Research Paper Volume 14, Issue 10 pp 4305—4325

MRTF-A-mediated protection against amyloid-β-induced neuronal injury correlates with restoring autophagy via miR-1273g-3p/mTOR axis in Alzheimer models

Wei Zhang1, , Yuewang Yang2, , Zifei Xiang3, , Jinping Cheng1, , Zhijun Yu3, , Wen Wang1, , Ling Hu3, , Fuyun Ma2, , Youping Deng4, , Zhigang Jin1, , Xiamin Hu2, ,

  • 1 Affiliated Wuhan Resources and Wisco General Hospital, University of Science and Technology, Wuhan, Hubei, China
  • 2 College of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
  • 3 College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, China
  • 4 Bioinformatics Core Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA

Received: March 22, 2021       Accepted: December 7, 2021       Published: May 23, 2022
How to Cite

Copyright: © 2022 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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 Aβ1-42-treated SH-SY5Y cells. Further, overexpression of MRTF-A reduces Aβ1-42-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.


AD: Alzheimer’s Disease; AVs: autophagic vacuoles; CNS: Central nervous system; MAP1LC3/LC3: microtubule associated protein1 light chain 3; mTOR: mammalian target of rapamycin; MRTF-A: Myocardia-Related Transcription Factors A; MWM: Morris Water Maze; NFT: neurofibrillary tangles; intracerebroventricularly: i. c. v; Aβ: β-amyloid; HRP: corresponding horseradish peroxidase; Hsa: Homo sapiens; LV: lentivirus; miRNAs: microRNAs; ncRNAs: non-coding RNAs; LV-NEG: LV-negative-EGFP; siRNAs: small-interfering RNA; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; 3-MA: 3-Methyladenine.