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

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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.