Rapid measurement of ISF Aβ40 clearance after Pgp inhibition. (A) Absolute baseline concentrations of ISF Aβ40 calculated using calibrated MIEs in the hippocampus of APP/PS1 mice are significantly increased (Student’s t test; *, P = 0.008) 60 min after XR9576 treatment (n = 8; mean = 283.9 ± 80.38; 80 mg/kg) compared with control mice (n = 15; mean = 99.12 ± 19.28). (B) ISF Aβ40 concentrations decrease in both groups after Compound E administration to block Aβ production. (C) Compound E levels in the brain reach ∼1,200-fold IC50 within 5 min of injection and remain ∼30-fold higher than IC50 at 60 min. (D) Log plot of percent Aβ change from baseline versus time for both XR9576-treated mice (n = 5) and control (n = 6) shows initial rates of clearance are very similar then begin to diverge 16 min after γ-secretase inhibition. (E) Overall half-life of Aβ40 is significantly slowed (Student’s t test; *, P = 0.016) after XR9576 treatment (control mean = 23.30 ± 4.55 min; XR9576 mean, 71.05 ± 16.01 min). Further analysis of the slopes between groups suggests two phases in Aβ40 clearance over time. Statistical analysis reveals no difference in rates over the first 15 min (F; Student’s t test, P = 0.698; control mean = 22.26 ± 4.09 min; XR9576 mean, 27.1 ± 12.41 min); however, rates from 16–60 min are significantly slowed in XR9576-treated mice (G; Student’s t test; *, P = 0.001; control mean, 30.44 ± 7.71 min; XR9576 mean, 84.08 ± 10.85 min). Error bars represent ± SEM.
