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    Azaphilones inhibit tau aggregation and dissolve tau aggregates in vitro

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    Paranjape_ACS_2015.pdf (4.288Mb)
    Issue Date
    2015-04-15
    Author
    Paranjape, Smita Ramesh
    Riley, Andrew Philip
    Somoza, Amber D.
    Oakley, C. Elizabeth
    Wang, Clay C. C.
    Prisinzano, Thomas E.
    Oakley, Berl R.
    Gamblin, Truman Chris
    Publisher
    ACS
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    Copyright © 2015 American Chemical Society
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    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, while 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 numbers 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.
    URI
    http://hdl.handle.net/1808/23831
    DOI
    https://doi.org/10.1021/acschemneuro.5b00013
    Collections
    • Molecular Biosciences Scholarly Works [581]
    Citation
    Paranjape, S. R., Riley, A. P., Somoza, A. D., Oakley, C. E., Wang, C. C. C., Prisinzano, T. E., … Gamblin, T. C. (2015). Azaphilones inhibit tau aggregation and dissolve tau aggregates in vitro. ACS Chemical Neuroscience, 6(5), 751–760. http://doi.org/10.1021/acschemneuro.5b00013

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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