Disease-modifying strategies in primary tauopathies

Tauopathies are neurodegenerative brain diseases that are characterized by the formation of intraneuronal inclusions containing the microtubule-associated protein tau. This major hallmark defines tau pathology which is predominant in primary tauopathies, while in secondary forms additional driving forces are involved. In the course of the disease, different brain areas degenerate and lead to severe defects of language, behavior and movement. Although neuropathologically heterogeneous, primary tauopathies share a common feature, which is the generation of abnormal tau species that aggregate and progress into filamentous deposits in neurons. Mechanisms that are involved in this disease-related process offer a broad range of targets for disease-modifying therapeutics. The present review provides an up-to-date overview of currently known targets in primary tauopathies and their possible therapeutic modulation. It is structured into four major targets, the post-translational modifications of tau and tau aggregation, protein homeostasis, disease propagation, and tau genetics. Chances, as well as obstacles in the development of effective therapies are highlighted. Some therapeutic strategies, e.g., passive or active immunization, have already reached clinical development, raising hopes for affected patients. Other concepts, e.g., distinct modulators of proteostasis, are at the ready to be developed into promising future therapies. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.