MicrogliaandastrocytesimmunefunctionsinAlzheimersDiseaseJulioFrancisco

FloridaInstituteofTechnology

MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE 1

Introduction

Formanyyears,thecentralnervoussystemwasbelievedtobedevoidofanimmune

systemhowever,suchideologyisnolongerheldtrue(Solito&Sastre,2013).Thebraintruly

possessanimmunesystembutwithseverallimitationsduetothelackoflymphocyte.Both

microglialcellsandastrocytesservedasinnateimmunecellswhichrespondtopathogensor

damagesinthebrain(Ransohoff&Brown,2012).Forinstance,microgliaandastrocytescan

respondtoaccumulationofamyloidbeta(A)plaqueandneurofibrillarytangles,whichare

thehallmarkcomponentsofAlzheimersdisease(AD)(Cornejo&vonBernhardi,2013).A

aggregationisknowntocausesynapticdysfunction,suchasmemoryandlearningdeficits

(Rivest,2009).

Tofurtherunderstandtheroleofimmunecellsinthebrain,ageneraloverviewofthe

molecularandcellularmechanismofmicrogliaandastrocytesimmuneresponsetoAplaque

willbediscussed.Also,thisreviewwilladdressfutureresearchfortreatingADthrough

improvingpatientsinnateimmuneresponse.

MicrogliaandAlzheimer'sdiseasepathogenesis

Microgliaareatypeofglialcellthatareresidentialmacrophageofthebrainandspinal

cord(Lawson,Perry,&Gordon,1992).Microgliaarepoorantigenpresentingcellswhichact

assentinelcellsinthecentralnervoussystem[CNS](Solito&Sastre,2012Rivest,2009).

MicrogliaareconstantlyscavengingtheCNSforplaques,neurondamages,andinfectious

agents(e.g.toxin).Oncesuchhazardousobjectaredetected,microgliaproducesanimmune

responsetotargetsuchobject(Gehrmann,Matsumoto,&Kreutzberg,1995).

InAlzheimer'sdisease,microgliacanrecognizescomponentsofAD,suchasamyloid

aggregation,throughtolllikereceptor4(TLR4)andotherreceptors(e.g.RAGE,CD136,and

SRPSOX)(Ransohoff&Brown,2012).TLR4activatesaseriesofeventsleadingtothe

MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE 2

releaseofsignalingmoleculessuchasinterleukinsandtumornecrosisfactorssuchasTNF

(Figure1)(Murphy,2011).InterleukinsandTNFeventuallyinduceanimmuneresponseby

releasingchemoattractantmoleculestorecruitimmunecells,suchasmicroglialcell,fromthe

bonemarrowtothebrainparenchyma.TheserecruitedcellswillleadtoAplaqueclearance

(Cornejo&vonBernhardi,2013).

Anotherimmuneresponseisviathecomplementsystem,whichisdesignedtolysis

(breakingdownofthecellmembrane),opsonize(makeacellmorevulnerabletobeing

phagocytize),activateaninflammatoryresponse,orphagocytized.Therearethreemain

complementsystempathways:classical,mannosebindinglectin[MBL],andalternative

pathways(seeFigure2forfurtherdetailsaboutthecomplementpathways)(Murphy,2011).

InAlzheimersdisease,theclassicalcomplementpathwayisusuallyactivatethrougha

triggeredenzymecascadeinordertoreduceAaccumulation.Also,severalcomplement

proteinscansuppressoractivatethepathogenesisofAD.Forexample,suppressionofthe

complementcomponent3protein(C3)increasesAaccumulationandneuronaldamages

(Kenne,Cudaback,Li,Montine,&Montine,2011).Ontheotherhand,signalingmolecule,

interferon(IFN),increasestheactivationofthecomplementsystem.Thisresultinthe

decreaseinAaccumulation(Kenne,Cudaback,Li,Montine,&Montine,2011).Therefore,

thecomplementsystemcanactaseitherneuroprotectionorneuronaldeterioration,

dependingonwhichcomplementproteinisactivated.Theactivationofcertaincomplement

proteinisdependingonthetypeofdangersignalinducedbythepathogen(Sjberg,Trouw,&

Blom,2009)

MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE 3

Lee,K.,Chow,Y.,Sharmili,V.,Abas,F.,Alitheen,N.B.M.,Shaari,K.,Israf,D.A.,Lajis,N.H.&Syahida,A.(2012).BDMC33,ACurcuminDerivativeSuppressesInflammatoryResponsesinMacrophageLikeCellularSystem:RoleofInhibitioninNFBandMAPKSignalingPathways.Int.J.Mol.Sci.,13(3),29853008:doi:10.3390/ijms13032985Figure1.TLR4Pathway.Tolllikereceptor4(TLR4)moleculeswouldrecognizeeitherexogenoussubstances(e.g.lipopolysaccharidefromthesurfaceofbacterialcells)orendogenouscompounds(e.g.Aplaqueandneurofibrillarytanglesinthebrain).Theamyloidbetaplaque(notshown)causestwoTLRstodimerize(orformacomplex).Next,anadaptormoleculecalledMyD88willbindtotheTIRdomainofthedimerizedTLR.MyD88recruitandactivesaproteincomplexcalledIRAK1/IRAK4kinasecomplex.IRAK4phosphorylate(introduceaphosphategroupto)IRAK1.IRAK1bindtothereceptor,TRAF.TheIRAK1/TRAFcomplexdissociatefromIRAK4(notshown).Next,aproteinkinasecalledTAK1phosphorylateanenzyme,IBkinase(IKK).IKKphosphorylateandubiquitinate(marksfordegradation)NFBinhibitor,causingthereleaseofNFB.NFBisatranscriptionfactorin

MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE 4

whichNFBistransporttothenucleus,whereitwouldbindtoDNAandinducetranscription(thefirststeptogeneexpression).Thiscausecytokinessignallingmoleculetobesecretedandthenmacrophagestoberecruited(Murphy,2011).

FromKolev,M.V.,Ruseva,M.M.,Harris,C.L.,Morgan,B.P.,&Donev,R.M.(2009).ImplicationofComplementSystemanditsRegulatorsinAlzheimersDisease.CurrentNeuropharmacology,7(1),18.doi:10.2174/157015909787602805Figure2.Complementsysteminresponsetoamyloidplaque.Thefollowingisanoverviewofthethreecomplementsystempathwayswhichincludeclassical,lectin(mannosebindinglectin),andalternativepathways.First,theclassicalpathwayinitiateswhenC1qreceptorrecognizesacomponentfromthemicrobialsurfaceoranantibodiespreboundedtothepathogen.Thischangestheconformationofthecomplementcomponent,C1rC1scomplex,whichtriggerstotheactivationofC1renzymaticactivity.ComplementfragmentC1cleavesC4intoC4aandC4b.TheC4bbindstothepathogensurface.Then,C4bbindstoC2,whichiscleavedbyC1stoproduceC2aandC2b.ThisproducesC3convertase.C3convertasecleavesC3intoC3aandC3b.SeveralC3adisperseawayandmediateinflammation.OtherC3bsbindtoC3convertaseformingC5convertase.C3bcomponentofC5convertasebindsC5,thetheC4b2aproteasecutsC5intoC5aandC5b.C5adispersesawayandmediatesinflammation,whileC5bstaysattachedonsurface.Thelectinpathway

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followasimilarschemeasclassicalpathway.TheonlydifferentistheclassicalpathwayincludeC1q,whilelectinpathwayincludemannosebindinglectin[MBL](Murphy,2011).

ThereisanegativeimmuneeffectofmicrogliaintheCNS.Microgliamayactually

contributetotheprogressionofneurodegeneration.Thisisduetothefactthatmicroglia

producereactiveoxygenandnitrogenspecies,proteolyticenzymes,glutamate,complement

factorsorinflammatorycytokinesinresponsetoAaccumulation,whichcanleadtothedeath

ofirreplaceableneurons(Walter,2007McGeer&McGeer,2001).

RelationshipofastrocytestoamyloiddepositsofAlzheimersdisease

Astrocytesoperateinaclosepartnershipwithneuronsinwhichastrocytesplayan

importantroleactingasanimmunecell.Astrocytesisalsoessentialinremovingcellular

debris,actingasanantigenpresentingcells,andphagocytosingcompoundssuchasAin

AD.However,astrocytescancausenegativeeffectswhenrespondingtoA.Thisincludean

imbalanceofcalciumlevelandtheproductionofcytotoxin(Vincent,Gasperini,Foa,&Small,

2010Cornejo&vonBernhardi,2013)

First,astrocytescancausesporadiccalciumsignalswhenexposedtoA,leadingto

thedeathofadjacentneurons.Inparticular,Adisruptsthecalciumhomeostasisofneurons

byartificiallyformingaporeinthemembranetobecomemorepermeableandbecomeleaky,

allowingionssuchascalciumtoentertheneuron.IfAplaquegeneratedaporewithinthe

membraneofanastrocyte,thentheastrocytesbecomessusceptibletoionsleakagesuchas

Ca2+ionleakage.Calciumisgenerallyrequiredforphysiologicaleventssucharesynaptic

synaptictransmissionandexcitotoxicity(Vincent,Gasperini,Foa,&Small,2010).SinceA

inducesaninfluxofcalciumintheastrocytes,therewouldbeariseinexcitotoxicity.

Excitotoxicityistheprocessofinducingneuronaldamagedordeathbytheexcessive

MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE 6

stimulatingneuronswithneurotransmitterssuchasglutamate(Manev,Favaron,Guidotti,&

Costa,1989).

Second,astrocytesdisplayavarietyofpatternrecognitionreceptors(PRRs),suchas

TLRs,doublestrandedRNAdependentproteinkinases,scavengerreceptors(SR),

nucleotidebindingoligomerizationdomains(NOD),andmannosereceptor(Farina,Aloisi,&

Meinl,2007).Byactivatingthesereceptorsthroughtheinteractionofaligandmolecule,

astrocytesproducecytotoxins(Cornejo&vonBernhardi,2013Murphy,2011).Cytokinesare

toxictoneurons,causingneuronaldeath.Duetothedeathofneuron,cognitivesynaptic

functionimpairmentusuallyoccurs(Cornejo&vonBernhardi,2013).Overall,productionof

cytotoxinscauseneuronaldisruptions,leadingtotheprogressionofAlzheimer'sdisease.

Past&FuturePharmacotherapeuticsTreatments

SinceitisnotclearwhethertherapeuticdrugscanrestorethecognitivefunctionofAD

patients,currentresearchesarefocusedonpreventingAlzheimersdiseasemorethancuring

preexistingones.SofartherehavebeennumerousattemptsaimedtoremovecerebralA.

SeveralattemptsincludethedevelopmentofbothpassiveandactiveAvaccinations

however,severalofthesedrugshavenegativeconsequences.Forexample,DaleSchenk

immunizedADmicewithA142peptide.Thispreventedbothcerebralamyloidaccumulation

andclearedexistingamyloidplaque.However,suchvaccinationwashaltedatphaseIIatrial

sincevaccinatedADpatientdevelopedasepticmeningoencephalitis,inflammationofthe

liningofthebrain(RezaiZadeh,Gate,Gowing,&Town,2011).

FuturedevelopmentofAvaccinationwillneedtobedesignedtoincreaseamyloid

peptideclearancewhileminimizingunsafesideeffects.Onetherapeuticstrategyisto

increasebrainrecruitmentandimproveamyloidclearancepotential.InhibitingTGFSmad

2/3signalallowsheterogeneousmononuclearphagocytestogainaccessintothebrain,

MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE 7

leadingtoagreaterphagocyticpotential(RezaiZadeh,Gate,Gowing,&Town,2011.Inother

words,bypreventingTGFSmad2/3signaling,therewouldbeadditionalphagocytesto

furthereliminatecerebralA,whichcouldreducetheprogressionofAlzheimersdisease.

ConcludingRemarks

MicroglialcellsandastrocytescouldpotentiallyleadtotheprogressionofAlzheimers

diseasehowever,alteringmicroglialcellsandastrocytesisthebestmethodinreducing

amyloidaccumulation.

Inadditiontotherapeuticstrategies,AvaccinationcanleadtoAclearance.Another

strategyistoincreasemononuclearphagocytestothebrainwhichcanleadtoaugmentation

ofamyloidclearancepotential.Thiswoulddecreaseamyloidinthebrainand,thus,potentially

alleviatethedevelopmentofAlzheimersdisease.

MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE 8

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