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

BIOL 215

Wenkai Li, wenkaili@mail.med.upenn.edu, Center for Neurodegenerative Disease Research and Department of Biochemistry and Molecular Biophysics, University of Pennsylvania School of Medicine, 3600 Spruce St., 3rd Floor, Maloney Bldg, Philadelphia, PA 19104, Jeffrey B. Sperry, sperryb@sas.upenn.edu, Department of Chemistry, Univerisity of Pennsylvania, Philadelphia, PA 19104, Alex Crowe, acrowe@mail.med.upenn.edu, Center for Neurodegenerative Disease Research, Univerisity of Pennsylvania, 3600 Spruce St., 3rd Floor, Maloney Bldg, Philadelphia, PA 19104, Amos B. Smith III, Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, The University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104, and Virginia MY. Lee, vmylee@mail.med.upenn.edu, Center for Neurodegenerative Disease Research, Department of Pathology and Lab Medicine, Univerisity of Pennsylvania, 3600 Spruce St., 3rd Floor, Maloney Bldg, Philadelphia, PA 19104.
Tau is a microtubule-associated protein, which forms intraneuronal filamentous inclusions in Alzheimer's disease (AD) and other tauopathies. The amount of tau aggregates has been correlated with neuron loss and the severity of dementia. Here we tested oleocanthal, the dialdehydic form of (-)deacetoxy-ligstroside aglycone found in olive oil, for inhibition of tau fibrillization in vitro and found that oleocanthal inhibits tau fibrillization through covalent modifications. With a hexapeptide corresponding to the fibrillization-required PHF motif (306VQIVYK311) in tau, we demonstrated that oleocanthal inhibits the polymerization of this peptide and modifies the lysine residue. This suggests that oleocanthal inhibits tau fibrillization via similar reactions with the amino groups in tau protein. FTIR experiments indicate that oleocanthal keeps tau in random coil state and prevents conformational change. SAR studies indicate that the two aldehydes and the C=C double bond are essential for the inhibitory activity of oleocanthal on tau fibrillization.
 

Frontiers in Chemical Biology
5:00 PM-7:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Biological Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007