Interaction between the APOE epsilon4 allele and the APH-1b c + 651T > G SNP in Alzheimer's disease.
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.
Poli
Maura
M
Section of Chemistry, Faculty of Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.
Gatta
Luisa Benerini
LB
Lovati
Carlo
C
Mariani
Claudio
C
Galimberti
Daniela
D
Scarpini
Elio
E
Biunno
Ida
I
Musicco
Massimo
M
Dominici
Roberto
R
Albertini
Alberto
A
Finazzi
Dario
D
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
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D008565:Membrane Proteins; C475155:APH1B protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases