Fig. 1

Inhibition of EV release by DDL-112 in an acute study and improvement in motor function as well as reduction of PK-resistant αSyn aggregates in the SN with chronic DDL-112 treatment of PD model mice. Acute study: a A scheme of the acute study protocol wherein mice were pre-treated with DDL-112 then received ICV injection of IL-1β before tissue collection is shown. b A representative transmission electron microscopy (TEM) image of the brain EV fraction. c Average concentrations of 50–200 nm size EVs from each treatment condition compared by Tunable Resistive Pulse Sensing (TRPS) analysis and levels. d Levels of DDL-112 in brain tissue of mice represented by the mean and SEM. e Representative images of immunoblot (IB) analysis of EV fractions from individual animals are shown; membranes were probed against exosomal markers (CD63 and Synt-1) with Ponceau S (PS) as the loading control. f Densitometry analysis of CD63 IB images. g Densitometry analysis of Syntenin-1 (Synt-1) IB images. Optical density (OD) is shown as percent of control. N = 4 animals per group. Statistical analysis was performed using one-way ANOVA with post-hoc Tukey comparison tests: *p < 0.05 and **p < 0.01. Chronic study: Behavioral/motor function assessment of h Challenging Beam (CB) error-step (Veh n = 8, DDL-112 n = 7), i pole test time to descend (Veh n = 7, DDL-112 n = 6; one mouse in each group was a non-performer), and j Open Field (OF) distance (cm) traveled per episode of movement (Veh n = 8, DDL-112 n = 6; on mouse in the DDL-112 group was a non-performer). k Animal weight with and without DDL-112 treatment is shown. l The area in percent with proteinase K (PK)-resistant αSyn aggregates in the global SN is graphed. (Veh n = 8, DDL-112 n = 7). m Brain levels of DDL-112 at the time of euthanasia (4 h after dosing) are shown. All data plotted minimum to maximum. Statistics performed using Student's unpaired t-test (*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001)