Genes: APP, NOS2
Mutations: APP KM670/671NL (Swedish), APP E693Q (Dutch), APP D694N (Iowa)
Modification: APP: Transgenic; NOS2: Knock-Out;
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Nos2tm1Lau Tg(Thy1-APPSwDutIowa)BWevn/Mmjax
Genetic Background: C57BL/6J; C57BL/6N
Availability: Jackson Labs: Stock# 009126; Cryopreserved. Charles River: CVN mouse
These bigenic mice harbor the APPSwDI transgene and a targeted null "mutation" of the nitric oxide synthase 2 (NOS2) locus. The APPSwDI transgene expresses APP (isoform 770) containing three mutations: Swedish K670N/M671L, Dutch E693Q, and Iowa D694N, under the control of the mouse Thy1 promoter.
Plaques especially in the thalamus and subiculum. Aggregated, hyperphosphorylated tau tangles. Neuronal loss especially of NPY neurons in the hippocampus and subiculum. More severe pathology than APPSwDI alone.
Severe learning and memory deficits. Impaired spatial memory compared to APPSwDI as measured by the radial arm maze and the Barnes maze at 52-56 weeks.
Decreased NPY staining throughout the hippocampus, particularly in the CA3 region and subiculum.
Compared to mice only harboring the APPSwDI transgene, these bigenic mice exhibit more severe pathology. The phenotypes of the individual mice have been reported (Davis et al., 2004 and Laubach et al., 1995).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Synaptic Loss
- Changes in LTP/LTD
Aβ deposits by 52 weeks. Particularly dense Aβ immunoreactivity in the subiculum and thalamus, including in the cerebral microvessels (Wilcock et al., 2008).
Extensive tau pathology by 52 weeks, including intraneuronal aggregates of hyperphosphorylated tau. Increased phosphorylated tau in bigenic mice compared to APPSwDI mice (Wilcock et al., 2008).
Significant neuron loss by 52 weeks in the hippocampus and subiculum, especially of neuropeptide Y neurons. Numerous Fluoro-Jade C+ neurons: 30% loss in the hippocampus, 35% loss in the subiculum (Wilcock et al., 2008).
Changes in LTP/LTD
Impairments in spatial memory by 52-56 weeks as measured by the radial arm maze and the Barnes maze. Bigenic mice more impaired than APPSwDI (Wilcock et al., 2008).
- Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, Van Nostrand WE. Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor. J Biol Chem. 2004 May 7;279(19):20296-306. PubMed.
- Laubach VE, Shesely EG, Smithies O, Sherman PA. Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10688-92. PubMed.
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