Pollwein P
Center for Molecular Biology Heidelberg (ZMBH), University of Heidelberg, Germany.
Biochem Biophys Res Commun. 1993 Jan 29;190(2):637-47. doi: 10.1006/bbrc.1993.1096.
A four- to fivefold overexpression of the gene for the Alzheimer amyloid precursor protein (APP) in individuals with Down's syndrome (DS) appears to be responsible for the fifty year earlier onset of Alzheimer's disease pathology in DS compared to the normal population. Elucidation of the mechanisms regulating the expression of the human APP gene might therefore be an important step forward in understanding the processes leading to Alzheimer's disease. Recently, an activating DNA fragment proximal to the transcriptional start site of the APP gene was identified, composed of two GC-elements, A and C, both required for full transcriptional activation (1). Here I present evidence that the transcription factor Sp1 can bind to element A and that another specific complex, called C2A, can be observed, which covers a region overlapping with the Sp1 binding site on the APP promoter. Gene transfer experiments with a truncated version of the APP promoter containing mutated binding sites for the factors mentioned above support that at least two different and independent regulatory pathways for APP gene expression might exist. An imbalance between these pathways is proposed to be a putative risk factor for the development of Alzheimer's disease.
唐氏综合征（DS）患者体内阿尔茨海默病淀粉样前体蛋白（APP）基因的过表达程度为正常水平的四到五倍，这似乎是导致DS患者比正常人群早五十年出现阿尔茨海默病病理特征的原因。因此，阐明调控人类APP基因表达的机制可能是在理解导致阿尔茨海默病的过程中向前迈出的重要一步。最近，在APP基因转录起始位点附近鉴定出一个激活DNA片段，它由两个GC元件A和C组成，这两个元件都是完全转录激活所必需的（1）。在此，我提供证据表明转录因子Sp1可以与元件A结合，并且可以观察到另一种特定的复合物，称为C2A，它覆盖了APP启动子上与Sp1结合位点重叠的区域。使用含有上述因子突变结合位点的APP启动子截短版本进行的基因转移实验表明，APP基因表达可能至少存在两种不同且独立的调控途径。这些途径之间的失衡被认为是阿尔茨海默病发展的一个潜在风险因素。
