NEURAL REGENERATION RESEARCH｜Vol 16｜No.6｜June 2021｜1127
Isle amyloid polypep ide & amyloid be a pep ide oles
in Alzheime ’s disease: wo igge s, one disease
So ia Fe ei a1, 2, #, Ana F. Raimundo1, 2, 3, #, Regina Menezes1, 2, 3, *, I o C. Ma ins4, *
Abs ac
Alzheime ’s disease (AD) is a neu odegene a i e diso de ha a ec s millions wo ldwide.
Due o popula ion ageing, he incidence o AD is inc easing. AD pa ien s de elop cogni i e
decline and demen ia, ea u es o which is known, equi ing pe manen ca e. This poses
a majo socio-economic bu den on heal hca e sys ems as AD pa ien s’ ela i es and
heal hca e wo ke s a e o ced o cope wi h ising numbe s o a ec ed people. Despi e
ecen ad ances, AD pa hological mechanisms a e no ully unde s ood. Ne e heless, i
is clea ha he amyloid be a (Aβ) pep ide, which o ms amyloid plaques in AD pa ien s’
b ains, plays a key ole. Type 2 diabe es, he mos common o m o diabe es, a ec s
hund eds o million people globally. Isle amyloid polypep ide (IAPP) is a ho mone co-
p oduced and sec e ed wi h insulin in panc ea ic β-cells, wi h a key ole in diabe es, as i
helps egula e glucose le els and con ol adiposi y and sa ia ion. Simila ly o Aβ, IAPP is
e y amyloidogenic, gene a ing in acellula amyloid deposi s ha cause β-cell dys unc ion
and dea h. I is now clea ha IAPP can also ha e a pa hological ole in AD, dec easing
cogni i e unc ion. IAPP ha ms he blood-b ain ba ie , di ec ly in e ac s and co-deposi s
wi h Aβ, p omo ing diabe es-associa ed demen ia. IAPP can cause a me abolic dys unc ion
in he b ain, leading o o he diabe es- ela ed o ms o AD. Thus, he e we discuss IAPP
associa ion wi h diabe es, Aβ and demen ia, in he con ex o wha we designa e a
“diabe es b ain pheno ype” AD hypo hesis. Such app oach helps o se a concep ual
amewo k o u u e IAPP-based d ugs agains AD.
Key Wo ds: agg ega ion; Alzheime ; amylin; amyloid; diabe es; isle amyloid polypep ide
h ps://doi.o g/10.4103/1673-5374.300323
Da e o submission: May 13, 2020
Da e o decision: June 15, 2020
Da e o accep ance: Augus 20, 2020
Da e o web publica ion: No embe 27, 2020
Demen ia and Amyloid Be a Pep ide
Demen ia a ec s a ound 50 million people wo ldwide, being
a social and economic bu den o he pa ien s, hei amilies
and heal h sys ems a ound he wo ld. AD, a e y common
o m o demen ia, is behind he inc eased demand o
esea ch on his key opic. I is linked o amyloid be a pep ide
(Aβ) amyloidogenesis and/o agg ega ion. Aβ is p edominan ly
ound as Aβ40 o Aβ42, wi h ei he 40 o 42 amino acids,
espec i ely. Inc eases o o al Aβ and/o o he Aβ42/Aβ40
a io co ela e signi ican ly wi h AD and cogni i e decline
(Ma ins e al., 2008; Kupe s ein e al., 2010). Impo an ly,
ex acellula Aβ42 amyloid plaques and in acellula Tau
deposi s a e ell- ale signs o AD, being explo ed as diagnos ic
ools, alongside o he changes in he b ain, wi h neu onal
loss being in a iably seen and ela ed wi h cogni i e decline
(Ma ins e al., 2008; Kupe s ein e al., 2010).
Diabe es and Isle Amyloid Polypep ide
Diabe es, pa icula ly ype 2, is cha ac e ized by insulin
esis ance o insu icien insulin p oduc ion, leading o
hype glycaemia, and agg ega ion and deposi ion o isle
amyloid polypep ide (IAPP), o amylin. This neu oendoc ine
ho mone is p oduced and sec e ed in conce wi h insulin,
inhibi ing bo h insulin and glucagon sec e ion, and con olling
Re iew
1iBET - Ins i u o de Biologia Expe imen al e Tecnológica, Oei as, Po ugal; 2CEDOC - Ch onic Diseases Resea ch Cen e , Faculdade de Ciências Médicas,
Uni e sidade No a de Lisboa, Lisboa, Po ugal; 3ITQB-NOVA, Ins i u o de Tecnologia Química e Biológica An ónio Xa ie , Uni e sidade No a de Lisboa, Oei as,
Po ugal; 4Ins i u o de Medicina Molecula , Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal
*Co espondence o: Regina Menezes, PhD, menezes@ibe .p , egina.menez[email p o ec ed]; I o C. Ma ins, PhD, i [email p o ec ed].
h ps://o cid.o g/0000-0002-9284-8599 (I o C. Ma ins); h ps://o cid.o g/0000-0003-0552-8480 (Regina Menezes);
h ps://o cid.o g/0000-0002-3582-3504 (Ana F. Raimundo); h ps://o cid.o g/0000-0002-0752-8938 (So ia Fe ei a)
#Bo h au ho s con ibu ed equally o his a icle.
Funding: This wo k was suppo ed by iNOVA4Heal h – UID/Mul i/04462/2019, a p og am inancially suppo ed by Fundação pa a a Ciência e Tecnologia/
Minis é io da Educação e Ciência, h ough na ional unds and co- unded by FEDER unde he PT2020 Pa ne ship Ag eemen , Funding om INTERFACE
P og amme, h ough he Inno a ion, Technology and Ci cula Economy Fund (FITEC), FCT ia PTDC/BIA-MOL/31104/2017 and UID/Mul i/04462/2019-SubP oj
iNOVA4Heal h C44 ( o RM), PD/BD/135504/2018 ( o AFR), Sociedade Po uguesa de Diabe ologia o he Nuno Cas elo-B anco P ize – 2016 ( o RM), and ICM
acknowledges FCT-MCTES P og am “Concu so de Es ímulo ao Emp ego Cien í ico” (CEECIND/01670/2017).
How o ci e his a icle: Fe ei a S, Raimundo AF, Menezes R, Ma ins IC (2021) Isle amyloid polypep ide & amyloid be a pep ide oles in Alzheime ’s disease:
wo igge s, one disease. Neu al Regen Res 16(6):1127-1130.
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1128 ｜NEURAL REGENERATION RESEARCH｜Vol 16｜No.6｜June 2021
Re iew
adiposi y and sa ia ion. IAPP is highly amyloidogenic, leading
o in acellula agg ega es and, ul ima ely, o ex acellula
amyloid s uc u es which cause β-cell dea h and a e p esen
in abou 90% o diabe ic pa ien s, being hus a key disease
ma ke (Wes e ma k e al., 2011).
Key Role o Isle Amyloid Polypep ide, also
Known as Amylin
This ho mone is i s syn hesized as 89 esidue, p ep oIAPP,
a e wa ds losing i s signal pep ide in he endoplasmic
e iculum, o ming p oIAPP, which ma u es in he la e Golgi
complex in o IAPP. IAPP is hen s o ed alongside insulin in
sec e o y esicles o be eleased in esponse o glucose
s imulus (Wes e ma k e al., 2011). When demand o insulin
ises, IAPP syn hesis also inc eases, o e loading he β-cell
p ocessing machine y and leading o he accumula ion o
unp ocessed IAPP o ms. These in e media es a e conside ed
highly amyloidogenic, p omo ing IAPP oligome iza ion and
amyloid deposi ion (Raimundo e al., 2020).
Isle Amyloid Polypep ide & Alzheime ’s Disease
I is cu en consensus ha his “diabe es-associa ed pep ide”
can con ibu e o AD. The indubi able ele ance o agg ega ed
Aβ-42 and phospho yla ed Tau on AD pa hophysiology led
AD esea ch o be e y ocused on hese p o eins and in
hei agg ega ion, making o he con ibu ing ac o s o AD
de elopmen o be somewha dis ega ded (Tiwa i e al., 2019;
Raimundo e al., 2020). One such ele an ac o , pa ially
o e looked be o e, is he con ibu ion o diabe es and IAPP
owa ds de eloping AD. The e is e idence ha besides he
known e ec in he panc eas, IAPP has a signi ican impac
a he cogni i e le el ha a e ele an o AD, ia se e al
mechanisms (Figu e 1).
I was shown ha ci cula ing oligome ized IAPP is ound
in AD pa ien s’ plasma and may accumula e in ex a-
panc ea ic issues, such as he b ain (Schul z e al., 2019).
IAPP agg ega ion is linked wi h hype amylinemia, as inc eased
IAPP p oduc ion leads o he appea ance o mis olded
and agg ega ed species, by a seeding-nuclea ion model
(Mukhe jee e al., 2017), which hen o igina e dele e ious
e ec s on he b ain and pe iphe al o gans. IAPP is able o
a ec b ain unc ions independen ly o Aβ42 (S odulski e al.,
2014). IAPP deposi s a e ound in AD pa ien s’ b ains (Jackson
e al., 2013), ha a e no necessa ily co-localized wi h Aβ42
and e en i he e is no clea sign o diabe es (Lu z & Meye ,
2015). Mo eo e , ele a ed le els o IAPP can di ec ly cause
b ain mic o ascula inju ies (Ly e al., 2017). IAPP and Aβ42 can
also in e ac , wi h IAPP ac ing as a seed o Aβ42 deposi ion,
o igina ing c oss-seeded oligome s (Oska sson e al., 2015).
This is co obo a ed by he ac ha Aβ42 sel -assembly can be
p e en ed by an agg ega ion blocke based on IAPP (Yan e al.,
2007) and ha p amlin ide, an IAPP analogue, p o ec s agains
AD ela ed neu odegene a ion and demen ia in gene al
(Pa ick e al., 2019). Thus, he egions esponsible o Aβ42-
IAPP c oss in e ac ion a e p obably high-a ini y binding si es
in ol ed in sel -agg ega ion. P amlin ide, as an IAPP analogue,
likely p e en s he c oss in e ac ions, o p omo es o -
pa hways, no conduci e o ib il o ma ion (Raimundo e al.,
2020). IAPP may also agg a a e Aβ42 e ec s ia ROS gene a ion
and he ailu e o insulin-deg ading enzyme o deg ade insulin,
IAPP and Aβ42 (Lim e al., 2010). Aβ40, he majo componen
o AD ce eb o ascula plaques, also in e ac s and c oss-seeds
wi h IAPP (Kandimalla e al., 2017; Raimundo e al., 2020). All
mechanisms, bo h Aβ-dependen and -independen , aid onse
and p og ession o AD.
Alzheime ’s Disease & Diabe es
AD is also ela ed wi h insulin esis ance, as glucose le els in
he b ain a e unbalanced, gi ing ise o he e minology ype
3 diabe es, as a o m o AD (Kandimalla e al., 2017). Al hough
his c ea es a no el pe spec i e o AD, as a me abolic disease,
i is somewha misleading and limi a i e. AD is abo e all a
b ain disease and i can ce ainly be igge ed solely by Aβ
ela ed pa hways, independen ly o any ole o diabe es and/
o IAPP. S ill, some o ms o AD, unde he gene al b ain
disease umb ella, co espond o a “diabe es b ain pheno ype”
(Raimundo e al., 2020). This is a la ge concep han ype
3 diabe es, as i includes all o ms o AD whe e IAPP and
ela ed playe s in e e e, including in he absence o ypical
diabe es bu whe e he b ain is a ec ed. Fo ins ance, a
b ain ha los he abili y o espond o glucose, insulin and/
o insulin-like g ow h ac o (IGF), can easily su e neu onal
loss (Ri e a e al., 2005). In addi ion, dec easing he ac i i y
o insulin/IGF signalling cascades appea s o p e en AD-
like neu odegene a ion in o he o ganisms, p obably by
a ou ing mo e compac amyloid ib ils ha a e less bioac i e
and mo e innocuous (El-Ami e al., 2014). Al hough insulin
me abolism clea ly has a ole on a leas some o m(s) o AD,
he mechanisms behind i a e no well unde s ood. Insulin
esis ance leads o highe ac i a ion o kinases, leading o Tau
phospho yla ion and, la e , cell dea h (A nold e al., 2018).
Insulin esis ance di ec ly inc eases Aβ42 and i s p ecu so
p o ein le els, hus con ibu ing o AD ia Aβ- ela ed
mechanisms (Kandimalla e al., 2017; Raimundo e al., 2020).
In sum, al e a ions in insulin/IGF me abolism and signalling
inc ease AD bioma ke s and dep i e he b ain o physiological
ac ions, such as neu onal g ow h, synapses o ma ion/
di e en ia ion, and he o e all synap ic plas ici y, equi ed o
he cogni i e unc ion and lacking in demen ia (Kandimalla e
al., 2017).
Diabe es B ain Pheno ype Hypo hesis
Gi en he molecula e idence, one canno igno e he link
be ween diabe es and AD. A he epidemiologic le el, i is also
clea ha diabe ic pa ien s ha e highe incidence o demen ia
and AD (O e al., 1999). The e a e wo possible explana ions:
on one hand, IAPP may damage he b ain, whe he by sel -
assembly o in concomi an ac ion wi h Aβ-42 (i is e en
possible o conside i he second amyloid in AD); on he
o he hand, IAPP dyshomeos asis a ec s he whole body,
including he b ain, p omo ing AD as a esul (O e al., 1999;
Kandimalla e al., 2017; S odulski e al., 2014; Mukhe jee e
al., 2017; Raimundo e al., 2020). Mo e esea ch is needed
o cla i y he ex en o hese dele e ious e ec s. We p opose
he concep o a “b ain diabe es pheno ype” as a wo king
hypo hesis, in which AD may be caused by a dys egula ion o
glucose me abolism in he b ain, a lack o unc ion o insulin
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NEURAL REGENERATION RESEARCH｜Vol 16｜No.6｜June 2021｜1129
and IGF signalling, as well as by IAPP di ec ly, wi h o wi hou
Aβ-media ed mechanisms. AD is abo e all a b ain disease,
and o cou se he e a e diabe es independen mechanisms
ha ce ainly occu . Howe e , he con ibu ion o diabe es
ela ed mechanisms and o IAPP di ec ly (wi h and wi hou
Aβ) mus also be ho oughly esea ched, unde ha wo king
hypo hesis.
O e all, his e iew aims a spa king he in e es o
in es iga o s and highligh ing he impo ance o glucose
Figu e 1 ｜Diabe es-induced molecula , cellula and s uc u al al e a ions in he AD b ain.
(A) IAPP oligome s a e mos ly o med wi hin sec e o y esicles o panc ea ic β-cells, being hen co- eleased wi h insulin in o he blood s eam in esponse o
speci ic s imuli. IAPP oligome s a e memb ane-pe meable and may comp omise he BBB and di use in o b ain pa enchyma. In b ain mic o ascula pe icy es o
AD pa ien s wi h T2D, IAPP o ms in acellula oxic inclusions leading o nuclei agmen a ion, au ophagy impai men and loss o cell iabili y and unc ion. IAPP
oligome s may also engage ecep o o ad anced glyca ion end p oduc s, p omo ing in lamma ion and exace ba ing ce eb o ascula damage, namely o he
BBB. I also acili a es oxic accumula ion o IAPP in he b ain, whe e IAPP can di ec ly in e ac wi h neu ons as well as mic oglia and as ocy es, ac i a ing hem
and con ibu ing o AD pa hology de elopmen . A high concen a ions, IAPP can ac upon neu onal ecep o s (e.g., AMY3) o modula e signaling cascades ha
a e associa ed wi h long- e m po en ia ion (LTP) dis up ion and, consequen ly, synap ic ailu e. (B) Despi e IAPP being able o a ec b ain unc ions aside om
Aβ42 pa hology, IAPP and Aβ42 a e clea ly able o in e ac wi h each o he , wi h IAPP accele a ing Aβ42 agg ega ion and deposi ion. In ac , diabe ic AD pa ien s
ha e c oss-seeded ib ils and oligome s accumula ed in he b ain and cons i u ed by hese wo pep ides. Bo h indi idual and co-agg ega es o IAPP and Aβ42 a e
p one o ac i a e glial cells which, in esponse, p oduce and elease in lamma o y media o s (e.g., cy okines), c ea ing a pa hological en i onmen de imen al
o neu ons. Di ec ac i a ion o AMY3 neu onal ecep o s ia IAPP and Aβ42 leads o inc eased cy osolic cAMP le els and downs eam ac i a ion o molecula
pa hways (e.g., PKA, MAPK, AKT and cFos) in ol ed in neu oin lamma ion, Aβ pa hology and cell dea h. As a esul , a Ca2+ pe u bed in lux may occu and
dis u b he ER homeos asis, con ibu ing o neu onal apop osis. (C) AD is also a me abolic disease in some ins ances. IDE deg ades no only excess insulin in he
b ain bu also o he subs a es, such as Aβ. I IDE is occupied wi h insulin, i is no longe ee o deg ade Aβ. This impai s Aβ clea ance, causing senile plaques o
be o med. When he b ain loses capaci y o deal wi h glucose, insulin and IGF, classical AD molecula bioma ke s (Aβ agg ega es) appea and nega i ely impac
c ucial neu onal unc ions. These e en s p og essi ely impai b ain homeos asis and p omo e massi e neu odegene a ion, leading o AD and demen ia. AD:
Alzheime ’s disease; AMY3: amylin-3 ecep o s; Aβ: amyloid be a pep ide; BBB: blood-b ain ba ie ; ER: endoplasmic e iculum; IAPP: isle amyloid polypep ide;
IDE: insulin-deg ading enzyme; IGF: insulin-like g ow h ac o ; RAGE: ecep o o ad anced glyca ion end p oduc s; T2D: ype 2 diabe es.
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me abolism, insulin/IGF esis ance and IAPP in AD. As AD is a
mul i- ac o ial disease, such pe spec i e shi may pa e he
way o much-needed e ec i e he apies o AD pa ien s.
Acknowledgmen s: We acknowledge he unding agencies as indica ed.
Au ho con ibu ions: ICM w o e he ini ial d a . SF, AFR, and RM
cons uc ed he igu e and espec i e legend. All au ho s equally
con ibu ed o concep ual design, w i ing and e ision, in o de o cla i y
he concep s s a ed and elabo a e he inal manusc ip .
Con lic s o in e es : None.
Financial suppo : This wo k was suppo ed by iNOVA4Heal h – UID/
Mul i/04462/2019, a p og am inancially suppo ed by Fundação pa a a
Ciência e Tecnologia / Minis é io da Educação e Ciência, h ough na ional
unds and co- unded by FEDER unde he PT2020 Pa ne ship Ag eemen ,
Funding om INTERFACE P og amme, h ough he Inno a ion, Technology
and Ci cula Economy Fund (FITEC), FCT ia PTDC/BIA-MOL/31104/2017
and UID/Mul i/04462/2019-SubP oj iNOVA4Heal h C44 ( o RM), PD/
BD/135504/2018 ( o AFR), Sociedade Po uguesa de Diabe ologia o
he Nuno Cas elo-B anco P ize – 2016 ( o RM), and ICM acknowledges
FCT-MCTES P og am “Concu so de Es ímulo ao Emp ego Cien í ico”
(CEECIND/01670/2017).
Copy igh license ag eemen : The Copy igh License Ag eemen has
been signed by all au ho s be o e publica ion.
Plagia ism check: Checked wice by iThen ica e.
Pee e iew: Ex e nally pee e iewed.
Open access s a emen : This is an open access jou nal, and a icles
a e dis ibu ed unde he e ms o he C ea i e Commons A ibu ion-
NonComme cial-Sha eAlike 4.0 License, which allows o he s o emix,
weak, and build upon he wo k non-comme cially, as long as app op ia e
c edi is gi en and he new c ea ions a e licensed unde he iden ical
e ms.
Re e ences
A nold SE, A ani akis Z, Macauley-Rambach SL, Koenig AM, Wang
HY, Ahima RS, C a S, Gandy S, Bue ne C, S oeckel LE, Hol zman
DM, Na han DM (2018) B ain insulin esis ance in ype 2 diabe es
and Alzheime disease: concep s and conund ums. Na Re Neu ol
14:168-181.
El-Ami T, Moll L, Ca alhal Ma ques F, Volo ik Y, Reu eni H, Cohen
E (2014) A no el inhibi o o he insulin/IGF signaling pa hway
p o ec s om age-onse , neu odegene a ion-linked p o eo oxici y.
Aging Cell 13:165-174.
Jackson K, Ba isone GA, Diaz E, Jin LW, DeCa li C, Despa F (2013)
Amylin deposi ion in he b ain: A second amyloid in Alzheime
disease? Ann Neu ol 74:517-526.
Kandimalla R, Thi umala V, Reddy PH (2017) Is Alzheime ’s disease
a ype 3 diabe es? A c i ical app aisal. Biochim Biophys Ac a Mol
Basis Dis 1863:1078-1089.
Kupe s ein I, B oe sen K, Benilo a I, Rozenski J, Jonckhee e W,
Debulpaep M, Vande s een A, Sege s-Nol en I, Van De We
K, Sub amaniam V, B aeken D, Callewae G, Ba ic C, D’Hooge
R, Ma ins IC, Rousseau F, Schymkowi z J, De S oope B (2010)
Neu o oxici y o Alzheime ’s disease Aβ pep ides is induced by
small changes in he Aβ42 o Aβ40 a io. EMBO J 29:3408-3420.
Lim YA, Rhein V, Baysang G, Meie F, Poljak A, Ra e y MJ, Guilhaus
M, I ne LM, Ecke A, Gö z J (2010) Abe a and human amylin
sha e a common oxici y pa hway ia mi ochond ial dys unc ion.
P o eomics 10:1621-1633.
Lu z TA, Meye U (2015) Amylin a he in e ace be ween me abolic
and neu odegene a i e diso de s. F on Neu osci 9:216.
Ly H, Ve ma N, Wu F, Liu M, Saa man KE, Nelson PT, Sle in JT,
Golds ein LB, Biessels GJ, Despa F (2017) B ain mic o ascula
inju y and whi e ma e disease p o oked by diabe es-associa ed
hype amylinemia. Ann Neu ol 82:208-222.
Ma ins IC, Kupe s ein I, Wilkinson H, Maes E, Vanb aban M,
Jonckhee e W, Van Gelde P, Ha mann D, D’Hooge R, De S oope
B, Schymkowi z J, Rousseau F (2008) Lipids e e ine Aβ amyloid
ib ils o neu o oxic p o o ib ils ha a ec lea ning in mice. EMBO
J 27:224-233.
Mukhe jee A, Mo ales-Scheihing D, Sal ado es N, Mo eno-Gonzalez
I, Gonzalez C, Taylo -P esse K, Mendez N, Shahnawaz M, Gabe
AO, Sabek OM, F aga DW, So o C (2017) Induc ion o IAPP amyloid
deposi ion and associa ed diabe ic abno mali ies by a p ion-like
mechanism. J Exp Med 214:2591-2610.
Oska sson ME, Paulsson JF, Schul z SW, Ingelsson M, Wes e ma k
P, Wes e ma k GT (2015) In i o seeding and c oss-seeding o
localized amyloidosis: A molecula link be ween ype 2 diabe es
and Alzheime disease. Am J Pa hol 185:834-846.
O A, S olk RP, an Ha skamp F, Pols HA, Ho man A, B e ele MM
(1999) Diabe es melli us and he isk o demen ia: The Ro e dam
S udy. Neu ology 53:1937-1942.
Pa ick S , Co igan R, G izzan i J, Mey M, Blai J , Pallas M, Camins A,
Lee HG, Casadesus G (2019) Neu op o ec i e e ec s o he amylin
analog, p amlin ide, on Alzheime ’s disease a e associa ed wi h
oxida i e s ess egula ion mechanisms. J Alzheime s Dis 69:157-
168.
Raimundo AF, Fe ei a S, Ma ins IC, Menezes R (2020) Isle amyloid
polypep ide: a pa ne in c ime wi h Aβ in he pa hology o
Alzheime ’s disease. F on Mol Neu osci 13:35.
Ri e a EJ, Goldin A, Fulme N, Ta a es R, Wands JR, de la Mon e
SM (2005) Insulin and insulin-like g ow h ac o exp ession and
unc ion de e io a e wi h p og ession o Alzheime ’s disease: link
o b ain educ ions in ace ylcholine. J Alzheime s Dis 8:247-268.
Schul z N, Janelidze S, Byman E, Min hon L, Nägga K, Hansson
O, Wenns öm M (2019) Le els o isle amyloid polypep ide in
ce eb ospinal luid and plasma om pa ien s wi h Alzheime ’s
disease. PLoS One 14:e0218561.
S odulski S, Sha ma S, Bachs e e AB, B els oa d JM, Pascual C, Xie
XS, Saa man KE, Van Eldik LJ, Despa F (2014) Neu oin lamma ion
and neu ologic de ici s in diabe es linked o b ain accumula ion o
amylin. Mol Neu odegene 9:30.
Tiwa i S, A lu i V, Kaushik A, Ynda A, Nai M (2019) Alzheime ’s
disease: Pa hogenesis, diagnos ics, and he apeu ics. In J
Nanomedicine 14:5541-5554.
Wes e ma k P, Ande sson A, Wes e ma k GT (2011) Isle amyloid
polypep ide, isle amyloid, and diabe es melli us. Physiol Re
91:795-826.
Yan LM, Velko a A, Ta a ek-Nossol M, And ee o E, Kapu nio u
A (2007) IAPP mimic blocks Aβ cy o oxic sel -assembly: C oss-
supp ession o amyloid oxici y o Aβ and IAPP sugges s a
molecula link be ween Alzheime ’s disease and ype II diabe es.
Angew Chem In Ed Engl 46:1246-1252.
C-Edi o s: Zhao M, Qiu Y; T-Edi o : Jia Y
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