NERVE GROWTH-FACTOR AND RAS REGULATE BETA-AMYLOID PRECURSOR PROTEIN GENE-EXPRESSION IN PC12 CELLS

The beta-amyloid protein, the major component of the vascular and plaq ue amyloid deposits that characterize Alzheimer's disease, derives fro m a larger beta-amyloid precursor protein (APP) that is expressed in b oth neural and nonneural cells. An increased expression of APP might a ctively contribute to the development of the pathology; however, the m echanisms involved in the regulation of APP gene expression are not ye t well under stood. In PC12 cells, a rat pheochromocytoma cell line, w e have demonstrated that nerve growth factor (NGF) induces the APP gen e expression and increases APP mRNA levels in the presence of 0.5 or 1 5% serum. Expression of activated ras in the PC12 cell subline UR61 al so leads to a significant increase in content, of APP transcripts, and . dominant negative mutant of ras blocks the NGF-induced response. Oth er ligands of tyrosine kinase receptors, such as fibroblast growth fac tor, which causes morphological differentiation, or epidermal growth f actor, which induces-cell growth, also increase APP mRNA levels in PC1 2 cells. These results suggest that ras mediates the induction of APP gene expression by NGF and other ligands of tyrosine kinase-receptors.