title: Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK.
abstract: CD200-CD200R signaling holds microglia in a quiescent state. Parkinson disease (PD) neurodegeneration may be associated with impairment of CD200-CD200R-mediated microglia silencing in the substantia nigra (SN). In this study, an anti-CD200R blocking antibody (ACDR) selectively and significantly enhanced the susceptibility of dopaminergic neurons to neurotoxicity induced by rotenone (Rot) and iron (Ir) in mesencephalic neuron/glia cultures. Microglia were shown to mediate dopaminergic neurotoxicity induced by ACDR/Rot (combination of ACDR and Rot) and ACDR/Ir (combination of ACDR and Ir). ACDR significantly enhanced the microglial activation induced by Rot and Ir in neuron/glia cultures. NADPH oxidase-mediated superoxide generation was a key contributor to dopaminergic neurotoxicity induced by ACDR/Rot and ACDR/Ir. p38 MAPK contributed to NADPH oxidase activation induced by ACDR/Rot and ACDR/Ir. Interestingly, there were a decrease in CD200 expression (mRNA and protein) and an enhancement of microglial response (MHCII mRNA and ICAM-1 protein) in the rat SN with aging. ICAM-1 expression was significantly inversely correlated with CD200 expression. These results strongly indicate the participation of SN CD200-CD200R dysfunction in the etiopathogenesis of PD and provide a new insight into the molecular mechanisms underlying the involvement of aging in PD and help to elucidate the mechanisms of the combined involvement of immune/inflammatory factors, environmental substances, and aging in PD.
authors.affiliation: Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. wangxijingcn@yahoo.com.cn
authors.forename: Xi-Jin
authors.initials: XJ
authors.lastname: Wang
authors.forename: Shi
authors.initials: S
authors.lastname: Zhang
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Yan
authors.forename: Yan-Xin
authors.initials: YX
authors.lastname: Zhao
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Zhou
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Lu
authors.forename: Jing-Dong
authors.initials: JD
authors.lastname: Zhang
mesh_terms: D000375:Aging; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D015870:Gene Expression; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D007501:Iron / Q000009:adverse effects; D008636:Mesencephalon / Q000378:metabolism / Q000503:physiopathology; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012402:Rotenone / Q000009:adverse effects; D013481:Superoxides / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; C495490:Cd200 protein, rat; D011971:Receptors, Immunologic; D012402:Rotenone; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; D007501:Iron; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; C042739:antigens, CD200; D004298:Dopamine