Structure and mechanism of action of tau aggregation inhibitors

Katryna Cisek, Grace L. Cooper, Carol J. Huseby, Jeff Kuret

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


Since the discovery of phenothiazines as tau protein aggregation inhibitors, many additional small molecule inhibitors of diverse chemotype have been discovered and characterized in biological model systems. Although direct inhibition of tau aggregation has shown promise as a potential treatment strategy for depressing neurofibrillary lesion formation in Alzheimer’s disease, the mechanism of action of these compounds has been unclear. However, recent studies have found that tau aggregation antagonists exert their effects through both covalent and non-covalent means, and have identified associated potency and selectivity driving features. Here we review small-molecule tau aggregation inhibitors with a focus on compound structure and inhibitory mechanism. The elucidation of inhibitory mechanism has implications for maximizing on-target efficacy while minimizing off-target side effects.

Original languageEnglish (US)
Pages (from-to)918-927
Number of pages10
JournalCurrent Alzheimer research
Issue number10
StatePublished - Dec 1 2014
Externally publishedYes


  • Aggregation
  • Alzheimer’s disease
  • Neurofibrillary tangle
  • Paired helical filaments
  • Tau

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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