Inhibition of Poly(ADP-ribose) Polymerase-1 Enhances Gene Expression of Selected Sirtuins and APP Cleaving Enzymes in Amyloid Beta Cytotoxicity

Poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs) are involved in the regulation of cell metabolism, transcription, and DNA repair. Alterations of these enzymes may play a crucial role in Alzheimer's disease (AD). Our previous results indicated that amyloid beta (A beta) peptides and inflammation led to activation of PARP1 and cell death. This study focused on a role of PARP1 in the regulation of gene expression for SIRTs and beta-amyloid precursor protein (beta APP) cleaving enzymes under A beta 42 oligomers (A beta O) toxicity in pheochromocytoma cells (PC12) in culture. Moreover, the effect of endogenously liberated A beta peptides in PC12 cells stably transfected with human gene for APP wild-type (APPwt) was analyzed. Our results demonstrated that A beta O enhanced transcription of presenilins (Psen1 and Psen2), the crucial subunits of gamma-secretase. A beta peptides in APPwt cells activated expression of beta-secretase (Bace1), Psen1, Psen2, and Parp1. The inhibitor of PARP1, PJ-34 in the presence of A beta O upregulated transcription of alpha-secretase (Adam10), Psen1, and Psen2, but also Bace1. Concomitantly, PJ-34 enhanced mRNA level of nuclear Sirt1, Sirt6, mitochondrial Sirt4, and Parp3 in PC12 cells subjected to A beta Os toxicity. Our data indicated that A beta peptides through modulation of APP secretases may lead to a vicious metabolic circle, which could be responsible for maintaining A beta at high level. PARP1 inhibition, besides activation of nuclear SIRTs and mitochondrial Sirt4 expression, enhanced transcription of enzyme(s) involved in beta APP metabolism, and this effect should be considered in its application against A beta peptide toxicity.