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ApoE isoform– and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy
Open accessAbstract
Tau-mediated neurodegeneration is a hallmark of Alzheimer’s disease. Primary tauopathies are characterized by pathological tau accumulation and neuronal and synaptic loss. Apolipoprotein E (ApoE)–mediated neuroinflammation is involved in the progression of tau-mediated neurodegeneration, and emerging evidence suggests that the gut microbiota regulates neuroinflammation in an APOE genotype–dependent manner. However, evidence of a causal link between the microbiota and tau-mediated neurodegeneration is lacking. In this study, we characterized a genetically engineered mouse model of tauopathy expressing human ApoE isoforms reared under germ-free conditions or after perturbation of their gut microbiota with antibiotics. Both of these manipulations reduced gliosis, tau pathology, and neurodegeneration in a sex- and ApoE isoform–dependent manner. The findings reveal mechanistic and translationally relevant interrelationships between the microbiota, neuroinflammation, and tau-mediated neurodegeneration.
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“Moreover, studies on animal models have provided compelling evidence that the altered gut microbiome drives neurodegenerative disease pathogenesis, primarily through the modulation of microglial functions and activation.54–57”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [56]
In the citing paper
“Interestingly, they observed sex-dependent and APOE isoform-dependent neuroprotection as the neuroprotective effects of antibiotic treatment were more pronounced in male mice expressing human APOE3 (TE3 mice).56”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [56]
In the citing paper
“However, the neuroprotective effects of gut microbiota depletion were diminished following microbiota restoration and SCFA supplementation.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [56]
In the citing paper
“Gut microbiota perturbation has also been shown to reduce reactive astrogliosis, promote a shift in astrocytes towards a more homeostatic-like state, and protect against amyloidosis and tau-mediated neurodegeneration.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [56]
In the citing paper
“In particular, FMT from age-matched control mice restored astrogliosis in antibiotic-treated APP/PS1-21 mice, while SCFAs supplementation restored the gliosis and tau pathology in GF TE4 mice.56,61”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [56]
In the citing paper
“Interestingly, these effects appear to be more prominent in male mice.56,61”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [56]
In the citing paper
“A recent study demonstrated that SCFA supplementation in GF TE4 mice mitigated the neuroprotective effects of GF rearing, resulting in increased gliosis and tau pathology.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [56]
In the citing paper
“Conversely, the depletion of SCFAs-producing bacteria using antibiotic treatment conferred protection against tau-mediated neurodegeneration and neuroinflammation in TE3 mice.56”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [56]
In the citing paper
“Moreover, the majority of studies that reported the detrimental effects of SCFAs were conducted using GF mice,56,190,196,199 which are functionally and structurally abnormal across various physiological functions.313”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [56]
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Metadata
- Authors
- Seo, D.-O., O’Donnell, D., Jain, N., Ulrich, J. D., Herz, J., Li, Y., Lemieux, M., Cheng, J., Hu, H., Serrano, J. R., Bao, X., Franke, E., Karlsson, M., Meier, M., Deng, S., Desai, C., Dodiya, H., Lelwala-Guruge, J., Handley, S. A., Kipnis, J., Sisodia, S. S., Gordon, J. I., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- The Edison Family Center for Genome Sciences and Systems Biology and the Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, MO, USA.
- University of Chicago (US)
- Corresponding author
- Holtzman, David M.
- ORCID
- Venue
- Science
- Published
- 2023-01-13
- Volume
- 379
- Issue
- 6628
- Pages
- eadd1236-eadd1236
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC9901565
- OpenAlex
- W4315928364
- Cited by
- 254
- References
- 43
- Citations by year
- 2026: 41 · 2025: 80 · 2024: 74 · 2023: 59
- FWCI
- 45.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Good Ventures Foundation
- National Institutes of Health (NS090934)
- National Institute on Aging (P30AG066444)
- National Institute of General Medical Sciences (T32GM007200)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK042086, P30DK056341, R01DK030292)
- National Institute of Neurological Disorders and Stroke (R01NS090934, RF1NS090934)
- 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
- tauopathy, apolipoprotein E isoforms, gut microbiota, neuroinflammation, neurodegeneration, Alzheimer's disease, germ-free mice, antibiotic perturbation, gliosis, sex differences
- MeSH terms
- Gastrointestinal Microbiome, Neuroinflammatory Diseases, Animals, Anti-Bacterial Agents, Apolipoproteins E, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, Sex Factors, tau Proteins, Tauopathies, Mice
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