Examining the potential clinical value of curcumin in the ...

Curcumin derived from turmeric is well documented for its anti-carcinogenic, antioxidant and anti-inflammatory properties. Recent studies show that curcumin ... Skiptomaincontent Accessibilityhelp Weusecookiestodistinguishyoufromotherusersandtoprovideyouwithabetterexperienceonourwebsites.Closethismessagetoacceptcookiesorfindouthowtomanageyourcookiesettings. 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BritishJournalofNutritionArticlecontentsAbstractBeneficialpropertiesofcurcumin–historicalperspectivePotentiallyneuroprotectivepropertiesofcurcumin:animalstudiesandinvitroanti-βamyloidactivityofcurcuminpreventsβamyloidaggregationFocusingonfindingsinanimalstudiesEffectsofcurcuminonhumancognitionEpigenetics,Alzheimer’sdiseaseandcurcuminCurcuminsafetyprofile,tolerability,bioavailabilityandmodeofadministrationCurcuminasafluorochrome/radioligandinAlzheimer’sdiseasediagnosisReferencesExaminingthepotentialclinicalvalueofcurcumininthepreventionanddiagnosisofAlzheimer’sdisease PublishedonlinebyCambridgeUniversityPress:  14December2015K.G.Goozee,T.M.Shah,H.R.Sohrabi,S.R.Rainey-Smith,B.Brown,G.Verdile andR.N.MartinsShowauthordetailsK.G.GoozeeAffiliation:McCuskerKARVIAHResearchCentre,AnglicanRetirementVillages,Sydney,NSW2154,Australia SchoolofMedicalSciences,CentreofExcellenceforAlzheimer’sDiseaseResearchandCare,EdithCowanUniversity,Joondalup,WA6027,Australia SchoolofPsychiatryandClinicalNeurosciences,UniversityofWesternAustralia,Crawley,WA6009,Australia T.M.ShahAffiliation:SchoolofMedicalSciences,CentreofExcellenceforAlzheimer’sDiseaseResearchandCare,EdithCowanUniversity,Joondalup,WA6027,Australia SirJamesMcCuskerAlzheimer’sDiseaseResearchUnit,HollywoodPrivateHospital,Nedlands,WA6009,Australia H.R.SohrabiAffiliation:SchoolofMedicalSciences,CentreofExcellenceforAlzheimer’sDiseaseResearchandCare,EdithCowanUniversity,Joondalup,WA6027,Australia SirJamesMcCuskerAlzheimer’sDiseaseResearchUnit,HollywoodPrivateHospital,Nedlands,WA6009,Australia S.R.Rainey-SmithAffiliation:SchoolofMedicalSciences,CentreofExcellenceforAlzheimer’sDiseaseResearchandCare,EdithCowanUniversity,Joondalup,WA6027,Australia SirJamesMcCuskerAlzheimer’sDiseaseResearchUnit,HollywoodPrivateHospital,Nedlands,WA6009,Australia B.BrownAffiliation:SchoolofMedicalSciences,CentreofExcellenceforAlzheimer’sDiseaseResearchandCare,EdithCowanUniversity,Joondalup,WA6027,Australia SirJamesMcCuskerAlzheimer’sDiseaseResearchUnit,HollywoodPrivateHospital,Nedlands,WA6009,Australia G.VerdileAffiliation:SchoolofMedicalSciences,CentreofExcellenceforAlzheimer’sDiseaseResearchandCare,EdithCowanUniversity,Joondalup,WA6027,Australia SirJamesMcCuskerAlzheimer’sDiseaseResearchUnit,HollywoodPrivateHospital,Nedlands,WA6009,Australia SchoolofPsychiatryandClinicalNeurosciences,UniversityofWesternAustralia,Crawley,WA6009,Australia SchoolofBiomedicalSciences,CurtinHealthInnovationResearchInstituteBiosciences,CurtinUniversity,Bentley,WA6102,Australia R.N.Martins*Affiliation:McCuskerKARVIAHResearchCentre,AnglicanRetirementVillages,Sydney,NSW2154,Australia SchoolofMedicalSciences,CentreofExcellenceforAlzheimer’sDiseaseResearchandCare,EdithCowanUniversity,Joondalup,WA6027,Australia SirJamesMcCuskerAlzheimer’sDiseaseResearchUnit,HollywoodPrivateHospital,Nedlands,WA6009,Australia SchoolofPsychiatryandClinicalNeurosciences,UniversityofWesternAustralia,Crawley,WA6009,Australia * *Correspondingauthor:ProfessorR.N.Martins,fax+61893474299,[email protected] Figures Metrics ArticlecontentsAbstractBeneficialpropertiesofcurcumin–historicalperspectivePotentiallyneuroprotectivepropertiesofcurcumin:animalstudiesandinvitroanti-βamyloidactivityofcurcuminpreventsβamyloidaggregationFocusingonfindingsinanimalstudiesEffectsofcurcuminonhumancognitionEpigenetics,Alzheimer’sdiseaseandcurcuminCurcuminsafetyprofile,tolerability,bioavailabilityandmodeofadministrationCurcuminasafluorochrome/radioligandinAlzheimer’sdiseasediagnosisReferencesSavePDFSavePDF(0.57mb)ViewPDF[Opensinanewwindow]SavetoDropboxSavetoGoogleDriveSavetoKindleShareCiteRights&Permissions[Opensinanewwindow]AbstractCurcuminderivedfromturmericiswelldocumentedforitsanti-carcinogenic,antioxidantandanti-inflammatoryproperties.Recentstudiesshowthatcurcuminalsopossessesneuroprotectiveandcognitive-enhancingpropertiesthatmayhelpdelayorpreventneurodegenerativediseases,includingAlzheimer’sdisease(AD).Currently,clinicaldiagnosisofADisonerous,anditisprimarilybasedontheexclusionofothercausesofdementia.Inaddition,phaseIIIclinicaltrialsofpotentialtreatmentshavemostlyfailed,leavingdisease-modifyinginterventionselusive.ADcanbecharacterisedneuropathologicallybythedepositionofextracellularβamyloid(Aβ)plaquesandintracellularaccumulationoftau-containingneurofibrillarytangles.DisruptionsinAβmetabolism/clearancecontributetoADpathogenesis.InvitrostudieshaveshownthatAβmetabolismisalteredbycurcumin,andanimalstudiesreportthatcurcuminmayinfluencebrainfunctionandthedevelopmentofdementia,becauseofitsantioxidantandanti-inflammatoryproperties,aswellasitsabilitytoinfluenceAβmetabolism.However,clinicalstudiesofcurcuminhaverevealedlimitedeffectstodate,mostlikelybecauseofcurcumin’srelativelylowsolubilityandbioavailability,andbecauseofselectionofcohortswithdiagnosedAD,inwhomthereisalreadymajorneuropathology.However,thefreshapproachoftargetingearlyADpathology(bytreatinghealthy,pre-clinicalandmildcognitiveimpairment-stagecohorts)combinedwithnewcurcuminformulationsthatincreasebioavailabilityisrenewingoptimismconcerningcurcumin-basedtherapy.TheaimofthispaperistoreviewthecurrentevidencesupportinganassociationbetweencurcuminandmodulationofADpathology,includinginvitroandinvivostudies.Wealsoreviewtheuseofcurcumininemergingretinalimagingtechnology,asafluorochromeforADdiagnostics.KeywordsCurcuminAlzheimer’sdiseaseAmyloidRetinalimaging Type FullPapers Information BritishJournalofNutrition , Volume115 , Issue3,14February2016,pp.449-465DOI:https://doi.org/10.1017/S0007114515004687[Opensinanewwindow] CreativeCommons ThisisanOpenAccessarticle,distributedunderthetermsoftheCreativeCommonsAttributionlicence(http://creativecommons.org/licenses/by/4.0/),whichpermitsunrestrictedre-use,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited. Copyright Copyright©TheAuthors2015 Withtheageingofmanypopulationsworldwide,itispredictedthatoverthenextfewdecadestherewillbeamarkedincreaseinthenumberofpeoplewithdementia.Currentestimationsshowthat35·6millionpeopleworldwidehavedementia,whichispredictedtomorethantripleto115millionby2050( ReferencePrinceandJackson 1 ).Ofallthedementiasub-types,Alzheimer’sdisease(AD)isthemostcommon.ADisaneurodegenerativedisease,whichischaracterisedclinicallybytheprogressivelossofmemoryandcognitivefunctioning.MajorpathologicalfeaturesofanADbrainincludetheaccumulationofextracellularplaquesandfibrils,intracellularneurofibrillarytangles(NFT),aswellaschronicinflammationandwidespreadsynapticandneuronalloss,leadingtobrainatrophyanddysfunction.ThedepositionofamyloidplaquesissuggestedasadefiningfeatureoftheADbrain,asNFTarefeaturedinotherneurodegenerativediseases( ReferenceLee,GoedertandTrojanowski 2 , ReferenceFrost,KanagasingamandMacaulay 3 )(althoughplaqueshavealsobeenreportedincasesofnon-ADdementias).Nevertheless,hyper-phosphorylatedtauprotein,themajorcomponentofNFT,mayhaveacriticalroleintheprogressionofAD,asitactstogetherwiththemajorproteincomponentofamyloidplaques,βamyloid(Aβpeptides),drivingneurodegeneration( ReferenceIttnerandGötz 4 , ReferenceIttner,KeandDelerue 5 ).TheAβpeptideisgeneratedfromitsparentmolecule,amyloidprecursorprotein(APP),viasequentialproteolyticprocessingbytheenzymesβ-APP-cleavingenzyme-1(BACE1)andγ-secretase( ReferenceKrishnaswamy,VerdileandGroth 6 ),togeneratemultipleAβformsofvaryingaminoacidlengths.Aβpeptidesaggregatereadilyintooligomersandfibrils,andsmalloligomersofthelonger,moreeasilyaggregating42-amino-acidform(Aβ1-42)areconsideredtobethemostneurotoxicAβspeciesintheADbrain.Amyloiddepositionisthoughttooccurearlyinthediseaseprocess( ReferenceVillemagne,BurnhamandBourgeat 7 ),andtheaccumulationofsmallAβaggregates(‘oligomers’)isthoughttohaveacriticalroleinearlypathogeniceventsthatincludetauhyperphosphorylationandaccumulation,oxidativestressandinflammatoryprocessesthatleadtoneurodegenerationintheADbrain( ReferenceIttnerandGötz 4 , ReferenceWalshandTeplow 8 , ReferenceO’Malley,OktavianiandZhang 9 ). Withnocurrenteffectivedisease-modifyingtreatmentsavailable,findingpharmacological/non-pharmacologicalstrategiestohaltorslowdiseaseprogressionisofsignificantimportance.ThefailureofpotentialpharmaceuticalsinhumanclinicaltrialshashighlightedtheneedforresearchintoearlydiagnosisofAD.Thisisbecauseoftheconsiderablesynapticloss,neuronallossandbrainshrinkagealreadypresentbythetimeADclinicalsymptomsemerge,withtreatmentsaimedatslowingtheprogressofthediseasemorelikelytobeeffectivebeforeonsetofsymptoms,preferablyattheearliestpre-clinicalstage.Thecontinuinglackofeffectivepharmaceuticaldrugshasalsopromptedtheevaluationofalternativetherapeutics,suchasnutraceuticals.Curcuminisoneexamplewhere,becauseofitspropertiesasananti-inflammatory,antioxidant,Aβ-loweringagentandAβaggregationinhibitor,itshowspotentialasatherapeuticforAD.Inaddition,becauseofitsabilitytofluoresceandbindAβ,curcuminhaspotentialasanimagingagentfordiagnostics.Thisreviewoutlinesinvitro,invivoandhumanstudiesthathaveevaluatedthetherapeuticpotentialofcurcumininAD,anditdiscussesrecentresearchthathasassessedcurcuminasadiagnostictoolthroughitsuseinemergingretinalimagingtechnologies.AllhumanstudiesidentifiedinthisreviewmetcurrentNationalInstituteofHealthandtheAlzheimer’sAssociationdiagnosticguidelines( ReferenceMcKhann,KnopmanandChertkow 10 ). Beneficialpropertiesofcurcumin–historicalperspective Curcuminisextractedfromturmeric,aspicethatisderivedfromtherhizomesofCurcumaLongaandwhichbelongstotheZingiberaceae(ginger)family.Turmericisaperennialherb,nativetothemonsoonforestsofsouth-eastAsia,anditiscommonlyusedinIndian,AsianandMiddleEasternfoods.Inadditiontobeingusedasaculinaryspice,turmeric(SanskritHaridra,meaningthatwhichisyellow)hasbeenafrequentlyprescribedherbalmedicine.Reputedforitsblood-purifyingabilities( ReferenceMajeed,BadmaevandMurrary 11 – ReferenceGoel,KunnumakkaraandAggarwal 13 ),AyurvedamedicineandtraditionalPersianandChinesemedicinehaveprescribedcurcuminforcenturiesforitsbody-cleansingproperties,aswellasforpainassociatedwithinflammationoftheskinandmuscles.Curcuminhasalsobeenprescribedforasthma,bronchialhyperreactivity,allergy,anorexia,coryza,cough,sinusitisandhepaticdisease( ReferenceAmmonandWahl 14 ). Only3–5%ofturmericcomprisestheyellow-pigmentedchemicallyactivecurcuminoids,beingcurcumin(diferuloylmethane),demethoxycurcumin(DMC)andbisdemethoxycurcumin(BDMC)( ReferenceBegum,JonesandLim 15 ).Curcumin,consideredthemosttherapeuticofthethreecurcuminoids,wasfirstisolatedin1815byVogelandPelletier( ReferenceZhou,BeeversandHuang 16 ),althoughitschemicalstructurewasnotconfirmeduntilalmostacenturylater( ReferenceMilobedeska,KostaneckiandLampe 17 ). Thetwenty-firstcenturyhaswitnessedrenewedinterestincurcumin’sreputedtherapeuticeffects,whichhasresultedinconsiderablescientificenquiryandreview( ReferenceGoel,KunnumakkaraandAggarwal 13 , ReferenceZhou,BeeversandHuang 16 , ReferenceHamaguchi,OnoandYamada 18 – ReferenceBasnetandSkalko-Basnet 21 ).Cellstudies( ReferencePan,Lin-ShiauandLin 22 – ReferenceZhang,BrowneandChild 24 )reportcurcumintopossesspowerfulanti-inflammatoryproperties,whereasfurtherresearchinavarietyofinflammatoryconditionsdemonstratesitspotential.Forexample,animalandcellculturestudiesshowthatcurcuminreducesinflammationinarthritis( ReferenceJoe,RaoandLokesh 25 , ReferenceJackson,HigoandHunter 26 );humancelllinestudiesshowthatcurcuminiseffectiveinthemanagementofirritablebowelsyndrome( ReferenceHanaiandSugimoto 27 )andinhumanclinicaltrialsforpsoriasisandotherskindisorders( ReferenceKurd,SmithandVanVoorhees 28 , ReferenceThangapazham,SharmaandMaheshwari 29 ).Anti-proliferativeandanti-angiogenicinfluencesofcurcuminhavealsobeendemonstrated,anditstherapeuticbenefitsareshowninhumancancercellandtissueculture,includingprostate( ReferenceTsui,FengandLin 30 ),breast( ReferenceLiuandChen 31 ),pancreatic( ReferenceFriedman,LinandBall 32 )andbowelcancer( ReferenceLim,LeeandHuang 33 ),aswellasheadandnecksquamouscellcarcinoma( ReferenceJackson-Bernitsas,IchikawaandTakada 34 ). Curcuminisalsoconsideredapowerfulantioxidant,reportedtobeseveraltimesmorepotentthanvitaminEasafree-radicalscavenger( ReferenceZhao,LiandHe 35 ).Curcumin’santi-inflammatoryandantioxidantpropertieshavemorerecentlybeeninvestigatedwithrespecttoAD,asitisnowwellestablishedthatoxidativestress( ReferenceMartins,HarperandStokes 36 )andchronicinflammationarecentralintheearlypathogenicstagesofAD( ReferenceHardyandSelkoe 37 ).However,inadditiontocurcuminalteringADdevelopmentthroughanti-inflammatoryandantioxidantproperties,curcumin’sabilitytobindtoAβ,influencedepositionandaggregation,whilepossiblyalsomodulatingtauprocessing,hasattractedconsiderableinterestinADresearchlaboratories( ReferenceHuangandJiang 38 – ReferenceMutsuga,ChambersandUchida 41 ). ExtracellularAβplaquesandintraneuronalhyper-phosphorylatedtauarerecognisedashallmarkneuropathologicalfeaturesofAD( ReferenceKosik,JoachimandSelkoe 42 – ReferenceMasters,MulthaupandSimms 44 )inadditiontooxidativestressandinflammation,anditisbelievedthatabnormalAβmetabolism,resultinginhighlevelsoftoxicAβoligomers,combinedwithoxidativestressandinflammationformanADpathogeniccycleofneurodegeneration.Whiletheinitiatingstepofthisneurodegenerationremainstobeelucidated,thesechangesarethoughttobegindecadesbeforeclinicaldiagnosis;infact,theaccumulationofAβhasbeenshowninradiologicalimagingtostart20yearsormorebeforethefirstclinicalsignsofAD( ReferenceVillemagneandRowe 45 ).Aβaccumulationisreportedtobeassociatedwithimpairedsynapticfunction( ReferenceHaassandSelkoe 46 ),reducedneuriteoutgrowth( ReferenceManczak,MaoandCalkins 47 ),cerebralatrophy( ReferenceCash,LiangandRyan 48 , ReferenceChetelat,VillemagneandVillain 49 )andreducedcognitiveperformance,particularlywhendepositedwithinthetemporalregion( ReferenceChetelat,VillemagneandPike 50 ).Synaptic/neuronallossandNFTloadhavebeenshowntocorrelatepositivelywithcerebralatrophyandcognitivedecline,whereascerebralAβloadalsocorrelateswithcognitivedecline,althoughtoalesserextent( ReferenceVillemagne,BurnhamandBourgeat 7 ).However,thereisalsoalargebodyofevidencesuggestingthatsmalloligomersofAβareparticularlytoxictoneurons,causingmembranedamage,Ca2+leakage,oxidativedamage,disruptionstoinsulinsignallingpathwaysandsynapticfunction,aswellasmitochondrialdamage( ReferenceReddy,TripathiandTroung 51 – ReferenceZhao,LuoandJang 53 ).Asmentionedabove,Aβ-inducedchangesarebelievedtooccurearlyinthediseaseprocess,andthefindingsindicatethatinterventionsthatcaninterrupttheproductionofAβorAβoligomers,orfacilitatetheirremovalfromthecentralnervoussystem,arehighlydesirable.Modelledprojectionssuggestthatdelayingtheonsetofdementiabyeven1yearmayreducetheworldwideburdenofcasesinpeopleover60yearsbyasmuchasapproximately10%( ReferenceJohnson,BrookmeyerandZiegler-Graham 54 ),whereastheintroductionofaninterventionthatdelaystheonsetofdementiaby5yearscouldreducetheincidencebyalmosthalf( ReferenceBrookmeyer,GrayandKawas 55 , ReferenceVickland,MorrisandDraper 56 ).Therefore,earlypre-clinicalpreventiontherapy,whichcouldinfluencetheaccumulationorclearanceofcerebralAβandtaupathology,and/orreduceoxidativestressandchronicinflammation,thusslowingorreversingthesepathologicalchanges,wouldbehighlysignificantforthereductionofADprevalence. Potentiallyneuroprotectivepropertiesofcurcumin:animalstudiesandinvitroanti-βamyloidactivityofcurcuminpreventsβamyloidaggregation TheAβpeptideaggregatesreadily,firstintosmallaggregatesofAβknownasAβoligomersandthentheseoligomersaggregatefurthertoformfibrils,largerfibrilsandultimatelyplaquesofAβ.Althoughplaquesandlargefibrilsaretheeasiesttodetectimmunohistochemically,theseareconsideredtoberelativelyinert:asmentionedabove,thereisnowconsiderableevidencethatsmallAβoligomersarethemainneurotoxicspecies( ReferenceBieschke,HerbstandWiglenda 57 ).Therefore,itisinterestingthatsubstantialdatafrominvitrostudiesindicatethatcurcumincanbindtoAβandinfluenceitsaggregation.Forexample,curcuminhasbeenshowntoinhibitfibrilformationandextension,aswellastodestabilisepre-formedfibrilsinadose-dependentmanner,effectiveatconcentrationsabout0·1–1·0µm ( ReferenceOno,HasegawaandNaiki 58 ).LaterstudieshavesimilarlyshownthatcurcumincaninhibittheformationofsmallAβaggregates(Aβoligomers)inadose-dependentmanner( ReferenceReinkeandGestwicki 59 , ReferenceYang,LimandBegum 60 ). StudieshaveinvestigatedhowcurcumininfluencesAβaggregation,anddifferenttheorieshaveemerged–forexample,onetheoryinvolvescurcuminbindingtometalions.BiometalssuchasCu(Cu(II))andZn(Zn(II))arefoundinabundanceinthebrain,particularlyatsynapses.DysregulationofmetalhomeostasiscanleadtothebindingoftheseparticularmetalionstoAβ,andmanystudieshaveshownthatthisbindingacceleratesAβaggregation.Infact,elevatedlevelsofcertainmetalionshavebeenassociatedwithAD( ReferenceGhalebani,WahlstromandDanielsson 61 ),andconsiderableresearchhasbeenundertakentounderstandthenormalrolesoftheseionsinthebrain,aswellastherolestheionsmayhaveindiseasepathogenesis,particularlytherolesofCu(II)andZn(II)onAβaggregation( ReferenceFallerandHureau 62 ).SomerecentstudieshavesuggestedthatcurcumincomplexeswithCu(II)and/orZn(II)andthatthisinhibitsthetransitionfromlessstructuredoligomertoβ-sheet-richAβprotofibrils,whichinturnactasseedingfactorsforfurtherAβfibrillisation( ReferenceBanerjee 63 ).Recentstudieslookingattheeffectofcurcuminandcurcuminderivativesonmetal-inducedAβaggregationhaveshownthatGd-linkedcurcumin(Gd-Cur,apotentialAβimagingagent),comparedwithcurcuminandCur-S,awater-solubleformofcurcumin,couldmodulateCu-inducedAβaggregationtoagreaterextent( ReferenceKochi,LeeandVithanarachchi 64 ),supportingtheconceptoftherapeuticanddiagnosticusesfortheGd-Curcompounds. Othertheoriesdonotinvolvemetalions;instead,theysuggestthatcurcumin’sabilitytobindAβandinhibititsaggregationisbecauseofcurcumin’sthreestructuralfeatures:ahydroxylsubstitutiononthearomaticendgroup,arigidlinkerregionbetween8and16Åinlengthandasecondterminalphenylgroup( ReferenceReinkeandGestwicki 59 ).Morerecentstudiesusingatomicforcemicroscopyhavefoundthatcurcumin(andanothersmall-moleculeinhibitorresveratrol)bindstotheNterminus(residues5–20)ofAβ1-42monomersandpreventsoligomersof1–2nminsizefrombecominglarger3–5nmoligomers( ReferenceFu,AucoinandAhmed 65 ).YetanotherrecentstudyhasusedNMRspectroscopytoinvestigatethestructuralmodificationsofAβ1-42aggregatesinducedbycurcumin,andfoundthatcurcumininducesmajorstructuralchangesintheAsp-23–Lys-28saltbridgeregionandneartheAβ1-42Cterminus( ReferenceMithu,SarkarandBhowmik 66 ).ThestudyalsousedelectronmicroscopytoshowthattheAβ1-42fibrilsaredisruptedbycurcumin.Interestingly,inaDrosophilaADmodel,curcumin-fedfliesshowedacceleratedconversionofpre-fibrillartofibrillarAβ,therebyreducingtheneurotoxicityofpre-fibrillarAβ ( ReferenceCaesar,JonsonandNilsson 67 ).Overall,curcumineffectsarenotlimitedtomodulationofAβaggregation,andfurtherstudiesareneededtodeterminewhicheffect(s)arethemostrelevantinpromotingbrainhealthinpathologicalcognitivedecline. Curcumininfluencesβamyloidproduction InvitrostudieshaveshownthatAβproductionisinfluencedbycurcumin,ascurcuminhasbeenfoundtoinhibittheproductionofAβpeptidesbyalteringAPPtraffickingthroughthesecretorypathway( ReferenceZhang,BrowneandChild 24 ).Zhangetal.treatedmouseprimarycorticalneuronswithdifferentconcentrationsofcurcumin(1–20μm)for24handfoundthatbothAβ1-40andAβ1-42levelssignificantlydecreasedcomparedwithcontrols.ItwassuggestedthatcurcumincouldstabiliseanimmatureformofAPPandreducetheamountreachingthecellsurface,thusbeingavailableforendocytosis–aprocessnecessaryforAβproduction.InanAPP-transfectedhumanembryonickidneycellculturemodel(SwAPPHEK293),BDMCwasshowntoreduceBACE1messengerRNA(mRNA)andproteinlevels,whereasDMConlyaffectedBACE1mRNAexpression( ReferenceLiu,LiandQiu 68 ).Furthermore,inotherstudiesusinganeuronalcellline(pheochromocytomacells–thePC12cellline)3–30µmcurcuminsuppressedAβ-inducedBACE1up-regulation( ReferenceShimmyo,KiharaandAkaike 69 , ReferenceLi,ZhangandSi 70 ).Mostrecently,instudiesofanADDrosophilamodel,itwasfoundthatthecurcumincomponentBDMCwasthemosteffectiveatrescuingthefliesfromthemorphologicalandbehaviouraldefectscausedbytheoverexpressionofAPPandBACE1 ( ReferenceWang,KimandLee 71 ),possiblyviainhibitionoftheBACE1enzyme.Recognisingcurcumin’sabilitytoreduceAβproduction,byreducingBACE1mRNAanditscorrespondingprotein( ReferenceSathya,PremkumarandKarthick 72 ),curcuminhasbeenusedasapotentpositivecontrolintheanalysisofothercompounds/drugsthattargetnotonlyBACE1butalsometalchelation,Aβaggregationandoxidation( ReferenceJiaranaikulwanitch,GovitrapongandFokin 73 ).Insupportofcurcumin’smetalchelationproperties,curcuminwasshowntopreventtheup-regulationofAPPandBACE1inducedbysupraphysiologicallevelsofthemetalionsCu(II)andMn( ReferenceLin,ChenandLi 74 ). Curcumincaninhibitβamyloid-inducedtoxicity PreviousstudiessupportthenotionthatcurcumincanreduceAβ-inducedtoxicity.AstudybyParketal.( ReferencePark,KimandCho 75 )usedPC12cellculturespre-treatedwith10μg/mlcurcuminbeforeAβexposure.Comparedwithcontrols,pre-treatedcellshadasignificantreductioninoxidativestress,aswellaslowerCainflux,resultinginprotectionagainstDNAdamageandcelldeath.Curcumin(1–30μm)hasalsobeenshowntoattenuatetheproductionofAβ-inducedradicalO2speciesinneuronalcellcultures,and20μmcurcuminhasbeenshowntopreventstructuralchangesinAβtowardsβ-sheet-richsecondarystructures( ReferenceShimmyo,KiharaandAkaike 69 ).Furthermore,theprotectioncurcuminprovidedtoPC12cellsandtohumanumbilicalveinendothelialcellsagainstAβ1-42-inducedinjurywasattributedbyKimetal. ( ReferenceKim,ParkandKim 76 )toantioxidantmechanismsofcurcuminoids.Morerecently,invitrostudiesofmicrogliahaveshownthatcurcumincandampeninflammatorypathwaysthatpromoteneurodegeneration( ReferenceShi,ZhengandLi 77 ).Inthisstudy,curcumindose-dependentlyimprovedviabilityagainstAβ-42-inducedinflammation,asitabolishesAβ-42-inducedIL-1β,IL-6andTNF-αproduction.CurcuminwasalsoshowntoreduceERK1/2andp38phosphorylation,whichwasthenshowntoreducecytokineproductionbythemicroglia( ReferenceShi,ZhengandLi 77 ). Curcumin’sneuroprotectivepropertiesmayalsobeattributedtoitsroleincellsignalling.CellsignallingbytheWntpathways,viathetranscriptionco-activatorβ-catenin,controlsembryonicdevelopment,cellularproliferationandneurogenesis.Disruptionstothispathwayhavebeenshowntohaveasignificantroleinthepathogenesisofdiversediseasessuchascancer,metabolicdiseases,osteoporosis,epilepsy,aswellasAD.InstudiesofAPP-transfectedneuroblastomacells,curcuminwasfoundtoactivatetheWnt/β-cateninsignallingpathwaybyinhibitingtheactivityofglycogensynthasekinase3β(GSK-3β)( ReferenceZhang,YinandShi 78 ).GSK-3βisanegativeregulatorofWnt,andthusloweringitsactivitywillactivateWnt.However,justasimportantly,constitutivelyactiveGSK-3βcontributestoaberranttauphosphorylationandNFTformation,whicharehallmarkpathologicalchangesinAD( ReferenceOlivia,VargasandInestrosa 79 ),andthuscurcumin-inducedinhibitionofGSK-3βmayalsoreduceNFTformation.However,thebenefitsofcurcumininattenuatingtauphosphorylationandaccumulationhaveyettobeinvestigatedthoroughly.Interestingly,AβoligomershavealsobeenshowntoinactivateWntinhippocampalslices,byinducingtheWntantagonistDickkopf-1( ReferencePurro,DickinsandSalinas 80 ).ThesestudiescollectivelysuggestthatcurcumincaninfluenceGSK-3βandWnt/β-cateninsignalling,whicharebothkeyfactorsinADpathogenesis( ReferenceWan,XiaandKalionis 81 ).Furthermore,ithasbeenshownrecentlythatactivationoftheWnt/β-cateninsignallingpathwayinhibitsthetranscriptionofBACE1bybindingofT-cellfactor-4totheBACE1promotergene,therebyreducingthegenerationofAβ ( ReferenceParr,MirzaeiandChristian 82 ).Otherrecentstudiesusingmolecularmodellingsoftwareprogramshaveidentifiedcurcuminandrosmarinicacidaspromisingligandsthatmimictheinhibitoryactionofpeptidylinhibitorsofcaspase-3( ReferenceKhan,AkhtarandSharma 83 ).TherelationshipsbetweenAD-relatedproteinsandpathwaysdiscussedaboveprovidefurtherindicationofcurcumin’stherapeuticpotentialforthepreventionofAD. Curcuminandtheclearanceofβamyloid Oneanti-ADtherapeuticapproachinvolvesenhancingtheclearanceofAβfromthebrain.SeveralmechanismshavebeenproposedtoassistnormalclearanceofAβfromthebrain,suchasenhancingreceptor-orapo-mediatedtransportacrosstheblood–brainbarrier(BBB),effluxofAβfromthebrainbeingthebasisoftheperipheralsinkhypothesis,targetedimmuneresponsestoAβ,dissolutionofamyloidfibrilsandmicroglialactivationresultinginphagocytosisofamyloidplaques,asreviewedbyBatesetal.( ReferenceBates,VerdileandLi 84 ).ThesignificanceoftheinnateimmunesysteminAβclearanceremainspertinenttointerventionandtreatmentmodalities.Althoughpreviousattemptstousevaccinestoaugmenttheimmuneresponsewerehaltedbecauseoftheincidenceofsterileencephalitis( ReferenceFoster,VerdileandBates 85 ),interestinthisarearemainsstrong.MacrophageactivityandphagocytosisofAβhasbeenreportedtobedeficientinAD,suggestingacontributoryfactortoAβaccumulation( ReferenceFiala,LinandRingman 86 ).Furthermore,alaterstudythatpre-treatedtheADmacrophageswithcurcuminoidsresultedinincreasedAβuptakein50%ofthemacrophages( ReferenceZhang,FialaandCashman 87 ). Curcumin’sabilitytoreduceoxidativedamageandamyloidpathologyinADtransgenicmice,demonstratedbyGarcia-Allozaetal.( ReferenceGarcia-Alloza,BorrelliandRozkalne 40 ),alsosuggeststhatcurcumincaninfluenceamyloid-inducedcytopathology,ormacrophageprocessingofamyloid.Garcia-Allozaetal.usedmulti-photonandinvivoimagingtorevealamarkedamyloidclearanceeffect,with30%plaquesizereductionandslowedplaquedevelopment,inanimalsreceivingcurcuminfor7dviaintravenoustailinjections.Fialaetal. ( ReferenceFiala,LinandRingman 86 )examinedcurcumin’seffectonenhancingphagocytosisofAβatamolecularlevel,andfoundthatcurcuminrestoredthenormalAβ-inducedup-regulationofthetranscriptionofβ-1,4-mannosyl-glycoprotein4β-N-acetylglucosaminyltransferase(MGAT3),anenzymethoughttobeinvolvedinphagocytosis.Otherproteinssuchastoll-likereceptorswerealsoup-regulated.TheseresultsindicatethatcurcuminmaycorrectimmunedefectsinADpatients,suggestinganovelapproachtoADimmunotherapy( ReferenceFiala,LiuandEspinosa-Jeffrey 88 ).Inmorerecentstudiesbythesamegroup,itwasfoundthat1α,25(OH)2-vitaminD3(1,25D3)couldrestorethedefectiveAβphagocytosisinADmacrophages,andthatanuclearvitaminDreceptorantagonistcouldblockthisphagocytosis.Allphagocytesseemedtorespondto1,25D3,yetonlyasubsetrespondedtocurcuminoidsbyup-regulatingMGAT3.Nevertheless,inthosewhodidrespond,furtherstudiesdemonstratedthatthe1,25D3boundtoapocketofthevitaminD3receptorthatinfluencesgenomicevents,andcurcuminoidsboundtoanon-genomicpocket( ReferenceMasoumi,GoldensonandGhirmai 89 , ReferenceMizwicki,MenegazandBarrientos-Durán 90 ),producedanadditiveeffect. Curcumineffectsonlipidmetabolism Earlyresearch( ReferenceSoniandKuttan 91 – ReferenceSreejayanandRao 93 )reportedthatcurcuminhadcholesterol-loweringability,supportedbyPescheletal. ( ReferencePeschel,KoertingandNass 94 )whoreportedthatcurcuminhasahypocholesterolaemiceffect,basedonitseffectonhepaticgeneexpression.Fengetal.( ReferenceFeng,OhlssonandDuan 95 )alsofoundcurcumintolowercholesterollevelsthroughsuppressionofNiemannPickC1-like1protein,whichisresponsiblefortheuptakeofcholesterolthroughvesicularendocytosiswithintheintestine.Anotherpotentialmechanismforthehypocholesterolaemiceffectofcurcuminwasrevealedinstudiesofratsfedahigh-fatdiet,inwhichcurcuminwasfoundtodecreasesignificantlytheserumlevelsofTAG,totalcholesterolandLDL-cholesterol,whencomparedwithacontrolgroup:curcuminwasfoundtoup-regulatemRNAlevelsofcholesterol7α-hydroxylase(CYP7A1),arate-limitingenzymeinthebiosynthesisofbileacidfromcholesterol( ReferenceKimandKim 96 ).Morerecently,treatmentofsimilarhigh-fatdiet-fedratswithcurcumincombinedwithpiperinewasfoundtoproducesimilarchangestotheserumlipidprofilesoftheratsandincreasedHDLlevels,resultinginsignificantup-regulationoftheactivitiesandgeneexpressionofapoA-I,lecithin–cholesterolacyltransferase,CYP7A1andtheLDLreceptor( ReferenceTu,SunandZeng 97 ).AshypercholesterolaemiacontinuestobeconsideredalikelycontributortoADrisk( ReferenceZambón,QuintanaandMata 98 , ReferenceRefolo,PappolaandMalester 99 ),theuseofcurcuminifproventolowercholesterolcouldrepresentanotherapproach,addingtothearmouryforADriskreduction. Curcuminandtelomerase Xiaoetal.( ReferenceXiao,ZhangandLin 100 ),investigatingtheroleoftelomerase(aribonuclearproteincomplexthatsynthesisesandelongatestelomericDNA)intheneuroprotectiveefficacyofcurcumin,foundcurcumintobeprotectiveagainstAβ-inducedoxidativestressandcelltoxicity.ThisneuroprotectionwaslostwhentelomerasewasinhibitedbytelomeraseRTsmallinterferingRNA,indicatingthattheneuroprotectionprovidedbycurcuminwasdependentonthepresenceoftelomerase. Focusingonfindingsinanimalstudies SeveralinvivostudieshavefoundthatAβdepositionandplaqueburdeninAD-modeltransgenicmiceisdecreasedfollowingtreatmentwithcurcumin( ReferenceGarcia-Alloza,BorrelliandRozkalne 40 , ReferenceYang,LimandBegum 60 , ReferenceLim,ChuandYang 101 , ReferenceWang,ThomasandZhong 102 ).CurcuminhasalsobeenfoundtoinhibitAβ-inducedtauphosphorylation( ReferenceMa,YangandRosario 103 ),toreducemicroglialactivation,indicatingareductionininflammation( ReferenceWang,ThomasandZhong 102 , ReferenceFrautschy,HuandKim 104 ),andreducedoxidativedamage( ReferenceFrautschy,HuandKim 104 ).OtherstudiesoftransgenicmousemodelsofADhaveshownthatcurcumincanreducegenomicinstabilityevents( ReferenceFenechandThomas 105 ). InthestudybyLimetal. ( ReferenceLim,ChuandYang 101 ),AD-modelTg2576miceaged10monthsoldwerefedacurcumindiet(160partspermillion(ppm))for6months.Theresultsshowedthatthecurcumindietsignificantlyloweredthelevelsofoxidisedproteins,theinflammatorycytokine,IL-1β,theastrocytemarkerglialfibrillaryacidicprotein(GFAP),solubleandinsolubleAβandalsoplaqueburden.ThestudyfoundthatthereductioninGFAPwaslocalised,suchthatincreasedactivitywasshowninareasaroundplaques,demonstratingastimulatoryeffectofcurcuminonthephagocytosisofplaquesbymicroglia.Frautschyetal. ( ReferenceFrautschy,HuandKim 104 ),usingSprague–DawleyratsinfusedwithAβ40andAβ42toinduceneurodegenerationandAβdeposits,foundthatdietarycurcumin(2000ppm(5·43μmol/g))suppressedAβ-inducedoxidativedamageandmemoryimpairment,andincreasedmicrogliallabellingwithinareasadjacenttoAβdeposits.Theyalsofoundthatcurcuminreversedchangesinsynaptophysinandpost-synapticdensity95(PSD-95)levels,associatedwithbrainplasticity,aswellasimprovedratperformanceinlengthandlatencywithinthewatermazetest( ReferenceFrautschy,HuandKim 104 ).InsimilarstudiesofagedTg2576AD-modelmicebyYangetal. ( ReferenceYang,LimandBegum 60 ),itwasdemonstratedthatcurcumininjectedperipherally(viathecarotidartery)cancrosstheBBBandbindtoamyloidplaquesandinhibittheformationofAβoligomersandfibrils( ReferenceYang,LimandBegum 60 ).Later,Begumetal.( ReferenceBegum,JonesandLim 15 )showedsimilarresultsandsuggestedthatthedienonebridgepresentinthechemicalstructureofcurcuminisnecessaryforthisreductioninplaquedepositionandthelowerproteinoxidationobservedinthecurcumin-treatedTg2576mice. Morerecently,Belviranlietal.( ReferenceBelviranli,OkudanandAtalik 106 )showedthatagedfemaleratssupplementedwithcurcuminfor12ddemonstratedimprovedspatialmemory(Morriswatermazetest),andtheirbrainsexhibitedreducedoxidativedamage.InotherstudiesusinganAβ-infusedmaleSprague–DawleyratmodelofAD,theeffectsofcombinedcurcuminoids,aswellastheindividualcurcuminconstituents,wereexaminedinrelationtogenesrelatedtosynapticplasticity.Thegenesthatwereinvestigatedincludedactin,Ca/calmodulin-dependentproteinkinasetypeIV,PSD-95andsynaptophysin,andsignificanteffectswerenoted;forexample,asignificantincreaseinsynaptophysinexpressionwasfoundfollowingtreatmentofthehippocampuswithcurcuminoids,andbothDMCandcurcuminwerefoundtoincreasePSD-95expressionseveral-fold( ReferenceAhmed,EnamandGilani 107 ),demonstratingresultssimilartotheearlierratstudycarriedoutbyFrautschyetal.( ReferenceFrautschy,HuandKim 104 ). Curcuminandneurogenesis Curcuminhasalsobeenfoundtostimulateproliferationofembryonicneuralprogenitorcellsandneurogenesisintheadulthippocampus,demonstratingotherpotentiallybeneficialeffectsonneuroplasticity( ReferenceKim,SonandPark 108 ).Inthisstudy,intraperitoneallyadministeredcurcuminactivatedextracellularsignal-regulatedkinases(ERK)andp38kinases,whichfunctionincellularsignaltransductionpathwaysthatareknowntobeinvolvedintheregulationofneuronalplasticityandstressresponses.Morerecently,ahybridcompoundofcurcuminandmelatonin(5-(4-hydroxy-phenyl)-3-oxo-pentanoicacid(2-(5-methoxy-1H-indol-3-yl)-ethyl)-amide),knownasZ-CM-I-1,developedwiththeaimofimprovingneuroprotectivepropertiesandBBBpermeability,wasfoundtoreduceAβaccumulationinthehippocampusandcortexofAPP/PS1transgenicmice,andtoincreasetheexpressionofthesynapticmarkerssynaptophysinandPSD-95,followingoraladministrationatadoseof50mg/kgfor3months( ReferenceGerenu,LiuandChojnacki 109 ),encouragingfurtherdevelopmentofthishybridcompound.APP/PS1micewerealsousedinanotherrecentstudy,whichtestedtheeffectof6months’dietarysupplementationwiththecurcuminderivative1,7-bis(4'-hydroxy-3'-trifluoromethoxyphenyl)-4-methoxycarbonylethyl-1,6-heptadiene-3,5-dione(FMeC1).ItwasfoundthatFMeC1supplementationresultedinlessAβdeposits,glialcellactivityandcognitivedeficits,whencomparedwithuntreated,curcumin-treatedorFMeC2-treatedmice,suggestingthatFMeC1haspotentialinthetreatmentofAD( ReferenceYanagisawa,IbrahimandTaguchi 110 ).Inratstudies,genetictranscriptionalresponsesalongwithenhancedhippocampalneurogenesiswasseen,following12weeksofadministrationofacurcumin-containingdiet,ascomparedwith6weeksofthisdiet,oracontroldiet( ReferenceDong,ZengandMitchell 111 ),providingfurtherevidencethatcurcuminmaybebeneficialthroughthepromotionofneuronalcellgrowth. Curcuminandtheblood–brainbarrier StudiesofratandmousemodelsofischaemicdamagefoundthatcurcumincouldprotecttheBBB,mostlikelybecauseofanti-inflammatoryandantioxidanteffects( ReferenceGhoneim,Abdel-NaimandKhalifa 112 , ReferenceThiyagarajanandSharma 113 ),andlaterstudiesofcerebralischaemiainratsfoundthatasingleintravenousinjectionofcurcumincouldreduceinfarctvolumeandneurologicaldeficit,possiblybecauseofinhibitionofinduciblenitricoxidesynthase( ReferenceJiang,WangandSun 114 ).Morerecentstudiessuggestthatcurcuminup-regulateshemeoxygenase-1expressiontoreducedamageandpermeabilityoftheBBB( ReferenceWang,GuandQin 115 ).Encouragingly,aninvivoratstudy,usingnanoparticulationofcurcumin,wasabletodemonstrateincreasedorgan,aswellasthebrain,perfusionbycurcumin,byprolongingretentiontimeinthehippocampusby83%andinthecerebralcortexby96%( ReferenceTsai,ChienandLin 116 ).Morerecently,anothergroupproducedahighlystablenanocurcuminformulation(particulesize<80nm)forusewithinaninvitroandinanADtransgenicmousemodel.Thestudyshowedhigherconcentrationsofthenanoformulationinplasmaandwithinthebraincomparedwithnon-capuslatedcurcuminorplacebo,whiledemonstratingsignificantimprovementsinworkingandcuedmemoryfunction( ReferenceCheng,YeungandHo 117 ). Curcuminanalogueswithsimilarbiologicalactivitytocurcumin,yetwithimprovedpharmacokineticcharacteristics,includingincreasedbioavailabilityandwatersolubility,arecontinuingtobedeveloped( ReferenceAnand,NairandSung 118 , ReferenceZonaandLaFerla 119 ),whilenewsyntheticproductsarealsoemerging( ReferenceZonaandLaFerla 119 ).Nanotechnologyisparticularlypromising,wherebynanoencapsulationmaybeabletoachieveasynergisticdrugdeliverysystem( ReferenceRe,GregoriandMasserini 120 ).Encouragingresultshavealreadybeenreportedinastudyexaminingcurcuminforuseinbreastcancerchemoprevention,whichusedinjectablepolymericmicroparticlesinmice,achievingbothsustainedbloodcurcuminlevelsforalmostamonthwhilemaximisingitsBBBpenetration,aswellasinhibitingtumourvasculature( ReferenceShahani,SwaminathanandFreeman 121 ).Otherstudiesexploringnanoparticletechnology( ReferenceChiu,LuiandMajeed 122 , ReferenceShaikh,AnkolaandBeniwal 123 )havebeenequallypromising.Forexample,followingtheintravenousadministrationofliposomalcurcumin,polymericnanocurcuminandpoly-lactic-co-glycolicacidco-polymer-curcumininrats,allofthesecompoundswerefoundtocrosstheBBB( ReferenceChiu,LuiandMajeed 122 ),whereasinanotherstudynanoparticlescontainingcurcuminwereshowntoincreaseoralbioavailability9-fold( ReferenceShaikh,AnkolaandBeniwal 123 ).FurtherevidenceofBBBpenetrationhasbeenobtainedinanimalmodelsusinglabelledcurcuminderivatives( ReferenceZonaandLaFerla 119 ). Curcuminandacetylcholinesterase Inadditiontotheeffectsabove,curcuminhasalsobeenshowntoinfluenceacetylcholinesteraseactivities( ReferenceAhmedandGilani 124 ),followingthesamepathwayasthecommonlyprescribedpharmaceuticals,acetylcholinesteraseinhibitors,whichareconsideredfirst-linemanagementinAD( ReferenceHamaguchi,OnoandYamada 18 , ReferenceGauthierandMolinuevo 125 ).TheadministrationofacetylcholinesteraseinhibitorshasbeenfoundincertaincircumstancestoslowtheprogressionofADsymptomsorevenreduceADsymptomsfora12-monthperiod,byinhibitingthebreakdownofacetylcholine,amajorneurotransmitter,depletedintheADbrain.Usinginvitroandexvivomodelsofacetylcholinesteraseactivity,Ahmedetal. ( ReferenceAhmed,EnamandGilani 107 )investigatedwhethercurcuminhadaninfluenceonacetylcholinesterasemechanisms,andrecordeddose-dependentinhibitoryeffectsinthefrontalcortexandinthehippocampaltissue;curcuminoidsalsodemonstratedsignificantattenuationofscopolamine-inducedamnesia.Furthermore,Ahmedetal.( ReferenceAhmed,EnamandGilani 107 )examinedtheinfluenceofcurcuminonspatialmemoryinamyloid-infusedADratmodels,reportingincreasedPSD-95andsynaptophysinexpressioninthehippocampusandamemory-enhancingeffect.Instudiesofstreptozotocin-induceddiabeticrats,curcuminhasbeenshowntopreventcholinergic-mediatedcorticaldysfunctions,whichareinducedbydiabetes( ReferencePeeyush,AntonyandSonan 126 ),andinmicetreatedwithokadaicacidtoinducememoryimpairmentorallyadministeredcurcuminhasbeenfoundtoimprovecholinergicfunctionandreduceinflammation,amongotherbeneficialeffects( ReferenceRajasekar,DwivediandTota 127 ).Furthermore,curcuminhasbeenshowntoreversealcohol-inducedcognitivedeficitsintheadultratbrain,partlybypreventingthealcohol-inducedactivationofacetylcholinesterase;curcuminalsoreducessignsofneuroinflammationintheserats( ReferenceTiwariandChopra 128 ).AnotherratstudyindicatedthatcurcuminmayinhibitacetylcholinesteraseactivityinAs-andAl-inducedtoxicitymodels( ReferenceOrhan 129 ). Despitealltheseanimalstudies,theinfluenceofcurcuminonacetylcholinesterasehasnotyetbeeninvestigatedinhumanclinicalstudies.Furthermore,mechanismsunderlyingmanyoftheeffectsdescribedabovearestillbeingcharacterised.However,thereisnowevidenceofcurcuminderivativesinfluencingproteasomalfunctionandAβdegradation,asdescribedbelow. Curcumin,proteasomefunctionandβamyloiddegradation Proteasomalactivityanditsroleinthedegradationofmostoxidisedproteinsislinkedwiththeprocessesofcellageing;itisalsobelievedthatage-relateddecreasesinproteasomeactivityweakensacell’scapacitytoremoveoxidativelymodifiedproteinsandthereforeencouragesthedevelopmentofdiseases( ReferenceBulteau,MoreauandSaunois 130 ).Curcuminhasbeendemonstratedtohaveastimulatoryeffectonproteasomalactivity,causinga46%increaseinactivityatdosesof1µm invitro,whereashigherdoses,notlikelytobeachievedinvivo,ledtodecreasedactivity( ReferenceCole,TeterandFrautschy 131 ).Morerecentstudieshaveshownthatasyntheticderivativeofcurcumin,CNB-001,canstimulateAβdegradationthroughbothproteasomesandlysosomes,andtheexperimentalinhibitionoftheproteasomepathwayredirectsclearancethroughlysosomes.OtherrecentCNB-001studieshaveprovidedalinkbetweenthefindingsofseveralotherAD-relatedbiochemicalchanges.Theseincludethefindingsthatlevelsoftheenzyme5-lipoxygenase(5-LOX)areelevatedinAD( ReferenceIkonomovic,AbrahamsonandUz 132 )andthatdisruptionofthisenzymeandsomephospholipasescanreduceADpathology( ReferenceQu,UzandManev 133 , ReferenceFiruzi,ZhuoandChinnici 134 );aswellasthatchronicstresscancausecellsignalling/over-activationofregulatorykinases,whichinturnleadstothephosphorylationoftheeukaryoticinitiationfactor-2α(eIF2α)anddisruptsthetranslationactivationofseveralmRNA,anddetectedinneurodegenerativediseasesincludingAD( ReferenceOhno 135 ).TheCNB-001studiesfoundthatCNB-001couldinhibit5-LOX,whichinducestheeIF2αphosphorylation.Furthermore,whenfedtoADtransgenicmice,CNB-001wasfoundtoincreaseeIF2αphosphorylation(aswellasheatshockprotein90andactivatingtranscriptionfactor4levels),improveAβclearanceandthereforelimittheaccumulationofsolubleAβandubiquitinatedaggregatedproteins.CNB-001hasalsobeenfoundtomaintaintheexpressionofsynapse-associatedproteinsandtoimprovememoryinthemice( ReferenceValera,DarguschandMaher 136 ).Thesestudiesindicatethatthecurcuminoidderivative’sinhibitionof5-LOXhaspotentialasatherapeuticapproach. Overall,cellcultureandanimalstudieshaveindicatedthatcurcuminhasconsiderablepotentialasaninhibitorofAβaggregation,asanantioxidant,ananti-inflammatoryandasaninhibitorofBACE1.Curcumin,amongitsmodalitiesofaction,hasalsoshownpromiseinfacilitatingAβclearance/degradation,inhibitingtauphosphorylation,promotingneurogenesisandmodulatingsynapticplasticity(Fig.1).Despitethesebenefits,thereisapaucityofpopulation-basedstudiesexaminingtheprotectiveroleofcurcuminoncognition. Fig.1 Curcumin:reportedmechanismsofaction.BACE1,β-APP-cleavingenzyme-1;Aβ,βamyloid;APP,amyloidprecursorprotein. Effectsofcurcuminonhumancognition OnlyahandfulofclinicalstudieshavebeencarriedouttoevaluatethecognitiveenhancingpotentialofcurcumininADpatients( ReferenceBaum,LamandCheung 137 , ReferenceRingman,FrautschyandCole 138 );however,thesehavenotbeenparticularlysuccessful.Reasonscouldbebecauseofthelowbioavailabilityofcurcumin( ReferenceBegum,JonesandLim 15 ),therebymarkedlyreducingitspotentialtoreachthebrainatsufficientconcentrationstoprovidebenefits.Alternatively,thesubjectsmayhavebeentreatedatastageofpathologythatistooadvancedforcurcumintoprovidebenefits.Nevertheless,thereareepidemiologicaldatathatsupporttheconceptthatcurcumincanreducetheriskofAD.Forexample,India,withanestimatedaveragedailyconsumptionofcurcuminbeing80–200mg( ReferenceBasnetandSkalko-Basnet 21 , ReferenceCommandeurandVermeulen 139 ),hasbeenreportedtohavealowerincidenceandprevalenceofAD( ReferenceGanguli,ChandraandKamboh 140 – ReferenceShaji,BoseandVerghese 142 ),althoughunder-reportingandclinicianaccessmaybeacontributor.Nevertheless,astudyof1010cognitivelyintactAsianparticipantsaged60–93yearshasfoundthatthosewhoconsumedcurry(whichcontainsturmeric)moreoften,comparedwiththosewhoatecurryveryrarelyornever,performedbetterontheMiniMentalStateExamination(MMSE)( ReferenceNg,ChiamandLee 143 ).Theseobservations,amongothers,supporttheconceptthatturmeric,andinparticularitscurcuminparticle,maypossessvaluableneuroprotectiveorcognitive-enhancingproperties.However,asmentionedabove,clinicaltrialsexaminingtheefficacyofcurcumininpatientswithcognitivedeclinehavebeendisappointing;however,morerecently,withstudiesusingimprovedformulationsandmoreappropriatecohorts,encouragingsignsareemerging( ReferenceCox,PipingasandScholey 144 ).Table1representsalistofongoing/completedclinicaltrialsthathaveusedcurcuminforthediagnosis,preventionortreatmentofAD.Thesetrialsarediscussedfurtherbelow. Table1StudiesusingcurcumininAlzheimer’sdisease(AD):diagnosis,preventionandtreatment Aβ,βamyloid;MMSE,MiniMentalStateExamination;PET,positronemissiontomography;FDG,fluorodeoxyglucose;MCI,mildcognitiveimpairment;NPIQ,Neuro-PsychiatricInventory-BriefQuestionnaire;fMRI,functionalMRI. Baumetal.( ReferenceBaum,LamandCheung 137 )randomisedADpatients(n34)toreceive1g(plus3gplacebo),4g(plus3gplacebo)or0goforalcurcumin(plus4gofplacebo),oncedaily.Participantsweregiventhechoiceofformulation,beingeitherpowderorcapsule.TheinterventiongroupdidnotdemonstratesignificantdifferencesinMMSEscoresorplasmaAβ-40levelsbetween0and6months;however,itwassuggestedthattheoutcomemeasureswerenotsensitiveorspecificenoughtodemonstrateeffects( ReferenceBaum,LamandCheung 137 ).Ringmanetal.( ReferenceRingman,FrautschyandTeng 145 )conducteda24-week,randomised,double-blind,placebo-controlledstudyevaluatingtheefficacyoftwodosagesofcurcumin(2and4g/d)inpatientswithmild-to-moderateAD,withanopen-labelextensionfor48weeks.Thiswasthefirststudytoincludemeasurementofcerebrospinalfluid(CSF)biomarkers.Thepreliminaryresultsshowednosignificantdifferencesincognitivefunction,inplasmaorCSFAβ-40/Aβ-42ortau,betweenplaceboandinterventiongroups;however,bioavailabilitywasagainreportedasalimitation,althoughthedosingwaswelltolerated. TheabovestudiesincludedAD-diagnosedparticipants,inwhomsignificantneurodegenerationandADpathologyalreadyexists.Giventhatthepathologicalchangesbegintwodecadesormorebeforethefirstrecognisablesymptoms( ReferenceVillemagneandRowe 45 ),targetinghealthyoldercohortsorthoseinthepre-clinicalorprodromalADphasewouldmorelikelyprovidebenefitsthroughslowingthepathogenicmechanisms.Considerablesynapticandneuronallosshasalreadyoccurredbythetimesymptomsappear,andtheantioxidant,anti-inflammatoryandAβ-loweringandanti-Aβaggregationpropertiesofcurcuminaremostlikelytobeofbenefitintheearlystages,forthepreventionofADpathogenesis.However,curcumintreatmentofADpatientsmaystillprovidemanybenefits,anditwarrantsfurtherclinicalevaluation. Morerecentstudieshaveevaluatedcurcumin’seffectsundernormalphysiologicalconditions.Inaplacebo-controlledstudytargetinghealthymiddle-agedsubjects(n38,40–60years),80mgofcurcumin(400mgofLongvida-optimisedcurcumin)wasgivenorallyfor4weekstoassessthehealth-promotingeffectsofcurcumin( ReferenceDiSilvestro,JosephandZhao 146 ).Thisstudy,becauseofthediversehealthclaimsofcurcumin,investigatedseveralbloodandsalivabiomarkers,toexaminetheeffectofcurcuminonmarkersassociatedwithlipids,inflammation,liverfunction,immunityandstress,aswellasAβlevels.Cognitivemeasureswerenotincludedintheirstudydesign.Statisticallysignificantresultswereshownforanumberofthesemarkersincludingincreasedcatalase,nitricoxideandantioxidantstatus,withloweredplasmaalanineaminotransferaseandTAG,butnottotalcholesterol.Inaddition,curcuminwasfoundtolowerplasmaAβlevels.Anotherinterestingfindingwasthatsalivaryamylasewasalsosignificantlylowered,whichisanenzymeassociatedwithadrenergicactivityduringstress( ReferencevanStegerena,RohlederbandEveraerda 147 ). Anumberofstudiesofcurcuminsupplementationinhealthyoldersubjectsarestillinprogress.However,onesuchstudyhasbeencompleted:arandomised,double-blindplacebo-controlledstudy(n60,60–85years)usingthesame80mg/dcurcuminformulationasusedbyDiSilvestroetal. ( ReferenceDiSilvestro,JosephandZhao 146 )(400mgofLongvida-optimisedcurcumin).Theauthorsreportedacute(1hpostdose)andchronic(1-monthduration)effectsofcurcuminintakeoncognition,moodandbloodbiomarkers( ReferenceCox,PipingasandScholey 144 ).Benefitsonattentionandworkingmemorywerereportedfollowingtheacuteadministrationofcurcumin,whereasatthe1-monthtimepoint,workingmemoryandmoodimproved.Alertnessandcontentednessalsoimprovedafteracute-on-chronictreatment. Althoughtheresultsaboveareencouraging,alternatemechanisms,includingmodulationofthestressresponse,mayhaveplayedapart.Amylase,showntobeloweredinanearlierstudyusingcurcumin( ReferenceDiSilvestro,JosephandZhao 146 ),isarecognisedbiomarkerofβ-adrenergicstimulation( ReferencevanStegerena,RohlederbandEveraerda 147 – ReferenceChatterton,VogelsongandLu 149 ),andimprovedattention,workingmemoryandcontentednessmaybelinkedtothismodeofaction.NoalterationsinbloodlevelsofAβ-40orAβ-42levelsweredetected,althoughthesearenotthoughttobereliablebiomarkersontheirown.Differencesincognitiveperformance,asdemonstratedinserial7-sanddelayedrecall,werenotsignificant( ReferenceCox,PipingasandScholey 144 ).Nevertheless,curcumindidenhancethelipidprofilebyloweringLDL,andincontrasttotheresultsfoundbyDiSilvestroetal. ( ReferenceDiSilvestro,JosephandZhao 146 ),Coxetal.( ReferenceCox,PipingasandScholey 144 )alsorecordedareductioninplasmatotalcholesterol.Long-termlipidchangessuchasthesemayhavesomeeffectonADrisk:asmentionedearlier,chronicconditionslinkedtoabnormallipidprofilessuchasobesityanddiabetesarelinkedwithahigherriskofAD.Interestingly,acasestudyreportedbyHishikawaetal.( ReferenceHishikawa,TakahashiandAmakusa 150 )foundthatthreesevere-stageADpatientstreatedwith100mg/doralcurcuminfor12weeks(inadditiontotheiralreadyprescribedacetylcholinesteraseinhibitor,donepezil)showedareductioninagitation,anxietyandirritability;onepatientalsoshowedimprovementinMMSEscore.Thismaysuggestaroleforcurcuminasaconcurrentintervention,anditsupportstheconceptthatcurcuminmayprovidebenefits,eveninadvancedstagesofAD;however,furtherresearchwouldberequiredtosupportthesesuggestions. Asmentionedearlier,severalotherclinicalstudiesarestillunderway,orresultshavenotyetbeenpublished;thus,withsofewclinicalstudieshavingbeencompleted,itisnotpossibletomakeanyconclusionsconcerningtheclinicalsignificanceofcurcumininenhancingcognition. Epigenetics,Alzheimer’sdiseaseandcurcumin EpigeneticalterationshavebeenreportedtooccurinAD( ReferenceMastroeni,GroverandDelvaux 151 – ReferenceChouliaras,RuttenandKenis 154 ).Asepigeneticalterationsaredynamic,thesealterationshavebeenproposedasatargetareaforADprevention.EpigeneticalterationsincludechangesinDNAmethylation,histonemodificationsorchangesinmiRNAexpression.Studiesincludingsomeclinicalstudiesofotherconditionshaveshownthatcurcuminhasthepotentialtoinduceepigeneticchanges( ReferenceTeiten,DicatoandDiederich 155 , ReferenceReuter,GuptaandPark 156 ).Forexample,epigeneticeffectsofcurcuminhavebeenshowninpatientswithbreastcancerandadvancedpancreaticcancer,andalsoinpeopleatriskofstroke,byprovidingvascularprotection( ReferenceDu,XieandWu 157 ).CurcuminhasbeenshowntoinhibitDNAmethyltransferase,histoneacetyltransferaseandhistonedeacetylase,andtomodulatemiRNA,forexampledown-regulatingmicroRNA-134andmicroRNA-124inculturedhippocampalslices,whichareassociatedwithanincreaseinthebrain-derivedneurotropicfactor(BDNF)( ReferenceSezginandDincer 158 ).BDNFhasbeenshowntoincreasehippocampalneuronalsurvivalandtoenhancesynapticplasticity.Furthermore,variantsoftheBDNFgenehavebeenlinkedtoseveralmentaldisorderssuchasmajordepressivedisorder(MDD)andschizophrenia,andlowlevelsofBDNFproteinarethoughttocontributetothepathologyofMDD.Interestingly,antidepressantshavealsobeenfoundtoincreasebloodlevelsofBDNF( ReferenceLi,XuandGao 159 ).DepressionisamajorriskfactorforAD,andthusthisBDNF-modifyingpropertyofcurcuminisofsignificantinterest.Otherrecentstudieshavealsofoundthatcurcumincanhaveasignificanteffectondepression( ReferenceLopresti,MaesandMarker 160 ),supportedtosomeextentbythestudiesdescribedabovebyCoxetal. ( ReferenceCox,PipingasandScholey 144 ) Manyotherstudieshavediscoveredthebeneficialepigeneticeffectsofcurcumininrelationtovariouscancersandrheumatoidarthritis,andnowsimilarbenefitsarebeingdiscoveredthatmayhaveanimpactontheriskandseverityofAD( ReferenceDavinelli,CalabreseandZella 161 ).Forexample,DNAmethylationinneurodegenerativediseases(andmanyotherconditionssuchasCVDandstroke)hasbeenlinkedtohighhomocysteinelevels,whichoccurwithageingandwithvitaminB12orfolatedeficiencies( ReferenceAnsari,MahtaandMallack 162 , ReferenceMattsonandShea 163 ).ChronicallyhighhomocysteinelevelsleadtoanabnormallyhighDNAmethylation( ReferenceFux,KloorandHermes 164 ),whichrequiresDNAmethyltransferase,andasmentionedabovecurcumininhibitsDNAmethyltransferase.However,ratstudiesofhomocysteineeffectssuggestthatcurcuminmaybeneuroprotective,andmayimprovelearningandmemorydeficits,byreducinglipidperoxidationandhighmalondialdehydelevels,bothofwhichareinducedbyhighhomocysteinelevels( ReferenceAtaie,SabetkasaeiandHaghparast 165 ).Therelativesignificanceofthesepotentialbenefitsofcurcumindietarysupplementationareclearlystillnotknown,andthusfurtherclinicalstudiesarerequiredtoevaluatetheneuroprotectiveroleofcurcumininducedbyepigeneticregulationforthepreventionofcognitivedecline. Curcuminsafetyprofile,tolerability,bioavailabilityandmodeofadministration Ascurcuminisacomponentofthespiceturmeric,itisnotsurprisingthatcurcuminhasbeenreportedtobeaverysafenutraceuticalwithalowside-effectprofile.However,itshouldbenotedthatwhilecurcuminhasbeenreportedtobesafeandwelltoleratedatdosesofupto8g/d( ReferenceCheng,HsuandLin 166 ),studieshavenotgonebeyond3months,andthusthelong-termeffectsofhighdosesofcurcuminarenotknown.Inaddition,withenhancedbioavailabilityandabsorptionnowpossiblewithnewformulations,theriskofincreasedtoxicityishigher,particularlyforpopulationstakingmedicationsmetabolisedbytheliverorforthosewithexistingliverimpairment( ReferenceBaum,LamandCheung 137 ).Nevertheless,althoughcurcuminmaynothavebeentestedwidelyforthepurposesofreducingneurodegeneration,ithasbeenclinicallytestedinpatientswithvariousconditionsandpro-inflammatorydiseasesincludingcancer,CVD,arthritis,Crohn’sdisease,ulcerativecolitis,irritableboweldisease,tropicalpancreatitis,pepticulcer,psoriasis,atherosclerosis,diabetes,diabeticnephropathyandrenalconditions,amongothers,andhasresultedinminimalsideeffectsandmanyhealthbenefits.Curcuminhasalsoprovidedprotectionagainsthepaticconditions,chronicarsenicexposureandalcoholintoxication( ReferenceGupta,KismaliandAggarwal 167 ). Curcumin’spleiotropiceffectsexplainitswidevarietyofapplications;forexample,ithasbeentestedforthepurposeofstentcoating,ascurcuminhasadvantageousanti-coagulantproperties( ReferencePan,TangandWeng 168 ).Inaddition,itcaninhibitthegenerationofbloodclottingfactorsXaandthrombinviatheextrinsicandintrinsicpathways( ReferenceDong-Chan,Sae-KwangandJong-Sup 169 ).Thesepropertiesdoindicatethatoneshouldbecautiouswhenprescribingcurcuminincombinationwithotherblood-thinningpreparations.Althoughthesafetyofcurcuminhasbeendemonstrated( ReferenceBaum,LamandCheung 137 , ReferenceRingman,FrautschyandTeng 145 ),inhumans,oralingestionofexistingformulationshaspresentedchallengesconcerningabsorptionandbioavailability( ReferenceRingman,FrautschyandTeng 145 , ReferenceBelkacemi,DogguiandDao 170 ).Theliteraturereportsthatoralcurcuminhasefficientfirst-passmetabolismandsomedegreeofintestinalmetabolism,includingglucuronidationandsulphation(althoughthisoccursmostlyintheliver);however,itisexcretedlargelyunconjugatedviatheintestine.CurcuminisalsounstableatneutralandalkalinepH.Thereappearstobeminimaldistributionofcurcumintotheliverorothertissuesbeyondthegastrointestinaltract( ReferenceSharma,StewardandGescher 171 ).Forexample,inratstudies,anoraldoseof500mg/kgresultedinapeakplasmaconcentrationofonly1·8ng/ml( ReferenceIreson,OrrandJones 172 ),withthemajormetabolitesbeingcurcuminsulphateandcurcuminglucuronide,whereasaclinicalstudyfoundthatoraldosesof4,6and8gofcurcumindailyfor3monthsyieldedserumcurcuminconcentrationsofonly0·51(sd0·11),0·63(sd0·06)and1·77(sd1·87)μm,respectively,withpeaklevelsat1–2hpostdosing( ReferenceCheng,HsuandLin 166 ).Unmodifiedcurcuminisreportedtoberetainedinthebloodfor2–5hinhumans,whereasretentionofamodifiedformofcurcumin–Biocurcumax-95(BCM-95)–isreportedasexceeding8h( ReferenceBennyandAnthony 173 ).Inorderforthecurcumintoelicitagreaternutraceuticalbenefit,itiscriticalthatmoreofitisabletoenterthebloodstream,itmusthavealongerhalf-lifeandalsocrosstheBBBtobeofsignificantbenefitinAD. Todate,mosthumancurcuminstudieshaveusedoralformulations.Absorptionandbioavailabilityhavecontinuedtobeahindrance,notaidedbythevariationofformulationsavailable.However,astechnologyhasadvancedandnewdeliveryapproacheshaveemerged,theuseofadjuvanttherapies,isomerisation,liposomes,micelles,phospholipidsandnanotechnologyalsoincrease.OneofthepotentialtherapeuticresultsofincreasingbloodlevelsofcurcumininhumanscanhopefullybeanticipatedfromADtransgenicmousestudies,inwhichtheintravenousadministrationofcurcumin(7·7mg/kgperd)for7dresultedinsignificantclearanceofcerebralAβload( ReferenceGarcia-Alloza,BorrelliandRozkalne 40 ).Alternateroutesofdeliveringcurcuminarealreadybeingusedforotherdisorders,suchastheuseoftopicaleyedrops,recommendedforthetreatmentofavarietyofophthalmicdisorders( ReferencePescosolido,GiannottiandPlateroti 174 ),andtransdermalapplicationusingencapsulatedcurcuminasananoemulsion,forthetreatmentofarthritis( ReferenceRachmawati,BudiputraandMauludin 175 ).Recently,thecurcuminderivativeFMeC1,originallyproducedasanMRIprobe,hasbeenproducedinaerosolformforinhalation.Astudyin5XFADtransgenicmicesuggestedimproveddistributioninthebrain,andimmunohistochemicalstudiesdemonstratedthatFMeC1absorbedfollowingaerosoldeliverydidbindtoamyloidplaquesinthemousebrains( ReferenceMcClure,YanagisawaandStec 176 ).ThistechniquemayalsobeusefulforAβimagingstudies;however,furtherstudiesareneededtovalidatethisnotion.Theabsorptionandbioavailabilityofcurcuminishighlyrelevant,andtheformulation,doseandmodeofdeliveryareeachimportantfactors.Multipleover-the-counterbrandsareavailable,andmostofthemclaimincreasedbioavailabilitycomparedwithunformulatedcurcumin;however,independentcomparativeanalysisisessential.TwoformulationsBCM-95( ReferenceAntony,MerinaandIyer 177 , ReferenceMerinaandAntony 178 )andLongvida( ReferenceRingman,FrautschyandTeng 145 )currentlyhavethestrongestindependentdataavailableinhumantrials.Forareviewofthemolecularstructureofcurcuminanditsderivatives,FMeC1andFMeC2,seeYanagisawaetal.( ReferenceYanagisawa,IbrahimandTaguchi 110 ),anddifferencesbetweenthepropertiesofCNB-001canbeexaminedaspreviouslypublished( ReferenceJayaraj,ElangovanandDhanalakshmi 179 – ReferenceLiu,DarguschandMaher 181 ). Tosummarise,curcuminhasbeentrialledatdosesashighas8g/d,andfoundtobewelltoleratedandsafe.However,asnewformulationsareemergingthatareshowingpromiseofincreasingbioavailability,BBBpermeabilityandlongerhalf-lives,theseformulationsalsoneedtobeevaluatedinfuturesafetyandtolerabilitytrials.Furthermore,asanycurcumintherapyislikelytobelong-terminnature,muchlongertreatmenttimesneedtobetrialled.Theanimalandclinicalstudiesthathaveinvestigatedtheroleofcurcuminhaveappliedavarietyofadministrationmodes,includingoral,subcutaneous,intraperitoneal,intravenous,topicalandthenasalroute( ReferencePrasad,TyagiandAggarwal 182 ).Humantrialsinvestigatingcurcumin’sneuroprotectivemechanismshavemostlyusedtheoralroute;however,futurestudiesshouldexploreotherroutesofadministration. Curcuminasafluorochrome/radioligandinAlzheimer’sdiseasediagnosis Turmerichasbeenusedasacolouringagentsinceancienttimes.In1989,Stockertetal.( ReferenceStockert,DelCastilloandGomez 183 )identifiedcurcuminasapotentialfluorochrome,ascurcuminwasfoundtofluoresceyellow/greenunderaviolet/blue(436nm)light,anditwasnotedtobindtoDNAandchromosomes,astreatmentoftissuesamplesandcellsampleswithdeoxyribonucleaseorTCApreventedthechromatinstaining.Morerecently,theseinnatefluorescentqualities(curcuminabsorbslightatabout420nmandemitsfluorescenceatabout530nminaqueoussolutions( ReferenceWang,WuandWang 184 )),andcurcumin’snaturalaffinitytobindwithAβ,promptedcurcumintobetestedasasafeplaque-labellingfluorochrome.AmousestudyinvestigatednovelderivativesofcurcuminandmeasuredtheirbindingaffinitiesforAβaggregates( ReferenceRyu,ChoeandLee 185 ).Thederivativewiththehighestaffinitywasthen(18F)-radiolabelledfortestingasaradioligandprobeforAβplaqueimaging;thecompoundalsohadsuitablelipophilicity,goodbrainuptakeandwasmetabolicallystableinthebrain.InanotherstudyconductedontransgenicADmice,multiphotonmicroscopywasusedtodemonstratethatcurcumincrossedtheBBBandlabelledAβplaquesandcerebrovascularamyloidangiopathy( ReferenceGarcia-Alloza,BorrelliandRozkalne 40 ).CurcuminhassincebeenusedinthelabellingofneuronalfibrillartauinclusionsinhumanbrainsamplesofADandprogressivesupranuclearpalsy( ReferenceMohorko,RepovšandPopovic 186 ).Morerecently,otherstudiesofAβimagingusedan19F-containingcurcuminderivativeinjectedperipherallyinAD-modelmicetodetectAβplaquesinthebrains,usingMRI( ReferenceYanagisawa,IbrahimandTaguchi 110 ).Furthermore,Koronyo-Hamaouietal.( ReferenceKoronyo-Hamaoui,KoronyoandLjubimov 187 )demonstratedcurcumin’svalueasastainingagentforAβbydetectingplaquesinhumanpostmortemretinaltissue,andalsoasabrainandretinalAβplaquetraceradministeredintravenouslyintransgenicmice.Importantly,thepathologyintheretinawasdetectedbeforethestageatwhichpathologyinthebraincouldbedetected,indicatingthatcurcuminmayhavepotentialasapre-clinicalADbiomarker.TheresearchalsosupportsthepreviousobservationthatcurcuminhastheabilitytocrosstheBBB,whichisessentialforitstherapeuticefficacy.Preliminarydatafromapilotstudy(n40)conductedbyourgroupundertakingretinalimagingusingcurcuminasafluorochromehada100%sensitivityand80·6%specificityforADdiagnosis( ReferenceFrost,KanagasingamandMacaulay 3 ).Anotherstudyrecruitedmildcognitiveimpairment(MCI)patients(n30)andadministered80mgofcurcumin(Meriva)twicedailyfor3dandfoundabnormaldepositsindifferentretinallayersbelievedtoberelatedtoneurodegeneration( ReferenceKayabasi,SergottandRispoli 188 ).Thestudyreportedthatcurcumincausedpatchyhypofluorescentspots;however,itdidnotquantifytheretinalamyloidplaques.Thefindingswereprimarilybasedonthedirectperceptionofthedepositsviaocularimaging.RecentstudieshaveagainusedMRI,thistimetodetectmagneticnanoparticlesmadeofsuperparamagneticironoxideconjugatedwithcurcumin,whichwerefoundtobindtoAβaggregatesinexvivoAD-modelmousebrains,afterinjectionwiththecurcuminconjugate( ReferenceCheng,ChanandFan 189 ).Otherrecentstudieshaveproducedanovelnanoimagingagent:poly(β-l-malicacid)containingcovalentlyattached(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid)gadoliniumandcurcumin.Theall-in-oneagentselectivelybindstoAβplaquesandcanbedetectedbyMRI( ReferencePatil,GangalumandWagner 190 ),thusprovidinganotherpromisingAβplaqueimagingagent. Curcumin,beingnon-toxic,accessibleandeconomical,thusbecomeshighlyattractiveforbothdiagnosticsandtherapeuticresearch.Asdiscussedabove,retinalimagingusingcurcuminfluorescenceiscurrentlybeingexaminedinourresearchcentreaspartoftheAustralianImaging,BiomarkersandLifestyleflagshipstudyofageing,andithasbeenfoundtobewelltoleratedbyparticipants.Thisapproach,combinedwithexaminationoftheretinalvascularfeatures( ReferenceFrost,MartinsandKanagasingam 191 ),maydeliveranoveldiagnostictoolthatprovidesamorereliableindicationofearlyADchanges,whichiseconomical,relativelynon-invasiveandwidelyapplicable. Limitationsofcurcuminandfuturedirections Ifallthepositiveresultsobservedininvitroandinvivoanimalstudiescouldbetranslatedintohumanstudies,thesignificanceofcurcumininADpreventionandtreatmentwouldbeconsiderable.TherecentstudybyCoxetal.( ReferenceCox,PipingasandScholey 144 )providedsomeencouragingoutcomesbyinvestigatingcognitivemarkers,butonlyacutechangesinattention,workingmemoryandmoodweresignificant.Noeffectswerereportedinlong-termmemoryorexecutivefunction;however,theshortdurationofthestudymayhavebeenalimitation.TheevidencethatcurcumincaninfluenceAβaggregationandAβclearance,supportinnateimmunesystems,reduceoxidativestress,enhancecognitionandimpedetheonsetofADinhumansremainselusive.However,nottobeoverlookedistheapplicationofcurcuminasadiagnosticfluorochrome,potentiallyassistingintheearlieridentificationofpre-clinicalstagesofAD,duringretinalscanning.Theuseofcurcuminasafluorochromewithinretinalamyloidimaging,combinedwithexaminationofretinalvascularfeatures,offersanoveldiagnosticapproachtoAD.Whileretinalimagingisacknowledgedasanon-invasive,economicalandeasilytranslatedtechnology,furthervalidationisrequiredbeforeitcanbeadoptedasanearlyADmarker. Enhancedoralformulationsofcurcuminareemerging,potentiallynegatingthepriorchallengesofabsorptionandbioavailability.However,consideringthedifferencesinproductformulation,andthemultitudeofcurcuminproductsalreadyavailable,comparativeanalysiswouldbeuseful.AstheprimaryfocusofADtreatmenthasturnedtoprimaryprevention,thepointofinterventionisalsocrucial:interventionsintroducedearly(>10yearsbeforetheonsetofADclinicalsymptoms)maypresentdifficultyestablishingstatisticallysignificantchanges,whereasinterventionsintroduced1–2yearsbeforetheonsetmaybelesseffectiveorineffectiveasthediseasepathologymayalreadybetooadvanced.Preventionstudiesdesignedwithlongerdurationarehighlydesirable;however,asnutraceuticalsgenerallydonotattractcommercialopportunity,realisingthesetypeofstudieswillbedifficulttoaccomplish. Theuseofcurcuminasanadjuncttherapytocholinesteraseinhibitors,particularlyintheearlystagesofAD,offersapotentiallynewareaofresearch.Asanxietyandstressarecommonco-morbiditiesinAD,andresearchhasshowncurcumintohaveeffectintheseareas,curcuminmayofferanappealingalternativetoantidepressantandantipsychotictherapies,whilepotentiallyofferingothersynergies,includinginfluencingtheunderlyingneuropathologyandenhancingcholinergicactivity.Inrecentyears,thefocusoncurcuminasacompoundofinterestforthepreventionofADhasbeenintensifying.TheresultsofongoingclinicaltrialswillhopefullyshedmorelightonthebenefitsofcurcumininthepreventionofAD.Inlinewithcurcumin’scomplexmodesofaction,outcomemeasuresshouldbeexpandedtoincludenotjustcognitivechanges;extensivebloodbiomarkerassaysshouldalsobecarriedout,aswellasimaging(e.g.measuringcerebralamyloidloadandpotentiallyretinalmarkers)tocharacterisecurcumin’seffectsmorefullyovertime,inapre-clinicalpopulation. Conclusion Todate,ADclinicaltrialshavenotbeenabletogeneratetheanticipatedbenefitsofcurcumin;however,thishasbeenbroadlyattributedtodifficultieswithabsorption,bioavailabilityandarguablythetimingandlengthofintervention.Asreviewedinthisarticle,thereissignificantevidencethatcurcumincanactonmultiplepathwaysidentifiedinthepathogenesisofAD.Itispossible,however,thatsporadicADinhumanswiththeassociatedcerebralatrophyandneuronaldeathmaybelessresponsivetocurcuminthantheADinducedintransgenicanimalmodelsofthedisease. Asdiscussedinthisreview,increasingthebioavailability,BBBpenetrationandsustainingthehalf-lifeofcurcuminremainsamajorfocusinrelationtoitsdose–response.Toachievethesamedegreeofefficacyinhumanstudiesascomparedwithanimalstudies,closerscrutinyoftheadministrationrouteandalsoformulationarerequired,asincreasingbioavailabilityandBBBpenetrationiscritical.Researchanalysingthedifferentoralformulationsislacking,andthisisanareaforfurtherinvestigation.Furthermore,asthepre-clinicalsignsofADarepresentdecadesbeforeitsclinicalonsetandmostofthelate-stageADclinicaltrialshaverecentlyfailed,interventionmustbefocusedatpreventingordelayingADonset.Itisreasonabletoincludehealthycommunity-dwellingolderadultsandthosewithsubjectivememorycomplaints,ininterventionstudieswithcurcumin,foralongerdurationwithlongitudinalfollow-up.Last,inclusionofAD-relatedbiomarkersandneuroimagingwouldaddtotheclinicalsignificanceofcurcumin’sefficacyinthepreventionofADandassociatedcognitivedecline. Acknowledgements TheauthorsgratefullyacknowledgethecombinedsupportoftheMcCuskerAlzheimer’sResearchFoundationandtheAnglicanRetirementVillages(ARV). K.G.G.issupportedbyagrantthroughtheFoundationforAgedCare,ARV,andascholarshipfromtheCo-operativeResearchCentreforMentalHealth.R.N.M.,T.M.S.,H.R.S.,S.R.R.-S.,B.B.andG.VaresupportedbytheEdithCowanUniversityandtheMcCuskerAlzheimer’sResearchFoundation.H.R.S.hasreceivedrenumerationfromPfizerandTakeda.R.N.M.isthefounderandchiefscientificofficerofthebiotechcompany,Alzhyme.G.V.issupportedbytheCurtinUniversitySeniorResearchFellowship(CRF140196)andtheNHMRC(APP1045507). Allauthorscontributedtotheliteraturesearch,analysisofthedatapublished,manuscriptwritingandrevisionsofthearticle. Theauthorsdeclarenoconflictsofinterestarisingfromtheconclusionsofthisresearch. References 1 1. Prince,M&Jackson,J(editors)(2009)Alzheimer’sDiseaseInternational:WorldAlzheimerReport.ExecutiveSummary.London:Alzheimer’sDiseaseInternational.GoogleScholar 2 2. 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