Determining the Role of Air Pollution in Alzheimers Disease Mechanisms and Pathology - PROJECT SUMMARY/ABSTRACT: Individuals that are exposed to airborne particulate matter (PM) from wildfires at the wildland-urban interface are at greater risk of developing Alzheimer’s disease (AD), especially older individuals and certain minorities. Though the aerosols from these fires could have indirect means to increase AD risk, inhaled PM can be found within the brain, opening the opportunity for a direct effect on AD processes. Airborne PM is increasingly recognized as a significant public health threat, impacting not only respiratory and cardiovascular health but also posing serious risks to neurological function. Fires at the wildland-urban interface (WUI) produce wildfire organic aerosols (WFOA) from burnt vegetation, as well as high levels of aerosolized copper from burnt building wiring and nanoplastics from burnt possessions. Our preliminary data demonstrates that aerosolized copper and WFOA, at real-world concentrations, rapidly increase brain Aβ levels in a mouse model of AD. Aβ is the peptide that accumulates in hallmark plaques in AD. High levels of Aβ in the brain facilitate its conversion to aggregated insoluble plaques and soluble Aβ oligomers. This proposal will aerosolize PM to determine the real-time acute effects on brain Aβ metabolism and the chronic effects on Ab metabolism and pathology in a mouse model of AD, as well as determine the cellular pathways by which these agents effect AD disease processes. As wildfires burn biomass, organic aerosols that include brown and black carbon (soot) are released into the air. Fresh WFOA impacts residents within tens of miles, but these aerosols can travel hundreds to thousands of miles, undergoing oxidative aging that transforms their chemical properties and increases their potential neurotoxicity. Pollutants exert toxicity through various mechanisms— for instance, copper triggers cell dysfunction and death via cuproptosis via pathways that include oxidative stress and lipid peroxidation, while ultrafine particles, like black carbon and nanoplastics, primarily promote neurotoxicity through inflammation and microglial activation. Our preliminary data demonstrate that copper and WFOA accelerate the rate of Ab aggregation in vitro, a hallmark of AD pathology. We have built a custom inhalation chamber for mice that enables us to measure real-time changes in brain interstitial fluid (ISF) Ab using in vivo microdialysis while mice are exposed to aerosolized PM. To our knowledge, this is the first such chamber to combine acute PM exposure with the simultaneous investigation of real-time AD-relevant cellular mechanisms perturbed in an AD mouse model. We exposed APP/PS1 mice to either aerosolized copper or WFOA for 2 hours twice a day for 5 days to mimic periodic exposure. Aerosolized copper, at concentrations reflecting polluted urban air, rapidly increased ISF Ab levels significantly above baseline after even a single exposure with periodic rises again during subsequent exposures. WFOA also significantly increased ISF Ab. We hypothesize that PM found at the WUI has a direct effect on reactive oxygen species and inflammation in the brain which enhances Ab aggregation and hinders Ab clearance from the brain. This proposal will use in vitro cell models to determine how PM, such as copper, nanoplastics, and WFOA, impacts Ab aggregation rate and reactive oxygen species generation (Aim 1). We will aerosolize these pollutants and assess real-time changes in brain ISF Ab in APP/PS1 mice (Aim 2). We will also investigate whether the effects of PM are due to oxidative stress or the downstream effects of oxidative stress, such as synaptic activity modulation or Aβ clearance, further defining WUI PM’s mechanisms of action in AD. Using a chronic inhalation chamber setup, we will also periodically aerosolize WFOA pollutants or a combination of WFOA, copper and nanoplastic together, as would be experienced at the WUI, over the course of several months to assess the long-term effe
