THE PROMOTER ACTIVITY OF THE GENE ENCODING ALZHEIMER BETA-AMYLOID PRECURSOR PROTEIN (APP) IS REGULATED BY 2 BLOCKS OF UPSTREAM SEQUENCES

Transcriptional regulation of the gene encoding the amyloid precursor protein (APP) may play an important role in the formation of the amyloid depositions observed in Alzheimer disease and Down syndrome patients. To determine the promoter sequence requirements for the expression of the APP gene, we constructed plasmids containing different parts of the APP gene promoter fused to the bacterial chloramphenicol acetyl transferase (CAT) gene. Transfection of these constructs into Hela and PC12 cells revealed the presence of two blocks of regulatory sequences in the APP promoter. One block extending from about -600 to -460 bp acts as a positive regulator as its removal results in a substantial decrease in promoter activity. A second block of sequences extending from -450 to -150 bp acts like a negative regulator. We have also observed that a 38 mer synthetic oligonucleotide encompassing the region -489 to -452 of the APP promoter stimulated the activity of the heterologous TK promoter, suggesting that this region may be part of an enhancer-like element. In addition, our results suggest that the effects of various APP promoter domains on its activity may be cell specific.