Fig. 1

Human brain tau isoforms and the cores of tau filaments from Alzheimer’s disease. a MAPT and the six tau isoforms expressed in adult human brain. MAPT consists of 16 exons (E). Alternative mRNA splicing of E2 (red), E3 (green) and E10 (yellow) gives rise to the six tau isoforms (352–441 amino acids). The constitutively spliced exons (E1, E4, E5, E7, E9, E11, E12 and E13) are shown in blue. E0, which is part of the promoter, and E14 are noncoding (white). E6 and E8 (violet) are not transcribed in human brain. E4a (orange) is expressed only in the peripheral nervous system. The repeats (R1-R4) are shown, with three isoforms having four repeats each (4R) and three isoforms having three repeats each (3R). The core regions of the tau filaments from AD brain (V306-F378, using the numbering of the 441 amino acid tau isoform) are underlined. b, c Cross-sections of the cryogenic electron microscopy (cryo-EM) densities and atomic models of the cores of paired helical (b, in blue) and straight (c, in green) tau filaments. Each filament core consists of two identical protofilaments extending from V306-F378 of tau, which are arranged base-to-base (b) or back-to-base (c). The cryo-EM maps of the filament cores are at 3.4–3.5 Å resolution. Unsharpened, 4.5 Å low-pass filtered density is shown in grey. Density highlighted with an orange background is reminiscent of a less-ordered β-sheet and could accommodate an additional 16 amino acids, which would correspond to a mixture of residues 259–274 (R1) from 3R tau and residues 290–305 (R2) from 4R tau. Adapted from [46]