1. Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production
- Author
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Jemila Houacine, Jean René Alattia, Dirk Beher, Freddy Radtke, Matteo Dal Peraro, Patrick C. Fraering, Ishrut Hussain, Rajwinder Lehal, Andrzej Fligier, Thomas Lemmin, and Mitko Dimitrov
- Subjects
Models, Molecular ,Magnetic Resonance Spectroscopy ,Molecular Sequence Data ,General Physics and Astronomy ,Disease ,Cleavage (embryo) ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,Mass Spectrometry ,03 medical and health sciences ,Amyloid beta-Protein Precursor ,0302 clinical medicine ,Piperidines ,Alzheimer Disease ,mental disorders ,Humans ,γ secretase ,Amino Acid Sequence ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Receptors, Notch ,Chemistry ,Imidazoles ,General Chemistry ,Protein Structure, Tertiary ,Alpha secretase ,Mutation ,Proteolysis ,Cancer research ,Mutant Proteins ,Amyloid Precursor Protein Secretases ,030217 neurology & neurosurgery - Abstract
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.
- Published
- 2012