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

杂色曲霉和 Th2 肺脑轴在阿尔茨海默病样神经病理学中的作用

• 批准号: 10391962
• 负责人: Michelle L Block
• 金额: $ 66.06万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391962
• 关键词: Affect; Agonist; Air Pollution; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Antibodies; Aspergillus; Asthma; Attenuated; Automobile Driving; Blood Circulation; Brain; C57BL/6 Mouse; Cells; Central Nervous System Diseases; Cognition; Data; Dementia; Disease Marker; Disease Progression; Elderly; Environment; Environmental Exposure; Environmental Risk Factor; Etiology; Exposure to; Genetic; Genetic Transcription; HMGB1 gene; Human; Immune; Immune response; Indoor environment; Infiltration; Inhalation; Inhalation Exposure; Interleukin-5; Link; Lung; Lung immune response; Measures; Memory; Microglia; Modification; Molds; Morphology; Mus; Mutation; Myeloid Cells; Neurites; Neurodegenerative Disorders; Neuroimmune; Pathogenesis; Pathology; Peripheral; Physiology; Process; Pulmonary Inflammation; Pulmonary Pathology; Respiratory Disease; Role; Senile Plaques; TLR4 gene; TREM2 gene; Testing; amyloid pathology; cohort; eosinophil; experimental study; frontal lobe; inhibitor; loss of function; neuroinflammation; neuropathology; pollutant; receptor; response

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.

项目概要 阿尔茨海默病 (AD) 是最常见的神经退行性疾病，也是痴呆症的主要原因 现有的 AD 治疗无法阻止疾病进展，这凸显了迫切需要 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 尽管空气污染等吸入性暴露与阿尔茨海默病有关，但很大程度上尚未被探索。 此外，外周免疫紊乱与 AD 发病机制相关，包括最近的证据 哮喘（具有肺部 Th2 反应）与 AD 风险增加有关。 致病机制和环境暴露尚不清楚。 室内环境与哮喘等呼吸道疾病有关。 表明真菌污染物可能会影响认知，而​​小鼠实验研究表明神经免疫和 我们的数据表明，接触活的花色曲霉（一种常见的丝状曲霉）会发生记忆变化。 与潮湿的室内环境和哮喘相关的真菌会导致肺部炎症和免疫 小鼠 Th2 肺部反应的细胞浸润指标，我们认为这与 A. 与这一前提一致，数据还记录了花斑变色龙的神经免疫变化。 花色吸入，包括额叶神经炎症转录标记物升高和 重要的是，数据表明，接触云芝会增加 β 值。 淀粉样蛋白 (Aβ) 斑块数量增加并增加 5xFAD 小鼠的营养不良性神经突，证明 A. 云芝吸入会增强 Aβ 病理学，这是 AD 的一个标志。从机制上讲，我们发现云芝。 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，这是遏制和清除所必需的 AD 中的斑块。吸入杂色蘑菇如何影响正常生理和过程中的神经免疫反应。 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 环境暴露的后果是通过外周神经系统调节神经免疫反应 我们观察到，当云芝菌发生变化时，免疫细胞的变化和循环因子会加剧中枢神经系统疾病。 暴露增强了 Aβ 病理学，多种循环因子增加，包括 IL-5 和 HMGB1。 我们的目标是探索 AIM1) IL-5、AIM2) HMGB1 和 AIM3) TREM2 对 A. versicolor 诱导的作用 肺部免疫反应、神经炎症和 Aβ 神经病理学这些发现将揭示关键。 Th2 肺脑轴中的机制负责 Th2 肺反应和云芝菌 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。