title: Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production.
abstract: 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.
authors.affiliation: Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH1015 Lausanne, Switzerland.
authors.forename: Mitko
authors.initials: M
authors.lastname: Dimitrov
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Alattia
authors.forename: Thomas
authors.initials: T
authors.lastname: Lemmin
authors.forename: Rajwinder
authors.initials: R
authors.lastname: Lehal
authors.forename: Andrzej
authors.initials: A
authors.lastname: Fligier
authors.forename: Jemila
authors.initials: J
authors.lastname: Houacine
authors.forename: Ishrut
authors.initials: I
authors.lastname: Hussain
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Matteo
authors.initials: M
authors.lastname: Dal Peraro
authors.forename: Dirk
authors.initials: D
authors.lastname: Beher
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Fraering
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects; D051880:Receptors, Notch / Q000378:metabolism
chemical_list: C555019:1-(1-(4-fluorophenyl)ethyl)-3-((3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)methylene)-2-piperidinone; C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D007093:Imidazoles; D050505:Mutant Proteins; D010880:Piperidines; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases