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.

中文翻译：

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内源性表达 3 和 4 重复 tau 亚型的新型 tau 繁殖小鼠模型的开发

异常淀粉样纤维化蛋白的聚集体在神经元之间传播并传播病理的“朊病毒样传播”现象作为神经退行性疾病的新机制引起了人们的关注。异常 tau 聚集体的积累或扩散与 tau 病变的临床症状之间存在很强的相关性。微管相关蛋白 tau (MAPT) 包含一个微管结合结构域，该结构域由三个或四个重复 (3R/4R) 组成，这是由于 MAPT 基因转录本的选择性 mRNA 剪接。尽管已经报道了许多 tau 传播模型，但大多数使用 4R 人类 tau 转基因小鼠或仅表达内源性 4R tau 的成年野生型小鼠，这些模型无法重现阿尔茨海默病的病理学，其中 3R 和 4R tau同时积累，或仅聚合 3R tau 的 Pick 病。这些缺陷可能反映了人类和啮齿动物 tau 同种型在大脑中的差异。为了克服这个问题，我们使用基因组编辑技术来生成表达相同比例的内源性 3R 和 4R tau 的小鼠，即使它们成年后也是如此。我们给这些小鼠注射了源自人类 tauopathy 患者大脑的不溶于肌糖基的部分，例如患有阿尔茨海默病（3R 和 4R tauopathy）、皮质基底节变性（4R tauopathy）或 Pick 病（3R tauopathy）的患者。在小鼠脑内注射后 8-9 个月，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具有 3R 和 4R tau，4R tau 仅存在于注射皮质基底节变性的大脑中，3R tau 仅存在于注射了 Pick 疾病的大脑中，所有这些都含有与注射种子中发现的相关的亚型。注射的异常 tau 被播种，并在注射部位和神经连接处积累，主要在同一部位内。发现新积累的异常 tau 在这些小鼠中是内源性的，并且已经跨越了物种屏障。特别重要的是，在注射皮克病的小鼠中观察到皮克的身体状内含物，并重现了皮克病的积累特征，这表明我们已经开发出第一个概括皮克病病理学的模型。这些模型不仅有助于阐明涉及 3R 和 4R 异构体的 tau 病理学的传播机制，