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

项目摘要/摘要 阿尔茨海默病和相关痴呆症(ADRD)给个人和公共卫生带来了重大负担， 目前几乎没有可用的干预措施来延缓或防止病情进展。神经发病机制 ADRD的发生既取决于遗传风险因素，也取决于非遗传风险因素；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 很大程度上没有成功。因此，在我们对连接的机制的理解上存在很大差距 全身性炎症导致ADRD的发病机制，预防我们有效降低风险的能力 通过以炎症通路为靶点来治疗痴呆症。目前的模型描绘了一个漫长的前兆阶段 在认知衰退开始之前。确定炎症活动的机械性途径 这一阶段将提供更精确的干预目标。全身性炎症 在哮喘中的发生代表了一个非常新的靶点来研究在 临床前阶段。哮喘是一种慢性炎症性呼吸道疾病，通常始于 儿童时期的痴呆症影响了大约10%的美国人口，并与患痴呆症的风险更大有关。 阿尔茨海默病的主要神经病理特征是淀粉样斑块和神经纤维缠结。 然而，神经炎症已经成为AD病理的一个重要组成部分。动物 哮喘模型显示，呼吸道可导致神经炎症和神经变性。 在人类中，我们展示了哮喘损害大脑的脑部成像证据 并与神经炎、淀粉样蛋白、tau和认知功能下降的生物标志物有关。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 哪种哮喘会影响大脑健康，并增加患阿尔茨海默病的风险。我们将纵向结合 轻度哮喘的人PET成像模型急性哮喘发作对小胶质细胞的影响 激活，和横断面PET成像比较无缘性哮喘患者的胶质细胞激活 严重程度各不相同。这将得到哮喘AD共病小鼠模型的补充 解决以下目标：(1)确定全身性和神经性炎症之间的机制联系 通过测量参与呼吸道反应的神经胶质细胞激活和关键信号通路的变化 哮喘的炎症(2)决定了生物标记物在淀粉样蛋白，Tau， 神经退行性变分类系统与哮喘严重程度和哮喘相关胶质细胞的关系 哮喘加速AD病理发展的变化及程度(3) 探索神经炎症与认知能力之间的关系。由此产生的 知识将描绘在慢性炎症性疾病中活跃的信号通路 ADRD风险，最终目标是刺激精确针对这些途径的新疗法。

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.