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.
IMR Colony, The Jackson Laboratory
Genetic Background | Generation |
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Allele Type | Gene Symbol | Gene Name |
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Targeted (Null/Knockout) | Nos2 | nitric oxide synthase 2, inducible |
Allele Type |
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Transgenic (Inserted expressed sequence, Humanized sequence) |
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-Nos2tm1Lau/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.
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 Nos2tm1Lau males (from B6.129P2-Nos2tm1Lau/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.
Expressed Gene | APP, amyloid beta precursor protein, human |
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Site of Expression |
Allele Name | targeted mutation 1, Victor E Laubach |
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Allele Type | Targeted (Null/Knockout) |
Allele Synonym(s) | iNOS-; iNOS KO; iNOS-; NOS2-; NOS2tm/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. |
Allele Name | transgene insertion B, William E Van Nostrand |
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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 |
When maintaining a live colony, mice homozygous for the targeted mutation and homozygous for the transgene may be bred together.
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.
Facility Barrier Level Descriptions
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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