Communicating Lung Dysfunction to the Brain in Alzheimer's Disease

总结 据估计，美国有500万人患有阿尔茨海默病（AD），预计将增长到16 到2050年，亿。确定和减轻相关的环境风险因素是目前的一项战略， 预防AD进展。在免疫过程中，外周免疫细胞与脑免疫细胞之间的通讯越来越受到重视。 疾病进展提示慢性外周炎性疾病可能影响大脑变化 在AD期间。基于哮喘患病率在老年人中增加的事实，我们将测试以下想法： 肺-脑通讯轴可以通过主要关注哮喘病理生理学而增强AD。我们 使用混合变应原诱导的哮喘小鼠模型的初步数据显示， 在雌性小鼠的脑细胞因子中，证实了肺和脑之间可能的炎症串扰。 此外，检查AD的转基因AppNL-G-F小鼠模型，我们观察到基础肺功能障碍， 由于AD，肺上皮中APP表达增加。更重要的是，这些小鼠的哮喘诱导 脑Aβ水平增加，支持AD不仅改变了肺部炎症， 但是额外的肺部炎症应激增强了脑中的AD病理学。我们将充分描述 目的1中AD相关肺功能障碍的时间变化，并确定肺上皮APP或Aβ 导致了AD相关的肺功能障碍在目标二中，我们将使用遗传方法， 评估特异性减弱肺中APP表达或Aβ产生是否足以减弱 哮喘表型，但也有能力的哮喘，以加强大脑的变化，在AD小鼠。最后，在Aim 第三，我们将确定AD小鼠中Aβ产生的药理学抑制是否足以 改善哮喘表型和AD的恶化。这项研究将定义AD的一个新方面， 包括肺功能障碍和哮喘向大脑传达变化的能力， 加剧AD。我们还将说明哮喘和AD中的双向肺脑轴， 一种情况可能会增加另一种情况的风险或严重程度。我们的工作成果将提供新的 了解可能与AD以外的需求相关的疾病合并症。最后，我们将定义一个 通过靶向脑外变化来减轻AD的新方法。

Summary An estimated 5 million individuals have Alzheimer’s disease (AD) in the US, which is expected to grow to 16 million by 2050. Identifying and mitigating relevant environmental risk factors is a current strategy to slow or prevent AD progression. The growing appreciation of peripheral to brain immune cell communication during disease progression suggests that chronic peripheral inflammatory disease may influence brain changes during AD. Based upon the fact that asthma prevalence increases in the elderly, we will test the idea that a lung-brain communication axis can potentiate AD by focusing mainly on asthma pathophysiology. Our preliminary data using a mixed allergen-induced mouse model of asthma demonstrated a significant increase in brain cytokines in female mice, validating possible crosstalk of inflammation between the lung and brain. Moreover, examining a transgenic AppNL-G-F mouse model of AD, we observed basal lung dysfunction and increased APP expression in the lung epithelium due to AD. More importantly, asthma induction in these mice increased brain Aβ levels, supporting the notion that there is not only altered lung inflammation because of AD, but additional lung inflammatory stress potentiates AD pathology in the brain. We will fully characterize the temporal changes in AD-related lung dysfunction in Aim one and determine whether lung epithelial APP or Aβ is responsible for the unique AD-associated lung dysfunction. In Aim two, we will use a genetic approach to assess whether attenuating APP expression or Aβ production specifically in the lung is sufficient to attenuate an asthma phenotype but also the ability of asthma to potentiate brain changes in AD mice. Finally, in Aim three, we will determine whether pharmacologic inhibition of Aβ production in AD mice is sufficient to ameliorate an asthma phenotype and exacerbation of AD. This study will define a novel aspect of AD that involves lung dysfunction and a largely uncharacterized ability of asthma to communicate changes to the brain to exacerbate AD. We will also illustrate a bi-directional lung-brain axis in asthma and AD in which either condition can increase the risk or severity of the other. The outcomes of our work will provide a new understanding of disease comorbidities that may be relevant to needs beyond AD. Finally, we will define a novel approach to attenuate AD by targeting changes outside the brain.