小胶质细胞在帕金森病中的双向作用：神经保护和疾病恶化

doi:10.3969/j.issn.1000-8535.2023.12.001

摘要/Abstract

摘要： 帕金森病（PD）是一种常见的与年龄相关的神经退行性疾病,其特点是黑质致密部内多巴胺能神经元的进行性丢失以及路易小体的积累。多巴胺能神经元的退化导致纹状体的多巴胺水平降低,最终出现静息性震颤、运动迟缓、肌肉僵硬和姿势不稳等运动症状,以及认知能力下降、嗅觉功能受损、精神异常和睡眠障碍等非运动症状。由于人口结构转变和全球老龄化,PD的不断增加对患者、家庭和社会构成重大负担。尽管广泛的研究已阐明了PD的病因学和潜在机制,但现有治疗主要集中在症状管理,无法阻止疾病的进展。小胶质细胞作为脑内重要的免疫细胞,对维持中枢神经系统的稳态具有关键作用。本文综述了PD研究,包括其病因学因素、分子机制和现有治疗策略。此外,审视了在PD样模型中涉及小胶质细胞的研究,深入探讨了小胶质细胞在疾病进展中的动态,并探究了小胶质细胞在促进或减轻疾病进展方面所扮演的错综角色。通过这样的探讨,本综述旨在为PD复杂的发病机制提供新的洞见和观点,激发出针对性治疗干预的创新思路。

关键词: 帕金森病, 小胶质细胞, 神经毒素模型, α-突触核蛋白模型, LRRK2模型

Abstract: Parkinson's disease（PD）,a prevalent age-related neurodegenerative disorder,is characterized by the progressive loss of dopaminergic neurons within the substantia nigra compacta（SNc）and the accumulation of Lewy bodies．The degeneration of dopaminergic neurons leads to diminished striatal dopamine levels,culminating in motor symptoms such as resting tremors,bradykinesia,muscle rigidity and postural instability,alongside non-motor manifestations encompassing cognitive decline,impaired olfactory function,psychological abnormalities and sleep disturbances．The escalating incidence of PD due to shifting demographics and global aging poses substantial burdens on patients,families and society．Although extensive research has elucidated the etiology and underlying mechanisms of PD,available treatments largely focus on symptom management and lack the capacity to halt disease progression．Microglia,as integral immune cells within the brain,wield pivotal influence over central nervous system homeostasis．This review presents a comprehensive synthesis of PD,encompassing its etiological factors,molecular mechanisms,and existing therapeutic strategies．Furthermore,we scrutinized research involving microglia in PD-like models,delving into the dynamics of microglia in disease progression and probing into the intricate roles that microglia assume in either fostering or mitigating disease advancement．By doing so,this review aims to furnish novel insights and perspectives that shed light on the intricate pathogenesis of PD,potentially sparking innovative concepts for targeted therapeutic interventions．

Key words: Parkinson's disease, microglia, neurotoxin model, alpha-synuclein model, LRRK2 model

王霞, 黄浪, 项宗勤, 牟斌, 曹海红, 刘振华, 唐北沙, 刘勇. 小胶质细胞在帕金森病中的双向作用：神经保护和疾病恶化[J]. 广州医药, 2023, 54(12): 1-12.

WANG Xia, HUANG Lang, XIANG Zongqin, MOU Bin, CAO Haihong, LIU Zhenhua, TANG Beisha, LIU Yong. Microglial involvement in Parkinson's disease progression：Neuroprotection and disease aggravation[J]. Guangzhou Medical Journal, 2023, 54(12): 1-12.

参考文献

[1] GBD 2016 Parkinson's Disease Collaborators.Global,regional,and national burden of Parkinson's disease,1990-2016:A systematic analysis for the Global Burden of Disease Study 2016BD 2016 Parkinson's Disease Collaborators.Global,regional,and national burden of Parkinson's disease,1990-2016:A systematic analysis for the Global Burden of Disease Study 2016[J].Lancet Neurol,2018,17(11):939-953.
[2] ASCHERIO A,SCHWARZSCHILD M A.The epidemiology of Parkinson's disease:Risk factors and prevention[J].Lancet Neurol,2016,15(12):1257-1272.
[3] ARMSTRONG M J,OKUN M S.Diagnosis and treatment of parkinson disease:A review[J].JAMA,2020,323(6):548-560.
[4] HIRSCH E C,ORIEUX G,MURIEL M P,et al.Nondopaminergic neurons in Parkinson's disease[J].Adv Neurol,2003(91):29-37.
[5] XU D C,CHEN Y,XU Y,et al.Signaling pathways in Parkinson's disease:molecular mechanisms and therapeutic interventions[J].Signal Transduct Target Ther,2023,8(1):73.
[6] KHOO T K,YARNALL A J,DUNCAN G W,et al.The spectrum of nonmotor symptoms in early Parkinson disease[J].Neurology,2013,80(3):276-281.
[7] RIZZO G,COPETTI M,ARCUTI S,et al.Accuracy of clinical diagnosis of Parkinson disease:A systematic review and meta-analysis[J].Neurology,2016,86(6):566-576.
[8] KRISMER F,PINTER B,MUELLER C,et al.Sniffing the diagnosis:Olfactory testing in neurodegenerative Parkinsonism[J].Parkinsonism Relat Disord,2017(35):36-41.
[9] CHOU K L,STACY M,SIMUNI T,et al.The spectrum of“off”in Parkinson's disease:What have we learned over 40 years?[J].Parkinsonism Relat Disord,2018(51):9-16.
[10] LANG A E,LOZANO A M.Parkinson's disease.First of two parts[J].N Engl J Med,1998,339(15):1044-1053.
[11] BADANJAK K,FIXEMER S,SMAJIĆ S,et al.The contribution of microglia to neuroinflammation in Parkinson's disease[J].Int J Mol Sci,2021,22(9):4676.
[12] MARRAS C,CANNING C G,GOLDMAN S M.Environment,lifestyle,and Parkinson's disease:Implications for prevention in the next decade[J].Mov Disord,2019,34(6):801-811.
[13] LANGSTON J W,BALLARD P,TETRUD J W,et al.Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis[J].Science,1983,219(4587):979-980.
[14] TANNER C M.Epidemiology of Parkinson's disease[J].Neurol Clin,1992,10(2):317-329.
[15] BORSCHE M,PEREIRA S L,KLEIN C,et al.Mitochondria and Parkinson's disease:Clinical,molecular,and translational aspects[J].J Parkinsons Dis,2021,11(1):45-60.
[16] IKEUCHI T,KAKITA A,SHIGA A,et al.Patients homozygous and heterozygous for SNCA duplication in a family with Parkinsonism and dementia[J].Arch Neurol,2008,65(4):514-519.
[17] HEDRICH K,WINKLER S,HAGENAH J,et al.Recurrent LRRK2(Park8)mutations in early-onset Parkinson's disease[J].Mov Disord,2006,21(9):1506-1510.
[18] HAUSER D N,HASTINGS T G.Mitochondrial dysfunction and oxidative stress in Parkinson's disease and monogenic parkinsonism[J].Neurobiol Dis,2013(51):35-42.
[19] KREBIEHL G,RUCKERBAUER S,BURBULLA L F,et al.Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1[J].PLoS One,2010,5(2):e9367.
[20] TWIG G,ELORZA A,MOLINA A J,et al.Fission and selective fusion govern mitochondrial segregation and elimination by autophagy[J].EMBO J,2008,27(2):433-446.
[21] KONG S M,CHAN B K,PARK J S,et al.Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes[J].Hum Mol Genet,2014,23(11):2816-2833.
[22] Pickrell A M,Youle R J.The roles of PINK1,parkin,and mitochondrial fidelity in Parkinson's disease[J].Neuron,2015,85(2):257-273.
[23] ZHU Y G,WANG C Y,YU M,et al.ULK1 and JNK are involved in mitophagy incurred by LRRK2 G2019S expression[J].Protein Cell,2013,4(9):711-721.
[24] BURRÉ J.The synaptic function of α-Synuclein[J].J Parkinsons Dis,2015,5(4):699-713.
[25] MELKI R.Role of different alpha-synuclein strains in synucleinopathies,similarities with other neurodegenerative diseases[J].J Parkinsons Dis,2015,5(2):217-227.
[26] BRIEGER K,SCHIAVONE S,MILLER F J Jr,et al.Reactive oxygen species:from health to disease[J].Swiss Med Wkly,2012(142):w13659.
[27] LEE D H,GOLD R,LINKER R A.Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases:therapeutic modulation via fumaric acid esters[J].Int J Mol Sci,2012,13(9):11783-11803.
[28] DIXON S J,LEMBERG K M,LAMPRECHT M R,et al.Ferroptosis:An iron-dependent form of nonapoptotic cell death[J].Cell,2012,149(5):1060-1072.
[29] DO VAN B,GOUEL F,JONNEAUX A,et al.Ferroptosis,a newly characterized form of cell death in Parkinson's disease that is regulated by PKC[J].Neurobiol Dis,2016(94):169-178.
[30] SURMEIER D J,SCHUMACKER P T.Calcium,bioenergetics,and neuronal vulnerability in Parkinson's disease[J].J Biol Chem,2013,288(15):10736-10741.
[31] SAZANOV L A.The mechanism of coupling between electron transfer and proton translocation in respiratory complex I[J].J Bioenerg Biomembr,2014,46(4):247-253.
[32] HAELTERMAN N A,YOON W H,SANDOVAL H,et al.A mitocentric view of Parkinson's disease[J].Annu Rev Neurosci,2014(37):137-159.
[33] MOGI M,HARADA M,KONDO T,et al.Transforming growth factor-beta 1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson's disease[J].Neurosci Lett,1995,193(2):129-132.
[34] MOGI M,HARADA M,KONDO T,et al.Interleukin-1 beta,interleukin-6,epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients[J].Neurosci Lett,1994,180(2):147-150.
[35] OUCHI Y,YAGI S,YOKOKURA M,et al.Neuroinflammation in the living brain of Parkinson's disease[J].Parkinsonism Relat Disord,2009(15 Suppl 3):S200-4.
[36] CHALLIS C,HORI A,SAMPSON T R,et al.Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice[J].Nat Neurosci,2020,23(3):327-336.
[37] KWON D K,KWATRA M,WANG J,et al.Levodopa-induced dyskinesia in Parkinson's disease:Pathogenesis and emerging treatment strategies[J].Cells,2022,11(23):3736.
[38] CONNOLLY B S,LANG A E.Pharmacological treatment of Parkinson disease:A review[J].JAMA,2014,311(16):1670-1683.
[39] VOON V,MEHTA A R,HALLETT M.Impulse control disorders in Parkinson's disease:Recent advances[J].Curr Opin Neurol,2011,24(4):324-330.
[40] MÜLLER T.Catechol-O-methyltransferase inhibitors in Parkinson's disease[J].Drugs,2015,75(2):157-174.
[41] TAN Y Y,JENNER P,CHEN S D.Monoamine Oxidase-B inhibitors for the treatment of Parkinson's disease:Past,present,and future[J].J Parkinsons Dis,2022,12(2):477-493.
[42] MRDJEN D,PAVLOVIC A,HARTMANN F J,et al.High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health,aging,and dsease[J].Immunity,2018,48(2):380-395.e6.
[43] van HOVE H,MARTENS L,SCHEYLTJENS I,et al.A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment[J].Nat Neurosci,2019,22(6):1021-1035.
[44] SIERRA A,de CASTRO F,DEL RÍO-HORTEGA J,et al.The “Big-Bang” for modern glial biology:Translation and comments on Pío del Río-Hortega 1919 series of papers on microglia[J].Glia,2016,64(11):1801-1840.
[45] GINHOUX F,GRETER M,LEBOEUF M,et al.Fate mapping analysis reveals that adult microglia derive from primitive macrophages[J].Science,2010,330(6005):841-845.
[46] YAN Y P,LANG B T,VEMUGANTI R,et al.Galectin-3 mediates post-ischemic tissue remodeling[J].Brain Res,2009 (1288):116-124.
[47] HUANG L,JIN J,CHEN K,et al.BDNF produced by cerebral microglia promotes cortical plasticity and pain hypersensitivity after peripheral nerve injury[J].PLoS Biol,2021,19(7):e3001337.
[48] MORSCH M,RADFORD R,LEE A,et al.In vivo characterization of microglial engulfment of dying neurons in the zebrafish spinal cord[J].Front Cell Neurosci,2015(9):321.
[49] SALTER M W,STEVENS B.Microglia emerge as central players in brain disease[J].Nat Med,2017,23(9):1018-1027.
[50] PLUVINAGE J V,HANEY M S,SMITH B A H,et al.CD22 blockade restores homeostatic microglial phagocytosis in ageing brains[J].Nature,2019,568(7751):187-192.
[51] LI X,LI Y,JIN Y,et al.Transcriptional and epigenetic decoding of the microglial aging process[J].Nat Aging,2023,3(10):1288-1311.
[52] HAMMOND T R,ROBINTON D,STEVENS B.Microglia and the Brain:Complementary partners in development and disease[J].Annu Rev Cell Dev Biol,2018(34):523-544.
[53] PAOLICELLI R C.Microglia states and nomenclature:A field at its crossroads[J].Neuron,2022,110(21):3458-3483.
[54] HANISCH U K,KETTENMANN H.Microglia:active sensor and versatile effector cells in the normal and pathologic brain[J].Nat Neurosci,2007,10(11):1387-1394.
[55] NIMMERJAHN A,KIRCHHOFF F,HELMCHEN F.Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo[J].Science,2005,308(5726):1314-1318.
[56] LIU Y U,YING Y,LI Y,et al.Neuronal network activity controls microglial process surveillance in awake mice via norepinephrine signaling[J].Nat Neurosci,2019,22(11):1771-1781.
[57] STOWELL R D,SIPE G O,DAWES R P,et al.Noradrenergic signaling in the wakeful state inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex[J].Nat Neurosci,2019,22(11):1782-1792.
[58] UMPIERRE A D,BYSTROM L L,YING Y,et al.Microglial calcium signaling is attuned to neuronal activity in awake mice[J].Elife,2020(9):e56502.
[59] MASUDA T,SANKOWSKI R,STASZEWSKI O,et al.Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution[J].Nature,2019,566(7744):388-392.
[60] TAN Y L,YUAN Y,TIAN L.Microglial regional heterogeneity and its role in the brain[J].Mol Psychiatry,2020,25(2):351-367.
[61] NGUYEN H M,GRÖSSINGER E M,HORIUCHI M,et al.Differential Kv1.3,KCa3.1,and Kir2.1 expression in “classically” and “alternatively” activated microglia[J].Glia,2017,65(1):106-121.
[62] YIN Z R,RAJ D,SAIEPOUR N,et al.Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer's disease[J].Neurobiol Aging,2017(55):115-122.
[63] GRABERT K,MICHOEL T,KARAVOLOS M H,et al.Microglial brain region-dependent diversity and selective regional sensitivities to aging[J].Nat Neurosci,2016,19(3):504-516.
[64] BISHT K,SHARMA K P,LECOURS C,et al.Dark microglia:A new phenotype predominantly associated with pathological states[J].Glia,2016,64(5):826-839.
[65] DAVIES D S,MA J,JEGATHEES T,et al.Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer's disease[J].Brain Pathol,2017,27(6):795-808.
[66] RAWJI K S,MISHRA M K,MICHAELS N J,et al.Immunosenescence of microglia and macrophages:Impact on the ageing central nervous system[J].Brain,2016,139(Pt 3):653-661.
[67] SPITTAU B.Aging microglia-phenotypes,functions and implications for age-related neurodegenerative diseases[J].Front Aging Neurosci,2017(9):194.
[68] NAVARRO V,SANCHEZ-MEJIAS E,JIMENEZ S,et al.Microglia in Alzheimer's disease:Activated,dysfunctional or degenerative[J].Front Aging Neurosci,2018(10):140.
[69] DOORN K J,GOUDRIAAN A,BLITS-HUIZINGA C,et al.Increased amoeboid microglial density in the olfactory bulb of Parkinson's and Alzheimer's patients[J].Brain Pathol,2014,24(2):152-165.
[70] PRINZ M,JUNG S,PRILLER J.Microglia biology:One century of evolving concepts[J].Cell,2019,179(2):292-311.
[71] SIERKSMA A,ESCOTT-PRICE V,DE STROOPER B.Translating genetic risk of Alzheimer's disease into mechanistic insight and drug targets[J].Science,2020,370(6512):61-66.
[72] SCHELTENS P,DE STROOPER B,KIVIPELTO M,et al.Alzheimer's disease[J].Lancet,2021,397(10284):1577-1590.
[73] A SIERRA,R C PAOLICELLI,H KETTENMANN.Cien Años de Microglía:Milestones in a Century of Microglial Research[J].Trends Neurosci,2019,42(11):778-792.
[74] BOOTH H D E,HIRST W D,WADE-MARTINS R.The role of astrocyte dysfunction in Parkinson's disease pathogenesis[J].Trends Neurosci,2017,40(6):358-370.
[75] LIDDELOW S A,GUTTENPLAN K A,CLARKE L E,et al.Neurotoxic reactive astrocytes are induced by activated microglia[J].Nature,2017,541(7638):481-487.
[76] TANSEY M G,GOLDBERG M S.Neuroinflammation in Parkinson's disease:Its role in neuronal death and implications for therapeutic intervention[J].Neurobiol Dis,2010,37(3):510-518.
[77] JOERS V,TANSEY M G,MULAS G,et al.Microglial phenotypes in Parkinson's disease and animal models of the disease[J].Prog Neurobiol,2017(155):57-75.
[78] HEPPNER F L,RANSOHOFF R M,BECHER B.Immune attack:The role of inflammation in Alzheimer disease[J].Nat Rev Neurosci,2015,16(6):358-372.
[79] LANGSTON J W,FORNO L S,TETRUD J,et al.Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure[J].Ann Neurol,1999,46(4):598-605.
[80] CZŁONKOWSKA A,KOHUTNICKA M,KURKOWSKA-JASTRZEBSKA I,et al.Microglial reaction in MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)induced Parkinson's disease mice model[J].Neurodegeneration,1996,5(2):137-143.
[81] SCHINTU N,FRAU L,IBBA M,et al.Progressive dopaminergic degeneration in the chronic MPTPp mouse model of Parkinson's disease[J].Neurotox Res,2009,16(2):127-139.
[82] GIULIANI F,HADER W,YONG V W.Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction[J].J Leukoc Biol,2005,78(1):135-143.
[83] WU D C,JACKSON-LEWIS V,VILA M,et al.Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease[J].J Neurosci,2002,22(5):1763-1771.
[84] SMEYNE R J,JACKSON-LEWIS V.The MPTP model of Parkinson's disease[J].Brain Res Mol Brain Res,2005,134(1):57-66.
[85] BARCIA C,SÁNCHEZ BAHILLO A,FERNÁNDEZ-VILLALBA E,et al.Evidence of active microglia in substantia nigra pars compacta of parkinsonian monkeys 1 year after MPTP exposure[J].Glia,2004,46(4):402-409.
[86] GAO H M,HONG J S,ZHANG W,et al.Synergistic dopaminergic neurotoxicity of the pesticide rotenone and inflammogen lipopolysaccharide:Relevance to the etiology of Parkinson's disease[J].J Neurosci,2003,23(4):1228-1236.
[87] WALSH S,FINN D P,DOWD E.Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat[J].Neuroscience,2011(175):251-261.
[88] KOROS C,SIMITSI A,STEFANIS L.Genetics of Parkinson's Disease:Genotype-phenotype correlations[J].Int Rev Neurobiol,2017(132):197-231.
[89] ESCHBACH J,DANZER K M.α-Synuclein in Parkinson's disease:Pathogenic function and translation into animal models[J].Neurodegener Dis,2014,14(1):1-17.
[90] DAWSON T M,KO H S,DAWSON V L.Genetic animal models of Parkinson's disease[J].Neuron,2010,66(5):646-661.
[91] MAGEN I,CHESSELET M F.Genetic mouse models of Parkinson's disease The state of the art[J].Prog Brain Res,2010(184):53-87.
[92] Masliah E,Rockenstein E,Veinbergs I,et al.Dopaminergic loss and inclusion body formation in alpha-synuclein mice:Implications for neurodegenerative disorders[J].Science,2000,287(5456):1265-1269.
[93] WAKAMATSU M,ISHII A,IWATA S,et al.Selective loss of nigral dopamine neurons induced by overexpression of truncated human alpha-synuclein in mice[J].Neurobiol Aging,2008,29(4):574-585.
[94] WATSON M B,RICHTER F,LEE S K,et al.Regionally-specific microglial activation in young mice over-expressing human wildtype alpha-synuclein[J].Exp Neurol,2012,237(2):318-334.
[95] GAO H M,ZHANG F,ZHOU H,et al.Neuroinflammation and α-synuclein dysfunction potentiate each other,driving chronic progression of neurodegeneration in a mouse model of Parkinson's disease[J].Environ Health Perspect,2011,119(6):807-814.
[96] BARKHOLT P,SANCHEZ-GUAJARDO V,KIRIK D,et al.Long-term polarization of microglia upon α-synuclein overexpression in nonhuman primates[J].Neuroscience,2012(208):85-96.
[97] SANCHEZ-GUAJARDO V,FEBBRARO F,KIRIK D,et al.Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson's disease[J].PLoS One,2010,5(1):e8784.
[98] GASSER T.Usefulness of genetic testing in PD and PD trials:A balanced review[J].J Parkinsons Dis,2015,5(2):209-215.
[99] ZIMPRICH A,BISKUP S,LEITNER P,et al.Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology[J].Neuron,2004,44(4):601-607.
[100] MOEHLE M S,WEBBER P J,TSE T,et al.LRRK2 inhibition attenuates microglial inflammatory responses[J].J Neurosci,2012,32(5):1602-1611.
[101] DU R H,SUN H B,HU Z L,et al.Kir6.1/K-ATP channel modulates microglia phenotypes:implication in Parkinson's disease[J].Cell Death Dis,2018,9(3):404.
[102] COLONNA M,BUTOVSKY O.Microglia function in the central nervous system during health and neurodegeneration[J].Annu Rev Immunol,2017(35):441-468.
[103] WANG L,GONG X,LIU Y,et al.CD200 maintains the region-specific phenotype of microglia in the midbrain and its role in Parkinson's disease[J].Glia,2020,68(9):1874-1890.
[104] SPITTAU B,WULLKOPF L,ZHOU X,et al.Endogenous transforming growth factor-beta promotes quiescence of primary microglia in vitro[J].Glia,2013,61(2):287-300.
[105] PATEL R K,PRASAD N,KUWAR R,et al.Transforming growth factor-beta 1 signaling regulates neuroinflammation and apoptosis in mild traumatic brain injury[J].Brain Behav Immun,2017(64):244-258.
[106] LIU Y,YU L,XU Y,et al.Substantia nigra Smad3 signaling deficiency:relevance to aging and Parkinson's disease and roles of microglia,proinflammatory factors,and MAPK[J].J Neuroinflammation,2020,17(1):342.
[107] RENTZOS M,NIKOLAOU C,ANDREADOU E,et al.Circulating interleukin-10 and interleukin-12 in Parkinson's disease[J].Acta Neurol Scand,2009,119(5):332-337.
[108] XU L,HE D,BAI Y.Microglia-mediated inflammation and neurodegenerative disease[J].Mol Neurobiol,2016,53(10):6709-6715.
[109] STEFANIS L,EMMANOUILIDOU E,PANTAZOPOULOU M,et al.How is alpha-synuclein cleared from the cell?[J].J Neurochem,2019,150(5):577-590.
[110] LEE H J,SUK J E,BAE E J,et al.Clearance and deposition of extracellular alpha-synuclein aggregates in microglia[J].Biochem Biophys Res Commun,2008,372(3):423-428.
[111] WANG Q,LIU Y,ZHOU J.Neuroinflammation in Parkinson's disease and its potential as therapeutic target[J].Transl Neurodegener,2015(4):19.