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

积雪草水提取物及其成分对阿尔茨海默病 5xFAD 小鼠模型认知影响的机制

• 批准号: 10285483
• 负责人: Amala Soumyanath
• 金额: $ 4.34万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10285483
• 关键词: Acids; Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Antioxidants; Biological; Biological Availability; Biology; Botanicals; Brain; Cell Death; Chemicals; Clinical; Clinical Trials; Cognition; Cognitive; Complement; Coupled; Data; Diet; Ensure; Female; Future; Gene Expression; Gotu kola; Grant; Health; Herb; Impaired cognition; In Vitro; Inflammatory; Liquid Chromatography; Literature; Mass Spectrum Analysis; Measurement; Measures; Mitochondria; Mus; Nervous System Physiology; Neurobiology; Neurologic; Neurons; Oxidative Stress; Parents; Pathogenesis; Pathology; Pathway interactions; Plasma; Play; Positioning Attribute; Preparation; Process; Reactive Oxygen Species; Reporting; Resolution; Role; Sampling; Senile Plaques; Standardization; Synapses; Testing; Tissue Sample; Tissues; Triterpenes; United States National Institutes of Health; Water; Wild Type Mouse; Work; abeta accumulation; aged; behavioral response; cognitive function; cognitive performance; cytokine; density; drinking water; effective therapy; glial activation; healthy aging; improved; in vivo; male; mitochondrial dysfunction; mouse model; multiple reaction monitoring; neuroinflammation; parent grant; pre-clinical; resilience; response; treatment strategy; voucher

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.

项目概要/摘要 氧化应激、线粒体功能障碍和神经炎症是神经系统的核心相互关联的过程。 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），它们一起增加促炎细胞因子。促炎性 细胞因子以及增加的 ROS 会对线粒体造成进一步的损害，从而使线粒体长期处于破坏性状态。 导致细胞死亡和认知能力下降的循环。这种潜在的生物学表明，多靶点 剂可能是 AD 的有效治疗策略。传统使用积雪草草药来改善 认知功能得到了大量临床前文献的支持。我们已经证明，水 积雪草提取物 (CAW) 增强突触密度，激活抗氧化反应途径， 改善孤立神经元以及衰老和 AD 小鼠模型中的线粒体缺陷，其中 CAW 还提高了认知能力。我们的体外初步数据也表明了抗炎作用 啼;然而，这还有待体内证实。 Aβ 积累的 5xFAD 小鼠模型显示 与野生型（WT）小鼠相比，神经炎症升高。该项目将检查标记物的变化 雄性和雌性 5xFAD 小鼠储存的大脑中存在神经炎症，这些小鼠的认知能力在以下情况下得到改善 他们的饮用水中经过 CAW 处理。我们还发现了三萜 (TT) 和咖啡酰奎尼酸 CAW 中存在的 CQA（CQA）在体外影响抗氧化剂、线粒体和突触健康，并可以改善认知 在 5xFAD 小鼠中。然而，这些化合物与神经保护活性的具体关联 CAW仍有待阐明。使用额外存储的大脑样本，我们将研究 CAW 或 饮食中混合等量的 TT 和 CQA，以抗氧化反应标记物、线粒体 雄性和雌性 5xFAD 小鼠的活动、突触密度、神经炎症和 Aβ 病理学。我们将 每次治疗后测量血浆中的 CQA 和 TT 水平，两者都与其生物效应相关 并探讨 CA​​W 给药时出现不同行为反应的原因 饮用水与饮食。该项目将通过评估 CAW 的作用为未来的 CAW 临床试验提供信息 神经炎症标记物作为 CA 目标参与的生物特征，使用 TT 的有效性和 CQA 作为化学标记来标准化 CAW 制剂以及 CAW 的最佳给药方式。 这项工作补充了家长资助调查 CAW、CQA 和 TT 的复原力促进作用 健康的老年小鼠，可能会出现氧化应激、线粒体功能下降和神经炎症。