Review Article

Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies

  • Nature Reviews Neurology volume 14, pages 2239 (2018)
  • doi:10.1038/nrneurol.2017.162
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Abstract

Most neurodegenerative diseases are proteinopathies, which are characterized by the aggregation of misfolded proteins. Although many proteins have an intrinsic propensity to aggregate, particularly when cellular clearance systems start to fail in the context of ageing, only a few form fibrillar aggregates. In Alzheimer disease, the peptide amyloid-β (Aβ) and the protein tau aggregate to form plaques and tangles, respectively, which comprise the histopathological hallmarks of this disease. This Review discusses the complexity of Aβ biogenesis, trafficking, post-translational modifications and aggregation states. Tau and its various isoforms, which are subject to a vast array of post-translational modifications, are also explored. The methodological advances that revealed this complexity are described. Finally, the toxic effects of distinct species of tau and Aβ are discussed, as well as the concept of protein 'strains', and how this knowledge can facilitate the development of early disease biomarkers for stratifying patients and validating new therapies. By targeting distinct species of Aβ and tau for therapeutic intervention, the way might be paved for personalized medicine and more-targeted treatment strategies.

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Acknowledgements

J.G. is supported by the Estate of Clem Jones AO, the Australian Research Council (grant DP160103812) and the National Health and Medical Research Council of Australia (NHMRC; grants GNT1037746 and GNT1127999). F.A.M. is supported by the Australian Research Council (grants DP170100125, LE0882864 and LE130100078) and the NHMRC (grant GNT1058769 and NHMRC Senior Research Fellowship GNT1060075). L.-G.B. is supported by the Peter Hilton Fellowship. The authors thank R. Tweedale for critically reading the manuscript.

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Affiliations

  1. Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, St Lucia Campus — Brisbane, Upland Road, Building 79, Brisbane, Queensland 4072, Australia.

    • Juan Carlos Polanco
    • , Chuanzhou Li
    • , Liviu-Gabriel Bodea
    • , Ramon Martinez-Marmol
    • , Frederic A. Meunier
    •  & Jürgen Götz

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Contributions

All authors researched data for the article, wrote the manuscript, made substantial contributions to discussions of its content and undertook review and/or editing of the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jürgen Götz.

Glossary

Long-term potentiation

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

Sumoylation

A post-translational modification involving conjugation with small ubiquitin-like modifiers (SUMOs).