The bidirectional lung brain-axis of amyloid-β pathology: ozone dysregulates the peri-plaque microenvironment
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The mechanisms underlying how urban air pollution affects Alzheimer’s disease (AD) are largely unknown. Ozone (O3) is a reactive gas component of air pollution linked to increased AD risk, but is confined to the respiratory tract after inhalation, implicating the peripheral immune response to air pollution in AD neuropathology. Here, we demonstrate that O3 exposure impaired the ability of microglia, the brain’s parenchymal immune cells, to associate with and form a protective barrier around Aβ plaques, leading to augmented dystrophic neurites and increased Aβ plaque load. Spatial proteomic profiling analysis of peri-plaque proteins revealed a microenvironment-specific signature of dysregulated disease-associated microglia protein expression and increased pathogenic molecule levels with O3 exposure. Unexpectedly, 5xFAD mice exhibited an augmented pulmonary cell and humoral immune response to O3, supporting that ongoing neuropathology may regulate the peripheral O3 response. Circulating HMGB1 was one factor upregulated in only 5xFAD mice, and peripheral HMGB1 was separately shown to regulate brain Trem2 mRNA expression. These findings demonstrate a bidirectional lung-brain axis regulating the central and peripheral AD immune response and highlight this interaction as a potential novel therapeutic target in AD.
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Exposure to ozone decreased the association of phagocytic microglia with amyloid plaques, impairing their ability to form a protective barrier and exacerbating dystrophic neuritis.
“In another study, exposure to ozone decreased the association of phagocytic microglia with amyloid plaques, impairing their ability to form a protective barrier and exacerbating dystrophic neuritis [33].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [33]
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“In another study, exposure to ozone decreased the association of phagocytic microglia with amyloid plaques, impairing their ability to form a protective barrier and exacerbating dystrophic neuritis [33].”
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- Authors
- Greve, H. J., Dunbar, A. L., Lombo, C. G., Ahmed, C., Thang, M., Messenger, E. J., Mumaw, C. L., Johnson, J. A., Kodavanti, U. P., Oblak, A. L., & Block, M. L.
- Affiliations
- Indiana University Indianapolis (US)
- Department of Pharmacology and Toxicology, The Stark Neurosciences Research Institute, Indiana University School of Medicine , Indianapolis, IN , USA
- Environmental Protection Agency (US)
- Richard L. Roudebush VA Medical Center (US)
- Corresponding author
- Block, Michelle L
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-03-28
- Volume
- 146
- Issue
- 3
- Pages
- 991-1005
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC10169526
- OpenAlex
- W4220770349
- Cited by
- 82
- References
- 64
- Citations by year
- 2026: 22 · 2025: 22 · 2024: 25 · 2023: 9 · 2022: 4
- FWCI
- 9.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- public-domain
- Locations
- Brain (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, public-domain)
- Funders
- VA Merit (I01 BX004161)
- NIH (RO1 ES029835GW, R01 ES028104)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Air Quality and Health Impacts
- Keywords
- ozone, air pollution, Alzheimer's disease, amyloid plaques, lung-brain axis, microglia, HMGB1, TREM2, 5xFAD mice, pulmonary immune response, dystrophic neurites, spatial proteomics, two-way communication
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Lung, Membrane Glycoproteins, Mice, Transgenic, Ozone, Receptors, Immunologic, Amyloid beta-Peptides, Microglia, HMGB1 Protein, Proteomics, Mice, Plaque, Amyloid
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