with oligomeric A beta increased Bim levels but decreased Bcl-2 levels, leading to the activation of Bax and neuronal cell death in hippocampal slice culture and in vivo. Furthermore, the inhibition of Bax activity either by Bax-inhibiting peptide or bax gene knockout significantly prevented oligomeric A beta-induced neuronal cell death. These findings are first to demonstrate that Bax has an essential role in oligomeric A beta-induced neuronal cell death, and that the targeting of Bax may be a therapeutic approach for AD. Cell Death and Disease (2012) 3, e309; doi:10.1038/cddis.2012.43; published online 17 May 2012