NOD.Cg-Tg(APPswe,PSEN1dE9)85Dbo Prkdc^scid Il2rg^tm1Wjl/HowJ

Stock number: 040812
Product name: NSG.APP/PS1
Research areas: Cancer Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Neurobiology Research, Research Tools, Virology Research

Description

NSG.APP/PS1 mice incorporate Prkdc^scid and Il2rg knock-out alleles on an NOD genetic background (NSG™) and express an APP/PS1 combination of humanized amyloid beta precursor protein modified with the Swedish mutation (APPswe) in addition to the exon-9-deleted variant of presenilin 1 (PS1-dE9) associated with familial Alzheimer's disease. The mice are severely immunocompromised, and develop amyloid plaques and increased glial activation by 8 months of age. No significant cognitive deficits are observed in males or females.

Detailed description

NSG.APP/PS1 mice were created through repeated crosses of APP/PS1 mice (Stock No. 034832-JAX) with NSG™ mice (Stock No. 005557).

APP/PS1 mice express an Alzheimer's disease-associated combination of humanized amyloid beta precursor protein modified with the Swedish mutation (APPswe) in addition to the exon-9-deleted variant of presenilin 1 (PS1-dE9). NSG™ mice express Prkdc^scid (protein kinase, DNA activated, catalytic polypeptide; severe combined immunodeficiency) along with an X-linked Il2rg (an interleukin 2 receptor, gamma chain) knock-out on an NOD genetic background. NSG™ background strains are severely immunocompromised. Animals are deficient in mature lymphocytes, immunoglobulin is not detectable in their serum, and natural killer (NK) cell cytotoxic activity is extremely low.

Amyloid plaques and increased glial cell activation were found in the hippocampus of these NSG.APP/PS1 mice by 8 months of age. The animals were hemizygous for the transgene, homozygous for Prkdc^scid, and either homozygous (females) or hemizygous (males) for the Il2rg allele. No significant cognitive deficits were demonstrated in males or females at this age, as determined by Spatial Novelty testing.

The donating laboratory maintained a colony in which females that were wildtype for the APP/PS1 (Tg(APPswe,PSEN1dE9)85Dbo) transgene and homozygous for the Prkdc^scid and Il2rg^tm1Wjl alleles were bred with males that were hemizygous for the APP/PS1 transgene, homozygous for Prkdc^scid, and hemizygous for the X-linked Il2rg^tm1Wjl allele.

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Development

APP/PS1 mice (Stock No. 034832-JAX) carrying the Tg(APPswe,PSEN1dE9)85Dbo transgene (Chromosome 9) on a C57BL/6 genetic background (N8+) were crossed with NSG™ mice expressing Prkdc^scid (Chromosome 16) and Il2rg^tm1Wjl (Chromosome X) on an NOD genetic background (Stock No. 005557) for 10 generations to create this NSG.APP/PS1 strain (Stock No. 040812).

In brief, to create the Tg(APPswe,PSEN1dE9)85Dbo transgene:
A cDNA for the mouse amyloid beta precursor protein (APP) was humanized within the amyloid beta (Αβ) region (R684H, F681Y, and G676R) and contains the human Swedish mutation (K595N/M596L; also known as K670N/M671L) linked to familial Alzheimer's disease. The PSEN1dE9 (PS1-dE9) transgenic component expresses cDNA for the human presenilin 1 (PSEN1) encoding the ΔE9 (exon-9-deleted) mutation, also associated with familial Alzheimer's disease. Both the APP and PSEN1 transgenes are expressed from the mouse prion protein (Prnp) promoter, which directs transgene expression predominantly to CNS neurons.

The APP and PSEN1 transgenic vectors were co-injected into B6C3HF2 pronuclei. More than 20 transgene copies of the transgene integrated on Chromosome 9 (Chr9:113,003,660-113,021,621; mouse mm10) causing a 1 bp duplication (MGI:3524957). Founder line 85 was obtained and the resulting colony was maintained through crosses to B6C3F1/J mice. Transgenic mice were then backcrossed to C57BL/6J for at least eight generations.

Generation of the NSG™ strain:
Female NOD.CB17-Prkdc^scid/J mice (Stock No. 001303) carrying a targeted knock-out of the mouse Prkdc gene (protein kinase, DNA activated, catalytic polypeptide; Chr. 16) were bred with male B6.129S4-Il2rg^tm1Wjl/J mice (Stock No. 003174) bearing a targeted knock-out of the mouse Il2rg gene (interleukin 2 receptor, gamma chain; Chr. X) to produce the NOD scid gamma (NSG™) strain.

The Prkdc^scid mutation involves a T-to-A transversion point mutation at a position corresponding to codon 4046 (codon 4095 in transcript ENSMUST00000023352.8) that creates a premature stop codon (p.Y4046*). The Il2rg^tm1Wjl allele incorporates a neomycin cassette that replaces part of exon 2 and all of exons 4-8, resulting in the loss of most of the extracellular domain and all of the transmembrane and cytoplasmic domains of the protein.

Allele

Symbol: Tg(APPswe,PSEN1dE9)85Dbo
Name: transgene insertion 85, David R Borchelt
MGI accession ID: MGI:3524957
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: 2xTg Ad; APdE9; APP/PS1; APP-PS1; APPswe/PS1dE9; APPswe/PS1deltaE9; Mo/Hu APPswe PS1dE9
Marker symbol: Tg(APPswe,PSEN1dE9)85Dbo
Marker name: transgene insertion 85, David R Borchelt
Marker synonyms: APdE9; APP/PS1; APPswe/PS1dE9; Mo/Hu APPswe PS1dE9
Chromosome: 9
Strain of origin: (C57BL/6 x C3H)F2
Expressed genes: APP,amyloid beta precursor protein,human; PSEN1,presenilin 1,human
Site of expression: Co-injected transgenes encoding a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9), both have independent mouse prion protein (PrP) promoter elements directing expression predominantly to CNS neurons.
Molecular note: Two transgenes inserted at a single locus in Chromosome 9 between Arpp21 and Pdcd6ip. Each transgene is controlled by the mouse prion promoter and contains a cDNA sequence. In one transgene the cDNA encodes a chimeric amyloid beta (A4) precursor protein (APPswe). In the second transgene the cDNA encodes the "DeltaE9" mutation of human presenilin 1. The DeltaE9 mutation of the human presenilin 1 gene is a deletion of exon 9 and corresponds to a form of early-onset Alzheimer's disease. The amyloid beta precursor protein coding sequences were altered by replacing mouse sequence encoding three amino acids of the A-beta domain with the human coding sequence for these residues. The chimeric amyloid beta (A4) precursor protein sequence was then further modified to encode the Swedish mutations K595N/M596L found in human. Both the transgenic peptide and holoprotein are detected by Signet Laboratories' monoclonal 6E10 antibody, which is specific for human sequence within this region. Human presenilin protein, which in high levels displaces detectable endogenous mouse protein, is immunodetected in the double transgenic mouse in whole brain protein homogenates. Human amyloid precursor protein is also immunodetected in these mice in whole brain protein homogenates. Transgene insertion occurred on Chr 9, causing a 1 bp duplication.
General note: Mice carrying this double transgene develop beta-amyloid deposits in the brain by 6 to 7 months of age.

Allele

Symbol: Prkdc^scid
Name: severe combined immunodeficiency
MGI accession ID: MGI:1857113
Generation method: Spontaneous
Synonyms: scid
Marker symbol: Prkdc
Marker name: protein kinase, DNA activated, catalytic polypeptide
Marker synonyms: DNAPDcs; DNAPK; DNA-PK; DNAPKc; DNA-PKC; DNA-PKcs; DNPK1; DOXNPH; dxnph; HYRC; HYRC1; IMD26; p350; S473K; slip; XRCC7
Chromosome: 16
Strain of origin: C.BKa-Igh^b/Icr
Site of expression: T and B lymphocytes.
Molecular note: A T-to-A transversion point mutation at a position corresponding to codon 4046 (codon 4095 in transcript ENSMUST00000023352.8) created a premature stop codon (p.Y4046*).

Allele

Symbol: Il2rg^tm1Wjl
Name: targeted mutation 1, Warren J Leonard
MGI accession ID: MGI:1857455
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: [KO]gammac; CD132^-; gammac^-; gc^-; Il2rg^tm1Wjll; IL2Rgamma^null
Marker symbol: Il2rg
Marker name: interleukin 2 receptor, gamma chain
Marker synonyms: [g]c; Ab2-183; Cd132; CIDX; common cytokine receptor gamma chain; common gamma chain; gamma C receptor; gamma(c); gammaC; gc; IL-2RG; IMD4; P64; SCIDX; SCIDX1
Chromosome: X
Strain of origin: 129S4/SvJae
Site of expression: Primarily lymphoid cells.
Molecular note: A neomycin resistance cassette replaced part of exon 3 and all of exons 4 - 8 of the gene, resulting in the loss of most of the extracellular domain and all of the transmembrane and cytoplasmic domains of the protein.