Azaphilones inhibit tau aggregation and dissolve tau aggregates in vitro

Smita R. Paranjape, Andrew P. Riley, Amber D. Somoza, C. Elizabeth Oakley, Clay C.C. Wang, Thomas E. Prisinzano, Berl R. Oakley, T. Chris Gamblin

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

The aggregation of the microtubule-associated protein tau is a seminal event in many neurodegenerative diseases, including Alzheimer's disease. The inhibition or reversal of tau aggregation is therefore a potential therapeutic strategy for these diseases. Fungal natural products have proven to be a rich source of useful compounds having wide varieties of biological activities. We have previously screened Aspergillus nidulans secondary metabolites for their ability to inhibit tau aggregation in vitro using an arachidonic acid polymerization protocol. One aggregation inhibitor identified was asperbenzaldehyde, an intermediate in azaphilone biosynthesis. We therefore tested 11 azaphilone derivatives to determine their tau assembly inhibition properties in vitro. All compounds tested inhibited tau filament assembly to some extent, and four of the 11 compounds had the advantageous property of disassembling preformed tau aggregates in a dose-dependent fashion. The addition of these compounds to the tau aggregates reduced both the total length and number of tau polymers. The most potent compounds were tested in in vitro reactions to determine whether they interfere with tau's normal function of stabilizing microtubules (MTs). We found that they did not completely inhibit MT assembly in the presence of tau. These derivatives are very promising lead compounds for tau aggregation inhibitors and, more excitingly, for compounds that can disassemble pre-existing tau filaments. They also represent a new class of anti-tau aggregation compounds with a novel structural scaffold.

Original languageEnglish
Pages (from-to)751-760
Number of pages10
JournalACS Chemical Neuroscience
Volume6
Issue number5
DOIs
StatePublished - May 20 2015

Bibliographical note

Publisher Copyright:
© 2015 American Chemical Society.

Keywords

  • Alzheimer's disease
  • Aspergillus
  • Aspergillus nidulans
  • Tau
  • aggregation inhibitor
  • azaphilone
  • microtubule-associated protein
  • natural products

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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