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Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Curcumin Prevents Neuroinflammation by Inducing Microglia to Transform into the M2-phenotype via CaMKKβ-dependent Activation of the AMP-Activated Protein Kinase Signal Pathway

Author(s): Peifeng Qiao, Jingxi Ma, Yangyang Wang, Zhenting Huang, Qian Zou, Zhiyou Cai* and Yong Tang*

Volume 17, Issue 8, 2020

Page: [735 - 752] Pages: 18

DOI: 10.2174/1567205017666201111120919

Price: $65


Background: Neuroinflammation plays an important role in the pathophysiological process of various neurodegenerative diseases. It is well known that curcumin has obvious anti-inflammatory effects in various neuroinflammation models. However, its effect on the modulation of microglial polarization is largely unknown.

Objective: This study aimed to investigate whether curcumin changed microglia to an anti-inflammatory M2-phenotype by activating the AMP-activated protein kinase (AMPK) signaling pathway.

Methods: LPS treatment was used to establish BV2 cells and primary microglia neuroinflammation models. The neuroinflammation mouse model was established by an intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) in the lateral septal complex region of the brain. TNF-α was measured by ELISA, and cell viability was measured by Cell Counting Kit-8 (CCK-8). The expression of proinflammatory and anti-inflammatory cytokines was examined by Q-PCR and Western blot analysis. Phenotypic polarization of BV2 microglia was detected by immunofluorescence.

Results: Curcumin enhanced AMPK activation in BV2 microglial cells in the presence and absence of LPS. Upon LPS stimulation, the addition of curcumin promoted M2 polarization of BV2 cells, as evidenced by suppressed M1 and the elevated M2 signature protein and gene expression. The effects of curcumin were inhibited by an AMPK inhibitor or AMPK knockdown. Calmodulin-dependent protein kinase kinase β (CaMKKβ) and liver kinase B1 (LKB1) are upstream kinases that activate AMPK. Curcumin can activate AMPK in Hela cells, which do not express LKB1. However, both the CaMKKβ inhibitor and siRNA blocked curcumin activation of AMPK in LPS-stimulated BV2 cells. Moreover, the CaMKKβ inhibitor and siRNA weaken the effect of curcumin suppression on M1 and enhancement of M2 protein and gene expression in LPS-stimulated BV2 cells. Finally, curcumin enhanced AMPK activation in the brain area where microglia were over-activated upon LPS stimulation in an in vivo neuroinflammation model. Moreover, curcumin also suppressed M1 and promoted M2 signature protein and gene expression in this in vivo model.

Conclusion: Curcumin enhances microglia M2 polarization via the CaMKKβ-dependent AMPK signaling pathway. Additionally, curcumin treatment was found to be neuroprotective and thus might be considered as a novel therapeutic agent to treat the neurodegenerative disease such as Alzheimer‘s disease, Parkinson's disease, etc.

Keywords: Curcumin, microglia, AMPK, neuroinflammation, cytokines, Parkinson's disease.

Panahi Y, Sahebkar A, Parvin S, Saadat A. A randomized controlled trial on the anti-inflammatory effects of curcumin in patients with chronic sulphur mustard-induced cutaneous complications. Ann Clin Biochem 2012; 49(Pt 6): 580-8.
[] [PMID: 23038702]
Momtazi-Borojeni AA, Haftcheshmeh SM, Esmaeili SA, Johnston TP, Abdollahi E, Sahebkar A. Curcumin: A natural modulator of immune cells in systemic lupus erythematosus. Autoimmun Rev 2018; 17(2): 125-35.
[] [PMID: 29180127]
Panahi Y, Ghanei M, Hajhashemi A, Sahebkar A. Effects of curcuminoids-piperine combination on systemic oxidative stress, clinical symptoms and quality of life in subjects with chronic pulmonary complications due to sulfur mustard: A randomized controlled trial. J Diet Suppl 2016; 13(1): 93-105.
[] [PMID: 25171552]
Panahi Y, Badeli R, Karami GR, Sahebkar A. Investigation of the efficacy of adjunctive therapy with bioavailability-boosted curcuminoids in major depressive disorder. Phytother Res 2015; 29(1): 17-21.
[] [PMID: 25091591]
Lelli D, Sahebkar A, Johnston TP, Pedone C. Curcumin use in pulmonary diseases: State of the art and future perspectives. Pharmacol Res 2017; 115: 133-48.
[] [PMID: 27888157]
Kim J, Jeong SW, Quan H, Jeong CW, Choi JI, Bae HB. Effect of curcumin (Curcuma longa extract) on LPS-induced acute lung injury is mediated by the activation of AMPK. J Anesth 2016; 30(1): 100-8.
[] [PMID: 26335543]
Chen H, Tang Y, Wang H, Chen W, Jiang H. Curcumin alleviates lipopolysaccharide-induced neuroinflammation in fetal mouse brain. Restor Neurol Neurosci 2018; 36(5): 583-92.
[] [PMID: 30010156]
Pluta R, Ułamek-Kozioł M, Czuczwar SJ. Neuroprotective and neurological/cognitive enhancement effects of curcumin after brain ischemia injury with Alzheimer’s disease phenotype. Int J Mol Sci 2018; 19(12): 4002.
[] [PMID: 30545070]
Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 2011; 11(11): 775-87.
[] [PMID: 22025055]
David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 2011; 12(7): 388-99.
[] [PMID: 21673720]
Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 2013; 229(2): 176-85.
[] [PMID: 23096265]
Fan H, Zhang K, Shan L, et al. Reactive astrocytes undergo M1 microglia/macrohpages-induced necroptosis in spinal cord injury. Mol Neurodegener 2016; 11: 14.
[] [PMID: 26842216]
Ghoochani A, Schwarz MA, Yakubov E, et al. MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis. Oncogene 2016; 35(48): 6246-61.
[] [PMID: 27157615]
Wang Y, Huang Y, Xu Y, et al. A dual AMPK/Nrf2 activator reduces brain inflammation after stroke by enhancing microglia M2 polarization. Antioxid Redox Signal 2018; 28(2): 141-63.
[] [PMID: 28747068]
Wang J, Ma MW, Dhandapani KM, Brann DW. Regulatory role of NADPH oxidase 2 in the polarization dynamics and neurotoxicity of microglia/macrophages after traumatic brain injury. Free Radic Biol Med 2017; 113: 119-31.
[] [PMID: 28942245]
Katsumoto A, Takeuchi H, Takahashi K, Tanaka F. Microglia in Alzheimer’s disease: Risk factors and inflammation. Front Neurol 2018; 9: 978.
[] [PMID: 30498474]
Rajan WD, Wojtas B, Gielniewski B, Gieryng A, Zawadzka M, Kaminska B. A randomized controlled trial on the anti-inflammatory effects of curcumin in patients with chronic sulphur mustard-induced cutaneous complications. Ann Clin Biochem 2018; 49(6): 580-8.
Lan X, Han X, Li Q, Yang QW, Wang J. Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol 2017; 13(7): 420-33.
[] [PMID: 28524175]
Che Y, Hou L, Sun F, et al. Taurine protects dopaminergic neurons in a mouse Parkinson’s disease model through inhibition of microglial M1 polarization. Cell Death Dis 2018; 9(4): 435.
[] [PMID: 29568078]
Zhou X, Cao Y, Ao G, et al. CaMKKβ-dependent activation of AMP-activated protein kinase is critical to suppressive effects of hydrogen sulfide on neuroinflammation. Antioxid Redox Signal 2014; 21(12): 1741-58.
[] [PMID: 24624937]
Zeng F, Wu Y. Custom-made ceria nanoparticles show a neuroprotective effect by modulating phenotypic polarization of the microglia. Angew Chem Int Ed Engl 2018; 57(20): 5808-12.
Hu X, Leak RK, Shi Y, et al. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol 2015; 11(1): 56-64.
[] [PMID: 25385337]
Sarna LK, Wu N, Hwang SY, Siow YL. Berberine inhibits NADPH oxidase mediated superoxide anion production in macrophages. Can J Physiol Pharmacol 2010; 88(3): 369-78.
[] [PMID: 20393601]
O’Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 2013; 493(7432): 346-55.
[] [PMID: 23325217]
Amato S, Man HY. Bioenergy sensing in the brain: The role of AMP-activated protein kinase in neuronal metabolism, development and neurological diseases. Cell Cycle 2011; 10(20): 3452-60.
[] [PMID: 22067656]
Sag D, Carling D, Stout RD, Suttles J. Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol 2008; 181(12): 8633-41.
Labuzek K, Liber S, Gabryel B, Adamczyk J, Okopień B. Metformin increases phagocytosis and acidifies lysosomal/endosomal compartments in AMPK-dependent manner in rat primary microglia. Naunyn Schmiedebergs Arch Pharmacol 2010; 381(2): 171-86.
[] [PMID: 20012266]
Bai A, Ma AG, Yong M, et al. AMPK agonist downregulates innate and adaptive immune responses in TNBS-induced murine acute and relapsing colitis. Biochem Pharmacol 2010; 80(11): 1708-17.
[] [PMID: 20797389]
Hawley SA, Fullerton MD, Ross FA, et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 2012; 336(6083): 918-22.
[] [PMID: 22517326]
Li Y, Li J, Li S, et al. Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK. Toxicol Appl Pharmacol 2015; 286(1): 53-63.
[] [PMID: 25791922]
Tong W, Wang Q, Sun D, Suo J. Curcumin suppresses colon cancer cell invasion via AMPK-induced inhibition of NF-κB, uPA activator and MMP9. Oncol Lett 2016; 12(5): 4139-46.
[] [PMID: 27895783]
Zhang F-J, Zhang H-S, Liu Y, Huang Y-H. Curcumin inhibits Ec109 cell growth via an AMPK-mediated metabolic switch. Life Sci 2015; 134: 49-55.
[] [PMID: 26037398]
Chu X, Cao L, Yu Z, et al. Hydrogen-rich saline promotes microglia M2 polarization and complement-mediated synapse loss to restore behavioral deficits following hypoxia-ischemic in neonatal mice via AMPK activation. J Neuroinflammation 2019; 16(1): 104.
[] [PMID: 31103039]
Grin’kina NM, Karnabi EE, Damania D, Wadgaonkar S, Muslimov IA, Wadgaonkar R. Sphingosine kinase 1 deficiency exacerbates LPS-induced neuroinflammation. PLoS One 2012; 7(5)e36475
[] [PMID: 22615770]
Ikram M, Saeed K, Khan A, et al. Natural dietary supplementation of curcumin protects mice brains against ethanol-induced oxidative stress-mediated neurodegeneration and memory impairment via Nrf2/TLR4/RAGE signaling. Nutrients 2019; 11(5)E1082
[] [PMID: 31096703]
Maiti P, Paladugu L, Dunbar GL. Solid lipid curcumin particles provide greater anti-amyloid, anti-inflammatory and neuroprotective effects than curcumin in the 5xFAD mouse model of Alzheimer’s disease. BMC Neurosci 2018; 19(1): 7.
[] [PMID: 29471781]
Zhang Y, Xu N, Ding Y, et al. Chemerin suppresses neuroinflammation and improves neurological recovery via CaMKK2/AMPK/Nrf2 pathway after germinal matrix hemorrhage in neonatal rats. Brain Behav Immun 2018; 70: 179-93.
[] [PMID: 29499303]
Zhang Y, Tao GJ, Hu L, et al. Lidocaine alleviates morphine tolerance via AMPK-SOCS3-dependent neuroinflammation suppression in the spinal cord. J Neuroinflammation 2017; 14(1): 211.
[] [PMID: 29096659]
Ng RC, Cheng OY, Jian M, et al. Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice. Mol Neurodegener 2016; 11(1): 71.
[] [PMID: 27884163]
Kelly ÁM, van Praag H. Exercise-induced modulation of neuroinflammation in models of Alzheimer’s disease. Brain Plast 2018; 4(1): 81-94.
[] [PMID: 30564548]
Dou F, Chu X, Zhang B, et al. EriB targeted inhibition of microglia activity attenuates MPP+ induced DA neuron injury through the NF-κB signaling pathway. Mol Brain 2018; 11(1): 75.
[] [PMID: 30563578]
Haenseler W, Sansom SN, Buchrieser J, et al. A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response. Stem Cell Reports 2017; 8(6): 1727-42.
[] [PMID: 28591653]
Hu X, Li P, Guo Y, et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 2012; 43(11): 3063-70.
[] [PMID: 22933588]
Liao B, Zhao W, Beers DR, Henkel JS, Appel SH. Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol 2012; 237(1): 147-52.
[] [PMID: 22735487]
Yu Y, Shen Q, Lai Y, et al. Anti-inflammatory effects of curcumin in microglial cells. Front Pharmacol 2018; 9: 386.
[] [PMID: 29731715]
Mounier R, Théret M, Arnold L, et al. AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. Cell Metab 2013; 18(2): 251-64.
[] [PMID: 23931756]
Lu DY, Tang CH, Chen YH, Wei IH. Berberine suppresses neuroinflammatory responses through AMP-activated protein kinase activation in BV-2 microglia. J Cell Biochem 2010; 110(3): 697-705.
[] [PMID: 20512929]
Chhor V, Le Charpentier T, Lebon S, et al. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Behav Immun 2013; 32: 70-85.
[] [PMID: 23454862]
Jeon SM. Regulation and function of AMPK in physiology and diseases. Exp Mol Med 2016; 48(7)e245
[] [PMID: 27416781]
Soltani A, Salmaninejad A, Jalili-Nik M, et al. 5′-Adenosine monophosphate-activated protein kinase: A potential target for disease prevention by curcumin. J Cell Physiol 2019; 234(3): 2241-51.
[] [PMID: 30146757]
Li J, McCullough LD. Effects of AMP-activated protein kinase in cerebral ischemia J Cereb Blood Flow Metab 2010; 30(3): 480-92.
[PMID: 20010958]
Ray B, Bisht S, Maitra A, Maitra A, Lahiri DK. Neuroprotective and neurorescue effects of a novel polymeric nanoparticle formulation of curcumin (NanoCurc™) in the neuronal cell culture and animal model: Implications for Alzheimer’s disease. J Alzheimers Dis 2011; 23(1): 61-77.
[] [PMID: 20930270]
Bisht S, Khan MA, Bekhit M, et al. A polymeric nanoparticle formulation of curcumin (NanoCurc™) ameliorates CCl4-induced hepatic injury and fibrosis through reduction of pro-inflammatory cytokines and stellate cell activation. Lab Invest 2011; 91(9): 1383-95.
[] [PMID: 21691262]
Zhai P, Xia CL, Tan JH, et al. Syntheses and evaluation of asymmetric curcumin analogues as potential multifunctional agents for the treatment of Alzheimer’s disease. Curr Alzheimer Res 2015; 12(5): 403-14.
[] [PMID: 25938868]
Kochi A, Lee HJ, Vithanarachchi SM, et al. Inhibitory activity of curcumin derivatives towards metal-free and metal-induced Amyloid-β aggregation. Curr Alzheimer Res 2015; 12(5): 415-23.
[] [PMID: 25938870]

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