Abstract

Alzheimer's disease is characterized by formation of plaques of amyloid beta peptide . 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 of the Abeta precursor protein 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 are ADR1, MIG1, and PuF, and for gain of function 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