Fig. 1

Screening aryloxypropanolamines derivatives for dissociative activity against Aβ aggregates. A Scheme of phenotypic screen for aryloxypropanolamines derivatives. B Inhibitory effects of synthesized compounds against Aβ(1–42) aggregation were evaluated using ThT fluorescence. C Dissociative effects of compounds. D Gel electrophoresis with PICUP and silver staining. E Disaggregation effects of YIAD001 and YIAD002 against Aβ(1–40) aggregates. Aggregation time for Aβ is indicated as “–” for 0 day, “+” for 3 days, and “++” for 6 days. All fluorescence intensities were normalized and statistically compared to Aβ(1–42)-only 3 days (+) control (100%). F–M YIAD001 (50 mg/kg/day, n = 6), YIAD002 (50 mg/kg/day, n = 6), and YIAD003 (50 mg/kg/day, n = 6) were orally administered to 4.5-month-old female 5XFAD mice for 5 weeks. F Brains were immunostained with 6E10 (green) and Hoechst (blue). G Illustration indicating the region for magnified brain image (left) and plaque count (right). H Plaque number and area of the whole brain of the mice were quantified. Dot blot assay using soluble fractions of cortical (I) and hippocampal (J) lysates with 6E10 and A11 antibodies. Immunoblot of soluble fractions of cortical (K) and hippocampal (L) lysates. Relative intensities of the blots were quantified in ratio to actin. M Schematic illustration and results of MWCO filtration and dot blot assay. Cortical lysates were denatured by GdnHCl and filtered through a 100 kDa MWCO filter to remove APP (100–140 kDa). All statistical comparisons were made with the normalized vehicle-treated 5XFAD mice. Full gels, brain images, and blot images are provided in additional files. One-way analysis of variance followed by Bonferroni’s post hoc comparisons tests were performed in all statistical analyses (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001). Data are presented as mean ± SEM. Abbreviations: Conc. = concentration, Agg. = aggregation, Cpd. = compound, Fluor. = fluorescent