B6.Cg-Nos2^tm1Lau Tg(Thy1-APPSwDutIowa)BWevn/Mmjax

Stock number: 009126
Product name: iNOS-; Tg-SwDI
Strain synonyms: APPSwDI/NOS2-/-, APPSwDI/NOS2 bigenic mice
Research areas: Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Metabolism Research, Mouse/Human Gene Homologs, Neurobiology Research, Research Tools

Description

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.

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.

Allele

Symbol: Tg(Thy1-APPSwDutIowa)BWevn
Name: transgene insertion B, William E Van Nostrand
MGI accession ID: MGI:3721992
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(Thy1-APPSwDutIowa)BWevn
Marker name: transgene insertion B, William E Van Nostrand
Chromosome: UN
Strain of origin: C57BL/6
Expressed genes: APP,amyloid beta precursor protein,human
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.

Allele

Symbol: Nos2^tm1Lau
Name: targeted mutation 1, Victor E Laubach
MGI accession ID: MGI:1857228
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Nos2
Marker name: nitric oxide synthase 2, inducible
Chromosome: 11
Strain of origin: 129P2/OlaHsd
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.