Microglia Acquire Distinct Activation Profiles Depending on the Degree of α-Synuclein Neuropathology in a rAAV Based Model of Parkinsons Disease 英文参考文献.docVIP

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Microglia Acquire Distinct Activation Profiles Depending on the Degree of α-Synuclein Neuropathology in a rAAV Based Model of Parkinsons Disease 英文参考文献.doc

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Microglia Acquire Distinct Activation Profiles Depending on the Degree of α-Synuclein Neuropathology in a rAAV Based Model of Parkinsons Disease 英文参考文献

MicrogliaAcquireDistinctActivationProfilesDepending ontheDegreeofa-SynucleinNeuropathologyinarAAV BasedModelofParkinson’sDisease VanesaSanchez-Guajardo1,FabiaFebbraro1,DenizKirik2,MarinaRomero-Ramos1,2* 1Central Nervous System Disease ModelingGroup,Department ofMedical Biochemistry, Aarhus University, Aarhus, Denmark, 2Department ofExperimentalMedical Science,BrainRepairandImaginginNeuralSystems,LundUniversity,Lund,Sweden Abstract Post-mortemanalysisofbrainsfromParkinson’sdisease(PD)patientsstronglysupportsmicrogliaactivationandadaptive immunityasfactorscontributingtodiseaseprogression.Suchresponsesmaybetriggeredbya-synuclein(a-syn),whichis known to be the main constituent of the aggregated proteins found in Lewy bodies in the brains of PD patients. To investigatethisweusedarecombinantviralvectortoexpresshumana-syninratmidbrainatlevelsthatinducedneuronal pathologyeitherintheabsenceorthepresenceofdopaminergiccelldeath,therebymimickingearlyorlatestagesofthe disease.MicrogliaactivationwasassessedbystereologicalquantificationofMac1+cells,aswellastheexpressionpatterns ofCD68andMCHII.Inourstudy,whena-syninducedneuronalpathologybutnotcelldeath,afasttransientincreasein microgliacellnumbersresultedinthelong-terminductionofMHCII+microglia,denotingantigen-presentingability.Onthe otherhand,whena-syninducedbothneuronalpathologyandcelldeath,therewasadelayedincreaseinmicrogliacell numbers,whichcorrelatedwithlong-lastingCD68expressionandamorphologyreminiscentofperipheralmacrophages.In additionT-lymphocyteinfiltration,asjudgedbythepresenceofCD4+andCD8+cells,showeddistinctkineticsdepending onthedegreeofneurodegeneration,andwassignificantlyhigherwhencelldeathoccurred.Wehavethusforthefirsttime shownthatthemicroglialresponsediffersdependingonwhethera-synexpressionresultsoncelldeathornot,suggesting that microglia may play different roles during disease progression. Furthermore, our data suggest that the microglial responseismodulatedbyearlyeventsrelatedtoa-synexpressioninsubstantianigr