Department of Biochemical Sciences, Sapienza University, Rome, Italy.
PLoS One. 2013 Sep 24;8(9):e72169. doi: 10.1371/journal.pone.0072169. eCollection 2013.
Amyloid beta peptide (Aβ) causes neurodegeneration by several mechanisms including oxidative stress, which is known to induce DNA damage with the consequent activation of poly (ADP-ribose) polymerase (PARP-1). To elucidate the role of PARP-1 in the neurodegenerative process, SH-SY5Y neuroblastoma cells were treated with Aβ25-35 fragment in the presence or absence of MC2050, a new PARP-1 inhibitor. Aβ25-35 induces an enhancement of PARP activity which is prevented by cell pre-treatment with MC2050. These data were confirmed by measuring PARP-1 activity in CHO cells transfected with amylod precursor protein and in vivo in brains specimens of TgCRND8 transgenic mice overproducing the amyloid peptide. Following Aβ25-35 exposure a significant increase in intracellular ROS was observed. These data were supported by the finding that Aβ25-35 induces DNA damage which in turn activates PARP-1. Challenge with Aβ25-35 is also able to activate NF-kB via PARP-1, as demonstrated by NF-kB impairment upon MC2050 treatment. Moreover, Aβ25-35 via PARP-1 induces a significant increase in the p53 protein level and a parallel decrease in the anti-apoptotic Bcl-2 protein. These overall data support the hypothesis of PARP-1 involvment in cellular responses induced by Aβ and hence a possible rationale for the implication of PARP-1 in neurodegeneration is discussed.
淀粉样β肽（Aβ）通过多种机制引起神经退行性变，包括氧化应激，已知氧化应激会导致 DNA 损伤，从而激活多聚（ADP-核糖）聚合酶 1（PARP-1）。为了阐明 PARP-1 在神经退行性过程中的作用，用 Aβ25-35 片段处理 SH-SY5Y 神经母细胞瘤细胞，同时存在或不存在新的 PARP-1 抑制剂 MC2050。Aβ25-35 诱导 PARP 活性增强，而 MC2050 预处理可防止这种增强。这些数据通过测量转染淀粉样前体蛋白的 CHO 细胞中的 PARP-1 活性以及在过度产生淀粉样肽的 TgCRND8 转基因小鼠的脑标本中体内证实。在 Aβ25-35 暴露后，观察到细胞内 ROS 显著增加。这些数据得到了以下发现的支持：Aβ25-35 诱导 DNA 损伤，进而激活 PARP-1。Aβ25-35 通过 PARP-1 也能够激活 NF-kB，因为 MC2050 处理可损害 NF-kB。此外，Aβ25-35 通过 PARP-1 诱导 p53 蛋白水平显著增加，并平行降低抗凋亡 Bcl-2 蛋白。这些总体数据支持 PARP-1 参与 Aβ 诱导的细胞反应的假说，因此讨论了 PARP-1 在神经退行性变中的可能作用。
