Nerve growth factor modulates the expression and secretion of β-amyloid precursor protein through different mechanisms in PC12 cells

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 nonneural 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 Has-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.