Journal of Alzheimer's disease : JADFeb 19, 2010

New genetically modified rat shows early brain changes and memory problems like Alzheimer's before plaques form

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 28, 2026

Abstract

A new transgenic rat line, McGill-R-Thy1-APP, exhibits early signs of Alzheimer’s disease pathology, with intraneuronal amyloid-beta accumulation evident by 1 week after birth.

The McGill-R-Thy1-APP rat expresses a modified human amyloid-beta precursor protein associated with Alzheimer's disease.
Intraneuronal amyloid-beta accumulation spreads throughout various cortical areas and the hippocampus by the first week of life.
By 6 months of age, these rats develop extracellular amyloid deposits and dense amyloid plaques, accompanied by glial activation.
Cognitive impairments are observed in the Morris water maze task starting at 3 months, prior to the presence of CNS plaques.
Older transgenic rats (13 months) show more pronounced spatial cognitive deficits that correlate with levels of soluble amyloid-beta in the cortex.

Simplified

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.

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New genetically modified rat shows early brain changes and memory problems like Alzheimer's before plaques form

Abstract

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