Development of the inhibitor for tangle formation of tau protein : Basic research for prevention of Altzheimer disease

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(1) The microtubule-binding domain (MBD) of tau protein is the region responsible for the PHF formation. We succeed in the preparation of an antibody Tau2r3, which selectively recognizes the MBD. The X-ray crystal structure analysis of the complex crystal of its variable region, Fab2r3, with the VQIINK fragment peptide of MBD clarified the overall complex structure. Now, we are investigating the recognition mode of MBD by the antibody at the atomic level. (2) The MBD interaction of a series of inhibitors we discovered so far were investigated by 1H-NMR and other physicochemical methods, and clarified the structural elements necessary for exhibiting the inhibitory activity, i. e., inhibitor has a planar aromatic ring including the polar atom (O or N) or polar group (NH or OH) on the ring. On the other hand, the PHF formation experiment of a series of tau mutants clarified the important of CH…π interaction between Ile308 and Tyr310 residues in the third repeat of MBD.