Mutations: APP KM670/671NL (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 Lars Nilsson.
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).
Transgenic mice containing human APP (isoform 695) containing both the Arctic (E693G) and Swedish (KM670/671NL) mutations under the murine Thy1 promoter.
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
- Synaptic Loss
- Changes in LTP/LTD
Extracellular amyloid plaque deposition starts at around 5-6 months of age (Lord et al., 2006) and is most consistently present in the cerebral cortex, hippocampus, and thalamus (Lillehaug et al., 2013).
Microgliosis and astrogliosis most prominent in the hippocampus, but also locally around deposits in the cerebral cortex and thalamus.
Changes in LTP/LTD
Transgene-dependent spatial learning impairment in the Morris water maze (4-8 months) (Lord et al., 2009) and in an Intellicage-based Passive Avoidance test (16 months)(Codita et al., 2010).
Research Models Citations
- 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.
- 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.
- 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.
- 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.
- 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. 2013 Oct 12; PubMed.
- Englund H, Sehlin D, Johansson AS, Nilsson LN, Gellerfors P, Paulie S, Lannfelt L, Pettersson FE. Sensitive ELISA detection of amyloid-beta protofibrils in biological samples. J Neurochem. 2007 Oct;103(1):334-45. PubMed.
- Sahlin C, Lord A, Magnusson K, Englund H, Almeida CG, Greengard P, Nyberg F, Gouras GK, Lannfelt L, Nilsson LN. The Arctic Alzheimer mutation favors intracellular amyloid-beta production by making amyloid precursor protein less available to alpha-secretase. J Neurochem. 2007 May;101(3):854-62. PubMed.