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Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes
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We demonstrated that an antibiotic cocktail (ABX)-perturbed gut microbiome is associated with reduced amyloid-β (Aβ) plaque pathology and astrogliosis in the male amyloid precursor protein (APP)SWE/presenilin 1 (PS1)ΔE9 transgenic model of Aβ amyloidosis. We now show that in an independent, aggressive APPSWE/PS1L166P (APPPS1-21) mouse model of Aβ amyloidosis, an ABX-perturbed gut microbiome is associated with a reduction in Aβ pathology and alterations in microglial morphology, thus establishing the generality of the phenomenon. Most importantly, these latter alterations occur only in brains of male mice, not in the brains of female mice. Furthermore, ABX treatment lead to alterations in levels of selected microglial expressed transcripts indicative of the “M0” homeostatic state in male but not in female mice. Finally, we found that transplants of fecal microbiota from age-matched APPPS1-21 male mice into ABX-treated APPPS1-21 male restores the gut microbiome and partially restores Aβ pathology and microglial morphology, thus demonstrating a causal role of the microbiome in the modulation of Aβ amyloidosis and microglial physiology in mouse models of Aβ amyloidosis.
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“Moreover, sex-specific differences have been noted, with female AD mouse models showing more pronounced microbiota-driven amyloid deposition and microglial activation compared to males140.”
From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [140]
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“and transplants of fecal microbiota of genotype- and age-matched male mice partially restored Aβ pathology and microglial morphology9.”
From Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice (2021) · cites this paper as [9]
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“These data are consistent with the association of microbiome perturbations induced by antibiotics with neuropathological measures in male mice overexpressing hAPP with the Swedish mutation and presenilin 1, and the ability of transplants of fecal microbiota of genotype- and age-matched male mice to partially restore neuropathology9.”
From Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice (2021) · cites this paper as [9]
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“Importantly, the AD pathologies in antibiotic-treated male mice were partially restored after 3-week FMT from age-matched male APP/PS1-21 mice.197”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [197]
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Metadata
- Authors
- Dodiya, H. B., Kuntz, T., Shaik, S. M., Baufeld, C., Leibowitz, J., Zhang, X., Gottel, N., Zhang, X., Butovsky, O., Gilbert, J. A., & Sisodia, S. S.
- Affiliations
- University of Chicago (US)
- Brigham and Women's Hospital (US)
- Scripps Institution of Oceanography (US)
- Corresponding author
- Sisodia, Sangram S.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2019-05-16
- Volume
- 216
- Issue
- 7
- Pages
- 1542-1560
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC6605759
- OpenAlex
- W2945327298
- Cited by
- 288
- References
- 71
- Citations by year
- 2026: 19 · 2025: 50 · 2024: 54 · 2023: 45 · 2022: 40 · 2021: 39 · 2020: 33 · 2019: 7
- FWCI
- 20.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- Cure Alzheimer’s Fund
- Open Philanthropy Project and Good Ventures Foundation
- Edward H. Levi Fund
- National Institute of Neurological Disorders and Stroke (1R01NS088137, R21NS104609, R21NS101673)
- National Institute on Aging (R01AG051812, R01AG054672)
- National Multiple Sclerosis Society
- Amyotrophic Lateral Sclerosis Association
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- gut microbiota, Alzheimer's disease, microglia, sex differences, antibiotic perturbation, fecal microbiota transplantation, astrocyte activation, neuroinflammation
- MeSH terms
- Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Animals, Anti-Bacterial Agents, Brain Diseases, Disease Models, Animal, Female, Male, Sex Factors, Amyloid beta-Protein Precursor, Microglia, Amyloid Neuropathies, Mice, Plaque, Amyloid
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