A novel transgenic rat model with a full Alzheimer's-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment.
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.
Leon
Wanda Carolina
WC
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Canneva
Fabio
F
Partridge
Vanessa
V
Allard
Simon
S
Ferretti
Maria Teresa
MT
DeWilde
Arald
A
Vercauteren
Freya
F
Atifeh
Ramtin
R
Ducatenzeiler
Adriana
A
Klein
William
W
Szyf
Moshe
M
Alhonen
Leena
L
Cuello
A Claudio
AC
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
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