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For many years, the central nervous system was believed to be devoid of an immune system; however, such ideology is no longer held true (Solito & Sastre, 2013). The brain truly possess an immune system but with several limitations due to the lack of lymphocyte. Both microglial cells and astrocytes served as innate immune cells which respond to pathogens or damages in the brain (Ransohoff & Brown, 2012). For instance, microglia and astrocytes can respond to accumulation of amyloidbeta (Aβ) plaque and neurofibrillary tangles, which are the hallmark components of Alzheimer’s disease (AD) (Cornejo & von Bernhardi, 2013). Aβ aggregation is known to cause synaptic dysfunction, such as memory and learning deficits (Rivest, 2009).
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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
MICROGLIAANDASTROCYTESFUNCTIONINALZHEIMERSDISEASE 5
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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