title: Aggravation of Alzheimer's disease due to the COX-2-mediated reciprocal regulation of IL-1β and Aβ between glial and neuron cells.
abstract: 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 β-protein (Aβ) 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)E2 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-1β (IL-1β) and Aβ between glial and neuron cells. In glioblastoma cells, COX-2 regulates the synthesis of IL-1β in a PGE2 -dependent manner. Moreover, COX-2-derived PGE2 signals the activation of the PI3-K/AKT and PKA/CREB pathways via cyclic AMP; these pathways transactivate the NF-κB p65 subunit via phosphorylation at Ser 536 and Ser 276, leading to IL-1β synthesis. The secretion of IL-1β 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, Aβ 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.
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China.
authors.forename: Pu
authors.initials: P
authors.lastname: Wang
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Guan
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Guo
authors.forename: Zhan-You
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D018450:Disease Progression; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D017362:Cyclic AMP Response Element-Binding Protein; D018840:HSP70 Heat-Shock Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D015232:Dinoprostone
keywords: Alzheimer's disease; cytokines; gene expression; neurodegenerative disease; signal transduction