Abstract
Cyclooxygenase-2 (COX-2) has been found to be induced during the early stage of Alzheimer’s disease (AD). Using mouse-derived astrocyte and APP/PS1 transgenic (Tg) mice as model systems, we firstly elucidated the mechanisms underlying COX-2 metabolic production including prostaglandin (PG)E2- and PGI2-mediated tumor necrosis factor α (TNF-α) regulation. Specifically, PGE2 accumulation in astrocyte activated the p38 and JNK/c-Jun signaling pathways via phosphorylation, resulting in TNF-α expression. In contrast, the administration of PGI2 attenuated the effects of PGE2 in stimulating the production of TNF-α by inhibiting the activity of TNF-α promoter and the binding activity of AP1 on the promoter of TNF-α. Moreover, our data also showed that not only Aβ1-42 oligomers but also Aβ1-42 fibrils have the ability to involve in mediating the antagonistic effects of PGE2 and PGI2 on regulating the expression of TNF-α via a p38- and JNK/c-Jun-dependent, AP1-transactivating mechanism. Reciprocally, the production of TNF-α finally accelerated the deposition of β-amyloid protein (Aβ)1-42 in β-amyloid plaques (APs), which contribute to the cognitive decline of AD.
Highlights
Cycooxygenase-2 (COX-2) and prostaglandins (PGs) were found to be upregulated at the early stage of Alzheimer’s disease (AD) two decades ago [1]
Because previous studies have suggested that tumor necrosis factor α (TNF-α) aggravates the pathogenesis of AD [21], we evaluated the expression levels of TNF-α in AD patients and amyloid precursor protein (APP)/ PS1 transgenic mice at 6 or 9 months of age
In line with these observations in AD patients, in 6-month-old APP/PS1 mice, TNF-α immunostaining was strongly increased in the cerebral cortex and dentate gyrus (DG) region of the hippocampus compared to that in wild type (WT) C57BL/6 mice (Figure 1D)
Summary
Cycooxygenase-2 (COX-2) and prostaglandins (PGs) were found to be upregulated at the early stage of Alzheimer’s disease (AD) two decades ago [1]. COX-2 exhibits multiple biological functions and is thought to regulate the pathogenesis of AD via its metabolic products, including PGE2, PGD2 [and its dehydration end product 15-deoxy-∆12,14-PGJ2 (15d-PGJ2)], PGI2, PGF2α and TXA2 [3]. Among these PGs, the roles of PGE2 and PGI2 in neuroinflammation have been a focus of study [4], because these PGs potentially contribute to the production of β-amyloid protein (Aβ) and the hyperphosphorylation of tau in the brain [5, 6]. Neuroinflammation is involved in Aβ deposition and tau phosphorylation [8], which contribute to the progression of AD
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