Common mouse models of tauopathy reflect early but not late human disease

Kathrin Wenger; Arthur Viode; Christoph N. Schlaffner; Patrick van Zalm; Long Cheng; Tammy Dellovade; Xavier Langlois; Anthony Bannon; Rui Chang; Theresa R. Connors; Derek Oakley; Bernhard Renard; Juri Rappsilber; Bradley Hyman; Hanno Steen; Judith A. Steen

doi:10.1186/s13024-023-00601-y

journal article Open Access Feb 02, 2023

Common mouse models of tauopathy reflect early but not late human disease

Kathrin Wenger Arthur Viode Christoph N. Schlaffner Patrick van Zalm Long Cheng

Tammy Dellovade Xavier Langlois Anthony Bannon Rui Chang

Theresa R. Connors Derek Oakley Bernhard Renard Juri Rappsilber

Bradley Hyman Hanno Steen

Judith A. Steen

Molecular Neurodegeneration Vol. 18 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1186/s13024-023-00601-y

Abstract

Abstract

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.

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References

Details

Published: Feb 02, 2023
Vol/Issue: 18(1)
License: View

Authors

Christoph N. Schlaffner

Humboldt-Universität zu Berlin

Funding

National Institute on Aging Award: R01 AG071858

Cite This Article

Kathrin Wenger, Arthur Viode, Christoph N. Schlaffner, et al. (2023). Common mouse models of tauopathy reflect early but not late human disease. Molecular Neurodegeneration, 18(1). https://doi.org/10.1186/s13024-023-00601-y

Common mouse models of tauopathy reflect early but not late human disease

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