Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Stock; Mutant Strain; Transgenic; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Generation N23pN1   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'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). 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 (C57BL/6J congenic, see Stock No. 005300) with two additional congenic strains, D2-R1.40 (DBA/2J congenic, see Stock No. 006472) and 129S1-R1.40 (129S1/SvImJ congenic, see Stock No's. 006409 / 008609). 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/J congenic, see Stock No. 006555) 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 (Stock No. 000646) for at least 21 generations prior to arrival at The Jackson Laboratory. This transgene inserted on Chromosome 13.

Control Information

	Control
	Wild-type from the colony
	000646 A/J
Considerations for Choosing Controls

Related Strains

Strains carrying   Tg(APPSw)40Btla allele

008609	129S1.129(Cg)-Tg(APPSw)40Btla/2J
006409	129S1.129(Cg)-Tg(APPSw)40Btla/J
005300	B6.129-Tg(APPSw)40Btla/J
006472	D2.129(B6)-Tg(APPSw)40Btla/J

View Strains carrying   Tg(APPSw)40Btla     (4 strains)

Strains carrying other alleles of APP

005301	B6.129S2-Tg(APP)8.9Btla/J
006406	B6.129S4-Tg(APPSwLon)96Btla/J
009126	B6.Cg-Nos2tm1Lau Tg(Thy1-APPSwDutIowa)BWevn/J
005864	B6.Cg-Tg(APPswe,PSEN1dE9)85Dbo/J
004662	B6.Cg-Tg(PDGFB-APP)5Lms/J
006293	B6.Cg-Tg(PDGFB-APPSwInd)20Lms/2J
006006	B6.Cg-Tg(Prnp-APP)A-2Dbo/J
006005	B6.Cg-Tg(Prnp-App/APPswe)E1-2Dbo/J
007049	B6.Cg-Tg(tetO-APPSwInd)885Dbo/J
004462	B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J
006004	B6C3-Tg(tetO-APPSwInd)885Dbo/J
007027	C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/J

View Strains carrying other alleles of APP     (12 strains)

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

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Alzheimer Disease; AD -

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

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 (MGI Ref ID J:42613)
  • 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
  • mice have 7- to 8-fold higher levels of Abeta1-42 peptide in their brains compared to Tg(PSEN1H163R)G9Btla hemizygotes
  • diffuse amyloid beta deposits are detected in the hippocampus and frontal cortex at 24-26 months of age
• other phenotype
• amyloid beta deposits (MGI Ref ID J:42613)
  • 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
  • mice have 7- to 8-fold higher levels of Abeta1-42 peptide in their brains compared to Tg(PSEN1H163R)G9Btla hemizygotes
  • diffuse amyloid beta deposits are detected in the hippocampus and frontal cortex at 24-26 months of age

Tg(APPSw)40Btla/Tg(APPSw)40Btla

        involves: 129S1/Sv * 129X1/SvJ

• nervous system phenotype
• amyloid beta deposits (MGI Ref ID J:58050)
  • homozygous mice have 15- to 20-fold higher levels of Abeta1-42 peptide in their brains compared to Tg(PSEN1H163R)G9Btla hemizygotes
  • extensive fibrillar amyloid beta deposits are detected in the hippocampus and frontal, cingulate and parietal cortex at 14-15 months of age
• other phenotype
• amyloid beta deposits (MGI Ref ID J:58050)
  • homozygous mice have 15- to 20-fold higher levels of Abeta1-42 peptide in their brains compared to Tg(PSEN1H163R)G9Btla hemizygotes
  • extensive fibrillar amyloid beta deposits are detected in the hippocampus and frontal, cingulate and parietal cortex at 14-15 months of age

Tg(APPSw)40Btla/Tg(APPSw)40Btla

        B6.129-Tg(APPSw)40Btla

• nervous system phenotype
• amyloid beta deposits (MGI Ref ID J:86629)
  • 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
• other phenotype
• amyloid beta deposits (MGI Ref ID J:86629)
  • 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

Tg(APPSw)40Btla/Tg(APPSw)40Btla

        D2.129-Tg(APPSw)40Btla

• nervous system phenotype
• *normal* nervous system phenotype (MGI Ref ID J:86629)
  • no amyloid beta deposits are observed in 13.5 month-old mice

View Research Applications

Research Applications

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

Mouse/Human Gene Homologs
Alzheimer's

Neurobiology Research
Alzheimer's Disease
      strains expressing mutant APP
Neurodegeneration

Research Tools
Neurobiology Research

APP related

Mouse/Human Gene Homologs
Alzheimer's

Neurobiology Research
Alzheimer's Disease
Neurodegeneration

Genes & Alleles

Gene & Allele Information

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

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 related

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]

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; 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]

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

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	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.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. The total number of animals provided, their gender and genotype will vary. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 13 and 16 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location). This strain is included in the Induced Mutant Resource Colony collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Wild-type from the colony
	000646 A/J
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

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Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

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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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Fax: 1-207-288-6150
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Terms of Use

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For Licensing and Use Restrictions view the link(s) below:
- Strain(s) not available to companies or for-profit entities.

Contact information

General inquiries

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phone:	207-288-6470
fax:	207-288-6655

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