Zhang Lingyu, Jiang Zhihao, Hu Shaozhen, Ni Haojie, Zhao Yijing, Tan Xiaoqin, Lang Yi, Na Risong, Li Yanwu, Du Qun, Li Qing X, Dong Yan
Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.
Medical Department, Wuhan City College, Wuhan, 430083, China.
Inflammation. 2024 Aug 24. doi: 10.1007/s10753-024-02133-z.
Alzheimer's disease (AD) is a neurodegenerative disease mainly characterized by cognitive impairment. Glycogen synthase kinase 3 (GSK3β) is a potential therapeutic target against AD. Isoorientin (ISO), a GSK3β substrate competitive inhibitor, plays anti-AD effects in in vitro and in vivo AD model. TFGF-18 is an ISO synthetic analog with improved potency, but its neuroprotective effect in vivo remains to be elucidated, and the underlying mechanisms of GSK3β inhibitor against AD need to be clarified. This study investigated the TFGF-18 and ISO effects on gut homeostasis and neuroinflammation in scopolamine (SCOP)-induced AD mice. And the protection on barrier function was observed in in vitro blood-brain barrier (BBB) model of mouse brain microvascular endothelial cells (bEnd.3). The results show that TFGF-18 and ISO improved cognitive function in SCOP-induced mice, and inhibited cholinergic system disorders and inflammation in the brain and intestine, decreased the level of lipopolysaccharides (LPS) in serum and intestine, protected the diversity and balance of intestinal microbiome, increased the expressions of tight junction protein (ZO-1, occludin), brain derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in the mouse brain and intestine. In addition, TFGF-18 and ISO protected against barrier damage in LPS-stimulated BBB model of bEnd.3 cells in vitro. TFGF-18 and ISO increased the ratio of p-GSK3β/GSK3β, suppressed toll-like receptors 4 (TLR-4) expression and nuclear factor kappa-B (NF-κB) activation in vivo and in vitro, and increased the expressions of β-catenin, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in vitro. In conclusion, The GSK3β inhibitors TFGF-18 and ISO modulate the gut homeostasis and barrier function to inhibit neuroinflammation and attenuate cognitive impairment by regulating NF-κB, β-catenin and Nrf2/HO-1 pathways.
阿尔茨海默病（AD）是一种主要以认知障碍为特征的神经退行性疾病。糖原合酶激酶3（GSK3β）是对抗AD的一个潜在治疗靶点。异荭草苷（ISO）作为一种GSK3β底物竞争性抑制剂，在体外和体内AD模型中发挥抗AD作用。TFGF - 18是一种活性增强的ISO合成类似物，但其体内神经保护作用仍有待阐明，GSK3β抑制剂对抗AD的潜在机制也需要明确。本研究调查了TFGF - 18和ISO对东莨菪碱（SCOP）诱导的AD小鼠肠道内环境稳态和神经炎症的影响。并且在小鼠脑微血管内皮细胞（bEnd.3）的体外血脑屏障（BBB）模型中观察到了对屏障功能的保护作用。结果表明，TFGF - 18和ISO改善了SCOP诱导小鼠的认知功能，抑制了脑和肠道中的胆碱能系统紊乱及炎症，降低了血清和肠道中脂多糖（LPS）的水平，保护了肠道微生物群的多样性和平衡，增加了小鼠脑和肠道中紧密连接蛋白（ZO - 1、闭合蛋白）、脑源性神经营养因子（BDNF）和胶质细胞源性神经营养因子（GDNF）的表达。此外，TFGF - 18和ISO在体外LPS刺激的bEnd.3细胞BBB模型中保护细胞免受屏障损伤。TFGF - 18和ISO在体内和体外均增加了p - GSK3β/GSK3β的比例，抑制了Toll样受体4（TLR - 4）的表达和核因子κB（NF - κB）的激活，并在体外增加了β - 连环蛋白、核因子红细胞2相关因子2（Nrf2）和血红素加氧酶 - 1（HO - 1）的表达。总之，GSK3β抑制剂TFGF - 18和ISO通过调节NF - κB、β - 连环蛋白和Nrf2/HO - 1信号通路来调节肠道内环境稳态和屏障功能，从而抑制神经炎症并减轻认知障碍。
