The Role of Aspergillus versicolor and the Th2 Lung-Brain Axis in Alzheimer's Disease-like Neuropathology

项目总结 阿尔茨海默病(AD)是最常见的神经退行性疾病，也是痴呆的主要原因 在老年人身上。现有的AD治疗方法无法阻止疾病的进展，突显出迫切需要 确定导致AD的潜在病因和病理生物学。环境风险因素在AD中的作用是 虽然吸入性暴露，如空气污染，已被认为与AD有关，但基本上未被探索。 此外，外周免疫紊乱与AD的发病机制有关，包括最近的证据 有肺Th2反应的哮喘与AD风险增加有关。然而，潜在的 可归咎的机制和环境暴露尚不清楚。暴露在潮湿的真菌生物气雾剂中， 室内环境与呼吸道疾病有关，如哮喘。关于人类小群体的研究 表明真菌污染物可能会影响认知，而对小鼠的实验研究表明，神经免疫和 记忆发生了变化。我们的数据表明，接触活的杂色曲霉，一种常见的丝状细菌 与潮湿的室内环境和哮喘有关的真菌会引起肺部炎症和免疫 我们认为，小鼠Th2肺反应的细胞浸润是A. 杂色会影响大脑。与这一前提一致的是，数据还证明了A。 吸入杂色，包括额叶和额叶神经炎症的转录标记物升高 皮质小胶质细胞形态改变。重要的是，数据显示，接触杂色曲霉会增加贝塔系数。 在5xFAD小鼠中，淀粉样蛋白(Aβ)斑块的数量和营养不良轴突的增加表明，A。 吸入杂色增强了β的病理，这是AD的一个特征。从机制上讲，我们发现杂色黄曲霉 暴露改变了5xFAD小鼠斑块周围的环境，导致斑块水平降低 相关的TREM2和较少的斑块相关小胶质细胞，这是包含和清除所必需的 AD的斑块。在正常生理和生理状态下，吸入杂色曲霉如何影响神经免疫反应 在正在进行的AD过程中的作用尚不清楚，但肺-脑轴假说认为，肺 环境暴露的后果通过外周调节神经免疫反应 免疫细胞变化和循环因子增强中枢神经系统疾病。我们观察到，当杂色黄曲霉 暴露使Aβ病理加重，几种循环因子升高，包括IL-5和HMGB1。因此， 我们的目的是探讨AIM1)IL-5、AIM2)HMGB1和AIM3)TREM2在杂色拟青霉诱导中的作用 肺免疫反应，神经炎症和Aβ神经病理学。这些发现将揭示关键 Th2肺-脑轴中负责Th2肺反应和杂色曲霉的机制 影响大脑并增强AD过程，创造干预和缓解的关键机会 神经病理学。

PROJECT SUMMARY Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and the leading cause of dementia in the elderly. Available AD treatment is unable to halt disease progression, highlighting the urgent need to identify the potential etiology and pathobiology driving AD. The role of environmental risk factors in AD is largely unexplored, although inhaled exposures, such as air pollution, have been implicated in AD. Additionally, peripheral immune perturbation is associated with AD pathogenesis, including recent evidence associating asthma, which has a pulmonary Th2 response, with increased AD risk. However, the underlying mechanisms and environmental exposures culpable are unknown. Exposure to fungal bioaerosols in damp, indoor environments is linked with respiratory diseases, such as asthma. Studies with small human cohorts suggest fungal pollutants may impact cognition, while experimental studies in mice show neuroimmune and memory changes. Our data demonstrate that exposure to live Aspergillus versicolor, a common filamentous fungus associated with damp indoor environments and asthma, causes pulmonary inflammation and immune cell infiltration indicative of a Th2 pulmonary response in mice, which we propose is culpable in how A. versicolor affects the brain. Consistent with this premise, data also document neuroimmune changes with A. versicolor inhalation, including elevated transcriptional markers of neuroinflammation in the frontal lobe and changes in cortical microglia morphology. Importantly, data show that A. versicolor exposure increases beta amyloid (Aβ) plaque number and augments dystrophic neurites in 5xFAD mice, demonstrating that A. versicolor inhalation augments Aβ pathology, a hallmark of AD. Mechanistically, we found that A. versicolor exposure changes the environment surrounding plaques in 5xFAD mice, causing lower levels of plaque associated TREM2 and fewer plaque associated microglia, which are necessary for containing and clearing plaques in AD. How A. versicolor inhalation affects the neuroimmune response during normal physiology and during ongoing AD processes is unknown, but the Lung-Brain Axis hypothesis holds that the pulmonary consequences of environmental exposures dysregulates the neuroimmune response through peripheral immune cell changes and circulating factors to augment CNS disease. We observed that when A. versicolor exposure augmented Aβ pathology, several circulating factors increased, including IL-5 and HMGB1. As such, our AIMS are to explore the role of AIM1) IL-5, AIM2) HMGB1 and AIM3) TREM2 on A. versicolor-induced pulmonary immune responses, neuroinflammation, and Aβ neuropathology. These findings will reveal key mechanisms in the Th2 Lung- Brain Axis responsible for how the Th2 pulmonary response and A. versicolor affect the brain and augment AD processes, creating critical opportunities to intervene and mitigate neuropathology.