Characterization of two APP gene promoter polymorphisms that appear to influence risk of late-onset Alzheimer's disease.
Alzheimer's disease (AD) is characterized by formation of plaques of amyloid beta peptide (Abeta). Autosomally-inherited or "familial" AD had been demonstrated only in connection with coding sequence mutations. We characterized DNA-protein interaction and expression influence of two polymorphisms that occur in the promoter (C<-->T at -3829 and T<-->C at -1023, +1 transcription start site) of the Abeta precursor protein (APP) gene. We report distinct functional differences in reporter expression and in DNA-protein interaction for variant sequences in both -3829 and -1023 polymorphic regions. The -3829T variant has reduced DNA-protein interaction and reporter expression compared to -3829C, while -1023C has greater DNA-protein interaction and reporter expression than -1023T. Our predictions for likely transcription factors for loss of function (-3829T) are ADR1, MIG1, and PuF, and for gain of function (-1023C) are E12/E47, ITF-2, and RFX2. Characterization of the activity of a regulatory polymorphism of the APP gene points towards understanding mechanisms that likely underlie the majority of AD cases and may contribute to promoter-based drug design.
Lahiri
Debomoy K
DK
Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 791 N. Union Drive, Indianapolis, IN 46202, USA. dlahiri@iupui.edu
Ge
Yuan-Wen
YW
Maloney
Bryan
B
Wavrant-De Vrièze
Fabienne
F
Hardy
John
J
D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001483:Base Sequence; D045744:Cell Line, Tumor; D003001:Cloning, Molecular / Q000379:methods; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D009447:Neuroblastoma; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D012306:Risk
D016564:Amyloid beta-Protein Precursor