Influence of systemic immune inflammation upon the tauopathy phenotype in mouse models

全身免疫炎症对小鼠模型tau蛋白病表型的影响

• 批准号: 9592680
• 负责人: David Morgan
• 金额: $ 41.82万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9592680
• 关键词: Influence; systemic; immune; inflammation; upon

 DESCRIPTION (provided by applicant): This project is in response to RFA "Immune and Inflammatory Mechanisms in AD". A consortium of investigators with expertise in mouse models, behavior, surgery, histopathology, neurochemistry, immunology, brain aging and Alzheimer's disease have been assembled to approach the problem of systemic immune system influences on the development of AD pathology, specifically tau deposition. Two major questions are addressed. The first question regards the role of physiological aging in the nervous system, the cellular/humoral circulation or both in regulating the accumulation of tau pathology or modulating its impact upon the CNS. We plan to discern the relative contribution of CNS versus systemic influences by attempting to rejuvenate or senesce the systemic circulation and monitor the impact upon the tau phenotype in the brain of young and old mice. Our preliminary data indicate that even by middle age mice have enhanced sensitivity to tau over- expression, with accumulation of pathology when tauopathy is initiated at 11 mo, but not at 4 mo. The second question regards the influence of immunostimulants as sterile mimetics of different types of infections. Lipopolysaccharide will be used as a prototype, but immunostimulants mimicking viral and fungal infections will also be examined. An extensive human literature indicates that infections or trauma resulting in delirium increase risk of AD and accelerate the course of cognitive decline. We further expect these immunostimulants will exacerbate the tau pathology, and synergize with the age of the mice. Finally, we will seek to counter the impacts of age or innate immunostimulants by reversing the effects of aging on specific proteins in the circulation. This is based on recent work by others that indicate the rejuvenating effects of parabiosis can be replicated by supplementation with a single protein shown to decline during aging. Other work shows the senescing effects of parabiosis can be replicated by another individual protein that increases with age. We will discover additional candidate proteins through proteomic analysis of plasma protein responses to age and immunostimulant treatment. Success in these aims will provide candidate targets to be explored for intervention in individuals with delirium to make the cognitive decline reversible, as in younger individuals, rather than contributing to the onset or progression of dementia.

 描述（由申请人提供）：该项目是对 RFA“AD 中的免疫和炎症机制”的回应，由在小鼠模型、行为、手术、组织病理学、神经化学、免疫学、大脑衰老和阿尔茨海默氏病方面具有专业知识的研究人员组成。聚集起来解决系统免疫系统对 AD 病理学发展的影响，特别是 tau 沉积，第一个问题涉及神经生理老化的作用。我们计划通过尝试恢复或衰老全身循环并监测对 CNS 的影响来辨别 CNS 与全身影响的相对贡献。我们的初步数据表明，即使到了中年小鼠，对 tau 过度表达的敏感性也会增强，当 tau 病在 11 个月时开始，而不是在 4 个月时，病理学就会积累。第二个问题是，免疫刺激剂作为不同类型感染的无菌模拟物的影响将被用作原型，但模拟病毒和真菌感染的免疫刺激剂也将被研究，大量的人类文献表明，感染或创伤会导致感染。谵妄会增加 AD 的风险并加速认知能力下降的过程，我们进一步预计这些免疫刺激剂会恶化 tau 病理学，并与小鼠的年龄产生协同作用。通过逆转衰老对循环中特定蛋白质的影响来对抗年龄或先天免疫刺激剂的影响这是基于其他人最近的研究，表明联体共生的恢复活力可以通过补充一种在衰老过程中会下降的蛋白质来复制。其他研究表明，联体共生的衰老效应可以通过另一种随年龄增长而增加的蛋白质来复制，我们将通过对血浆蛋白对年龄和免疫刺激治疗的反应进行蛋白质组学分析来发现其他候选蛋白质。提供对谵妄患者进行干预的候选目标，以使认知能力下降可逆转，就像年轻人一样，而不是导致痴呆症的发作或进展。