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.

Abstract

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 availability of novel tracers to track tau.

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Figure 1: Tau biology: genomic organization and isoform expression.
Figure 2: Sites of tau post-translational modifications.
Figure 3: Types of tau post-translational modifications and therapeutic targeting.
Figure 4: Tau pathomechanisms and direct therapeutic targeting.
Figure 5: Tau pathomechanisms and indirect therapeutic targeting.

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Acknowledgements

The authors acknowledge support by the Estate of Dr Clem Jones AO, the Government of Queensland (DSITI), the Australian Research Council (DP160103812) and the National Health and Medical Research Council of Australia (GNT1037746, GNT1127999). The authors thank R. Tweedale for critically reading the manuscript.

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Correspondence to Jürgen Götz.

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Alternative splicing

A mechanism by which exons or portions of exons or non-coding regions within a pre-mRNA that is transcribed from a single gene are differentially joined or skipped, resulting in transcripts from which multiple protein isoforms are generated.

Haplotypes

Groups of alleles of different genes on a single chromosome that are linked closely enough to be inherited together; for example, the linked genes of the major histocompatibility complex.

Interactome

All the interactions between biological entities in cells and organisms considered as a whole.

Overexpression artefact

A phenotype seen in transgenic animal models that potentially results from the expression of the transgene at higher levels than the endogenous protein, owing to the choice of promoter for transgene expression, the chromosomal integration site of the transgene and the copy number.

Long-term depression

A cellular mechanism underlying learning and memory that involves an activity-dependent reduction in synaptic efficacy that lasts hours or longer following a long patterned stimulus.

Long-term potentiation

A cellular mechanism underlying learning and memory that involves a persistent increase in synaptic strength following high-frequency stimulation.

Braak staging

A system formulated by Braak and Braak for staging Alzheimer disease severity using a tau-specific antibody on brain sections, based on the premise that tau pathology spreads sequentially from the mesial temporal lobe (stages I and II), extending to the limbic regions (stages III and IV, when dementia manifests) and then the neocortex (stages V and VI).

Cis/trans-isomerase

A type of enzyme that catalyses the isomerization of geometric isomers, thereby affecting the activity of conformation-specific enzymes such as protein phosphatase 2A (PP2A).

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Li, C., Götz, J. Tau-based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discov 16, 863–883 (2017). https://doi.org/10.1038/nrd.2017.155

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