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

 描述（由申请人提供）：本项目是对RFA“AD中的免疫和炎症机制”的回应。一个具有小鼠模型、行为、手术、组织病理学、神经化学、免疫学、脑老化和阿尔茨海默病专业知识的研究者联盟已经被召集起来，以解决全身免疫系统影响AD病理学发展的问题，特别是tau沉积。两个主要问题得到解决。第一个问题涉及神经系统、细胞/体液循环或两者中生理老化在调节tau病理学积累或调节其对CNS的影响中的作用。我们计划通过尝试恢复或衰老体循环并监测对年轻和老年小鼠脑中tau表型的影响来辨别CNS与全身影响的相对贡献。我们的初步数据表明，即使是中年小鼠也对tau过度表达具有增强的敏感性，当tau病变在11个月时开始时，病理学积累，但在4个月时没有。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。脂多糖将被用作原型，但模拟病毒和真菌感染的免疫刺激剂也将被检查。大量人类文献表明，导致谵妄的感染或创伤会增加AD的风险，并加速认知能力下降的进程。我们进一步预期这些免疫刺激剂将加剧tau病理学，并与小鼠的年龄协同作用。最后，我们将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工作，这些工作表明，通过补充一种在衰老过程中下降的单一蛋白质，可以复制联体共生的恢复效果。其他研究表明，共生的衰老效应可以被另一种随年龄增长而增加的蛋白质复制。我们将通过对血浆蛋白对年龄和免疫刺激剂治疗的反应进行蛋白质组学分析来发现其他候选蛋白。这些目标的成功将为谵妄患者的干预提供待探索的候选目标，以使认知能力下降可逆，就像年轻人一样，而不是促进痴呆症的发作或进展。

 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.