Authors:
Mitko Dimitrov, Jean-René Alattia, Thomas Lemmin, Rajwinder Lehal, Andrzej Fligier, Jemila Houacine, Ishrut Hussain, Freddy Radtke, Matteo Dal Peraro, Dirk Beher, & Patrick C. Fraering
Summary:
Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical γ-secretase modulators affect the processing of APP by the γ-secretase complex and the production of the amyloid-beta peptide Aβ42, the accumulation of which is considered causative of Alzheimer’s disease. Here we demonstrate that mutations in the transmembrane domain of APP causing aggressive early-onset familial Alzheimer’s disease affect both γ- and ε-cleavage sites, by raising the Aβ42/40 ratio and inhibiting the production of AICD50–99, one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to γ-secretase modulators, which shift Aβ42 production towards the shorter Aβ38, but unequivocally spare the ε-site and APP- and Notch-ICDs production. Molecular simulations suggest that familial Alzheimer’s disease mutations modulate the flexibility of the APP transmembrane domain and the presentation of its γ-site, modifying at the same time, the solvation of the ε-site.
Source:
Nature Communications; 4, 2246 (08/02/13)