Cyclooxygenase-2 and presenilin-1 gene expression induced by interleukin-1beta and amyloid beta 42 peptide is potentiated by hypoxia in primary human neural cells.

Lipid messengers and amyloid beta (Abeta) peptides generated by cyclooxygenase-2 (COX-2) and presenilin-1 (PS1) mediate pro-inflammatory signaling and neural degeneration in Alzheimer's disease (AD) brain. This study provides data showing that the COX-2 and PS1 genes each transcribe rare, highly labile RNA species that display early response gene behavior in human neural (HN) cells in primary culture, down-regulation during human neural development, and up-regulation in AD neocortex and hippocampal CA1. Together, interleukin-1beta and amyloid beta42 peptide [IL-1beta+Abeta42] synergistically activated COX-2 and PS1 gene expression preceded by increases in AP1-, STAT1alpha-, and in particular NF-kappaBp50/p65- and HIF-1alpha-DNA binding. These events were markedly potentiated by hypoxia and blocked by the antioxidant alpha-phenyl-N-tert-butyl nitrone. Broad transcription profiling further indicated that hypoxia-induced, [IL-1beta+Abeta42]-treated HN cells display robust induction of COX-2 and PS1 as well as a pro-inflammatory gene family that includes NF-kappaBp50/p105, IL-1beta precursor, and cytosolic phospholipase A2 genes. These findings indicate a novel [IL-1beta+Abeta42]-mediated, hypoxia-enhanced, free radical-triggered gene program that drives inflammatory gene signaling and suggest a mechanism by which hypoxia during aging contributes episodically to amyloidogenesis, inflammation, and AD pathophysiology.