Morito, Takahiro;
Qi, Mohan;
Kamano, Naoko;
Sasaguri, Hiroki;
Bez, Sumi;
Foiani, Martha;
Duff, Karen;
... Watamura, Naoto; + view all
(2025)
Human MAPT knockin mouse models of frontotemporal dementia for the neurodegenerative research community.
Cell Reports: Methods
, 5
(4)
, Article 101024. 10.1016/j.crmeth.2025.101024.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Human MAPT knockin mouse models of frontotemporal dementia for the neurodegenerative research community |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.crmeth.2025.101024 |
| Publisher version: | https://doi.org/10.1016/j.crmeth.2025.101024 |
| Language: | English |
| Additional information: | ª 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/). |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemical Research Methods, Cell Biology, Biochemistry & Molecular Biology, CRYO-EM STRUCTURES, ALZHEIMER-DISEASE, TRANSGENIC MICE, NEUROFIBRILLARY DEGENERATION, BETA-DEPOSITION, AMYLOID-BETA, TAU, APP, PATHOLOGY, BRAIN |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10211400 |
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