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Updated: Aug 11, 2025
An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons
Published on: May 23, 2019
Common mouse models of tauopathy reflect early but not late human disease
Kathrin Wenger1, Arthur Viode2, Christoph N Schlaffner2,3
1F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital and Harvard, Medical School; Center for Life Science, RM 12030, 3 Blackfan Circle, Boston, MA 02115, USA.
Background:
Mouse models that overexpress human mutant Tau (P301S and P301L) are commonly used in preclinical studies of Alzheimer's Disease (AD) and while several drugs showed therapeutic effects in these mice, they were ineffective in humans. This leads to the question to which extent the murine models reflect human Tau pathology on the molecular level.
Methods:
We isolated insoluble, aggregated Tau species from two common AD mouse models during different stages of disease and characterized the modification landscape of the aggregated Tau using targeted and untargeted mass spectrometry-based proteomics. The results were compared to human AD and to human patients that suffered from early onset dementia and that carry the P301L Tau mutation.
Results:
Both mouse models accumulate insoluble Tau species during disease. The Tau aggregation is driven by progressive phosphorylation within the proline rich domain and the C-terminus of the protein. This is reflective of early disease stages of human AD and of the pathology of dementia patients carrying the P301L Tau mutation. However, Tau ubiquitination and acetylation, which are important to late-stage human AD are not represented in the mouse models.
Conclusion:
AD mouse models that overexpress human Tau using risk mutations are a suitable tool for testing drug candidates that aim to intervene in the early formation of insoluble Tau species promoted by increased phosphorylation of Tau.
Insights
Alzheimer
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Alzheimer's Disease (AD) mouse models overexpressing human mutant Tau are widely used.
- Therapeutic effects in mice often do not translate to human efficacy.
- The molecular fidelity of mouse models to human Tau pathology is questioned.
Purpose of the Study:
- To compare the molecular Tau pathology in common AD mouse models with human AD.
- To assess the suitability of mouse models for preclinical Alzheimer's drug testing.
Main Methods:
- Isolation of insoluble, aggregated Tau species from P301S and P301L Tau mouse models at different disease stages.
- Proteomic characterization of Tau modifications using mass spectrometry.
- Comparison of murine Tau modifications to human AD and P301L mutation dementia patients.
Main Results:
- Both mouse models accumulate insoluble Tau species, with aggregation driven by progressive phosphorylation.
- Phosphorylation patterns reflect early-stage human AD and P301L dementia.
- Key late-stage human AD modifications like Tau ubiquitination and acetylation are absent in the models.
Conclusions:
- AD mouse models with human Tau mutations are valuable for studying early Tau phosphorylation.
- These models can be used to test drugs targeting the initial stages of insoluble Tau formation.
- Limitations exist regarding the representation of late-stage Tau modifications in current mouse models.
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