| Date post: | 14-Apr-2018 |
| Category: |
Documents |
| Upload: | paramitha-dps |
| View: | 229 times |
| Download: | 0 times |
of 58
7/30/2019 0331041
1/58
ProteinsinDisease1041
IncreasedriskofAlzheimer sdiseaseinTypeIIdiabetes:insulinresistanceofthebrainorinsulin-inducedamyloidpathology?
G.J.Biessels1andL.J.Kappelle2DepartmentofNeurology,RudolfMagnusInstituteofNeuroscience,
UniversityMedicalCenter,Utrecht,TheNetherlands
Abstract
TypeIIdiabetesmellitus
(DM2)isassociatedwithanincreasedriskofcognitivedysfunction
7/30/2019 0331041
2/58
anddementia.TheincreasedriskofdementiaconcernsbothAlzheimer sdiseaseandvasculardementia.Althoughsomeuncertaintyremainsintotheexactpathogenesis,severalmechanisms
throughwhichDM2mayaffectthebrainhavenowbeenidentified.First,factors
relatedtothe
metabolicsyndrome, aclusterofmetabolicandvascularriskfactors
(e.g.dyslipidaemiaandhypertension)thatiscloselylinkedtoDM2,
7/30/2019 0331041
3/58
maybeinvolved. Anumberoftheseriskfactorsarepredictorsofcerebrovasculardisease,acceleratedcognitivedeclineanddementia.Secondly,hyperglycaemiamaybeinvolved,through
adverseeffectsofpotentially
toxic glucosemetabolitesonthebrainanditsvasculature.
Thirdly,insulinitselfmaybeinvolved.Insulincandirectlymodulatesynapticplasticityand
learningandmemory,anddisturbancesininsulinsignallingpathwaysin
7/30/2019 0331041
4/58
theperipheryandinthebrainhaverecentlybeenimplicatedinAlzheimer sdiseaseandbrainaging.Insulinalsoregulatesthemetabolismof-amyloidand
tau,thebuildingblocksofamyloidplaquesandneurofibrillarytangles,theneuropathologicalhallmarks
ofAlzheimer sdisease.Inthispaper,theevidencefortheassociationbetweenDM2
anddementiaandforeachoftheseunderlyingmechanismswill
7/30/2019 0331041
5/58
bereviewed,withemphasisontheroleofinsulinitself.
DM(diabetesmellitus)isassociatedwithslowlyprogressiveend-organdamageinthebrain
[1].Mildtomoderateimpairmentsofcognitivefunctioninghasbeenreportedboth
inpatientswithDM1(TypeIDM)[2],andinpatientswithDM2(TypeIIDM)[3,4].Clinicallyrelevantdeficits,however,mainlyoccur
inelderlypatientswithDM2[5],whomayexperienceproblemswithday-to-dayfunctioningduetotheir
7/30/2019 0331041
6/58
cognitiveimpairments[6].ThepotentialimpactofDMoncognitionintheelderlyisfurtheremphasizedbyseverallargeepidemiologicalsurveysthatreport
anincreasedincidenceofdementiaamongDMpatients,apparentlyconcerningbothAlzheimer sdisease
andvasculardementia[3,7 9].TheobservationthattheeffectsofDMon
thebrainaremostpronouncedintheelderlyhasbeen
7/30/2019 0331041
7/58
attributedtoaninteractionbetweenDMandthenormalagingprocessofthebrain[10,11].DifferencesbetweenthepathophysiologyofDM1andDM2
arealsolikelytoplay arole[11],asthelatterisby
farthemostcommonformamongtheelderly.InDM1,theprincipaldefect
isanautoimmune-mediateddestructionofpancreatic-cells,leadingtoinsulin
7/30/2019 0331041
8/58
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
7/30/2019 0331041
9/58
beaddressed,atDepartmentofNeurology,G03.228,UniversityMedicalCenterUtrecht,POBox85500,3508GAUtrecht,TheNetherlands
2OnbehalfoftheUtrechtDiabeticEncephalopathyStudyGroup(seeAcknowledgements)
arelativeinsulindeficiency.Moreover,DM2occursinthecontextof aclusterof
metabolicandvascularriskfactors,whichisreferredtoas
7/30/2019 0331041
10/58
theso-called
metabolicsyndrome [12].Themetabolicsyndromeitself,withorwithouthyper-glycaemia,isassociatedwithatheroscleroticcardiovasculardisease,ischaemicstrokeand
withcognitivedeclineanddementia[13]. Akeyquestionisthereforewhetherdisturbances
ininsulinandglucosemetabolismorotherfactorsfromthemetabolicsyndromelead
toimpairedcognitioninDM2.Thepresentworkaimsto
7/30/2019 0331041
11/58
provideanoverviewonthewaysinwhichdisturbancesinglucoseandinsulinmetabolismandotherfactorsrelatedtothemetabolicsyndromemaybeimplicatedintheacceleratedcognitivedeclineandthe
increasedriskofdementiainpatientswithDM2(Figure1).
Cognitive
dysfunctionanddementiainDM2:underlyingmechanisms
Aroleforhyperglycaemia?
Severallinesofevidencesuggestthat
toxic effectsofhyperglycaemia
7/30/2019 0331041
12/58
areinvolvedinthedevelopmentofdiabeticend-organdamagetothebrain[14].Hyperglycaemicrodents,forexample,expresscognitiveimpairmentsandfunctionalandstructuralalterationsinthebrain[14].Toxic
effectsofhighglucoselevelsaremediatedthroughanenhancedfluxofglucosethroughtheso-calledpolyolandhexosaminepathways,disturbances
ofintracellularsecondmessengerpathways,animbalanceinthegenerationandscavenging
C
2005BiochemicalSociety
7/30/2019 0331041
13/58
BiochemicalSocietyTransactions(2005)Volume33,part 5
Figure 1
SuggestedpathogenesisofcognitivedeclineinDM2Insulinresistanceandriskfactorsrelated
tothemetabolicsyndromeleadtoDM2.Theadverseeffectsofthemetabolic
syndromeandDM2onthebrainaremediatedthroughischaemiccerebrovasculardisease,in
concertwithotherfactorsfromthemetabolicsyndrome.Hyperglycaemiaplaysanadditionalrolethrough
toxic effectsonbrain
7/30/2019 0331041
14/58
tissueandthedevelopmentofcerebralmicroangiopathy.Alterationsininsulinmetabolismcanalsodirectlyaffectthebrain,throughinvolvementinsynapticplasticityandamyloid
andtaumetabolism.Ischaemiccerebrovasculardiseaseplaysamodulatingroleintheselatterprocesses.
ofreactiveoxygenspecies,andby
advancedglycationofimportantfunctionalandstructuralproteins[15].Theseprocessesdirectlyaffectbraintissueandleadtomicrovascularchanges
inthebrain[11,14].
Still,hyperglycaemiaisunlikely
7/30/2019 0331041
15/58
tobetheonlyfactorinthedevelopmentofcognitiveimpairmentsinDM2:previousstudiesinDM2patientsdonotinvariablyshowanassociationbetweenchronichyperglycaemia,asassessedbyHbA1levels,andtheseverityofcognitiveimpairments[3,10].
Moreover,changesincognitionmayalreadydevelopin
pre-diabeticstages,suchas
impairedglucosetolerance,orinnewlydiagnosedDM2patientsthathavenotyet
beenexposedtolong-termhyperglycaemia[16,17].
Arole
7/30/2019 0331041
16/58
forthemetabolicsyndrome?
DM2andinsulinresistancearecloselyassociatedwithfactorssuchasobesity,atherogenicdyslipidaemia[elevatedtriacylglycerollevel,smallLDL(low-densitylipoprotein)particles,lowHDL(high-densitylipoprotein)cholesterol]
,raisedbloodpressure,andpro-thromboticandpro-inflammatorystates.Togetherthesefactorsconstitute
themetabolicsyndrome,orinsulinresistancesyndrome[12,18]. Anumberoffactorsfrom
thissyndromehavebeenidentifiedasindependentpredictorsofcerebrovascular
7/30/2019 0331041
17/58
disease,ischaemicstrokeandacceleratedcognitivedeclineanddementia(e.g.[13,16,19 21]).Thecombinedoccurrenceoftheseriskfactorsinthemetabolicsyndromemight
reinforcetheseeffects[19,22 24].Giventheclusteringofinsulinresistance,hypertensionand
dyslipidaemiainDM2itmaybedifficulttodeterminewhichfactoristhe
primedeterminantinthedevelopmentofcognitivedysfunction.Themain
7/30/2019 0331041
18/58
question,however,istodetermineifthemetabolicsyndromeisindeed
astrongpredictorofcognitivedysfunctioninDM2,andifthiseffectis(partially)independentofdisturbancesinglucoseand
insulinmetabolism.
Involvementofischaemiccerebrovasculardisease?
DM2andthemetabolic
syndromeareriskfactorsforatherosclerosisofthecarotidandintracranialarteries[22,25]
,thusincreasingtheriskofstroke,andofcognitive
7/30/2019 0331041
19/58
declineanddementia[26].Inthelongterm,exposuretohyperglycaemiainDMmayleadtoabnormalitiesincerebralcapillaries,suchasbasement
membranethickening[27].Thesemicrovascularchangesmayalsoleadtochronicand
insidiousischaemiaofthebrain,thuscontributing,forexample,tothedevelopmentof
subcorticalwhite-matterlesions.On apopulationleveltheselesionsareassociated
7/30/2019 0331041
20/58
withcognitiveimpairments,particularlyrelatedtofrontallobefunctions[28].Althoughwhite-matterlesionsarealsocommonamonghealthyelderlysubjects,theirprevalenceand
severityisincreasedinpatientswithvascularriskfactorsorischaemicvasculardisease,
andindementedpatients[28].MRI(magneticresonanceimaging)studiesinDM2patientsindeedshowanincreasedseverityofwhite-matter
lesions{[29],andS.M.Manschotetal.,Utrecht
7/30/2019 0331041
21/58
DiabeticEncephalopathyStudyGroup(seeAcknowledgements),unpublishedwork},andanincreasedincidenceof(silent)braininfarcts[30].
Aninteractionwith
aging?AstheeffectsofDMonthebrainaremostpronounced
intheelderly,onemaysuggestthattheagingbrainismoresusceptible
totheeffectsofDMorthattheeffectsof
7/30/2019 0331041
22/58
DMandaginginteract.Infact,severalofthemechanismsthatareassumedtomediatethetoxiceffectsofhyperglycaemiaonthebrain,such
asoxidativestress,theaccumulationofadvancedglycationend-productsandmicroangiopathy,arealso
involvedinbrainaging[11].Moreover,experimentalstudiesindicatethatthebehavioural
andneurophysiologicalconsequencesofDMareaccentuatedbyaging[31]
7/30/2019 0331041
23/58
.WearecurrentlyaddressingthisissuebycomparingcognitivefunctioningandbrainMRIinagedDM1andDM2patientswithcontrols[32].
OurresultssuggestthatthecognitiveimpairmentsandMRchangesarelessmarked
intheagedDM1patients(averagedurationofDM35years),than
inDM2(averageknowndurationofDM 9years)patientsof
7/30/2019 0331041
24/58
similarage(A.M.A.Brandsetal.,UtrechtDiabeticEncephalopathyStudyGroup,unpublishedwork).Thissuggeststhat,inadditiontoage,differencesin
thepathophysiologyofDM1andDM2arelikelytobeimportantdeterminantsof
theeffectsofDM2onthebrain.
Directeffectsofinsulinon
thebrain?
Anincreasingamountofevidencelinksinsulin
7/30/2019 0331041
25/58
itselftocognitivedeclineanddementiainDM2[33 35].First,alterationsincerebralinsulinreceptorsignallingmaybeinvolved,as acerebralequivalentof
peripheralinsulinresistance.Secondly,insulinmayaffectthemetabolismofA(amyloid)and
tau,twoproteinsthatrepresentthebuilding
C
2005BiochemicalSociety
7/30/2019 0331041
26/58
ProteinsinDisease1043
blocksofamyloidplaquesandneurofibrillarytangles,theneuropathologicalhallmarksofAlzheimer sdisease.
Insulinisnot amajor
regulatorofglucoseuseinthebrain,incontrastwithitsprominentaction
inperipheraltissuessuchasliver,muscleandfat[36].Still,insulin
anditsreceptorarewidelydistributedthroughoutthebrain,with
7/30/2019 0331041
27/58
particularabundanceindefinedareas,suchasthehypothalamusandthehippocampus[37],andplay aroleintheregulationoffoodintakeand
bodyweight[36].Inaddition,insulinappearstoactas a
neuromodulator.
Itinfluencesthereleaseandre-uptakeofneurotransmitters,andalsoappearsto
improvelearningandmemory[37].Theinitialcomponentsof
7/30/2019 0331041
28/58
7/30/2019 0331041
29/58
inthelevelofinsulinandthenumberofitsreceptorsinthebrain[39].InAlzheimer sdiseasethisage-relatedreductionincerebral
insulinlevelsappearstobeaccompaniedbydisturbancesoftheinsulinreceptorsignalling[39],leadingtothequalificationofAlzheimer sdiseaseas aninsulin-resistantbrainstate [40].
TherelationbetweeninsulinandthemetabolismofAandtauisalso
receivingincreasingattention[33,35].Aisderivedfromthe
7/30/2019 0331041
30/58
so-calledamyloidprecursorprotein.AftersecretionintotheextracellularspaceAcanaggregatewithotherproteins,toformsenileplaques.Alternatively,excessiveAcanbeclearedthroughLDL-receptor-relatedproteinmediatedendocytosis,
orthroughdirectextracellularproteolyticdegradation[41].ThislatterprocessinvolvesIDE(insulin-degradingenzyme)[42].Insulinappearstostimulate
Asecretion,andinhibitstheextracellulardegradationofAbycompetitionfromIDE[33]. Arecenthistopathologicalstudyofthe
hippocampusinpatientswithAlzheimer sdiseasereportedmarkedreductionsin
7/30/2019 0331041
31/58
IDEexpression,andIDEmRNAlevels,relativetocontrols[43].Interestingly,thisreducedexpressiononlyoccurredinpatientswiththeAPOE(apolipoproteinE)
e4allele.AninteractionwiththeAPOEe4genotypehasalsobeendemonstrated
fortheriskofAlzheimer sdiseaseinDMpatients[8],anobservation
thatwassupportedbyneuropathologicalresults[8].
Although
7/30/2019 0331041
32/58
theconceptsof
cerebralinsulinresistance,and
insulin-inducedamyloidpathology areanattractiveexplanationforsomeoftheeffectsofDM2onthe
brain,therearestillmanylooseends.Incontrastwiththeincreasingbody
ofknowledgeonthemechanismsofinsulinresistanceinperipheraltissues[44],
weknowrelativelylittleonhowDM2anditstreatment
7/30/2019 0331041
33/58
affectcerebralinsulinanditsreceptor.Moreover,theknowledgeontheroleofinsulininbrainphysiologyisfarfromcomplete.Forexample,in
apparentcontrastwithpreviousobservationsthathippocampalinsulinreceptorexpressionandsignallingin
ratsareup-regulatedfollowing aspatiallearningtaskin awatermaze[45],mice
with atargetedknockoutofinsulinreceptorsinthebrainreadily
7/30/2019 0331041
34/58
learnthissametask[46].Hopefully,ongoingresearch
inthisrapidlyevolvingfieldofresearchwillclarifytheseissues.
Conclusion
Severalmechanismsmaybeinvolvedinacceleratedcognitivedeclineandtheincreaseof
dementiainpatientswithDM2(Figure1).Becausethesedifferentmechanismsinteract
atseverallevels,itisunlikelythatfuturestudieswill
7/30/2019 0331041
35/58
detect asinglefactorthatlinkDMtoimpairedcognition.Itmaybepossible,however,toidentifyprocesses,orclustersofriskfactors,thatexplain
atleastpartoftheassociation,andcanbetargetedbypreventivemeasures.
Thesepreventivemeasuresmaynotonlyincludeimprovementofglycaemiccontrol[47],
butcouldalsobedirectedatvascularriskfactorsandinsulinmetabolism.Infact,thereisalreadysomeevidence
7/30/2019 0331041
36/58
fromstudiesinnon-DMpatientsthattheselatterapproachesmaybesuccessful.Forexample,treatmentofvascularriskfactors,suchashypertension,maydecrease
theincidenceofdementiainthecontextofischaemiccerebrovasculardisease[48].
Moreover, arecentexploratoryrandomizedplacebocontrolledtrialwiththeinsulin-sensitizingcompoundrosiglitazoneshowedanameliorationofbothcognitivedeclineand
abnormalitiesincerebrospinalfluidAinnon-DMpatientswithearlyAlzheimer sdisease[49].Thechallengeforfuturestudies
7/30/2019 0331041
37/58
willbetodeterminewhatpreventivestrategyshouldbeappliedinwhichDM2patient,atwhatstageofthedisease.
TheUtrechtDiabetic
EncephalopathyStudyGroupconsistsof(inalphabeticalorder):DepartmentofClinicalNeurophysiology:
A.C.vanHuffelen;DepartmentofInternalMedicine:H.W.deValk;JuliusCenterfor
HealthSciencesandPrimaryCare:A.Algra,G.E.H.M.Rutten;Department
7/30/2019 0331041
38/58
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
7/30/2019 0331041
39/58
issupportedbytheDutchDiabetesResearchFoundation(grants2001.00.023and2003.01.004).
References
1Biessels,G.J.,Kappelle,A.C.,Bravenboer,
B.,Erkelens,D.W.andGispen,
W.H.(1994)Diabetologia37,643 650 2Brands,
A.M.A.,Biessels,G.J.,DeHaan,E.H.F.,Kappelle,L.J.andKessels,
R.P.C.(2005)DiabetesCare28,726 735 3Stewart,R.andLiolitsa,
7/30/2019 0331041
40/58
D.(1999)Diabet.Med.16,93 112 4Awad,N.,Gagnon,M.andMessier,C.(2004)J.Clin.Exp.Neuropsychol.26,1044 1080 5Ryan,C.M.and
Geckle,M.(2000)DiabetesMetab.Res.Rev.16,308 315 6Sinclair,A.J.,Girling,
A.J.andBayer,A.J.(2000)DiabetesRes.Clin.Pract.
50,203 212 7Ott,
A.,Stolk,R.P.,VanHarskamp,F.,Pols,
7/30/2019 0331041
41/58
H.A.,Hofman,A.andBreteler,
M.M.(1999)Neurology53,1937 1942 8Peila,R.,Rodriguez,B.L.andLauner,L.J.(2002)Diabetes51,1256 1262 9
Arvanitakis,Z.,Wilson,R.S.,Bienias,J.L.,Evans,D.A.andBennett,
D.A.(2004)Arch.Neurol.61,661 666
C
2005BiochemicalSociety
7/30/2019 0331041
42/58
BiochemicalSocietyTransactions(2005)Volume33,part 5
10Strachan,M.W.J.,Deary,I.J.,Ewing,F.M.E.andFrier,B.M.(1997)DiabetesCare
20,438 445
11Biessels,G.J.,VanderHeide,L.P.,Kamal,
A.,Bleys,R.L.andGispen,W.H.(2002)Eur.J.Pharmacol.441,1 14
12AdultTreatmentPanelIII(2001)JAMA,J.Am.Med.
7/30/2019 0331041
43/58
Assoc.285,2486 2497
13Kalmijn,S.,Foley,D.,White,L.,Burchfiel,C.M.,Curb,J.D.,Petrovitch,H.,Ross,
G.W.,Havlik,R.J.andLauner,L.J.(2000)Arterioscler.Thromb.Vasc.Biol.20,
2255 2260
14Gispen,W.H.andBiessels,G.J.(2000)TrendsNeurosci23,542 549
15Brownlee,M.(2001)Nature(London)414,813 820
7/30/2019 0331041
44/58
16Kalmijn,S.,Feskens,E.J.M.,Launer,L.J.,Stijnen,T.andKromhout,D.(1995)Diabetologia38,1096 1102
17Vanhanen,M.,
Koivisto,K.,Kuusisto,J.,Mykkanen,L.,Helkala,E.L.,Hanninen,
T.,Riekkinen,P.S.,Soininen,H.andLaakso,M.(1998)DiabetesCare
21,398 402
18Meigs,J.B.(2000)Am.J.Epidemiol.
7/30/2019 0331041
45/58
152,908 911
19Kuusisto,J.,Koivisto,K.,Mykkanen,L.,Helkala,E.L.,Vanhanen,M.,Hanninen,T.,Py
orala,K.,Riekkinen,P.andLaakso,M.(1993)
Hypertension
22,771 779
20Kuusisto,J.,Koivisto,K.,Mykkanen,L.
,Helkala,E.L.,Vanhanen,M.,Hanninen,T.,
7/30/2019 0331041
46/58
Kervinen,K.,Kesaniemi,Y.A.,Riekkinen,P.J.andLaakso,M.(1997)Br.Med. J315,1045 1049
21Whitmer,R.A.,Gunderson,E.P.,
Barrett-Connor,E.,Quesenberry,Jr,C.P.andYaffe,K.(2005)Br.Med.J.
330,1360
22Kernan,W.N.,Inzucchi,S.E.,Viscoli,C.M.,
Brass,L.M.,Bravata,D.M.andHorwitz,R.I.(2002)Neurology
7/30/2019 0331041
47/58
59,809 815
23Golden,S.H.,Folsom,A.R.,Coresh,J.,Sharrett,A.R.,Szklo,M.andBrancati,F.(2002)Diabetes51,
3069 307624Yaffe,K.,Kanaya,A.,Lindquist,K.,Simonsick,
E.M.,Harris,T.,Shorr,R.I.,Tylavsky,F.A.andNewman,A.B.
(2004)JAMA,J.Am.Med.Assoc.292,2237 2242
25
7/30/2019 0331041
48/58
Beckman,J.A.,Creager,M.A.andLibby,P.(2002)JAMA,J.Am.Med.Assoc.287,2570 2581
26Hofman,A.,Ott,A.,
Breteler,M.M.,Bots,M.L.,Slooter,A.J.,VanHarskamp,F.,
vanDuijn,C.N.,VanBroeckhoven,C.andGrobbee,D.E.(1997)Lancet349,
151 154
27Mankovsky,B.N.,Metzger,B.E.,Molitch,
7/30/2019 0331041
49/58
M.E.andBiller,J.(1997)
J.DiabetesComplications10,228 24228Pantoni,L.,Leys,D.,Fazekas,F.,Longstreth,Jr,W.T.
,Inzitari,D.,Wallin,A.,Filippi,M.,Scheltens,P.,
Erkinjuntti,T.andHachinski,V.(1999)AlzheimerDis.Assoc.Disord.13,S49 S54
29Biessels,G.J.,Manschot,S.M.andTheDiabeticEncephalopathy
7/30/2019 0331041
50/58
StudyGroup(2003)J.Neurol.250,P718.Abstract
30Vermeer,S.E.,denHeijer,T.,Koudstaal,P.J.,Oudkerk,M.,Hofman,
A.andBreteler,M.M.(2003)Stroke34,392 396
31Kamal,A.,
Biessels,G.J.,Duis,S.E.J.andGispen,W.H.(2000)Diabetologia43,500 506
32Brands,A.M.A.,Kessels,R.P.C.andTheDiabeticEncephalopathy
7/30/2019 0331041
51/58
StudyGroup(2003)JINS9,583 584,Abstract
33Gasparini,L.andXu,H.(2003)TrendsNeurosci.26,404 406
34Watson,G.S.and
Craft,S.(2004)Eur.J.Pharmacol.490,97 113
35delaMonte,
S.M.andWands,J.R.(2005)J.AlzheimersDis.7,45 61
36Schwartz,
M.W.andPorte,Jr,D.(2005)Science307,375 379
7/30/2019 0331041
52/58
37Zhao,W.Q.,Chen,H.,Quon,M.J.andAlkon,D.L.(2004)Eur.J.Pharmacol.490,71 81
38Saltiel,A.R.andKahn,
C.R.(2001)Nature(London)414,799 806
39Frolich,L.,Blum-Degen,D.
,Bernstein,H.G.,Engelsberger,S.,Humrich,J.,Laufer,S.,
Muschner,D.,Thalheimer,A.,Turk,A.,Hoyer,
7/30/2019 0331041
53/58
7/30/2019 0331041
54/58
R.E.,Selkoe,D.J.andGuenette,S.(2003)Proc.Natl.Acad.Sci.U.S.A.100,4162 4167
43Cook,D.G.,Leverenz,J.B.,McMillan,
P.J.,Kulstad,J.J.,Ericksen,S.,Roth,R.A.,Schellenberg,G.D.
,Jin,L.W.,Kovacina,K.S.andCraft,S.(2003)Am.J.Pathol.
162,313 319
44LeRoith,D.andZick,Y.
7/30/2019 0331041
55/58
(2001)DiabetesCare24,588 597
45Zhao,W.,Chen,H.,Xu,H.,Moore,E.,Meiri,N.,Quon,M.J.
andAlkon,D.L.(1999)J.Biol.Chem.274,34893 34902
46Schubert,M.
,Gautam,D.,Surjo,D.,Ueki,K.,Baudler,S.,
Schubert,D.,Kondo,T.,Alber,J.,Galldiks,
7/30/2019 0331041
56/58
N.,Kustermann,E.etal.(2004)Proc.Natl.Acad.Sci.U.S.A.101,3100 3105
47AreosaSastre,A.GrimleyEvans,V.(2003)Cochrane
Database.Syst.Rev.CD003804
48Erkinjuntti,T.,Roman,G.,Gauthier,
S.,Feldman,H.andRockwood,K.(2004)Stroke35,1010 1017
49
Watson,G.S.,Reger,M.A.,Cholerton,B.A.,Asthana,
7/30/2019 0331041
57/58
S.,Baker,L.D.,Rhoads,K.W.,Plymate,S.R.,Fishel,M.A.,Kahn,S.E.andCraft,S.(2004)Neurobiol.Aging25,S83
Received20June2005
C
2005BiochemicalSociety
7/30/2019 0331041
58/58
