A scheme of reciprocal interaction between APP-CT positioning relative to the membrane and PS1 conformation . Wild type PS1/γ-secretase can exist in an "open" and "close" conformational states that correlate with production of Aβ40 and Aβ42, respectively (Lleo, 2004, Berezovska 2005), with the "open" conformation being a predominant state (A). The C-terminus of APP bearing FAD mutation(s) associated with the increased Aβ42/40 ratio (orange/red) positions closer to the membrane (B), compared to that in the wild type APP (A). When incorporated into wild type PS1/γ-secretase, it can induce conformational change of PS1 by bringing PS1 NT and CT closer together . On the other hand, when wild type APP is incorporated into FAD-mutant PS1/γ-secretase that predominantly exist in a "closed" conformation, the position of APP C-terminus changes and comes closer to the membrane (C).