Abstract
Objective: 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.Results: 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.Conclusion: Overexpression of WT1-AS can inhibit the miR-375/SIX4 axis, OSI and neuronal apoptosis in AD by inhibiting WT1 expression.Methods: 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.
Highlights
Neurodegenerative disease is an umbrella term for a range of conditions that is associated with the loss of synapses between neurons in the brain [1]
LncRNA WT1-AS was poorly expressed in SHSY5Y cells treated with Aβ25-35 and inhibited oxidative stress injury (OSI) and apoptosis induced by Aβ25-35
And timely detection and diagnosis are the cornerstones to improving the prognosis of human malignant diseases [40], which highlights the need for novel detection methods that provide more flexibility and accuracy than traditional methods
Summary
Neurodegenerative disease is an umbrella term for a range of conditions that is associated with the loss of synapses between neurons in the brain [1]. One such disorder, Alzheimer's disease (AD), is recognized as the most common neurodegenerative disease in elderly individuals and is characterized by progressive cognitive impairment and memory loss [2, 3]. Aging has been identified as the foremost cause of neurodegenerative diseases, and the incidence of neurodegenerative diseases is expected to surge with an increase in aging populations over the few decades [4]. Recent decades have witnessed a surge in investigations on mitochondrial defects and oxidative stress, such that an increasing number of studies support the notion that that mitochondrial defects and oxidative stress exert negative effects on the upstream pathological events of AD, which has paved the way in providing a theoretical basis for the early diagnosis and treatment of AD [8, 9]
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