FIGURE 5.

Single 24 h dose of each lead tau degrader has a prolonged effect on tau reduction. (A) Schematic of the assay implemented to measure effect of lead degraders (QC-01-175, FMF-06-038, FMF-06-049) on tau levels of FTD neurons (A152T or P301L) differentiated for 6 weeks. After 24 h incubation with each degrader and medium compound washout, neurons were analyzed over an 8-day time-course by western blot of tau and P-tau levels. Graph on the right illustrates the proposed possible outcomes for the trajectory of tau levels over time post-treatment. (B–G) FTD tau-A152T neurons (B,D,F) or tau-P301L (C,E,G) were treated with QC-01-175 (B,C), FMF-06-038 (D,E) or FMF-06-049 (F,G) for 24 h, followed by compound washout (red arrows). Total tau (TAU5), P-tau S396 and actin were measured by western blot over a period of 8 days post-treatment. Representative blots are shown, and graph data points represent mean densitometry (bands within brackets) ± SD for n = 2 biological replicates. Dotted lines highlight the% of total tau and P-tau in neurons after 8 days, relative to day 0/vehicle samples.