Atypical antipsychotics attenuate neurotoxicity of β-amyloid(25-35) by modulating Bax and Bcl-XL/S expression and localization

We have demonstrated recently that atypical antipsychotics possess neuroprotective actions in H2O2-mediated and serum-withdrawal models of cell death. In the present study, we compared the ability of atypical and typical antipsychotics to protect against an insult mediated by Abeta(25-35), an apoptogenic fragment of the Alzheimer's disease-related beta-amyloid (Abeta) peptide. Treatment of PC12 cell cultures with Abeta(25-35) did not significantly alter total cellular expression levels of Bax, a proapoptotic Bcl-2 family member, or levels of Bcl-X-L, an antiapoptotic analogue. Treatment with Abeta(25-35), however, did result in mitochondrial translocation of Bax, which effectively increased the mitochondrial ratio of Bax to Bcl-XL. This relative increase in proapoptotic molecules was reduced by pretreatment with atypical (quetiapine and olanzapine) and typical (haloperidol) antipsychotics. We also observed a selective increase in proapoptotic Bcl-X-S immunodetection in haloperidol-treated cells, which was evident particularly in the mitochondrial compartment. This increase in proapoptotic molecules may account for the lower neuroprotective potential of haloperidol, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) reduction assay. The disparate neuroprotective effects of atypical and typical anti psychotics/neuroleptics may be due to their respective abilities to regulate pro- and antiapoptotic protein translocation and expression. (C) 2003 Wiley-Liss, Inc.