Mechanisms underlying the cognitive effects of Centella asiatica water extract and constituent compounds in the 5xFAD mouse model of Alzheimer's Disease

项目总结/摘要 氧化应激、线粒体功能障碍和神经炎症是神经系统疾病的核心的相互关联的过程。 阿尔茨海默病（AD）的发病机制和进展。线粒体功能障碍会增加 活性氧（ROS），并且这些一起增加促炎细胞因子。促炎 细胞因子，沿着增加的ROS，引起线粒体的进一步损伤， 导致细胞死亡和认知能力下降的周期。这种潜在的生物学表明， 药物可能是AD的有效治疗策略。传统使用积雪草草药，以改善 认知功能得到大量临床前文献的支持。我们已经证明， 积雪草提取物（CAW）增强突触密度，激活抗氧化反应途径， 改善分离神经元以及衰老和AD小鼠模型中的线粒体缺陷，其中CAW 也提高了认知能力。我们的体外初步数据还表明， CAW;然而，这仍有待于在体内证实。Aβ蓄积的5xFAD小鼠模型显示 与野生型（WT）小鼠相比，神经炎症升高。本项目将研究 来自雄性和雌性5xFAD小鼠的储存大脑中的神经炎症，这些小鼠的认知在以下情况下得到改善： 在饮用水中添加CAW。我们还发现了三萜（TT）和咖啡酰奎宁酸 CAW中存在的CQA影响体外抗氧化剂，线粒体和突触健康，并可改善认知 在5xFAD小鼠中。然而，这些化合物与神经保护活性的特异性关联， CAW仍有待阐明。使用额外储存的大脑样本，我们将研究CAW或 等量的TTs和CQA混合在饮食中，对抗氧化反应的标志物，线粒体 活性、突触密度、神经炎症和Aβ病理学。我们将 测量每次治疗后血浆中的CQA和TT水平，两者都与其生物效应相关 并探讨在给予CAW时观察到的不同行为反应的原因。 饮用水和饮食中。该项目将通过评估以下因素的作用，为CAW的未来临床试验提供信息： 神经炎性标志物作为CA靶点接合的生物学特征，使用TT的有效性， CQA作为标准化CAW制剂的化学标志物，以及CAW的最佳给药方式。 这项工作补充了父母补助金，调查CAW，CQA和TT的弹性促进作用， 健康老年小鼠，其中可能发生氧化应激、线粒体功能下降和神经炎症。

Project Summary/Abstract Oxidative stress, mitochondrial dysfunction and neuroinflammation are inter-related processes central to the pathogenesis and progression of Alzheimer's disease (AD). Mitochondrial dysfunction increases levels of reactive oxygen species (ROS), and together these increase pro-inflammatory cytokines. Pro-inflammatory cytokines, along with the increased ROS, cause further damage to mitochondria perpetuating a destructive cycle that contributes to cell death and cognitive decline. This underlying biology suggests that a multi-targeted agent could be an effective treatment strategy for AD. The traditional use of Centella asiatica herb to improve cognitive function is supported by a substantial body of preclinical literature. We have shown that a water extract of Centella asiatica (CAW) enhances synaptic density, activates the antioxidant response pathway and improves mitochondrial deficits in isolated neurons as well as in mouse models of aging and AD, in which CAW also improved cognitive performance. Our in vitro preliminary data also suggest anti-inflammatory effects of CAW; however, this remains to be confirmed in vivo. The 5xFAD mouse model of Aβ accumulation shows elevated neuroinflammation compared to wild type (WT) mice. This project will examine changes in markers of neuroinflammation in stored brains from male and female 5xFAD mice whose cognition improved following treatment with CAW in their drinking water. We have also found also triterpenes (TTs) and caffeoylquinic acids (CQAs) present in CAW affect antioxidant, mitochondrial and synaptic health in vitro and can improve cognition in 5xFAD mice. However, the specific associations of these compounds with the neuroprotective activities of CAW remain to be elucidated. Using additional stored brain samples, we will investigate the effects CAW or equivalent amounts of TTs and CQAs mixed in the diet, on markers of antioxidant response, mitochondrial activity, synaptic density, neuroinflammation and Aβ pathology in male and female 5xFAD mice. We will measure CQA and TT levels in the plasma following each treatment, both to corelate to their biological effects and to explore reasons for the differential behavioral response seen when CAW was administered in the drinking water versus in the diet. This project will inform future clinical trials of CAW by evaluating the role of neuroinflammatory markers as biological signatures of target engagement by CA, the validity of using TT and CQA as chemical markers to standardize CAW preparations, and the optimum mode of administration of CAW. This work complements the parent grant investigating resilience promoting effects of CAW, CQAs and TTs in healthy aged mice, where oxidative stress, declining mitochondrial function and neuroinflammation may occur.