Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau

In Alzheimer's disease and related tauopathies, tau fibrillizes and aggregates into neurofibrillary tangles. Unpublished data of Li et al. indicate an inhibitory effect of oleocanthal on Aβ fibrillization, so I was reasoned that oleocanthal might inhibit tau fibrillization as well. Herein it is demonstrated that oleocanthal abrogates fibrillization of tau by locking tau into the naturally unfolded state. Using PHF6 peptide consisting of the amino acid residues VQIVYK, a hexapeptide within the third repeat of tau that is essential for fibrillization, it was shown 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.

Figure: Human tau constructs, structure of oleocanthal and Schiff base reaction between oleocanthal and lysine side chain.
Li et al., J. Neurochem. 2009

Oleocanthal is a potential future treatment of Alzheimer's disease as it prevents the alteration of a specific protein associated with the development of the disease.

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