Mutations: APP K670_M671delinsNL (Swedish), APP I716F (Iberian)
Modification: APP: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: Apptm2.1Tcs/Apptm2.1Tcs
Genetic Background: C57BL/6
Availability: Available through Takaomi Saido
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 APPNL-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.
APPNL-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. Aβ1-42 and pyroglutamate Aβ are present in plaques; Aβx-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).
APPNL-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 (APPNL) or with the Swedish, Arctic, and Iberian mutations (APPNL-G-F). In general, the phenotypes in the APPNL mice are less severe than the APPNL-F mice and the phenotypes in the APPNL-G-F are more severe, including more aggressive amyloid deposition. In some respects, the APPNL model can be considered a relevant negative control for APPNL-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 APPNL-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.
Available to nonprofit organizations with MTA and for-profit organizations with license. Contact Takaomi Saido.
APPNL (Swedish mutation only)
APPNL-G-F (Swedish, Arctic, and Iberian mutations)
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Changes in LTP/LTD
Homozygotes develop amyloid plaques starting at 6 months in the cortex and hippocampus. Heterozygotes develop amyloidosis after 24 months. Plaques contained Aβ1-42 and pyroglutamate Aβ (Aβ3(pE)-42); Aβx-40 was a minor species.
Absent; although elevated levels of phosphorylated tau are observed in dystrophic neurites around plaques.
Microglia and activated astrocytes accumulate with age, starting around 6 months of age, concurrent with plaque formation.
Reduced synaptophysin and PSD95 immunoreactivities associated with Aβ plaques at 9-12 months.
Changes in LTP/LTD
Memory impairment in homozygous mice at 18 months as measured by the Y maze test. APPNL/NL mice (with Swedish mutation only) were unimpaired at this age. No significant deficit was seen in the Morris water maze at 18 months.
Last Updated: 07 Apr 2014
- 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.
- Nilsson P, Saito T, Saido TC. New mouse model of Alzheimer's. ACS Chem Neurosci. 2014 Jul 16;5(7):499-502. Epub 2014 May 22 PubMed.
- Zhang H, Wu L, Pchitskaya E, Zakharova O, Saito T, Saido T, Bezprozvanny I. Neuronal Store-Operated Calcium Entry and Mushroom Spine Loss in Amyloid Precursor Protein Knock-In Mouse Model of Alzheimer's Disease. J Neurosci. 2015 Sep 30;35(39):13275-86. PubMed.
- Huang Y, Skwarek-Maruszewska A, Horré K, Vandewyer E, Wolfs L, Snellinx A, Saito T, Radaelli E, Corthout N, Colombelli J, Lo AC, Van Aerschot L, Callaerts-Vegh Z, Trabzuni D, Bossers K, Verhaagen J, Ryten M, Munck S, D'Hooge R, Swaab DF, Hardy J, Saido TC, De Strooper B, Thathiah A. Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models. Sci Transl Med. 2015 Oct 14;7(309):309ra164. PubMed.