Human MAPT knockin mouse models of frontotemporal dementia for the neurodegenerative research community.

IF 4.3 Q1 BIOCHEMICAL RESEARCH METHODS

Cell Reports Methods Pub Date : 2025-04-21 Epub Date: 2025-04-11 DOI:10.1016/j.crmeth.2025.101024

Takahiro Morito, Mohan Qi, Naoko Kamano, Hiroki Sasaguri, Sumi Bez, Martha Foiani, Karen Duff, Seico Benner, Toshihiro Endo, Hiroshi Hama, Hiroshi Kurokawa, Atushi Miyawaki, Hiroshi Mizuma, Naruhiko Sahara, Masafumi Shimojo, Makoto Higuchi, Takaomi C Saido, Naoto Watamura

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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^{P301S;Int10+3;S320F} 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^{P301S;Int10+3;S320F} mice with App knockin, App^NL-G-F, 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.

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人类MAPT敲入额颞叶痴呆小鼠模型的神经退行性研究社区。

现有的额颞叶痴呆（FTD）模型可能不能完全概括该疾病的病理生理。为了产生更多与病理生理相关的FTD模型，我们设计了携带三重突变的MAPT敲入小鼠系，其中MAPTP301S；Int10+3；S320F系在6个月前就表现出强大的tau病理。严重的tau积聚主要发生在丘脑、下丘脑和杏仁核，轻度累及皮质和海马，导致突触丧失、脑萎缩和ftd样行为异常。将MAPTP301S、Int10+3、S320F小鼠与App knockin、AppNL-G-F进行杂交，小鼠的皮层和海马的tau病理明显增强，突出了β-淀粉样蛋白与tau之间的相互作用。这些发现奠定了突变小鼠作为研究FTD和其他牛头病变机制的有价值的模型，为体内药物筛选提供了相关平台。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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