Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau
Open Access
- 21 July 2009
- journal article
- Published by Wiley in Journal of Neurochemistry
- Vol. 110 (4), 1339-1351
- https://doi.org/10.1111/j.1471-4159.2009.06224.x
Abstract
Tau is a microtubule‐associated protein that promotes microtubule assembly and stability. In Alzheimer’s disease and related tauopathies, tau fibrillizes and aggregates into neurofibrillary tangles. Recently, oleocanthal isolated from extra virgin olive oil was found to display non‐steroidal anti‐inflammatory activity similar to ibuprofen. As our unpublished data indicates an inhibitory effect of oleocanthal on amyloid β peptide fibrillization, we reasoned that it might inhibit tau fibrillization as well. Herein, we demonstrate that oleocanthal abrogates fibrillization of tau by locking tau into the naturally unfolded state. Using PHF6 consisting of the amino acid residues VQIVYK, a hexapeptide within the third repeat of tau that is essential for fibrillization, we show that oleocanthal forms an adduct with the lysine via initial Schiff base formation. Structure and function studies demonstrate that the two aldehyde groups of oleocanthal are required for the inhibitory activity. These two aldehyde groups show certain specificity when titrated with free lysine and oleocanthal does not significantly affect the normal function of tau. These findings provide a potential scheme for the development of novel therapies for neurodegenerative tauopathies.Keywords
This publication has 49 references indexed in Scilit:
- High throughput screening for small molecule inhibitors of heparin-induced tau fibril formationBiochemical and Biophysical Research Communications, 2007
- Convenient Synthesis of 6,6-Bicyclic Malonamides: A New Class of Conformationally Preorganized Ligands for f-Block Ion BindingThe Journal of Organic Chemistry, 2006
- A Century of Alzheimer's DiseaseScience, 2006
- A Simple High-Performance Liquid Chromatography Method for the Determination of Throat-Burning Oleocanthal with Probated Antiinflammatory Activity in Extra Virgin Olive OilsJournal of Agricultural and Food Chemistry, 2006
- Oleocanthal in olive oil: Between myth and realityMolecular Nutrition & Food Research, 2006
- Tau Phosphorylation, Aggregation, and Cell ToxicityJournal of Biomedicine and Biotechnology, 2006
- Mediterranean Diet and Cardiovascular HealthAnnals of the New York Academy of Sciences, 2005
- Tau gene mutations and their effectsMovement Disorders, 2005
- Tau is a candidate gene for chromosome 17 frontotemporal dementiaAnnals of Neurology, 1998
- Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulinJournal of Molecular Biology, 1977