The elusive tau molecular structures: can we translate the recent breakthroughs into new targets for intervention?

Scheme of tau showing domain organization. Depending of the isoform, tau has an N-terminal extension with 0, 1, or 2 inserts (tau0N, tau1N, tau2N, respectively), the presence of N1 and N2 inserts depending on exon 2 and exon 3, respectively. The microtubule-binding region (MTBR) has three (tau3R) or four (tau4R) repeats, the presence of R2 depending on exon 10. MTBR repeats R1 to R4 (31 or 32 residues for each repeat and inter-repeat region) have similar sequences. The PHF6* and PHF6 peptides are located in R2 and R3, respectively. The longest tau isoform corresponds to 441 amino-acid residues (or tau2N4R) and the shortest to tau352 amino-acid residues (or tau0N3R). Tau fragments K18, K19 and dGAE are mentioned in the text. The proline-rich region or PRR has many phosphorylation sites, combination of pS202/pT205 and pS208 forms the AT8 monoclonal antibody epitope. Antibody 18F12 recognizes a conformational epitope at the junction of N1 and N2 inserts. The 18–28 motif of tau is primate specifi