Research Models

APPSwDI x NOS2 Knock-out

Synonyms: APPSwDI/NOS2 bigenic mice, APPSDI/NOS2KO, CVN

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Species: Mouse
Genes: APP, NOS2
Mutations: APP K670_M671delinsNL (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

Neuropathology

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.

Cognition/Behavior

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.

Modification Details

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).

The parental origin of the transgenes was shown to influence AD-related pathology in another model, 5xFAD (C57BL6), in which the Thy1 promoter drives transgene expression, possibly due to genomic imprinting of the promoter (Sasmita et al.,  2025). While this phenomenon has not yet been demonstrated in APPSwDI x NOS2 Knock-out mice, users of this model should be aware of the findings in 5xFAD mice when designing and documenting breeding strategies.

Note

This model was previously available through The Jackson Lab as Stock# 009126.

Related Strains

iNOS knockout- B6;129P2-Nos2tm1Lau/J. Available through The Jackson Laboratory Stock# 002596.

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

No Data

  • Gliosis
  • Synaptic Loss
  • Changes in LTP/LTD

Plaques

Aβ deposits by 52 weeks. Particularly dense Aβ immunoreactivity in the subiculum and thalamus, including in the cerebral microvessels (Wilcock et al., 2008).

Tangles

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).

Neuronal Loss

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).

Gliosis

Unknown.

Synaptic Loss

Unknown.

Changes in LTP/LTD

Unknown.

Cognitive Impairment

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).

Last Updated: 30 Jan 2025

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References

Research Models Citations

  1. Tg-SwDI (APP-Swedish,Dutch,Iowa)
  2. 5xFAD (C57BL6)

Paper Citations

  1. 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.
  2. 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.
  3. Sasmita AO, Ong EC, Nazarenko T, Mao S, Komarek L, Thalmann M, Hantakova V, Spieth L, Berghoff SA, Barr HJ, Hingerl M, Börensen F, Hirrlinger J, Simons M, Stevens B, Depp C, Nave KA. Parental origin of transgene modulates amyloid-β plaque burden in the 5xFAD mouse model of Alzheimer's disease. Neuron. 2025 Jan 20; Epub 2025 Jan 20 PubMed.

External Citations

  1. The Jackson Laboratory Stock# 002596.
  2. JAX MMRRC Stock# 034849
  3. Charles River: CVN mouse

Further Reading