Alzheimer’s Disease & Treatment - Open Access...

Down Syndrome for A Better Understanding Alzheimer Disease

London J

Université Paris-Diderot, Sorbonne Paris Cité, BFA, UMR8251, CNRSF-72205, Paris, France

Email: [email protected]

Chapter 2

Alzheimer’s Disease &Treatment

1. Introduction

A) Alzheimer disease (AD)

AD is the most common of dementia and affect millions individuals worldwhilecharacterizedmainlybylossofmemoryandcognitivedeclinebutalsobysensoryandmotorimpairments.MostADcasesaresporadic(SAD98%ofcases)atagemorethan60yearsbutsomehaveageneticinheritance(2%around)atageearlierthan60yearsandsomeateven40years[1].TheautosomaldominantAD(ADAD)arerelatedtomutationsonpresenilin1(PSEN1 ; chromosome14;18-50%ADADcases)andpresenilin2(PSEN2 ;chromosome1; <5% ADADcases)andonAmyloidPrecusorProtein(APP ;chromosome21;10-15%ADADcases).

Atthebiochemicallevel,SADorADADischaracterizedbyextracellulardepositsofsynaptotoxicβ-amyloid(Aβ)peptides,mainlyAβ40andAβ42peptides infibrilsstructuresformingamyloidsenileplaques(SPs)andbyintraneuronalneurofibrillarytanglesofanormallyphosphorylatedTauproteins(NTFs)[2,3].

Theseneuronalchanges induceprogressiveneuronalandsynapticdeficits leading tomanydeficitincludingaprogressivecognitivedecline.Theyarepresentmayyearsbeforetheapparitionoftheearlyclinicalsymptomsandthiswindowofmorethan10yearsmayoffernotonlymethodsforearlydiagnosisbutalsoearlytreatmentsinthediseaseprocessbeforeitistoosevere.

TheSPsbeginaccordingtoBraakstagesmainlyintheneocortexforphase1,spreadingtotheallocortexandtheninphase3tothediencephalicenuclei,thestriatumandthecholinergic

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nucleiof theforebrain,and inphase4and5 tootherbrainnucleiandcerebellum[4]. SPsaccumulationprecedebymanyyearsthefirstclinicalsymptomsofADbutsomeindividualsnever develop dementia despite the presence of SPs.Aβ peptides are present undermanyspeciesderivedfromtheclivagebyαandβsecretasesoftheAPPproteinderivedfromtheclivagebyβandγsecretasesoftheAPPproteinbutthemainspeciesareAβ40andAβ42; thesepeptidesundergoabnormalconfigurationswhichbyspreadingleadtoaggregatespresentinSPsmainlyduethehydrophobic25-35sequenceoftheAβ[5].

NFTs are present in cell bodies and apical dendrites and in abnormal neurites.Theneurofibrillary lesionsaremainlydue toaggregatesof the tauproteinwhich isabnormallyphosphorylatedinspecificsitesmainlyonthreonine212 (7-8molofphosphateinNTFsinsteadof2-3molincontroltauprotein[6]. HyperphosphorylatedTauproteintendstodissociatefrommicrotubules and thus induces axonal impairment.NTFs develop in the brain through sixBraakstagesstartingassilentinthetransenthorinalstagethentothethelimbicstagefortheincipientADandattheneocorticalstageforfullAD[7].MoreovertauhyperphosphorylationcanbeinducedbyAbetasolubledimers[8].

BesidesSPsandNTFs,neurotrophinssuchasBDNF(Brain-derivedneurotrophicfactor)andmonoaminessuchas serotonin (5-HT:5-hydroxytryptamine)are involved inADsincetheyregulatecooperativelysomeaspectsofneurogenesis,neuralplasticityandsurvivalduringaginginordertoallowthebraintorespondtoenvironmentaldemandswhichmaybeverydetrimenta.ManymonaminesarmodifiedinindivualswithAdandinmicemodellingAD[9].InAD,BDNFisdecreasedinthehippocampusandtheAβ42peptidemightcompromiseBDNFbothproductionandsignaling,leadingtoneuronaldegeneration[10].Reduced5-HTlevelsisoneofthemarkersofacceleratingcognitivedeclineinAD [11].OthermonoaminesDA,NAarealsoreducedincertainbrainareas(frontalandtemporalcortex,hippocampus)frominvidualswithADbutalsoinvariousbrainareasfromtheAPP/PS1mousemodelthatdevelopcerebralamyloidosis[12].Manypatientswithmildcognitiveimpairment(MCI)displaysomeoftheearlyclinicalsymptomsofAD.AmongthemsomewillbeatriskfordeveloppingADandsomewillnot.

B) Down syndrome (DS)

DSissofarconsideredasthemajorgeneticcauseofintellectualdisability.Downsyndrome(DS)isageneticdisorderthatresultsfromthetriplicationofentireorpartofchromosome21(Chr21)andoccursin1every1000/1500livebirthswithoutfamilyinheritance.IndividualswithDSarenotcharacterizedbyonesymptombutpresentseveralpathologicalphenotypeswhichtheaccumulationoftheminducestheso-calledDSphenotypewhichishighlyvariableamong individuals andduring aging [13]. Life expectancy in theDSpopulation is shortercomparedtonon-DSindividuals,butimprovementsinmedicalcareanddrugtreatmentshave

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Alzheimer’sDisease&Treatment

significantlycontributedtoamelioratethelifequalityofthispopulationwhichnowapproaches65-70yearsandthusmaybeconcernedwithADasthegeneralpopulation.

Although the increased dosage of Chr21 genes might be one of the causes of thephenotypicalalterationsofDS,thepresenceoftrisomicgenesalsoaffectstheexpressionofdisomicgenes,which,inturn,maygainaberrantexpressionandcontributetosomeclinicalmanifestations. Brain development defects induces intellectual disabilities which affectlanguage,learning,memorybutalsomotor,sensoryandsleepdeficits.Moreoveritisreportedthat individuals with DS exhibit accelerating aging, behavioural abnormalities and earlyneurodegenerationwhichmaybeconsideredasmajorproblemsforthispopulation.

SeveralearlystudiessupportthelinkbetweentheDSphenotypeandanincreasedriskofADdevelopment[14;15;16].TheincidenceofdementiaamongDSpatientsis10%intheagerange35–50,55%intheagerange50–60,andbecomes75%abovetheageof60years,butADneuroanatomopathologyispresentinvirtuallyalladultswithDSolderthan40years.Despitetheseubiquitousstigmates,theprevalenceofdementiaisvariablerangingfrom30-75%atage65andmostofthecasesofdementiainindividualswithDSoccuraround50-55years.Nevertheless,thereisaratherlargesubsetofagedpersonswithDSwhodonotdevelopclinicalsignsofdementiaatanyage.Moreoveritisreportedthatinpeculiarcases,onewomanof78yearsandonemanof65years, theabsenceof theAPPgene in triplicate leaves theindividualswithoutthebiochemicalhallmarksofADandconsequentlynodementiaalthoughtheypresenttherestoftheDSphenotype[17-18].ThisrarepatientsconfirmthecrucialroleofAPPintheneuropathologicalandclinicalfindingsofADinindividualswithDS.However,althoughplaqueshavebeendetectedinyoungDSautopsysamples,andeveninsomefetalsamples,itisonlyinlatemiddleagethatpeoplewithDSdevelopADpathology[13;19]. Thesenileplaques aremainlydue to the abnormalmetabolismof theAPPprotein thegeneofwhichisonchromosome21andtheNTFareduetotheabnormalphosphorylationoftheTauproteinwhichmightbepartiallyduetosomechromosome21phosphatasesgenesandalsotosomesAPPαdimers[8].

In thefirst study to comprehensively characterizeDS sampleswith andwithoutADdiagnosisinport-mortembrainsamplesandintheCSF,evidentserotoninergicandnoradrenergicdeficitswerefoundinDSADversusearlyADinvidualsandtoalesserextentinDSversushealthycontrols[20].

AlthoughtheclinicalfeaturesandespeciallythetimecoursemightbedifferentinADinthegeneralpopulationandinindividualswithDS,thebiochemistryandpathologyofADinpeoplewithDSandinthetypicalpopulationareessentiallyidentical,thecurrent«amyloidcascadehypothesis»isbelievedtoapplytobothpopulations.Thus,thepopulationwithDSrepresentthebesthumanmodeltoapproachADfeaturesseveraldecadesbeforetheirreverible

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dementiaoccurs.

2. Common Features between Individuals with DS and AD

TheageofonsetofdementiainindividualswithDSismuchearlier(35%attheageof60years)thantheinSAD(70-80)butissimilar(under60)totheautosomaldominantAD(ADAD)[1].

ThusADinDSindividualsconstituethelargerhumangroupwitharatherhomogeneousgeneticbackgroundtostudythemolecularpathwaysleadinginsomecasestodementia(DSAD)andthusallowingawindowtotestearlymarkersandbetterunderstandingthecourseofthisADdevastingdisease.

Although, thedefinitivediagnosisforADinthegeneralpopulationisoftengivenpostmortembybrainexamination,manyscalesofevaluationofthecognitivedeteriorationarenowused.UnlikefamilialAD,dementiainindividualswithDSisstillnotwelldescribedalthoughitaccountsforthemajorityofgeneticADcases.ThescalesusedforADevaluationsarenotgoodenoughforeapopulationlikeDSthathasasatbaselinesomecognitive impairmentsespeciallyincomprehension,memoryandlanguage.Nevertheless,theCAMDEX–DShasbeenvalidatedasareliabletoolforassessingclinicaldementiainpeoplewithDS[21],theRapidAssessmentofcognitivefunctioninDownsyndrome(RADD)[22] andthenovelBehavioralandPsychologicalSymptomsofDementia inDownSyndrome(BPSD-DS)are reported in[23], which in combination with an amyloid PET scan should increase the confidence ofdementiaofAlzheimer’stypeinDS.AgoodpresentationofthesimilaritiesanddifferencesbetweenclinicalpresentationsinDS,AD(orSAD)andADADalsonamedFADisgivenintheupdatedreviewparZisandStrydominwhichtheyreportalsothecomparisonofDSandADforbiomarkers[24].

2.1. Aβ peptides

Briefley, in the plasmaAβ40 andAβ42 levels are higher in individualswithDS; inDSAD,Aβ42tendstoincreasewhileAβ40decreasethustheratioAβ42/Aβ40hasnotthesametimecoursetoevaluatedementiaasinAD.InCSF,AβlevelshavebeenshowntoincreaseinchildhoodandthendecreasewhenSPsstarttodepositsimilarlytowhatisobservedinAD[19].

PositronEmissionTomographyimaging(PETscan)withligandssuchas[11C]-Pittsburghcompound–B(PIB)enables«in vivo »quantificationandlocalizationoffibrillarAβdepositsandalsotangles [25].

HigherPIBbindinglevelsincorticalandsubcorticalregionsoftheDSbrainwereobservedinparticipantswithhigherage,lowercognitiveperformanceonneuropsychologicalassessment,

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andinthosewithadiagnosisofdementia[26,27,28].IntheirworkbyPETandvolumetricRMN[29]:they concludethatresultsfrompopulationswithamyloidoverproduction(DSandADAD) compared to the general populationmaybe generalizable because all populationsaccumulatethesameamyloidaggregatesandexperiencethesameoveralltemporalprogressionofADinwhichamyloidaccumulationprecedesneurodegenerationanddementia.

Increasedglobalamyloid-βwas related todecline inverbalepisodicmemory,visualepisodicmemory,executivefunctioning,andfinemotorprocessingspeed.ParticipantswhowereconsistentlyPiB+demonstratedworseningofepisodicmemory[30]. Othermodalitiesarenowdeveloppedsuchasdiffusiontensororretinalimagingtoimproveearlydiagnostic[31].

2.2. Tau

Microtubule-associated-protein tau is hyperphosphorylated and abnormallyphophorylatedinADandaggregatesinpairedhelicalfilaments(PHFs)inNTFs.Thepretanglestate, the intraneuonal tangles and the extyraneurocellular NTFs can be differentiated byspecifictoparticularTauepitopes[32].Ingeneral,NFTsfollowasimilardistributioninDSasinAD,startinginentorhinalcortexandspreadingtohippocampusandlaterneocortex,butatahigherdensityinDScomparedtoADbrain.IntheplasmathetaulevelsarehigherinADgroupsthaninthegeneralpopulation.InindividualswithDStheselevelsarealsohighereveninnondementedones[19].

2.3. APOE alleles and AD risk factor

APOE is a hepatocerebral lipoprotein that regulates the transport and deposition ofcholesterol.Evidencesuggeststhatharboringoneorbothapolipoproteinε4alleles(APOε4)mayincreasetheriskforADduetotheapoEasanessentialcatalystoftheamyloidcascadeandasubsequentlossoffunction[33,34].

InheritanceofonecopyofthealleleincreasesADriskfour-foldwhileinheritanceoftwocopiesincreasesriskten-foldinthegeneralpopulationTheAPOε4 allelealsoincreasesdementiariskinDS,albeittoalowerextentthaninAD.Atthebiochemicallevelthisincreasedriskisporbablyduetothepresenceofanamino-terminalapoEfragmentinboththefrontalcortexandhippocampusoftheDS-ADbrain[35].

2.4. Vascular pathology

VascularpathologyiscommoninthesusceptibiltytoADinthegeneralpopulation.Thecontributionofvascularpathologytodementiamayplayasimilarroleinageofonsetand/ortherateofprogressionofADinDS(DSAD)[36].Microbleeds(Bs)weremorefrequentinDScasesrelativetocontrolsbutpresenttoasimilarextentassporadicAD.Thisaligned

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with cerebral amyloidangiopathy (CAA) scores,withmoreextensiveCAA inDS relativeto controls inbothbrain regions.CAAwas alsomore frequent inDSADcases relative tosporadicAD[37].Moreover,asreportedintherecentstudythatvascularormetabolicimagingmight provide earlier information regardingADpathogenesis [38]. In the hippocampus ofolderDSADindividuals,Myoinositol (MI) ishigher,Nacetylaspartate(NAA)is lowerandglutamate-glutaminecomplex (Glx) isunchangedwhencompared tonon-dementedpeoplewithDS.

2.5. Oxidative stress

Oxidativestress(OS)resultsfromaccumulationofoxidizedanddamagedmoleculeswhicharenotremovedbytheantioxidantdefensesystem(superoxidedismutases(SOD1,2and3),glutathioneperoxidase(GPx),catalaseetc)andthuscandamagevariouscellularandextracellularcomponents.ThechronicSOD1overexpressioninallcellsthatcharacterizesthetrisomy21 subjects and the consequent over-generationof endogenoushydrogenperoxideapparentlyisnotadequatelycompensatedbytherelativelymodestupregulationofcatalaseandGPx.Therefore,thischronicimbalancebetweenthelevelsofbothimportantantioxidantenzymes(SOD/CAT+GPX)andtheircorrespondingsubstratesinducingthegenerationofthemostdeleterioushydroxylradical(HO.),mightbethebasisforDSdisturbances.BiomarkersofoxidativestressaresignificantlyelevatedinDS[39].Theanti-oxidantsystemisaffectedinDSandthisdefectisworstenedduringaging[40].TheSOD1hasbeenshowntobeelevatedin the neocortex and the hippocampus of individualswithDS orAD [41]. Indeed loss ofantioxidantenzymesandanincreasedinproteinmodificationhavebeenreportedinAD[42,43].

2.6. Mitochondria

Alteredmetabolism ofAPPmight be related tomitochondrial dysfunction [44] andmutationsinmitochondrialDNAhavebeenrelatedtoADchangesinthegeneralpopulationaswellasintheDSone[45].

Several studies have shown that alterations of mitochondrial structure and functionassociatedwithan impairmentof reactiveoxygenspecies(ROS)homeostasisarecriticallylinkedtoDSpathogenesis.Deficitsinenergymetabolismduetomitochondrialdysfunctionsnegativelyaffectneuronalfunction,survivalandcentralnervoussystem(CNS)developmentwhichrequiresATPandoccurasanearlyeventinintellectualdisability-linkeddiseasesandseveralformsofdementialikeAD[46].OverexpressionofAPPmaypromotemitochondrialdysfunctioninDSindependentofaberrantAβdeposition.

ArecentreviewgivesasurveyoftheroleofmichondriaanditsimpairedfunctionsinrelationtooxidativestressbothinDSandAD[47].

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2.7. mTOR Pathway

mTOR influencesAβdepositionand tauaggregationand thus is associatedwith thepathogenesis and progression ofAD and similarly in DS [28]. Briefly mTOR activationaffectstheregulationofAβgeneration/clearanceandtau-phosphorylationbyinhibitionoftheautophagyandbyinteractionwithseveralkeysignalingpathways,includingPI3K/Akt,GSK-3β,AMPKandinsulin/IGF.InhibitingmTORactivationforthetreatmentandpreventionofADandAD-likedementia inDShasbeenpointedbutmuchworkneed tobedonebeforegoingtoatrial[28].

2.8. Endosomes

IntracellularAβislocalizedtoendosomeswhichareresponsiblefortheturn-overandthedegradationoftheproteinswithincells.Earlyendosomesareamajorsiteofamyloidprecursorprotein(APP)processingandaconvergencepointformoleculesofpathologicrelevancetoAD. Neuronal endosome enlargement, reflecting altered endocytic function, is a disease-specificresponsethatdevelopsyearsbeforetheearlieststageofADandDS[48].Endosomalpathologycontributessignificantly toAβoverproductionandaccumulation insporadicADand inADassociatedwithDSandmaysignifyearlierdisease-relevantdisturbancesof thesignalingfunctionsofendosomes.OneofthemainpointregardingendosomesisthatlargeendosomesmightbeanhallmarkforearlydetectionforADinDSandalsoforADinthegeneralpopulation.More recently enlarged endosomes were detected in bloodmononuclear cellsandlymphoblastoidcell lines(LCLs)fromindividualswithADusingimmunofluorescenceandconfocalmicroscopyshowingthatitmaybeabiomarker[49].Thevolumesofenlargedendosomes correlate to [C11] PiB cortical index but not to the amyloid-beta, tau andphosphorylated tau levelsmeasured in thecerebrospinalfluid.Moreover theenlargmentofendosomesinDSisatleastpartiallyduetosynaptojaninpresentinthreecopies[50].

2.9. Mis-segregation in AD

In their analysis [51] of thousands of cells from 27AD and 13 control individualsshowedthatfibroblastsfromADpatientsweremorethantwiceaslikelytoexhibittrisomy21comparedtofibroblastsfromcontrolindividuals.Theincreasedfrequencyoftrisomy21cells infibroblasts fromADpatientswas significant and independentof age.Furthermore,thechromosomemis-segregationwasassociatedwithalltypesofAD,includingsporadicandfamilialADcarryingamutationineitherPS1orPS2.

3. Differences Between DS and AD Regarding Pathological Aging

3.1. Clinical aspects

IntheDSpopulation,theprevalenceofdementiaincreasesrapidlyaftertheageof30

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yearsalthoughdataareverydifferentfromtheveryfewcohortsstudied.TheoverallprevalenceofdementiainadultswithDSisestimatedat6.8%withanincreasewithagefrom8.9%inindividualsupto49yearsto32.1%inindividualsfrom55to59yearsoldbutithasalsobeenreported higheras33%amongindividualswithDSaged30to39years,55%amongthoseaged40to59years,and77%forindividualsabovetheageof60years.Itshouldbepointoutthatindividualswhonowadaysreacholdagesarethosewhodidnothavecardiacabnormalitieswhichmostoftenwereletalwithoutcardiacsurgeryavailablesince30yearsindeveloppedcountries[19;29].ArecentstudyshowssomepredictionsaboutsurvivalofpeoplewithDSaccordingtotheoccurrenceofAD[52].

Bycomparison,theprevalenceofdementiainthegeneralpopulationisestimatedas4%below65years,15%between65and74years,43%between75and84years,and38%overtheageof85years[29].

3.2. Amyloid and tau aspects

Theearlystudyon42casesofDSunder40yearsdemonstratetheAβdepositionwithinthehippocampusandparahippocampalgyruspriortoNFTinneuronsordystrophicneuriteswithinSPs[53].MoreoverinthisstudyandothersitisreportedthatAβdepositioninchildhoodandteensmightbemorefrequentthanpreviouslyestimatedinDSandalsothaninthegeneralpopulation.Bothinfants,childrenandteenswithDSaccumulateintracellularAβpriortotheaccumulationofextracellularAβdeposits[54].

Aβ production from APP nonspecific proteolytic cleavage leads to heterogeneousAβ (includingAβ40/42/43) in a possible endosomal/lysosomal location [55]. There is anaccumulation of intracellularAβ within neurons in DS at a much earlier age than in thegeneralpopulation.MoreoverAβmeasuredbiochemicallyincreaseduringagingsuggestinganaccelerationphasetodiseasedevelopment[56].

Schupfandcolleaguesreported that increasing levelsofplasmaAβ40anddecreasedAβ42wereinDSgoodpredictorsofconversiontodementia [57].Indeed,adultswithDSwithdecreasingplasma42overtimewere5timesmorelikelytobecomedementedwithin4years.Similarly,inaseparateprospectivestudyon405personswithDS,thoseadultsinthehighestlevelsofplasmaAβ42andAβ40alsohad thehighest riskofdevelopingdementiaoveranaverage4.7yearperiodoftime[58].

PIBbindinginDS,firstappearinginstriatum,beganaroundage40andwasstronglyassociatedwithdementiaandcognitivedecline.Theabsenceofasubstantialtimelagbetweenamyloidaccumulationandcognitivedeclinecontrastsinsporadic/familialAD[27].ThestudybyPET imaging [59] has shown that inDSbrain,Aβbinds to (18F)florbetaben and thatthisbindingincreaseswithage. Increasedglobalamyloid-βwasrelatedtodeclineinverbal

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episodicmemory,visualepisodicmemory,executivefunctioning,andfinemotorprocessingspeed.ParticipantswhowereconsistentlyPiB+demonstratedworseningofepisodicmemory [60].

Regardingβamyloidpeptides,itisinterestingtonotethatBACE-2,achromosome21proteinwhichactivatesBACE1,wasobservedonlyinneuronsofadultswithDSbutnotinyoungpeopleandinindividualswithAD.

FewstudieshavefocusedontauproteinsinthecourseofADinDSbutarecentoneshedanewlightonthisoldcontroverseaboutthefirsthallmarksinAD[61].

3.3. Other biochemical aspects

As in theADbrain, themajorityofproteinshavebeendemonstrated tobeoxidized(OS),thusthenotionthataberrantproteinoxidationinDSmaycontributetoADdevelopmentisrelevant.InDSbrain,despiteincreasedOSlevels,nochangesinHO-1proteinlevelshasbeen observed in young subjects, whereas increased levels characterize adultDS subjectsundergoingAD-likeneurodegeneration.Interestingly,increasedofHO-1inDS/ADsubjectsisnotcomparablewiththatobservedinADsubjects.Thisphenomenonseemslikelylinkedtothetrisomyofchromosome21BACH1gene,whichencodesforthenuclearrepressorofHO-1gene[62].IndeedHNEmodifiedproteinshavebeenshowninexcessinDSbrain [63].

AccumulatingevidencealsosuggeststhatimpairedironhomeostasisisanearlyeventinADprogressionbutalsoinDSAD[64].Irondyshomeostasisleadstoalossoffunctioninseveralenzymesrequiringironasacofactor,theformationoftoxicoxidativespecies,andtheelevatedproductionofbeta-amyloidproteins.DSmightrepresentaspecificcaseofgeneticallyencodedOS.Indeed,thereareanumberoftrisomicgenes,thatdirectlyorindirectlyaffectsROSlevels,eitherbycausingincreasedROSproductionordecreasingtheantioxidantresponse[65].ThemolecularmechanismslinkingirondysregulationtoneurodegenerationinDSarestillpoorlyunderstood.

4. Chromosome 21 Genes Involved Directly or Indirectly in AD

TheentiresequenceofhumanChromosome21isnowknownandthereare233codinggenes,299longnon-codinggenes(Ensemblrelease78)and29microRNAs(miRBaserelease21).AfterinvestigationwithSwiss-ProtandanalysiswithGeneOntologyAnnotation,the207proteinsfoundencodedonChr21: i) takepart in87differentbiologicalprocesses,and11proteinsareinvolvedinsignaltransduction;ii)have81differentmolecularfunctionsamongwhichDNAbindingandtranscriptionfactoractivityarethemostprevalentwith15proteins;iii)arelocalizedin26differentcellularcomponents,nucleusandtheplasmamembranewith19and15proteins,respectively,arethemostpredominantcellularlocalizations[66].

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Somechromosome21genesmightbeimportanttobetterunderstanddirectlyAD.Moreoversomeofchromosome21genescanregulateothergenesandsignallingproteininvolvedinAD.Themostimportantchromosome21genesknownnowtobeinvolvedinADare:APP,BACE2,BACH1,DYR1A,ETS2,RCAN1,S100β, SOD1,SYNAPTOJANIN.These genes encodeproteinswhichhavebeenshowntobeimportantforsomeoftheDSphenotypeincludingtheAD[67].

APP •

ThegenecodingfortheAPPproteinisonchromosome21anditspromoterisregulatedbyEts-2ananothergeneofchromosome21whichisoverexpressedinDSexplainingatleastpartiallythefactthatAPPismorethan1.5expressedinDScellsandtissues.APPhasalreadybementionnedpreviouslyasthesourceoftheamyloidpeptideswhichduetotheirabnormalfoldingwillleadtoagregatesandlaterontofibrills[68].ButitshouldbealsopointoutthattheproteolyticcleavagebyαsecretasegivesthesAPPαextracellularfragmentwhichhasbeenshowntobebeneficialforsomecognitivefunctionsespeciallymemory,forneuriteoutgrowth,preventsAβgenerationandtauphosphorylation,counteracttheAβeffectsandfinallydisruptAPPdimers[69].ThesAPPαextracellularfragmentispresentatlowerlevelsinindividualswithADthanincontrols.Itspotentialbeneficialrolefromanombilicalcordsourcehasbeenrecentlyassayed inanimalmodels forADandshown tobemediatedbycomplementC1q [70].

BACE-2•

BACE-2 cleavesAPP,isincreasedinDSand thuscontributestoincreasedAβproduction[71.MoreoverBACE-2activatesBACE1,oneoftheproteolyticenzymeoftheamyloidcascade[72].

BACH1•

BACH1 is a basic leucine-zipper protein and the nuclear repressor of HO-1 gene.IncreasedBach1expressionlevelsareinvolved,overall,inrepressingtheinductionofHO-1in DS cases, thus reducing HO-1 overexpression in stress conditions as observed inAD.OverexpressionofBACH1isalsorelatedtooxidizedspecies[62].

CBS•

CBSlevelsinDSbrainsareapproximatelythreetimesgreaterthanthoseinthenormalindividuals andCBS is localized to astrocytes and those surrounding senileplaques in thebrainsofDSpatientswithAD[73].CBSisthemainenzymeproducingH2S.CBSactivityisreducedinADbrainsandthedecreaseinH2Smaybeinvolvedinsomeaspectsofthecognitivedecline inAD [74].Moreover, several experiments have shown in different rat ormurine

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modelsofADthatH2Scouldbebeneficial[75].

TheCBSoverexpressioninducesmonoaminepathwaysalterationsinvariousbrainareasofCBStransgenicmiceaccordingtosexandage[76].ThusthesealterationsbyCBSover-expressionmightbeinvolvedinthedevelopmentalabnormalitiesincognitioninDSchildrenandthatmayleadtoADinDSadults.

DYRK1A•

TheDYRK1AgeneencodestheproteinDYRK1Awhichisaserine/threoninekinase.Dyrk1AisoverexpressedinSPsfromADindividualsandisakeymoleculebridgingβ-amyloidproductionandtauphosphorylationinAD[77].ItphosphorylatestauproteinmakingitabettersubstrateforGSK3βphosphorylation,andDYRK1Aphosphorylatesalternatesplicingfactorsleadingtoanincreaseratioof3R:4Rtau,whichisassociatedwithneurodegeneration;consistentwiththisfinding,thereisanincreaseinthenumberofDYRK1A-positiveand3R-positiveNFTsinmiddle-agedandolderDSbraincomparedtosporadicAD[78].OverexpressionofDYRK1AitatleastpartiallyresponsiblefortheexcessivesynapticinhibitioninpeoplewithDSwhichcanbereversesbothinindividualswithDS andinanimalmodelsbyinhibitingDYRK1Awithcatecholcompounds[79;80;81].MoreoverDYRK1Aoverexpressionmodulatesmonoaminesneurotransmitters in transgenicmicealteringboth the serotoninergicand thedopaminergicpathways[82].

ETS2•

Overexpression of ETS2 in DS may play a role in the pathogenesis of the brainabnormalities in DS and possiblyAD [83]. Degeneration of DS neurons was reduced bydominant-negativeETS2,suggestingthatincreasedETS2expressionpromotesDSneuronalapoptosis.Inthehumanbrain,ETS2expressionwasfoundinneuronsandastrocytes.StrongETS2 immunoreactivitywas observed in DS/AD and sporadicAD brains associatedwithdegenerativemarkerssuchasBax,intracellularAbeta,andhyperphosphorylatedtau[84].

RCAN1 •

RCAN1levelsareincreasedinthebrainofDSandADpatientsbutalsointhehumanbrainwithnormalaging[85]. RCAN1hasbeenimplicatedinseveralneuronalfunctionsincludinghippocampalplasticity.ItsoverexpressionisinvolvedinAD[86].Itisalsoinvolvedtocontrolthetightlycoordinatedprocessoffission/fusioninmitochondria(parra)andthusit inducesmitochondrialdefectsseeninagingandAD[87].MoreoverRCAN1increasessusceptibilitytooxidativestress.

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S100β•

S100βexpressionlevelsareincreasedinbothDSandADastrocytesinassociationwithneuriticplaques[88].Inaddition,chronicoverexpressionofS100βcontributestoincreasedneuronalandneuriticAPPexpressionwithconsequentacceleratedamyloiddeposition,aswellasabnormalgrowthofneuritesinβ-amyloidplaques,similartoobservationsinmiddle-agedDSpatients[89].

SOD1•

TheSOD1 is localized in theneocortexandhippocampus from individualswithDSorAD[41].TheSOD1activity is increasedandnotcompensatedbycatalaseorGPXthusleadingtotheoverproductionofROS.

SOD1 overexpression induces aberrant neuronal and mitochondrial proteins inhippocampusof transgenicmice [90]andalters the20Sproteasomeduringaging[91,92].Theanti-oxidantsystemisaffectedinDSandthisdefectisworstenedduringaging[40].ItisalsoalteredinAD[42].

Synaptojanin•

Thephosphoinositidephosphatasesynaptojanin1(SYNJ1)iskeyregulatorofsynapticfunctionSynaptojanin(Synj)andadualphosphatasewhichregulatestheHedgehogpathway(Hh).IthasbeenshownthatreductionofSynaptojanin1(SYNJ1),themainphosphoinositol(4,5)-biphosphate phosphatase (PI(4,5) P2-degrading enzyme) in the brain and synapses,acceleratesAβclearanceinADmicemodel[93].ItisoverexpressedinDSbrainandinAPOE4carrierswithearlyADandhighlyoverexpressedinindividualswithDS/AD[94].

SynaptojaninisinvolvedinthehomosostasisofinositolscompoundsandisoverexpressedinDSbrain[95].ItsmetabolismisalteredinthebrainofTs65Dnmice,themostcommonlyusedmodelofDS.ThisdefectisrescuedbyrestoringSYNJ1todisomyinTs65DnmiceandisrecapitulatedintransgenicmiceoverexpressingSYNJ1fromBACconstructs[96].IthasbeenshowntobeinvolvedintheaginghippocampusmemorydeficitsinthremodelsofAD[97].

5. Animal Models to Study AD in DS Models

ThefirstmodelsforDownsyndromeweretransgenicmiceforsomekeygenessuchasSOD1,APP,S100βandCBSandsomeknout-miceforsomeofthemwerealsousefultounderstandtheroleofsomeofthesegeneseithersolelyor inacomplexgenotype.Humanchromosome21hasorthologousgenesonMMU16,17and10andmostofthepartialtrisomicmurinemodelshavebeenreviewedin[81;98].

Thefirstpartialtrisomicviablemodel,Ts65Dn,hasbeendevelopedbyMurielDavisson

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intheearly90’s[99]andistrisomicforabout120orthologsofHsa21proteinencodinggenesthroughasegmentaltrisomyforMmu16butitcontainsalsoasegmentofabout10MboftheMmu17,whichcontains60proteinencodinggenes,noneofwhicharehomologoustoHsa21genes

Anothermousemodel forDS,Ts1Cje,hasshorterMmu16 trisomy than theTs65Dnmouse,contains62orthologsofHsa21genes,andexcludesthegenesegmentcontainingAPPandSOD1.

TheMs1Ts65micearetrisomicfortheregionofdifferencebetweenTs1CjeandTs65Dn,contains56orthologsofHsa21geneswithingeneticsegmentfromMrp139toSod1.AnotherrelativelynovelmodelforDSistheTs2CjemousemodelTs(Rb(12.1716))2Cje(Ts2).

AmoreaccuratemousemodelforDSmodelhavebeendevelopedbytheteamofYuthatcarriescompleteaneuploidy(spanningtheentireHsa21syntenicregion)thetripleaneuploidmicecontainstheMmu10(Ts1Yey),theMmu17(Ts2Yey)andtheMmu16(Ts3Yey).

AnotableDSmodelwascreatedfromthetrans-speciesinsertionofHsa21.TheTc1mousemodelforDScarriesmostofhumanchromosome21inadditiontothenormalcomplementofmousechromosomes,andistrisomicforapproximately212Hsa21protein-encodinggenesbutnottheAPPgene[100].

Therelationshipsbetwwenthesemodelsandtheirproperties inrelationtoalzheimerdiseasearepresentedin[101,102].

DSmousemodelshavealsobeeninvestigatedforbetterunderstandingtheroleofdifferentgenesegmentsofHsa21onADpathologyandmemoryimpairmentassociatedwithDSAD.In thesemodels someof theDScharacteristicshavebeen investigated regardingcognitivedeficitsbiologicalmechanismsinvolvedinDSADincludingextracellularamyloidβprotein(Aβ)accumulation,intraneuronalneurofibrillarytangles(NFTs)deposition,BFCNcellloss,neuronlossinlocuscoeruleus(LC),hippocampalabnormalities,imbalanceofneurotrophicfactors,alterationsinlong-termpotentiation(LTP),abnormalendosomalsignaling,presenceofneuroinflammationandoxidativestressandmorerecentlyneurotransmitters.

The results obtained in these different models have been reported in recent studies [101;103]andmostofthemhavebeenusedtopre-clinicalapproaches.Morerecentlyanewmodel for studyingADandespeciallypreclinical stageshavebeendeveloppedusinga ratinjectedbyadeno-associatedviruses(AAV)codingforhumanmutantAPP751containingtheSwedishandLondonmutationsandPS1(theM146Lmutation)cDNAsintothehippocampiadultrats[104].

Beforedescribingthepre-clinicalapproaches,wewilldeveloppedasmallparagraph

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onneurotransmittersaswethinkthattheabnormalitiesinneurotransmitterscontentshavenotbeenenoughconsideredinpreclinicalapproaches.

5.1. Neurotransmitters

Themonaminesystemhasbeenstudiedinafewstudieseitherfrompost-mortembraintissuesfromindividualswithADorDSorbothDSADandinsomeanimalmodels.Brieflyin human tissues, a reduction of noradrenergic and serotonergic pathwaysweremeasuredpathways inDSADversusearlyonsetofAD(EOAD)and toa lesserextent inDSversuscontrols[20].DSandDSADpresentsimilarmonaminergicprofileswhichmightberelatedtoearlyamyloiddepositioninDS.

ArecentstudywasperformedonAPP/PS1mice[12]andshowednoageeffectincontrolmiceaccordingtoage6,12,16,24monthsbutaregionsepcificchangesforallmonoaminesin18monthsAPP/PS1micecomparedtocontrols.

ThemonoaminespathwaysevaluatedinyoungTs65Dnmiceversuscontrolsshowedthat a) the noradrenergic systemwasmainly affected by aging and not aneuploidy, b) thedopaminergicsystemwasbarelyaffectedinTs65Dn,c)theserotonergicwasreduced(5-HTand5-HIAAlevels)inthehippocampusofyoungTs65Dnversuscontrolsbutnotinagedones[105].Theseresultsarequitedifferentfromthoseobtainedtransgenicmiceoverexpressingthe singleDYRK1A showingmajor deficits in serotonin contents for the four brain areasandmajordeficitsindopamineandadrenalinecontentsespeciallyinthehypothalamus[82].Thesedifferencesbetweenthetwostudiesmightbeduetocompensationbetweendifferentchromosome21genesandnonchromosome21genespresentintheTs65Dnmice.

ThesametypeofstudiesshouldbeperformedontransgenicmiceforimportantT21genesrelatedtoDSandneurotransmissionasitwasdoneforCBStrangenicmice[76]andalsoinothermodelsofT21especiallyinratmodelswhichseemtobemoreaccuratetostudyADinDS[106].

Neurotransmitters-basesstrategiesareplausiblefortargetingcognitivedeclineinADandDS[107,108].

6. Pre-Clinical Approaches for AD in DS Models

A) Search for biomarkers

Inthesametimeasresearchersaretryingtofindtherapeuticalapproaches,muchworkisdonetofindbiomarkersfortheconversionofADinindividualswithDS.ThesebiomarkersfoundeitherinDSorinADnonDSwillbenefitforbothofthepopulations.

InDS, the higher levels ofAβ40 orAβ42/Aβ40 correlateswith the onset ofAD in

15


DS.TheformationoftanglesiscorrelatedwithcognitivedeclineandPETstudiesofglucosemetabolismmightprovideevidenceofbrainatrophyandADchanges inDS.Moreoverasreported in the review by [109], many other markers show either decreases or increases;proNGF,MMP’1,TNFα,IL6,IL-10,SAH,SAM/SAH(fromthechromosome21CBSgene)exhibithigherlevelswhileserumMHPG,CSForexinAshowlowerlevels.

The combined use of DYRK1, BDNF (brain-derived neurotrophic factor) andhomocysteinemeasuredinthebloodoftwounrelatedADpatientcohortsandage-matchedcontrolshasshowedtogiveasensitivityof0.952,aspecificityof0.889andanaccuracyof0.933intestingforAD[110].ThesameapproachiscurrentlyusedforDSintheprogressionofDSAD.

TheratmodelusingAAV(AAV-AD)identifiedintheplasmaofthevariousagedanimals41proteinsat8monthsand21proteinsat30monthswhicharespecificallydysregulatedinthecourseofADpathologyandthusidentifyingseveralstepsbeforeacuteclinicalhallmarks[104].

B) Inhibition of some DSAD hallmarks

Oxidative stress is a link betwwenAD and DS [111]. Although since many years,treatmentshavebeenfocusedonantioxidantswithoutrealtherapeuticalprogress,astudyshednewlightattheantioxidantstatusinthebloodofDSchildren,beforeandafter6monthsofdailyantioxidantsupplementationwithvitaminsEand C[112]. Beforetheantioxidanttherapy,DSpatientspresenteddecreasedGSTactivityandGSHdepletion;elevatedSOD,CAT,GR,GGTandMPOactivities;increaseduricacidlevels;whileGPxandG6PDactivitiesaswellasvitaminEandTBARSlevelswereunaltered.Aftertheantioxidantsupplementation,SOD,CAT,GPx,GR,GGTandMPOactivitiesweredownregulated,whileTBARScontentswerestronglydecreasedinDS.ThesametypeofstudyshouldbedoneastheresultobtainedinasurveyoftrialswithvitaminEonlyinmildcognitiveimpairmentandAlzheimer’sindividualsfailtoimprovecognitivefunction,globalseverityoractivitiesofdailyliving[113]. Otheranti-oxidantcompoundsshouldbemoreinvestigated:CoenzymeQ10,curcumintoinduceBDNF,melatonin.

Inflammatory processes in BFCN degeneration can be modulated by minocycline-treatment which inhibits microglial activation, prevents progressive BFCN decline andmarkedlyimprovesperformanceoftheTs65Dnmiceonaworkingandreferencememorytask[114].

mTOR signalling and its aberrant modulation in DS andAD age-related cognitive-declineaffectscrucialneuronalpathways.ItwasrecentlyreportedthatintranasalrapamycinereversemanyADhallmarks. Indeed in theTs65Dnmice this treatment could reduceAPP

16


levels,APPprocessingandAPPmetabolitesproduction,aswellas,tauhyperphosphorylationandareductionofoxidativestressmarkers[115].

Modulationofneurotransmission.ThegroupofSahelihasfocusedsincemanyyearson-thepossiblitythatneurotransmitter-basedstrategiesandmoresepcificallythenoradrenergicsystemcouldbeatargettherapyforDSandAD[107;108].TheGABAergicsystemisalsoagoodapproachandtheuseof antagonistsofGABAreceptorsincludingpentylenetetrazol(PTZ)toreduceperturbationsoftheexcitatory/inhibitorybalancetowardsanexcessofGABAmightbefructfuldespitenegativeresultsuptodate [81;116]. Neurodegenerationcanalsobeat leastpreventedbyestrogen treatmentwhichpartially rescuedworkingmemory (T-mazetest)andpreventedneurodegenerationinagedTs65Dnanimals(11to17-monthsold)[117,118].

Regarding the endosomeabnormalities,partially reductionofβ-secretase1 (BACE1)-bydeletingoneBACE1 alleleblockeddevelopmentofage-relatedendosomeenlargementinthemedial septalnucleus, cerebralcortexandhippocampus,andprevented lossofcholineacetyltransferase (ChAT)-positive medial septal nucleus neurons. It was also reported thepossibility thatstudies focusedondysregulationofsignalingendosomemay identifysometherapeutictargetsforpreventingDSAD[10].

Exosomehasbeenshownasatherapeuticapproachforneurodegenerativedisease- [120]. ExosomesecretionisenhancedinthebrainsofDSpatients,inamousemodelofthediseaseandinDSfibroblasts.Furthermore,increasedlevelsofthetetraspaninCD63,aregulatorofexosomebiogenesis,wereobservedinDSbrains.AsCD63knockdowndiminishedexosomereleaseandworsenedendosomalpathology inDSfibroblasts, itwasshown in theTs65Dnmicethat the increasedCD63expressionenhancedexosomerelease tomitigateendosomalabnormalitiesinDS[121].ExosomemightbeabiomarkerforADinDS[122].

APPmetabolismmodulation-

Itwasshownthatlong-termexposuretoenvironmentalenrichmentreducesAβoligomersandrescuesspatial-memoryabilitiesin12-month-oldtrisomicmice[123].

TheTs65Dnmice,asamodel forDSandalsoforDSADhasbeenusedfor immunisationagainstAbetaoligomers[124].IntheStatesAC ImmuneandUCSD represents the firstmajorclinicaltrialbyapharmaceuticalcompanyforAlzheimer’sintheDownsyndromepopulation.Thestudyisfocusedondevelopingavaccinethattargetstheaminoacidsof the Aβ peptides specifically involved in their misfolding, thus preventing theiraggregation,theformationandplaqueaccumulation,andpromotingplaqueremoval.

InhibitionofDYRK1A-

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EGCG(Epigallocatechin-3-gallate)inhibitsDYRK1AactivityinvitroinseveralmurinemodelsofDSandmicetreatmentwithEGCGrestoressomeoftheDS-associateddeficitspresentinthesemodels[79].EGCGisnotonlyaninhibitorofthebiologicalactivityofDYRK1AbutitalsobindstheTauproteininitsphosphorylatedregion,hinderingtheaccessofthisregiontosomekinaseandmodyfyingthetridimentionalstructureoftheprotein.ThesethreecombinedfunctionsofEGCGregardingTauproteinpreventitsaggregationwhichisakeyprotagonistofneuronalcelldeath[125].EGCGshowsprotectiveeffectsagainstAβ-inducedneurotoxicityandregulatessecretoryprocessingofsAPPαviathePKCpathway.AdministrationofEGCG(2mg/kg)tomicefor7or14dayssignificantlydecreasedmembrane-boundholoproteinAPPlevels,withaconcomitantincreaseinsAPPαlevelsinthehippocampus.TheroleofEGCGinrelationtoADisreveiwedby[126].CombinedtreatmentwithenvironmentenrichmentandEGCGameliorateslearningdeficitsandhippocampalalterationsinTs65Dnmice[127].NewDYRK1Ainhibitorsarecurrentlystudiesinamnylaboratories[128,129].

C) Induced pluripotent stem cell (IPs) and deciphering AD in DS

Theuseorpluripotentstemcelltechnologyhasgivendramaticincreaseinourpossibilityforabetterknowledgeofthemecanismandthedevelopmentofdrugsinneurodegenerativedisease [130].A new inhibitor ofDYRK1A, nammedALGERNON (altered generation ofneurons)wasfoundinascreenforofneuralstemcells(NSCs)[131].ThiscompoundwasfoundtorescueproliferativedeficitsinTs65Dn-derivedneurospheresandhumanNSCsderivedfromindividualswithDS.Moreover,administrationofALGERNONtopregnantTs1CJedamsrescuedaberrantcorticalformationinDSmouseembryosandpreventedthedevelopmentofabnormalbehaviorsinDSoffspring.ThesedatasuggestthattheneurogenicphenotypeofDScanbepreventedbyALGERNONprenataltherapy.AspartoftheneurogenicphenotypeisalsoconnectedtoAD,thistypeofexperimentscanleadtofurtherevaluateifthesecorrectedmicewillpresentalsosomerescueoftheDSADphenotypealthoughtheTs1CjemicedonothavetheAPPgeneintriplicate.

AnotherrecentstudyshowpromissingresultsregardingAD,bytheuseofpluripotentIPScfromDSindividuals[132].ItcouldbeshownthatinvitrogeneratedDSneuralcellshaveabnormalAβmetabolismandincreasedexpressionofAD-associatedchromosome21genes(BACE2,RCAN1,ETS2).TheseresultsshowthatitispossibletostudyAD-typepathologythroughthestudyofIPSCfromDSindividuals.

7. Conclusions

The close relationshipsbetween chromosome21genes involved in theonset ofADinthegeneralpopulationandtheirpresenceinthirdcopiesinindividualswithDSyieldnewopportunitiestobetterunderstandthecourseofAD,findbiomarkersandinnovativetherapiesforAD in thegeneral population (SAD) through theprecise studyof the courseofAD in

18


this special geneticpopulation (DSAD). It is crucial to identifybiomarkers forAD in thispopulationsoastobeabletodeterminetheefficacyofanynewtreatmentearlyinthecourseoftheunderlyingdiseaseprocessandwellbeforetheAD-relatedpathologyandcerebralatrophyhavebecomeestablished.ThusthenumerousmicemodelspresentforDSandtheircombinationwithotherssuchasthosesilencingspecificchromosome21geneareandwillbeveryusefultoassaynewdrugtherapies.ButmicearenotmenandthemainimportantpersonsarethosewithDSorADorboth.Inthatperspective,theEuniceKennedyShriverNationalInstituteofChildHealthandHumanDevelopment(NICHD)andtheNationalInstituteonAging(NIA),bothpartsoftheNationalInstitutesofHealth,arepartneringonaninitiativetoidentifybiomarkersandtracktheprogressionofAlzheimer’sDiseaseinadultswithDS.MoreoverACImmuneandUCSDaretryingtodevelopforindividualswithDSavaccinespecificfortheabnormalfoldingoftheabetapeptides.

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