Fig. 1

Tau protein structure and isoforms. a Tau protein is encoded by the MAPT gene located on chromosome 17, consisting of 16 exons. Exons 1, 4, 5, 7, 9, 11, 12 and 13 are constitutively expressed in all human tau isoforms. Exons −1, 8 and 14 are never transcribed, while exons 4a and 6 are only transcribed in non-canonical isoforms. Exons 2 and 3 encode for the N-terminal repeats, N1 and N2, respectively. Exons 9–12 encode four repeat motifs, R1-R4, which comprise the microtubule-binding domain (MTBD). In general, tau consists of four domains, the N-terminus, Proline-rich domain, MTBD and the C-terminus. b Alternative splicing exons 2, 3 and 10 produces six unique human isoforms, characterized by the inclusion and exclusion of N1, N2 and R2. Isoforms range in size from 352 amino acids (0 N3R) to 441 amino acids (2 N4R). In the healthy adult human CNS, 3R and 4R isoforms are expressed in relatively equal ratios, and disruption of this balance is implicated in tauopathies. c Additional tau isoforms have been described in humans and other species. The inclusion of exon 4a produces a large isoform termed Big Tau. Other isoforms include the presence of exon 6 (6 +, 6p and 6 d tau) or a truncated isoform that includes a portion of intron 12 (W-tau). Created in BioRender