Regulation of the amyloid precursor protein (APP) gene promoter by hypoxia

Alzheimer's disease is more prevalent following periods of ischemia and the accompanying hypoxia (1% O2). The amyloid precursor protein (APP) is implicated in the pathogenesis of Alzheimer's disease. Sequence analysis of the APP promoter revealed that it contained three putative Hypoxia Response Elements (HREs) which may bind the Hypoxia Inducible Factor-1 (HIF-1) and induce hypoxic regulation of the promoter. We examined APP promoter activity and APP expression during hypoxia in PC12-AC cells. Reporter gene assays showed that APP promoter activity is activated by both hypoxia (6 to 48 hours) and over-expression of a HIF-1 subunit (HIF-1alpha). Exposure of cells to hypoxia resulted in an increase in APP gene expression as well as an accumulation of both the APP and HIF-1alpha protein. Electrophoretic mobility shift assays (EMSAs) indicated that HIF-1 may not bind to the APP promoter. These results suggest that hypoxia-induced APP promoter activation may be HIF-1 independent.