Air Pollution, Elevated Brain Iron and Alzheimer's Disease

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ABSTRACT Numerous epidemiological studies have now linked air pollution (AP) with Alzheimer’s Disease (AD) and cognitive decline. Idiopathic AD, the most common form of dementia in the US, is a female-biased neurodegenerative disease of unknown etiology. In addition to the accumulation of plaques and tangles, AD is also characterized by marked elevations in brain levels of the redox active metal, iron (Fe), giving rise to a brain metal dyshomeostasis hypothesis for AD. The basis for the elevated Fe is not clear, but this supplement hypothesizes that exposures to Fe contamination from the ultrafine particle (UFP) component of AP, considered the most reactive component of AP, to which exposures can begin in utero and be lifelong following birth, contributes to the AD phenotype. Indeed, post-birth, such UFPs and associated contaminants move directly into blood stream, bypassing macrophages to each brain; UFPs can also be directly taken up into brain via olfactory and trigeminal nerves, bypassing the blood brain barrier. Our data from mice exposed via inhalation to concentrated ambient UFPs confirms significant elevation of brain Fe and alterations in other essential brain metals as well. Like most neurodegenerative diseases, AD is heterogeneous in expression which could reflect the geographical differences in the extent of Fe contamination. Interestingly, in that regard, the levels of highest Fe emissions in the U.S. overlap with areas of highest Alzheimer’s disease mortality. In preliminary data obtained from early postnatal exposures of both male and female mice, numerous female-specific features of AD have been seen: increased olfactory bulb microglial activation, consistent with nasal olfactory uptake, decreased trajectory of neuronal cell counts in nucleus accumbens, and increased levels of total hippocampal amyloids and tau at PND90. Ventriculomegaly, another feature seen in AD, was found in both sexes. The aim of this proposed supplement is to extend our current studies of AP-induced brain metal contamination, which to date has focused on neurodevelopmental disorders, to examine the effects of a 6 week exposure of adult mice to Fe UFPs at multiple time-points post exposure. Outcome measures will include neuropathological features of AD, specifically hyperphosphyorylated tau, beta amyloids, ventriculomegaly, myelination, and oxidative stress and ferroptosis, with behavioral measures of executive function. This supplement should establish a model that could be critical to defining mechanisms of AD and sex-related differences in vulnerability, as well as to provide data that is important to regulation of AP, and consequently to public health protection.