Department of Endocrinology, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China.
Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China.
Aging (Albany NY). 2020 Dec 27;13(3):4590-4604. doi: 10.18632/aging.202418.
Diabetic encephalopathy (DE) is a global concern and Gordian knot worldwide. miRNA-132 (miR-132) is a class of negative gene regulators that promote diabetic pathologic mechanisms and its complications. However, the molecular mechanisms of miR-132 in DE are elusive, thus an alternative therapeutic strategy is urgently in demand. The present study explored the protective effect and the underlying mechanism of miR-132 on DE via the GSK-β/Tau signaling pathway. Experimentally, a type 2 DM rat model was developed by incorporating a high-fat diet and streptozotocin injection. Further, the DE model was screened via the Morris Water Maze test. Primary hippocampal neurons and HT-22 cells were used for analysis. We found that hyperglycemia exacerbates cognitive impairment in T2DM rats. When we isolated the primary hippocampus neurons, the expression of miR-132 RNA was low in both the DE hippocampus and primary neurons. GSK-3β and Tau 404 were highly expressed in injured HT-22 cells and diabetic hippocampal tissues. miR-132 downregulated the expression of GSK-3β. Besides, a binding and colocalized relationship between GSK3β and Tau was also reported. These findings suggest that miR-132 exerts protective effects from DE injury by repressing GSK-3β expression and alleviating Tau hyperphosphorylation in HT-22 cells and hippocampus tissues.
糖尿病脑病 (DE) 是一个全球性的问题，也是一个世界性的难题。miRNA-132 (miR-132) 是一类负向基因调节剂，可促进糖尿病的病理机制及其并发症的发生。然而，miR-132 在 DE 中的分子机制尚不清楚，因此迫切需要一种替代的治疗策略。本研究通过 GSK-β/Tau 信号通路探讨了 miR-132 对 DE 的保护作用及其潜在机制。实验中，通过高脂饮食和链脲佐菌素注射建立 2 型糖尿病大鼠模型。进一步通过 Morris 水迷宫试验筛选 DE 模型。原代海马神经元和 HT-22 细胞用于分析。我们发现高血糖加重了 2 型糖尿病大鼠的认知障碍。当我们分离原代海马神经元时，DE 海马和原代神经元中的 miR-132 RNA 表达均较低。GSK-3β 和 Tau 404 在受损的 HT-22 细胞和糖尿病海马组织中高表达。miR-132 下调了 GSK-3β 的表达。此外，还报道了 GSK3β 和 Tau 之间存在结合和共定位关系。这些发现表明，miR-132 通过抑制 GSK-3β 的表达和减轻 HT-22 细胞和海马组织中 Tau 的过度磷酸化，对 DE 损伤发挥保护作用。
