title: Aberrant amyloid precursor protein (APP) processing in hereditary forms of Alzheimer disease caused by APP familial Alzheimer disease mutations can be rescued by mutations in the APP GxxxG motif.
abstract: The identification of hereditary familial Alzheimer disease (FAD) mutations in the amyloid precursor protein (APP) and presenilin-1 (PS1) corroborated the causative role of amyloid-beta peptides with 42 amino acid residues (Abeta42) in the pathogenesis of AD. Although most FAD mutations are known to increase Abeta42 levels, mutations within the APP GxxxG motif are known to lower Abeta42 levels by attenuating transmembrane sequence dimerization. Here, we show that aberrant Abeta42 levels of FAD mutations can be rescued by GxxxG mutations. The combination of the APP-GxxxG mutation G33A with APP-FAD mutations yielded a constant 60% decrease of Abeta42 levels and a concomitant 3-fold increase of Abeta38 levels compared with the Gly(33) wild-type as determined by ELISA. In the presence of PS1-FAD mutations, the effects of G33A were attenuated, apparently attributable to a different mechanism of PS1-FAD mutants compared with APP-FAD mutants. Our results contribute to a general understanding of the mechanism how APP is processed by the gamma-secretase module and strongly emphasize the potential of the GxxxG motif in the prevention of sporadic AD as well as FAD.
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.
authors.forename: Lisa-Marie
authors.initials: LM
authors.lastname: Munter
authors.forename: Anne
authors.initials: A
authors.lastname: Botev
authors.forename: Luise
authors.initials: L
authors.lastname: Richter
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hildebrand
authors.forename: Veit
authors.initials: V
authors.lastname: Althoff
authors.forename: Christoph
authors.initials: C
authors.lastname: Weise
authors.forename: Daniela
authors.initials: D
authors.lastname: Kaden
authors.forename: Gerd
authors.initials: G
authors.lastname: Multhaup
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D020816:Amino Acid Motifs; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D045744:Cell Line, Tumor; D019281:Dimerization; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D053763:Presenilins / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D053763:Presenilins
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