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Planta Med 2014; 80(01): 77-85
DOI: 10.1055/s-0033-1360180
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Inhibition of Tau Aggregation by Three Aspergillus nidulans Secondary Metabolites: 2,ω-Dihydroxyemodin, Asperthecin, and Asperbenzaldehyde

Smita R. Paranjape
1   Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
,
Yi-Ming Chiang
2   Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
3   Graduate Institute of Pharmaceutical Science, Chia Nan University School of Pharmacy and Science, Tainan, Taiwan
,
James F. Sanchez
2   Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
,
Ruth Entwistle
1   Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
,
Clay C. C. Wang
2   Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
4   Department of Chemistry, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA, USA
,
Berl R. Oakley
1   Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
,
T. Chris Gamblin
1   Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
› Author Affiliations
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Publication History

received 28 June 2013
revised 25 October 2013

accepted 22 November 2013

Publication Date:
10 January 2014 (online)

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Abstract

The aggregation of the microtubule-associated protein tau is a significant event in many neurodegenerative diseases including Alzheimerʼs 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 activity. We have screened Aspergillus nidulans secondary metabolites containing aromatic ring structures for their ability to inhibit tau aggregation in vitro using an arachidonic acid polymerization protocol and the previously identified aggregation inhibitor emodin as a positive control. While several compounds showed some activity, 2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde were potent aggregation inhibitors as determined by both a filter trap assay and electron microscopy. In this study, these three compounds were stronger inhibitors than emodin, which has been shown in a prior study to inhibit the heparin induction of tau aggregation with an IC50 of 1–5 µM. Additionally, 2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde reduced, but did not block, tau stabilization of microtubules. 2,ω-Dihydroxyemodin and asperthecin have similar structures to previously identified tau aggregation inhibitors, while asperbenzaldehyde represents a new class of compounds with tau aggregation inhibitor activity. Asperbenzaldehyde can be readily modified into compounds with strong lipoxygenase inhibitor activity, suggesting that compounds derived from asperbenzaldehyde could have dual activity. Together, our data demonstrates the potential of 2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde as lead compounds for further development as therapeutics to inhibit tau aggregation in Alzheimerʼs disease and neurodegenerative tauopathies.

Key words

tau - microtubule-associated protein - Trichocomaceae - Aspergillus nidulans - Alzheimerʼs disease

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