Reciprocal relationship between APP positioning relative to the membrane and PS1 conformation

Background Several familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the Aβ 42/40 ratio without increasing total Aβ production. In the present study, we analyzed the impact of FAD mutations and γ-secretase modulators (GSMs) that alter the Aβ 42/40 ratio on APP C-terminus (CT) positioning relative to the membrane, reasoning that changes in the alignment of the APP intramembranous domain and presenilin 1 (PS1) may impact the PS1/γ-secretase cleavage site on APP. Results By using a Förster resonance energy transfer (FRET)-based technique, fluorescent lifetime imaging microscopy (FLIM), we show that Aβ 42/40 ratio-modulating factors which target either APP substrate or PS1/γ-secretase affect proximity of the APP-CT to the membrane and change PS1 conformation. Conclusions Thus, we propose that there is a reciprocal relationship between APP-CT positioning relative to the membrane and PS1 conformation, suggesting that factors that modulate either APP positioning in the membrane or PS1 conformation could be exploited therapeutically.