Transcriptional regulation of APH‐1A and increased γ‐secretase cleavage of APP and Notch by HIF‐1 and hypoxia

The proteolytic cleavage of Alzheimer β‐amyloid precursor protein (APP) and signaling receptor Notch is mediated by the PS/γ‐secretase complex, which consists of presenilins, nicastrin, APH‐1, and PEN‐2. Although the four components are known to coordinately regulate each other at the protein level, information regarding their transcription regulation is scarce. Here we characterized the 5′‐flanking region of the human APH‐1A gene and identified a 271‐bp fragment containing the transcription initiation site for the promoter activity. Sequence analysis, mutagenesis, and gel shift studies revealed a binding of AP4 and HIF‐1 to the promoter, which affects the promoter activity. Activation of HIF‐1 by short‐term NiCl2 treatments (a condition of chemical hypoxia) dramatically increased APH‐1A mRNA and protein expression, accompanied by increased secretion of Aβ and decreased APP CTFs formation, indicative of an increase in γ‐secretase activity. NiCl2 treatments had little effect on APP and the other three components of the γ‐secretase complex. The cellular concentration of Notch intracellular domain (NICD) was also increased by the hypoxic treatment. Our results demonstrate that APH‐1A expression and the γ‐secretase mediated Aβ and Notch NICD generation are regulated by HIF‐1, and the specific control of APH‐1A expression may imply physiological functions uniquely assigned to APH‐1A.— Wang, R., Zhang, Y‐W., Zhang, X., Liu, R., Zhang, X., Hong, S., Xia, K., Xia, J., Zhang, Z., Xu, H. Transcriptional regulation of APH‐1A and increased γ‐secretase cleavage of APP and Notch by HIF‐1 and hypoxia. FASEB J. 20, E614–E622 (2006)