Mechanical Stretching-Induced Traumatic Brain Injury Is Mediated by the Formation of GSK-3β-Tau Complex to Impair Insulin Signaling Transduction

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...

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Autores principales: Pei-Wen Cheng, Yi-Chung Wu, Tzyy-Yue Wong, Gwo-Ching Sun, Ching-Jiunn Tseng
Formato: article
Lenguaje:EN
Publicado: MDPI AG 2021
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Acceso en línea:https://doaj.org/article/e89258d1c66c49afb00856c2bb208c1a
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Sumario: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)<sup>S9</sup>/p-Tau protein levels, which caused a neuronal injury. Following 6 and 24 h of stretching, GSK-3β<sup>S9</sup> was directly bound to p-Tau<sup>S396</sup>. 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.