Abstract
BackgroundSeveral familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the Aβ42/40 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 Aβ42/40 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.ResultsBy using a Förster resonance energy transfer (FRET)-based technique, fluorescent lifetime imaging microscopy (FLIM), we show that Aβ42/40 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.ConclusionsThus, 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.
Highlights
Several familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the Ab42/40 ratio without increasing total Ab production
The detailed molecular mechanism responsible for different presenilin 1 (PS1) conformational states, and underlying the precision of APP cleavage by PS1/g-secretase is currently unknown, we found that the “closed” conformation of PS1 is consistently linked to a higher Ab42/40 ratio, whereas the “open” conformation is associated with a lower Ab42/40 ratio [26,27,28]
The Ab42/40 ratio-raising APP mutations increase the proximity between APP-CT and the membrane First, we measured the effect of V717I, V717K or I716F mutations located in the transmembrane domain of APP on the Ab42/40 ratio in Chinese Hamster Ovary (CHO) cells transiently transfected with the mutant APP constructs
Summary
Several familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the Ab42/40 ratio without increasing total Ab production. We analyzed the impact of FAD mutations and g-secretase modulators (GSMs) that alter the Ab42/40 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/g-secretase cleavage site on APP. Secretase is responsible for cleavage of a number of type I membrane proteins, including amyloid precursor protein (APP) and Notch, and is comprised of presenilin 1 or 2, Aph, Pen and Nicastrin [1,2,3,4,5].
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