Transcriptional Regulation of The Alzheimer's Disease-related Gene, Nicastrin

The gamma-secretase complex mediates the final cleavage of APP to generate the principal component of amyloid plaques in the brains of Alzheimer's disease patients. Four integral membrane proteins (PS, NCT, PEN-2 and APH-1) are essential and sufficient for gamma-secretase activity. To identify the promoter of human nicastrin gene (NCT), its 5'-flanking region has been characterized and a 270 bp fragment containing the TSS (transcription start site) for the promoter activity has been identified. EMSA assays confirmed that all four AP-1 binding sites and two NFAT sites in the NCT promoter region were able to bind relative transcription factors in vitro. Mutations, as well as treatment with PDTC, which adjust the regulatory effect of AP-1 and NFAT, altered NCT promoter activity in both HeLa cells and rat cortical neurons. The results demonstrated that AP-1 and NFAT are involved in the regulation of hNCT transcription and suggest that balanced activation of AP-1 and NFAT ensures a strict temporal and tissue-specific control of NCT transcription.