Effect of lncRNA WT1-AS regulating WT1 on oxidative stress injury and apoptosis of neurons in Alzheimer's disease via inhibition of the miR-375/SIX4 axis.

Quanbao Wang, Xiumin Ge, Jie Zhang, Licheng Chen

Aging 2020 Nov 21

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To study the effect of lncRNA WT1-AS on oxidative stress injury (OSI) and apoptosis of neurons in Alzheimer's disease (AD) and its specific mechanisms related to the microRNA-375 (miR-375)/SIX4 axis and WT1 expression. After bioinformatic prediction, WT1-AS was found to be downregulated in Aβ25-35treated SH-SY5Y cells, and WT1-AS overexpression inhibited WT1 expression. WT1 could target miR-375 to promote its expression. miR-375 bound to SIX4, and miR-375 overexpression inhibited SIX4 expression. WT1-AS inhibited OSI and apoptosis, while WT1 and miR-375 overexpression or SIX4 silencing reversed the WT1-AS effect on OSI and apoptosis. In vivo experiments revealed that WT1-AS improved learning/memory abilities and inhibited OSI and apoptosis in AD mice. Overexpression of WT1-AS can inhibit the miR-375/SIX4 axis, OSI and neuronal apoptosis in AD by inhibiting WT1 expression. Related lncRNAs were identified, and miR-375 downstream targets were predicted. WT1-AS, WT1, miR-375 and SIX4 expression was detected in a cell model induced by Aβ25-35. The binding of WT1 with miR-375 and that of miR-375 with SIX4 were further confirmed. Adenosine triphosphate (ATP), reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and lactate dehydrogenase (LDH) activities, and apoptosis levels were tested after mitochondrial membrane potential observation. Learning/memory abilities and neuronal apoptosis were tested in a mouse model.

Citation

Quanbao Wang, Xiumin Ge, Jie Zhang, Licheng Chen. Effect of lncRNA WT1-AS regulating WT1 on oxidative stress injury and apoptosis of neurons in Alzheimer's disease via inhibition of the miR-375/SIX4 axis. Aging. 2020 Nov 21;12(23):23974-23995