Biochemical Society Transactions (2005) 33, (10411044) (Printed in Great Britain)

Astract
P!"
Focus Topics at BioScience2005
#ncreased ris$ o% Al&heimer's disease in Ty(e ##
diaetes) ins*lin resistance o% the rain or ins*lin+
ind*ced amyloid (atholo,y-
G./. Biessels
1
and 0./. 1a((elle
2
Department of Neurology, Rudolf Magnus nstitute of Neuroscience, !ni"ersity Medical
#enter, !trec$t, T$e Net$erlands
1ey 2ords) %l&$eimer's disease, (rain aging, cogniti"e dysfunction, insulin)induced amyloid,
meta(olic syndrome, Type dia(etes mellitus*
Are3iations *sed) %, )amyloid+ %,-., apolipoprotein .+ DM, dia(etes mellitus+ DM1,
Type DM+ DM2, Type DM+ D., insulin)degrading en&yme+ /D/, lo0)density lipoprotein+
MR, magnetic resonance imaging*
1
To 2hom corres(ondence sho*ld e addressed, at Department of Neurology, 102*223,
!ni"ersity Medical #enter !trec$t, ,- Bo4 35500, 2503 1% !trec$t, T$e Net$erlands (email
,.4.iessels5ne*ro.a&*.nl).
2
6n ehal% o% the 7trecht !iaetic 8nce(halo(athy St*dy Gro*( (see
Ac$no2led,ements)
Astract
Type dia(etes mellitus 5DM26 is associated 0it$ an increased ris7 of cogniti"e dysfunction
and dementia* T$e increased ris7 of dementia concerns (ot$ %l&$eimer's disease and
"ascular dementia* %lt$oug$ some uncertainty remains into t$e e4act pat$ogenesis, se"eral
mec$anisms t$roug$ 0$ic$ DM2 may affect t$e (rain $a"e no0 (een identified* First, factors
related to t$e 8meta(olic syndrome9, a cluster of meta(olic and "ascular ris7 factors 5e*g*
dyslipidaemia and $ypertension6 t$at is closely lin7ed to DM2, may (e in"ol"ed* % num(er of
t$ese ris7 factors are predictors of cere(ro"ascular disease, accelerated cogniti"e decline and
dementia* Secondly, $yperglycaemia may (e in"ol"ed, t$roug$ ad"erse effects of potentially
8to4ic9 glucose meta(olites on t$e (rain and its "asculature* T$irdly, insulin itself may (e
in"ol"ed* nsulin can directly modulate synaptic plasticity and learning and memory, and
distur(ances in insulin signalling pat$0ays in t$e perip$ery and in t$e (rain $a"e recently
(een implicated in %l&$eimer's disease and (rain aging* nsulin also regulates t$e meta(olism
of )amyloid and tau, t$e (uilding (loc7s of amyloid pla:ues and neurofi(rillary tangles, t$e
neuropat$ological $allmar7s of %l&$eimer's disease* n t$is paper, t$e e"idence for t$e
association (et0een DM2 and dementia and for eac$ of t$ese underlying mec$anisms 0ill (e
re"ie0ed, 0it$ emp$asis on t$e role of insulin itself*
DM 5dia(etes mellitus6 is associated 0it$ slo0ly progressi"e end)organ damage in t$e (rain
;1<* Mild to moderate impairments of cogniti"e functioning $as (een reported (ot$ in patients
0it$ DM1 5Type DM6 ;2<, and in patients 0it$ DM2 5Type DM6 ;2,=<* #linically rele"ant
deficits, $o0e"er, mainly occur in elderly patients 0it$ DM2 ;5<, 0$o may e4perience pro(lems
0it$ day)to)day functioning due to t$eir cogniti"e impairments ;><* T$e potential impact of DM
on cognition in t$e elderly is furt$er emp$asi&ed (y se"eral large epidemiological sur"eys t$at
report an increased incidence of dementia among DM patients, apparently concerning (ot$
%l&$eimer's disease and "ascular dementia ;2,?@A<* T$e o(ser"ation t$at t$e effects of DM on
t$e (rain are most pronounced in t$e elderly $as (een attri(uted to an interaction (et0een
DM and t$e normal aging process of t$e (rain ;10,11<* Differences (et0een t$e
pat$op$ysiology of DM1 and DM2 are also li7ely to play a role ;11<, as t$e latter is (y far t$e
most common form among t$e elderly* n DM1, t$e principal defect is an autoimmune)
mediated destruction of pancreatic )cells, leading to insulin deficiency, 0$ereas in DM2 t$e
principal defect is insulin resistance, leading to a relati"e insulin deficiency* Moreo"er, DM2
occurs in t$e conte4t of a cluster of meta(olic and "ascular ris7 factors, 0$ic$ is referred to as
t$e so)called 8meta(olic syndrome9 ;12<* T$e meta(olic syndrome itself, 0it$ or 0it$out
$yperglycaemia, is associated 0it$ at$erosclerotic cardio"ascular disease, isc$aemic stro7e
and 0it$ cogniti"e decline and dementia ;12<* % 7ey :uestion is t$erefore 0$et$er
distur(ances in insulin and glucose meta(olism or ot$er factors from t$e meta(olic syndrome
lead to impaired cognition in DM2* T$e present 0or7 aims to pro"ide an o"er"ie0 on t$e 0ays
in 0$ic$ distur(ances in glucose and insulin meta(olism and ot$er factors related to t$e
meta(olic syndrome may (e implicated in t$e accelerated cogniti"e decline and t$e increased
ris7 of dementia in patients 0it$ DM2 5Figure 16*
9o,niti3e dys%*nction and dementia in !:2) *nderlyin, mechanisms
A role %or hy(er,lycaemia-
Se"eral lines of e"idence suggest t$at 8to4ic9 effects of $yperglycaemia are in"ol"ed in t$e
de"elopment of dia(etic end)organ damage to t$e (rain ;1=<* Byperglycaemic rodents, for
e4ample, e4press cogniti"e impairments and functional and structural alterations in t$e (rain
;1=<* To4ic effects of $ig$ glucose le"els are mediated t$roug$ an en$anced flu4 of glucose
t$roug$ t$e so)called polyol and $e4osamine pat$0ays, distur(ances of intracellular second
messenger pat$0ays, an im(alance in t$e generation and sca"enging of reacti"e o4ygen
species, and (y ad"anced glycation of important functional and structural proteins ;15<* T$ese
processes directly affect (rain tissue and lead to micro"ascular c$anges in t$e (rain ;11,1=<*
Still, $yperglycaemia is unli7ely to (e t$e only factor in t$e de"elopment of cogniti"e
impairments in DM2C pre"ious studies in DM2 patients do not in"aria(ly s$o0 an association
(et0een c$ronic $yperglycaemia, as assessed (y B(%1 le"els, and t$e se"erity of cogniti"e
impairments ;2,10<* Moreo"er, c$anges in cognition may already de"elop in 8pre)dia(etic
stages9, suc$ as impaired glucose tolerance, or in ne0ly diagnosed DM2 patients t$at $a"e
not yet (een e4posed to long)term $yperglycaemia ;1>,1?<*
A role %or the metaolic syndrome-
DM2 and insulin resistance are closely associated 0it$ factors suc$ as o(esity, at$erogenic
dyslipidaemia ;ele"ated triacylglycerol le"el, small /D/ 5lo0)density lipoprotein6 particles, lo0
BD/ 5$ig$)density lipoprotein6 c$olesterol<, raised (lood pressure, and pro)t$rom(otic and
pro)inflammatory states* Toget$er t$ese factors constitute t$e meta(olic syndrome, or insulin
resistance syndrome ;12,13<* % num(er of factors from t$is syndrome $a"e (een identified as
independent predictors of cere(ro"ascular disease, isc$aemic stro7e and accelerated
cogniti"e decline and dementia 5e*g* ;12,1>,1A@21<6* T$e com(ined occurrence of t$ese ris7
factors in t$e meta(olic syndrome mig$t reinforce t$ese effects ;1A,22@2=<* 1i"en t$e
clustering of insulin resistance, $ypertension and dyslipidaemia in DM2 it may (e difficult to
determine 0$ic$ factor is t$e prime determinant in t$e de"elopment of cogniti"e dysfunction*
T$e main :uestion, $o0e"er, is to determine if t$e meta(olic syndrome is indeed a strong
predictor of cogniti"e dysfunction in DM2, and if t$is effect is 5partially6 independent of
distur(ances in glucose and insulin meta(olism*
#n3ol3ement o% ischaemic cerero3asc*lar disease-
DM2 and t$e meta(olic syndrome are ris7 factors for at$erosclerosis of t$e carotid and
intracranial arteries ;22,25<, t$us increasing t$e ris7 of stro7e, and of cogniti"e decline and
dementia ;2><* n t$e long term, e4posure to $yperglycaemia in DM may lead to a(normalities
in cere(ral capillaries, suc$ as (asement mem(rane t$ic7ening ;2?<* T$ese micro"ascular
c$anges may also lead to c$ronic and insidious isc$aemia of t$e (rain, t$us contri(uting, for
e4ample, to t$e de"elopment of su(cortical 0$ite)matter lesions* -n a population le"el t$ese
lesions are associated 0it$ cogniti"e impairments, particularly related to frontal lo(e functions
;23<* %lt$oug$ 0$ite)matter lesions are also common among $ealt$y elderly su(Dects, t$eir
pre"alence and se"erity is increased in patients 0it$ "ascular ris7 factors or isc$aemic
"ascular disease, and in demented patients ;23<* MR 5magnetic resonance imaging6 studies
in DM2 patients indeed s$o0 an increased se"erity of 0$ite)matter lesions E;2A<, and S*M*
Mansc$ot et al*, !trec$t Dia(etic .ncep$alopat$y Study 1roup 5see %c7no0ledgements6,
unpu(lis$ed 0or7F, and an increased incidence of 5silent6 (rain infarcts ;20<*
An interaction 2ith a,in,-
%s t$e effects of DM on t$e (rain are most pronounced in t$e elderly, one may suggest t$at
t$e aging (rain is more suscepti(le to t$e effects of DM or t$at t$e effects of DM and aging
interact* n fact, se"eral of t$e mec$anisms t$at are assumed to mediate t$e to4ic effects of
$yperglycaemia on t$e (rain, suc$ as o4idati"e stress, t$e accumulation of ad"anced
glycation end)products and microangiopat$y, are also in"ol"ed in (rain aging ;11<* Moreo"er,
e4perimental studies indicate t$at t$e (e$a"ioural and neurop$ysiological conse:uences of
DM are accentuated (y aging ;21<* Ge are currently addressing t$is issue (y comparing
cogniti"e functioning and (rain MR in aged DM1 and DM2 patients 0it$ controls ;22<* -ur
results suggest t$at t$e cogniti"e impairments and MR c$anges are less mar7ed in t$e aged
DM1 patients 5a"erage duration of DM H25 years6, t$an in DM2 5a"erage 7no0n duration of
DM A years6 patients of similar age 5%*M*%* Brands et al*, !trec$t Dia(etic .ncep$alopat$y
Study 1roup, unpu(lis$ed 0or76* T$is suggests t$at, in addition to age, differences in t$e
pat$op$ysiology of DM1 and DM2 are li7ely to (e important determinants of t$e effects of
DM2 on t$e (rain*
!irect e%%ects o% ins*lin on the rain-
%n increasing amount of e"idence lin7s insulin itself to cogniti"e decline and dementia in DM2
;22@25<* First, alterations in cere(ral insulin receptor signalling may (e in"ol"ed, as a cere(ral
e:ui"alent of perip$eral insulin resistance* Secondly, insulin may affect t$e meta(olism of %
5)amyloid6 and tau, t0o proteins t$at represent t$e (uilding (loc7s of amyloid pla:ues and
neurofi(rillary tangles, t$e neuropat$ological $allmar7s of %l&$eimer's disease*
nsulin is not a maDor regulator of glucose use in t$e (rain, in contrast 0it$ its prominent action
in perip$eral tissues suc$ as li"er, muscle and fat ;2><* Still, insulin and its receptor are 0idely
distri(uted t$roug$out t$e (rain, 0it$ particular a(undance in defined areas, suc$ as t$e
$ypot$alamus and t$e $ippocampus ;2?<, and play a role in t$e regulation of food inta7e and
(ody 0eig$t ;2><* n addition, insulin appears to act as a 8neuromodulator9* t influences t$e
release and re)upta7e of neurotransmitters, and also appears to impro"e learning and
memory ;2?<* T$e initial components of t$e insulin receptor signalling cascade in t$e (rain are
largely similar to t$ose of t$e perip$ery ;2?,23<, (ut t$e do0nstream targets of t$e cascade
are :uite different, pro(a(ly in"ol"ing, among ot$ers, neuronal glutamate receptors ;2?<*
Distur(ances in cere(ral insulin signalling pat$0ays may (e in"ol"ed in %l&$eimer's disease
and (rain aging ;22@25<* %ging is associated 0it$ reductions in t$e le"el of insulin and t$e
num(er of its receptors in t$e (rain ;2A<* n %l&$eimer's disease t$is age)related reduction in
cere(ral insulin le"els appears to (e accompanied (y distur(ances of t$e insulin receptor
signalling ;2A<, leading to t$e :ualification of %l&$eimer's disease as 8an insulin)resistant (rain
state9 ;=0<*
T$e relation (et0een insulin and t$e meta(olism of % and tau is also recei"ing increasing
attention ;22,25<* % is deri"ed from t$e so)called amyloid precursor protein* %fter secretion
into t$e e4tracellular space % can aggregate 0it$ ot$er proteins, to form senile pla:ues*
%lternati"ely, e4cessi"e % can (e cleared t$roug$ /D/)receptor)related protein mediated
endocytosis, or t$roug$ direct e4tracellular proteolytic degradation ;=1<* T$is latter process
in"ol"es D. 5insulin)degrading en&yme6 ;=2<* nsulin appears to stimulate % secretion, and
in$i(its t$e e4tracellular degradation of % (y competition from D. ;22<* % recent
$istopat$ological study of t$e $ippocampus in patients 0it$ %l&$eimer's disease reported
mar7ed reductions in D. e4pression, and D. mRN% le"els, relati"e to controls ;=2<*
nterestingly, t$is reduced e4pression only occurred in patients 0it$ t$e %,-. 5apolipoprotein
.6 = allele* %n interaction 0it$ t$e %,-. = genotype $as also (een demonstrated for t$e
ris7 of %l&$eimer's disease in DM patients ;3<, an o(ser"ation t$at 0as supported (y
neuropat$ological results ;3<*
%lt$oug$ t$e concepts of 8cere(ral insulin resistance9, and 8insulin)induced amyloid pat$ology9
are an attracti"e e4planation for some of t$e effects of DM2 on t$e (rain, t$ere are still many
loose ends* n contrast 0it$ t$e increasing (ody of 7no0ledge on t$e mec$anisms of insulin
resistance in perip$eral tissues ;==<, 0e 7no0 relati"ely little on $o0 DM2 and its treatment
affect cere(ral insulin and its receptor* Moreo"er, t$e 7no0ledge on t$e role of insulin in (rain
p$ysiology is far from complete* For e4ample, in apparent contrast 0it$ pre"ious o(ser"ations
t$at $ippocampal insulin receptor e4pression and signalling in rats are up)regulated follo0ing
a spatial learning tas7 in a 0ater ma&e ;=5<, mice 0it$ a targeted 7noc7out of insulin receptors
in t$e (rain readily learn t$is same tas7 ;=><* Bopefully, ongoing researc$ in t$is rapidly
e"ol"ing field of researc$ 0ill clarify t$ese issues*
9oncl*sion
Se"eral mec$anisms may (e in"ol"ed in accelerated cogniti"e decline and t$e increase of
dementia in patients 0it$ DM2 5Figure 16* Because t$ese different mec$anisms interact at
se"eral le"els, it is unli7ely t$at future studies 0ill detect a single factor t$at lin7 DM to
impaired cognition* t may (e possi(le, $o0e"er, to identify processes, or clusters of ris7
factors, t$at e4plain at least part of t$e association, and can (e targeted (y pre"enti"e
measures* T$ese pre"enti"e measures may not only include impro"ement of glycaemic
control ;=?<, (ut could also (e directed at "ascular ris7 factors and insulin meta(olism* n fact,
t$ere is already some e"idence from studies in non)DM patients t$at t$ese latter approac$es
may (e successful* For e4ample, treatment of "ascular ris7 factors, suc$ as $ypertension,
may decrease t$e incidence of dementia in t$e conte4t of isc$aemic cere(ro"ascular disease
;=3<* Moreo"er, a recent e4ploratory randomi&ed place(o)controlled trial 0it$ t$e insulin)
sensiti&ing compound rosiglita&one s$o0ed an amelioration of (ot$ cogniti"e decline and
a(normalities in cere(rospinal fluid % in non)DM patients 0it$ early %l&$eimer's disease ;=A<*
T$e c$allenge for future studies 0ill (e to determine 0$at pre"enti"e strategy s$ould (e
applied in 0$ic$ DM2 patient, at 0$at stage of t$e disease*
T$e !trec$t Dia(etic .ncep$alopat$y Study 1roup consists of 5in alp$a(etical order6C
Department of #linical Neurop$ysiologyC %*#* "an Buffelen+ Department of nternal MedicineC
B*G* de Ial7+ Julius #enter for Bealt$ Sciences and ,rimary #areC %* %lgra, 1*.*B*M* Rutten+
Department of Medical ,$armacologyC G*B* 1ispen+ Department of NeurologyC %* %lgra, 1*J*
Biessels, /*J* Kappelle, S*M* Mansc$ot, J* "an 1iDn+ Department of Neuropsyc$ology and
Belm$olt& Researc$ nstituteC %*M*%* Brands, .*B*F* de Baan, R*,*#* Kessels, .* "an den
Berg+ Department of RadiologyC J* "an der 1rond, all part of t$e !ni"ersity Medical #enter,
!trec$t, T$e Net$erlands* T$e researc$ of t$e Study 1roup is supported (y t$e Dutc$
Dia(etes Researc$ Foundation 5grants 2001*00*022 and 2002*01*00=6*
;e%erences
1 Biessels, 1*J*, Kappelle, %*#*, Bra"en(oer, B*, .r7elens, D*G* and 1ispen, G*B* 51AA=6
Dia(etologia 3<, >=2@>50
Medline 1st #itation
2 Brands, %*M*%*, Biessels, 1*J*, De Baan, .*B*F*, Kappelle, /*J* and Kessels, R*,*#* 520056
Dia(etes #are 2=, ?2>@?25
Medline 1st #itation
2 Ste0art, R* and /iolitsa, D* 51AAA6 Dia(et* Med* 1>, A2@112
Medline #rossref 1st #itation 2nd 2rd
= %0ad, N*, 1agnon, M* and Messier, #* 5200=6 J* #lin* .4p* Neuropsyc$ol* 2>, 10==@1030
Medline #rossref 1st #itation
5 Ryan, #*M* and 1ec7le, M* 520006 Dia(etes Meta(* Res* Re"* 1>, 203@215
Medline #rossref 1st #itation
> Sinclair, %*J*, 1irling, %*J* and Bayer, %*J* 520006 Dia(etes Res* #lin* ,ract* 50, 202@212
Medline 1st #itation
? -tt, %*, Stol7, R*,*, Ian Bars7amp, F*, ,ols, B*%*, Bofman, %* and Breteler, M*M* 51AAA6
Neurology 53, 1A2?@1A=2
Medline 1st #itation
3 ,eila, R*, Rodrigue&, B*/* and /auner, /*J* 520026 Dia(etes 51, 125>@12>2
Medline 1st #itation 2nd 2rd
A %r"anita7is, L*, Gilson, R*S*, Bienias, J*/*, ."ans, D*%* and Bennett, D*%* 5200=6 %rc$*
Neurol* >1, >>1@>>>
Medline #rossref 1st #itation
10 Strac$an, M*G*J*, Deary, *J*, .0ing, F*M*.* and Frier, B*M* 51AA?6 Dia(etes #are 20, =23@
==5
Medline 1st #itation 2nd
11 Biessels, 1*J*, Ian der Beide, /*,*, Kamal, %*, Bleys, R*/* and 1ispen, G*B* 520026 .ur* J*
,$armacol* 441, 1@1=
Medline #rossref 1st #itation 2nd 2rd =t$
12 %dult Treatment ,anel 520016 J%M%, J* %m* Med* %ssoc* 2=5, 2=3>@2=A?
#rossref 1st #itation 2nd
12 KalmiDn, S*, Foley, D*, G$ite, /*, Burc$fiel, #*M*, #ur(, J*D*, ,etro"itc$, B*, Ross, 1*G*,
Ba"li7, R*J* and /auner, /*J* 520006 %rterioscler* T$rom(* Iasc* Biol* 20, 2255@22>0
Medline 1st #itation 2nd
1= 1ispen, G*B* and Biessels, 1*J* 520006 Trends Neurosci 23, 5=2@5=A
Medline #rossref 1st #itation 2nd 2rd
15 Bro0nlee, M* 520016 Nature 5/ondon6 414, 312@320
#rossref 1st #itation
1> KalmiDn, S*, Fes7ens, .*J*M*, /auner, /*J*, StiDnen, T* and Krom$out, D* 51AA56
Dia(etologia 3=, 10A>@1102
Medline 1st #itation 2nd
1? Ian$anen, M*, Koi"isto, K*, Kuusisto, J*, My77anen, /*, Bel7ala, .*/*, Banninen, T*,
Rie77inen, ,*S*, Soininen, B* and /aa7so, M* 51AA36 Dia(etes #are 21, 2A3@=02
Medline 1st #itation
13 Meigs, J*B* 520006 %m* J* .pidemiol* 152, A03@A11
Medline #rossref 1st #itation
1A Kuusisto, J*, Koi"isto, K*, My77Mnen, /*, Bel7ala, .*/*, Ian$anen, M*, BMnninen, T*,
,yNrMlM, K*, Rie77inen, ,* and /aa7so, M* 51AA26 Bypertension 22, ??1@??A
Medline 1st #itation 2nd
20 Kuusisto, J*, Koi"isto, K*, My77anen, /*, Bel7ala, .*/*, Ian$anen, M*, Banninen, T*,
Ker"inen, K*, Kesaniemi, O*%*, Rie77inen, ,*J* and /aa7so, M* 51AA?6 Br* Med* J 315, 10=5@
10=A
1st #itation
21 G$itmer, R*%*, 1underson, .*,*, Barrett)#onnor, .*, Puesen(erry, Jr, #*,* and Oaffe, K*
520056 Br* Med* J* 330, 12>0
1st #itation
22 Kernan, G*N*, n&ucc$i, S*.*, Iiscoli, #*M*, Brass, /*M*, Bra"ata, D*M* and Bor0it&, R**
520026 Neurology 5?, 30A@315
Medline 1st #itation 2nd
22 1olden, S*B*, Folsom, %*R*, #ores$, J*, S$arrett, %*R*, S&7lo, M* and Brancati, F* 520026
Dia(etes 51, 20>A@20?>
Medline 1st #itation
2= Oaffe, K*, Kanaya, %*, /ind:uist, K*, Simonsic7, .*M*, Barris, T*, S$orr, R**, Tyla"s7y, F*%*
and Ne0man, %*B* 5200=6 J%M%, J* %m* Med* %ssoc* 2?2, 222?@22=2
#rossref 1st #itation
25 Bec7man, J*%*, #reager, M*%* and /i((y, ,* 520026 J%M%, J* %m* Med* %ssoc* 2=<, 25?0@
2531
#rossref 1st #itation
2> Bofman, %*, -tt, %*, Breteler, M*M*, Bots, M*/*, Slooter, %*J*, Ian Bars7amp, F*, "an DuiDn,
#*N*, Ian Broec7$o"en, #* and 1ro((ee, D*.* 51AA?6 /ancet 34?, 151@15=
Medline #rossref 1st #itation
2? Man7o"s7y, B*N*, Met&ger, B*.*, Molitc$, M*.* and Biller, J* 51AA?6 J* Dia(etes
#omplications 10, 223@2=2
#rossref 1st #itation
23 ,antoni, /*, /eys, D*, Fa&e7as, F*, /ongstret$, Jr, G*T*, n&itari, D*, Gallin, %*, Filippi, M*,
Sc$eltens, ,*, .r7inDuntti, T* and Bac$ins7i, I* 51AAA6 %l&$eimer Dis* %ssoc* Disord* 13, S=A@
S5=
Medline 1st #itation 2nd
2A Biessels, 1*J*, Mansc$ot, S*M* and T$e Dia(etic .ncep$alopat$y Study 1roup 520026 J*
Neurol* 250, ,?13* %(stract
1st #itation
20 Iermeer, S*.*, den BeiDer, T*, Koudstaal, ,*J*, -ud7er7, M*, Bofman, %* and Breteler, M*M*
520026 Stro7e 34, 2A2@2A>
Medline #rossref 1st #itation
21 Kamal, %*, Biessels, 1*J*, Duis, S*.*J* and 1ispen, G*B* 520006 Dia(etologia 43, 500@50>
Medline #rossref 1st #itation
22 Brands, %*M*%*, Kessels, R*,*#* and T$e Dia(etic .ncep$alopat$y Study 1roup 520026
JNS ?, 532@53=, %(stract
1st #itation
22 1asparini, /* and Qu, B* 520026 Trends Neurosci* 2>, =0=@=0>
Medline #rossref 1st #itation 2nd 2rd =t$
2= Gatson, 1*S* and #raft, S* 5200=6 .ur* J* ,$armacol* 4?0, A?@112
Medline #rossref 1st #itation 2nd
25 de la Monte, S*M* and Gands, J*R* 520056 J* %l&$eimers Dis* <, =5@>1
Medline 1st #itation 2nd 2rd
2> Sc$0art&, M*G* and ,orte, Jr, D* 520056 Science 30<, 2?5@2?A
Medline #rossref 1st #itation 2nd
2? L$ao, G*P*, #$en, B*, Puon, M*J* and %l7on, D*/* 5200=6 .ur* J* ,$armacol* 4?0, ?1@31
Medline #rossref 1st #itation 2nd 2rd =t$
23 Saltiel, %*R* and Ka$n, #*R* 520016 Nature 5/ondon6 414, ?AA@30>
#rossref 1st #itation
2A Frolic$, /*, Blum)Degen, D*, Bernstein, B*1*, .ngels(erger, S*, Bumric$, J*, /aufer, S*,
Musc$ner, D*, T$al$eimer, %*, Tur7, %*, Boyer, S* et al* 51AA36 J* Neural Transm* 105, =22@
=23
Medline #rossref 1st #itation 2nd
=0 Boyer, S* 51AA36 J* Neural Transm* 105, =15@=22
Medline #rossref 1st #itation
=1 /ing, O*, Morgan, K* and Kals$e7er, N* 520026 nt* J* Bioc$em* #ell Biol* 35, 1505@1525
Medline #rossref 1st #itation
=2 Farris, G*, Mansourian, S*, #$ang, O*, /indsley, /*, .c7man, .*%*, Frosc$, M*,*, .c7man,
#*B*, Tan&i, R*.*, Sel7oe, D*J* and 1uenette, S* 520026 ,roc* Natl* %cad* Sci* !*S*%* 100,
=1>2@=1>?
Medline #rossref 1st #itation
=2 #oo7, D*1*, /e"eren&, J*B*, McMillan, ,*J*, Kulstad, J*J*, .ric7sen, S*, Rot$, R*%*,
Sc$ellen(erg, 1*D*, Jin, /*G*, Ko"acina, K*S* and #raft, S* 520026 %m* J* ,at$ol* 1>2, 212@
21A
Medline 1st #itation
== /e Roit$, D* and Lic7, O* 520016 Dia(etes #are 24, 533@5A?
Medline 1st #itation
=5 L$ao, G*, #$en, B*, Qu, B*, Moore, .*, Meiri, N*, Puon, M*J* and %l7on, D*/* 51AAA6 J* Biol*
#$em* 2<4, 2=3A2@2=A02
Medline #rossref 1st #itation
=> Sc$u(ert, M*, 1autam, D*, SurDo, D*, !e7i, K*, Baudler, S*, Sc$u(ert, D*, Kondo, T*, %l(er,
J*, 1alldi7s, N*, Kustermann, .* et al* 5200=6 ,roc* Natl* %cad* Sci* !*S*%* 101, 2100@2105
Medline #rossref 1st #itation
=? %reosa Sastre, %* 1rimley ."ans, I* 520026 #oc$rane Data(ase* Syst* Re"* #D00230=
1st #itation
=3 .r7inDuntti, T*, Roman, 1*, 1aut$ier, S*, Feldman, B* and Roc70ood, K* 5200=6 Stro7e 35,
1010@101?
Medline #rossref 1st #itation
=A Gatson, 1*S*, Reger, M*%*, #$olerton, B*%*, %st$ana, S*, Ba7er, /*D*, R$oads, K*G*,
,lymate, S*R*, Fis$el, M*%*, Ka$n, S*.* and #raft, S* 5200=6 Neuro(iol* %ging 25, S32
1st #itation
Recei"ed 20 June 2005