针对Ras活动阻止淀粉样Beta-Induced异常的神经元细胞周期重新和死亡之间的关系

Title:Targeting Ras Activity Prevented Amyloid Beta-Induced Aberrant Neuronal Cell Cycle Re-Entry and Death

Volume: 13 Issue: 11

Author(s): M. Murat Koseoglu, Bagdeser Akdogan Ozdilek, Umidahan Djakbarova, Ayse Gulusur

Affiliation:

关键词: 阿尔茨海默氏症、淀粉样βAβ42 / Aβ40比率、细胞周期、farnesylthiosalisylic酸、低聚物。

摘要: Several studies suggest that soluble Amyloid β (Aβ) oligomer-induced aberrant neuronal cell cycle re-entry is the initial trigger for a significant part of the neuronal degeneration and loss in Alzheimer's disease (AD). In this study, we investigated the role of Ras, which is a well-known protooncoprotein, in soluble Aβ oligomer-induced aberrant neuronal cell cycle activation and subsequent cell loss using retinoic acid differentiated human SH-SY5Y neuroblastoma cells as model system. In line with previous literature, we showed that in vitro preparations of soluble Aβ42 oligomers triggered cell cycle activation but not cell proliferation. As a new finding, we showed that Farnesylthiosalicylic acid (FTS), a specific chemical Ras inhibitor, prevented soluble Aβ42 oligomer preparation-induced cell cycle activation. Moreover, we showed that the expression of dominant negative mutant H-Ras (S17N) prevented soluble Aβ42 oligomer preparation-induced cell cycle activation, confirming the specific role of Ras in this pathway. As a possible better mimic of the situation in the AD brain, we prepared soluble oligomers from Aβ42 : Aβ40 (3:7) peptide mixture and showed that this oligomer preparation similarly induced cell cycle activation which was also inhibited by the Ras inhibitor. Finally, we showed that FTS prevented soluble Aβ42 oligomer preparationinduced cell death in our retinoic acid differentiated SH-SY5Y cells. Overall, our results strongly suggest that Ras activity is required for soluble Aβ oligomer-induced aberrant neuronal cell cycle reentry and subsequent neuronal loss, which are considered important mechanisms in AD pathogenesis.

Cite this article as:

M. Murat Koseoglu, Bagdeser Akdogan Ozdilek, Umidahan Djakbarova, Ayse Gulusur , Targeting Ras Activity Prevented Amyloid Beta-Induced Aberrant Neuronal Cell Cycle Re-Entry and Death, Current Alzheimer Research 2016; 13 (11) . https://dx.doi.org/10.2174/1567205013666160625074520