Experimental Models of Tauopathy - From Mechanisms to Therapies.

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.