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.

概括 据估计，美国有 500 万人患有阿尔茨海默病 (AD)，预计这一数字将增至 16 人 到 2050 年，识别和减轻相关环境风险因素是减缓或缓解环境风险的当前战略。 预防 AD 进展。 疾病表明慢性周围炎症性疾病的进展可能会影响大脑的变化 基于老年人哮喘患病率增加的事实，我们将检验以下观点： 肺-脑通讯轴可以通过主要关注哮喘病理生理学来增强 AD。 使用混合过敏原诱导的哮喘小鼠模型的初步数据表明， 在雌性小鼠的脑细胞因子中，验证了肺部和大脑之间炎症可能的串扰。 此外，在检查 AD 转基因 AppNL-G-F 小鼠模型时，我们观察到基础肺功能障碍和 AD 导致肺上皮中 APP 表达增加，更重要的是，这些小鼠诱发哮喘。 大脑 Aβ 水平增加，支持这样的观点：AD 不仅改变了肺部炎症， 但额外的肺部炎症应激会加剧大脑中的 AD 病理。 目标一：AD 相关肺功能障碍的时间变化，并确定肺上皮 APP 或 Aβ 导致独特​​的 AD 相关肺功能障碍。在目标二中，我们将使用遗传方法来治疗。 评估特异性减弱肺部 APP 表达或 Aβ 产生是否足以减弱 哮喘表型以及哮喘增强 AD 小鼠大脑变化的能力 最后，在 Aim 中。 第三，我们将确定对 AD 小鼠中 Aβ 产生的药物抑制是否足以 改善哮喘表型和 AD 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，这在很大程度上是未知的 我们还将说明哮喘和 AD 中的双向肺脑轴，其中任一者。 情况可能会增加其他情况的风险或严重程度，我们的工作成果将提供新的结果。 了解可能与 AD 以外的需求相关的疾病合并症。 通过针对大脑外部的变化来减轻 AD 的新方法。