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TRANSCRIPT
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ProteinsinDisease1041
IncreasedriskofAlzheimer sdiseaseinTypeIIdiabetes:insulinresistanceofthebrainorinsulin-inducedamyloidpathology?
G.J.Biessels1andL.J.Kappelle2DepartmentofNeurology,RudolfMagnusInstituteofNeuroscience,
UniversityMedicalCenter,Utrecht,TheNetherlands
Abstract
TypeIIdiabetesmellitus
(DM2)isassociatedwithanincreasedriskofcognitivedysfunction
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anddementia.TheincreasedriskofdementiaconcernsbothAlzheimer sdiseaseandvasculardementia.Althoughsomeuncertaintyremainsintotheexactpathogenesis,severalmechanisms
throughwhichDM2mayaffectthebrainhavenowbeenidentified.First,factors
relatedtothe
metabolicsyndrome, aclusterofmetabolicandvascularriskfactors
(e.g.dyslipidaemiaandhypertension)thatiscloselylinkedtoDM2,
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maybeinvolved. Anumberoftheseriskfactorsarepredictorsofcerebrovasculardisease,acceleratedcognitivedeclineanddementia.Secondly,hyperglycaemiamaybeinvolved,through
adverseeffectsofpotentially
toxic glucosemetabolitesonthebrainanditsvasculature.
Thirdly,insulinitselfmaybeinvolved.Insulincandirectlymodulatesynapticplasticityand
learningandmemory,anddisturbancesininsulinsignallingpathwaysin
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theperipheryandinthebrainhaverecentlybeenimplicatedinAlzheimer sdiseaseandbrainaging.Insulinalsoregulatesthemetabolismof-amyloidand
tau,thebuildingblocksofamyloidplaquesandneurofibrillarytangles,theneuropathologicalhallmarks
ofAlzheimer sdisease.Inthispaper,theevidencefortheassociationbetweenDM2
anddementiaandforeachoftheseunderlyingmechanismswill
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bereviewed,withemphasisontheroleofinsulinitself.
DM(diabetesmellitus)isassociatedwithslowlyprogressiveend-organdamageinthebrain
[1].Mildtomoderateimpairmentsofcognitivefunctioninghasbeenreportedboth
inpatientswithDM1(TypeIDM)[2],andinpatientswithDM2(TypeIIDM)[3,4].Clinicallyrelevantdeficits,however,mainlyoccur
inelderlypatientswithDM2[5],whomayexperienceproblemswithday-to-dayfunctioningduetotheir
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cognitiveimpairments[6].ThepotentialimpactofDMoncognitionintheelderlyisfurtheremphasizedbyseverallargeepidemiologicalsurveysthatreport
anincreasedincidenceofdementiaamongDMpatients,apparentlyconcerningbothAlzheimer sdisease
andvasculardementia[3,7 9].TheobservationthattheeffectsofDMon
thebrainaremostpronouncedintheelderlyhasbeen
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attributedtoaninteractionbetweenDMandthenormalagingprocessofthebrain[10,11].DifferencesbetweenthepathophysiologyofDM1andDM2
arealsolikelytoplay arole[11],asthelatterisby
farthemostcommonformamongtheelderly.InDM1,theprincipaldefect
isanautoimmune-mediateddestructionofpancreatic-cells,leadingtoinsulin
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deficiency,whereasinDM2theprincipaldefectisinsulinresistance,leadingto
Keywords:Alzheimer sdisease,brainaging,cognitivedysfunction,insulin-inducedamyloid,metabolic
syndrome,TypeIIdiabetesmellitus.Abbreviationsused:A,-amyloid;APOE,apolipoproteinE;DM,
diabetesmellitus;DM1,Type IDM;DM2,TypeIIDM;IDE,insulin-degradingenzyme;LDL,
low-densitylipoprotein;MRI,magneticresonanceimaging.1Towhomcorrespondenceshould
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beaddressed,atDepartmentofNeurology,G03.228,UniversityMedicalCenterUtrecht,POBox85500,3508GAUtrecht,TheNetherlands
2OnbehalfoftheUtrechtDiabeticEncephalopathyStudyGroup(seeAcknowledgements)
arelativeinsulindeficiency.Moreover,DM2occursinthecontextof aclusterof
metabolicandvascularriskfactors,whichisreferredtoas
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theso-called
metabolicsyndrome [12].Themetabolicsyndromeitself,withorwithouthyper-glycaemia,isassociatedwithatheroscleroticcardiovasculardisease,ischaemicstrokeand
withcognitivedeclineanddementia[13]. Akeyquestionisthereforewhetherdisturbances
ininsulinandglucosemetabolismorotherfactorsfromthemetabolicsyndromelead
toimpairedcognitioninDM2.Thepresentworkaimsto
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provideanoverviewonthewaysinwhichdisturbancesinglucoseandinsulinmetabolismandotherfactorsrelatedtothemetabolicsyndromemaybeimplicatedintheacceleratedcognitivedeclineandthe
increasedriskofdementiainpatientswithDM2(Figure1).
Cognitive
dysfunctionanddementiainDM2:underlyingmechanisms
Aroleforhyperglycaemia?
Severallinesofevidencesuggestthat
toxic effectsofhyperglycaemia
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areinvolvedinthedevelopmentofdiabeticend-organdamagetothebrain[14].Hyperglycaemicrodents,forexample,expresscognitiveimpairmentsandfunctionalandstructuralalterationsinthebrain[14].Toxic
effectsofhighglucoselevelsaremediatedthroughanenhancedfluxofglucosethroughtheso-calledpolyolandhexosaminepathways,disturbances
ofintracellularsecondmessengerpathways,animbalanceinthegenerationandscavenging
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BiochemicalSocietyTransactions(2005)Volume33,part 5
Figure 1
SuggestedpathogenesisofcognitivedeclineinDM2Insulinresistanceandriskfactorsrelated
tothemetabolicsyndromeleadtoDM2.Theadverseeffectsofthemetabolic
syndromeandDM2onthebrainaremediatedthroughischaemiccerebrovasculardisease,in
concertwithotherfactorsfromthemetabolicsyndrome.Hyperglycaemiaplaysanadditionalrolethrough
toxic effectsonbrain
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tissueandthedevelopmentofcerebralmicroangiopathy.Alterationsininsulinmetabolismcanalsodirectlyaffectthebrain,throughinvolvementinsynapticplasticityandamyloid
andtaumetabolism.Ischaemiccerebrovasculardiseaseplaysamodulatingroleintheselatterprocesses.
ofreactiveoxygenspecies,andby
advancedglycationofimportantfunctionalandstructuralproteins[15].Theseprocessesdirectlyaffectbraintissueandleadtomicrovascularchanges
inthebrain[11,14].
Still,hyperglycaemiaisunlikely
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tobetheonlyfactorinthedevelopmentofcognitiveimpairmentsinDM2:previousstudiesinDM2patientsdonotinvariablyshowanassociationbetweenchronichyperglycaemia,asassessedbyHbA1levels,andtheseverityofcognitiveimpairments[3,10].
Moreover,changesincognitionmayalreadydevelopin
pre-diabeticstages,suchas
impairedglucosetolerance,orinnewlydiagnosedDM2patientsthathavenotyet
beenexposedtolong-termhyperglycaemia[16,17].
Arole
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forthemetabolicsyndrome?
DM2andinsulinresistancearecloselyassociatedwithfactorssuchasobesity,atherogenicdyslipidaemia[elevatedtriacylglycerollevel,smallLDL(low-densitylipoprotein)particles,lowHDL(high-densitylipoprotein)cholesterol]
,raisedbloodpressure,andpro-thromboticandpro-inflammatorystates.Togetherthesefactorsconstitute
themetabolicsyndrome,orinsulinresistancesyndrome[12,18]. Anumberoffactorsfrom
thissyndromehavebeenidentifiedasindependentpredictorsofcerebrovascular
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disease,ischaemicstrokeandacceleratedcognitivedeclineanddementia(e.g.[13,16,19 21]).Thecombinedoccurrenceoftheseriskfactorsinthemetabolicsyndromemight
reinforcetheseeffects[19,22 24].Giventheclusteringofinsulinresistance,hypertensionand
dyslipidaemiainDM2itmaybedifficulttodeterminewhichfactoristhe
primedeterminantinthedevelopmentofcognitivedysfunction.Themain
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question,however,istodetermineifthemetabolicsyndromeisindeed
astrongpredictorofcognitivedysfunctioninDM2,andifthiseffectis(partially)independentofdisturbancesinglucoseand
insulinmetabolism.
Involvementofischaemiccerebrovasculardisease?
DM2andthemetabolic
syndromeareriskfactorsforatherosclerosisofthecarotidandintracranialarteries[22,25]
,thusincreasingtheriskofstroke,andofcognitive
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declineanddementia[26].Inthelongterm,exposuretohyperglycaemiainDMmayleadtoabnormalitiesincerebralcapillaries,suchasbasement
membranethickening[27].Thesemicrovascularchangesmayalsoleadtochronicand
insidiousischaemiaofthebrain,thuscontributing,forexample,tothedevelopmentof
subcorticalwhite-matterlesions.On apopulationleveltheselesionsareassociated
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withcognitiveimpairments,particularlyrelatedtofrontallobefunctions[28].Althoughwhite-matterlesionsarealsocommonamonghealthyelderlysubjects,theirprevalenceand
severityisincreasedinpatientswithvascularriskfactorsorischaemicvasculardisease,
andindementedpatients[28].MRI(magneticresonanceimaging)studiesinDM2patientsindeedshowanincreasedseverityofwhite-matter
lesions{[29],andS.M.Manschotetal.,Utrecht
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DiabeticEncephalopathyStudyGroup(seeAcknowledgements),unpublishedwork},andanincreasedincidenceof(silent)braininfarcts[30].
Aninteractionwith
aging?AstheeffectsofDMonthebrainaremostpronounced
intheelderly,onemaysuggestthattheagingbrainismoresusceptible
totheeffectsofDMorthattheeffectsof
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DMandaginginteract.Infact,severalofthemechanismsthatareassumedtomediatethetoxiceffectsofhyperglycaemiaonthebrain,such
asoxidativestress,theaccumulationofadvancedglycationend-productsandmicroangiopathy,arealso
involvedinbrainaging[11].Moreover,experimentalstudiesindicatethatthebehavioural
andneurophysiologicalconsequencesofDMareaccentuatedbyaging[31]
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.WearecurrentlyaddressingthisissuebycomparingcognitivefunctioningandbrainMRIinagedDM1andDM2patientswithcontrols[32].
OurresultssuggestthatthecognitiveimpairmentsandMRchangesarelessmarked
intheagedDM1patients(averagedurationofDM35years),than
inDM2(averageknowndurationofDM 9years)patientsof
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similarage(A.M.A.Brandsetal.,UtrechtDiabeticEncephalopathyStudyGroup,unpublishedwork).Thissuggeststhat,inadditiontoage,differencesin
thepathophysiologyofDM1andDM2arelikelytobeimportantdeterminantsof
theeffectsofDM2onthebrain.
Directeffectsofinsulinon
thebrain?
Anincreasingamountofevidencelinksinsulin
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itselftocognitivedeclineanddementiainDM2[33 35].First,alterationsincerebralinsulinreceptorsignallingmaybeinvolved,as acerebralequivalentof
peripheralinsulinresistance.Secondly,insulinmayaffectthemetabolismofA(amyloid)and
tau,twoproteinsthatrepresentthebuilding
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ProteinsinDisease1043
blocksofamyloidplaquesandneurofibrillarytangles,theneuropathologicalhallmarksofAlzheimer sdisease.
Insulinisnot amajor
regulatorofglucoseuseinthebrain,incontrastwithitsprominentaction
inperipheraltissuessuchasliver,muscleandfat[36].Still,insulin
anditsreceptorarewidelydistributedthroughoutthebrain,with
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particularabundanceindefinedareas,suchasthehypothalamusandthehippocampus[37],andplay aroleintheregulationoffoodintakeand
bodyweight[36].Inaddition,insulinappearstoactas a
neuromodulator.
Itinfluencesthereleaseandre-uptakeofneurotransmitters,andalsoappearsto
improvelearningandmemory[37].Theinitialcomponentsof
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inthelevelofinsulinandthenumberofitsreceptorsinthebrain[39].InAlzheimer sdiseasethisage-relatedreductionincerebral
insulinlevelsappearstobeaccompaniedbydisturbancesoftheinsulinreceptorsignalling[39],leadingtothequalificationofAlzheimer sdiseaseas aninsulin-resistantbrainstate [40].
TherelationbetweeninsulinandthemetabolismofAandtauisalso
receivingincreasingattention[33,35].Aisderivedfromthe
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so-calledamyloidprecursorprotein.AftersecretionintotheextracellularspaceAcanaggregatewithotherproteins,toformsenileplaques.Alternatively,excessiveAcanbeclearedthroughLDL-receptor-relatedproteinmediatedendocytosis,
orthroughdirectextracellularproteolyticdegradation[41].ThislatterprocessinvolvesIDE(insulin-degradingenzyme)[42].Insulinappearstostimulate
Asecretion,andinhibitstheextracellulardegradationofAbycompetitionfromIDE[33]. Arecenthistopathologicalstudyofthe
hippocampusinpatientswithAlzheimer sdiseasereportedmarkedreductionsin
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IDEexpression,andIDEmRNAlevels,relativetocontrols[43].Interestingly,thisreducedexpressiononlyoccurredinpatientswiththeAPOE(apolipoproteinE)
e4allele.AninteractionwiththeAPOEe4genotypehasalsobeendemonstrated
fortheriskofAlzheimer sdiseaseinDMpatients[8],anobservation
thatwassupportedbyneuropathologicalresults[8].
Although
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theconceptsof
cerebralinsulinresistance,and
insulin-inducedamyloidpathology areanattractiveexplanationforsomeoftheeffectsofDM2onthe
brain,therearestillmanylooseends.Incontrastwiththeincreasingbody
ofknowledgeonthemechanismsofinsulinresistanceinperipheraltissues[44],
weknowrelativelylittleonhowDM2anditstreatment
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affectcerebralinsulinanditsreceptor.Moreover,theknowledgeontheroleofinsulininbrainphysiologyisfarfromcomplete.Forexample,in
apparentcontrastwithpreviousobservationsthathippocampalinsulinreceptorexpressionandsignallingin
ratsareup-regulatedfollowing aspatiallearningtaskin awatermaze[45],mice
with atargetedknockoutofinsulinreceptorsinthebrainreadily
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learnthissametask[46].Hopefully,ongoingresearch
inthisrapidlyevolvingfieldofresearchwillclarifytheseissues.
Conclusion
Severalmechanismsmaybeinvolvedinacceleratedcognitivedeclineandtheincreaseof
dementiainpatientswithDM2(Figure1).Becausethesedifferentmechanismsinteract
atseverallevels,itisunlikelythatfuturestudieswill
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detect asinglefactorthatlinkDMtoimpairedcognition.Itmaybepossible,however,toidentifyprocesses,orclustersofriskfactors,thatexplain
atleastpartoftheassociation,andcanbetargetedbypreventivemeasures.
Thesepreventivemeasuresmaynotonlyincludeimprovementofglycaemiccontrol[47],
butcouldalsobedirectedatvascularriskfactorsandinsulinmetabolism.Infact,thereisalreadysomeevidence
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fromstudiesinnon-DMpatientsthattheselatterapproachesmaybesuccessful.Forexample,treatmentofvascularriskfactors,suchashypertension,maydecrease
theincidenceofdementiainthecontextofischaemiccerebrovasculardisease[48].
Moreover, arecentexploratoryrandomizedplacebocontrolledtrialwiththeinsulin-sensitizingcompoundrosiglitazoneshowedanameliorationofbothcognitivedeclineand
abnormalitiesincerebrospinalfluidAinnon-DMpatientswithearlyAlzheimer sdisease[49].Thechallengeforfuturestudies
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willbetodeterminewhatpreventivestrategyshouldbeappliedinwhichDM2patient,atwhatstageofthedisease.
TheUtrechtDiabetic
EncephalopathyStudyGroupconsistsof(inalphabeticalorder):DepartmentofClinicalNeurophysiology:
A.C.vanHuffelen;DepartmentofInternalMedicine:H.W.deValk;JuliusCenterfor
HealthSciencesandPrimaryCare:A.Algra,G.E.H.M.Rutten;Department
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ofMedicalPharmacology:W.H.Gispen;DepartmentofNeurology:A.Algra,G.J.Biessels,L.J.Kappelle,S.M.Manschot,J.vanGijn;DepartmentofNeuropsychologyandHelmholtz
ResearchInstitute:A.M.A.Brands,E.H.F.deHaan,R.P.C.Kessels,E.vandenBerg;
DepartmentofRadiology:J.vanderGrond,allpartoftheUniversityMedical
Center,Utrecht,TheNetherlands.TheresearchoftheStudyGroup
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issupportedbytheDutchDiabetesResearchFoundation(grants2001.00.023and2003.01.004).
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