Tau aggregation and its interplay with amyloid-β

Rebecca M. Nisbet*, Juan-Carlos Polanco, Lars M. Ittner, Jürgen Götz

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

192 Citations (Scopus)
16 Downloads (Pure)

Abstract

Neurofibrillary tangles and amyloid plaques constitute the hallmark brain lesions of Alzheimer’s disease (AD) patients. Tangles are composed of fibrillar aggregates of the microtubule-associated protein tau, and plaques comprise fibrillar forms of a proteolytic cleavage product, amyloid-β (Aβ). Although plaques and tangles are the end-stage lesions in AD, small oligomers of Aβ and tau are now receiving increased attention as they are shown to correlate best with neurotoxicity. One key question of debate, however, is which of these pathologies appears first and hence is upstream in the pathocascade. Studies suggest that there is an intense crosstalk between the two molecules and, based on work in animal models, there is increasing evidence that Aβ, at least in part, exerts its toxicity via tau, with the Src kinase Fyn playing a crucial role in this process. In other experimental paradigms, Aβ and tau have been found to exert both separate and synergistic modes of toxicity. The challenge, however, is to integrate these different scenarios into a coherent picture. Furthermore, the ability of therapeutic interventions targeting just one of these molecules, to successfully neutralize the toxicity of the other, needs to be ascertained to improve current therapeutic strategies, such as immunotherapy, for the treatment of AD. Although this article is not intended to provide a comprehensive review of the currently pursued therapeutic strategies, we will discuss what has been achieved by immunotherapy and, in particular, how the inherent limitations of this approach can possibly be overcome by novel strategies that involve single-chain antibodies.

Original languageEnglish
Pages (from-to)207-220
Number of pages14
JournalActa Neuropathologica
Volume129
Issue number2
DOIs
Publication statusPublished - 24 Jan 2015
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2014. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Alzheimer’s disease
  • Amyloid-β (Aβ)
  • Frontotemporal dementia
  • Immunotherapy
  • Neurotoxicity
  • scFvs (single-chain variable antibody fragments)
  • Tau

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