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: The Jackson Lab; available through the JAX MMRRC Stock# 034849; Cryopreserved. Charles River: CVN mouse
Abundant plaques, especially in the thalamus and subiculum. Aggregated, hyperphosphorylated tau tangles. Neuronal loss, especially of neuropeptide Y (NPY) neurons in the hippocampus and subiculum. Compared to Tg-SwDI mice, the bigenic mice exhibit more severe pathology.
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.
These bigenic mice are a cross between APP transgenic mice (Tg-SwDI) and a strain deficient in iNOS, that is, nitric oxide synthase 2 (NOS2) (see below). The APP transgene expresses isoform 770 containing three mutations: Swedish (K670N/M671L), Dutch (E693Q), and Iowa (D694N), under the control of the mouse Thy1 promoter (Davis et al., 2004). The NOS2 mice have a targeted null "mutation" of the NOS2 locus generated by using a neomycin cassette to replace exons 12 and 13, which encode the calmodulin-binding domain (Laubach et al., 1995).
This model was previously available through The Jackson Lab as Stock# 009126.
iNOS knockout- B6;129P2-Nos2tm1Lau/J. Available through The Jackson Laboratory Stock# 002596.
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
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).
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).
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).
Research Models Citations
- 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. Epub 2004 Feb 25 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.