# The Role of Peripheral Immune Cell Trafficking in Ozone-Induced Alzheimer's Disease Neuropathology

> **NIH NIH RF1** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $1,735,512

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and the leading cause of dementia
in the elderly. Current treatment is unable to halt disease progression, emphasizing the importance of
understanding the etiology and pathobiology underlying AD. High levels of urban air pollution have been
associated with increased AD risk and elevated amyloid plaque load in humans, but the underlying
mechanisms are poorly understood. Ozone (O3), a reactive gas component of urban air pollution, is linked to
increased AD risk, but confined to the respiratory tract after inhalation, implicating a role for the peripheral
immune response to air pollution in AD neuropathology. Microglia, the resident parenchymal myeloid cells in
the brain, are reported to be key mediators of AD neuropathology, but recent evidence also supports a
potential role for peripheral immune cells, such as neutrophils. Yet, how these myeloid cells become
pathologically dysregulated in AD is largely unknown. We have previously shown that O3 inhalation triggers a
pro-inflammatory pulmonary immune response that is associated with a persistent neuroimmune response in
mice and rats. How O3 inhalation affects the neuroimmune response during normal physiology and during
ongoing AD processes is poorly understood. The Lung-Brain Axis hypothesis holds that the pulmonary
consequences of inhaled environmental exposures dysregulates the neuroimmune response in part, through
peripheral immune cell changes to augment CNS disease pathology, critical concepts that we propose to
directly test here. We hypothesize that O3 exposure causes neuroimmune changes and exacerbates Aβ
neuropathology via peripheral immune cell trafficking and that CXCR2 and VEGF are primary mechanisms in
this process. As such, our aims are to: 1) Define the role of CXCR2 in the O3-induced neuroimmune
response; 2) Examine the role of CXCR2 in the O3-induced impairment of microglial plaque association and
augmentation of amyloid neuropathology; 3) Confirm the role of VEGF in O3-induced augmentation of beta
amyloid neuropathology and neurotoxicity. These findings will reveal key mechanisms (peripheral immune
cell/neutrophil trafficking, CXCR1, and VEGF) in the Lung-Brain Axis responsible for how the peripheral
immune compartment affects the brain and augments AD processes, identifying key opportunities to mitigate
AD neuropathology.

## Key facts

- **NIH application ID:** 10467207
- **Project number:** 1RF1AG077826-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Adrian Lynn Oblak
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,735,512
- **Award type:** 1
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467207

## Citation

> US National Institutes of Health, RePORTER application 10467207, The Role of Peripheral Immune Cell Trafficking in Ozone-Induced Alzheimer's Disease Neuropathology (1RF1AG077826-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10467207. Licensed CC0.

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