A.129(B6)-Tg(APPSw)40Btla/Mmjax

MMRRC Stock No:: 34841-JAX

Cryo Recovery

Overview

Also Known As: A-R1.40

These R1.40 transgenic mice express all mRNA and protein isoforms of the human amyloid beta (A4) precursor protein APP containing the Familial Alzheimer's Disease (FAD) Swedish mutation K670N/M671L, and may be useful in studying the pathogenesis of Familial Alzheimer's Disease and possible therapeutic treatments.

Donating Investigator

Bruce Lamb, Indiana University School of Medicine

Genetic overview

Genetic Background	Generation

Tg(APPSw)40Btla

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

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Research Applications

Neurobiology Research
Research Tools
Mouse/Human Gene Homologs

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Details

Detailed Description

These R1.40 transgenic mice express all mRNA and protein isoforms of the human amyloid beta (A4) precursor protein APP containing the Familial Alzheimer's Disease (FAD) Swedish mutation K670N/M671L. Transgene expression (mRNA and full-length protein) is 2 to 3 fold the endogenous mouse App expression level in the hemizygous state in brain tissue as revealed by RT-PCR and Western Blot analysis. Transgene expression pattern mimics endogenous mouse gene expression patterns. The donating investigator reports increased mortality in young homozygous animals (higher incidence in females). 3 to 4 month old transgenic mice, maintained on a C57BL/6J background, exhibit spontaneous seizure-like events (abnormal spiking) in EEG readings, without abnormal behavior and are more susceptible to kainic acid induced seizures (Vogt et al. Neurobiol Aging 2009). These R1.40 transgenic mice may be useful in studying the pathogenesis of Familial Alzheimer's Disease and possible therapeutic treatments.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype could vary from that originally described. A publication (Lehman et al. 2003 Hum Mol Genet 12:2949) compares the well characterized B6-R1.40 strain (B6.129-Tg(APPSw)40Btla/Mmjax) with two additional congenic strains, D2-R1.40 (D2.129(B6)-Tg(APPSw)40Btla/Mmjax) and 129S1-R1.40 (129S1.129(Cg)-Tg(APPSw)40Btla/Mmjax). While these three congenic strains have similar levels of holo-APP in brain tissue, the levels of brain APP C-terminal fragments (CTFs) vary depending upon genetic background. Brain and plasma levels of amyloid beta-40 and -42 are variable as well (B6-R1.40 > 129S1-R1.40 > D2-R1.40). In addition, the congenic strains exhibited dramatic alterations in the age of onset of amyloid beta deposition; in contrast to 14 month old homozygous B6-R1.40 mice, homozygous D2-R1.40 and 129S1-R1.40 mice do not develop amyloid beta deposits in the parietal or frontal cortex even by 20 months of age. The donating investigator further reports that the A-R1.40 strain (A.129(B6)-Tg(APPSw)40Btla/Mmjax) exhibits levels of amyloid beta comparable to the B6-R1.40 strain, but with later onset. Therefore, APP processing and amyloid beta metabolism and deposition are modified by the genetic background. While the 129S1-R1.40 strain can be easily maintained as homozygotes, the donating investigator reports increased mortality in young homozygotes on the other genetic backgrounds, with D2-R1.40 and A-R1.40 more severely affected than B6-R1.40.

Development

A 650 kb YAC transgene containing the entire human amyloid beta (A4) precursor protein (APP) gene, and approximately 250 kb of flanking sequence, was altered to include the Swiss mutation K670N/M671L associated with Familial Alzheimer's Disease (FAD). This transgene was injected into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Founder animals (line R1.40) were established and bred to C57BL/6J for eight generations. After this, transgenic mice were bred to A/J for at least 21 generations prior to arrival at the MMRRC at The Jackson Laboratory. This transgene inserted on Chromosome 13.

Expression Data

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

Selected References

Lamb BT; Call LM; Slunt HH; Bardel KA; Lawler AM; Eckman CB; Younkin SG; Holtz G; Wagner SL; Price DL; Sisodia SS; Gearhart JD. 1997. Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice. Hum Mol Genet 6(9):1535-41PubMed: 9285791 MGI: J:42613

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Genetics

Tg(APPSw)40Btla

Allele Symbol: Tg(APPSw)40Btla

Allele Name	transgene insertion 40, Bruce Lamb
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	transgene insertion 40, Bruce Lamb; Tg(APPSw)40Btla
Gene Symbol and Name	Tg(APPSw)40Btla, transgene insertion 40, Bruce Lamb
Gene Synonym(s)	R1.40; R1.40-YAC; APP^K670/M671; APP^K670N/M671L
Promoter	APP, amyloid beta precursor protein, human
Expressed Gene	APP, amyloid beta precursor protein, human
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Chromosome	13
Molecular Note	The transgenic insertion comprises four to eight copies of a 650-kb YAC containing the entire 400-kb human amyloid precursor protein gene with the Swiss familial Alzheimer disease (FAD) mutation and approximately 250 kb of flanking human DNA. The double mutation (K670N/M671N) comprises a G-to-A transition converting the lysine codon at position 670 to an asparagine codon and an A-to-C transversion replacing the methionine at amino acid 671 with leucine. RT-PCR and western blot analysis revealed that hemizygous transgenic mice express all major human APP mRNA and protein isoforms in brain, in parallel with the corresponding mouse versions, at approximately three times the levels of the latter. Total brain levels of the Alzheimer disease- associated 42-amino acid amyloid-beta peptide detected by ELISA are 7-8-fold and 15-20-fold higher, respectively, in mice hemizygous and homozygous for the mutant gene than in hemizygotes for the wildtype human gene. Levels of a cell-associated, beta-secretase-generated 13.5 kDa C-terminal peptide containing the amyloid beta domain and of soluble amyloid beta peptides are significantly elevated in brains of mice with the mutant, versus wildtype, transgene, while alpha-secretase products are diminished.
Mutations Made By	Bruce Lamb, Indiana University School of Medicine

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 Genotype

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

Neurobiology Research
- Alzheimer's Disease
  - strains expressing mutant APP
- Epilepsy
  - electroconvulsive seizures
  - increased susceptibility to kainate-induced seizures
- Neurodegeneration
Research Tools
- Neurobiology Research
Mouse/Human Gene Homologs
- Alzheimer's

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Tg(APPSw)40Btla/0
involves: 129S1/Sv * 129X1/SvJ

homeostasis/metabolism phenotype

amyloid beta deposits
- diffuse amyloid beta deposits are detected in the hippocampus and frontal cortex at 24-26 months of age
- mice have 7- to 8-fold higher levels of Abeta1-42 peptide in their brains compared to Tg(PSEN1H163R)G9Btla hemizygotes
- mice have higher levels of total A-beta protein and the cleaved A-beta 1-42(43) peptide than Tg(APP)8.9Btla mice, but levels are lower than those in Tg(APPSwLon)96Btla mice

nervous system phenotype

amyloid beta deposits
- diffuse amyloid beta deposits are detected in the hippocampus and frontal cortex at 24-26 months of age
- mice have 7- to 8-fold higher levels of Abeta1-42 peptide in their brains compared to Tg(PSEN1H163R)G9Btla hemizygotes
- mice have higher levels of total A-beta protein and the cleaved A-beta 1-42(43) peptide than Tg(APP)8.9Btla mice, but levels are lower than those in Tg(APPSwLon)96Btla mice

Genotype: Tg(APPSw)40Btla/Tg(APPSw)40Btla
involves: 129S1/Sv * 129X1/SvJ

homeostasis/metabolism phenotype

amyloid beta deposits
- extensive fibrillar amyloid beta deposits are detected in the hippocampus and frontal, cingulate and parietal cortex at 14-15 months of age
- homozygous mice have 15- to 20-fold higher levels of Abeta1-42 peptide in their brains compared to Tg(PSEN1H163R)G9Btla hemizygotes

nervous system phenotype

amyloid beta deposits
- extensive fibrillar amyloid beta deposits are detected in the hippocampus and frontal, cingulate and parietal cortex at 14-15 months of age
- homozygous mice have 15- to 20-fold higher levels of Abeta1-42 peptide in their brains compared to Tg(PSEN1H163R)G9Btla hemizygotes

Genotype: Tg(APPSw)40Btla/Tg(APPSw)40Btla
B6.129-Tg(APPSw)40Btla

homeostasis/metabolism phenotype

amyloid beta deposits
- all animals show amyloid beta (Abeta) deposits in the parietal cortex at 13.5 months of age, but no animals have deposits at 5 months

nervous system phenotype

amyloid beta deposits
- all animals show amyloid beta (Abeta) deposits in the parietal cortex at 13.5 months of age, but no animals have deposits at 5 months

Genotype: Tg(APPSw)40Btla/Tg(APPSw)40Btla
D2.129-Tg(APPSw)40Btla

mammalian phenotype

nervous system phenotype
- no amyloid beta deposits are observed in 13.5 month-old mice

References

Lamb BT; Call LM; Slunt HH; Bardel KA; Lawler AM; Eckman CB; Younkin SG; Holtz G; Wagner SL; Price DL; Sisodia SS; Gearhart JD. 1997. Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice. Hum Mol Genet 6(9):1535-41PubMed: 9285791 MGI: J:42613

Additional - Tg(APPSw)40Btla related

Technical Support

Contact Technical Support

Genotyping Protocols
- QPCR: Generic APP human genomic or cDNA
- Standard PCR: Tg(APPSw)40Btla
- MELT: Generic APP MCA human genomic
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, transgenic carriers may be bred together, to wildtype siblings, or to A/J inbred mice. Because of the increased mortality in young homozygous animals (higher incidence in females), maintaining the colony by breeding homozygotes together is only recommended when sufficient colony size is permitted.
- Additional Breeding and Husbandry Support
Citation
When using the A.129(B6)-Tg(APPSw)40Btla/Mmjax mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #34841 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.

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Questions about Terms of Use

Additional Use Restrictions Apply

Not Available to Companies or for Commercial Use

Strain(s) not available to companies or for-profit entities.

Licensing Information

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Email: TechTran@jax.org

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Also Known As: A-R1.40

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Expression Data

Selected References

Tg(APPSw)40Btla

Allele Symbol: Tg(APPSw)40Btla

Disease Terms

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

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Tg(APPSw)40Btla/0involves: 129S1/Sv * 129X1/SvJ

homeostasis/metabolism phenotype

nervous system phenotype

Genotype: Tg(APPSw)40Btla/Tg(APPSw)40Btlainvolves: 129S1/Sv * 129X1/SvJ

homeostasis/metabolism phenotype

nervous system phenotype

Genotype: Tg(APPSw)40Btla/Tg(APPSw)40BtlaB6.129-Tg(APPSw)40Btla

homeostasis/metabolism phenotype

nervous system phenotype

Genotype: Tg(APPSw)40Btla/Tg(APPSw)40BtlaD2.129-Tg(APPSw)40Btla

mammalian phenotype

References

Additional - Tg(APPSw)40Btla 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

Genotype: Tg(APPSw)40Btla/0
involves: 129S1/Sv * 129X1/SvJ

Genotype: Tg(APPSw)40Btla/Tg(APPSw)40Btla
involves: 129S1/Sv * 129X1/SvJ

Genotype: Tg(APPSw)40Btla/Tg(APPSw)40Btla
B6.129-Tg(APPSw)40Btla

Genotype: Tg(APPSw)40Btla/Tg(APPSw)40Btla
D2.129-Tg(APPSw)40Btla