Figure 2.

Selective inhibition of Aβ42 secretion after JNJ-40418677 treatment (0.2 nM–300 µM) in cell culture supernatants of APP WT SKNBE-2 cells (A) and primary rat cortical neuronal cultures (B). Levels of secreted Aβ42 and Aβtotal as measured with elisa and cellular toxicity as measured with a WST-1 assay are expressed as a percentage inhibition compared with values in vehicle-treated control cells (mean ± SEM). The mean IC₅₀ value for Aβ42 inhibition is 200 and 185 nM for APP WT SKNBE-2 cells (n = 10) and primary rat cortical neurones (n = 37) respectively. (C) Selective decrease of Aβ42 and increase of Aβ38 after JNJ-40418677 (10 µM) treatment in a cell-free γ-secretase assay. Aβ40 levels remained unchanged. Recombinant CTF-β substrate was incubated with an enriched γ-secretase preparation as described, and Aβ38, Aβ40 and Aβ42 levels were analysed by Western blotting utilizing antibody 6E10. Treatment with 1 µM DAPT reduced the production of all Aβ species analysed.