| Autor: |
Zhang W; Affiliated Wuhan Resources and Wisco General Hospital, University of Science and Technology, Wuhan, Hubei, China., Yang Y; College of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China., Xiang Z; College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, China., Cheng J; Affiliated Wuhan Resources and Wisco General Hospital, University of Science and Technology, Wuhan, Hubei, China., Yu Z; College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, China., Wang W; Affiliated Wuhan Resources and Wisco General Hospital, University of Science and Technology, Wuhan, Hubei, China., Hu L; College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, China., Ma F; College of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China., Deng Y; Bioinformatics Core Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA., Jin Z; Affiliated Wuhan Resources and Wisco General Hospital, University of Science and Technology, Wuhan, Hubei, China., Hu X; College of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China. |
| Abstrakt: |
Myocardia-Related Transcription Factors-A (MRTF-A), which is enriched in the hippocampus and cerebral cortex, has been shown to have a protective function against ischemia hypoxia-induced neuronal apoptosis. However, the function of MRTF-A on β-amyloid peptide (Aβ)-induced neurotoxicity and autophagy dysfunction in Alzheimer's disease is still unclear. This study shows that the expression of MRTF-A in the hippocampus of Tg2576 transgenic mice is reduced, and the overexpression of MRTF-A mediated by lentiviral vectors carrying MRTF-A significantly reduces the accumulation of hippocampal β-amyloid peptide and reduces cognition defect. Overexpression of MRTF-A inhibits neuronal apoptosis, increases the protein levels of microtubule-associated protein 1 light chain 3-II (MAP1LC3/LC3-II) and Beclin1, reduces the accumulation of SQSTM1/p62 protein, and promotes autophagosomes-Lysosomal fusion in vivo and in vitro . Microarray analysis and bioinformatics analysis show that MRTF-A reverses Aβ-induced autophagy impairment by up-regulating miR-1273g-3p level leading to negative regulation of the mammalian target of rapamycin (mTOR), which is confirmed in Aβ 1-42 -treated SH-SY5Y cells. Further, overexpression of MRTF-A reduces Aβ 1-42 -induced neuronal apoptosis. And the effect was abolished by miR-1273g-3p inhibitor or MHY1485 (mTOR agonist), indicating that the protection of MRTF-A on neuronal damage is through targeting miR-1273g-3p/mTOR axis. Targeting this signaling may be a promising approach to protect against Aβ-induced neuronal injury. |
