title: Interaction between the APOE epsilon4 allele and the APH-1b c + 651T > G SNP in Alzheimer's disease.
abstract: The gamma-secretase complex is a multimeric aspartyl protease which plays a pivotal role in the production of amyloid beta-peptide, the main component of senile plaques in Alzheimer's disease (AD). APH-1a and APH-1b have been recently identified as important subunits of the gamma-secretase complex. We previously studied sequence variations in both genes and their association with AD in a small Italian population. The rare polymorphism c + 651T > G in APH-1b showed a possible interaction with the Apolipoprotein E (APOE) epsilon4 allele in the AD population sample. We extended our genetic analysis to 449 AD patients and 435 controls and, in AD cases, we found a significant interaction (P=0.001) between the allelic variants in the two genes, resulting in a marked increase of the relative risk for AD (OR=28.6). Despite the amino acid substitution does not seem to modify either the intracellular localization or the half-life of APH-1b protein, these data suggest that a cooperative mechanism involving APOE and APH-1b plays a role in the susceptibility to develop AD.
authors.affiliation: Section of Chemistry, Faculty of Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Poli
authors.forename: Luisa Benerini
authors.initials: LB
authors.lastname: Gatta
authors.forename: Carlo
authors.initials: C
authors.lastname: Lovati
authors.forename: Claudio
authors.initials: C
authors.lastname: Mariani
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.forename: Ida
authors.initials: I
authors.lastname: Biunno
authors.forename: Massimo
authors.initials: M
authors.lastname: Musicco
authors.forename: Roberto
authors.initials: R
authors.lastname: Dominici
authors.forename: Alberto
authors.initials: A
authors.lastname: Albertini
authors.forename: Dario
authors.initials: D
authors.lastname: Finazzi
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D019943:Amino Acid Substitution / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D010450:Endopeptidases; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D007558:Italy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D008565:Membrane Proteins; C475155:APH1B protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases