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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and displays the characteristics of chronic neurodegenerative disorders
The amyloid b-protein (Ab) metabolic processes in AD are not thoroughly understood, the beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) led the way to the hypothesis that cyclooxygenase (COX) activity that of the inducible isoform cyclooxygenase 2 (COX-2) is involved in the cascade of events leading to neurodegeneration in AD
Heat shock protein 70 mediated the effects of COX-2 on inducing the synthesis of PGE2 and cAMP; this synthesis in turn regulates IL-1b expression in human- or rat-derived glial cells
Summary
Alzheimer’s disease (AD) is the most common form of dementia and displays the characteristics of chronic neurodegenerative disorders. Prior works have shown that COX-2 expression is elevated in AD brain (Pasinetti & Aisen, 1998; Ho et al, 1999) and that this expression is correlated with clinical dementia (Ho et al, 2001). In vitro studies suggest that COX-2 up-regulation in the AD brain may be mediated by the exposure of neurons to Ab, which may contribute to Ab neurotoxicity (Pasinetti & Aisen, 1998). Recent studies revealed that long-term in vivo treatment of amyloid precursor protein (APP) transgenic mice with NSAIDs significantly diminished Ab deposition (Lim et al, 2000) and improved behavior (Lim et al, 2001). Cross talk between COX-2 and Ab may play a key role in mediating the development and progression of AD
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