title: A novel transgenic rat model with a full Alzheimer's-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment.
abstract: Alzheimer's disease (AD) is a neurodegenerative pathology in which amyloid-beta (Abeta) peptide accumulates in different brain areas leading to deposition of plaques and a progressive decline of cognitive functions. After a decade in which a number of transgenic (Tg) mouse models mimicking AD-like amyloid-deposition pathology have been successfully generated, few rat models have been reported that develop intracellular and extracellular Abeta accumulation, together with impairment of cognition. The generation of a Tg rat reproducing the full AD-like amyloid pathology has been elusive. Here we describe the generation and characterization of a new transgenic rat line, coded McGill-R-Thy1-APP, developed to express the human amyloid-beta precursor protein (AbetaPP) carrying both the Swedish and Indiana mutations under the control of the murine Thy1.2 promoter. The selected mono-transgenic line displays an extended phase of intraneuronal Abeta accumulation, already apparent at 1 week after birth, which is widespread throughout different cortical areas and the hippocampus (CA1, CA2, CA3, and dentate gyrus). Homozygous Tg animals eventually produce extracellular Abeta deposits and, by 6 months of age, dense, thioflavine S-positive, amyloid plaques are detected, associated with glial activation and surrounding dystrophic neurites. The cognitive functions in transgenic McGill-R-Thy1-APP rats, as assessed using the Morris water maze task, were found already altered as early as at 3 months of age, when no CNS plaques are yet present. The spatial cognitive impairment becomes more prominent in older animals (13 months), where the behavioral performance of Tg rats positively correlates with the levels of soluble Abeta (trimers) measured in the cortex.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Wanda Carolina
authors.initials: WC
authors.lastname: Leon
authors.forename: Fabio
authors.initials: F
authors.lastname: Canneva
authors.forename: Vanessa
authors.initials: V
authors.lastname: Partridge
authors.forename: Simon
authors.initials: S
authors.lastname: Allard
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ferretti
authors.forename: Arald
authors.initials: A
authors.lastname: DeWilde
authors.forename: Freya
authors.initials: F
authors.lastname: Vercauteren
authors.forename: Ramtin
authors.initials: R
authors.lastname: Atifeh
authors.forename: Adriana
authors.initials: A
authors.lastname: Ducatenzeiler
authors.forename: William
authors.initials: W
authors.lastname: Klein
authors.forename: Moshe
authors.initials: M
authors.lastname: Szyf
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.forename: A Claudio
authors.initials: AC
authors.lastname: Cuello
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D011939:Mental Recall / Q000502:physiology; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D011930:Reaction Time / Q000235:genetics; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012333:RNA, Messenger; C493466:Slc17a7 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2