背景:性别是晚发性阿尔茨海默病(AD)的重要危险因素,通常归因于雌激素的下降。植物雌激素secoisolariciresinol二葡萄糖苷(SDG)已显示出抗炎和神经保护作用。然而,SDG对女性AD的保护作用和机制尚不清楚.
方法:10月龄雌性APPswe/PSEN1dE9(APP/PS1)转基因小鼠用SDG处理,通过一系列行为和生化实验评估其对雌性AD模型认知障碍的潜在改善作用。使用HPLC-MS定量肠道微生物代谢产物肠二醇(END)和肠内酯(ENL)的血清水平。采用相关分析和广谱抗生素鸡尾酒(ABx)治疗来证明END和ENL参与SDG\对雌性APP/PS1小鼠的认知改善作用。此外,在三个月龄的C57BL/6J小鼠中构建了急性神经炎症模型,这些小鼠用脂多糖(LPS)治疗,并接受静脉注射G蛋白偶联雌激素受体(GPER)抑制剂G15,研究雌激素受体GPER在SDG赋予的认知益处中的中介作用。
结果:SDG管理导致空间上的显着改善,认可,雌性APP/PS1小鼠的工作记忆。观察到神经保护作用,包括CREB/BDNF和PSD-95的表达增强,β-淀粉样蛋白(Aβ)沉积减少,TNF-α水平降低,IL-6和IL-10。SDG还改变了肠道微生物群组成,增加END和ENL的血清水平。相关分析表明END,ENL,认知表现,海马Aβ相关蛋白mRNA表达,和皮质神经炎症细胞因子水平。肠道微生物群的去除抑制了END和ENL的产生,并消除了SDG的神经保护作用。此外,发现GPER介导SDG对神经炎症反应的抑制作用。
结论:这些研究结果表明,SDG促进了肠道微生物代谢产物END和ENL的产生,抑制大脑β-淀粉样蛋白沉积,激活GPER以增强CREB/BDNF信号通路,并抑制神经炎症反应。因此,SDG在雌性小鼠中发挥神经保护作用并改善与AD相关的认知障碍。
BACKGROUND: Gender is a significant risk factor for late-onset Alzheimer\'s disease (AD), often attributed to the decline of estrogen. The plant estrogen secoisolariciresinol diglucoside (SDG) has demonstrated anti-inflammatory and neuroprotective effects. However, the protective effects and mechanisms of SDG in female AD remain unclear.
METHODS: Ten-month-old female APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with SDG to assess its potential ameliorative effects on cognitive impairments in a female AD model through a series of behavioral and biochemical experiments. Serum levels of gut microbial metabolites enterodiol (END) and enterolactone (ENL) were quantified using HPLC-MS. Correlation analysis and broad-spectrum antibiotic cocktail (ABx) treatment were employed to demonstrate the involvement of END and ENL in SDG\'s cognitive improvement effects in female APP/PS1 mice. Additionally, an acute neuroinflammation model was constructed in three-month-old C57BL/6J mice treated with lipopolysaccharide (LPS) and subjected to i.c.v. injection of G15, an inhibitor of G protein-coupled estrogen receptor (
GPER), to investigate the mediating role of the estrogen receptor
GPER in the cognitive benefits conferred by SDG.
RESULTS: SDG administration resulted in significant improvements in spatial, recognition, and working memory in female APP/PS1 mice. Neuroprotective effects were observed, including enhanced expression of CREB/BDNF and PSD-95, reduced β-amyloid (Aβ) deposition, and decreased levels of TNF-α, IL-6, and IL-10. SDG also altered gut microbiota composition, increasing serum levels of END and ENL. Correlation analysis indicated significant associations between END, ENL, cognitive performance, hippocampal Aβ-related protein mRNA expression, and cortical neuroinflammatory cytokine levels. The removal of gut microbiota inhibited END and ENL production and eliminated the neuroprotective effects of SDG. Furthermore,
GPER was found to mediate the inhibitory effects of SDG on neuroinflammatory responses.
CONCLUSIONS: These findings suggest that SDG promotes the production of gut microbial metabolites END and ENL, which inhibit cerebral β-amyloid deposition, activate
GPER to enhance CREB/BDNF signaling pathways, and suppress neuroinflammatory responses. Consequently, SDG exerts neuroprotective effects and ameliorates cognitive impairments associated with AD in female mice.