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

项目总结/摘要 阿尔茨海默病和相关痴呆症（ADRD）造成了重大的个人和公共卫生负担， 目前可用于延迟或预防进展的干预很少。神经发病机制 ADRD的发生取决于遗传和非遗传风险因素;后者似乎 通过炎症途径加速AD的发展。慢性炎性疾病 损害大脑健康并增加痴呆症风险，但抗炎药物试验一直是 基本上不成功。因此，在我们对连接的机制的理解中存在着一个重大的差距。 全身性炎症能使ADRD的发病机制，阻止我们有效降低风险的能力 治疗痴呆症的方法。目前的模型描绘了一个漫长的前驱期 在认知能力下降之前识别活跃的机械性炎症通路 在这一阶段将提供更精确的干预目标。全身性炎症， 发生在哮喘代表了一个高度新颖的目标，研究机制途径的运作， 临床前阶段。哮喘是一种慢性炎症性气道疾病， 儿童痴呆症影响约10%的美国人口，并与痴呆症的风险更大有关。 AD的主要神经病理特征是淀粉样蛋白斑块和神经纤维缠结。 然而，神经炎症已成为AD病理学的重要组成部分。动物 哮喘模型显示，气道炎症和神经退行性变可导致 在人类中，我们展示了大脑成像证据，表明哮喘损害了大脑 本发明涉及神经系统炎症、淀粉样蛋白、tau蛋白和认知衰退的生物标志物。在这里， 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，增加患AD的风险。我们将联合收割机纵向 轻度哮喘患者PET成像模拟急性哮喘发作对小胶质细胞的影响 激活和横断面PET成像，以比较 不同的严重程度。这将通过哮喘AD合并症的小鼠模型来补充， 解决以下目标：（1）确定系统性和神经炎症之间的机制联系 通过测量神经胶质细胞活化和参与气道反应的关键信号通路的变化， 哮喘中的炎症（2）决定了淀粉样蛋白，Tau， 神经退行性变分级系统与哮喘严重程度及哮喘相关神经胶质细胞的关系 改变和哮喘加速AD病理学发展的程度，以及（3） 探索神经炎症与认知表现之间的关系。所得 知识将描绘慢性炎症性疾病中的信号通路， ADRD风险，最终目标是刺激精确靶向这些途径的新治疗。

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.