Advances in tau-based drug discovery

Abstract

INTRODUCTION: Tauopathies, including Alzheimer's disease (AD) and some frontotemporal dementias, are neurodegenerative diseases characterised by pathological lesions comprised of tau protein. There is currently a significant and urgent unmet need for disease-modifying therapies for these conditions and recently attention has turned to tau as a potential target for intervention. AREAS COVERED: Increasing evidence has highlighted pathways associated with tau-mediated neurodegeneration as important targets for drug development. Here, the authors review recently published papers in this area and summarise the genetic and pharmacological approaches that have shown efficacy in reducing tau-associated neurodegeneration. These include the use of agents to prevent abnormal tau processing and increase tau clearance, therapies targeting the immune system, and the manipulation of tau pre-mRNA to modify tau isoform expression. EXPERT OPINION: Several small molecule tau-based treatments are currently being assessed in clinical trials, the outcomes of which are eagerly awaited. Current evidence suggests that therapies targeting tau are likely, at least in part, to form the basis of an effective and safe treatment for Alzheimer's disease and related neurodegenerative disorders in which tau deposition is evident.

Figure 1

(A) The human tau gene showing exons −1 to 14. Exons 1, 4, 5, 7, 9, 11, 12 and 13 are translated in all tau isoforms. Exons 2, 3 and 10 are alternatively spliced to generate six tau isoforms in the human CNS. The 38 known exonic and intronic FTDP-17T tau mutations are shown. (B) The six isoforms of human CNS tau, showing the regulated alternative splicing of exons 2, 3, and 10. Absence of N1 and N2 gives rise to 0N tau, inclusion of N1 produces 1N, and inclusion of both N1 and N2 generates 2N tau isoforms. R1-R4 represent the four imperfect repeat microtubule-binding domains, R2 being encoded by exon 10. Isoforms lacking R2 produce 3R tau and inclusion of R2 results in 4R tau isoforms. The phosphorylation sites on tau identified in Alzheimer brain are indicated below the 2N4R tau isoform. S, serine; T, threonine; Y, tyrosine.

Figure 2

Illustration of the various tau-based therapeutic strategies currently under investigation. Modifying tau alternative splicing can be achieved by targeting tau pre-mRNA, phosphorylation and aggregation can be reduced by the use of immunotherapy, kinase inhibitors, PP2A inducers and disaggregating agents, tau clearance and degradation can be enhanced by targeting the proteasome and lysosomal-autophagy machinery, and loss of the microtubule binding function of tau can be corrected by microtubule-stabilising agents.