Overview

Also Known As:APPSwDI/NOS2-/-, APPSwDI/NOS2 bigenic mice, iNOS-; Tg-SwDI

These APPSwDI/NOS2 bigenic mice harbor the APPSwDI transgene and a targeted "null" mutation of the nitric oxide synthase 2 (Nos2) locus. Homozygous bigenic mice (APPSwDI/NOS2^-/-) progress from Aβ production and amyloid deposition to hyperphosphorylated normal mouse tau at Alzheimer's disease-associated epitopes, aggregation and redistribution of tau to somatodendritic regions of neurons, significant neuronal loss (including loss of interneurons), moderate-severe cerebral amyloid angiopathy, and severe learning and memory deficits. This Alzheimer's disease-like pathology is also accompanied by robust behavioral changes. These APPSwDI/NOS2 bigenic mice may be useful in studying Alzheimer's disease progression and the role of nitric oxide in altering chronic neurological disease processes.

Donating Investigator

IMR Colony, The Jackson Laboratory

Genetic overview

Genetic Background	Generation

Tg(Thy1-APPSwDutIowa)BWevn

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

Nos2^tm1Lau

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Nos2	nitric oxide synthase 2, inducible

View Genetics

Research Applications

Research Tools
Neurobiology Research
Internal/Organ Research
Immunology, Inflammation and Autoimmunity Research
Metabolism Research
Mouse/Human Gene Homologs

View All Research Applications

Details

Detailed Description

These APPSwDI/NOS2 bigenic mice harbor the APPSwDI transgene and a targeted "null" mutation of the nitric oxide synthase 2 (Nos2) locus. Expression of the APPSwDI transgene (a neuronally derived human amyloid beta-precursor protein [APP or AβPP] 770 isoform containing three Alzheimer's disease-associated mutations [Swedish K670N/M671L, Dutch E693Q and Iowa D694N] all under the control of the mouse thymus cell antigen 1, theta [Thy1] promoter) produces amyloid-beta (Aβ) peptides that cannot be transported out of the brain across the cerebrovascular interface and results in Aβ peptide accumulation at the blood vessels (see C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax). The Nos2 mutation results in loss of inducible NOS (iNOS) expression which alters physiological functions related to disease and injury (see B6.129P2-Nos2^tm1Lau/J). Homozygous bigenic mice (APPSwDI/NOS2^-/-) progress from Abeta; production and amyloid deposition to hyperphosphorylated normal mouse tau at Alzheimer's disease-associated epitopes, aggregation and redistribution of tau to somatodendritic regions of neurons, significant neuronal loss (including loss of interneurons), moderate-severe cerebral amyloid angiopathy, and severe learning and memory deficits. This Alzheimer's disease-like pathology is also accompanied by robust behavioral changes. Compared to mice only harboring the APPSwDI transgene, these APPSwDI/NOS2 bigenic mice exhibit more severe human Alzheimer's disease pathology and additional human Alzheimer's disease features, and may be useful in studying Alzheimer's disease progression and the role of nitric oxide in altering chronic neurological disease processes.

Development

To generate this double mutant colony, homozygous Tg(Thy1-APPSwDutIowa)BWevn females (from C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax) were bred with heterozygous or homozygous Nos2^tm1Lau males (from B6.129P2-Nos2^tm1Lau/J). The resulting double mutant animals were bred together to produce this strain.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at the MMRRC at The Jackson Laboratory. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, 4 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to the MMRRC at The Jackson Laboratory were on a mixed C57BL/6J ; C57BL/6N genetic background.

Expression Data

Expressed Gene	APP, amyloid beta precursor protein, human
Site of Expression
Site of Expression

Selected References

Colton CA; Wilcock DM; Wink DA; Davis J; Van Nostrand WE; Vitek MP. 2008. The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP. J Alzheimers Dis 15(4):571-87PubMed: 19096157 MGI: J:143551

View All References

Genetics

Tg(Thy1-APPSwDutIowa)BWevn

Allele Symbol: Tg(Thy1-APPSwDutIowa)BWevn

Allele Name	transgene insertion B, William E Van Nostrand
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	APPSwDI; Tg-SwDI; Tg-SwDI/B
Gene Symbol and Name	Tg(Thy1-APPSwDutIowa)BWevn, transgene insertion B, William E Van Nostrand
Gene Synonym(s)
Promoter	Thy1, thymus cell antigen 1, theta, mouse, laboratory
Expressed Gene	APP, amyloid beta precursor protein, human
Strain of Origin	C57BL/6
Chromosome	UN
Molecular Note	A transgenic construct containing 2.1kb of the human amyloid beta-precursor protein, APP gene, 770 isoform, with the Swedish K670N/M671L, Dutch E693Q and Iowa D694N mutations, under the control of the mouse thymus cell antigen 1, theta, Thy1, promoter was injected into fertilized C57BL/6 mouse eggs. Founder line B was subsequently established and homozygotes generated. Human amyloid beta precursor protein expression is detected in the brains of transgenic mice. Two other lines, A anc C were also generated, with line A having similar levels of transgene expression and amyloid beta accumulation to line B while line C has 2-fold higher expression of human Amyloid beta-precursor protein and shows 4-fold higher accumulations of soluble and insoluble AB peptides in the brain.
Mutations Made By	William Van Nostrand, Stony Brook University

Nos2^tm1Lau

Allele Symbol: Nos2^tm1Lau

Allele Name	targeted mutation 1, Victor E Laubach
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	iNOS-; iNOS KO; iNOS^-; NOS2-; NOS2^tm/Lau; Nos2tm1Lau
Gene Symbol and Name	Nos2, nitric oxide synthase 2, inducible
Gene Synonym(s)
Strain of Origin	129P2/OlaHsd
Chromosome	11
Molecular Note	A neomycin cassette replaced exons 12 and 13 of the gene, which encode the calmodulin-binding domain. Northern and Western blots of IFNg/LPS-stimulated peritoneal macrophages showed no detectable Nos2 mRNA or protein, respectively.
Mutations Made By	Dr. Victor Laubach, University of Virginia Health Sci. Ctr.

Disease/Phenotype

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

Alzheimer's disease

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Research Tools
- Immunology, Inflammation and Autoimmunity Research
  - genes regulating susceptibility to infectious disease and endotoxin
- Neurobiology Research
- Toxicology Research
  - free radical research
Neurobiology Research
- Neurodegeneration
- Alzheimer's Disease
  - strains expressing mutant APP
- Behavioral and Learning Defects
Internal/Organ Research
- Wound Healing
  - delayed/impaired
Metabolism Research
- Free Radical Research
Mouse/Human Gene Homologs
- Alzheimer's

Genotype: Nos2^tm1Lau related

Immunology, Inflammation and Autoimmunity Research
- Inflammation
  - Inflammatory bowel disease
Neurobiology Research
- Alzheimer's Disease

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Nos2^tm1Lau/Nos2^tm1Lau Tg(Thy1-APPSwDutIowa)BWevn/?
involves: C57BL/6

behavior/neurological phenotype

abnormal spatial reference memory
- mice make more errors in the radial-arm water maze than single Tg(Thy1-APPSwDutIowa)BWevn transgenics, especially on subsequent days, indicating slowed learning and/or retrieval of the task
- mice show increased impaired performance on the Barnes maze compared to single Tg(Thy1-APPSwDutIowa)BWevn transgenics

cellular phenotype

increased neuron apoptosis

homeostasis/metabolism phenotype

amyloid beta deposits
- amyloid beta deposits in the hippocampus, in the subiculum and thalamus
- deposits are observed by 52 weeks of age

nervous system phenotype

abnormal brain interneuron morphology
- 65% loss of NPY interneurons in the hippocampus

abnormal hippocampus CA3 region morphology
- neuronal loss
- thinning of the CA3 and subiculum, with a 40% loss of neurons in the CA3 region

amyloid beta deposits
- amyloid beta deposits in the hippocampus, in the subiculum and thalamus
- deposits are observed by 52 weeks of age

decreased neuron number
- neuronal loss is observed in hippocampus, subiculum and CA3

decreased subiculum size
- 35% loss of neurons in the subiculum
- neuronal loss

hippocampal neuron degeneration
- 30% loss of neurons in the hippocampus
- 50% reduction in neuropeptide Y-immunopositive neurons overall throughout the hippocampus, a 65% reduction in the CA3 region, and 50% reduction in the subiculum

increased neuron apoptosis

neurodegeneration
- 30% loss of NeuN-immunopositive neurons in the hippocampus, 35% loss in the subiculum, and 40% loss in the CA3 region of the hippocampus
- loss of neuropeptide Y-immunopositive neurons particularly in the CA3 region and in the subiculum

tau protein deposits
- hyperphosphorylated tau is seen in the brain and in neuronal processes associated with blood vessels
- mice show intraneuronal aggregrates of tau

References

Colton CA; Wilcock DM; Wink DA; Davis J; Van Nostrand WE; Vitek MP. 2008. The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP. J Alzheimers Dis 15(4):571-87PubMed: 19096157 MGI: J:143551

Additional - Nos2^tm1Lau related

Additional - Tg(Thy1-APPSwDutIowa)BWevn related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Nos2alternate4
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, mice homozygous for the targeted mutation and homozygous for the transgene may be bred together.
- Additional Breeding and Husbandry Support
Citation
When using the iNOS-; Tg-SwDI mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #34849 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Also Known As:APPSwDI/NOS2-/-, APPSwDI/NOS2 bigenic mice, iNOS-; Tg-SwDI

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Expression Data

Selected References

Tg(Thy1-APPSwDutIowa)BWevn

Allele Symbol: Tg(Thy1-APPSwDutIowa)BWevn

Nos2tm1Lau

Allele Symbol: Nos2tm1Lau

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Nos2tm1Lau related

Mammalian Phenotype Terms by Genotype

Genotype: Nos2tm1Lau/Nos2tm1Lau Tg(Thy1-APPSwDutIowa)BWevn/?involves: C57BL/6

behavior/neurological phenotype

cellular phenotype

homeostasis/metabolism phenotype

nervous system phenotype

References

Additional - Nos2tm1Lau related

Additional - Tg(Thy1-APPSwDutIowa)BWevn related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Nos2^tm1Lau

Allele Symbol: Nos2^tm1Lau

Genotype: Nos2^tm1Lau related

Genotype: Nos2^tm1Lau/Nos2^tm1Lau Tg(Thy1-APPSwDutIowa)BWevn/?
involves: C57BL/6

Additional - Nos2^tm1Lau related