Early-Onset and Robust Amyloid Pathology in a New Homozygous Mouse Model of Alzheimers Disease 英文参考文献.docVIP

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Early-Onset and Robust Amyloid Pathology in a New Homozygous Mouse Model of Alzheimers Disease 英文参考文献.doc

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Early-Onset and Robust Amyloid Pathology in a New Homozygous Mouse Model of Alzheimers Disease 英文参考文献

Early-OnsetandRobustAmyloidPathologyinaNew HomozygousMouseModelofAlzheimer’sDisease AntjeWilluweit1*,JoachimVelden1¤a,RobertGodemann1,AndreManook2,FritzJetzek3 ,Hartmut Tintrup4¤b,GuntherKauselmann4,BrankoZevnik4,GjermundHenriksen2,AlexanderDrzezga2, JohannesPohlner1¤c,MichaelSchoor4,JohnA.Kemp1,HeinzvonderKammer1* 1Evotec Neurosciences GmbH, Hamburg, Germany, 2Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universita¨t Mu¨nchen, Munich, Germany,3EvotecTechnologiesGmbH,Hamburg,Germany,4TaconicArtemisGmbH,Cologne,Germany Abstract Background:Transgenicmiceexpressingmutatedamyloidprecursorprotein(APP)andpresenilin(PS)-1or-2havebeen successfullyusedtomodelcerebralb-amyloidosis,oneofthecharacteristichallmarksofAlzheimer’sdisease(AD)pathology. However,theuseofmanytransgeniclinesislimitedbyprematuredeath,lowbreedingefficienciesandlateonsetandhigh inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterizationofanewhomozygousdouble-transgenicmouselinethataddressesmostoftheseissues. Methodology/PrincipalFindings:Thetransgenicmouseline(ARTE10)wasgeneratedbyco-integrationoftwotransgenes carrying the K670N/M671L mutated amyloid precursor protein (APPswe) and the M146V mutated presenilin 1 (PS1) both undercontrolofaneuron-specificpromoter.Mice,hemi-aswellashomozygousforbothtransgenes,areviableandfertile withgoodbreedingcapabilitiesandalowrateofprematuredeath.TheydeveloprobustAD-likecerebralb-amyloidplaque pathology with glial inflammation, signs of neuritic dystrophy and cerebral amyloid angiopathy. Using our novel image analysis algorithm for semi-automatic quantification of plaque burden, we demonstrate an early onset and progressive plaquedepositionstartingat3monthsofageinhomozygousmicewithlowinter-animalvariabilityand100%-penetrance of the phenotype. The plaques are readily detected in vivo by PiB, the standard human PET tracer for AD. In addition, ARTE10micedisplayearlyl