Gao Dan, Hao Jin-Ping, Li Bo-Ya, Zheng Ceng-Ceng, Miao Bei-Bei, Zhang Li, Li Ya-Li, Li Lin, Li Xing-Jie, Zhang Lan
Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, 100053, China.
Senior Department of Infectious Diseases, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, China.
Eur J Pharmacol. 2023 Aug 15;953:175809. doi: 10.1016/j.ejphar.2023.175809. Epub 2023 Jun 14.
Alzheimer's disease (AD), also known as senile dementia, is the most common degenerative disease of the central nervous system. Neuroinflammation is currently believed to be a crucial factor in the progression of AD, while its exact mechanism remains unclear. In this study, we demonstrated that AD transgenic mice exhibited cognitive deficits accompanied by the elevated serum and brain inflammation. Treating with a natural active ingredient tetrahydroxy stilbene glucoside (TSG) from the Chinese herb Polygonum multiflorum that has been well known for its unique anti-aging effect, learning-memory ability of AD mice was distinctly improved. Meanwhile, it was observed that the expressions of serum inflammatory cytokines and the activation of microglia in cerebral cortex and hippocampus were suppressed after TSG treatment, which was probably attributable to the decrease of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggered immune response and NLRP3 inflammasome activation. Furthermore, cell culture experiments employing LPS combined with IFN-γ induced microglia activation showed that TSG reversed the polarization status of M1-type microglia to restore the quiescence, and cGAS-STING elevation was observed in the activated microglia and normalized by TSG incubation. In addition, TSG suppressed the production of inflammatory cytokines such as IL-1β, IL-6, TNF-α, IFN-α and IFN-β, as well as the expression of IFN regulatory proteins such as IFIT1 and IRF7 in the LPS/IFN-γ-stimulated inflammatory response in BV2 cell. Finally, it was also verified that TSG are, in part, through a cGAS-STING dependent pathway and triggered NLRP3 inflammasome activation to inhibit neuroinflammation through interfering with cGAS-STING inhibitors. Taken together, our findings highlight the health benefits of TSG and its potential application in preventing cognitive disorders by inhibiting neuroinflammation through cGAS-STING signaling pathway in AD.
阿尔茨海默病（AD），也称为老年性痴呆，是中枢神经系统最常见的退行性疾病。目前认为神经炎症是AD进展的关键因素，但其确切机制仍不清楚。在本研究中，我们证明AD转基因小鼠表现出认知缺陷，并伴有血清和脑内炎症升高。用中药何首乌中一种具有独特抗衰老作用的天然活性成分四羟基二苯乙烯苷（TSG）进行治疗后，AD小鼠的学习记忆能力明显提高。同时，观察到TSG治疗后血清炎性细胞因子的表达以及大脑皮层和海马中小胶质细胞的活化受到抑制，这可能归因于环状GMP-AMP合酶（cGAS）和干扰素基因刺激因子（STING）触发的免疫反应及NLRP3炎性小体活化的减少。此外，采用脂多糖（LPS）联合干扰素-γ诱导小胶质细胞活化的细胞培养实验表明，TSG逆转了M1型小胶质细胞的极化状态以恢复其静息状态，并且在活化的小胶质细胞中观察到cGAS-STING升高，而TSG孵育可使其恢复正常。此外，TSG抑制了BV2细胞中LPS/干扰素-γ刺激的炎症反应中炎性细胞因子如白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α、干扰素-α和干扰素-β的产生，以及干扰素调节蛋白如干扰素诱导蛋白1（IFIT1）和干扰素调节因子7（IRF7）的表达。最后，还证实TSG部分是通过cGAS-STING依赖性途径并通过干扰cGAS-STING抑制剂触发NLRP3炎性小体活化来抑制神经炎症。综上所述，我们的研究结果突出了TSG的健康益处及其通过AD中的cGAS-STING信号通路抑制神经炎症在预防认知障碍方面的潜在应用。
