Jul 13, 2017

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

Molecular Neurobiology
Przemysław L WencelRobert P Strosznajder


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 (Aβ) 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 (βAPP) cleaving enzymes under Aβ42 oligomers (AβO) toxicity in pheochromocytoma cells (PC12) in culture. Moreover, the effect of endogenously liberated Aβ peptides in PC12 cells stably transfected with human gene for APP wild-type (APPwt) was analyzed. Our results demonstrated that AβO enhanced transcription of presenilins (Psen1 and Psen2), the crucial subunits of γ-secretase. Aβ peptides in APPwt cells activated expression of β-secretase (Bace1), Psen1, Psen2, and Parp1. The inhibitor of PARP1, PJ-34 in the presence of AβO upregulated transcription of α-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 AβOs toxicity. Our data indicated that Aβ ...Continue Reading

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Mentioned in this Paper

Metabolic Process, Cellular
Transcriptional Regulation
PSEN2 protein, human
SIRT4 gene

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