Increasing evidence supports that the Lung-Brain Axis may be a common mechanism regulating diverse CNS diseases. More specifically, how pulmonary damage due to toxicant exposure (ex. paraquat - Parent RO1 vs. Aspergillus versicolor-Supplement) regulates common and/or discordant neurodegenerative processes in Parkinson's disease and Alzheimer's disease (AD) is poorly understood. The over-arching hypothesis of this supplement integrated with the parent RO1 is that the specific type of pulmonary pathology (paraquat: pro- inflammatory/oxidative stress vs. Aspergillus versicolor: allergic pulmonary response) causes both a common and distinct profile of circulating peripheral signals with unique CNS effects, which is further modified by specific ongoing CNS disease processes. While most CNS research has focused on outdoor pollution, individuals in the U.S. spend approximately 87% of their time indoors. Mold from damp environments (ex. A. versicolor) is a common indoor air pollutant associated with allergic pulmonary responses, such as asthma. Importantly, recent evidence suggests a potential link between mold exposure and cognitive deficits. Interestingly, asthma (an allergic pulmonary response associated with mold exposure) has been linked to increased risk of AD and several anti-asthmatic drugs that inhibit the allergic pulmonary response have been shown to ameliorate cognitive decline and neuroinflammation in AD mouse models. Further, murine models of asthma have been shown to result in cognitive decline and neuroinflammation. However, the mechanisms by which an allergic pulmonary response, particularly in response to mold, might impact cognition and AD are unknown. To begin to address these questions with the supplement, we test the specific hypothesis that indoor air pollution (Aspergillus versicolor, a common mold associated with asthma and trigger of the allergic pulmonary response) causes the release of brain regulating circulating factors (Lung-Brain Axis, ex. HMGB1), triggers neuroinflammation, impairs cognition, and augments AD-like neuropathology. Preliminary data demonstrate that moderate A. versicolor inhalation exposure over 4 weeks results in neuroinflammation and significant changes in the broad neuroinflammation transcriptome, demonstrating that there are CNS effects with a moderate exposure to mold in control animals. Therefore our specific aims are to:
AIM1) Discern the Role of Aspergillus versicolor inhalation on the Lung-Brain Axis and AD-like neuropathology. If successful, these findings will be among the first to demonstrate that mold, an indoor air pollutant associated with allergic asthma, can augment AD-like neuropathology and provide much needed insight into the mechanisms of the Lung-Brain Axis (assessed in the parent RO1), which is a critical foundation for future basic science and epidemiology research in AD.
These findings will reveal key mechanisms defining how pulmonary damage and Aspergillus versicolor trigger a pro-inflammatory response in the brain to deleteriously impact central nervous system health and cognitive function in Alzheimer's disease, creating critical opportunities to intervene and mitigate pathology.
