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| Please refer to the Mutant Mouse Regional Resource Center (MMRRC) for ordering information and strain details on B6.129-Tg(APPSw)40Btla/Mmjax
MMRRC Stock Number 034831. As a designated MMRRC center, The Jackson Laboratory will continue to distribute these mice at the same high health and quality standards but ordering is exclusively provided through the MMRRC. | |||||||||||||||||||
| 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. | |||||||||||||||||||
- Description
- Disease & phenotype
- Genes & alleles
- Genotyping
- Health & care
- References
- Pricing & purchasing
- Terms of use
Description
Strain Information
Former Names B6.129-Tg(APPSw)40Btla/J (Changed: 10-AUG-11 ) Type Congenic; Mutant Strain; Transgenic; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Donating Investigator Bruce Lamb, The Cleveland Clinic Foundation 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 Disease (FAD) Swedish mutation K670N/M671L. Transgene expression (mRNA and full-length protein) is two to three 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. Levels of the beta- secretase generated human APP derivative, C-terminal 13.5kDA fragment, are elevated in brain tissue. ELISA enzyme-linked immunosorbent assay (ELISA) analysis of brain homogenates show a significant increase in total amyloid-beta peptides and 42 amino acid length amyloid beta peptides. By 14 months of age, homozygous mice develop both parenchymal and vascular amyloid beta deposits, which first appear in the frontal cortex and then spread into the hippocampus. 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.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 APPK670N/M671L associated with Familial Alzheimer's Disease. This transgene was injected into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Founder animals (line R1.40) were backcrossed to C57BL/6J for 21 generations prior to arrival at the MMRRC at The Jackson Laboratory.
Related Strains
Alzheimer's Disease Models
View Alzheimer's Disease Models (108 strains)
006409 129S1.129(Cg)-Tg(APPSw)40Btla/Mmjax 006555 A.129(B6)-Tg(APPSw)40Btla/Mmjax 006472 D2.129(B6)-Tg(APPSw)40Btla/Mmjax
Additional Web Information
Visit the Alzheimer's Disease Mouse Model Resource site for helpful information on Alzheimer's Disease and research resources.
Phenotype
Phenotype Information
- Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.
Alzheimer Disease; AD
- Potential model based on transgenic expression of an ortholog of a human gene that is associated with this disease. Phenotypic similarity to the human disease has not been tested. Cerebral Amyloid Angiopathy, App-Related (APP)
assigned by genotype
Tg(APPSw)40Btla/Tg(APPSw)40Btla
B6.129-Tg(APPSw)40Btla
- 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 (MGI Ref ID J:86629)
- other 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 (MGI Ref ID J:86629)
The following phenotype information may relate to a genetic background differing from this JAX® Mice strain.
Tg(APPSw)40Btla/0
involves: 129S1/Sv * 129X1/SvJ
- nervous system phenotype
- amyloid beta deposits
- 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 (MGI Ref ID J:42613)
- mice have 7- to 8-fold higher levels of Abeta1-42 peptide in their brains compared to Tg(PSEN1H163R)G9Btla hemizygotes (MGI Ref ID J:58050)
- diffuse amyloid beta deposits are detected in the hippocampus and frontal cortex at 24-26 months of age (MGI Ref ID J:58050)
- other phenotype
- amyloid beta deposits
- 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 (MGI Ref ID J:42613)
- mice have 7- to 8-fold higher levels of Abeta1-42 peptide in their brains compared to Tg(PSEN1H163R)G9Btla hemizygotes (MGI Ref ID J:58050)
- diffuse amyloid beta deposits are detected in the hippocampus and frontal cortex at 24-26 months of age (MGI Ref ID J:58050)
Tg(APPSw)40Btla/Tg(APPSw)40Btla
D2.129-Tg(APPSw)40Btla
- nervous system phenotype
- *normal* nervous system phenotype
- no amyloid beta deposits are observed in 13.5 month-old mice (MGI Ref ID J:86629)
This mouse can be used to support research in many areas including:
APP relatedMouse/Human Gene Homologs
Alzheimer's
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
Neurobiology Research
Alzheimer's Disease
Neurodegeneration
Genes & Alleles
Gene & Allele Information provided by MGI
| Allele Symbol | Tg(APPSw)40Btla | ||
|---|---|---|---|
| Allele Name | transgene insertion 40, Bruce Lamb | ||
| Allele Type | Transgenic (random, expressed) | ||
| Common Name(s) | APPK670/M671; APPK670N/M671L; R1.40; R1.40-YAC; | ||
| Mutation Made By | Bruce Lamb, The Cleveland Clinic Foundation | ||
| Strain of Origin | (129X1/SvJ x 129S1/Sv)F1-Kitl<+> | ||
| ES Cell Line Name | R1 | ||
| ES Cell Line Strain | (129X1/SvJ x 129S1/Sv)F1-Kitl<+> | ||
| Expressed Gene | APP, amyloid beta (A4) precursor protein, human | ||
| Promoter | APP, amyloid beta (A4) precursor protein, human | ||
| 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. [MGI Ref ID J:42613] [MGI Ref ID J:58050] [MGI Ref ID J:73622] | ||
Genotyping
Genotyping Information
Genotyping Protocols
Tg(APP), QPCR
Tg(APPSw)40Btla, Standard PCR
Helpful Links
Genotyping resources and troubleshooting
References
References provided by MGI
Selected Reference(s)
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):1535-41. [PubMed: 9285791] [MGI Ref ID J:42613]
Additional References
Tg(APPSw)40Btla relatedChen J; Herrup K. 2012. Glutamine acts as a neuroprotectant against DNA damage, beta-amyloid and H2O2-induced stress. PLoS One 7(3):e33177. [PubMed: 22413000] [MGI Ref ID J:186926]
Chiocco MJ; Lamb BT. 2007. Spatial and temporal control of age-related APP processing in genomic-based beta-secretase transgenic mice. Neurobiol Aging 28(1):75-84. [PubMed: 16387391] [MGI Ref ID J:117963]
Ghosal K; Stathopoulos A; Pimplikar SW. 2010. APP intracellular domain impairs adult neurogenesis in transgenic mice by inducing neuroinflammation. PLoS One 5(7):e11866. [PubMed: 20689579] [MGI Ref ID J:163067]
Kulnane LS; Lamb BT. 2001. Neuropathological characterization of mutant amyloid precursor protein yeast artificial chromosome transgenic mice. Neurobiol Dis 8(6):982-92. [PubMed: 11741394] [MGI Ref ID J:73622]
Lamb BA; Bardel KA; Kulnane LS; Anderson JJ; Holtz G; Wagner SL; Sisodia SS; Hoeger EJ. 1999. Amyloid production and deposition in mutant amyloid precursor protein and presenilin-1 yeast artificial chromosome transgenic mice. Nat Neurosci 2(8):695-7. [PubMed: 10412057] [MGI Ref ID J:58050]
Lehman EJ; Kulnane LS; Gao Y; Petriello MC; Pimpis KM; Younkin L; Dolios G; Wang R; Younkin SG; Lamb BT. 2003. Genetic background regulates beta-amyloid precursor protein processing and beta-amyloid deposition in the mouse. Hum Mol Genet 12(22):2949-56. [PubMed: 14506131] [MGI Ref ID J:86629]
Ryman D; Gao Y; Lamb BT. 2008. Genetic loci modulating amyloid-beta levels in a mouse model of Alzheimer's disease. Neurobiol Aging 29(8):1190-8. [PubMed: 17400334] [MGI Ref ID J:140915]
Salehi A; Delcroix JD; Belichenko PV; Zhan K; Wu C; Valletta JS; Takimoto-Kimura R; Kleschevnikov AM; Sambamurti K; Chung PP; Xia W; Villar A; Campbell WA; Kulnane LS; Nixon RA; Lamb BT; Epstein CJ; Stokin GB; Goldstein LS; Mobley WC. 2006. Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51(1):29-42. [PubMed: 16815330] [MGI Ref ID J:122937]
Varvel NH; Bhaskar K; Kounnas MZ; Wagner SL; Yang Y; Lamb BT; Herrup K. 2009. NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease. J Clin Invest 119(12):3692-702. [PubMed: 19907078] [MGI Ref ID J:155100]
Varvel NH; Bhaskar K; Patil AR; Pimplikar SW; Herrup K; Lamb BT. 2008. Abeta oligomers induce neuronal cell cycle events in Alzheimer's disease. J Neurosci 28(43):10786-93. [PubMed: 18945886] [MGI Ref ID J:144634]
Vogt DL; Thomas D; Galvan V; Bredesen DE; Lamb BT; Pimplikar SW. 2009. Abnormal neuronal networks and seizure susceptibility in mice overexpressing the APP intracellular domain. Neurobiol Aging :. [PubMed: 19828212] [MGI Ref ID J:169998]
Wilkinson BL; Cramer PE; Varvel NH; Reed-Geaghan E; Jiang Q; Szabo A; Herrup K; Lamb BT; Landreth GE. 2012. Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer's disease. Neurobiol Aging 33(1):197.e21-32. [PubMed: 20696495] [MGI Ref ID J:188232]
Yang Y; Varvel NH; Lamb BT; Herrup K. 2006. Ectopic cell cycle events link human Alzheimer's disease and amyloid precursor protein transgenic mouse models. J Neurosci 26(3):775-84. [PubMed: 16421297] [MGI Ref ID J:104514]
Health & husbandry
Health & Colony Maintenance Information
Colony Maintenance
Breeding & Husbandry When maintaining a live colony, transgenic carriers may be bred together, to wildtype siblings, or to C57BL/6J 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.
Pricing and Purchasing
Pricing, Supply Level & Notes, Controls
This strain is currently Transferred.
General Supply Notes
- Genomic DNA is available for this strain from the Mouse DNA Resource.
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