高糖诱导miRNA-485-5p/DISC1通路异常致糖尿病认知功能障碍的机制研究

Cognitive impairment is the main clinical manifestation of diabetic encephalopathy, seriously affecting the life quality of patients. However, the pathogenesis of diabetic encephalopathy has not yet been elucidated. Our previous study found that high glucose environment could induce the expression of schizophrenia disrupted gene 1 (DISC1) is decreased in neurons, accompanied by the significant increase of tau phosphorylation and Aβ production, suggesting that DISC1 may act as the key molecule in the process of AD-like pathological changes in diabetes; Bioinformatics analysis and our preliminary data further showed that miRNA-485-5p may regulate the decrease of DISC1 expression under the condition of high glucose. Oxidative stress may play an important role in the regulation of miRNA-485-5p expression in neurons. On the basis of our previous studies and by using of cell model, diabetic model mice and knock-in/knock-out mice, We intend to clarify the pathophysiological significance of DISC1 in diabetic cognitive dysfunction, to explore the key role of miRNA-485-5p in regulating the expression of DISC1, and further to clarify the molecular mechanism of oxidative stress regulating the expression of miRNA-485-5p. We could further understand of the pathogenesis of cognitive impairment in diabetes and provide a new theoretical basis for early prevention and treatment of diabetic encephalopathy.

认知功能障碍是糖尿病脑病的主要临床表现，严重影响患者生活质量，但糖尿病脑病发病机制一直尚未阐明。我们前期研究发现高糖环境可诱导神经元精神分裂症断裂基因1（DISC1）表达下调，并伴有tau磷酸化程度显著增强，Aβ产生增加，提示DISC1在糖尿病发生AD样病变过程中可能发挥“中心调节器”作用；生物信息学分析和预实验结果进一步发现miRNA-485-5p可能是介导高糖所致DISC1表达下调的潜在因子，且氧化应激在调控神经元miRNA-485-5p表达中可能发挥重要作用。在前期研究基础上，本项目拟采用细胞模型、糖尿病模型鼠和基因敲入/敲除小鼠为研究对象，明确DISC1在糖尿病认知功能障碍中的病理生理学意义，探讨miRNA-485-5p在其中所发挥的关键作用，阐明氧化应激对miRNA-485-5p表达调控的具体分子机制，以期深化对糖尿病认知功能障碍发病机理的认识并为早期防治提供新的理论依据。

认知功能障碍是糖尿病脑病的主要临床表现，严重影响患者生活质量，但糖尿病脑病发病机制一直尚未阐明。我们的研究发现高糖环境可诱导神经元精神分裂症断裂基因1（DISC1）表达下调，并伴有tau磷酸化程度显著增强，Aβ产生增加，因此，我们进一步通过建立糖尿病模型小鼠以及高糖诱导的神经元细胞模型，在动物和细胞水平明确了DISC1表达下调在糖尿病认知功能障碍中的作用；确定并证明了miRNA-485-5p/DISC1通路在糖尿病认知功能障碍中所发挥的关键作用：高糖环境下神经元内miRNA-485-5p通过调控DISC1表达下调可导致GSK3β活性增强，从而调控tau蛋白过度磷酸化和Aβ生成增多，进而导致神经元毒性。细胞实验结果进一步证明了DISC1蛋白中198-237氨基酸残基的结构域可与GSK3β存在相互作用，并可抑制GSK3β活性；高糖刺激下由于miRNA-485-5p调控DISC1表达下调，导致GSK3β失去活性抑制效应，进而导致GSK3β活化。这些研究结果为理解DISC1表达下调导致糖尿病脑病中神经元退变的机制提供了新信息，为减缓糖尿病脑病神经毒性提供了新的分子靶标。