Mutations: APP KM670/671NL (Swedish), APP V717F (Indiana)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6C3-Tg(tetO-APPSwInd)885Dbo/Mmjax
Genetic Background: C57BL/6 x C3HeJ; backcrossed to C57BL/6
Availability: The Jackson Lab; available through the JAX MMRRC Stock# 034834; Cryopreserved
This model enables regulated expression of mutant APP using a tet-off system. The APP transgene bears both the Swedish and Indiana mutations under the control of a tetracycline-responsive promoter. When bred to transgenic mice expressing reverse tertracyclin-controlled transactivator protein (rtTA) or tetracycline-controlled transactivator protein (tTA), the expression of the APP transgene can be turned off with the tetracycline analog, doxycycline, in bigenic animals.
Four lines of bigenic animals were reported simultaneously (Jankowsky et al., 2005). All four lines express APP protein at levels 10-30 fold higher than endogenous mouse APP and the transgene is nearly completely suppressed (>95 percent) following doxycycline treatment for as little as two weeks. Of the four lines, line 885 was the highest expressing line and required the most doxycycline for transgene suppression (see also line 107 and line 102).
When bred to animals producing tTA under the control of the CAMKIIα promoter, bigenic mice overproduce Aβ42 and deposit amyloid as early as two months of age. Amyloid burden increases with age, and by nine months, the hippocampus and cortex have extensive amyloid pathology. Suppression of the APP transgene with doxycycline halts the progression of amyloid pathology. Mice also have progressive neuronal atrophy especially in the granule cell layer of the dentate gyrus (Jankowsky et al., 2005).
Behaviorally, bigenic mice exhibit severe hyperactivity. These mice run in circles around the perimeter of their cages and display other abnormal hyperactive behavior. The penetrance of the hyperactivity phenotype was close to one hundred percent. This phenotype confounds behavioral testing.
This model was previously available through The Jackson Lab as Stock# 006004.
Mouse APP695 with a humanized Aβ region and the Swedish (KM570/571NL) and Indiana (V617F) mutations downstream of a tetracycline-responsive promoter and mouse prion protein exons 1-2.
This strain is bred on a congenic background.
Available through the JAX MMRRC Stock# 034844 (formerly Jackson Lab Stock# 007049).
Research Models Citations
- Jankowsky JL, Slunt HH, Gonzales V, Savonenko AV, Wen JC, Jenkins NA, Copeland NG, Younkin LH, Lester HA, Younkin SG, Borchelt DR. Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease. PLoS Med. 2005 Dec;2(12):e355. Epub 2005 Nov 15 PubMed.