MicrogliaandastrocytesimmunefunctionsinAlzheimersDisease

JulioFrancisco
FloridaInstituteofTechnology

MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE

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

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

Lee,K.,Chow,Y.,Sharmili,V.,Abas,F.,Alitheen,N.B.M.,Shaari,K.,Israf,D.A.,Lajis,N.H.
&Syahida,A.(2012).BDMC33,ACurcuminDerivativeSuppressesInflammatoryResponses
inMacrophageLikeCellularSystem:RoleofInhibitioninNFBandMAPKSignaling
Pathways.Int.J.Mol.Sci.,13(3),29853008:doi:10.3390/ijms13032985

Figure1.TLR4Pathway.
Tolllikereceptor4(TLR4)moleculeswouldrecognizeeither
exogenoussubstances(e.g.lipopolysaccharidefromthesurfaceofbacterialcells)or
endogenouscompounds(e.g.Aplaqueandneurofibrillarytanglesinthebrain).Theamyloid
betaplaque(notshown)causestwoTLRstodimerize(orformacomplex).Next,anadaptor
moleculecalledMyD88willbindtotheTIRdomainofthedimerizedTLR.MyD88recruitand
activesaproteincomplexcalledIRAK1/IRAK4kinasecomplex.IRAK4phosphorylate
(introduceaphosphategroupto)IRAK1.IRAK1bindtothereceptor,TRAF.TheIRAK1/TRAF
complexdissociatefromIRAK4(notshown).Next,aproteinkinasecalledTAK1
phosphorylateanenzyme,IBkinase(IKK).IKKphosphorylateandubiquitinate(marksfor
degradation)NFBinhibitor,causingthereleaseofNFB.NFBisatranscriptionfactorin

MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE

whichNFBistransporttothenucleus,whereitwouldbindtoDNAandinducetranscription
(thefirststeptogeneexpression).Thiscausecytokinessignallingmoleculetobesecreted
andthenmacrophagestoberecruited(Murphy,2011).

FromKolev,M.V.,Ruseva,M.M.,Harris,C.L.,Morgan,B.P.,&Donev,R.M.(2009).
ImplicationofComplementSystemanditsRegulatorsinAlzheimersDisease.
Current
Neuropharmacology
,7(1),18.doi:10.2174/157015909787602805

Figure2.Complementsysteminresponsetoamyloidplaque.
Thefollowingisan
overviewofthethreecomplementsystempathwayswhichincludeclassical,lectin(mannose
bindinglectin),andalternativepathways.First,theclassicalpathwayinitiateswhenC1q
receptorrecognizesacomponentfromthemicrobialsurfaceoranantibodiespreboundedto
thepathogen.Thischangestheconformationofthecomplementcomponent,C1rC1s
complex,whichtriggerstotheactivationofC1renzymaticactivity.ComplementfragmentC1
cleavesC4intoC4aandC4b.TheC4bbindstothepathogensurface.Then,C4bbindsto
C2,whichiscleavedbyC1stoproduceC2aandC2b.ThisproducesC3convertase.C3
convertasecleavesC3intoC3aandC3b.SeveralC3adisperseawayandmediate
inflammation.OtherC3bsbindtoC3convertaseformingC5convertase.C3bcomponentof
C5convertasebindsC5,thetheC4b2aproteasecutsC5intoC5aandC5b.C5adisperses
awayandmediatesinflammation,whileC5bstaysattachedonsurface.Thelectinpathway

MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE

followasimilarschemeasclassicalpathway.Theonlydifferentistheclassicalpathway
includeC1q,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
2+
Ca
ionleakage.Calciumisgenerallyrequiredforphysiologicaleventssucharesynaptic

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

MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE

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
immunizedADmicewithA
peptide.Thispreventedbothcerebralamyloidaccumulation
142
andclearedexistingamyloidplaque.However,suchvaccinationwashaltedatphaseIIatrial
sincevaccinatedADpatientdevelopedasepticmeningoencephalitis,inflammationofthe
liningofthebrain(RezaiZadeh,Gate,Gowing,&Town,2011).
FuturedevelopmentofAvaccinationwillneedtobedesignedtoincreaseamyloid
peptideclearancewhileminimizingunsafesideeffects.Onetherapeuticstrategyisto
increasebrainrecruitmentandimproveamyloidclearancepotential.InhibitingTGFSmad
2/3signalallowsheterogeneousmononuclearphagocytestogainaccessintothebrain,

MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE

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.

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