Fig. 8: Structure-based inhibition of tau aggregation.

a Structure-based design of a thermodynamic strong VQIVYK-targeting capper variant sequence (V1W), using full-length tau fibril polymorph cryo-EM structures. Structure representation were prepared using YASARA (v21.8.26). b CAP1 tandem peptide design of the V1W capping variant sequence, incorporating Arg gatekeeper residues and a GS-linker. c, d The CAP1 peptide inhibits both c VQIVYK and d heparin-induced aggregation of recombinant full-length tau (rTau), as shown by Th-T aggregation kinetics. e High affinity binding of CAP1 to tau aggregation seeds (purple curve, 145 ± 49 nM) produced from sonicating heparin-induced tau fibrils (Supplementary Fig. S6). No binding was determined for CAP1 to soluble monomeric tau (green curve), suggesting a high specificity of aggregated species. Curves are shown as mean values ± SD (n = 3 biologically independent samples). f Dose-dependent inhibition of tau seeding in the FRET biosensor cell line after pre-treatment of rTau (125 nM). An inhibitory concentration value (IC₅₀) of 207 nM was determined using curve fitting analysis. Curves are shown as mean values ± SD (n = 3 biologically independent samples). g Pre-treatment of individual brain extract samples (shown as A1, A2 and A3 (for neuropathological details see Supplementary Table 3) isolated from AD patients (500x dilution) with the CAP1 peptide (500 nM) significantly reduces the fraction of cells containing tau inclusions (three samples, tested in duplicates, n = 6). Bar plots are represented as mean values ±SD. Statistical significance was determined using one-way ANOVA with Tukey’s test for multiple comparisons. h Representative images of biosensor cells treated with heparin-induced tau seeds pre-incubated with incremental dosage of the CAP1 peptide (Bar = 100 μm). Higher CAP1 concentrations significantly reduce the formation of tau inclusions shown as FRET-intensive puncta (n = 3 independent repeats). i Representative images of biosensor cells (Bar = 50 μm) treated with AD extracts with and without CAP1 preatreatment (500 nM) (n = 3 independent repeats). Source data are provided as a Source Data file.