A novel transgenic rat model with a full alzheimer's - Like amyloid pathology displays pre - Plaque intracellular amyloid -β- Associated cognitive impairment

Wanda Carolina Leon, Fabio Canneva, Vanessa Partridge, Simon Allard, Maria Teresa Ferretti, Arald Dewilde, Freya Vercauteren, Ramtin Atifeh, Adriana Ducatenzeiler, William Klein, Moshe Szyf, Leena Alhonen, A. Claudio Cuello

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)113-126
Number of pages14
JournalJournal of Alzheimer's Disease
Volume20
Issue number1
DOIs
StatePublished - 2010

Keywords

  • Alzheimer's disease
  • amyloid-β oligomers
  • cognitive impairment
  • intracellular amyloid-β
  • transgenic rat

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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