Human MAPT knockin mouse models of frontotemporal dementia for the neurodegenerative research community
Existing models of frontotemporal dementia (FTD) may not fully recapitulate the pathophysiology of the disease. To generate more pathophysiologically relevant FTD models, we engineered MAPT knockin mouse lines carrying triple mutations, among which the MAPT<sup>P301S;Int10+3;S320F</sup> line exhibited robust tau pathology starting before 6 months of age. Severe tau accumulation was predominantly observed in the thalamus, hypothalamus, and amygdala with milder involvement of the cortex and hippocampus, leading to synaptic loss, brain atrophy, and FTD-like behavioral abnormalities. Crossbreeding MAPT<sup>P301S;Int10+3;S320F</sup> mice with App knockin, App<sup>NL-G-F</sup>, mice markedly enhanced tau pathology in the cortex and hippocampus, highlighting the interplay between β-amyloid and tau. These findings establish the mutant mice as valuable models for investigating the mechanisms underlying FTD and other tauopathies, providing a relevant platform for in vivo drug screening.
Authors
- Meng Qi (ORCID: https://orcid.org/0000-0001-6680-7964)
- Martha Foiani (ORCID: https://orcid.org/0000-0003-4157-2606)
- Makoto Higuchi (ORCID: https://orcid.org/0000-0002-3934-5810)
- Karen Duff (ORCID: https://orcid.org/0000-0002-6177-868X)
- Hiroshi Hama (ORCID: https://orcid.org/0000-0002-1967-7519)
- Naruhiko Sahara (ORCID: https://orcid.org/0000-0003-2122-5797)
- Sumi Bez (ORCID: https://orcid.org/0000-0002-8971-5103)
- Takaomi C. Saido (ORCID: https://orcid.org/0000-0003-1970-6903)
- A. Miyawaki
- Hiroshi Mizuma (ORCID: https://orcid.org/0000-0001-8970-9486)
- Naoto Watamura (ORCID: https://orcid.org/0000-0001-7971-7378)
- T Morito (ORCID: https://orcid.org/0009-0002-8611-9151)
- Seico Benner
- Masafumi Shimojo (ORCID: https://orcid.org/0000-0003-4491-7294)
- Naoko Kamano (ORCID: https://orcid.org/0000-0001-8249-7433)
- Hiroki Sasaguri (ORCID: https://orcid.org/0000-0003-2550-9156)
- Toshihiro Endo
- Hiroshi Kurokawa
Institutions
- National Institute for Environmental Studies (JP)
- RIKEN Center for Brain Science (JP)
- National Institutes for Quantum Science and Technology (JP)
- UK Dementia Research Institute (GB)
- Institut de Recherche et d’Innovation (FR)
- University College London (GB)
Publication Details
- Journal
- Cell Reports Methods
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.crmeth.2025.101024
- Citations
- 5
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 4.21
Funders
- Alzheimer's Association
- Cell Science Research Foundation
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science London
- Japan Society for the Promotion of Science
- RIKEN