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HindawiPublishingCorporationMediatorsofInflammationVolume2013,ArticleID260925,9pageshttp://dx.doi.org/10.1155/2013/260925

ReviewArticle

Role of Neuroinflammation in Adult Neurogenesis andAlzheimer Disease: Therapeutic Approaches

Almudena Fuster-Matanzo,1,2 María Llorens-Martín,1,2

Félix Hernández,1,2 and Jesús Avila1,2

1DepartmentofMolecularNeurobiology,CentrodeBiolog´iaMolecularSevero

Ochoa(CSIC-UAM),Madrid,Spain2CentrodeInvestigaci´edicaenRedsobreEnfermedadesNeurodegenerativas

(CIBERNED,ISCIII),28031Madrid,Spain

onBiom´



CorrespondenceshouldbeaddressedtoJes´

usAvila;[email protected]

Received29November2012;Accepted12March2013

AcademicEditor:

DiegoGomez-Nicola

Copyright©2013AlmudenaFuster-Matanzoetal.Thisis

anopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,whichpermits

unrestricteduse,distribution,andreproductioninanymedium,providedthe



originalworkisproperlycited.

Neuroinflammation,aspecializedimmuneresponsethattakesplaceinthecentralnervoussystem,hasbeenlinkedto

neurodegenerativediseases,andspecially,ithasbeenconsideredasahallmarkofAlzheimer

disease,themostcommoncauseofdementiaintheelderlynowadays.Furthermore,neuroinflammation

hasbeendemonstratedtoaffectimportantprocessesinthebrain,



suchastheformationofnewneurons,commonlyknownasadultneurogenesis.Forthis,manytherapeuticapproacheshavebeendevelopedinordertoavoid

ormitigatethedeleteriouseffectscausedbythechronicactivationoftheimmune

response.Consideringthis,inthispaperwerevisetherelationshipsbetweenneuroinflammation,Alzheimer

disease,andadultneurogenesis,aswellasthecurrenttherapeutic



approachesthathavebeendevelopedinthefield.

1. IntroductionTheinflammatoryresponseisanearly,specializedimmunereactiontotissuedamageor

pathogeninvasion.Inthecentralnervoussystem(CNS),thisprocessisknownas

neuroinflammationandischaracterizedbytheactivationofthemicrogliaandastrocytespopulation

[13],theincreaseinconcentrationofdifferentcytokines,andchemokinesand,undercertain



conditions,thedisruptionofthebloodbrainbarrierandthesubsequentinvasionofcellsfromthehematopoieticsystemtotheinjurysite[4].Thus,theburdenof

protectingCNSfrominjuryfallsonaspecificgroupofcells:microglia,astrocytes,

andmastcells.Mastcellscanbefoundwithinthebrainandtheir

functionsincludetheattractantandactivationofotherimmunecells



bysecretingproinflammatorycytokines,andchemoattractants[5].Astrocytesalsocontributetotheimmuneresponsebyliberatingbothpro-andanti-inflammatorycytokines,chemokinesandcomplementcomponents[6].Finally,microglia(CNS-residentmacrophages)

representthemaineffectorcellsoftheimmunesystemintheCNS.Under

physiologicalconditions,theystayasaquiescent

population.Inresponseto

aninfectionorinjury,theyactivateacquiringareactiveinflammatory



phenotypecharacterizedbyanincreasedproliferation,morphologicalchanges,andthereleaseofseveralinflammatorymoleculessuchascytokines,reactiveoxygenspecies,andnitricoxide

[7].

SomeaspectsoftheneuroinflammatoryresponseresultbeneficialforCNS

outcomes.Amongthesebenefits,neuroprotectionphenomena,themaintenanceofneurogenesisasamechanism

ofbrainrepair,themobilizationofneuralprecursorsforrepair,



remyelination,andevenaxonalregenerationareincluded[8,9].However,neuroinflammationcanbeharmfultoo,leadingtoneuronaldamage.Benefitsanddetrimentsbalancedepends

largelyonthemagnitudeoftheimmuneresponse.Inthissense,itisimportanttodistinguish

betweenthetwotypesofresponsesinwhichinflammatorymechanismhastraditionallybeen

classified:acuteandchronicinflammation.Thefirstonecomprisesthe



immediateandearlyresponsetoaninjuriousagentandisbasicallyadefensiveresponsethatpavesthewayforrepairofthedamagedsite

beingtypicallyshort-livedandunlikelytobedetrimentaltolong-termneuronalsurvival[10].

Thechronic



MediatorsofInflammation

responseoccurswhentheharmfulstimuluspersistsovertimeandcontrarytotheacuteform,itisa

long-standingandoftenself-perpetuatingneuroinflammatoryresponsewhichintheend,resultsindetrimental

consequencesforneurons[11].Bothacuteandchronicresponseshavebeenrelatedwith

neurodegenerativedisorders.Thus,strokeandinjurywouldassociatewithacute



neuroinflammationwhilediseasessuchasmultiplesclerosisorAlzheimerdisease(AD)wouldbeassociatedwiththechronicformoftheresponse.Inthisscenario,

anotherimportantprocesscommonlyrelatedwithneurodegenerationandneuroinflammationemerges;theformationof

newneuronsintheadulthoodoradultneurogenesis.

Adultneurogenesisoccurs

inmammalsprincipallyintwobrainregions:thesubventricularzone



(SVZ)andthesubgranularzone(SGZ)ofthehippocampus.Theneuronalprecursorcells(NPCs)thatexistinbothareasareasubsetofastrocytesthatgiverisetointermediateprogenitorswhichmigrateanddifferentiateintonewneurons

ofthehippocampus(inSGZneurogenesis)ortheolfactorybulb(inSVZneurogenesis)

[12].Adultneurogenesishasbeenfoundtobealteredinseveralneurodegenerativedisorders

suchasParkinsonsdisease,Huntingtonsdisease,andAD(fora



review,see[13]).Ontheotherhand,neuroinflammationisacommonfeatureofallthesepathologiesand,asitwillbecommentedindetail

later,ithasalsoarelevantinfluenceonadultneurogenesis.

Due

totheinterconnectionamongtheseprocesses,itisimportanttoconsiderthemas

awhole,takingintoaccountthatalterationsaffectinganyof



themwouldprobablyhaveconsequencesonthetwoothers.

Inthisreview,wewillsummarizetheroleofneuroinflammationinbothadult

neurogenesisandAlzheimerdisease.Relatedtothispathology,wewillfinallyrevisethe

recentadvancesconcerningtherapeuticapproacheswithneuroinflammatorymechanismsasamaintarget.

2. Neuroinflammation and Adult NeurogenesisIthasbeenwidelydemonstratedthatneuroinflammationaffects



adultneurogenesishavingbothdetrimentalandbeneficialconsequenceswhichcanresultinenhancementand/orinhibitionoftheprocess.Thefinalresultdependslargelyon

howmicroglia,macrophages,and/orastrocytesareactivatedandthedurationoftheinflammation

[14].Furthermore,thebalancebetweenthebenefitsandthedetrimentswillhavea

profoundimpactontheefficiencyofbrainrepair[15],which



isofgreatimportanceinthecontextoftheneurodegenerativedisorders.

Itisknownthatmicroglia,asthefirstimmunologicalbarrieragainst

pathogensandenvironmentalinsults[16],exerttheaforementioneddualeffectsonadultneurogenesis,

resultinginproorantineutogenicoutcomes.

2.1.ProneurogenicEffects.Animportant

studyperformedbySierraandcolleaguesdemonstratedthatrestingmicroglia



playacrucialroleinregulatingthebalanceofnewbornneuronsinthehippocampusthankstotheirphagocyticcapacities[17].Ofthethousandsof

newcellsbornintheSGZofthedentategyrus,onlyapart

ofthemdifferentiateandmaturateintofullymatureneurons.Atleasthalfof

thesecellsdie,probablythroughapoptosis,withinthefirstfew



daystoweeksaftertheyareborn[1821].Sierraetal.

[17]provideddatathatattributedtomicrogliathefunctionofremoving

thoseapoptoticnewcellsbyphagocytosis.Furthermore,theyimportantlyprovedthatthisaction

didnotrequiretheactivationofthemicroglialpopulation.Recently,ithasbeen

reportedthatnotonlymicrogliaareessentialforadultneurogenesis



buttheirfunctionsandactivityareimportantlyregulatedbyneuronalprogenitorcellstoo.Thus,NPC-derivedsecretedfactorsarecapableofmodulatingmicrogliaactivation,proliferation,

andphagocytosis[22].Thiscrosstalkpersistsduringneuronlifetime,sinceadultneuronsare

demonstratedtoregulatemicrogliaactivationbyconstitutivelyexpressionofseveralneuroimmunoregulatoryproteinssuch

asCD200,CX3CL1(orfractalkine),CD47,CD55,orHMGB1(for



areviewsee[23]).FurtherevidenceoftheproneurogeniceffectsofunchallengedmicrogliacomesfromtheworkofWaltonandcolleagues.Byinvitro

studiestheyshowedthatthispopulationreleasesfactorsthatrescueneuroblastsandinstruct

neuronalcelldifferentiation[24].

However,notonlyrestingmicrogliaexertbenefits

onadultneurogenesis.Theacquisitionofanactivephenotype,under



certainconditions,canbebeneficialtoo[16],thankstotheliberationofanti-inflammatorycytokineswithabroadrangeofactionsonneurogenesis.Amongthese,

wecanhighlightinterleukin-4and-10(IL-4,IL-10)andtransforminggrowthfactor-beta(TGF-..).

Itisalsoimportanttokeepinmindthatcytokinesclassicallyconsideredas

proinflammatory,suchasinterleukin-6(IL-6),interleukin1-..(IL-1..),andtumor



necrosisfactor-..(TNF-..)canbeinvolvedinthecreationofapermissiveenvironmentforneurorepairtoo[25],asseveralstudieshavedemonstrated(seeTable

1).

Finally,notonlycytokinesderivedfrommicrogliacanpositivelyregulate

neurogenesis.Otherfactorsproducedbyimmunesystemcellswhichareinvolvedinthe

neuroinflammatoryresponsehavebeenshowntohavecertaininfluence.This



isthecaseforgranulocyte-macrophagecolonystimulatingfactor(GM-CSF)[26]andthegranulocyte-colonystimulatingfactor(G-CSF),withremarkableeffectsonthedifferentiationofNSC

invitro[27](Table1).

2.2.AntineurogenicEffects.Neuroinflammation,althoughbeneficialas

aphysiologicalresponsetomaintainbrainhomeostasis,canhavedetrimentaleffectsespeciallywhen

itturnsouttobeachronicresponse.Activatedmiroglia



releaseproinflammatorycytokineswhichhavebeenshowntoaffectlargelyneurogenesis.TheaforementionedIL-6,TNF-..,andIL-1..butalsointerleukin-1-alpha(IL-1..),interleukin-18(IL18)andinterferon-..

(IFN-..)havedetrimentalconsequencesforproliferationand/ordifferentiationofNSC(Table1).Among

factorsnotreleasedbymicroglia,CCL11oreotaxin1,asmallchemokineknownby

itsimplicationinallergicresponses,hasbeenrecentlylinkedto



adultneurogenesisandageing[28].Whenadministeredsystemicallytoyoungmice,




eotaxinisabletoimpairneurogenesisproducingasaconsequence,learningandmemorydeficits[28].Furthermore,itseems

toaffectdirectlythenumberandsizeofneurospheresformedfromprimaryNPCs

[28],suggestingthatprecursorcellsprobablyhavereceptorscapableofbindingthecytokine.

Finally,itisespeciallynoteworthytokeepin



mindthatmostoftheaforementionedfactorsarenotonlyproducedbymicroglia,butforastrocytestoo,whichcontributetothepathogenesisofneurodegenerative

disordersaswillbecommentedlater.

Theeffectsoftheabovementioned

cytokinesonneurogenesisaresummarizedinTable1.

3. Neuroinflammation and Alzheimer DiseaseNeurodegenerativediseases

arecharacterizedbytheprogressivelossofneuronsfromspecific



regionsoftheCNS,whichisbelievedtoaccountforthecognitiveandmotorimpairmentssufferedbypatientswiththeseneurodegenerativedisorders.Importantly,inflammation

isaprocessthathasbeencloselyrelatedtotheonsetofmanyofthesediseases,suchasAmyotrophicLateralSyndrome(ALS),

MultipleSclerosis(MS),ParkinsonsDisease(PD)andAlzheimerDisease(AD)[29 33].Indeed,

aberrantinflammatoryresponsesarebelievedtoplayarolein



theetiologyofthesedisorders.

Atpresent,ADisthemostcommoncauseofdementiaintheelderly.Itisestimatedthat

27millionpeopleareaffectedworldwide[34]andthisnumberisexpectedto

tripleby2050duetotheincreaseofthepopulationlifeexpectancy[35].

ADisaneurodegenerativedisorderwhichaffectsbrainregionsthat



controlmemoryandcognitivefunctions,whichimpliesthatpatientsfinallylosetheirmemoryandabilitytolearn,toreason,tocommunicateandtocarry

outdailyactivities[36].TherearetwodifferenttypesofAlzheimerDisease,familiar

AlzheimerDisease(FAD)andSporadicAlzheimerDisease(SAD),andtheoriginofthe

diseasecouldbedifferentinbothfamilialandsporadiccases.



IntermsofFAD,mutationsinthreedifferentgenes(presenilin-1PS-1,presenilin2PS-2andamyloidprecursorproteinAPP)arelikelytopromotethe

onsetofthediseasewhereasforSAD,differentriskfactorsmightbeinvolved.

Nevertheless,downstreamtheinitialcausesofthediseasesomecommonfactorsmaybe

involved[37].Atamolecularlevel,ADischaracterizedby



thepresenceoftwomainhystopathologicalhallmarks:senileplaques(extracellularaggregatescomposedbyamyloidpeptideorA..)andneurofibrillarytangles(intracellularaggregatescomposedby

hyperphosphorylatedformsoftauprotein).A..resultsfromthecleavageofAPPand,

althoughitseemstohaveimportantdevelopmentalfunctionsincelldifferentiationandpossibly

intheestablishmentofsynapses[38,39],itsfunctionsin



adultbrainstillremainunclear.Ontheotherhand,tauprotein,themajorcomponentofneurofibrillarytangles,isamicrotubuleassociatedproteinwhichcontributes

tothenormalfunctionofthisintracellularsupportstructure.Underpathogenicconditions,tau

ishighlyphosphorylatedreducingitsabilitytobindtomicrotubules

[40]

andfavoringtheformationofproteinaggregates.Asapart



oftheinflammatoryresponse,gliosisisacommonfeatureofAD.Activatedastrocytesandmicrogliaarecharacteristicallyfoundinabundancenearneuronsandplaques.

Besides,ADbrainsshowincreasedexpressionofseveralpro-inflammatorycytokineswhicharehardly

foundinnormalbrains[6164].Themainhypothesisproposesthechronicinflammatoryreaction

asaresponsetotheaccumulationofA..plaquesand



tangles[65].Althoughinitialinflammatoryresponsecanbebeneficial,chronicactivationofastrocytesandmicrogliahasbeenshowntoinducenecrosisinadjacentneurons

byreleasingreactiveoxygenintermediates,nitricoxide,proteolyticenzymes,complementaryfactors,orexcitatory

aminoacids[66].

A..andtheirprecursorAPParepotentactivators

ofglialcells[67,68].Thus,A..bindstothe



microglialcellsurfaceregulatingextracellularsignalregulatedkinase(ERK)andmitogen-activatedproteinkinase(MAPK)pathwayswhichinducesproinflammatorygeneexpressionleadingtocytokineand

chemokineproduction[69].Severalchemokinesandtheirreceptorshavebeenfoundtobe

upregulatedintheADbrain.Forexample,macrophageinflammatoryprotein(MIP)-1..hasbeen

detectedinreactiveastrocytesnearbyA..plaques[70].Inthe



samemanner,changesinlevelsofmanycytokineshavebeendescribednotonlyinADbrainsbutalsoinbloodandcerebrospinalfluidfrom

patients.Thus,increasedlevelsofIL-1..,IL-1..,IL-6,TNF-..,andGM-SFhavebeenreportedinbrain

tissue[71,72].Inserumfrompatients,anincreaseineotaxin,acytokine

recentlylinkedtoadultneurogenesisandageinghasbeenalso



detected

[28]and,correlatingtothis,anincreaseintheexpressionofitsreceptor,CCR3,hasbeenfoundinADbrains,especially

inmicroglia[73].Importantly,severalworksdescribeinteractionsbetweencomponentsofthesenile

plaquesandcytokines,whichcouldbegeneratingapositivefeedbackloopforthe

neuroinflammatoryprocess[74].Forexample,A..proteinisableto



potentiatethesecretionofIL-6andIL-8underseveralconditions[75].Similarly,astrocytesmightbeactivatedbyA..[76],contributingtogeneratingaproinflammatory

environmentviatheliberationofseveralcytokinesandchemokines.However,insomesituations

theroleofmicrogliahasbeenshowntobebeneficial,sincetheactivation

ofthispopulationcandecreasetheaccumulationofA..thanks



totheirphagocyticabilitywhichfacilitatestheclearanceanddegradationoftheaggregates[77].Besides,microgliacanbebeneficialtoothroughthesecretionof

growthfactorssuchastheglia-derivedneurotrophicfactor(GDNF)whichfavorsneuronsurvival

[78].Similarly,arelativelyunknowncytokine,fractalkine,whichhasbeendemonstratedtohave

importantneuroprotectivecharacteristics,hasbeenrecentlylinkedtothedisease.



Thus,fractalkinesignaling(withitsonlyreceptorCX3CR1)hasbeenfoundtobealteredinADbrainsinwhichreducedlevelsofthecytokine

hasbeendescribed[79].

Finally,itisnoteworthytokeepin

mindthatalthoughneuronshavebeentraditionallybelievedtobepassivebystandersin

neuroinflammation,theyseemtocontributetotheproductionofneuroinflammatory



molecules,aphenomenonthatcouldberelevantinAD.Thus,the




Table1:Effectsofdifferentcytokinesonneurogenesis.

CytokineEffectsonneurogenesisReferencesIL-1..Increasedastrocyte

lineage[41]IL-1..StimulationofNPCsproliferationanddifferentiationDecreasedproliferation,survival,and

neuronaldifferentiation[42][43]Increasedastrocytedifferentiation[44]IL-4Increasedoligodendrogenesis[45]IL-6

IL-10Decreasedproliferation,survival,andneuronaldifferentiationDifferentiationofNSC



toneuronallineagesIncreasedneurogenesisIncreasedproliferation[46][47][48][49][50][51]IL-18DecreasedsurvivalIncreasedneuronaldifferentiation[52]IFN-..Decreasedproliferationand

survivalofmultipotentprogenitorsPromotionofdifferentiationandneuriteoutgrowth[53][54][55]

CCL11(eotaxin-1)DecreasedSox-2progenitors,proliferation,andneuronaldifferentiation[28]CX3CL1(fractalkine)Decreased

neurogenesis[56]GM-CSFStimulationofNPCsdifferentiation[57]G-CSFPromotes



NPCsdifferentiation[27]TGF-..DecreasedproliferationIncreasedsurvivalandneuraldifferentiation[58][59][60]

productionofIL-1,IL-6,andTNF-..byneurons

hasbeenreported.Indeed,theseneuronalchemokinesactasmessengersbetweenneuronsand

glialcells(forareview,see[80]).

Asneuroinflammationrepresentsan

importanthallmarkinADand,asithasbeenshown



inSection2,ithasaremarkableinfluenceonadultneurogenesis,modulatingtheinflammatoryenvironmentcouldbebeneficialnotonlyforimprovingthedeficitsdirectlyprovoked

bythediseasebutalsoforstimulatingtheendogenousabilityofthebrain

forrepairingthedamage.Inthissense,itisimportanttohighlightthat,

especiallyinAD,understandingtheroleofadultneurogenesisis



ofgreatimportanceconsideringthatoneoftheneurogeniczonesisthehippocampus,structureresponsibleforcognitiveandlearningcapacitieswhichislargelyaffected

inADpatients.

Todate,itisnotfullyunderstoodhowadultneurogenesisisaffectedin

neurodegenerativedisorders.InAD,contradictoryresultshavebeenobtainedfromthestudyof

severalanimalmodelsandthestudyofbraintissueby



biochemicalandhistologicalapproaches.Differenteffectsonproliferation,differentiation,andsurvivalhavebeenreportedinADtransgenicanimalmodelswithmutationsinAPPand

tauorinboth(forareview,see[81]).Besides,alterationsaffectingNPCs

anddifferentiationofnewbornneuronshavebeendescribedinaglycogen-synthasekinase3

overexpressingmousemodel(GSK-3..hasbeenproposedasakey



proteininAD[82]),withanimportantroleofmicrogliaasamediatorofthesedamagingeffects[83,84]amongwhich,morphologyalterationsof

newbornneuronsareincluded[85].Inhumans,firstdatawereobtainedbyNagy

andcolleaguesin1997[86].In

thispioneerwork,theauthorsreportedanincreaseinKi-67marker(stainingproliferating

cells)inthehippocampusfromADpatients.In2004,Jin



etal.confirmedthisresultrestrictingitspecificallytoneurons[87].However,in2006,anothergroup,althoughreportedanincreaseintheproliferativestatus

ofpresenileADbrains,theydemonstratedthattheseprecursorsfinallydifferentiatedintoglial

cells[88].

Consequently,althoughadultneurogenesisremainsanunknownfieldto

befurtherexploredinAlzheimerdisease,itislikelyto



beaffectedinthedisease.Takingintoaccountthatthisprocessisknowntocontributetolearningandmemory[8991],anappropriateformto

improvethesubsequentdeficitsincognitivefunctionsassociatedtoADwouldresultfrom

modulatingfactors,suchasthoseimplicatedinneuroinflammation,directlyrelatedtothecorrect

formationofthenewbornneurons.Finally,wecannotforgetthat



adultneurogenesisdeclineswithage,beinganotsocommoneventintheelderly[92],afactthatreinforcesevenmoretheideaof

preservingorstimulatingitasabrainrepairmechanism.

4. Therapeutic ApproachesBased

ontheevidencethatinvolvesneuroinflammationinthepathogenesisofAlzheimerdisease,researchers

havefocusedtheireffortsonthedevelopmentofantiinflammatorydrugs



asatreatmentoptionforpatientswithAD.DrugssuchastheNSAIDsandglucocorticoidsteroidshavebeenstudied.

4.1.NSAIDs.NSAIDs

istheabbreviationfornonsteroidalanti-inflammatorydrugs. Theyconstitutealargefamilyof




compoundswhichincludesthesalicylate,propionicacid,aceticacid,fenamate,oxicam,andtheCOX-2inhibitorclasses(enzymeswhich

regulatethehomeostaticproductionofprostanoids,implicatedintheinflammatoryresponse)[36].Epidemiological

evidencesindicatethatNSAIDsmaylowertheriskofdevelopingAD[9395],since

patientssufferingfromrheumatoidarthritisandosteoarthritishavebeenshown



toinverselycorrelatewiththeriskofdevelopAD.Althoughbeneficialeffectshavebeenobservedbothinvitroandinvivo(forareview,

see[80]),unfortunately,clinicaltrialsofNSAIDsinADpatientshavenotbeen

veryfruitful[96],especiallyinthecaseofCOX-2inhibitors.Thus,COX-2inhibitorrofecoxibandthe

COX-1andCOX2inhibitornaproxen,wereunabletoslowthe



progressionofthediseaseinpatientswithmild-moderateAD[97].Asapossiblehypothesis,itcouldbepostulatedthatNSAIDsmightbeusefultopreventthepathologybutineffectiveoncethe

diseaseoccurs.

4.2.GlucocorticoidSteroids.Thesecompoundsareconsideredaspotent

anti-inflammatoryagentsthatmodulatethetranscriptionofseveralinflammatorymoleculesreducing,forexample,

theexpressionofproinflammatorycytokinesandcomplementproteins[98].However,



theresultsobtainedinADpatientshavenotbeenverypromising.Thus,theuseofsomeglucocorticoidsteroids,suchasprednisone,hasnotrevealed

anybenefitintermsofslowingcognitivedecline[99].However,othertherapieshave

beendevelopednotdirectlydirectedtoreduceinflammationbuttothemaintargets

thatinducethechronicactivationofthesemechanisms,suchas



A..plaquesortauprotein.

4.3.A..-BasedImmunizationStrategies.theefficacyofthesetherapieshasbeendemonstratedinmousemodelsofthe

disease.In1999,SchenkandcolleaguesprovedinanAPPmutantmicethat

A..-directedvaccinationpreventedthedevelopmentofneuriticA..plaquesreducingtheminolder

animals[100].Furthermore,vaccinationwaseffectiveinreducingage-dependentlearning



deficitswhichcorrelatedwithreductionsinbothsolubleA..andtau[101].AlthoughAPPmodeldoesnotrecapitulateallcommonfeaturesofAD,they

resembleanearlypreclinicalphaseofthedisease,whichmaybetheoptimal

phasetoinitiateatherapyforpreventingthedisorder[102].Importantly,efficacyof

thevaccinewasalsofoundinanonhumanprimate,the



Caribbeanvervet[103].Regardingthepromisingresultsobtainedinanimalmodels,aclinicaltrialwaslaunchedwithAN-1792containingpreaggregatedsyntheticA..42 andtheadjuvant

QS-21[104].Although6%ofthepatientsdevelopedmeningoencephalitis,someothersdevelopedA..-antibody

titresthatcorrelatedwithaslowcognitivedecline[105],andthisresultencouraged

thedevelopmentofseveralantibodyfragmentsandhumanizedA..-specificantibodies,



whicharecurrentlyinvariousstagesofclinicaltrials[102].Timewilltellwhetherthesetherapiesareeffectiveenoughtohaltthedisease.4.4.

Tau-BasedImmunizationApproaches.Firstapproachapplyingtau-basedimmunizationwascarriedoutbyRosenmann

andcolleaguesin2006byinjectingC57BL/6wild-typeanimalswithfull-recombinanthumantau.Theexperimentsareunsuccessfulsincethe

vaccinationcausedencephalitis[106].Subsequently,othergroupstriedactiveimmunization



approachesusingtauphosphopeptides,obtainingpromisingresultsintautransgenicmodels,inwhichtheywereabletopreventtaupathologyintheabsenceof

obvioussideeffects(forareview,see[107]).However,oneofthemainproblemsderivedfromthese

studiesisthedifficultytotranslatethemintoclinicalpractice.Thisisdue

tothefactthatthevaccinationswereobservedtoprevent



tau-relatedproblemswhenadministeredpriortotheappearanceofanypathologyorcognitivedeficit,somethingthat,nowadays,wouldbeimpossibleregardingthecurrentdiagnosis

methods.Atpresent,thetau-targetedtherapiesthatareinclinicaltrialstargettau

phosphorylationbyGSK-3,microtubulestability,andaggregation[108].

Finally,itis

importanttohighlightthatconsideringthatA..pathologydependson



thepresenceoftau[109,110]andthatA..depositionisabsentinmanytauopathies(neurodegenerativediseasesassociatedwiththepathologicalaggregationoftau),it

isabsolutelynecessarytopursueatau-targetedtreatmentprobablyincombinationwithan

A..targetingapproach.

5. Concluding RemarksAlthoughmechanismsunderlayingAlzheimerdiseaseremainunclear,neuroinflammation

seemstobeacommonfeaturetoneurodegenerativediseaseswith



animportantcontributiontothepathology,affectingamongothers,physiologicalprocesseswitharepairingfunctionsuchastheadultneurogenesisprocess.Thus,modulatingneuroinflammation

bytargetingcausingagentsor/andtryingtoamelioratetheirharmfuleffectscouldbe

ofgreatimportancetopossibly,preventADpathologyandcontributetostimulateendogenous

repairingmechanismsastheformationofnewneurons.



Acknowledgments

ThisworkwassupportedbyGrantsfromtheSpanishMinistryofScienceandTechnology(SAF2010-15525),theComunidaddeMadrid(S-SAL-0253-2006),theCentrodeInvestigaci´edicaenRed

sobreEnfermedadesNeu

onBiom´rodegenerativas(CIBERNED,ISCIII),andtheSpanish

PlanNacional.

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