Communicating Lung Dysfunction to the Brain in Alzheimer's Disease

阿尔茨海默氏病将肺功能障碍传达给大脑

• 批准号: 10711004
• 负责人: Colin K Combs
• 金额: $ 170.36万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711004
• 关键词: Abeta synthesis; Address; Adrenal Cortex Hormones; Affect; Age; Allergens; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Asthma; Attenuated; Behavior; Biology; Blood; Brain; Cause of Death; Cell Communication; Chronic; Chronic lung disease; Communication; Data; Disease; Disease Progression; Elderly; Encephalitis; Environmental Risk Factor; Epithelium; Exposure to; Female; Functional disorder; Gene Proteins; Genetic; Gliosis; Human; Immune; Individual; Inflammation; Inflammatory; Inhalation; Interruption; Intervention; Knock-in; Lung; Lung diseases; Mechanics; Mus; Neurodegenerative Disorders; Organ; Outcome; Peripheral; Phenotype; Predisposition; Prevalence; Pulmonary Inflammation; Respiratory Disease; Respiratory System; Risk; Risk Factors; Role; Severities; Steroids; Stress; System; Testing; Transgenic Mice; Transgenic Model; Transgenic Organisms; Wild Type Mouse; Work; airway inflammation; airway remodeling; asthma exacerbation; asthma model; asthmatic; beta secretase; beta-site APP cleaving enzyme 1; chronic inflammatory disease; chronic inflammatory lung disease; comorbidity; cytokine; demented; fluticasone; genetic approach; human disease; immune cell infiltrate; immunoreactivity; inhibitor; male; mouse model; mutant; novel; novel strategies; novel therapeutic intervention; pharmacologic; prevent; protein expression; pulmonary function; pyroglyphid

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.

摘要 据估计，美国有500万人患有阿尔茨海默病(AD)，预计这一数字将增加到16 到2050年将达到100万。确定和减轻相关的环境风险因素是当前减缓或 防止AD进展。外周到大脑免疫细胞通讯的日益重视 疾病进展提示慢性外周炎症性疾病可能会影响大脑的变化 在AD期间。基于哮喘患病率在老年人中增加的事实，我们将测试一种 肺-脑交通轴可通过主要关注哮喘的病理生理学来加强AD的发病。我们的 使用混合过敏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，验证了肺部和大脑之间可能存在的炎症串扰。 此外，通过检测转基因的AppNL-G-F小鼠AD模型，我们观察到基础肺功能障碍和 AD大鼠肺上皮细胞APP表达增加。更重要的是，这些小鼠的哮喘诱因 大脑Aβ水平升高，支持这样一种观点，即AD不仅改变了肺部炎症， 但额外的肺炎性应激会加剧大脑中的AD病理。我们将全面描述 Aim One中AD相关肺功能障碍的时间变化并确定肺上皮APP或Aβ 是导致独一无二的AD相关肺功能障碍的原因。在目标二中，我们将使用遗传方法来 评估减弱APP的表达或肺组织特异性产生的β是否足以减毒 哮喘不仅是一种表型，而且是哮喘增强AD小鼠大脑变化的能力。最后，在AIM中 第三，我们将确定药物对AD小鼠Aβ产生的抑制是否足以 改善哮喘的表型和AD的恶化。这项研究将定义AD的一个新方面 涉及肺功能障碍和哮喘向大脑传达变化的能力，这种能力在很大程度上还没有明确的特征 加重阿尔茨海默病我们还将说明哮喘和阿尔茨海默病的双向肺-脑轴 这种情况会增加另一种情况的风险或严重性。我们的工作成果将为我们提供一个新的 了解可能与阿尔茨海默病以外的需求相关的疾病并存。最后，我们将定义一个 通过靶向大脑外的变化来减轻AD的新方法。