Overview

Also Known As: PS1M146VKI, The Miles W. Miller Mouse

These mice carry a targeted mutation of the mouse Psen1 gene that results in expression of a presenilin-1 protein with the human familial Alzheimer's disease-linked mutation PS1M146V.

Donating Investigator

George M Martin, University of Washington

Genetic overview

Genetic Background	Generation

Psen1^tm1Mpm

Allele Type	Gene Symbol	Gene Name
Targeted	Psen1	presenilin 1

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Research Applications

Developmental Biology Research
Neurobiology Research
Mouse/Human Gene Homologs

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

The targeted allele (PS1M146VKI) causes a mutation of the mouse Psen1 gene that results in expression of a presenilin-1 protein with the human familial Alzheimer's disease-linked mutation PS1M146V. The neo cassette was deleted from the targeted allele (using a CMV-Cre transgenic line of mice). Published findings indicate that this alteration should not influence the level of expression of mutant PS1. Northern blot analysis and RT-PCR determined mRNA expression of the targeted mutant allele is normal. Homozygous PS1M146VKI mice produce only the mutant gene product. Mice that express this targeted allele are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Neurodegeneration seen in wild-type mice caused by excitotoxin kainate treatment is increased and accelerated in this mutant strain. Cultured cells expressing the mutant protein exhibit perturbed neuronal calcium homeostasis. This mutant mouse strain represents a model that may be useful in studies of familial Alzheimer's disease in humans.

Development

A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was utilized in constructing this mutant. A mutagenized DNA sequence of exon 5 of the mouse Psen1 gene was targeted for the Psen1 allele. The construct was electroporated into 129X1/SvJ x 129S1/Sv-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric male animals were bred to C57BL/6 females to produce mice heterozygous for the mutation. These mice were then bred to a CMV-cre transgenic strain to delete the neo cassette from the targeted allele.

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Guo Q; Fu W; Sopher BL; Miller MW; Ware CB; Martin GM; Mattson MP. 1999. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 5(1):101-6PubMed: 9883847 MGI: J:51950

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Genetics

Psen1^tm1Mpm

Allele Symbol: Psen1^tm1Mpm

Allele Name	targeted mutation 1, Mark P Mattson
Allele Type	Targeted
Allele Synonym(s)	targeted mutation 1, Mark P Mattson; Psen1^tm1Mpm
Gene Symbol and Name	Psen1, presenilin 1
Gene Synonym(s)	alzheimer disease 3 homolog; S182; Ad3h; AD3; Ad3h; presenilin-1; PS-1; PS1; FAD; ACNINV3
Promoter	Psen1, presenilin 1, mouse, laboratory
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Chromosome	12
Molecular Note	Point mutations were introduced into the coding region of exon 5 that altered the codons corresponding to amino acids 145 and 146 from isoleucine and methionine to valine and valine, respectively, and a BstEII restriction site. A lox-P flanked neomycin cassette was also introduced into exon 4. F2 mice exhibited the expected polymorphism of the targeted allele when genomic DNA was amplified with exon 5 specific primers and the products were digested with the appropriate restriction enzyme. Northern blot analysis of total brain RNA using a Psen1 specific antibody showed that the targeted allele was expressed at normal physiological levels in homozygous mutant mice.
Mutations Made By	George Martin, University of Washington

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Alzheimer's disease 3

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Alzheimer's disease

Research Areas By Genotype

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

Genotype: Psen1^tm1Mpm related

Developmental Biology Research
- Postnatal Lethality
  - Homozygous
- Neurodevelopmental Defects
- Skeletal Defects
Neurobiology Research
- Alzheimer's Disease
- Behavioral and Learning Defects
- Neurodegeneration
- Neurodevelopmental Defects
Mouse/Human Gene Homologs
- Alzheimer's

Neurobiology Research
- Alzheimer's Disease
  - Presenilin mutants

Mammalian Phenotype Terms by Genotype

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

Genotype: Psen1^tm1Mpm/Psen1^tm1Mpm
involves: 129S1/Sv * 129X1/SvJ * C57BL/6

cellular phenotype

increased susceptibility to neuronal excitotoxicity
- cultured hippocampal neurons show increased susceptibility to death induced by glutamate, due to impaired calcium homeostasis, increased oxidative stress, and mitochondrial dysfunction
- kainate-induced degeneration and death of CA3, CA1, and hilar neurons is accelerated and increased in mutants compared to wild-type

homeostasis/metabolism phenotype

increased susceptibility to neuronal excitotoxicity
- cultured hippocampal neurons show increased susceptibility to death induced by glutamate, due to impaired calcium homeostasis, increased oxidative stress, and mitochondrial dysfunction
- kainate-induced degeneration and death of CA3, CA1, and hilar neurons is accelerated and increased in mutants compared to wild-type

mammalian phenotype

behavior/neurological phenotype
- homozygotes do not exhibit a deficit in contextual fear learning at 3 months of age
- homozygous mice do not differ in performance in Morris water maze or in contextual fear conditioning

nervous system phenotype

increased susceptibility to neuronal excitotoxicity
- cultured hippocampal neurons show increased susceptibility to death induced by glutamate, due to impaired calcium homeostasis, increased oxidative stress, and mitochondrial dysfunction
- kainate-induced degeneration and death of CA3, CA1, and hilar neurons is accelerated and increased in mutants compared to wild-type

neurodegeneration
- homozygotes are hypersensitive to seizure-induced synaptic degeneration and necrotic neuronal death in the hippocampus

References

Guo Q; Fu W; Sopher BL; Miller MW; Ware CB; Martin GM; Mattson MP. 1999. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 5(1):101-6PubMed: 9883847 MGI: J:51950

Additional References

Guo Q; Sebastian L; Sopher BL; Miller MW; Glazner GW; Ware CB; Martin GM; Mattson MP. 1999. Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a PS1 mutation. Proc Natl Acad Sci U S A 96(7):4125-30PubMed: 10097174 MGI: J:54086
Zhu H; Guo Q; Mattson MP. 1999. Dietary restriction protects hippocampal neurons against the death-promoting action of a presenilin-1 mutation. Brain Res 842(1):224-9PubMed: 10526115 MGI: J:57847
Leissring MA; Akbari Y; Fanger CM; Cahalan MD; Mattson MP; LaFerla FM. 2000. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol 149(4):793-8PubMed: 10811821 MGI: J:62231
Chan SL; Mayne M; Holden CP; Geiger JD; Mattson MP. 2000. Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J Biol Chem 275(24):18195-200PubMed: 10764737 MGI: J:62820
Oddo S; Caccamo A; Shepherd JD; Murphy MP; Golde TE; Kayed R; Metherate R; Mattson MP; Akbari Y; LaFerla FM. 2003. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39(3):409-21PubMed: 12895417 MGI: J:84847

Additional - Psen1^tm1Mpm related

Technical Support

Contact Technical Support

Genotyping Protocols
- Restriction Enzyme Digest: Psen1^tm1Mpm
- Pyrosequencing: Psen1^tm1Mpm
- End Point Analysis: Psen1^tm1Mpm-EP
- Genotyping resources and troubleshooting
Breeding Considerations

This strain originated on a B6;129 background, and has been backcrossed to C57BL/6 for at least 7 generations (11/01).
- Additional Breeding and Husbandry Support
Citation
When using the PS1M146VKI mouse strain in a publication, please cite the originating article(s) and include JAX stock #004193 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

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service	Genotype	Price
	Heterozygous or wildtype for Psen1<tm1Mpm>

We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We 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.

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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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Licensing Information

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Also Known As: PS1M146VKI, The Miles W. Miller Mouse

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Psen1tm1Mpm

Allele Symbol: Psen1tm1Mpm

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Genotype

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

Genotype: Psen1tm1Mpm related

Mammalian Phenotype Terms by Genotype

Genotype: Psen1tm1Mpm/Psen1tm1Mpminvolves: 129S1/Sv * 129X1/SvJ * C57BL/6

cellular phenotype

homeostasis/metabolism phenotype

mammalian phenotype

nervous system phenotype

References

Additional References

Additional - Psen1tm1Mpm related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Psen1^tm1Mpm

Allele Symbol: Psen1^tm1Mpm

Genotype: Psen1^tm1Mpm related

Genotype: Psen1^tm1Mpm/Psen1^tm1Mpm
involves: 129S1/Sv * 129X1/SvJ * C57BL/6

Additional - Psen1^tm1Mpm related