Fig. 7.

Brain-Shuttle mediated transport of BACE1 inhibitors necessary for Aβ production inhibition in the brain. (a and b) Relevant Aβ reduction 5–48 h after systemic application seen with the non-conjugated BACE1 peptide inhibitors in plasma (a) but not in brain (b). The two lipidated constructs BACE1_palm and BACE1_chol showed higher potency than BACE1. (c and d) Aβ reduction 5–48 h after systemic application of BS-conjugated BACE1 peptide inhibitors in plasma (c) as well as in the brain (d). Plasma reduction was similar between comparable BS-coupled and un-coupled BACE1 inhibitors and reached 50% over 48 h. In brain the highest reduction was seen 24 h after application. Bars are colour coded, 5 h (green), 24 h (blue) and 48 h (orange) post i.v. dosing. (e and f) Plasma pharmacokinetics of BS-BACE1 (blue), BS-BACE1_chol (orange) and a control IgG (black) were analyzed 5–48 h after single intravenous dose of 10 mg/kg. The concentration of BS-BACE1 and BS-BACE1_chol in plasma was lower and in brain higher than for the non-BBB permeable control IgG. AUC_5–48h (μg h/ml) in plasma was 47.0 (BS-BACE1), 55.2 (BS-BACE_chol) and 131.5 (control IgG). AUC_5–48h (ng h/ml) in brain was 775.4 (BS-BACE1), 557.5 (BS-BACE_chol) and 58.9 (control IgG). Red dashed line represents 50% Aβ inhibition. Values plotted are means ± SEM (n = 3). *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 (t-test, compared to control IgG–dosed animals).