A Novel Transgenic Rat Model with a Full Alzheimer's-Like Amyloid Pathology Displays Pre-Plaque Intracellular Amyloid-β-Associated Cognitive Impairment

Article type: Research Article

Authors: Leon, Wanda Carolina^{a; 1} | Canneva, Fabio^{a; 1} | Partridge, Vanessa^a | Allard, Simon^a | Ferretti, Maria Teresa^a | DeWilde, Arald^a | Vercauteren, Freya^{a; 2} | Atifeh, Ramtin^a | Ducatenzeiler, Adriana^a | Klein, William^b | Szyf, Moshe^a | Alhonen, Leena^c | Cuello, A. Claudio^{a; d; e; *}

Affiliations: [a] Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada | [b] Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Institute for Neuroscience, Chicago, IL, USA | [c] Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland | [d] Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada | [e] Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

Correspondence: [*] Correspondence to: A. Claudio Cuello, 3655 Promenade Sir William Osler, H3G 1Y6, Montreal, QC, Canada. Tel.: +1 514 398 3618; Fax: +1 514 398 8317; E-mail: [email protected].

Note: [1] WL and FC equally contributed to the experimental work.

Note: [2] Present affiliation: Sleep Research Centre, Université de Montreal, Faculty of Medicine, Sacré-Coeur Hospital, Montreal, QC, Canada.

Abstract: 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.

Keywords: Alzheimer's disease, amyloid-β oligomers, cognitive impairment, intracellular amyloid-β, transgenic rat

DOI: 10.3233/JAD-2010-1349

Journal: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 113-126, 2010