Species: Mouse
Genes: APP
Mutations: APP K670_M671delinsNL (Swedish), APP I716F (Iberian)
Modification: APP: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: App^tm2.1Tcs/App^tm2.1Tcs
Genetic Background: C57BL/6
Availability: Available through Takaomi Saido

Summary

Untangling the effects of elevated Aβ from those due to APP overexpression is a common challenge when interpreting the phenotypes of APP transgenic mice. The APP^NL-F model avoids potential artifacts introduced by APP overexpression by using a knock-in approach to express APP at wild-type levels while producing elevated pathogenic Aβ. Specifically, the APP knock-in construct contains a humanized Aβ region along with two pathogenic mutations, the Swedish “NL” and the Iberian “F”. Due to the use of the endogenous mouse APP promoter, the construct is expressed with appropriate cell-type and temporal specificity. Aβ begins to accumulate in these animals around six months of age. There is a pronounced elevation of Aβ42 due to the combined effect on APP proteolysis of the Swedish and Iberian mutations, which increase total Aβ and Aβ42, respectively.

APP^NL-F mice recapitulate several AD-associated pathologies, including amyloid plaques in the cortex and hippocampus, synaptic loss, and microgliosis and astrocytosis, especially in the vicinity of plaques. Aβ_1-42 and pyroglutamate Aβ are present in plaques; Aβ_x-40 was a minor species. Neurofibrillary tangles and neurodegeneration were not detected, although elevated levels of phosphorylated tau are observed in dystrophic neurites around plaques. At very advanced ages, 24 months or more, some hints of tau pathology are observed in the hippocampus, but they are stochastic in nature and possibly artifact (personal communication, Takaomi Saido).

APP^NL-F mice show signs of cognitive impairment at 18 months, specifically memory impairment as measured by the Y maze. No significant deficit was seen in the Morris water maze (Saito et al., 2014).

In parallel with the development of these mice, two other related strains were created that express mutant APP with the Swedish mutation alone (APP^NL) or with the Swedish, Arctic, and Iberian mutations (APP^NL-G-F). In general, the phenotypes in the APP^NL mice are less severe than the APP^NL-F mice and the phenotypes in the APP^NL-G-F are more severe, including more aggressive amyloid deposition. In some respects, the APP^NL  model can be considered a relevant negative control for APP^NL-F mice as the two models produce equivalent levels of APP and certain proteolytic products, such as AICD. Therefore, the effects of the Iberian mutation, notably an increase in the Aβ42/Aβ40 ratio, can be more easily identified.

In addition to being a stand-alone model, the advantages of the APP^NL-F strain make it a good candidate for generating a variety of double mutants when the aim is to examine the effects of elevated Aβ in the context of wild-type levels of APP. For example, when bred to calpastatin knockout mice, the progeny recapitulated some of the phenotypes that previously had been observed in APP transgenic/calpastatin knockout mice, such as exacerbated amyloidosis, gliosis, and memory impairment, but other phenotypes were not confirmed, including effects on survival and tau phosphorylation, suggesting the latter phenotypes may have been due to APP overexpression.

Availability

Available to nonprofit organizations with MTA and for-profit organizations with license. Contact Takaomi Saido.

Related Models

APP^NL  (Swedish mutation only)

APP^NL-G-F (Swedish, Arctic, and Iberian mutations)

Phenotype Characterization

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References

Paper Citations

1. Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC. Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13 PubMed.

Other Citations

1. APPNL-G-F

Further Reading