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Updated: Jul 2, 2026
An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons
Published on: May 23, 2019
Select microbial metabolites promote tau aggregation in a murine tauopathy model
Sabeen A Kazmi1, Franciscus Chandra2, Michael Wasney3
1Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA. sak14@g.ucla.edu.
Abstract:
The gut microbiome is emerging as a modifier of risk for neurodegenerative diseases, but underlying mechanisms remain poorly understood. Here, we show that the hTau.P301S mouse model for progressive tauopathy develops alterations in the composition and function of the gut microbiome that are not recapitulated in amyloid-based 5xFAD or 3xTg models for Alzheimer's disease. Disrupting the gut microbiome via chronic antibiotic treatment exacerbates cognitive deficits and tau pathology in hTau.P301S mice, demonstrating a causal influence of the microbiome on tau-driven disease progression. This corresponds with widespread alterations in microbiome-dependent metabolites in the sera and brains of hTau.P301S mice, including subsets that correlate with the severity of tau pathology. By screening against tau biosensor cells, we identify select microbial metabolites-trimethylamine-N-oxide, 3-indoxyl sulfate, phenol sulfate, thymidine, and 2'deoxyuridine-that promote tau seeding and aggregation. Systemic administration of these metabolites worsens cognitive impairment and tau pathology in hTau.P301S mice. These findings establish a mechanistic link between the gut microbiome, serum and brain metabolites, as well as tau aggregation, suggesting that select microbial metabolites could potentially serve as therapeutic targets for tau-driven diseases.
Insights
The gut microbiome influences tau pathology in neurodegenerative diseases. Specific microbial metabolites worsen cognitive deficits and tau aggregation, suggesting potential therapeutic targets.
Area of Science:
- Neuroscience
- Microbiology
- Metabolomics
Background:
- The gut microbiome's role in neurodegenerative diseases is increasingly recognized but poorly understood.
- Mechanisms linking gut dysbiosis to neurodegeneration require elucidation.
Purpose of the Study:
- To investigate the gut microbiome's influence on tauopathy progression in a mouse model.
- To identify specific microbial metabolites that affect tau pathology.
Main Methods:
- Utilized the hTau.P301S mouse model for progressive tauopathy.
- Administered chronic antibiotics to disrupt the gut microbiome.
- Analyzed microbiome composition, serum and brain metabolites, and tau pathology.
- Screened microbial metabolites for their effect on tau seeding and aggregation in vitro.
- Administered identified metabolites systemically to assess their impact on cognitive deficits and tau pathology in vivo.
Main Results:
- hTau.P301S mice exhibited gut microbiome alterations not seen in Alzheimer's disease models.
- Antibiotic-induced microbiome disruption exacerbated cognitive deficits and tau pathology.
- Microbiome-dependent metabolites in serum and brain correlated with tau pathology severity.
- Specific metabolites (trimethylamine-N-oxide, 3-indoxyl sulfate, phenol sulfate, thymidine, 2'deoxyuridine) promoted tau seeding and aggregation.
- Systemic administration of these metabolites worsened cognitive impairment and tau pathology.
Conclusions:
- The gut microbiome causally influences tau-driven disease progression.
- Specific microbial metabolites are mechanistically linked to tau aggregation and neurodegeneration.
- Targeting microbial metabolites presents a potential therapeutic strategy for tauopathies.
