Genes: APP, PSEN1
Mutations: APP KM670/671NL (Swedish), PSEN1 A246E
Modification: APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6C3-Tg(APP695)3Dbo Tg(PSEN1)5Dbo/J
Genetic Background: Origin: (C57BL/6J x C3H/HeJ)F2
Availability: The Jackson Lab: Stock# 003378; Cryopreserved
These double transgenic mice were generated in the mid-1990s by David Borchelt, Sangram Sisodia, and colleagues at Johns Hopkins. The mice were made by crossing two transgenic lines, one expressing human PSEN1 with the A246E mutation and another line expressing chimeric APP with the Swedish mutation (see APPSwe line C3-3). The double transgenics develop age-associated amyloid pathology and deficits in hippocampal-dependent memory. Although both transgenes are expressed at relatively high levels throughout the brain (see Borchelt et al., 1996), amyloid plaques are generally restricted to specific regions, primarily within the medial temporal lobe.
By two to three months of age, the ratio of Aβ1–42(43) to Aβ1–40 is elevated by about 50 percent in double transgenic mice compared with mice expressing APPswe alone or double transgenics coexpressing APPswe and wild-type human PSEN1 (Borchelt et al., 1996). Numerous amyloid plaques deposit in a region-specific manner by nine to 12 months of age. Plaques begin in the hippocampus and subiculum and later extend to areas throughout the cortex, remaining particularly dense in the subiculum. The striatum and thalamus are relatively spared as late as 18 months of age (Borchelt et al., 1997; Liu et al., 2002). Plaques contain both Aβ42 and Aβ40 (Borchelt et al., 1997; Jankowsky et al., 2004). Dystrophic neurites and reactive astrocytes occur in areas affected by amyloid plaques (Borchelt et al., 1997).
Sex-specific differences have been observed in this model. Notably, Aβ-related pathology is more severe in female mice. Levels of Aβ42 and Aβ40 meausured in hippocampal homogenate by ELISA are higher in females at 4, 12, and 17 months of age. In addition, the overall amyloid burden is higher in females at 12 and 17 months of age; plaques were not observed in either sex at four months of age (Wang et al., 2003).
Male APPSwe/PSEN1(A246E) mice develop age-associated cognitive impairment. In the Morris water maze, a measure of hippocampal-dependent spatial memory, both acquisition and retention were impaired in 11 to 12-month-old mice, compared with wild-type littermates. In contrast, the double transgenics performed normally on a position discrimination task in the T-maze, which does not depend on the hippocampus. At three to four months of age, the double transgenics performed normally on both the water maze and the T-maze tasks (Puoliväli et al., 2002). It is not known if female mice develop a similar memory deficit.
These double transgenic mice were generated by crossing mice expressing human PSEN1 with the A246E mutation under the control of the mouse prion protein promoter with mice expressing chimeric APP (isoform 695) with the Swedish mutation, also directed by the mouse prion promoter. The chimeric APP protein was created by replacing the mouse Aβ sequence with the cognate human sequence.
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
By 9 months of age, amyloid plaques develop in the hippocampus and subiculum, later extending to the cortex (Borchelt et al., 1997). The striatum and thalamus are relatively spared out to 18 months of age. Amyloid pathology is more severe in female mice, with a greater amyloid burden measured at 12 and 17 months of age (Wang et al., 2003).
There was no difference in neuronal numbers in the cingulate cortex compared with wild-type mice (Xiang et al., 2002).
By one year of age, reactive gliosis is observed in the cortex and hippocampus and is associated with dystrophic neurites (Borchelt et al., 1997).
Changes in LTP/LTD
Age-associated cognitive impairment, as measured by the Morris water maze, was observed in 11 to 12-month-old males. Both acquisition and retention were impaired. No impairment at 3-4 months of age. At both time points mice performed normally on a position discrimination task in the T-maze (Puoliväli et al., 2002).
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.
- Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996 Nov;17(5):1005-13. 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.
- Liu L, Ikonen S, Heikkinen T, Heikkilä M, Puoliväli J, van Groen T, Tanila H. Effects of fimbria-fornix lesion and amyloid pathology on spatial learning and memory in transgenic APP+PS1 mice. Behav Brain Res. 2002 Aug 21;134(1-2):433-45. 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.
- Wang J, Tanila H, Puoliväli J, Kadish I, van Groen T. Gender differences in the amount and deposition of amyloidbeta in APPswe and PS1 double transgenic mice. Neurobiol Dis. 2003 Dec;14(3):318-27. PubMed.
- Puoliväli J, Wang J, Heikkinen T, Heikkilä M, Tapiola T, van Groen T, Tanila H. Hippocampal A beta 42 levels correlate with spatial memory deficit in APP and PS1 double transgenic mice. Neurobiol Dis. 2002 Apr;9(3):339-47. PubMed.
- van Groen T, Kiliaan AJ, Kadish I. Deposition of mouse amyloid beta in human APP/PS1 double and single AD model transgenic mice. Neurobiol Dis. 2006 Sep;23(3):653-62. PubMed.