The Neuroprotective Effects of SIRT1 in Mice Carrying the APP/PS1 Double-Transgenic Mutation and in SH-SY5Y Cells Over-Expressing Human APP670/671 May Involve Elevated Levels of α7 Nicotinic Acetylcholine Receptors

Abstract

Background: Both the silent information regulator-1 (SIRT1) and α7 nicotinic acetylcholine receptors (α7 nAChR) play important roles in the pathogenesis of Alzheimer's disease (AD), but interactions between these two remain largely unknown. Our present aim was to determine whether the neuroprotective effect of SIRT1, due to inhibition of aggregation of the β-amyloid peptide (Aβ), involves activation of α7 nAChR. Methods: In present study, four-month-old mice carrying the APP/PS1 mutation were administered resveratrol (RSV, a stimulator of SIRT1) or suramin (an inhibitor) once daily for two months, following which their spatial learning and memory were assessed using the Morris water maze test. Deposits of Aβ in vivo were detected by near-infrared imaging (NIRI) and confocal laser scanning. SH-SY5Y cells over-expressing human APP670/671 (SH-SY5Y/APPSWE cells) were treated with RSV, suramin, U0126 (an inhibitor of the MAPK/ERK1/2 pathway) or methyllycaconitine (MLA, an inhibitor of α7 nAChR), as well as transiently transfected with SIRT1 silencing RNA. Levels of proteins and mRNA were determined by Western blotting and qRT-PCR, respectively. Findings: The results show that the learning and memory of mice carrying the APP/PS1 mutation had declined by 6 months of age and the levels of SIRT1 and α7 nAChR in their hippocampus and cortex were lowered. Activation of SIRT1 improved their spatial learning and memory and reduced the production and aggregation of Aβ in the hippocampus and cerebral cortex; whereas inhibition of SIRT1 had the opposite effects. In addition, activation of SIRT1 increased the levels of both α7 nAChR and αAPP in the brains these animals. Finally, activation of SIRT1 elevated the levels of phosphor-ERK1/2, while inhibition of ERK1/2 counteracted the increase in α7 nAChR caused by RSV. Interpretation: These findings indicate that neuroprotection by SIRT1 may involve increasing levels of α7 nAChR through activation of the MAPK/ERK1/2 signaling pathway. Funding Statement: This work was financed by grants from the Natural Science Foundation of China (U1812403), and the Foundation of Guizhou Province of China (2014-06, 2014-6008, 2016-4001). Declaration of Interests: The authors declare that they have no competing interests. Ethical Approval Statement: All animal experimental procedures were performed in accordance with the guidelines of the Animal Ethical and Experimental Committee of Guizhou Medical University.