Regional distribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease

Abstract

Cyclooxygenase-2 (COX-2), a key enzyme in prostanoid biosynthesis, may represent an important therapeutic target in Alzheimer's disease (AD). In the present study, we explored the regulation of COX-2 in the hippocampal formation in sporadic AD. Using semiquantitative immunocytochemical techniques, we found that in AD cases (vs. age-matched controls) neurons of the CA1-CA4 subdivisions of the hippocampal pyramidal layer showed elevation of COX-2 signal; COX-2 levels correlated with amyloid plaque density. In contrast, the level of COX-2 immunostaining in the dentate gyrus granule neurons was not elevated in AD. No expression of COX-2 in cells with glial morphology was found in any case examined. In parallel, in vitro studies found that neurons derived from transgenic mice with neuronal overexpression of COX-2 are more susceptible to beta-amyloid (Abeta) toxicity, with potentiation of redox impairment. The results indicate elevated expression of neuronal COX-2 in subregions of the hippocampal formation in AD and that such elevation may potentiate Abeta-mediated oxidative stress.

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

“…1B) indicated that human COX-2 and the PS1-463 RNA possess relatively short half-lives, of 3 and 4 -5 h, respectively. Conversely, PS2 variants 1 and 2 RNAs have half-lives of Ն10 h, just less than the half-life of ␤-actin RNA, which is Ն12 h (11,33). This is the first report of COX-2 and PS1 RNA half-lives of ϳ3-5 h in primary human neural cells; these are analogous to COX-2 half-lives found in human IMR-90 and temporal lobe neocortex (9).…”

“…COX-2 expression may be further induced in astrocytes and microglia in response to elevated A␤42 and/or IL-1␤ during aging or in AD (5-9), because both cytokines and ROS trigger NF-Bp50/p65-mediated transcription from COX-2 and related inflammatory genes (9 -14). Moreover, although the majority of gene transcripts are down-regulated in AD hippocampus (4,9,13,21,43,44), certain RNAs encoding inflammatory mediators exhibit overexpression (7)(8)(9)(10)(11)(12)(13). COX-2 and PS1 RNA message in human embryonic (E7-E30) and adult (1-75 years) brain coincides with the most active neurogenesis, followed by coordinate downregulation of COX-2 and PS1 RNA abundance during aging (r 2 ϭ 0.9, p Ͻ 0.03; Fig.…”

“…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)(8)(9)(10)(11), and transgenic mice overexpressing human COX-2 in hippocampal neurons develop neuronal apoptosis and cognitive deficits in an age-dependent manner (11)(12)(13)(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)(16)(17)(18).…”

Differential activation of subtype purinergic receptors modulates Ca2+ mobilization and COX‐2 in human microglia

“…Inflammatory stimuli such as lipopolysaccharide (LPS) and cytokines such as TNF␣ and IL-1␤ have been found to enhance COX-2 expressions in microglia (Minghetti and Levi, 1995;Bauer et al, 1997). In pathological conditions, elevated COX-2 expressions have been observed in AD brain and ALS spinal cord (Ho et al, 1999;Yasojima et al, 1999Yasojima et al, , 2001.…”

A doença de Alzheimer: aspectos fisiopatológicos e farmacológicos

“…Um possível modo de ação para a eficácia dos antiinflamatórios não-esteroidais seria o bloqueio específico da isoforma ciclooxigenase-2 (COX-2) no cérebro de pacientes portadores da doença de Alzheimer 42 . Estudos têm demonstrado que o RNA mensageiro (RNAm) da COX-2 esteve consideravelmente aumentado em áreas afetadas pela doença de Alzheimer 48 , sugerindo o envolvimento da COX-2 nessa doença. De fato, a aplicação de Aβ (1-42) (5 microM) em culturas humanas de micróglia durante 8 horas induziu a expressão e o aumento da produção das citocinas pró-inflamatórias IL-6, IL-1β, TNF-α, da COX-2 e IL-8 48 .…”