Investigating the mechanisms by which systemic inflammation promotes Alzheimer’s disease: Asthma as a model and modifiable risk factor

研究全身炎症促进阿尔茨海默病的机制：哮喘作为模型和可改变的危险因素

• 批准号: 10661382
• 负责人: NIZAR N JARJOUR
• 金额: $ 226.11万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661382
• 关键词: Acceleration; Acute; Address; Affect; Airway Disease; Allergens; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer' s neuropathogenesis; Alzheimer’s disease biomarker; Amyloid; Animal Model; Anti-Inflammatory Agents; Asthma; Binding; Biological Markers; Black American; Blood; Brain; Brain imaging; Cells; Childhood; Chronic; Classification; Complement; Dementia; Development; Environmental Exposure; Extrinsic asthma; Functional disorder; Genetic; Goals; Human; IL17 gene; Impaired cognition; Individual Differences; Inflammasome; Inflammation; Inflammatory; Inhalation; Intervention; Link; Location; Lung; Measures; Memory; Microglia; Modeling; Mus; Nerve Degeneration; Neurites; Neurocognitive; Neurofibrillary Tangles; Neuroglia; Normal Range; Pathogenesis; Pathway interactions; Pattern; Performance; Pharmaceutical Preparations; Phase; Population; Population Study; Positron-Emission Tomography; Prevention; Public Health; Relative Risks; Research; Rheumatoid Arthritis; Risk; Risk Factors; Risk Reduction; Role; Sampling; Senile Plaques; Severities; Signal Pathway; Sleep; Specificity; Synapses; System; Testing; Time; Underserved Population; Woman; airway inflammation; asthma model; behavior measurement; brain health; chronic inflammatory disease; circulating biomarkers; cognitive performance; cognitive task; comorbidity; dementia risk; density; design; experience; glial activation; human data; human model; indexing; knowledge of results; modifiable risk; mouse model; neuroinflammation; neuropathology; non-genetic; novel; novel therapeutic intervention; pre-clinical; precision medicine; prevent; radioligand; response; systemic inflammatory response; tau Proteins; tau-1

Project Summary / Abstract Alzheimer’s disease and related dementias (ADRD) pose major personal and public health burdens, with few interventions currently available to delay or prevent progression. The neuropathogenesis of ADRD is dependent on both genetic and non-genetic risk factors; the latter appearing to accelerate AD development via inflammatory pathways. Chronic inflammatory diseases compromise brain health and increase dementia risk, yet anti-inflammatory drug trials have been largely unsuccessful. Thus, a major gap exists in our understanding of the mechanisms that connect systemic inflammation to the pathogenesis of ADRD, preventing our ability to effectively reduce risk of dementia by targeting inflammatory pathways. Current models portray a long prodromal phase preceding onset of cognitive decline. Identifying the mechanistic inflammatory pathways active during this phase would provide more precise intervention targets. The systemic inflammation that occurs in asthma represents a highly novel target for study of mechanistic pathways operational in the preclinical phase. Asthma is a chronic inflammatory airway disease that typically begins in childhood, affects ~10% of the US population and is associated with greater risk for dementia. Primary neuropathological features of AD are amyloid-ß plaques and neurofibrillary tangles. However, neuroinflammation has emerged as an important component of AD pathology. Animal models of asthma show that neuroinflammation and neurodegeneration can result from airway inflammation and in humans, we show brain imaging evidence that asthma compromises brain health and relates to biomarkers of neuroinflammation, amyloid, tau, and cognitive decline. Here, we propose to use [18F]-FEPPA PET imaging to assess neuroinflammation as a mechanism by which asthma impacts brain health and confers greater risk for AD. We will combine longitudinal human PET imaging in mild asthma to model effects of an acute asthma episode on microglial activation, and cross-sectional PET imaging to compare glial activation in unprovoked asthma at varying severity levels. This will be complemented by a mouse model of asthma AD comorbidity to address the following aims: (1) identify mechanistic links between systemic and neuroinflammation by measuring changes in glial activation and key signaling pathways involved in response to airway inflammation in asthma (2) determine how patterns of biomarker expression in the Amyloid, Tau, Neurodegeneration classification system relate to asthma severity and asthma-related glial alterations and the extent to which asthma accelerates development of AD pathology and (3) explore the relationship between neuroinflammation and cognitive performance. The resulting knowledge will delineate the signaling pathways active in chronic inflammatory diseases that confer ADRD risk, with the ultimate goal to spur novel treatments that precisely target these pathways.

项目摘要 /摘要 阿尔茨海默氏病和相关痴呆症（ADRD）构成了主要的个人和公共卫生伯恩斯， 目前，很少有干预措施延迟或防止进展。神经病发生 ADRD的依赖于遗传和非遗传危险因素；后者似乎 通过炎症途径加速AD开发。慢性炎症性疾病 损害大脑健康并增加痴呆症风险，但抗炎药物试验已经是 很大程度上没有成功。这是我们对连接机制的理解中存在的一个主要差距 系统性炎症对ADRD的发病机理，阻止了我们有效降低风险的能力 通过靶向炎症途径的痴呆症。当前的模型描绘了一个长期的阶段 在认知能力下降之前。识别有效的机械炎症途径 在此阶段，将提供更精确的干预目标。系统性炎症 发生在哮喘中是研究机械途径在 临床前阶段。哮喘是一种慢性炎症性气道疾病，通常从 童年，影响约10％的美国人口，与更大的痴呆风险有关。 AD的主要神经病理特征是淀粉样蛋白斑块和神经原纤维缠结。 但是，神经炎症已成为AD病理学的重要组成部分。动物 哮喘的模型表明，神经炎症和神经退行性可以由气道引起 炎症和人类，我们显示脑成像证据表明哮喘会损害大脑 健康和与神经炎症，淀粉样蛋白，tau和认知能力下降的生物标志物的关系。这里， 我们建议使用[18F] -Feppa PET成像来评估神经炎症作为一种机制 哮喘会影响大脑健康，并承认广告的风险更大。我们将结合纵向 在轻度哮喘中的人类宠物成像，以建模急性哮喘发作对小胶质细胞的影响 激活和横截面PET成像以比较无端哮喘的神经胶质激活 严重程度的不同。这将通过合并症的鼠标模型完成 解决以下目的：（1）确定系统性和神经炎症之间的机械联系 通过测量响应气道的胶质激活和关键信号通路的变化 哮喘（2）中的炎症确定生物标志物表达的模式如何在淀粉样蛋白，tau中， 神经变性分类系统与哮喘严重程度和与哮喘相关的神经胶质有关 变化和哮喘在多加速AD病理发展的程度和（3） 探索神经炎症与认知表现之间的关系。结果 知识将描述慢性炎症性疾病中活跃的信号通路 ADRD风险，其最终目标是刺激精确针对这些途径的新型治疗方法。