Mechanical stretching-induced traumatic brain injury is mediated by the formation of gsk-3β-tau complex to impair insulin signaling transduction

Pei Wen Cheng, Yi Chung Wu, Tzyy Yue Wong, Gwo Ching Sun, Ching Jiunn Tseng

研究成果: Article同行評審

摘要

Traumatic brain injury confers a significant and growing public health burden. It is a major environmental risk factor for dementia. Nonetheless, the mechanism by which primary mechanical injury leads to neurodegeneration and an increased risk of dementia-related diseases is unclear. Thus, we aimed to investigate the effect of stretching on SH-SY5Y neuroblastoma cells that proliferate in vitro. These cells retain the dopamine-β-hydroxylase activity, thus being suitable for neuromechanistic studies. SH-SY5Y cells were cultured on stretchable membranes. The culture conditions contained two groups, namely non-stretched (control) and stretched. They were subjected to cyclic stretching (6 and 24 h) and 25% elongation at 1 Hz. Following stretching at 25% and 1 Hz for 6 h, the mechanical injury changed the mitochondrial membrane potential and triggered oxidative DNA damage at 24 h. Stretching decreased the level of brain-derived neurotrophic factors and increased amyloid-β, thus indicating neuronal stress. Moreover, the mechanical injury downregulated the insulin pathway and upregulated glycogen synthase kinase 3β (GSK-3β)S9 /p-Tau protein levels, which caused a neuronal injury. Following 6 and 24 h of stretching, GSK-3βS9 was directly bound to p-TauS396. In contrast, the neuronal injury was improved using GSK-3β inhibitor TWS119, which downregulated amyloid-β/p-Taus396 phosphorylation by enhancing ERK1/2T202/Y204 and AktS473 phosphorylation. Our findings imply that the neurons were under stress and that the inactivation of the GSK3β could alleviate this defect.

原文English
文章編號1650
期刊Biomedicines
9
發行號11
DOIs
出版狀態Published - 2021 11月

All Science Journal Classification (ASJC) codes

  • 醫藥(雜項)
  • 生物化學、遺傳與分子生物學 (全部)

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