Species: Rat
Genes: APP
Mutations: APP K670_M671delinsNL (Swedish), APP V717F (Indiana)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: F344-Tg(APP)21Besey
Genetic Background: Fischer 344
Availability: Available from the Rat Resource & Research Center, Stock# 00636; cryorecovery, sperm

Summary

APP21 rats express human APP₆₉₅ containing the Swedish and Indiana mutations, driven by the ubiquitin-C promoter (Agca et al., 2008). Although these rats do not spontaneously develop amyloid pathology, they can serve as hosts for exogenously seeded amyloid deposits (Rosen et al., 2012). Cognitive deficits and neurodegeneration have been reported, but further studies are required to determine whether these phenotypes are age- or gender-dependent.

This transgenic line was generated via lentiviral vector infection of Fischer 344 zygotes (Agca et al., 2008). Two founders, designated APP21 and APP31, showed germline transmission, and each carried a single copy of the transgene. The higher-expressing line, APP21, is described here.

Human APP is expressed in brain, heart, liver, and lung. The level of APP mRNA in the brain is approximately three times higher in homozygous transgenic rats than in non-transgenic animals. Immunoreactivity for human APP/Aβ was observed in pyramidal neurons throughout the cerebral cortex and in hippocampal subfields CA1 and CA3, as well as in granule cells of the dentate gyrus (Agca et al., 2008).

Neuropathology

No extracellular amyloid deposits were observed in homozygous transgenic rats up to 30 months of age. However, diffuse plaques and perivascular amyloid deposits were seen in homozygous transgenic rats nine months after intra-hippocampal injection of extracts from Alzheimer’s brains (Rosen et al., 2012). Induced hydrocephalus also led to the appearance of cerebral amyloid angiopathy, and accelerated the accumulation of intraneuronal Aβ in APP21 rats (Silverberg et al., 2015).

Necrotic neurons were observed in the hippocampi and cortices of female rats by 19 months of age (Agca et al., 2016; Klakotskaia et al., 2018), but male rats did not exhibit cortical neuron loss, assessed as the number of NeuN-positive cells (Weishaupt et al., 2018). It remains to be seen whether there are gender differences when the same techniques are used to assess neuron loss in both males and females.  

It has been reported that neurofibrillary tangles were present in hippocampal neurons of 18- to 19-month-old female rats, but this conclusion was based on the appearance of “flame-shaped” profiles in hematoxylin-and-eosin-stained sections, and awaits confirmation using silver-staining methods (Agca et al., 2016). Male rats were not examined in these histological studies.

A normal age-dependent activation of microglia in white matter tracts might be accelerated in APP21 rats: Fifteen-month APP21 rats have significantly more cells that express MHCII (a marker for activated microglia) in the corpus callosum and internal capsule than do non-transgenic rats, but this difference disappears by 19 months (Weishaupt et al., 2018).

Cognition/behavior

In a longitudinal study that included only males, rats were tested in the Morris water maze at 3, 10, 13, 16, and 19 months (Weishaupt et al., 2018). Compared with non-transgenic animals, APP21 rats took longer to find the hidden platform during training trials, but rats of both genotypes performed similarly in memory tests conducted 24-72 hours later. (However, it should be noted that, in this study, the non-transgenic animals performed more poorly than expected, with all groups performing only slightly above chance levels.) APP21 rats also showed deficits in reversal learning in the water maze at 19 months, the only age tested using this paradigm.

In the Barnes maze, a cohort containing both male and female APP21 rats performed similarly to non-transgenic animals at 10 months of age (Agca et al., 2016). At 14 months, female APP21 rats showed deficits in the acquisition and reversal phases of a Barnes maze test (Klakotskaia et al., 2018); this study did not test males. Similar to the findings when male rats were tested in the Morris water maze, female APP21 rats performed as well as non-transgenic animals when memory was tested several days after training in the Barnes maze.

Modification Details

A lentiviral vector carrying a human APP₆₉₅ transgene was injected into Fischer 344 zygotes. This transgene contains the Swedish and Indiana mutations and is driven by the ubiquitin-C promoter.

Related Strain

APP21+PS1. APP21+PS1 transgenic rats express human APP with the Swedish and Indiana mutations and human PSEN1 with the L166P mutation. Both transgenes are driven by the ubiquitin-C promoter. These rats exhibit amyloid pathology, neurodegeneration, and behavioral deficits (Agca et al., 2016; Klakotskaia et al., 2018).

Phenotype Characterization

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References

Paper Citations

1. Agca C, Fritz JJ, Walker LC, Levey AI, Chan AW, Lah JJ, Agca Y. Development of transgenic rats producing human beta-amyloid precursor protein as a model for Alzheimer's disease: transgene and endogenous APP genes are regulated tissue-specifically. BMC Neurosci. 2008;9:28. PubMed.
2. Rosen RF, Fritz JJ, Dooyema J, Cintron AF, Hamaguchi T, Lah JJ, LeVine H 3rd, Jucker M, Walker LC. Exogenous seeding of cerebral β-amyloid deposition in βAPP-transgenic rats. J Neurochem. 2012 Mar;120(5):660-6. Epub 2011 Nov 18 PubMed.
3. Silverberg GD, Miller MC, Pascale CL, Caralopoulos IN, Agca Y, Agca C, Stopa EG. Kaolin-induced chronic hydrocephalus accelerates amyloid deposition and vascular disease in transgenic rats expressing high levels of human APP. Fluids Barriers CNS. 2015;12(1):2. Epub 2015 Jan 24 PubMed.
4. Agca C, Klakotskaia D, Schachtman TR, Chan AW, Lah JJ, Agca Y. Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention. BMC Neurosci. 2016 Jul 7;17(1):46. PubMed.
5. Klakotskaia D, Agca C, Richardson RA, Stopa EG, Schachtman TR, Agca Y. Memory deficiency, cerebral amyloid angiopathy, and amyloid-β plaques in APP+PS1 double transgenic rat model of Alzheimer's disease. PLoS One. 2018;13(4):e0195469. Epub 2018 Apr 11 PubMed.
6. Weishaupt N, Liu Q, Shin S, Singh R, Agca Y, Agca C, Hachinski V, Whitehead SN. APP21 transgenic rats develop age-dependent cognitive impairment and microglia accumulation within white matter tracts. J Neuroinflammation. 2018 Aug 28;15(1):241. PubMed.

Other Citations

1. APP21+PS1

External Citations

1. Rat Resource & Research Center, Stock# 00636

Further Reading

No Available Further Reading