Cyclooxygenase-2 and Presenilin-1 Gene Expression Induced by Interleukin-1β and Amyloid β42 Peptide Is Potentiated by Hypoxia in Primary Human Neural Cells

Abstract

Inflammatory signaling networks are activated at the onset of neurodegeneration in Alzheimer's disease (AD) 1 brain (1-6).Expression of the inducible, membrane-associated prostaglandin (PG) endoperoxide synthase cyclooxygenase-2 (COX-2), which catalyzes the rate-limiting step in the generation of pro-inflammatory PGs and eicosanoids, is up-regulated in AD (7-11), and transgenic mice overexpressing human COX-2 in hippocampal neurons develop neuronal apoptosis and cognitive deficits in an age-dependent manner (11-14). Presenilin-1 (PS1) and PS1 C-terminal fragments, integral membrane proteins that are developmentally expressed during neurogenesis, function in the generation of amyloidogenic A␤ peptides from ␤-amyloid precursor protein (␤APP) (15-18). Transgenic animals bearing PS1 mutations or PS1/␤APP doubly transgenic animals display accelerated A␤ generation and microglial activation that increase synchronously with A␤ deposition (14 -19). As a consequence, hundred-fold increases in microglialderived IL-1␤, related cytokines, and pro-inflammatory lipid mediators form an amplifying cascade of brain inflammatory response (6, 20 -23). Microglial cytokine hyperactivation strongly correlates with increased ␤APP processing and aggregation of A␤ peptides into neurotoxic senile plaques, the neuropathologic hallmark of AD brain (12,(15)(16)(17).During the microglial-mediated inflammatory response to A␤ deposition in AD, overexpression of IL-1␤ not only further promotes amyloidogenesis (20 -23) but also induces an oxygensensitive transcription factor (TF) series that includes AP1, STAT1␣, and NF-Bp50/p65 (24 -27). In the human association neocortex in AD, DNA-binding activities for these TFs, as well as IL-1␤, are sharply elevated (9,24,26). Therefore, IL-1␤-triggered AP1-, NF-Bp50/p65-, and STAT1␣-sensitive genes have strong potential to propagate inflammatory signaling in the brain (20 -27). Although IL-1␤ up-regulates both ␤APP and COX-2 gene transcription and post-translational processing of ␤APP into neurotoxic A␤ peptides (20 -23, 27), IL-1␤-triggered neural inflammation may also be induced by hypoxia (28 -30). The hypoxia-inducible factor (HIF-1, a heterodimeric DNAbinding protein consisting of a cytokine-, oxygen-and growth factor-regulated HIF-1␣ and a constitutive HIF-1␤/aryl hydrocarbon receptor nuclear transporter element) normally promotes the expression of adaptive genes under hypoxic conditions. However, during pathophysiologic conditions involving ischemia and/or hypoxia, HIF-1␣ overexpression drives aberrant gene expression with rapid progression to the lethal phenotype (28,29). It is interesting that IL-1␤ partially mimics cellular hypoxia, leading to increased HIF-1␣-DNA binding and activation of COX-2 and PS2 in human gingival and syno-

Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1β via Presenilin in Pancreatic β-Cells

“…Interestingly, presenilin-1 has been localized to the mitochondria in other cell types (62,63) and mitochondrial respiration was decreased in knock-in mice with a presenilin-1 gain-of-function mutation (64). Studies also point to the up-regulation of presenilins in hypoxic conditions (12,24,27,65), similar to our observation that hypoglycemia increases presenilin-1 expression. Together, these findings indicate that presenilins interact with intracellular Ca 2ϩ homeostasis and metabolism on many levels.…”

Synergism in the repression of COX-2- and TNFα-induction in platelet activating factor-stressed human neural cells

“…TNFα and OX-2 RNA C and protein levels, as well as PGE 2 abundance, provide a useful index for the inflammatory status of brain cells [2,6,13]. In this study we show that specific combinations of inflammatory repressors, including the glucocorticoid BUDeR [13,14], the novel PAF antagonist LAU-0901 [15,16], and the electron spin trap and free radical scavenger PBN [17][18][19], are effective in repressing PAF-triggered pathogenic events in an HN cell model used to study inflammatory and neurodegenerative mechanisms [2,13,14,20]. While each of these compounds were found to repress PAF-induced TNFα, COX-2 and PGE 2 up-regulation, their combinatorial use together was found to exhibit significant synergism in modulating PAFinduced pathogenic signals.…”

“…1. Briefly, neuronalglial co-cultures of HN cells (Cambrex Cell Systems, Walkersville, MD) were grown to ∼70% confluence (∼50,000 cells per well) in 3.5-cm diameter well COSTAR plates at 37°C, 5% CO 2 /20% O 2 /75% N 2 in a neural progenitor maintenance medium (NPMM; CC-4241; Cambrex) [14,18,20]. NPMM contained human epidermal and fibroblast growth factors, gentamicin/ amphotericin B, and neural survival factor-1; at source HN cells tested negative for HIV-1, hepatitis B and C, mycoplasma, bacteria, yeast, and fungi (Cambrex).…”

Biphasic Role of Nuclear Factor-k B on Cell Survival and COX-2 Expression in SOD1 Tg Astrocytes after Oxygen Glucose Deprivation

“…The waterand lipid-soluble antioxidant PBN is a ROS scavenger and inhibits NF-kB p50/p65-binding activity (Butterfield et al, 1998). Furthermore, PBN inhibited COX-2 expression (Bazan and Lukiw, 2002) and catalytic activity in a macrophage cell culture . Phenylnitrone (PBN) also prevented neoplasia in rat liver not only by its radical scavenging activity but also by inhibiting COX-2 activity at the catalytic level (Nakae et al, 1998).These results coincide very well with our results on increased cell viability after OGD when treated with PBN, suggesting that quenching of free radicals and inhibiting COX-2 activity at the catalytic level during hypoxia in SOD1 Tg and WT astrocytes suppressed cell death.…”