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 worldwhile characterized mainly by loss of memory and cognitive decline but also by sensory and motor impairments. Most AD cases are sporadic (SAD 98% of cases) at age more than 60 years but some have a genetic inheritance (2% around) at age earlier than 60 years and some at even 40 years [1]. The autosomal dominant AD (ADAD) are related to mutations on presenilin 1 (PSEN1 ; chromosome 14 ; 18-50% ADAD cases) and presenilin 2 (PSEN2 ; chromosome 1; <5% ADAD cases) and on Amyloid Precusor Protein (APP ; chromosome 21; 10-15% ADAD cases). At the biochemical level, SAD or ADAD is characterized by extracellular deposits of synaptotoxic β-amyloid (Aβ) peptides, mainly Aβ40 and Aβ42 peptides in fibrils structures forming amyloid senile plaques (SPs) and by intraneuronal neurofibrillary tangles of anormally phosphorylated Tau proteins (NTFs) [2,3]. These neuronal changes induce progressive neuronal and synaptic deficits leading to many deficit including a progressive cognitive decline. They are present may years before the apparition of the early clinical symptoms and this window of more than 10 years may offer not only methods for early diagnosis but also early treatments in the disease process before it is too severe. The SPs begin according to Braak stages mainly in the neocortex for phase 1, spreading to the allocortex and then in phase 3 to the diencephalice nuclei, the striatum and the cholinergic
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Down Syndrome for A Better Understanding Alzheimer Disease
London J
Université Paris-Diderot, Sorbonne Paris Cité, BFA, UMR8251, CNRSF-72205, Paris, France
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).
Theseneuronalchanges induceprogressiveneuronalandsynapticdeficits leading tomanydeficitincludingaprogressivecognitivedecline.Theyarepresentmayyearsbeforetheapparitionoftheearlyclinicalsymptomsandthiswindowofmorethan10yearsmayoffernotonlymethodsforearlydiagnosisbutalsoearlytreatmentsinthediseaseprocessbeforeitistoosevere.
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].
DSissofarconsideredasthemajorgeneticcauseofintellectualdisability.Downsyndrome(DS)isageneticdisorderthatresultsfromthetriplicationofentireorpartofchromosome21(Chr21)andoccursin1every1000/1500livebirthswithoutfamilyinheritance.IndividualswithDSarenotcharacterizedbyonesymptombutpresentseveralpathologicalphenotypeswhichtheaccumulationoftheminducestheso-calledDSphenotypewhichishighlyvariableamong individuals andduring aging [13]. Life expectancy in theDSpopulation is shortercomparedtonon-DSindividuals,butimprovementsinmedicalcareanddrugtreatmentshave
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].
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].
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].
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.
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
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
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].
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
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].
TheSOD1 is localized in theneocortexandhippocampus from individualswithDSorAD[41].TheSOD1activity is increasedandnotcompensatedbycatalaseorGPXthusleadingtotheoverproductionofROS.
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].
Anothermousemodel forDS,Ts1Cje,hasshorterMmu16 trisomy than theTs65Dnmouse,contains62orthologsofHsa21genes,andexcludesthegenesegmentcontainingAPPandSOD1.
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].
Themonaminesystemhasbeenstudiedinafewstudieseitherfrompost-mortembraintissuesfromindividualswithADorDSorbothDSADandinsomeanimalmodels.Brieflyin human tissues, a reduction of noradrenergic and serotonergic pathwaysweremeasuredpathways inDSADversusearlyonsetofAD(EOAD)and toa lesserextent inDSversuscontrols[20].DSandDSADpresentsimilarmonaminergicprofileswhichmightberelatedtoearlyamyloiddepositioninDS.
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.
InDS, the higher levels ofAβ40 orAβ42/Aβ40 correlateswith the onset ofAD in
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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.
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
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].
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.
The close relationshipsbetween chromosome21genes involved in theonset ofADinthegeneralpopulationandtheirpresenceinthirdcopiesinindividualswithDSyieldnewopportunitiestobetterunderstandthecourseofAD,findbiomarkersandinnovativetherapiesforAD in thegeneral population (SAD) through theprecise studyof the courseofAD in
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this special geneticpopulation (DSAD). It is crucial to identifybiomarkers forAD in thispopulationsoastobeabletodeterminetheefficacyofanynewtreatmentearlyinthecourseoftheunderlyingdiseaseprocessandwellbeforetheAD-relatedpathologyandcerebralatrophyhavebecomeestablished.ThusthenumerousmicemodelspresentforDSandtheircombinationwithotherssuchasthosesilencingspecificchromosome21geneareandwillbeveryusefultoassaynewdrugtherapies.ButmicearenotmenandthemainimportantpersonsarethosewithDSorADorboth.Inthatperspective,theEuniceKennedyShriverNationalInstituteofChildHealthandHumanDevelopment(NICHD)andtheNationalInstituteonAging(NIA),bothpartsoftheNationalInstitutesofHealth,arepartneringonaninitiativetoidentifybiomarkersandtracktheprogressionofAlzheimer’sDiseaseinadultswithDS.MoreoverACImmuneandUCSDaretryingtodevelopforindividualswithDSavaccinespecificfortheabnormalfoldingoftheabetapeptides.
20.DekkerAD,VermeirenY,Carmona-IraguiM,BenejamB,VidelaL,GelpiE,AertsT,DVanDamD,FernándezS, LMartin JJ Monoaminergic impairment in Down syndrome withAlzheimer’s disease compared to early-onsetAlzheimer’sdisease.AlzheimersDement(Amst)2017;10:99-111.
63. Barone E, Head E, Butterfield DA, Perluigi M HNE-modified proteins in Down Syndrome: involvement indevelopmentofAlzheimerdiseaseneuropathology.FreeRadicBiolMed.2017;111:262-269.
76.LondonJNdiayeFK,BuiLC,SouchetB,DaubigneyF,MagnanC,LuquetS,DairouJ,JanelN,RouchCAlterationsin the Serotonin and Dopamine Pathways by Cystathionine Beta Synthase Overexpression in Murine Brain MolNeurobiol2018;sep20.
77.KimuraR,KaminoK,YamamotoM,NuripaA,KidaT,KazuiH,HashimotoR,TanakaT,KudoT,YamagataH,TabaraY,MikiT,AkatsuH,KosakaK,FunakoshiE,NishitomiK,SakaguchiG,KatoA,HattoriH,UemaT,TakedaMTheDYRK1Agene, encoded in chromosome21Down syndromecritical region, bridgesbetweenbeta-amyloidproductionandtauphosphorylationinAlzheimerdisease.HumMolGenet.2007;16(1):15-23.
90. Shin JH, London J, Le PecheurM,WeitzdoerferR,HoegerH, LubecGAberrant neuronal andmitochondrialproteinsinhippocampusoftransgenicmiceoverexpressinghumanCu/Znsuperoxidedismutase1FreeRadicBiolMed2004;37(5):643-53.
96.VoronovSV,FrereSG,GiovediS,PollinaEA,BorelC,ZhangH,SchmidtC,AkesonEC,WenkMR,CimasoniL,ArancioO,DavissonMT,AntonarakisSE,GardinerK,DeCamilliP,DiPaoloGSynaptojanin1-linkedphosphoinositidedyshomeostasis and cognitive deficits in mouse models of Down’s syndrome. Proc Natl Acad Sci USA 2008;105(27):9415-20.
106.XuH,WangZ,ZhuL,SuiZ,BiW,LiuR,BiK,LiQTargetedNeurotransmittersProfilingIdentifiesMetabolicSignatures in Rat Brain by LC-MS/MS:Application in Insomnia, Depression andAlzheimer’s DiseaseMolecules2018;23(9):2375.
119.JiangY,RigogliosoA,PeterhoffCM,PawlikM,SatoY,BleiwasC,StavridesP,SmileyJF,GinsbergSD,MathewsPM, Levy E, Nixon RA. Partial BACE1 reduction in a Down syndrome mouse model blocksAlzheimer-relatedendosomalanomaliesandcholinergicneurodegeneration:roleofAPP-CTFNeurobiolAging2016;39:90-8.
125. Gueroux M Fleau C, Slozeck M, Laguerre M, Pianet I Epigallocatechin 3-Gallate as an Inhibitor of TauPhosphorylationandAggregation:AMolecularandStructuralInsight.JPrevAlzheimersDis2017;4(4):218-225.
127.Catuara-SolarzS,Espinosa-Carrasco J,Erb I,LangohrK,Gonzalez JR,NotredameC,DierssenMCombinedTreatment With Environmental Enrichment and (-)-Epigallocatechin-3-Gallate Ameliorates Learning Deficits andHippocampalAlterationsinaMouseModelofDownSyndromeeNeuro2016;3(5):0103-16.2016.
128.NeumannF,GourdainS,AlbacC,DekkerAD,BuiLC,DairouJ,Schmitz-AfonsoI,HueN,Rodrigues-LimaF,DelabarJM,PotierMC,LeCaërJP,TouboulD,DelatourB,CariouK,DoddRH.DYRK1Ainhibitionandcognitiverescue in aDown syndromemousemodel are inducedbynewfluoro-DANDYderivativesSciRep2018; 8: 2859.Publishedonline2018Feb12.