TY - JOUR
T1 - A novel transgenic rat model with a full alzheimer's - Like amyloid pathology displays pre - Plaque intracellular amyloid -β- Associated cognitive impairment
AU - Leon, Wanda Carolina
AU - Canneva, Fabio
AU - Partridge, Vanessa
AU - Allard, Simon
AU - Ferretti, Maria Teresa
AU - Dewilde, Arald
AU - Vercauteren, Freya
AU - Atifeh, Ramtin
AU - Ducatenzeiler, Adriana
AU - Klein, William
AU - Szyf, Moshe
AU - Alhonen, Leena
AU - Cuello, A. Claudio
PY - 2010
Y1 - 2010
N2 - Alzheimer's disease (AD) is a neurodegenerative pathology in which amyloid-β (Aβ) 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 Aβ 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-β precursor protein (AβPP) 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 Aβ 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 Aβ 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 Aβ (trimers) measured in the cortex.
AB - Alzheimer's disease (AD) is a neurodegenerative pathology in which amyloid-β (Aβ) 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 Aβ 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-β precursor protein (AβPP) 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 Aβ 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 Aβ 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 Aβ (trimers) measured in the cortex.
KW - Alzheimer's disease
KW - amyloid-β oligomers
KW - cognitive impairment
KW - intracellular amyloid-β
KW - transgenic rat
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UR - http://www.scopus.com/inward/citedby.url?scp=77953020162&partnerID=8YFLogxK
U2 - 10.3233/JAD-2010-1349
DO - 10.3233/JAD-2010-1349
M3 - Article
C2 - 20164597
AN - SCOPUS:77953020162
VL - 20
SP - 113
EP - 126
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 1
ER -