Prostate apoptosis response-4 enhances secretion of amyloid beta peptide 1-42 in human neuroblastoma IMR-32 cells by a caspase-dependent pathway

Prostate apoptosis response-4 (Par-4) is a leucine zipper protein that prom otes neuronal cell death in Alzheimer's disease (AD). Neuronal degeneration in AD may result from extracellular accumulation of amyloid beta peptide ( A beta) 1-42. To examine the effect of Par-4 on A beta secretion and to rec oncile amyloid/apoptosis hypotheses of AD, we generated IMR-32 cell lines t hat overexpress Par-4 and/or its leucine zipper domain. Overexpression of P ar-4 did not significantly affect levels of the endogenously expressed beta amyloid precursor protein but drastically increased the A beta (1-42)/A be ta (total) ratio in the conditioned media about 6-8 h after trophic factor withdrawal. Time course analysis of caspase activation reveals that Par-4 o verexpression exacerbated caspase activation, which is detectable within 2 h after trophic factor withdrawal. Furthermore, inhibition of caspase activ ity by the broad spectrum caspase inhibitor BD-fmk significantly attenuated the Par-4-induced increase in A beta 1-42 production. In addition, the eff ects of Par-4 on secretion of A beta 1-42 were consistently blocked by co-e xpression of the leucine zipper domain, indicating that the effect of Par-4 on A beta secretion may require its interaction with other protein(s). The se results suggest that Par-4 increases secretion of A beta 1-42 largely th rough a caspase-dependent pathway after apoptotic cascades are initiated.