Molecular Mechanism and Functional Role of Magnesium in Neuroinflammation in Alzheimer's Disease

镁在阿尔茨海默病神经炎症中的分子机制和功能作用

• 批准号: 10392710
• 负责人: Donghui Zhu
• 金额: $ 7.04万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392710
• 关键词: Aging; Alzheimer' s Disease; Amyloid beta-42; Amyloid beta-Protein; Career Choice; Cognitive deficits; Dementia; Development; Enzymes; Female; Functional disorder; Future; In Vitro; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Knowledge; Latino; Magnesium; Measurement; Mediating; Mentors; Mitochondria; Molecular; Mus; NADPH Oxidase; Neurodegenerative Disorders; Neurosciences; Oxidative Stress; PTGS2 gene; Pathway interactions; Reactive Oxygen Species; Research; Research Activity; Research Personnel; Risk Factors; Role; Structure; Synapses; Synaptic plasticity; TNF gene; Testing; Training; Vertebral column; Work; cytokine; doctoral student; effective therapy; efficacy study; experience; morris water maze; mouse model; neuroinflammation; novel; novel therapeutics; object recognition; programs; skills; tau Proteins; therapeutic target

This supplement is to support a PhD student Ariel Nieves who is a Latino female and a citizen of USA. The candidate Ariel Nieves will participate in the following research activities related to Aim 1: Efficacy and mechanism of Mg2+ on reducing oxidative stress and neuroinflammation and Aim 2: Efficacy and mechanism of Mg2+ on inhibiting Aβ-induced synaptic loss and dysfunction. In Aim 1, the candidate will examine if and how elevated Mg2+ level will reduce reactive oxygen species (ROS) originated from mitochondria and/or NADPH oxidase after oligomeric Aβ42 stimulation. Then, we will investigate the involvement of NFκB pathway-mediated inflammation, and if elevated Mg2+ level will inhibit pro-inflammatory enzymes COX-2 and iNOS expression, as well as cytokines secretion (e.g., IL-1, IL-6, and TNFα). Last, to further validate the protective role of Mg2+ in oxidative stress and inflammation suppression, similar testing will be carried out in neuro-inflammatory AD mouse models. In Aim 2, the candidate will study the efficacy of Mg2+ on Aβ-induced alterations in synaptic structures (e.g. spine and PSD-95) and function (e.g. AMPAR-mediated mEPSCs), as well as on inhibition of Aβ-induced tau hyperphosphorylation and mitochondrial fragmentation in vitro. In addition, synaptic plasticity and cognitive deficits in AD mouse after Mg2+ treatment will be evaluated using LTP/LTD measurements as well as Morris water maze and novel-object recognition task, respectively. A robust training plan has been put in place for the candidate to contribute intellectually to the research, and to enhance her research skills and knowledge regarding the field of neuroscience related to aging and Alzheimer’s research. Ariel’s research capability will be substantially enhanced through a rigorous training and become a productive researcher after the training. Moreover, the trainee’s development will be enhanced through a program of structured mentoring activities to provide the skills, knowledge and experience to prepare her to excel in her career paths. The mentoring plan follows the guidance of recognized scientific and professional standards on how to enhance trainee’s experience.

这一补充是为了支持美国公民、拉丁裔女性博士生艾丽尔·尼维斯。这个 候选人艾丽尔·尼维斯将参加以下与目标1有关的研究活动：功效和 镁离子减轻氧化应激和神经炎症的机制及目的2：疗效和机制 镁离子抑制A-β诱导的突触丢失和功能障碍在目标1中，候选人将检查是否以及如何 升高的镁离子水平将减少源于线粒体和/或NADPH的活性氧物种(ROS) 寡聚体Aβ42刺激后的氧化酶。然后，我们将研究核因子κB途径介导的参与 炎症，如果升高的镁水平会抑制促炎酶COX-2和iNOS的表达，AS 以及细胞因子的分泌(如IL-1、IL-6和肿瘤坏死因子α)。最后，进一步验证了镁离子的保护作用。 氧化应激和炎症抑制，类似的测试将在神经炎性AD中进行 老鼠模型。在目标2中，候选人将研究镁离子对A-β诱导的突触改变的效果 结构(如脊柱和PSD-95)和功能(如AMPAR介导的mEPSCs)以及对 β在体外诱导tau蛋白过度磷酸化和线粒体断裂。此外，突触的可塑性 此外，还将使用LTP/LTD测量来评估镁离子治疗后AD小鼠的认知障碍 分别作为Morris水迷宫和新奇物体识别任务。 已经制定了一个强有力的培训计划，让候选人在智力上为研究做出贡献， 并加强她在神经科学领域的研究技能和知识 阿尔茨海默氏症研究。Ariel的研究能力将通过严格的培训和 培训结束后，成为一名多产的研究人员。此外，学员的发展将通过以下方式得到加强 一个有组织的指导活动计划，为她提供技能、知识和经验，为她做好准备 在她的职业道路上出类拔萃。指导计划遵循公认的科学和专业指导 关于如何提高学员体验的标准。