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

作者：Dimitrov Mitko; Alattia Jean Rene; Lemmin Thomas; Lehal Rajwinder; Fligier Andrzej; Houacine Jemila; Hussain Ishrut; Radtke Freddy; Dal Peraro Matteo; Beher Dirk; Fraering Patrick C^*

来源：Nature Communications, 2013, 4(1): 2246.

DOI：10.1038/ncomms3246

Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical gamma-secretase modulators affect the processing of APP by the gamma-secretase complex and the production of the amyloid-beta peptide A beta 42, 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 gamma- and epsilon-cleavage sites, by raising the A beta 42/40 ratio and inhibiting the production of AICD50-99, one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to gamma- secretase modulators, which shift A beta 42 production towards the shorter A beta 38, but unequivocally spare the epsilon-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 gamma- site, modifying at the same time, the solvation of the epsilon-site.

• 出版日期2013-8