Genes: APP, PSEN1
Mutations: APP KM670/671NL (Swedish), PSEN1: deltaE9
Modification: APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Tg(APP695)3Dbo Tg(PSEN1dE9)S9Dbo/J
Genetic Background: Line C3-3: C57BL/6J; Line S-9: hybrid strain C3H/HeJ;C57BL/6J) backcrossed to C57BL/6J
Availability: The Jackson Lab; available through the JAX MMRRC Stock# 034833; Cryopreserved
These double transgenic mice were created by breeding mice that express mutant APP (line C3-3) with mice that express mutant PSEN1 (line S-9). Line C3-3 mice express a chimeric mouse/human APP (isoform 695) which is driven by the mouse prion promoter. The Swedish mutation was introduced into the APP sequence in order to increase total Aβ generation (Borchelt et al., 1996; Savonenko et al., 2003). Line S-9 mice (Lee et al., 1997) express human PSEN1 lacking exon 9, which models the AD-associated mutations involving deletion of exon 9, variously known as ΔE9, dE9, deltaE9, Δ9, or delE9.
The double transgenic mice are viable and fertile. Unlike C3-3 single transgenic mice, which do not develop amyloid deposits until beyond 18 months of age (Borchelt et al., 1997), the double transgenic mice have visible plaque deposition at six months of age with an even greater amyloid burden at 18 months. Cognitive impairment occurs subsequent to plaque deposition; APPSwe/PSEN1dE9 mice are indistinguishable from nontransgenic mice on cognitive tasks at six months, but by 18 months perform less well than either single transgenics or wild-type animals (Savonenko et al., 2005).
Some AD patients with ΔE9 mutations develop neuropathology that is atypical for AD, including large "cotton wool" amyloid deposits in the cortex with a relative absence of compact dense core plaques. APPSwe/PSEN1dE9 mice, however, do not display cotton wool plaques, but instead have compact dense core deposits typical of AD (Jankowsky et al., 2004).
This model was previously available through The Jackson Lab as Stock# 005866.
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
Plaques are present in the hippocampus and cortex by 6 months of age.
Changes in LTP/LTD
Age-related cognitive deficits. Episodic memory appears to be more sensitive than reference memory. No differences at 6 months of age, but detectable at 18 months (Savonenko et al., 2005).
Research Models Citations
- Borchelt DR, Davis J, Fischer M, Lee MK, Slunt HH, Ratovitsky T, Regard J, Copeland NG, Jenkins NA, Sisodia SS, Price DL. A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet Anal. 1996 Dec;13(6):159-63. PubMed.
- Savonenko AV, Xu GM, Price DL, Borchelt DR, Markowska AL. Normal cognitive behavior in two distinct congenic lines of transgenic mice hyperexpressing mutant APP SWE. Neurobiol Dis. 2003 Apr;12(3):194-211. PubMed.
- Lee MK, Borchelt DR, Kim G, Thinakaran G, Slunt HH, Ratovitski T, Martin LJ, Kittur A, Gandy S, Levey AI, Jenkins N, Copeland N, Price DL, Sisodia SS. Hyperaccumulation of FAD-linked presenilin 1 variants in vivo. Nat Med. 1997 Jul;3(7):756-60. PubMed.
- Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron. 1997 Oct;19(4):939-45. PubMed.
- Savonenko A, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong MP, Price DL, Tang F, Markowska AL, Borchelt DR. Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis. 2005 Apr;18(3):602-17. PubMed.
- 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. Epub 2003 Nov 25 PubMed.
No Available Further Reading