The Role of G Protein-coupled

8/4/2019 The Role of G Protein-coupled

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Alzheimers disease (AD) is a erodegeeratie dis order characterized the accmlatio of protei aceos aggregates ad erofirillar lesios composedof the amloid peptide ad the hperphosphorlatedmicrotle associated protei ta, respectiel. CrretAD therapies mail target acetl choliesterase (AChE),which roadl stimlates choliergic eros. Howeer,erodegeeratio is ot limited to a specific erotras mitter sstem. Gltamatergic, serotoergic, adreergicad peptidergic erotrasmitter sstems are also dereg lated i AD. Impaired eroal sigallig ma affect theproteolsis of the amloid precrsor protei (APP) adpromote amloid formatio i the AD rai. I addi tio, amloid toxicit ad erodegeeratio ma affecterotrasmissio, sggestig the iolemet of com plex positie feedack loops i the pathogeesis of thedisease. Coseqetl, a complemetar approach thaticldes stimlatio or promotio of erotrasmissioi additio to lowerig the amloid rde is a attractie

therapetic strateg for the treatmet of AD.Seeral stdies hae preseted compellig eidece

implicatig G protei copled receptors (GPCRs) ithe pathogeesis of AD ad i mltiple stages of theprocessig of APP. Seqetial cleaage of APP the , ad secretases, which are reglated GPCRs,determies the extet of amloid peptide geeratio(FIG. 1), ad amloid ca directl or idirectl affectGPCR fctio. I this Reiew, we discss the GPCRsthat hae ee implicated i choliergic, gltamatergic,adreergic ad serotoergic dsfctio i AD, focs ig o GPCR modlatio of the , , ad secretases,amloid depositio ad amloid plaqe formatio.

We address the iolemet of GPCRs i the amloidcascade ad pharmacological approaches to target theptatie therapetic properties of AD associated GPCRs.We also riefl discss the role of GPCRs i amloid mediated toxicit ad eroiflammatio.

Regulation ofa-secretaseThree ezmes, elogig to the ADAM (a disitegriad metalloproteiase) famil ADAM9, ADAM10 adADAM17 are ptatie secretases (reiewed iReF. 1). Cleaage of APP secretase occrs withithe amloid peptide seqece, precldig amloid geeratio ad prodcig the solle amio termialectodomai of APP (sAPP) ad a memrae achored83 amio acid carox termial fragmet (C83) (FIG. 1).Sseqet cleaage of C83 the secretase complexields the APP itracelllar domai (AICD) ad a shortfragmet termed p3. sAPP has erotrophic ad ero protectie properties2,3 ad ehaces log term potetia

tio (LTP)4. Lower leels of sAPP hae also ee fodi the cererospial flid (CSF) of patiets with AD5,sggestig that decreased secretase actiit ma co trite to the deelopmet of AD. Ths, secretase hastherapetic potetial, althogh frther work is eeded toealate the coseqeces of icreased secretase acti it i the rai. Of ote, it remais clear whether p3 istrl iocos6 as is geerall assmed.

The secretase mediated cleaage of APP is reg lated protei kiase C (PKC)7,8, cclic AMPproteikiase A (PKA)911, mitoge actiated protei kiase(MAPK)extracelllar sigal reglated kiase (ERK) 12ad phosphatidliositol 3 kiase (PI3K) 13. Specificall,

Department for Molecular

and Developmental Genetics,

Flanders Institute for

Biotechnology (VIB),

Leuven, Belgium, and Center

for Human Genetics,

Catholic University of Leuven,

Leuven, Belgium.

emails: Bart.Destrooper@

cme.vibkuleuven.be;

[email protected]

kuleuven.be

doi:10.1038/nrn2977

The role of G protein-coupledreceptors in the pathology of

Alzheimers diseaseAmantha Thathiah and Bart De Strooper

Abstract | G protein-coupled receptors (GPCRs) are involved in numerous key

neurotransmitter systems in the brain that are disrupted in Alzheimers disease (AD).

GPCRs also directly influence the amyloid cascade through modulation of the -, - and-secretases, proteolysis of the amyloid precursor protein (APP), and regulation of amyloid-

degradation. Additionally, amyloid- has been shown to perturb GPCR function. Emerging

insights into the mechanistic link between GPCRs and AD highlight the potential of this class

of receptors as a therapeutic target for AD.

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-secretase -secretase

M1 mAChRM3 mAChRmGluR1mGluR2mGluR55-HT2A5-HT2C5-HT4(d)5-HT4(e/g)CRHR1PACR

2ARGPR3CXCR2

2ARGPR3CXCR2

DORA2AR

p3

AICDC83 C99

sAPPsAPP

A

APP

AICD

ADAM

-secretase BACE1

-secretase

actiatio of these sigallig cascades shifts APP meta olism towards the secretase mediated pathwa adawa from secretase mediated amloid geera tio14,15(FIG. 1). Coersel, a recet std sggests thatchroic, rather tha acte, actiatio of PKC differ etiall reglates the PKC ad PKC isozmes, lead ig to icreased amloid geeratio 16. neertheless,meros stdies hae sggested that GPCRs ad acti

atio of their dowstream sigal cascades icreases theo amloidogeic processig of APP.

Muscarinic acetylcholine receptors. Mscariic acetl cholie receptors (mAChRs), a famil of fie receptorstpes (M1M5)17,18, hae ee implicated i thepathophsiolog of major diseases of the CnS, icld ig AD19 (BOX 1). Agoist idced actiatio of theM1 ad M3 mAChRs, which are copled to phosph oiositide hdrolsis ad PKC actiatio, stimlatessAPPrelease in vitro20,21, implicatig mAChR actiatioi icreased secretase actiit (FIG. 2). This effect islocked treatmet with a PKC ihiitor or a ms cariic atagoist20,21. Frthermore, the effect ca emimicked phorol esters, which directl actiate

PKC ad stimlate icreased release of sAPP15 ad p3(ReF. 14), ad decreased amloid geeratio 14,15.

The M1 mAChR is the most adat stpe ithe cortex ad hippocamps17,18,22, two major rairegios that deelop amloid plaqes ad erofiril lar tagles (nFTs) i AD. Postsaptic M1 mAChRsalso pla a major part i hippocamps depedet lear ig ad memor ad, i particlar, short term memorad memor cosolidatio23, which is impaired i AD2426.Therefore, cosiderale efforts hae ee directedtowards deelopig M1 mAChR selectie agoists thatare capale of restorig the cogitie deficits i patietswith AD. I a mose model of AD, a selectie M1 mAChRagoist, AF267b, redces the amloid ad ta relatedpathologies i the hippocamps ad cereral cortex, adresces impairmets i hippocamps depedet lear ig ad memor27. The effect o amloid seems to emediated a icrease i PKC actiatio, ERK1 adERK2 phosphorlatio, ad a icrease i ADAM17expressio, whereas the effect o ta is mediated aredctio i glcoge sthase kiase 3 (GSK3) acti

it ad a correspodig redctio i ta phosphorla tio27. Ths, the deelopmet of M1 selectie agoists forthe treatmet of AD cold proide a smptomatic ad adisease modifig treatmet i oe compod.

Geetic alatio stdies proide additioal spportfor the deelopmet of a M1 specific therap, as iac tiatio of the M1 mAChR leads to a strog icrease iamloid geeratio ad amloid plaqe formatio ia mose model of AD28. Althogh it has ee difficlt tosthesize fll specific M1 mAChR agoists, a allos teric M1 mAChR agoist, TbPD, was recetl reportedto e highl selectie for the M1 mAChR i rodets29.Perhaps most importatl, M1 selectie therap woldaoid the geeral icrease i ACh leels that followsadmiistratio of AChE ihiitors, which actiates allmAChRs, icldig the M2 ad M4 mAChRs thereceptor stpes that ihiit sAPP release ad aggra

ate amloid geeratio 28,30 egatig the eeficialeffects of M1 mAChR stimlatio.

Metabotropic glutamate receptors. Treatmet of primareroal cltres ad rai slices with a geeral meta otropic gltamate receptor (mGlR) agoiststimlatessAPPsecretio31, sggestig that oe or moremGlRsare liked to the processig of APP secretase. Thishas prompted frther iestigatio ito the iolemetof specific mGlR stpes i the pathogeesis of AD.

based o their pharmacolog, seqece homol og, G protei coplig ad associatio with specificsecod messeger sstems, mGlRs are diided itothree grops: grop I (mGlR1 ad mGlR5), grop II(mGlR2 ad mGlR3) ad grop III (mGlR4,mGlR6, mGlR7 ad mGlR8)32. Grop I mGlRsare positiel copled to phospholipase C (PLC)33ad participate i the reglatio of saptic plasticit34 adpostsaptic gltamatergic excitailit35. Grop IIad grop III mGlRs are egatiel copled to ade ll cclase, ihiit cAMP prodctio ad actiate theMAPK ad PI3K pathwas36,37. Grop I mGlR likedPLC actiit is dowreglated i the cereral cortex

Figure 1 | Mdlatn f APP png by GPcr. Cleavage of amyloid

precursor protein (APP) by -secretase generates the soluble amino-terminal

ectodomain of APP (sAPP) and the carboxy-terminal fragment C83. Subsequentcleavage of C83 by the -secretase complex yields the APP intracellular domain(AICD) and a short fragment termed p3. Several G protein-coupled receptors (GPCRs),

including muscarinic, metabotropic and serotonergicreceptors modulate

-secretase-mediated proteolysis. Alternatively, cleavage of APP by -secretasegenerates sAPP and the C-terminal fragment C99. Subsequent cleavage of C99 bythe -secretase complex yields the AICD and the amyloid- peptide. Of the GPCRsthat regulate this processing, the -opioid receptor (DOR) and the adensoine A

2A

receptor (A2A

R) have been shown to modulate -secretase-mediated cleavage of APP,whereas the

2adrenergic receptor (

2-AR), G protein-coupled receptor 3 (GPR3), and

CXC-chemokine receptor 2 (CXCR2) have been shown to modulate -secretase-mediated cleavage of C99 or C83. A, amyloid-; ADAM, a disintegrin andmetalloproteinase; BACE1, -site APP-converting enzyme 1; CRHR1, corticotrophin-releasing hormone (CRH) receptor type I; 5-HT, 5-hydroxytryptamine (serotonin);

mAChR, muscarinic acetylcholine receptor; mGluR, metabotropic glutamate

receptor; PAC1R, pituitary adenylate cyclase 1 receptor.

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74 | FEbRuARy 2011 | vOLuME 12 www.nat.m/vw/n



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Synaptoneurosome

A purifid synaps, containing

a prsynaptic sac

(synaptosom) attachd to a

rsad postsynaptic sac

(nurosom), that is modsty

nrichd for synaptic protins.

of patiets with AD38, ad in vitro data idicate thatmGlR5 stimlatio icreases the traslatio of APPmRnA39. b cotrast, mGlR2 is oerexpressed ithe hippocamps of patiets with AD40. Iterestigl,mGlR2 stimlatio leads to ERK actiatio, ta phos phorlatio ad a redctio i oxidatie stress idcederoal ctotoxicit41(FIG. 2).

A recet std demostrates that grop I mGlRstimlatio ofsynaptonurosoms leads to actiatio of ad secretases (ased o the accmlatio of C83 adC99, respectiel) ad icreased release of amloid

40

(ReF. 42), the 40 amio acid isoform of amloid that isati amloidogeic in vivo43.

Similar to grop I mGlRs,

grop II mGlR stimlatio actiates the ad secretases. Howeer, grop II mGlR stimlatio elicitsthe release of amloid

42 the 42 amio acid isoform

of amloid that aggregates ito amloid mch morerapidl tha amloid

40in vitro (reiewed i ReF. 44)

which is the predomiat isoform of amloid thataccmlates i the rais of patiets with AD ad isessetial for seedigamloid depositio in vivo45, 46.The grop II mGlR mediated icrease i amloid

42

cold e locked with a specific grop II mGlR atag oist, with ol a trasiet idctio of amloid

40

geeratio42. Ths, preglatio of grop I mGlR sig allig ma icrease saptic amloid

40geeratio,

whereas dowreglatio of grop II mGlR sigalligma decrease saptic amloid

42geeratio, spport

ig the ihiitio of grop II mGlRs as a therapeticapproach for AD. Ideed, grop II mGlR ihiitorsehace hippocamps depedet cogitie fctiosi rodets47, althogh the effect o amloid geeratioremais to e determied. It is also clear how grop IImGlRs ad grop I mGlRs prodce differetial effectso amloid

40ad amloid

42release.

5hydroxytryptamine receptors. Seeral lies of eidecesggest that 5 hdroxtrptamie (5 HT; also kow asserotoi) sigallig is impaired i AD, ad stdies iaimal models hae show the potetial of this recep tor sstem i particlar the 5 HT

2, 5 HT

4ad 5 HT

6

receptor stpes as therapetic targets to address thecogitie deficits i AD.

5 HT stimlates sAPP release throgh actiatio ofthe 5 HT

2A

ad 5 HT2C

receptors. 5 HT2A

receptor id ig is decreased i the AD rai48, ad polmorphic ari atios hae ee descried for the 5 HT

2Agee that ma

e risk factors for hallciatios49, aggressio50 ad majordepressio51 i AD. Althogh there is eidece to sggestthat the 5 HT

2Aad 5 HT

2Creceptors modlate sAPP

secretio in vitro52 ad in vivo53(FIG. 2), frther stdiesare reqired to determie whether this effect is mediated a chage i or secretase actiit ad whether thiseffect correlates with a chage i amloid geeratio.

The 5 HT4

receptors are highl expressed i the hip pocamps, asal gaglia ad amgdala54, ad mightalso e ioled i the memor ad cogitio defectsi AD. Applicatio of 5 HT to Chiese hamster oar

(CHO) cells that stal express the 5 HT 4 receptorehaces sAPP release10. Similarl, in vivo admiistra tio of prcalopride, a 5 HT

4agoist, to C57bL/6j mice

ad a ADtrasgeic mose model leads to a icreasei sAPP leels i the hippocamps ad cortex. Thiseffect is locked pretreatmet with the 5 HT

4receptor

atagoist GR125487 (ReF. 55). Pharmacological actia tio of the 5 HT

4receptor also stimlates ACh release

i the rat frotal cortex ad improes choliergic fc tio56, which is importat for memor acqisitio adretetio. Iterestigl, actiatio of the 5 HT

4receptor

leads to a redctio i amloid geeratio i eroalcltres from a mose model of AD57.

Box 1 | The cholinergic and amyloid cascade hypotheses

Th amyld aad hypth

The amyloid cascade hypothesis postulates that gradual changes in the metabolism and aggregation of amyloid-initiates a cascade of neuronal and inflammatory injury that culminates in extensive neuronal dysfunction and cell death

associated with neurotransmitter deficits and dementia145,146.

Th hlng hypthThe cholinergic hypothesis posits that a dysfunction in acetylcholine (ACh)-containing neurons substantially contributes

to the cognitive decline observed in Alzheimers disease (AD)147. This is based on the observation that cholinergic

transmission has a fundamental role in cognition and is disrupted in patients with AD148,149.

cnvgn f th amyld aad and hlng hypth

ACh is a key neurotransmitter involved in learning and memory150 that binds to distinct receptor subtypes in the brain:

nicotinic ACh receptors (nAChRs) and muscarinic ACh receptors (mAChRs). Nicotinic neurotransmission is implicated in the

pathogenesis of AD (TABle 1). Additional evidence suggests that the major mAChR subtypes involved in AD are the

postsynaptic M1 mAChRs, which mediate the effects of ACh, and the presynaptic M2 mAChRs, which inhibit ACh release151, 152.

Amyloid- deposition may contribute to the cholinergic dysfunction in AD by decreasing the release of presynapticACh and impairing the coupling of postsynaptic M1 mAChRs with G proteins. This leads to decreased signal

transduction, impairments in cognition, a reduction in the levels of amyloid precursor protein (APP), the generation of

more neurotoxic amyloid- and a further decrease in ACh release111. Genetic ablation of the M1 mAChR in atransgenicmouse model of AD decreases the production of the soluble amino-terminal ectodomain of APP (sAPP), increasesamyloid- generation and exacerbates the amyloid plaque pathology28, supporting the development of M1-selectiveagonists. In addition, M1 mAChR activation reduces tau phosphorylation27,153 and alleviates hippocampus-dependent

memory impairments27

, making M1 mAChRs a compelling therapeutic target for AD. Furthermore, receptor subtypespecificity will be of key importance as M2 and M4 mAChRs seem to inhibit sAPP release and potentially aggravateamyloid- generation28,30, and activation of nAChRs exacerbates the tau pathology154.

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Table 1 | G protein-coupled receptors reported to be involved in Alzheimers disease

rpt sbtyp Agnt antagnt snd mng Md f atn rlvan t AD rf

mAChR M1 or M3mAChR

Carbachol PLC, PKC and DAGPIP2 hydrolysis

a-secretase(unconfirmed)

sAPP andAb 15, 20, 21

AF267B PKC, ERK1 and ERK2GSK3b

ADAM17 Ab42 and tauNo effect on Ab

40

27

AF102B PIP2 hydrolysis a-secretase(unconfirmed)

Ab 177, 178

TBPB ND a-secretase(unconfirmed)

sAPPa andAb40 29

Group ImGluR

mGluR1 ormGluR5

DHPG ND a- orb-secretase C83, C99 and Ab40 42

mGluR1a ACPD PLCPIP2 hydrolysis


sAPP and sAPPa 31, 179, 180

Melittin PLA2 a-secretase(unconfirmed)

sAPP 180

Group IImGluR

mGluR2 ormGluR3

DCG-IV AC, MAPK and PI3KcAMP

a-secretase(mainly)b-secretase(transiently)

C83, C99 (transiently)and Ab

42

42

mGluR2 LY379268 ERK ND tau 41

5-HT2R 5-HT

2AR 5-HT PLA2

PIP2 hydrolysisa-secretase(unconfirmed)

sAPP and APLP2 52

5-HT2C

R 5-HT PLA2 and PKCPIP2 hydrolysis


sAPP and APLP2 52

Dexnorfenfluramine(DEXNOR)

ND a-secretase(unconfirmed)

Ab42 52, 53

5-HT4R Prucalopride or

renzaprideAC, Rac, Rap and EPACcAMP


sAPPa (in vitro andin vivo)

10, 55, 181

RS 67333 ND ND Ab 57

5-HT4(d)R Prucalopride ND a-secretase(unconfirmed)

sAPPa andAb 182

5-HT4(e/g)

R 5-HT PKA(H89)Rac, Rapand EPAC


sAPPaNo effect on Ab

10, 181

5-HT6R SB-74257 and SAM-531

(antagonists)*ND GABA

ACh and GluImproved cognitionand memory

63, 64(reviews)

CRHR1 CRH ACNF-B a-secretase(unconfirmed)

sAPPa 67

PAC1R PACAP ERK1, ERK2, PI3K

and PKC (partially,independent of MAPK)

a-secretase(ADAM10)

sAPPa 74

DOR DADLE ND b- and g-secretase Ab40 and Ab42 78

b2AR Isoproterenol orclenbuterol

ND g-secretase Ab40 and Ab42 80

ICI 118,551 (antagonist) ND Amyloid plaques

GPR3 Overexpression ND g-secretase Ab40 and Ab42 92

Genetic ablation Ab40 and Ab42CXCR2 SB-225002 (antagonist) ND g-secretase

expressionAb40 and Ab42 99

PI3K, ERK1 and ERK2 tau 183

AT2R Ab

42treatment ND AT2R oligomers

M1 mAChRsignalling

tau andneurodegeneration

110, 184

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As with 5 HT2A

, the post mortem rais of patietswith AD displa a redctio i the mer of 5 HT

4

receptor idig sites i the hippocamps58. Howeer, itremais clear whether the effects of the 5 HT

4recep

tor o APP metaolism are directl liked to a icreasei the actiit of the secretases or a effect o celllartraffickig of APP. neertheless, the eeficial effects oAPP processig ad the ehaced cogitie perform ace osered in vivo proide a theoretical fodatiofor frther deelopmet of 5 HT receptor mediated ADtherapetics.

I the CnS, the 5 HT6

receptor is mail localized ithe striatm, hippocamps ad cortex i rodets59, adpredomiatl i the cadate cles ad to a lesserextet the hippocamps ad amgdala i hmas 60.Althogh the 5 HT

6receptor has ot ee show to

directl modlate secretase actiit, 5 HT6

receptoratagoism improes cogitio ad memor forma tio ad retetio61. This effect is proal mediated icreasig the release of gltamate ad/or ACh,which ehaces memor cosolidatio (reiewedi ReF. 62).

Table 1 (cont.) | G protein-coupled receptors reported to be involved in Alzheimers disease

rpt sbtyp Agnt antagnt snd mng Md f atn rlvan t AD rf

A2A

R Caffeine (antagonist) ND b-secretasePS1 expression

Ab40 and Ab42 119

SCH 58261 (antagonist) p38 MAPK Ab toxicity 118, 120, 185

CCR2 Ab42

treatment ND ND CCL2 127

Genetic ablation(Tg2576)

Ab40 and Ab42 128

CX3CR1 Genetic ablation

(3xTgAD)ND ND Neuronal loss 131

GLP1R (Val8)GLP1 ND ND Ab42 or Ab2535 toxicity 164, 165

Exendin-4 ND Ab40 164

Exendin (19) MAPK, ERK1 and ERK2 Improved cognition 172

AMYreceptor

AC187 (antagonist) Caspase activation(JNK and p38 MAPK?)

ND Ab toxicity 175

a7nAChR Nicotine p38 MAPK ND tauNo effect on Ab

40or Ab

42

a7nAChR

154

Nicotine ND ND Ab40 and Ab42Amyloid plaqueformation

186,187

Ab42

treatment ERK1, ERK2 and JNK1 ND tau 188

Ab42

treatment ERK2 and CREB ND a7nAChR 189, 190

Ab42

treatment ND nAChR currents 191

Genetic ablation(PDAPP)

ND No effect on Aborplaque formation

synaptic markers andLTP Improved cognition

192

NMDAreceptor

Memantine** orMK-801 (antagonist)

NA Channel blocker APP, sAPP, sAPPa, Ab40

and Ab42

190, 193196

FPRL1 Ab42

treatment PLD, ERK1 and ERK2 ND Internalization of Ab 197

SSTR Somatostatin ND Neprilysin Ab42 139

*These compounds are in Phase II trials for the treatment of AD. **This compound has US Food and Drug Administration approval for the treatment of AD.Ab, amyloid-b; AC, adenylate cyclase; ACPD, 1-aminocyclopentane-1,3-dicarboxylic; AD, Alzheimer's disease; ADAM, a disintegrin and metalloproteinase; AMY,amyloid; APLP2, amyloid-like protein 2; A

2AR, adenosine 2A receptor; b

2AR, b

2adrenergic receptor; AT

2R, angiotensin type 2 receptor; cAMP, cyclic AMP; CCL2,

CC-chemokine ligand 2; CCR2, CC-chemokine receptor 2; CREB, cyclic AMP-responsive element-binding protein; CRHR1, corticotrophin-releasing hormonereceptor type I; CXCR2, CXC-chemokine receptor 2; CX

3CR1, CX

3C-chemokine receptor 1; DAG, diacyl glycerol; DHPG, dihydroxyphenylglycine; DOR, -opioid

receptor; EPAC, exchange protein directly activated by cAMP 1; ERK, extracellular signal-regulated kinase; FPRL1, formyl peptide receptor-like 1; GLP1R,glucagon-like peptide 1 receptor; Glu, glutamate; GPR3, G protein-coupled receptor 3; GSK3b, glycogen synthase kinase 3b; 5-HTR, 5-hydroxytryptaminereceptor; JNK, Jun N-terminal kinase; NA, not applicable; LTP, long-term potentiation; mAChR, muscarinic acetylcholine receptor; MAPK, mitogen-activated proteinkinase; mGluR, metabotropic glutamate receptor; nAChR, nicotinic acetylcholine receptor; ND, not determined; NF-B, nuclear factor B; PACAP, pituitaryadenylate cyclase-activating polypeptide; PAC

1R, pituitary adenylate cyclase 1 receptor; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol-4,5-

bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PS1, presenilin 1; sAPP, solubleamyloid precursor protein; sAPPa, soluble amino-terminal ectodomain of APP; SSTR, somatostatin receptor.

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Gi/o ATP

ERK1/2PI3K

sAPPAtau

sAPPC83AAPP synthesis

sAPPAtau

Potentiation ofNMDAR currents

Cognitive deficits

cAMPGGGq GGGqGG

AC

Agonistbinding

Agonistbinding

Agonistbinding

ERK1/2JAKSTATADAM17GSK3

Cognitivedeficits

G GGG G GG G

PKC

Antagonistbinding

Agonistbinding

Agonistbinding

PLCPLA

sAPPA

Improved cognitionand memory

sAPP

Gq/11Gi/o

5 HT6

receptor atagoists hae met with some sc cess i Phase I ad Phase II cliical trials. Cogitieimproemet was osered i patiets with AD treatedwith Sb 742457 followig completio of a Phase II cli ical trial. SAM 531, aother 5 HT

6receptor atagoist,

has also completed a iitial Phase II cliical trial withsome sccess (reiewed i ReFS 63,64). Iterestigl, apolmorphism i the 5HT

6gee seems to e a risk fac

tor for AD, as patiets with AD are more likel to carrthe C267Tallele ariat65, ad 5 HT

6receptor expres

sio is decreased i the prefrotal cortex of patietswith AD66.

Corticotrophinreleasing hormone receptor type I.Actiatio of the corticotrophi releasig hormoe(CRH) receptor tpe I (CRHR1) CRH stimlates aicrease i the release of sAPP i rat cereellar e ros, ad to a lesser extet i the hma erolastomaIMR32 cell lie ad i mose hippocampal HT22 cells67,althogh it remais to e determied whether this ismediated secretase. brai areas affected i ADshow morphological aormalities i CRH cotaiigeros ad also a dramatic redctio i the CRH le els68,69. Moreoer, cogitie impairmet is accompaied decreased cocetratios of CRH i the cererospial

Figure 2 | GPcr gnallng and th -ta pathway. G protein-coupled receptors (GPCRs) exert their multiplefunctions through a complex network of intracellular signalling pathways. Ligand-bound GPCRs activate heterotrimeric

G proteins, inducing the exchange of GDP for GTP and the formation of a GTP-bound G subunit and the release of a Gdimer. The G protein subunits then activate specific secondary effector molecules, such as adenylyl cyclase (AC),

phospholipase C (PLC) and phospholipase A2 (PLA2), leading to the generation of secondary messengers and activation of

extracellular signal-regulated kinase 1/2 (ERK1/2), Janus kinase (JAK) and phophoinositide 3-kinase (PI3K), and modulation

of the -secretase pathway. In the case of the M1muscarinic acetylcholine receptor (M1 mAChR), the group I metabotropic

glutamate receptors (mGluRs) and the 5-hydroxytryptamine receptors 5-HT2A/2C

R and 5-HT4R, agonist stimulation leads to an

increase in soluble amyloid precursor protein (sAPP) release, a decrease in amyloid- (A) generation, a decrease in tauphosphorylation and/or an alleviation of the cognitive deficits in a mouse model of Alzheimers disease (AD). Conversely,

agonist stimulation of the Group II mGluRs leads to an increase in amyloid-42

generation, tau phosphorylation and an

exacerbation of the cognitive deficits in an AD mouse model. In the case of the 5-HT6

receptor (5-HT6R), antagonism of the

receptor leads to an improvement in cognition. Solid arrows represent direct signalling pathways and dashed arrows

represent signalling via intermediates that are not shown. ACh, acetylcholine; ADAM, a disintegrin and metalloproteinase;

cAMP, cyclic AMP; GSK3, glycogen synthase kinase 3; NMDAR, NMDA receptor; PKC, protein kinase C; sAPP, solubleamino-terminal ectodomain of APP; STAT, signal transducer and activator of transcription.

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flid70. A possile applicatio of CRH for the treatmetof AD is mail ased o the memor ehacig effectsof CRH i rodets71.

Pituitary adenylate cyclase 1 receptor. The pititaradelate cclase 1 receptor (PAC

1R) is a GPCR that

is stimlated the eropeptide pititar adelatecclase actiatig polpeptide (PACAP). The receptoris primaril localized to the hpothalams t is alsoexpressed i the cereral cortex ad hippocamps72,areas of the hma rai affected AD. The major formof PACAP, composed of 38 amio acids (PACAP38), hasee show to improe memor i rats73. Together witha C termial trcated form, PACAP27, it stimlatesa icrease i sAPP release74. This effect is locked a road spectrm metalloprotease ihiitor ad aADAM10 specific ihiitor, GI254023X 74. Ths, stim latio of PAC

1R ehaces secretase actiit. Althogh

the moleclar mechaism of this effect has ot ee el cidated, eropeptide hormoes sch as PACAP27 adPACAP38 displa a high flx rate across the loodrai

arrier (bbb)75, which shold permit the in vivo exami atio of the effect of PACAP i a trasgeic mosemodel of AD.

Regulation ofb-secretaseThe secretase bACE1 ( site APP coertig ezme 1),is a tpe I trasmemrae aspartl protease that is actie atlow pH ad is predomiatl localized i acidic itracell lar compartmets, sch as edosomes ad the transGolgietwork.Cleaage of APP bACE1 geerates a sollen termial ectodomai of APP (sAPP ) ad the n ter mis of amloid . Sseqet cleaage of the mem rae od C termial fragmet C99 the secretaselierates the amloid peptide species (FIG. 1).

bACE1 is adatl expressed i eros i the rai.Bace1/ mice are iale ad fertile, facilitatig the stdof the role of this ezme i AD. bACE1 deficiec ia AD mose model arogates amloid geeratio,amloid patholog, electrophsiological dsfctio adcogitie deficits, implig that therapetic ihiitio ofbACE1 wold decrease geeratio of all amloid species. Howeer, Bace1/ mice displa pheotpic aor malities that are related to the processig of additioalproteis bACE1, sggestig that therapetic ihii tio of bACE1 cold hae aderse side effects (reiewedi ReFS 76,77). neertheless, bACE1 is argal theprimar therapetic target to deter amloid geera

tio. Detailed strctral aalsis of bACE1 has led tothe discoer of ma trasitio state ased ihiitorswith actiit i the low aomolar rage, althogh thein vivo efficac of these compods is limited ecasemost of them do ot peetrate the bbb or are actielexported from the rai P glcoprotei. Recet ei dece sggests that GPCRs sch as the opioid recep tor (DOR)78 cold proide a therapetic opportit tomodlate bACE1 ad amloid geeratio .

and opioid receptors. The opioid receptors, whichpla importat parts i learig ad memor, aredereglated i specific regios of the AD rai79. There

is eidece to sggest that the DOR, together with the 2

adreergic receptor (2AR), promotes the secretase

mediated cleaage of the APP C termial fragmet afterits geeratio secretase 80. A more recet std the same grop sggested that actiatio of the DORpromotes the traslocalizatio of a complex cosistigof the DOR, secretase ad secretase from the cellsrface to the late edosomes ad lsosomes (LEL),which reslts i ehaced ad secretase proteolsisof APP78. I a mose model of AD, admiistratio ofatridole, a selectie DOR atagoist, improed spa tial learig ad referece memor, ad redced theamloid plaqe rde78. Similarl, in vivo kock dowof the DOR redced amloid

40accmlatio i the

hippocamps of a AD mose model. Howeer, therewas o effect o the more hdrophoic (ad thereforemore toxic) amloid

42(ReF. 78). b cotrast, admi

istratio of a opioid receptor (MOR) atagoist hado effect o amloid geeratio or amloid plaqeformatio ad was ale to reerse the learig admemor deficiec of the AD mose model78, althogh

aother grop reported improed spatial memor rete tio i this trasgeic AD mose model81.

DOR idig is decreased i the amgdala ad e tral ptame, ad MOR idig is decreased i thehippocamps ad siclm79 of post mortem raisamples from patiets with AD. Eleated hippocampalleels of ekephali, the ligad for these receptors, haeee detected i AD trasgeic mice ad i the hmaAD rai81,82. Excessie stimlatio ekephali macople the opioid receptors from G proteis, reslt ig i receptor iteralizatio83,84 ad redced receptoridig i patiets with AD79,85. These adaptie chagesi opioid receptor expressio i respose to icreasedekephali leels might limit the efficac of opioidreceptor atagoists i AD ad cold explai the ari ale effects of differet DOR atagoists o amloid geeratio i AD trasgeic mose models.

Regulation ofg-secretaseThe secretase complex is composed of for itegralmemrae proteis: the cataltic compoet preseili 1(PS1) or PS2 ad the essetial cofactors icastri,aterior pharx defectie 1 (APH1) ad preseiliehacer 2 (PEn2)86. Proteolsis of the cleaage prod ct C83 the secretase complex geerates a short p3fragmet, which precldes formatio of amloid . bcotrast, proteolsis of the secretase prodct C99

the secretase complex geerates the amloid pep tide, which rages i legth from 35 to 43 resides(FIG. 1). The majorit of amloid prodced is 40 amioacids i legth (amloid

40), whereas a small proportio

(~10%) is the 42 reside ariat (amloid 42

). Seeral secretase ihiitors hae ee deeloped t the haelimited cliical efficac owig to the seere side effectsassociated with ihiitio of the notch receptor, which isa sstrate for secretase proteolsis. Therefore, deter miatio of the celllar mechaisms that specificallreglate amloid geeratio secretase is of crcialimportace for derstadig the factors that case ADad cold highlight ew therapetic targets.

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b2adrenergic receptor. Stimlatio of

2AR icreases

amloid geeratio in vitro, idepedetl of aeleatio i cAMP leels80. I a AD trasgeic mosemodel, treatmet with a

2AR agoist or atagoist

respectiel icreased ad decreased the amloid plaqerde80. It has ee sggested that the

2AR costit

tiel associates with PS1 at the plasma memrae addergoes clathri mediated edoctosis together withthe secretase complex followig agoist stimlatio 80.This proposed localizatio of the secretase i LELcompartmets, which is spported other stdies87,88,cold promote cleaage of C99 ad there the geera tio of amloid 80. As a therapetic applicatio, it wille importat to determie whether

2AR actiatio

also modlates cleaage of the notch receptor, gie theaderse side effects of targetig secretase discssedaoe. Importatl, the

2AR is expressed i the hip

pocamps ad the cortex i hmas89, ad polmor phisms i the gee ecodig the

2AR are associated

with a icreased risk of deelopig sporadic late oset AD90, proidig spport for the potetial cliical

releace of the in vitro ad AD mose model fidigs.

G proteincoupled receptor 3. G protei copledreceptor 3 (GPR3) is a orpha GPCR with a ptatieligad91 that has ot ee alidated92,93. The receptor wasidetified as a modlator of amloid geeratio i ahigh throghpt fctioal geomics scree desigedto idetif potetial therapetic targets for AD92. GPR3is strogl expressed i eros i the hippocamps,amgdala, cortex, etorhial cortex ad thalams i theormal hma rai94,95, ad its expressio is icreasedi a sset of patiets with sporadic AD92.

Seeral lies of eidece spport the iolemet ofGPR3 i the geeratio of amloid . In vitro models of ADsggest that this effect is idepedet of its ailit to stim late the prodctio of cAMP92. I a AD trasgeic mosemodel96, hippocampal oerexpressio of GPR3 ehacedamloid

40ad amloid

42geeratio i the asece

of a effect o secretase expressio 92. Geetic alatio ofGpr3 i these mice dramaticall redced amloid

40ad

amloid 42

leels92, demostratig that edogeos GPR3is ioled i amloid geeratio. Frther in vitro std ies sggested that GPR3 promotes icreased associatioof the idiidal secretase complex compoets withideterget resistat memrae domais ad stailizes thematre secretase complex 92.

Ths, similar to the 2AR, the effect of GPR3 sigal

lig o amloid geeratio is ot mediated throgh aeleatio i cAMP leels. Rather, oth GPCRs modlatethe traffickig ad/or localizatio of the secretase com plex to memrae domais where it ca more efficietlprocess the secretase prodct C99. Importatl, the invitro effect of GPR3 expressioo amloid geeratiooccrs i the asece of a effect o notch process ig, sggestig that GPR3 ca selectiel target specific secretase pathwas.

CXCchemokine receptor 2. The CXC chemokie receptortpe 2 (CXCR2) is adatl expressed i eros adis strogl preglated i a spoplatio of eritic

plaqes i the post mortem hma AD rai 97,98. I aAD trasgeic mose model, treatmet with the CXCR2atagoist Sb 225002 redces amloid

40leels99 ad

is accompaied a redctio i PS1C termial frag met (CTF) leels, resltig i a proale decrease ithe proteolticall actie matre secretase complex 99.Crossig the Cxcr2deficiet mose with a AD tras geic mose also reslts i a decrease i amloid

40

ad amloid 42

geeratio, ad secretase complexexpressio100. In vitro eidece sggests that atagoismof CXCR2 redces expressio leels of other secretasecomplex compoets, ihiitig geeratio of oth theAICD ad the notch itracelllar domai. WhetherCXCR2 is ioled i ehaced troer, degradatio orstailizatio of the PS1CTF has ot ee determied.Howeer, ihiitio of J n termial kiase (JnK)actiit, which is ioled i sigallig dowstream ofCXCR2, correlates with redced phosphorlatio adstailit of the PS1CTF101,102. Gie that atagoism ofCXCR2 leads to geeral chages i secretase expres sio ad actiit, it will e challegig to therapeticall

target CXCR2.

GPCRs and amyloid-b toxicityOe of the most pzzlig aspects of the amloid cascadehpothesis is wh amloid exerts a erotoxic effecto cells. There is o clear correlatio etwee exposreof the rai to amloid plaqes ad erodegeera tio ad, i cell cltre models, the toxicit associatedwith amloid is ariale ad poorl derstood. Smalloligomeric strctres of amloid , kow as amloid deried diffsile ligads (ADDLs) 103, case sapto toxicit, iterferig with gltamate sigallig at seeralleels, icldig direct ad idirect effects o Ca2+ leels,edoctosis, ad possil memrae damage ad cls terig of arios memrae proteis. A frther com plicatio is that a compoet of the toxicit associatedwith amloid might e the coseqece of a geeralmechaism sch as iteractio with the plasma mem rae, which cold affect mltiple GPCRs. Moreoer,seeral GPCRs are ioled i eroiflammatio, witheeficial or detrimetal effects o amloid mediatedtoxicit depedig o the model der iestigatio.

Ths, it remais clear how the iolemet ofGPCRs i amloid mediated toxicit ca e clii call exploited. Stdies o the agiotesi tpe 2 recep tor (AT

2R), the adeosie A2A receptor (A2AR) ad

CC chemokie receptor 2 (CCR2) proide isight ito

this complicated matter.

Angiotensin type 2 receptor. Agiotesi II ad theAT

2R hae ee implicated i seeral CnS fctios,

icldig eroal apoptosis104, ehaior105 admemor106. Actiatio of AT

2R ihiits stimlatio

of Gi/o

ad Gq/11

the AT1receptor107. Iterestigl,

costittie ad mscariic agoist depedet Gq/11

sigallig is also impaired i the AD rai108,109. Thereis eidece that oxidatie stress, idced eleatedamloid leels, leads to dimerizatio of AT

2R110.

Frther eleatio i amloid leels iitiates oli gomerizatio of AT

2R dimers ad seqestratio of

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Gq/11 Gq/11

ROSA

Alzheimers diseasepathology

Tau

PKC

Gq/11

Gq/11

AT2

R oligomers. The sseqet decrease iM1 mAChRG

q/11coplig ad actiatio correlates

with hippocampal erodegeeratio, ta phosphor latio ad eroal loss, cotritig to the deelop met ad exaceratio of the eropatholog of AD(reiewed i ReF. 111) (FIG. 3). This std idicates thatstimlatio of M1 mAChR sigallig , which alleiatesthe aetiopatholog of AD (discssed aoe), might ote sfficiet to improe cogitio i patiets owigto cocomitat toxic effects of the accmlatio ofamloid o other receptors ad their dowstreamsigallig pathwas.

Adenosine A2A

receptor. The adeosie receptors

are GPCRs that are classified as A1, A 2A, A2b ad A3receptors. A

1ad A

3receptors ihiit adell cclase

throgh Gi/o

proteis, whereas A2A

adA2b

receptorsstimlate adell cclase throgh G

sproteis112. The

A2A

Rs are mail expressed i striatal eros i thehma rai. I patiets with AD, the are also a datl expressed i microglia, the hippocamps adthe cortex113. Expressio of the A

1ad A

2Areceptors

is eleated i the frotal cortex of post mortem raisof patiets with AD114. A

2AR deficiet mice displa

improed spatial recogitio memor115, whereasin vivo oerexpressio of the A

2AR leads to memor

deficits116. Coseqetl, pharmacological lockade

or gee disrptio of adeosie A2A

Rs cofers ero protectio (FIG. 4a). Frthermore, caffeie, aA

1ad

A2A

receptor atagoist, is eroprotectie agaistamloid idced erotoxicit i cltred eros ofrats117 ad agaist amloid idced cogitie impair mets i mice118(FIG. 4b). Log term admiistratio ofcaffeie to APP trasgeic mice also improes cogitioad redces amloid

40ad amloid

42geeratio,

ad is accompaied a modest redctio i PS1 adbACE1 protei expressio leels119. This is spported stdies i rats sig a selectie A

2AR atagoist,

SCH 58261, which is protectie agaist amloid 42

idced saptotoxicit ad memor impairmet118,120.Howeer, earlier stdies hae sggested that caffeie,

ia raodie receptor reglated itracelllar calcimrelease chaels, stimlates a icrease i amloid geeratio in vitro121. neertheless, caffeie also stim lates acetlcholie release, a effect that is mediated lockade of the A

1AR122,123. Collectiel, these fidigs

sggest that the adeosiergic sstem is a promisigtherapetic aee for the maagemet of the cogitiedsfctio i AD.

Chemokine receptors.Microglia are macrophages ofthe CnS. The hae ee show to srrod amloidplaqes oth i patiets with AD ad i AD tras geic mose models124 , t whether the hae

Figure 3 | Amyld- txty and dglatn f AT2r and M1 mAchr gnallng . Oxidative stress and amyloid-

(A) accumulation leads to an increase in reactive oxygen species (ROS) generation and dimerization of angiotensin type 2receptors (AT

2R). An increase in levels of the protein-crosslinking enzyme transglutaminase, as occurs in Alzheimers

disease, and further A deposition trigger crosslinking and subsequent oligomerization of AT2R dimers. The AT

2R

oligomers sequester Gq/11

and thereby inhibit Gq/11

from coupling to M1 muscarinic acetylcholine receptors (M1

mAChRs). Sequestration of Gq/11

results in tau phosphorylation, neuronal degeneration and Alzheimers disease

progression. PKC, protein kinase C. Figure is reproduced, with permission, from REF. 111 (2009) American Associationfor the Advancement of Science.

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JNK

eeficial or detrimetal effects o plaqe formatioremais clear. Chemokie receptors are GPCRsthat are expressed microglia. CCR2 is reqiredfor macrophage ifiltratio at sites of axoal ijri the hippocamps125. The mai ligad for CCR2,CC chemokie ligad 2 (CCL2; also kow as MCP1),has ee localized to matre amloid plaqes i theAD rai126. Stimlatio of microglia ad astrocteswith amloid leads to a eleatio i CCL2 leels 127.I a mose model of AD, Ccr2 deficiec correlateswith decreased microglial accmlatio ad icreasedamloid depositio 128.

A recet std sggests the chemokie receptorCX

3C chemokie receptor 1 (CX

3CR1) plas a part i

the recritmet of microglia to ijred eros129,130ad is ioled i eroal loss131. The effect o am loid plaqe load was ot assessed i this AD mosemodel. neertheless, a redctio i or almost com plete alatio of microglia does ot affect the amloidplaqe load132 i aother AD mose model, sggestigthat microglia are ot essetial for iitiatio of cereral

amloidosis.

GPCRs and amyloid-b degradationPromotig amloid clearace from the rai isa alteratie therapetic strateg to ihiitio ofamloid geeratio. Sch a approach is the asis forthe passie ad actie immotherap with amloid specific atiodies. Howeer, stimlatio of GPCRs, iparticlar the somatostati receptor, cold represet aiterestig alteratie approach to promotig amloid clearace, as these GPCRs idce expressio of amloid degradig ezmes, sch as eprilsi, i the rai.A comiatio of memor ehacemet, eroprotec tio ad ati amloid actiit makes this a attractietherapetic approach for AD.

Somatostatin receptors. Somatostati (also kowas somatotropi release ihiitig factor, SRIF) is areglator peptide with two ioactie forms, SRIF14ad SRIF28, which are widel expressed throghotthe CnS ad fctio i erotrasmissio, proteisecretio ad cell proliferatio133,134.

Expressio of the two most adat SRIF recep tors i the rai, somatostati receptor tpe 2 (SSTR2)ad SSTR4, is redced i the cortex of hma patietswith AD135. Iterestigl, itracereroetriclar ijec tio of amloid

2535reslts i a selectie decrease i

SSTR2 mRnA ad protei leels i the temporal cor tex of rats, whereas cogitie deficits correlate withredced SRIF cocetratios i the CSF 136 or middlefrot grs (brodma area 9)137. SRIF leels are alsoredced i the CSF136, cortex135 ad hippocamps138 ofpatiets with AD.

Compellig eidece sggests that SRIF is a modla tor of eprilsi actiit i the rai139. neprilsi, oeof the mai amloid degradig ezmes, reglatesthe stead state leels of amloid

40ad amloid

42

in vivo140. SRIF has ee show to sigificatleleateeprilsi leels i primar mrie cortical eroalcltres, which accompaies a redctio i amloid

42

leels139. Coersel, eprilsi actiit ad localizatioare altered i the hippocamps of SRIF deficiet mice,with a correspodig icrease i amloid

42leels139.

There are coflictig reslts from AD trasgeic mosemodels, which show either a icrease141 or a decreasei SRIF leels142. Frther work is ecessar to clarif thecase of the chages i SRIF leels i these AD models.

Additional modulators of APP metabolism

This Reiew highlights the role of GPCRs ad theirsigal trasdctio cascades i themetaolism ofAPP. Howeer, meros additioal effectors ad

Figure 4 | Adnn A2A

pt and amyld--mdatd txty. a | Amyloid- (A) deposition has been shown toactivate the p38 mitogen-activated protein kinase (MAPK) signalling pathway, which leads to A-induced neurotoxicity.Pharmacological blockade of the adenosine A

2Areceptor (A

2AR) with the compound SCH 58261 reduces A-induced p38

MAPK phosphorylation, synaptotoxicity and cognitive impairment. b | Similarly, caffeine, an A2A

R antagonist, is also

protective against A-mediated toxicity and may regulate the expression levels of the -secretase, via the cRaf-1/nuclearfactor-B pathway and presenilin 1, which leads to a decrease in A

40and A

42deposition and is protective against

cognitive impairment in an Alzheimers disease mouse model. Solid arrows represent direct signalling pathways and

dashed arrows represent signalling via intermediates that are not shown. JNK, Jun N-terminal kinase.

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o GPCRs hae ee implicated as modlators ofAPP cataolism ad metaolism. These stdies haeee thoroghl addressed i a reiew Slack adWrtma143. briefl, growth factors sch as ere growthfactor which sigals throgh erotrophic trosiekiase receptor tpe 1 (nTRK1) ad ere growth fac tor receptor (nGFR; also kow as p75nTR), a memerof the tmor ecrosis factor receptor famil as wellas epidermal growth factor ad firolast growth factorhae ee show to ehace APP sthesis ad sAPPsecretio. I additio, seeral iflammator ctokiesare eleated i the serm ad/or rais of patiets with

AD, ad arios ctokies, iterlekis ad prostagla di E2 hae also ee implicated i the modlatio ofAPP sthesis, sAPP secretio ad/or amloid depo sitio. besides erotrasmitters, growth factors adctokies, the hormoe sigallig molecles oestrogead testosteroe, asopressi ad radkii hae alsoee implicated i the reglatio of APP sthesis admetaolism.

Concluding remarks

nmeros drg discoer efforts target the ihiitioof amloid prodctio, the preetio of amloid aggregatio ad the ehacemet of amloid clearace.

Althogh these ma seem to e straightforward io chemical pathwas, seeral feedack loops ehaceot ol amloid depositio t also its toxicit,clearace ad oerall impact o memor fctio aderoal health. Sch feedack loops also impl that amootherap will ot e sfficiet to preet the pro gressio of AD. based o the discssio aoe, it isclear that seeral GPCRs are ioled at ma stagesof AD disease progressio (TABle 1). There also seemsto e a pathologicall reiforcig loop etwee tpe 2diaetes ad AD, with GPCRs proidig a aeefor therapetic iteretio for oth diseases (BOX 2).

Drgs that target GPCRs cold diersif the smpto matic therapetic portfolio for AD ad potetiall pro

ide disease modifig treatmets. I this sese, thecomplemet the crret areas of iestigatio, which areprimaril focsed o secretase ihiitors77 ad amloidimmotherap144.

Gie that the crret ati amloidogeic therapder deelopmet is cosidered to e most effectieas a preetatie measre or i earl stages of AD, addi tioal drgs that preferetiall ehace cogitio willecome a ecessar complemet to treatmet, espe ciall as the disease progresses to more adaced stages.I this regard, GPCRs represet the largest therapetic

Box 2 | GPCRs, diabetes and Alzheimers disease

Glagn-lk pptd 1 pt

Type 2 diabetes (T2D) has been identified as a risk factor for Alzheimers disease (AD) 155, and insulin signalling has a role

in learning and memory156-158, which potentially links insulin resistance to AD dementia. Indeed, deregulated insulin

signalling has been observed in brains of patients with AD and may contribute to the development of AD159. The

combination of insulin with other antidiabetic medications is also associated with lower amyloid plaque density and a

diminution of the cognitive decline associated with AD160,161.

Strategies have therefore been developed to normalize insulin signalling in the brain to deter the progression of AD162

.One promising intervention is the use of the incretin hormone glucagon-like peptide 1 (GLP1) as a treatment for

neurodegenerative diseases163. In vivo administration of GLP1 or exendin-4, a more stable analogue of GLP1, reduces

endogenous levels of amyloid-40

in the mouse brain and protects against cell death164. In addition, GLP1 and the stable

analogue (Val8)GLP1 enhance long-term potentiation (LTP) and reverse the LTP impairment induced by amyloid-25-35

administration in rodents, which might underlie an improvement in cognitive function165. Most recently, (Val8)GLP1 also

prevented amyloid-40

-induced impairment in late-phase LTP, and spatial learning and memory in rodents166. Some

evidence also suggests that the desensitization of insulin receptors that occurs in AD can be reversed by activation of

GLP1 receptors (GLP1Rs)167.GLP1 binds to GLP1R, which activates diverse signalling pathways, including cyclic AMP, protein kinase A,

phospholipase C, phosphatidylinositol 3-kinase, protein kinase C and mitogen-activated protein kinase168171.

GLP1R-deficient mice display an impairment in synaptic plasticity163 and a decrease in the acquisition of contextual

learning, a learning deficit that can be reversed following hippocampal gene transfer ofGlp1r172. By contrast,

overexpression of GLP1R through hippocampal gene transfer markedly enhanced learning and memory in rodents172.

Taken together, these studies suggest that the GLP1R represents a novel and promising therapeutic target for AD.

Amyln ptAmylin (also known as islet amyloid polypeptide) is a peptide that was first isolated from amyloid deposits from the

pancreatic islets of Langerhans of patients with type 2 diabetes173. Interestingly, human amylin, which acts through the

G protein-coupled amylin receptor, possesses amyloidogenic and neurotoxic properties similar to amyloid-174.Accordingly, treatment of rat neuronal cultures with an amylin receptor antagonist, AC187, attenuates amyloid-

42- and

amylin-induced neurotoxicity by blocking caspase activation175. It would be interesting to determine whether treatment

with GLP1 could alleviate the cognitive deficits, and to determine the expression levels of GLP1R in this diabetic AD

mouse model.

Most recently, studies conducted by crossing two T2D mouse models with an AD mouse model have provided further

mechanistic insight into the relationship between diabetes and AD, demonstrating that the onset of diabetes exacerbates

cognitive dysfuntion in the absence of an elevation in amyloid- levels and leads to increased cerebrovascular inflammationand amyloid angiopathy176. Conversely, the diabetic AD mice display an accelerated diabetic phenotype relative to the

diabetic mouse model alone, suggesting that the amyloid pathology may adversely affect the T2D and vice versa.

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Alzheimer disease: a multifactorial view on the

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secreted amyloid precursor protein conferred by a

C-terminal heparin-binding domain.J. Neurochem.

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3. Small, D. H. et al. A heparin-binding domain in the

amyloid protein precursor of Alzheimers disease is

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target i the pharmacetical idstr ad proideample opportities for AD related drg deelop met. neertheless, progress i the field is hampered the difficlt i deelopig highl receptor specificligads ad the aderse side effects of crretl aail ale drgs. Recet adaces i the GPCR field sggest

that a more fctioal approach towards the classifi catio of GPCRs, which are ow orgaized accordigto strctral similarit, might ehace the therape tic potetial of GPCRs ad assist i the deelopmetof selectie GPCR cadidate drgs for AD ad maother diseases.

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