Lahiri Debomoy K, Ge Yuan-Wen, Maloney Bryan, Wavrant-De Vrièze Fabienne, Hardy John
Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 791 N. Union Drive, Indianapolis, IN 46202, USA.
Neurobiol Aging. 2005 Nov-Dec;26(10):1329-41. doi: 10.1016/j.neurobiolaging.2004.11.005. Epub 2004 Dec 22.
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.
阿尔茨海默病（AD）的特征是形成β淀粉样肽（Aβ）斑块。常染色体遗传或“家族性”AD仅与编码序列突变有关。我们对β淀粉样前体蛋白（APP）基因启动子（转录起始位点+1处-3829位的C→T和-1023位的T→C）中出现的两种多态性的DNA-蛋白质相互作用及表达影响进行了表征。我们报告了-3829和-1023多态性区域中变异序列在报告基因表达和DNA-蛋白质相互作用方面存在明显的功能差异。与-3829C相比，-3829T变异体的DNA-蛋白质相互作用和报告基因表达降低，而-1023C的DNA-蛋白质相互作用和报告基因表达比-1023T更强。我们预测功能丧失（-3829T）可能的转录因子为ADR1、MIG1和PuF，功能获得（-1023C）可能的转录因子为E12/E47、ITF-2和RFX2。对APP基因调控多态性活性的表征有助于理解大多数AD病例可能的潜在机制，并可能有助于基于启动子的药物设计。
