Tau-based therapies in neurodegeneration: opportunities and challenges

Key Points Aggregates of the microtubule-associated protein tau are a defining feature of a group of neurodegenerative disorders collectively known as tauopathies and are a hallmark lesion of Alzheimer disease. Tau exists as six major isoforms in the adult human brain and is subject to massive post-translational modifications, including phosphorylation, acetylation, ubiquitylation and truncation. The advent of novel biomarkers such as PET tracers and the lower regulatory hurdles for treating rare forms of tauopathy, such as progressive supranuclear palsy, have facilitated clinical trials targeting tauopathies. Drug development has also been facilitated by transgenic animal models and by better insights into the physiological and pathological roles of tau and its different isoforms. An interesting new thread has been added to the field with the hypothesis that tau pathology propagates extracellularly. Some challenges faced in the treatment of tauopathies are specific to tau, whereas others, such as the presence of the blood–brain barrier, represent a general challenge in the treatment of diseases of the brain. Clinical trials targeting tau have included more than a dozen diverse (and not yet exhausted) strategies in recent years. Aggregates of the microtubule-associated protein tau are a defining feature of several neurodegenerative disorders, including Alzheimer disease (AD). Given the recent failures of several amyloid-β-targeted therapies for AD, interest is growing in tau as an alternative target, and this Review describes preclinical and clinical studies of tau-based approaches in the light of recent advances in the understanding of the physiological and pathological roles of tau. Aggregates of the microtubule-associated protein tau are a defining feature of several neurodegenerative diseases that are collectively known as tauopathies, and constitute one of the hallmark lesions of Alzheimer disease (AD). Given the lack of efficacy to date of amyloid-β-targeted therapies for AD, interest is growing in tau as a potential alternative target. Several drug candidates, which are now in clinical trials, aim to reduce tau levels or to prevent the aggregation or pathological post-translation modifications of this protein. In this Review, we discuss preclinical and clinical studies in light of an increased understanding of the physiological and pathological roles of tau, advances in animal models of tauopathy, the identification of novel targets and the availabi