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

作者：Zhang, Wei; Yang, Yuewang; Xiang, Zifei; Cheng, Jinping; Yu, Zhijun; Wang, Wen; Hu, Ling; Ma, Fuyun; Deng, Youping; Jin, Zhigang^*; Hu, Xiamin^*

来源：Aging-US, 2022, 14(10): 4305-4325.

• Alzheimer disease
• autophagy
• miR-1273g-3p
• MRTF-A
• mTOR

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 beta-amyloid peptide (A beta)-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 beta-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 A beta-induced autophagy impairment by up-regulating miR1273g-3p level leading to negative regulation of the mammalian target of rapamycin (mTOR), which is confirmed in A beta(1-42)-treated SH-SY5Y cells. Further, overexpression of MRTF-A reduces A beta(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 A beta-induced neuronal injury.

• 单位
  上海大学