PTI-777 disrupts Aβ 1–42 fibrils. (a) Dose-dependent disruption/disaggregation of Aβ 1–42 fibrils by PTI-777 as assessed by Thioflavin T fluorometry. PTI-777 significantly (p < 0.001) disrupted/disaggregated Aβ 1–42 fibrils in a dose-dependent manner. **p < 0.01, ***p < 0.001, by Student’s t-test. Bars represent mean +/− SEM. n = 4. (b) Dose-dependent inhibition of Congo red binding to Aβ 1–42 fibrils by PTI-777. ***p < 0.001, by Student’s t-test. Bars represent mean +/− SEM. n = 4. (c–f) PTI-777 caused a marked disruption/disaggregation of β-sheet secondary structure for Aβ 1–42 fibrils, and prevented Aβ 1–40 fibril formation, as determined by CD spectroscopy. (c) PTI-777 at 3 days caused a decrease in β-sheet of Aβ 1–42 fibrils at a PTI-777:Aβ 1–42 (wt/wt) ratio of 0.1:1, as shown by a decrease in the in the ~218 nm minima curve. (d) By 7 days of co-incubation, PTI-777 caused an even greater disruption of the β-sheet secondary structure in Aβ 1–42 fibrils. (e) PTI-777 at 3 days completely prevented Aβ 1–40 fibril formation as demonstrated by a complete flattening of the characteristic β-sheet minima observed in Aβ 1–40 fibrils alone. (f) A similar inhibition of Aβ 1–40 β-sheet formation was observed with PTI-777 at 7 days.