Species: Mouse
Genes: APP, PSEN1
Mutations: APP K670_M671delinsNL (Swedish), PSEN1: deltaE9
Modification: APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: CAST.Cg-Tg(APPswe,PSEN1dE9)85Dbo/How
Genetic Background: CAST/EiJ
Availability: Available from The Jackson Laboratory, Stock #25973.

Summary

In an effort to mimic the genetic diversity seen in human populations, scientists have crossed popular transgenic mouse models of Alzheimer’s disease with mice of various genetic backgrounds (see 28 Dec 2018 news; 21 Jun 2019 news).  CAST.APP/PS1 mice are among a set of models created by backcrossing APPswe/PSEN1dE9 mice to three different “wild-derived” strains—inbred strains created in the laboratory from subspecies of house mice caught in the wild less than 50 years ago (Onos et al., 2019). (The other two models, WSB.APP/PS1 and PWK.APP/PS1, are described in detail elsewhere.) The forebears of the CAST strain (Mus mus castaneus) were trapped in Thailand. The CAST strain differs from the widely used C57BL6 inbred strain at around 23 million sites in the genome.

For the initial characterization of these mice, a behavioral battery was conducted on animals between 6 and 8 months of age, after which tissue was harvested for neuropathological and transcriptomic analyses

Levels of the transgenic APPswe and PSEN1dE9 transcripts in brain were similar between the three wild-derived strains and APPswe/PSEN1dE9 on a C57BL6 background (“B6.APP/PS1”). APP protein levels were also similar in CAST.APP/PS1 and B6.APP/PS1 brains. However, female CAST.APP/PS1 mice have higher levels of Aβ42 in their brains than do B6.APP/PS1 females.

Neuropathology | Behavior and cognition | Transcriptomics | Modification Details |Related Strains

Neuropathology

Thioflavin S-positive amyloid plaques are present in the cortex and hippocampus by 8 months of age, with more severe plaque pathology in females than in males. Compared with B6.APP/PS1 mice, CAST.APP/PS1 mice have fewer plaques and particularly lack small plaques. Pronounced cerebral amyloid angiopathy is seen in CAST.APP/PS1 mice, a pathological feature that is absent from B6.APP/PS1 animals.

Plaque-associated microgliosis is present in 8-month CAST.APP/PS1 brains. The number of IBA1-positive microglia surrounding each plaque is greater in CAST.APP/PS1 compared with B6.APP/PS1, as is the number of plaque-associated microglia that express the proliferation marker KI-67.  (In the absence of amyloid pathology, non-transgenic CAST mice have fewer IBA1+ cells in their brains, compared with non-transgenic C57BL6 mice.)

Compared with their non-transgenic littermates, CAST.APP/PS1 mice have fewer neurons in area CA1 of the hippocampus. Cortical neuron numbers do not differ between the genotypes.

Tau pathology, assessed using the phospho-tau antibody AT8, is confined to dystrophic neurites surrounding plaques.

Behavior and cognition

CAST mice are more active than C57BL6 mice, and the APP and PSEN1 transgenes led to increased activity in both genetic backgrounds.

Two different tests in the Y-maze were used to evaluate working memory and short-term memory.  Both tests take advantage of the natural tendency of mice to explore new spaces.  Working memory, as commonly assessed using spontaneous alternation in the Y maze, was similar in CAST.APP/PS1 mice and their non-transgenic littermates. Short-term memory was assessed in a novel test, in which mice were introduced into one arm of the maze and allowed 10 minutes to explore that arm and a second arm (the third arm was blocked). Thirty minutes later, mice were returned to the maze, which now had all three arms open. It was expected that mice with intact working memory would spend more time exploring the previously blocked arm (i.e., they would recognize this arm as novel) than the other two arms. Using this test, working memory was judged to be impaired in CAST.APP/PS1 males; the effects of the transgenes could not be determined in females, as even wild-type CAST females were unable to do this test.

Transcriptomics

RNA-Seq was used to quantify transcripts in the brains of 8-month mice. Background strain, rather than presence of the transgenes, drove most of the differences when transcriptomes were compared between mice from four backgrounds—the three wild-derived strains and C57BL6—with and without APP and PSEN1 transgenes. Weighted Gene Co-expression Analysis identified a module of co-expressed genes that did depend on transgene status; this module included endogenous mouse App and Psen1, and was enriched for genes expressed in microglial and other myeloid cells.

Modification Details

APPswe/PSEN1dE9 mice were made by co-injecting two vectors encoding mutant APP and mutant PSEN1. The APP sequence encodes a chimeric mouse/human APP (Mo/HuAPP695swe) that was “humanized” by modifying three amino acids. In addition, the Swedish mutation was introduced. The PSEN1 sequence encodes human presenilin-1 lacking exon 9 (dE9). Expression of both genes was directed to the CNS with the mouse prion protein promoter. The transgenes inserted at a single locus, Chr9:113003660 (Build GRCm38/mm10), causing a 1 bp duplication that does not affect any known genes (Goodwin et al., 2019). APPswe/PSEN1dE9 mice originally were created on a hybrid C57BL/6 x C3H background; subsequently the transgenes were placed on a congenic C57BL/6J background through backcrossing. The latter line (B6.Cg-Tg(APPswe, PSEN1dE9)85Dbo/Mmjax), referred to here as  B6.APP/PS1, is available from The Jackson Laboratory, MMRRC Stock #34832-JAX (formerly JAX Stock #005864).

To produce CAST.APP/PS1 mice (JAX Stock #25973), B6.APP/PS1 were backcrossed with CAST/EiJ (JAX Stock #000928) for at least six generations.

Related Strains

APPswe/PSEN1dE9 (line 85). This is the original APPswe/PSEN1dE9, on a hybrid C57BL/6 x C3H background.

Phenotype Characterization

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References

News Citations

1. Missing Ingredient: New Mice Model Alzheimer’s Genetic Variability 28 Dec 2018
2. Wild Mice Inject Genetic Diversity into Models of Alzheimer’s Disease 21 Jun 2019

Research Models Citations

1. APPswe/PSEN1dE9 (C57BL6)
2. WSB.APP/PS1
3. PWK.APP/PS1
4. APPswe/PSEN1dE9 (line 85)

Paper Citations

1. Onos KD, Uyar A, Keezer KJ, Jackson HM, Preuss C, Acklin CJ, O'Rourke R, Buchanan R, Cossette TL, Sukoff Rizzo SJ, Soto I, Carter GW, Howell GR. Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation. PLoS Genet. 2019 May;15(5):e1008155. Epub 2019 May 31 PubMed.
2. Goodwin LO, Splinter E, Davis TL, Urban R, He H, Braun RE, Chesler EJ, Kumar V, van Min M, Ndukum J, Philip VM, Reinholdt LG, Svenson K, White JK, Sasner M, Lutz C, Murray SA. Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis. Genome Res. 2019 Mar;29(3):494-505. Epub 2019 Jan 18 PubMed.

External Citations

1. The Jackson Laboratory, MMRRC Stock #34832-JAX
2. JAX Stock #25973
3. JAX Stock #000928
4. The Jackson Laboratory, Stock #25973

Further Reading