Clem Jones Centre for Ageing Dementia Research (CJCADR) Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Australia.
Adv Exp Med Biol. 2019;1184:381-391. doi: 10.1007/978-981-32-9358-8_28.
Animal models have been instrumental in reproducing key aspects of human tauopathy. In pursuing these efforts, the mouse continues to have a prominent role. In this chapter, we focus on models that overexpress wild-type or mutant forms of tau, the latter being based on mutations found in familial cases of frontotemporal dementia. We review some of these models in more detail and discuss what they have revealed about the underlying pathomechanisms, as well as highlighting new developments that exploit gene editing tools such as TALEN and CRISPR. Interestingly, when investigating the role of tau in impairing cellular functions, common themes emerge. Because tau is a scaffolding protein that aggregates in the somatodendritic domain under pathological conditions, it traps proteins such as parkin and JIP1, preventing them from executing their normal function in mitophagy and axonal transport, respectively. Another aspect is the emerging role of tau in the translational machinery and the finding that the somatodendritic accumulation of tau in Alzheimer's disease may in part be due to the induction of the de novo synthesis of tau by amyloid-β via the Fyn/ERK/S6 pathway. We further discuss treatment strategies such as tau-based vaccinations and therapeutic ultrasound and conclude by discussing whether there is a future for animal models of tauopathies.
动物模型在复制人类 tau 病的关键方面发挥了重要作用。在进行这些研究时，老鼠继续发挥着突出的作用。在本章中，我们重点介绍了过度表达野生型或突变型 tau 的模型，后者基于家族性额颞叶痴呆病例中发现的突变。我们更详细地回顾了其中的一些模型，并讨论了它们揭示的潜在病理机制，同时强调了利用 TALEN 和 CRISPR 等基因编辑工具的新进展。有趣的是，当研究 tau 在损害细胞功能中的作用时，出现了一些共同的主题。由于 tau 是一种支架蛋白，在病理条件下聚集在体树突域中，因此它会捕获 parkin 和 JIP1 等蛋白，阻止它们分别在细胞自噬和轴突运输中执行正常功能。另一个方面是 tau 在翻译机制中的新兴作用，以及发现阿尔茨海默病中 tau 的体树突积累部分可能是由于淀粉样蛋白-β 通过 Fyn/ERK/S6 通路诱导 tau 的从头合成。我们进一步讨论了基于 tau 的疫苗接种和治疗性超声等治疗策略，并最后讨论了 tau 病动物模型是否有未来。
