Species: Mouse
Genes: APP
Mutations: APP K670_M671delinsNL (Swedish), APP E693G (Arctic)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Strain Name: N/A
Genetic Background: C57BL/6J
Availability: Available through Stina Syvänen or Lars Nilsson.

Summary

The inclusion of the Arctic mutation along with the Swedish mutation in the transgene results in more prominent Aβ pathology, including elevated soluble Aβ aggregates such as Aβ protofibrils, greater accumulation of Aβ inside neurons, and more robust senile plaques than typically observed with the Swedish mutation alone (e.g. Tg-Swe).

Similar to postmortem Alzheimer's disease brain, biochemical dissolution of deposited Aβ in this model requires formic acid (Philipson et al., 2009). In the double mutant mice, intraneuronal Aβ aggregation is first observed at one month of age (Lord et al., 2006; Philipson et al., 2009) and extracellular plaque deposition starts at around five to six months of age (Lord et al., 2006). Congophilic parenchymal plaque deposition is usually the dominating neuropathological feature, but some individual mice show high levels of CAA, which is usually most pronounced in the thalamus. Aβ protofibrils can be detected in brain TBS extracts from mice at two months of age and peak around 12-14 months of age (Lord et al., 2009). The plaques in these mice have a different morphological structure as compared to transgenic mice bearing the Swedish mutation alone, in that they have been shown to emit fluorescence at different wavelengths when stained with luminescent polymers (conformational amyloid ligands). The plaque population is also more homogenous in size and structure as compared to Tg-Swe, with plaque consistently most evident in the cerebral cortex, hippocampus and thalamus (Lillehaug et al., 2013). An anatomic atlas of the Tg-ArcSwe model is available at the Rodent Brain Workbench. At four months, cerebrospinal fluid levels of Aβ are elevated, and CSF tau protofibrils can also be detected (personal communication, Lars Nilsson).

Modification Details

Transgenic mice containing human APP (isoform 695) containing both the Arctic (E693G) and Swedish (KM670/671NL) mutations under the murine Thy1 promoter.

Phenotype Characterization

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References

Paper Citations

1. Philipson O, Hammarström P, Nilsson KP, Portelius E, Olofsson T, Ingelsson M, Hyman BT, Blennow K, Lannfelt L, Kalimo H, Nilsson LN. A highly insoluble state of Abeta similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice. Neurobiol Aging. 2009 Sep;30(9):1393-405. PubMed.
2. Lord A, Kalimo H, Eckman C, Zhang XQ, Lannfelt L, Nilsson LN. The Arctic Alzheimer mutation facilitates early intraneuronal Abeta aggregation and senile plaque formation in transgenic mice. Neurobiol Aging. 2006 Jan;27(1):67-77. PubMed.
3. Philipson O, Lannfelt L, Nilsson LN. Genetic and pharmacological evidence of intraneuronal Abeta accumulation in APP transgenic mice. FEBS Lett. 2009 Sep 17;583(18):3021-6. PubMed.
4. Lord A, Englund H, Söderberg L, Tucker S, Clausen F, Hillered L, Gordon M, Morgan D, Lannfelt L, Pettersson FE, Nilsson LN. Amyloid-beta protofibril levels correlate with spatial learning in Arctic Alzheimer's disease transgenic mice. FEBS J. 2009 Feb;276(4):995-1006. PubMed.
5. Lillehaug S, Syverstad GH, Nilsson LN, Bjaalie JG, Leergaard TB, Torp R. Brainwide distribution and variance of amyloid-beta deposits in tg-ArcSwe mice. Neurobiol Aging. 2014 Mar;35(3):556-64. Epub 2013 Oct 12 PubMed.

Other Citations

1. Tg-Swe

External Citations

1. Rodent Brain Workbench

Further Reading