Fig. 2.

Effect of 138 AD-derived PS1 mutations on the abilities of the corresponding γ-secretase variants to generate Aβ42 and Aβ40. The amounts of Aβ42 and Aβ40 produced by WT γ-secretase are normalized. The relative amounts of Aβ42 and Aβ40 produced by these 138 γ-secretase variants are shown here. The vast majority of these variants exhibit reduced production of both Aβ42 and Aβ40. In particular, production of Aβ42 as well as Aβ40 was abrogated to background levels for 11 γ-secretase variants, including S178P, S212Y, Q223R, S230I, I238M, K239N, T245P, L271V, T274R, T291P, and E318G. Only 10 γ-secretase variants exhibit increased cleavage activities toward both Aβ42 and Aβ40 compared with WT γ-secretase.