Genes: APP, PSEN1
Mutations: APP KM670/671NL (Swedish), PSEN1: deltaE9
Modification: APP: Transgenic; PSEN1: Transgenic;
Disease Relevance: Alzheimer's Disease
Strain Name: B6C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax
Genetic Background: C57BL/6 x C3H)F2
Availability: Jackson Labs: Stock# 004462; Live
These transgenic mice were made by coinjecting two vectors encoding mutant APP and mutant PSEN1. The APP sequence encodes a chimeric mouse/human APP (Mo/HuAPP695swe) which was “humanized” by modifying three amino acids, and the Swedish mutation was introduced. The PSEN1 sequence encodes human presenilin 1 lacking exon 9 (dE9) and which therefore models AD-associated mutations in PSEN1 resulting in exclusion of exon 9, variously known as ΔE9, dE9, deltaE9, Δ9, or delE9. Expression of both genes was directed to the CNS with the mouse prion promoter.
Like the APPSwe/PSEN1dE9 mice generated by crossing transgenic APP animals with those expressing PSEN1dE9, these mice begin to develop Aβ deposits by six months of age with abundant plaques in the hippocampus and cortex by nine months (Jankowsky et al., 2004). Plaques continue to increase up to twleve months (Garcia-Alloza et al., 2006). Tangles are not typical in these animals. Astrocytosis increases in parallel with plaque deposition, with severe gliosis starting around six months, especially in areas around plaques. The degree of GFAP-positive staining progressively increases with age, with extensive staining throughout the cortex by 15 months (Kamphuis et al., 2012).
The behavior of these animals has been well-characterized. They have impaired spatial learning by twelve months as measured by the Morris water maze, specifically during acquisition of the hidden platform sub-task and the probe trial but not in the visible platform test (Lalonde et al., 2005). They have been shown to commit more errors during the Morris water maze at 13 months, but not at seven months (Volianskis et al., 2008). These mice have a high incidence of spontaneous seizures and epileptiform discharges as detected by video-EEG with an associated increase in mortality.
Deficits in synaptic plasticity have been observed. Specifically, deficits in transient long term potentiation (t-LTP) have been observed by three months, although the degree of impairment is not related to age from three to twelve months (Volianskis et al., 2008).
This strain does not carry the retinal degeneration allele Pde6brd1.
Jackson Labs: Stock# 005864 B6.Cg-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax Backcrossed onto a C57 background for at least eight generations.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
Occasional Aβ deposits can be found by 6 months with abundant plaques in the hippocampus and cortex by 9 months (Jankowsky et al., 2004) and a progressive increase in plaques up to 12 months (Garcia-Alloza et al., 2006).
Minimal astrocytosis at 3 months; significant astrocytosis by 6 months, especially in areas around plaques. Extensive GFAP+ staining at 15 months and later throughout the cortex (Kamphuis et al., 2012).
Changes in LTP/LTD
Transient long term potentiation (t-LTP) is reduced by 3 months. The degree of impairment is not related to age from 3 to 12 months (Volianskis et al., 2008).
Impairment in the Morris water maze at 12 months, specifically during acquisition of the hidden platform sub-task and the probe trial but not in the visible platform test (Lalonde et al., 2005). At 13 months the mice commit more errors in the Morris water maze, but not at 7 months (Volianskis et al., 2008).
Research Models Citations
- Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet. 2004 Jan 15;13(2):159-70. PubMed.
- Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP. Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis. 2006 Dec;24(3):516-24. PubMed.
- Kamphuis W, Mamber C, Moeton M, Kooijman L, Sluijs JA, Jansen AH, Verveer M, de Groot LR, Smith VD, Rangarajan S, Rodríguez JJ, Orre M, Hol EM. GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS One. 2012;7(8):e42823. PubMed.
- Lalonde R, Kim HD, Maxwell JA, Fukuchi K. Exploratory activity and spatial learning in 12-month-old APP(695)SWE/co+PS1/DeltaE9 mice with amyloid plaques. Neurosci Lett. 2005 Dec 23;390(2):87-92. PubMed.
- Volianskis A, Køstner R, Mølgaard M, Hass S, Jensen MS. Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1δE9-deleted transgenic mice model of ß-amyloidosis. Neurobiol Aging. 2010 Jul;31(7):1173-87. PubMed.
No Available Further Reading