46 Air pollution, metal oxides, and sex-specific neurodegeneration

Abstract A hallmark of neurodegenerative disorders, including Alzheimer’s Disease (AD), is regional brain “iron (Fe) overload”. What has not been considered is the potential life-long exposure to Fe via air pollution (AP) as a contributor to elevated brain Fe and AD risk. AP has been linked in multiple studies to increased risk for AD with PM2.5 associated with increased risk for dementia, reduced memory and processing speed, and increased cognitive impairment. Our data and others examining Fe in olfactory bulb and frontal cortex of AD brain report the abundant presence of magnetite (Fe3+ iron oxide) nanoparticles, consistent with an exogenous rather than endogenous source. Filling this gap is a critical step forward for modelling and determining the mechanistic underpinnings of how PM2.5 contributes to memory loss and neurodegenerative risk. To address this, 10-wk-old C57Bl/6 mice were randomly exposed to HEPA-filtered air or 1.5 ng/L iron-oxide UFP particles for two hours daily for 20 d and then allowed to age. Acutely and at 12-mo, Fe-exposed females had memory deficits, and lower novel object recognition indices. At 18, but not 12 mo, Fe-exposed male mice were significantly hypoactive in locomotor assays, with more foot slips on balance beam. Significant shifts in brain amino acid metabolism and neurotransmitter balance were observed at each timepoint. Further, sex-specific tau accumulation, redox activation, and white matter damage was seen in olfactory bulb and frontal cortex. Taken together, these data indicate that iron-oxide exposures alter neuroanatomical, neurochemical, and behavioural patterns in a sex-dependent fashion with relevance for neurodegenerative risk.