Species: Mouse
Genes: APP
Mutations: APP K670_M671delinsNL (Swedish), APP I716F (Iberian), APP E693G (Arctic)
Modification: APP: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: App^tm3.1Tcs/App^tm3.1Tcs
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-G-F model avoids potential artifacts introduced by APP overexpression by using a knock-in approach to express APP at wild-type levels and with appropriate cell-type and temporal specificity. APP is not overexpressed, but levels of pathogenic Aβ are elevated due to the combined effects of three mutations associated with familial Alzheimer's disease. Specifically, the APP construct, which contains a humanized Aβ region, includes the Swedish “NL”, the Iberian “F”, and the Arctic “G” mutations. These mutations promote Aβ toxicity by increasing total Aβ production (Swedish mutation), increasing the Aβ42/Aβ40 ratio (Iberian mutation), and promoting Aβ aggregation through facilitating oligomerization and reducing proteolytic degradation (Arctic mutation).

Like the related APP^NL-F mice, which express the Swedish and Iberian mutations, APP^NL-G-F mice accumulate Aβ and recapitulate several AD-associated pathologies, including amyloid plaques, synaptic loss, and microgliosis and astrocytosis, especially in the vicinity of plaques. The presence of the Arctic mutation accelerates the pathology relative to APP^NL-F mice, and leads to particularly severe phenotypes. Aβ deposition is observed starting at two months and is nearly saturated by seven months. In contrast to APP^NL-F mice, the APP^NL-G-F mice develop subcortical amyloidosis in addition to cortical amyloidosis, consistent with the neuropathology observed in patients with the Arctic mutation. Neurofibrillary tangles and neurodegeneration are not detected (Saito et al., 2014), although phosphorylated tau is elevated in dystrophic neurites around plaques (personal communication, Takaomi Saido).

The mice also display age-associated cognitive impairment, specifically memory impairment as measured by the Y maze starting at six months. The cognitive impairment in APP^NL-G-F mice is more severe than the impairment in APP^NL-F mice, occurring about three times faster.

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-F (Swedish 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-F

Further Reading