Abstract
Although oligomeric β-amyloid (Aβ) has been suggested to have an important role in Alzheimer disease (AD), the mechanism(s) of how Aβ 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 Aβ-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 Aβ. Here, we found that treatment with oligomeric Aβ 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 Aβ-induced neuronal cell death. These findings are first to demonstrate that Bax has an essential role in oligomeric Aβ-induced neuronal cell death, and that the targeting of Bax may be a therapeutic approach for AD.
Highlights
Previous studies found that expression levels of Bcl-2 family proteins, such as Bax, Bak, Bad, Bcl-2, Bim, Bcl-w and Bcl-x are altered in the vulnerable neurons in Alzheimer disease (AD).[4]
As the N-terminus exposure is an early step of Bax activation that occurs in the cytosol, we analyzed this conformational change of Bax with a monoclonal antibody (6A7) recognizing the epitope in the N-terminus of Bax.[9]
We demonstrate that oligomeric Ab altered the expression levels of Bcl-2, Bim and Bax, and that the genetic or pharmacological ablation of Bax activity suppresses oligomeric Ab-mediated neurotoxicity in both ex vivo and in vivo
Summary
Previous studies found that expression levels of Bcl-2 family proteins, such as Bax, Bak, Bad, Bcl-2, Bim, Bcl-w and Bcl-x are altered in the vulnerable neurons in AD.[4]. Overexpression of anti-apoptotic proteins, Bcl-w, or genetic ablation of a proapoptotic effecter, Bim, significantly protected neurons against fibrillar Ab-induced apoptosis in neuroblastoma cell lines and primary neuron culture.[13,14] Giovanni et al.[15] reported that fibrillar Ab-induced cell death is dependent on Bax in primary neuron culture These results have never been confirmed in vivo or in a more physiologically relevant model, and all the previous studies examined the toxicity of fibrillar Ab, not oligomeric Ab. to advance our understanding of the involvement of Bcl-2 protein family as the major mechanism of oligomeric Ab-induced neuronal cell death, in this study, we examined the effect of oligomeric Ab on the regulation of Bcl-2/Bim/Bax and its functional importance in neuronal cell death in the organotypic hippocampal culture and mouse model for Ab toxicity
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