Development of a novel tau propagation mouse model endogenously expressing 3 and 4 repeat tau isoforms
Development of a novel tau propagation mouse model endogenously expressing 3 and 4 repeat tau isoforms
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DOI：
10.1093/brain/awab289
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发表时间：
2022-02-01
期刊：
影响因子：
14.5
通讯作者：
Hasegawa, Masato
中科院分区：
文献类型：
--
作者：
Hosokawa, Masato;Masuda-Suzukake, Masami;Hasegawa, Masato
异常淀粉样纤维化蛋白聚集在神经元之间增殖并传播病理的“朊病毒样增殖”现象作为神经退行性疾病的新机制正受到关注。异常tau聚集物的积累或扩散与tau病的临床症状有很强的相关性。微管相关蛋白tau （MAPT）含有一个微管结合结构域，该结构域由3或4个重复序列（3R/4R）组成，这是由于MAPT基因转录本的替代mRNA剪接所致。虽然已经报道了许多tau繁殖模型，但大多数模型使用的是仅表达内源性4R tau的4R人tau转基因小鼠或成年野生型小鼠，这些模型无法再现3R和4R tau同时积聚的阿尔茨海默病或仅聚集3R tau的匹克病的病理。这些缺陷可能反映了人类和啮齿动物大脑中tau亚型的差异。为了克服这个问题，我们使用基因组编辑技术产生了表达内源性3R和4R tau比例相等的小鼠，即使在它们成年后也是如此。我们给这些小鼠注射了取自人类牛头病患者大脑的萨尔科齐不溶性组分，这些患者包括阿尔茨海默病（3R和4R牛头病）、皮质基底变性（4R牛头病）或皮克病（3R牛头病）。在小鼠脑内注射8-9个月后，组织病理学和生化分析显示，tau的异常积累是种子依赖性的，在阿尔茨海默病注射的大脑中有3R和4R tau，在皮质基底变性注射的大脑中只有4R tau，在匹克病注射的大脑中只有3R tau，所有这些都含有与注射种子中发现的亚型相关的亚型。注射的异常tau被播种，并积聚在注射部位和神经连接处，主要是在同一部位。在这些小鼠中发现新积累的异常tau是内源性的，并且跨越了物种屏障。特别重要的是，在匹克病注射小鼠中观察到匹克病的体样包涵体，并且重现了匹克病特征的积累，这表明我们已经开发了第一个概括匹克病病理的模型。这些模型不仅有助于阐明涉及3R和4R亚型的tau病理学的传播机制，而且还可以重现tau病变的病理，这将导致新的治疗药物的发现。
The phenomenon of 'prion-like propagation' in which aggregates of abnormal amyloid-fibrilized protein propagate between neurons and spread pathology, is attracting attention as a new mechanism in neurodegenerative diseases. There is a strong correlation between the accumulation or spread of abnormal tau aggregates and the clinical symptoms of tauopathies. Microtubule-associated protein tau (MAPT) contains a microtubule-binding domain that consists of three or four repeats (3R/4R) due to alternative mRNA splicing of transcripts for the MAPT gene. Although a number of models for tau propagation have been reported, most use 4R human tau transgenic mice or adult wild-type mice expressing only endogenous 4R tau and these models have not been able to reproduce the pathology of Alzheimer's disease in which 3R and 4R tau accumulate simultaneously, or that of Pick's disease in which only 3R tau is aggregated. These deficiencies may reflect differences between human and rodent tau isoforms in the brain. To overcome this problem, we used genome editing techniques to generate mice that express an equal ratio of endogenous 3R and 4R tau, even after they become adults. We injected these mice with sarkosyl-insoluble fractions derived from the brains of human tauopathy patients such as those afflicted with Alzheimer's disease (3R and 4R tauopathy), corticobasal degeneration (4R tauopathy) or Pick's disease (3R tauopathy). At 8-9 months following intracerebral injection of mice, histopathological and biochemical analyses revealed that the abnormal accumulation of tau was seed-dependent, with 3R and 4R tau in Alzheimer's disease-injected brains, 4R tau only in corticobasal degeneration-injected brains and 3R tau only in Pick disease-injected brains, all of which contained isoforms related to those found in the injected seeds. The injected abnormal tau was seeded, and accumulated at the site of injection and at neural connections, predominantly within the same site. The abnormal tau newly accumulated was found to be endogenous in these mice and to have crossed the species barrier. Of particular importance, Pick's body-like inclusions were observed in Pick's disease-injected mice, and accumulations characteristic of Pick's disease were reproduced, suggesting that we have developed the first model that recapitulates the pathology of Pick's disease. These models are not only useful for elucidating the mechanism of propagation of tau pathology involving both 3R and 4R isoforms, but can also reproduce the pathology of tauopathies, which should lead to the discovery of new therapeutic agents.