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Curcumin Ameliorates the Reduction Effect of PGE2 on Fibrillar ?-Amyloid Peptide (1-42)-Induced Microglial Phagocytosis through the Inhibition of EP2-PKA Signaling in N9 Microglial Cells.

ABSTRACT: Inflammatory activation of microglia and ? amyloid (A?) deposition are considered to work both independently and synergistically to contribute to the increased risk of Alzheimer's disease (AD). Recent studies indicate that long-term use of phenolic compounds provides protection against AD, primarily due to their anti-inflammatory actions. We previously suggested that phenolic compound curcumin ameliorated phagocytosis possibly through its anti-inflammatory effects rather than direct regulation of phagocytic function in electromagnetic field-exposed N9 microglial cells (N9 cells). Here, we explored the prostaglandin-E2 (PGE2)-related signaling pathway that involved in curcumin-mediated phagocytosis in fibrillar ?-amyloid peptide (1-42) (fA?42)-stimulated N9 cells. Treatment with fA?42 increased phagocytosis of fluorescent-labeled latex beads in N9 cells. This increase was attenuated in a dose-dependent manner by endogenous and exogenous PGE2, as well as a selective EP2 or protein kinase A (PKA) agonist, but not by an EP4 agonist. We also found that an antagonist of EP2, but not EP4, abolished the reduction effect of PGE2 on fA?42-induced microglial phagocytosis. Additionally, the increased expression of endogenous PGE2, EP2, and cyclic adenosine monophosphate (AMP), and activation of vasodilator-stimulated phosphoprotein, cyclic AMP responsive element-binding protein, and PKA were depressed by curcumin administration. This reduction led to the amelioration of the phagocytic abilities of PGE2-stimulated N9 cells. Taken together, these data suggested that curcumin restored the attenuating effect of PGE2 on fA?42-induced microglial phagocytosis via a signaling mechanism involving EP2 and PKA. Moreover, due to its immune modulatory effects, curcumin may be a promising pharmacological candidate for neurodegenerative diseases.

SUBMITTER: He GL

PROVIDER: S-EPMC4732694 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Curcumin Ameliorates the Reduction Effect of PGE2 on Fibrillar β-Amyloid Peptide (1-42)-Induced Microglial Phagocytosis through the Inhibition of EP2-PKA Signaling in N9 Microglial Cells.

He Gen-Lin GL Luo Zhen Z Yang Ju J Shen Ting-Ting TT Chen Yi Y Yang Xue-Sen XS

PloS one 20160129 1

Inflammatory activation of microglia and β amyloid (Aβ) deposition are considered to work both independently and synergistically to contribute to the increased risk of Alzheimer's disease (AD). Recent studies indicate that long-term use of phenolic compounds provides protection against AD, primarily due to their anti-inflammatory actions. We previously suggested that phenolic compound curcumin ameliorated phagocytosis possibly through its anti-inflammatory effects rather than direct regulation o ...[more]

PMID: 26824354

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Project description:BackgroundReactive microglia are associated with ?-amyloid (A?) deposit and clearance in Alzhiemer's Disease (AD). Paradoxically, entocranial resident microglia fail to trigger an effective phagocytic response to clear A? deposits although they mainly exist in an "activated" state. Oligomeric A? (oA?), a recent target in the pathogenesis of AD, can induce more potent neurotoxicity when compared with fibrillar A? (fA?). However, the role of the different A? forms in microglial phagocytosis, induction of inflammation and oxidation, and subsequent regulation of phagocytic receptor system, remain unclear.ResultsWe demonstrated that A?(1-42) fibrils, not A?(1-42) oligomers, increased the microglial phagocytosis. Intriguingly, the pretreatment of microglia with oA?(1-42) not only attenuated fA?(1-42)-triggered classical phagocytic response to fluorescent microspheres but also significantly inhibited phagocytosis of fluorescent labeled fA?(1-42). Compared with the fA?(1-42) treatment, the oA?(1-42) treatment resulted in a rapid and transient increase in interleukin 1? (IL-1?) level and produced higher levels of tumor necrosis factor-? (TNF-?), nitric oxide (NO), prostaglandin E2 (PGE2) and intracellular superoxide anion (SOA). The further results demonstrated that microglial phagocytosis was negatively correlated with inflammatory mediators in this process and that the capacity of phagocytosis in fA?(1-42)-induced microglia was decreased by IL-1?, lippolysaccharide (LPS) and tert-butyl hydroperoxide (t-BHP). The decreased phagocytosis could be relieved by pyrrolidone dithiocarbamate (PDTC), a nuclear factor-?B (NF-?B) inhibitor, and N-acetyl-L-cysteine (NAC), a free radical scavenger. These results suggest that the oA?-impaired phagocytosis is mediated through inflammation and oxidative stress-mediated mechanism in microglial cells. Furthermore, oA?(1-42) stimulation reduced the mRNA expression of CD36, integrin ?1 (Itgb1), and Ig receptor Fc?RIII, and significantly increased that of formyl peptide receptor 2 (FPR2) and scavenger receptor class B1 (SRB1), compared with the basal level. Interestingly, the pre-stimulation with oA?(1-42) or the inflammatory and oxidative milieu (IL-1?, LPS or t-BHP) significantly downregulated the fA?(1-42)-induced mRNA over-expression of CD36, CD47 and Itgb1 receptors in microglial cells.ConclusionThese results imply that A? oligomers induce a potent inflammatory response and subsequently disturb microglial phagocytosis and clearance of A? fibrils, thereby contributing to an initial neurodegenerative characteristic of AD. Antiinflammatory and antioxidative therapies may indeed prove beneficial to delay the progression of AD.

Dataset Information

Curcumin Ameliorates the Reduction Effect of PGE2 on Fibrillar ?-Amyloid Peptide (1-42)-Induced Microglial Phagocytosis through the Inhibition of EP2-PKA Signaling in N9 Microglial Cells.

Publications

Curcumin Ameliorates the Reduction Effect of PGE2 on Fibrillar β-Amyloid Peptide (1-42)-Induced Microglial Phagocytosis through the Inhibition of EP2-PKA Signaling in N9 Microglial Cells.

Similar Datasets

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