科研之友
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摘要
Alzheimer's disease (AD) is the most common form of dementia and displays the characteristics of chronic neurodegenerative disorders; amyloid plaques (AP) that contain amyloid b-protein (Ab) accumulate in AD, which is also characterized by tau phosphorylation. Epidemiological evidence has demonstrated that long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) markedly reduces the risk of AD by inhibiting the expression of cyclooxygenase 2 (COX-2). Although the levels of COX-2 and its metabolic product prostaglandin (PG) E-2 are elevated in the brain of AD patients, the mechanisms for the development of AD remain unknown. Using human-or mouse-derived glioblastoma and neuroblastoma cell lines as model systems, we delineated the signaling pathways by which COX-2 mediates the reciprocal regulation of interleukin-1 beta (IL-1 beta) and Ab between glial and neuron cells. In glioblastoma cells, COX-2 regulates the synthesis of IL-1 beta in a PGE(2)-dependent manner. Moreover, COX-2- derived PGE(2) signals the activation of the PI3-K/AKT and PKA/CREB pathways via cyclic AMP; these pathways transactivate the NF-kappa B p65 subunit via phosphorylation at Ser 536 and Ser 276, leading to IL-1 beta synthesis. The secretion of IL-1 beta from glioblastoma cells in turn stimulates the expression of COX-2 in human or mouse neuroblastoma cells. Similar regulatory mechanisms were found for the COX-2 regulation of BACE-1 expression in neuroblastoma cells. More importantly, Ab deposition mediated the inflammatory response of glial cells via inducing the expression of COX-2 in glioblastoma cells. These findings not only provide new insights into the mechanisms of COX-2-induced AD but also initially define the therapeutic targets of AD.
- 出版日期2014-8
- 单位东北大学
