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.
Bazan
Nicolas G
NG
Neuroscience Center and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112-2272, USA.
Lukiw
Walter J
WJ
D016229:Amyloid beta-Peptides / Q000502:physiology*; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics*; D007700:Kinetics; D008565:Membrane Proteins / Q000235:genetics*; D010446:Peptide Fragments / Q000502:physiology*; D053764:Presenilin-1; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); D012313:RNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases