Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

Pathological amino acid substitutions in the amyloid precursor protein (APP) and chemical ? secretase modulators affect the processing of APP by the ? secretase complex and the production of the amyloid beta peptide Aß42 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 ? and e cleavage sites by raising the Aß42/40 ratio and inhibiting the production of AICD50 99 one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to ? secretase modulators which shift Aß42 production towards the shorter Aß38 but unequivocally spare the e 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 ? site modifying at the same time the solvation of the e site. © 2009 2012 IEEE.