Villa A, Latasa M J, Pascual A
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
J Neurochem. 2001 May;77(4):1077-84. doi: 10.1046/j.1471-4159.2001.00315.x.
The beta-amyloid protein, component of the senile plaques found in Alzheimer brains is proteolytically derived from the beta-amyloid precursor protein (APP), a larger membrane-associated protein that is expressed in both neural and non-neural cells. Overexpression of APP might be one of the mechanisms that more directly contributes to the development of Alzheimer's disease. The APP gene expression is regulated by a number of cellular mediators including nerve growth factor (NGF) and other ligands of tyrosine kinase receptors. We have previously described that NGF increases APP mRNA levels in PC12 cells. However, the molecular mechanisms and the precise signalling pathways that mediate its regulation are not yet well understood. In the present study we present evidence that NGF, and to a lesser extent fibroblast growth factor and epidermal growth factor, stimulate APP promoter activity in PC12 cells. This induction is mediated by DNA sequences located between the nucleotides - 307 and - 15, and involves activation of the Ras-MAP kinase signalling pathway. In contrast, we have also found that NGF-induced secretion of soluble fragments of APP into the culture medium is mediated by a Ras independent mechanism.
β-淀粉样蛋白是在阿尔茨海默病患者大脑中发现的老年斑的组成成分，它是由β-淀粉样前体蛋白（APP）经蛋白水解衍生而来的。APP是一种更大的膜相关蛋白，在神经细胞和非神经细胞中均有表达。APP的过度表达可能是更直接导致阿尔茨海默病发生发展的机制之一。APP基因的表达受多种细胞介质调控，包括神经生长因子（NGF）和酪氨酸激酶受体的其他配体。我们之前曾描述过，NGF可增加PC12细胞中APP mRNA的水平。然而，介导其调控的分子机制和精确信号通路尚未完全清楚。在本研究中，我们提供证据表明，NGF以及在较小程度上的成纤维细胞生长因子和表皮生长因子，可刺激PC12细胞中APP启动子的活性。这种诱导作用是由位于核苷酸-307至-15之间的DNA序列介导的，并且涉及Ras-MAP激酶信号通路的激活。相比之下，我们还发现，NGF诱导的APP可溶性片段分泌到培养基中是由一种不依赖Ras的机制介导的。
