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

 描述(申请人提供)：该项目是对RFA“AD中的免疫和炎症机制”的回应。一个由小鼠模型、行为学、外科手术、组织病理学、神经化学、免疫学、脑老化和阿尔茨海默病等领域的专家组成的研究小组已经聚集在一起，探讨系统免疫系统对AD病理发展的影响，特别是tau沉积。文中提出了两个主要问题。第一个问题涉及神经系统、细胞/体液循环或两者在调节tau病理堆积或调节其对中枢神经系统的影响方面所起的作用。我们计划通过尝试恢复或衰老体循环，并监测对幼年和老年小鼠脑内tau表型的影响，来辨别中枢神经系统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的过度表达也有更高的敏感性，当tau疗法在11mo开始时病理堆积，但在4mo时不是。第二个问题认为免疫刺激剂的影响是对不同类型感染的无菌模拟。将使用脂多糖作为原型，但也将检查模仿病毒和真菌感染的免疫刺激剂。一份广泛的人类文献表明，感染或创伤导致精神错乱会增加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将加剧tau的病理，并与小鼠的年龄协同作用。最后，我们将寻求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，通过补充一种随着年龄增长而下降的单一蛋白质，可以复制异种共生的恢复活力的效果。其他工作表明，异种生物的衰老效应可以通过另一种随着年龄增加的个体蛋白质来复制。我们将通过对血浆蛋白对AGE和免疫刺激治疗反应的蛋白质组学分析来发现更多的候选蛋白质。这些目标的成功将为对精神错乱患者进行干预提供候选靶点，使认知能力下降可逆，就像年轻人一样，而不是导致痴呆症的发生或发展。

 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.