Laboratory of Preclinical Research and Environmental Agents, Department of Neurosurgery, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106, Warsaw, Poland.
LSU Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA, 70112, USA.
Mol Neurobiol. 2018 Jun;55(6):4612-4623. doi: 10.1007/s12035-017-0646-8. Epub 2017 Jul 12.
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 peptides through modulation of APP secretases may lead to a vicious metabolic circle, which could be responsible for maintaining Aβ at high level. PARP1 inhibition, besides activation of nuclear SIRTs and mitochondrial Sirt4 expression, enhanced transcription of enzyme(s) involved in βAPP metabolism, and this effect should be considered in its application against Aβ peptide toxicity.
聚（ADP-核糖）聚合酶（PARPs）和沉默调节蛋白（SIRTs）参与细胞代谢、转录和 DNA 修复的调节。这些酶的改变可能在阿尔茨海默病（AD）中发挥关键作用。我们之前的研究结果表明，淀粉样β（Aβ）肽和炎症导致 PARP1 的激活和细胞死亡。本研究集中研究了 PARP1 在 Aβ42 寡聚体（AβO）毒性下调节 SIRTs 和β-淀粉样前体蛋白（βAPP）裂解酶基因表达的作用，该毒性在培养的嗜铬细胞瘤细胞（PC12）中。此外，还分析了在稳定转染人野生型 APP 基因的 PC12 细胞中内源性释放的 Aβ 肽的作用。我们的研究结果表明，AβO 增强了早老素（Psen1 和 Psen2）的转录，早老素是 γ-分泌酶的关键亚基。APPwt 细胞中的 Aβ 肽激活了β-分泌酶（Bace1）、Psen1、Psen2 和 Parp1 的表达。在 AβO 存在的情况下，PARP1 的抑制剂 PJ-34 上调了 α-分泌酶（Adam10）、Psen1 和 Psen2 的转录，但也上调了 Bace1 的转录。同时，PJ-34 增强了 PC12 细胞中 AβO 毒性的核 Sirt1、Sirt6、线粒体 Sirt4 和 Parp3 的 mRNA 水平。我们的数据表明，Aβ 肽通过调节 APP 分泌酶可能导致一个恶性代谢循环，这可能是导致 Aβ 处于高水平的原因。PARP1 抑制除了激活核 SIRTs 和线粒体 Sirt4 的表达外，还增强了参与βAPP 代谢的酶的转录，在应用其对抗 Aβ 肽毒性时应考虑这种作用。
