Prostate Apoptosis Response-4 Enhances Secretion of Amyloid β Peptide 1-42 in Human Neuroblastoma IMR-32 Cells by a Caspase-dependent Pathway

Abstract

Prostate apoptosis response-4 (Par-4) is a leucine zipper protein that promotes neuronal cell death in Alzheimer's disease (AD). Neuronal degeneration in AD may result from extracellular accumulation of amyloid β peptide (Aβ) 1-42. To examine the effect of Par-4 on Aβ secretion and to reconcile amyloid/apoptosis hypotheses of AD, we generated IMR-32 cell lines that overexpress Par-4 and/or its leucine zipper domain. Overexpression of Par-4 did not significantly affect levels of the endogenously expressed β amyloid precursor protein but drastically increased the Aβ 1-42/Aβtotal ratio in the conditioned media about 6-8 h after trophic factor withdrawal. Time course analysis of caspase activation reveals that Par-4 overexpression exacerbated caspase activation, which is detectable within 2 h after trophic factor withdrawal. Furthermore, inhibition of caspase activity by the broad spectrum caspase inhibitor BD-fmk significantly attenuated the Par-4-induced increase in Aβ 1-42 production. In addition, the effects of Par-4 on secretion of Aβ 1-42 were consistently blocked by co-expression of the leucine zipper domain, indicating that the effect of Par-4 on Aβ secretion may require its interaction with other protein(s). These results suggest that Par-4 increases secretion of Aβ 1-42 largely through a caspase-dependent pathway after apoptotic cascades are initiated.