# Air Pollution, Elevated Brain Iron and Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $380,834

## Abstract

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.

## Key facts

- **NIH application ID:** 10285494
- **Project number:** 3R01ES032260-02S1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Deborah A Cory-Slechta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,834
- **Award type:** 3
- **Project period:** 2020-09-18 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285494

## Citation

> US National Institutes of Health, RePORTER application 10285494, Air Pollution, Elevated Brain Iron and Alzheimer's Disease (3R01ES032260-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10285494. Licensed CC0.

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