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 A beta(42/40) ratio without increasing total A beta production. In the present study, we analyzed the impact of FAD mutations and g-secretase modulators (GSMs) that alter the A beta(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/gamma-secretase cleavage site on APP. Results: By using a Forster resonance energy transfer (FRET)-based technique, fluorescent lifetime imaging microscopy (FLIM), we show that A beta(42/40) ratio-modulating factors which target either APP substrate or PS1/gamma-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.