Li Wai Yin, Lee Cheuk Yan, Lee Kwan Ming, Zhang Ge, Lyu Aiping, Yue Kevin Kin Man
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, People's Republic of China.
Department of Biology, Hong Kong Baptist University, Hong Kong, People's Republic of China.
Diabetes Metab Syndr Obes. 2022 Oct 17;15:3153-3166. doi: 10.2147/DMSO.S382927. eCollection 2022.
Diabetes mellitus (DM) is characterized by chronic hyperglycemia and diabetic complications. Exacerbated cortical neuronal degeneration was observed in Alzheimer's disease (AD) patients with DM. In fact, DM is now considered a risk factor of AD, as DM-induced activation of stress responses in the central nervous system (CNS) such as oxidative stress and neuroinflammation may lead to various neurodegenerative disorders. Methylglyoxal (MG) is one of the most reactive advanced glycation end-product (AGE) precursors. Abnormal accumulation of MG is observed in the serum of diabetic patients. As MG is reported to promote brain cells impairment in the CNS, and it is found that AGEs are abnormally increased in the brains of AD patients. Therefore, the effect of MG causing subsequent symptoms of AD was investigated.
5-week-old C57BL/6 mice were intraperitoneally injected with MG solution for 11 weeks. The Morris water maze (MWM) was used to examine the spatial learning ability and cognition of mice. After MG treatment, MTT assay, real-time PCR analyses, and Western blot were performed to assess the harvested astrocytes and hippocampi.
Significantly longer escape latency and reduced percentage time spent in the target quadrant were observed in the 9-week-MG-treated mice. We have found in both in vitro and in vivo models that MG induced astrogliosis, pro-inflammatory cytokines, AD-related markers, and ERK activation. Further, trend of normalization of the tested markers mRNA expressions were observed after ERK inhibition.
Our in vivo results suggested that MG could induce AD symptoms and results implied that ERK may regulate the promotion of inflammation and Aβ formation in MG-induced reactive astrocytes. Taken together, MG may participate in the dysfunction of brain cells resulting in possible diabetes-related neurodegeneration by promoting astrogliosis, Aβ production, and neuroinflammation through the ERK pathway. Our findings provide insight of targeting ERK as a therapeutic application for diabetes-induced AD.
糖尿病（DM）的特征是慢性高血糖和糖尿病并发症。在患有DM的阿尔茨海默病（AD）患者中观察到皮质神经元变性加剧。事实上，DM现在被认为是AD的一个危险因素，因为DM诱导的中枢神经系统（CNS）应激反应激活，如氧化应激和神经炎症，可能导致各种神经退行性疾病。甲基乙二醛（MG）是最具反应性的晚期糖基化终产物（AGE）前体之一。在糖尿病患者的血清中观察到MG的异常积累。由于据报道MG会促进CNS中的脑细胞损伤，并且发现AD患者大脑中的AGEs异常增加。因此，研究了MG导致AD后续症状的作用。
对5周龄的C57BL/6小鼠腹腔注射MG溶液，持续11周。使用莫里斯水迷宫（MWM）来检测小鼠的空间学习能力和认知。MG处理后，进行MTT分析、实时PCR分析和蛋白质印迹，以评估收获的星形胶质细胞和海马体。
在接受9周MG处理的小鼠中观察到显著更长的逃避潜伏期和在目标象限花费的时间百分比降低。我们在体外和体内模型中均发现，MG诱导了星形胶质细胞增生、促炎细胞因子、AD相关标志物和ERK激活。此外，在ERK抑制后观察到测试标志物mRNA表达的正常化趋势。
我们的体内结果表明，MG可诱导AD症状，结果暗示ERK可能调节MG诱导的反应性星形胶质细胞中炎症和Aβ形成的促进作用。综上所述，MG可能通过ERK途径促进星形胶质细胞增生、Aβ产生和神经炎症，从而参与脑细胞功能障碍，导致可能的糖尿病相关神经退行性变。我们的研究结果为将ERK作为糖尿病诱导的AD的治疗应用靶点提供了见解。
