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

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性疾病，也是导致痴呆的主要原因 在老年人中。现有的AD治疗无法阻止疾病进展，这突出表明迫切需要 确定驱动AD的潜在病因学和病理生物学。环境危险因素在AD中的作用是 虽然吸入暴露，如空气污染，在很大程度上未被探索，但已涉及AD。 此外，外周免疫紊乱与AD发病机制有关，包括最近的证据 将具有肺Th 2应答的哮喘与AD风险增加相关联。然而，底层 机制和环境暴露的罪责是未知的。暴露在潮湿的真菌生物气溶胶中， 室内环境与哮喘等呼吸道疾病有关。小型人类队列研究 这表明真菌污染物可能会影响认知能力，而小鼠的实验研究显示， 记忆改变我们的数据表明，暴露于活的杂色曲霉，一种常见的丝状真菌， 真菌与潮湿的室内环境和哮喘有关，引起肺部炎症和免疫系统疾病。 细胞浸润表明小鼠的Th 2肺反应，我们认为这是A. 变色会影响大脑与此前提一致，数据也记录了A. 变色吸入，包括额叶神经炎症的转录标志物升高， 皮质小胶质细胞形态学改变。重要的是，数据显示A.变色暴露增加β 淀粉样蛋白（Aβ）斑块数量和增加5xFAD小鼠营养不良的神经突起，表明A. 变色吸入增强Aβ病理，这是AD的标志。从机理上讲，我们发现A. versicolor 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TREM 2和更少的斑块相关的小胶质细胞，这是容纳和清除 AD中的斑块。如何A.变色吸入影响正常生理过程中的神经免疫反应， 在进行中的AD过程是未知的，但肺脑轴假说认为，肺 环境暴露的后果通过外周神经免疫反应失调， 免疫细胞变化和循环因子增加CNS疾病。我们观察到，当A. versicolor 暴露增强Aβ病理，几种循环因子增加，包括IL-5和HMGB 1。因此，在本发明中， 本研究旨在探讨AIM 1）IL-5、AIM 2）HMGB 1和AIM 3）TREM 2在A.变色诱导的 肺免疫反应、神经炎症和Aβ神经病理学。这些发现将揭示 Th 2肺-脑轴中负责Th 2肺反应的机制和A. versicolor 影响大脑并增强AD过程，创造干预和缓解AD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.