1. Alzheimer's amyloid beta-peptide (1-42) induces cell death in human neuroblastoma via bax/bcl-2 ratio increase: an intriguing role for methionine 35
M E Clementi, M Pezzotti, F Orsini, B Sampaolese, D Mezzogori, C Grassi, B Giardina, F Misiti Biochem Biophys Res Commun. 2006 Mar 31;342(1):206-13. doi: 10.1016/j.bbrc.2006.01.137. Epub 2006 Feb 3.
The beta amyloid (Abeta), the major protein component of brain senile plaques in Alzheimer's disease, is known to be directly responsible for the production of free radicals toxic to brain tissue and the redox state of Met-35 residue seems to play a particular and critical role in peptide's neurotoxic actions. In this study, we investigated, in human neuroblastoma cells (IMR-32), the relationship between the oxidative state of methionine, and both neurotoxic and pro-apoptotic actions induced by Abeta-peptide, comparing the effects of native peptide, in which the Met-35 is present in the reduced state, with those of a modified peptide with oxidized Met-35 (Abeta(1-42)(35Met-ox)), as well as an Abeta-derivative with Met-35 substituted with norleucine (Abeta(1-42)(35Nle)). The obtained results show that Abeta induces a time-dependent decrease in cell viability; Abeta(1-42)(35Met-ox) was significantly less potent, though inducing a remarkable decrease in cell viability compared to control. On the contrary, no toxic effects were observed after treatment with Abeta(1-42)(35Nle). Abeta-peptide as well as the amyloid modified peptide with oxidized Met-35 induced the pro-apoptotic gene bax over-expression after 24 h, whereas Abeta(1-42)(35Nle) had no effect. Conversely, bcl-2, an anti-apoptotic gene, became highly down-regulated by Abeta peptide treatment, in contrast to that evidenced by the Abeta(1-42)(35Met-ox) peptide. Finally, Abeta caused an increase in caspase-3 activity to be higher with respect to that shown by Abeta(1-42)(35Met-ox) while Abeta(1-42)(35Nle) had no effect. These results support the hypothesis that Abeta-induced neurotoxicity occurs via bax over-expression, bcl-2 down-regulation, and caspase-3 activation, first indicating that methionine 35 redox state may alter this cell death pathway.
2. Direct interaction between selenoprotein R and Aβ42
Chao Wang, Ping Chen, Xiaohong He, Zaisheng Peng, Siqiang Chen, Renli Zhang, Jinquan Cheng, Qiong Liu Biochem Biophys Res Commun. 2017 Aug 5;489(4):509-514. doi: 10.1016/j.bbrc.2017.05.182. Epub 2017 Jun 1.
Amyloid-β (Aβ) peptides have taken a central role in AD research, the aggregation of Aβ peptide is involved in the progression of Alzheimer's disease (AD). The 35th amino acid was methionine (Met) in Aβ peptides and it's redox state is critical in determining the biological activity of Aβ. It has been suggested that oxidation of Met35 (Met35O) plays a key role in the formation of paranuclei and in the control of oligomerization pathway choice. As an antioxidative selenoenzyme, Selenoprotein R (SelR) plays important roles in reducing the R-form of MetO to Met to maintain intracellular redox balance. However, the relationship between SelR and Aβ was little investigated. Here, we found that SelR can directly interact with Aβ42, and the interaction between SelR and Aβ42 was verified by fluorescence resonance energy transfer (FRET), co-immunoprecipitation (co-IP), and pull-down assays. SelR is closely related to AD, its biological functions in human brain become a research focus. This work implies that SelR makes it capable of modulating Aβ42 aggregation and provides a novel avenue for further study on the mechanism of SelR in AD prevention.
