Species: Rat
Genes: APP
Mutations: APP K670_M671delinsNL (Swedish), APP V717F (Indiana)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: HsdBrl:WH Wistar
Availability: Breeding pairs available via a royalty agreement with McGill University; contact Adriana Ducatenzeiler.

Summary

The McGill-R-Thy1-APP transgenic rat expresses human APP₇₅₁ with the Swedish and Indiana mutations, under the control of the murine Thy1.2 promoter. These rats are among the most extensively studied of the existing APP transgenic rat lines. Homozygous animals show age-dependent accumulation of amyloid plaques, gliosis, cholinergic synapse loss, and cognitive impairment.

McGill-R-Thy1-APP transgenic rats carry one copy of the transgene per haploid genome, and transgenic APP is expressed throughout the forebrain (Leon et al., 2010).

Neuropathology | Electrophysiology | Cognition/behavior | Imaging and CSF biomarkers | Other | Modification details

Neuropathology

Amyloid pathology. Intraneuronal Aβ is seen in the hippocampus and cortex in homozygous rats as young as one week old (Leon et al., 2010). Extracellular amyloid plaques appear at 6 months of age, first in the subiculum. By 13 months, plaques are seen throughout the hippocampus and are beginning to appear in cortex (Leon et al., 2010). By 18 months, plaques are present throughout the cortex, and are also seen in the amygdala and thalamus in the animals with the most plaques (Heggland et al., 2015). ThioS-positive dense-core plaques are associated with dystrophic neurites and gliosis. Vascular amyloid deposits are not seen in these rats (Leon et al., 2010).

Hemizygous animals also display intraneuronal Aβ beginning as early as one week of age, and with rare exceptions (Heggland et al., 2015) do not deposit extracellular Aβ during their lifetimes (Leon et al., 2010).

Gender does not appear to affect amyloid deposition (Heggland et al., 2015).

Gliosis. In homozygous transgenic rats, increased microglial density is seen in the subiculum by 6 months of age, with some microglia adopting a less ramified shape and orienting toward Aβ-containing neurons. By 18 months, microglial density is increased throughout the cortex and hippocampus; many cells have a fully amoeboid (activated) shape and cluster around plaques (Hanzel et al., 2014). Astroglial density is also increased at 6 months in hippocampus (Hanzel et al., 2014).

Synapse loss. A reduction in cholinergic synaptic boutons was seen at 20 months in homozygous transgenic rats (Iulita et al., 2017).

Neuron loss. A 22 percent reduction in the number of neurons was seen in the subiculum of homozygous transgenic rats at 18 months, compared with wild-type animals; the genotypes did not differ with regard to neuron number in CA1, lateral entorhinal cortex, or medial entorhinal cortex (Heggland et al., 2015).

Electrophysiology

Impairments in short- and long- term potentiation in CA1 were seen in rats as young as 3.5 months, prior to the deposition of amyloid plaques. Antibodies directed against Aβ, BACE1 inhibition, and γ-secretase inhibition all reversed these impairments, providing strong evidence that these deficits in synaptic plasticity were caused by Aβ (Qi et al., 2014).

Cognition/behavior

McGill-R-Thy1-APP rats have been behaviorally characterized using a variety of tests. These animals are amenable to the administration of multi-test batteries, allowing the calculation of composite cognitive scores (Galeano et al., 2014; Iulita et al., 2014).

Morris water maze. Homozygous rats showed impairments in acquisition of the Morris water maze task by 3 months of age, and also performed poorly in a probe trial administered 24 hours after the last training session; however, it is not clear whether poor performance in the probe trial represents a memory deficit or reflects failure to learn the task (Leon et al., 2010). Hemizygous rats were able to learn the task at 3 months of age, performing similarly to wild-type animals during the acquisition phase, but showed memory impairment in the probe trial (Galeano et al., 2014).

Elevated plus maze. Hemizygous males performed similarly to wild-type rats when tested at 3, 6, and 12 months of age (Galeano et al., 2014).

Open field test. Hemizygous males made fewer entries into, and spent less time in, the center of an open field, compared with wild-type rats when tested at 6 and 12 months of age (Galeano et al., 2014).

Novel object recognition. In cohorts containing both males and females, hemizygous and homozygous McGill-R-Thy1-APP rats were able to discriminate between novel and familiar objects at 3 months of age, although they did not show as strong an interest in the novel object as wild-type rats did. By 13 months, the transgenic rats showed only a slight preference for the novel object (Iulita et al., 2014). In a second study using only males, hemizygous McGill-R-Thy1-APP rats and wild-type rats performed similarly when tested at 3, 6, and 12 months of age, with both genotypes showing more interest in the novel object than in the familiar object (Galeano et al., 2014).

Y-maze. Hemizygous males have been tested in the Y-maze. Transgenic rats did not differ from wild-type rats with regard to total arm entries, at least up to a year of age. However, spontaneous alternation was impaired in transgenic rats by 6 months (Galeano et al., 2014).

Fear conditioning. Hemizygous and homozygous transgenic rats showed deficits in the acquisition of the fear response as early as 3 months of age (Iulita et al., 2014).

Visual discrimination. Homozygous transgenic rats exhibited severe deficits in an operant visual discrimination task at 4-6 months of age (Wilson et al., 2017).

Other. Hemizygous animals displayed normal neurological reflexes at least until 9 months of age, including righting response, eye blink, ear twitch, and limb withdrawal, orienting response to a visual stimulus, and startle response to an auditory stimulus (Galeano et al., 2014).

Imaging and CSF biomarkers

Amyloid-PET. There was no specific uptake of the amyloid-binding PET tracer [18F]NAV4694 in 9-11-month-old homozygotes, but by 16 to 19 months, amyloid deposition was observed in the olfactory bulb, hippocampus, amygdala, infralimbic, insular, perirhinal, piriform, and entorhinal cortices (Parent et al., 2017). No sex differences were observed.

FDG-PET. Hypometabolism was observed in ventral orbital, secondary motor, cingulate, prelimbic, barrel, and entorhinal cortices, ventral thalamus and medial geniculate, hippocampus, and inferior colliculus of homozygotes at 16 to 19 months of age; cerebral glucose uptake was normal at 9 to 11 months (Parent et al., 2017). No sex differences were observed.

Resting state fMRI. Disrupted cingulate network connectivity was apparent by 9 to 11 months in homozygous McGill-R-Thy1-APP rats (Parent et al., 2017). No sex differences were observed.

Structural MRI. Longitudinal measurements revealed an average 8 percent decrease in hippocampal volume between approximately 11 months and 16 to 19 months of age in homozygous transgenic animals (Parent et al., 2017). No sex differences were observed.

Proton magnetic resonance spectroscopy. Proton magnetic resonance spectroscopy (MRS) has been used to measure metabolites—including glutamate, GABA, glutamine, N-acetyl aspartate (NAA, believed to be a marker of neuronal health), myo-inositol (mIns, associated with astrogliosis), taurine, total creatine, and total choline—in the brains of McGill-R-Thy1-APP rats in vivo. Differences in metabolite levels between homozygous transgenic rats and wild-type controls were found in the dorsal hippocampus and frontal cortex at 3, 9, and 12 months (Nilsen et al., 2012). A second study examined gender differences, focusing on the dorsal hippocampus. While no gender differences in metabolite levels were observed in non-transgenic animals, male McGill-R-Thy1-APP rats had lower levels of mIns and NAA than did female transgenic animals (Nilsen et al., 2014). In addition, similar levels of metabolites were measured in female transgenic and wild-type rats, but male McGill-R-Thy1-APP rats had lower levels of glutamate, NAA, and total choline than did wild-type rats.

CSF biomarkers. Longitudinal measurements revealed an average 28 percent drop in the levels of CSF Aβ42 between approximately 9 to11 months and 16 to 19 months of age in homozygous transgenic animals (Parent et al., 2017).

Other

Proteomic analysis of the hippocampus revealed alterations primarily in pathways related to cellular responses to stress, protein homeostasis, and neuronal structure at 3 months of age, and in pathways related to energy metabolism at 12 months in homozygous McGill-R-Thy1-APP rats compared with wild-type rats (Do Carmo et al., 2018).

Markers of inflammation—including COX-2, IL-1β, TNF-α—were found to be upregulated in the hippocampi and cortices of homozygous McGill-R-Thy1-APP rats, even prior to plaque deposition (Hanzel et al., 2014). Immunohistochemistry showed partial co-localization of these markers with intra-neuronal Aβ.

Modification details

Pronuclei of HsdBrl:WH Wistar zygotes were injected with a DNA construct including the entire coding region of human APP₇₅₁ and approximately 900 bp of 3' non-translated sequence (Leon et al., 2010). The transgene contains the Swedish and Indiana mutations and is driven by the murine Thy1.2 promoter.

Phenotype Characterization

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References

Paper Citations

1. Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, Vercauteren F, Atifeh R, Ducatenzeiler A, Klein W, Szyf M, Alhonen L, Cuello AC. A novel transgenic rat model with a full Alzheimer's-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimers Dis. 2010;20(1):113-26. PubMed.
2. Heggland I, Storkaas IS, Soligard HT, Kobro-Flatmoen A, Witter MP. Stereological estimation of neuron number and plaque load in the hippocampal region of a transgenic rat model of Alzheimer's disease. Eur J Neurosci. 2015 May;41(9):1245-62. Epub 2015 Mar 25 PubMed.
3. Hanzel CE, Pichet-Binette A, Pimentel LS, Iulita MF, Allard S, Ducatenzeiler A, Do Carmo S, Cuello AC. Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2249-62. Epub 2014 Mar 28 PubMed.
4. Iulita MF, Bistué Millón MB, Pentz R, Aguilar LF, Do Carmo S, Allard S, Michalski B, Wilson EN, Ducatenzeiler A, Bruno MA, Fahnestock M, Cuello AC. Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease. Neurobiol Dis. 2017 Dec;108:307-323. Epub 2017 Sep 1 PubMed.
5. Qi Y, Klyubin I, Harney SC, Hu N, Cullen WK, Grant MK, Steffen J, Wilson EN, Do Carmo S, Remy S, Fuhrmann M, Ashe KH, Cuello AC, Rowan MJ. Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents. Acta Neuropathol Commun. 2014 Dec 24;2:175. PubMed.
6. Galeano P, Martino Adami PV, Do Carmo S, Blanco E, Rotondaro C, Capani F, Castaño EM, Cuello AC, Morelli L. Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer's disease. Front Behav Neurosci. 2014;8:321. Epub 2014 Sep 16 PubMed.
7. Iulita MF, Allard S, Richter L, Munter LM, Ducatenzeiler A, Weise C, Do Carmo S, Klein WL, Multhaup G, Cuello AC. Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study. Acta Neuropathol Commun. 2014 Jun 5;2:61. PubMed.
8. Wilson EN, Abela AR, Do Carmo S, Allard S, Marks AR, Welikovitch LA, Ducatenzeiler A, Chudasama Y, Cuello AC. Intraneuronal Amyloid Beta Accumulation Disrupts Hippocampal CRTC1-Dependent Gene Expression and Cognitive Function in a Rat Model of Alzheimer Disease. Cereb Cortex. 2017 Feb 1;27(2):1501-1511. PubMed.
9. Parent MJ, Zimmer ER, Shin M, Kang MS, Fonov VS, Mathieu A, Aliaga A, Kostikov A, Do Carmo S, Dea D, Poirier J, Soucy JP, Gauthier S, Cuello AC, Rosa-Neto P. Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities. J Neurosci. 2017 Dec 13;37(50):12263-12271. Epub 2017 Nov 2 PubMed.
10. Nilsen LH, Melø TM, Sæther O, Witter MP, Sonnewald U. Altered neurochemical profile in the McGill-R-Thy1-APP rat model of Alzheimer's disease: a longitudinal in vivo (1) H MRS study. J Neurochem. 2012 Nov;123(4):532-41. PubMed.
11. Nilsen LH, Melø TM, Witter MP, Sonnewald U. Early differences in dorsal hippocampal metabolite levels in males but not females in a transgenic rat model of Alzheimer's disease. Neurochem Res. 2014 Feb;39(2):305-12. Epub 2013 Dec 17 PubMed.
12. Do Carmo S, Crynen G, Paradis T, Reed J, Iulita MF, Ducatenzeiler A, Crawford F, Cuello AC. Hippocampal Proteomic Analysis Reveals Distinct Pathway Deregulation Profiles at Early and Late Stages in a Rat Model of Alzheimer's-Like Amyloid Pathology. Mol Neurobiol. 2018 Apr;55(4):3451-3476. Epub 2017 May 13 PubMed.

Other Citations

1. Adriana Ducatenzeiler

Further Reading

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