researchandperspectivesinalzheimer’sdisease FondationIpsen Editor YvesChristen,FondationIpsen,Paris(France) EditorialBoard YvesAgid,HôpitalPitiéSalpêtrière,Paris(France) AlbertAguayo,McGillUniversity,Montreal(Canada) BrianH.Anderton,InstituteofPsychiatry,London(GB) RaymondT.Bartus,Alkermes,Cambridge(USA) AndersBjörklund,UniversityofLund(Sweden) FloydBloom,ScrippsClinicandResearchFoundation,LaJolla(USA) FrançoisBoller,InsermU324,Paris(France) CarlCotman,UniversityofCalifornia,Irvine(USA) PeterDavies,AlbertEinsteinCollegeofMedicine,NewYork(USA) AndreDelacourte,InsermU422,Lille(France) StevenFerris,NewYorkUniversityMedicalCenter,NewYork(USA) Jean-FrançoisFoncin,HôpitalPitiéSalpêtrière,Paris(France) FrançoiseForette,HôpitalBroca,Paris(France) FredGage,SalkInstitute,LaJolla(USA) DmitryGoldgaber,StateUniversityofNewYorkStoneBrook(USA) JohnHardy,NationalInstituteofHealth,Bethesda(USA) Jean-JacquesHauw,HôpitalPitiéSalpêtrière,Paris(France) ClaudeKordon,InsermU159,Paris(France) KennethS.Kosik,HarvardMedicalSchool,CenterforNeurological DiseasesandBrighamandWomen’sHospital,Boston(USA) JacquesMallet,HôpitalPitiéSalpêtrière,Paris(France) ColinL.Masters,UniversityofMelbourne,Parkville(Australia) StanleyI.Rapoport,NationalInstituteonAging,Bethesda(USA) BarryReisberg,NewYorkUniversityMedicalCenter,NewYork(USA) AllenRoses,DukeUniversityMedicalCenter,Durham(USA) DennisJ.Selkoe,HarvardMedicalSchool,CenterofNeurological DiseasesandBrighamandWomen’sHospital,Boston(USA) MichaelL.Shelanski,ColumbiaUniversity,NewYork(USA) Pierre-MarieSinet,HôpitalNecker,Paris(France) PeterSt.George-Hyslop,UniversityofToronto,Toronto(Canada) RobertTerry,UniversityofCalifornia,LaJolla(USA) EdouardZarifian,CentreHospitalierUniversitaire,Caen(France) M. Jucker K. Beyreuther C. Haass R.M. Nitsch Y. Christen (Eds.) Alzheimer: 100 Years and Beyond With143Figures 123 MathiasJucker KonradBeyreuther DepartmentofCellularNeurology CentreforMolecularBiology HertieInstituteforClinicalBrainResearch TheUniversityofHeidelberg UniversityofTübingen NeuenheimerFeld282 72076Tübingen 6900Heidelberg Germany Germany e-mail:[email protected] e-mail: [email protected] ChristianHaass RogerM.Nitsch Adolf-Butenandt-Institute DivisionofPsychiatryResearch DepartmentofBiochemistry UniversityofZurich LaboratoryforAlzheimer’s 8008Zurich andParkinson’sDiseaseResearch Switzerland Ludwig-Maximilians-University e-mail:[email protected] 80336Munich Germany YvesChristen e-mail:[email protected] FoundationIPSEN PourlaRechercheThérapeutique 24,rueErlanger 75781ParisCedex16 France e-mail:[email protected] CoverillustrationbyIngramPinn ISSN 0945-6066 ISBN-10 3-540-37651-8 SpringerBerlinHeidelbergNewYork ISBN-13 978-3-540-37651-4 SpringerBerlinHeidelbergNewYork Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthematerialisconcerned, specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broadcasting,reproduction onmicrofilmorinanyotherway,andstorageindatabanks.Duplicationofthispublicationorpartsthereof ispermittedonlyundertheprovisionsoftheGermanCopyrightLawofSeptember9,1965,initscurrent version,andpermissionsforusemustalwaysbeobtainedfromSpringer.Violationsareliableforprosecution undertheGermanCopyrightLaw. SpringerisapartofSpringerScience+BusinessMedia springer.com ©Springer-VerlagBerlinHeidelberg2006 Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispublicationdoesnotimply, evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevantprotectivelawsand regulationsandthereforefreeforgeneraluse. Productliability:Thepublisherscannotguaranteetheaccuracyofanyinformationaboutdosageandappli- cationcontainedinthisbook.Ineveryindividualcasetheusermustchecksuchinformationbyconsulting therelevantliterature. Editor:SimonRallison Deskeditor:AnneClaus Coverdesign:WMXDesign,Heidelberg,Germany Typesettingandproduction:LE-TEXJelonek,Schmidt&VöcklerGbR,Leipzig,Germany Printedonacid-freepaper 27/3100/YL 543210 SPIN11808305 Acknowledgements TheeditorswishtothankSimoneEberle,AstriddeGerardandthelocalcommittee fortheorganisationofthemeetinginTübingenandMary–LynnGagefortheediting ofthebook OnehundredyearsofAlzheimerresearch Fewmedicalorscientificaddresseshavesounmistakeablymadehistoryasthepresenta- tiondeliveredbyAloisAlzheimeronNovember4,1906inTübingen.Theone-hundred year anniversary of that event has been marked on several occasions in 2006, most notablyattheverysiteoftheoriginallecture,namelytheInstituteofPsychiatryofthe UniversityofTübingeninGermanyonNovember2–5,2006. Thecelebratoryevent,“Alzheimer100YearsandBeyond”organizedontheiniti- ationoftheAlzheimercommunityinGermanyandworldwide,incollaborationwith theFondationIpsen,wasthehighlightoftheYearofAlzheimer.However,beyondthese fewmonthsoftributes,thecentennialoffersauniqueopportunitytoassessboththe progress achieved and the uncertainties remaining. This volume, a collection com- prised mainly of articles by the invited speakers and also of a few other prominent researchers,ismeanttobearecordofthoseevents. OverthelastcenturyofAlzheimerresearch(1906-2006),remarkableprogresshas beenachievedinmanyareas: – Progresstowardsunderstandingthepathogenesis:Inthisfieldprogresshasbeenvery muchdependentondevelopmentsintechnologyandotherspecialityareas.Thiswas truefromtheverystart:AloisAlzheimer’sresearchwouldnothavebeenpossible without then-nascent microscopic staining techniques. It has proven true again overthelastfewdecades,withmolecularandcellularbiology,genetics,andbrain imagingallmakingcontributionswhilebenefitingfromrelatedfields.Forinstance, thediscoveryoftheroleofapolipoproteinEenabledAlzheimerscientiststoapply research findings from the cardiovascular field. On the other hand, research into the pathogenesis of Alzheimer’s disease revealed fundamental findings regarding proteinaggregation,orregulatedintramembraneproteolysisthathasnotonlybeen appliedtootherneurodegenerativediseasesbutalsopavedtheroadtounderstanding completelyunexpectedsignallingpathways. – Recognitionofthediseaseandclinicaltreatment.Althoughnocurehasbeenfound forAlzheimer’sdiseaseyet,theoutlookispromising.Alzheimer’sdiseasehasceased tobeconsideredasaninescapableconsequenceofageing. – Economicandsocialconsiderations.Withtheagingofoursocietyoverthelast100 years, there has been a continuousincrease in the number of Alzheimer patients andtheburdenforindividualcare-takers,aswellassocialandmedicalinstitutions. Demographyhashelpedtomakethepublicawareandpreparedofthesocialand economicconsequencesofthisdevastatingformofdementia. Yet,noneoftheadvancesmadehaveyetculminatedinafullysatisfactoryoutcome. Thepathogenicmechanismsofthediseaseremaininadequatelyunderstoodandareat VIII OnehundredyearsofAlzheimerresearch thecentreofseriouscontroversy,suchasdeterminingwhethertheobservedlesionsin postmortembrainsofpatientswithAlzheimer’sdiseasearethecauseoraconsequence ofthedisease;innocountryhavethepublicauthoritiesprovidedfullyforpatients; andtreatmentoptionsremainlargely insufficient,despitehopefrom varioussymp- tomatictreatmentsandongoingpromisingclinicalstudiestargetingthepathological mechanisms. Despitetheseshortcomings,thelastonehundredyearshavebeenfullandactive ones. The aim of the meeting held in November 2006 in Tübingen, like that of this volume,isnottolayoutthefinallegacyofascientificcorpusthatis,tothecontrary, constantly-developing,nortocrownthecontributionsofaspecificresearcher,atthe expenseofhiscolleaguesorcompetitors.Instead,itistohonortheworkaccomplished andprovidematerialforthehistoryofscience.Weaskedtheinvitedauthorstopresent theirpioneeringresearchexplainingtheconditionsunderwhichtheywereconducted from their viewpoint, and thus intentionally leaving room for a certain degree of subjectivity.Theirtestimonialscontainunavoidablysomecontradictions,inparticular regardingtheirpartincertainessentialdiscoveries.Theeditorsofthisbookdidnot, atanytime,wishtotakesidesinthepossibleownershipsquabbles,butonlytoprovide readerswithinformationfromtheveryindividualswhohavemadeAlzheimerresearch whatitis,overthepastfewdecades.Theonlyeditingchangesrelatedtoformalone-no articlewaschangedinsubstance,nonewerecensuredandnonewererejected.Some authorsinvitedtopresenttheirresearchatthemeetinginTübingenwereunabletohand intheircontributionsintime,howevercontributedsignificantlytothemeeting,such asMoniqueBreteler,NickFox,MichaelHutton,StevenPaul,GerardD.Schellenberg, SangramS.Sisodia,BengtWinblad,BruceYankner. Lastly, several of the pioneers passed away too early to be able to attend the Tübingen meeting and contribute to this work: George Glenner, Henry Wisniewski, Tsunao Saitoh, Eva Braak, Jean-Louis Signoret, Yvon Lamour, Nelson Butler, Luigi Amaducci,andothers.Wededicatethisvolumetothem. MathiasJucker KonradBeyreuther ChristianHaass RogerNitsch YvesChristen Some“players”oftheADstory(1987–2006) OnehundredyearsofAlzheimerresearch XI 01Paris,1988,StanleyRapoport,CharlesEpstein 02Paris,1988,CarletonGajduzek,HenryWisniewski 03Paris,1987,DennisSelkoe 04Angers,1987,frontrow:AnnickPouplard-Bartheleix,ToshiharuIshii,MrsIshii,TaiheiMiyakawa–backrow: PhilippeBrachet,ColinMasters,KonradBeyreuther,HughFudenberg,HenryWisniewski,MrsGlenner,George Glenner,JacquelineMervaillie,MrsMiyakawa,DennisSelkoe,JeanEmile,PietEikelenboom,JeanLapresle,Yves Christen,AndréDelacourte 05Angers,1987,ToshiharuIshii,YvesChristen,GeorgeGlenner 06Paris,1988,CarletonGajduzek,YvesChristen,FrançoiseForette XII OnehundredyearsofAlzheimerresearch 07Montpellier,1988,AllenRoses,AnnieSaunders 08Paris,1989,MarshalFolstein,StanleyRapoport 09Toulouse,1989,TsunaoSaitoh,RudolphTanzi 10Toulouse,1989,Jean-JaquesHauw 11Paris,1988and2006(CharlesdeGaulleairport),ChristineVanBroeckhoven 12Toulouse,1989,JohnBlass,PeterDavies 13Toulouse,1989,AndréRascol,Jean-LouisSignoret 14Toulouse,1989,RudolphTanzi,YvesAgid 15Toulouse,1989,AndréDelacourte,HenryWisniewski,KrystinaWisniewski,TsunaoSaitoh,UshiBeyreuther, KonradBeyreuther,AndrewHaynes,JohnAtack,JayPettergrew,FrançoisBoller,JacquelineMervaillie,Yves Christen,KennethKosik