Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation N7+3F3p+N1 (28-NOV-04)   Donating Investigator George Martin,   University of Washington

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 Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Psen1

003615	B6.129-Psen1tm1Shn/J
007605	B6;129P-Psen1tm1Vln/J
003822	B6;129S-Psen1tm1Shn/J

View Strains carrying other alleles of Psen1     (3 strains)

Additional Web Information

Congenic Nomenclature
JAX^® NOTES, Summer 2004; 494. New Mouse Models for Alzheimer's Disease Research.
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 3 - Models with phenotypic similarity to human disease where etiologies involve orthologs.1
	Alzheimer Disease; AD - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

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.

Psen1^tm1Mpm/Psen1^tm1Mpm

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6

• nervous system phenotype
• abnormal hippocampus function (MGI Ref ID J:51950)
  • kainate-induced degeneration and death of CA3, CA1, and hilar neurons is accelerated and increased in mutants compared to wild-type
• neurodegeneration (MGI Ref ID J:51950)
  • homozygotes are hypersensitive to seizure-induced synaptic degeneration and necrotic neuronal death in the hippocampus
  • cultured hippocampal neurons show increased susceptibility to death induced by glutamate, due to impaired calcium homeostasis, increased oxidative stress, and mitochondrial dysfunction
• behavior/neurological phenotype
• *normal* behavior/neurological phenotype (MGI Ref ID J:91277)
  • 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

View Research Applications

Research Applications

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

Neurobiology Research
Alzheimer's Disease (Presenilin mutants)

Psen1^tm1Mpm related

Developmental Biology Research
Neurodevelopmental Defects
Postnatal Mortality (Homozygous)
Skeletal Defects

Mouse/Human Gene Homologs
Alzheimer's

Neurobiology Research
Alzheimer's Disease
Behavioral and Learning Defects
Neurodegeneration
Neurodevelopmental Defects

Genes & Alleles

Gene & Allele Information

Allele Symbol		Psen1tm1Mpm
Allele Name		targeted mutation 1, Mark P Mattson
Allele Type		Targeted (knock-in)
Common Name(s)		PS-1 M146V KI; PS1KI; PS1M146V; PS1M146VKI-;
Mutation Made By		George Martin,   University of Washington
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<+>
Gene Symbol and Name		Psen1, presenilin 1
Chromosome		12
Gene Common Name(s)		AD3; Ad3h; FAD; PS-1; PS1; S182; alzheimer disease 3 homolog; presenilin-1;
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. 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. [MGI Ref ID J:51950]

Genotyping

Genotyping Information

Genotyping Protocols

Psen1^tm1Mpm, REST, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

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):101-6. [PubMed: 9883847]  [MGI Ref ID J:51950]

Additional References

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):18195-200. [PubMed: 10764737]  [MGI Ref ID J:62820]

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):4125-30. [PubMed: 10097174]  [MGI Ref ID J:54086]

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):793-8. [PubMed: 10811821]  [MGI Ref ID J:62231]

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):409-21. [PubMed: 12895417]  [MGI Ref ID J:84847]

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):224-9. [PubMed: 10526115]  [MGI Ref ID J:57847]

Psen1^tm1Mpm related

Billings LM; Oddo S; Green KN; McGaugh JL; Laferla FM. 2005. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron 45(5):675-88. [PubMed: 15748844]  [MGI Ref ID J:99604]

Boeras DI; Granic A; Padmanabhan J; Crespo NC; Rojiani AM; Potter H. 2008. Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy. Neurobiol Aging 29(3):319-28. [PubMed: 17169464]  [MGI Ref ID J:135054]

Caccamo A; Oddo S; Billings LM; Green KN; Martinez-Coria H; Fisher A; LaFerla FM. 2006. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 49(5):671-82. [PubMed: 16504943]  [MGI Ref ID J:107582]

Chan SL; Culmsee C; Haughey N; Klapper W; Mattson MP. 2002. Presenilin-1 mutations sensitize neurons to DNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12. Neurobiol Dis 11(1):2-19. [PubMed: 12460542]  [MGI Ref ID J:125448]

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):18195-200. [PubMed: 10764737]  [MGI Ref ID J:62820]

Clinton LK; Billings LM; Green KN; Caccamo A; Ngo J; Oddo S; McGaugh JL; LaFerla FM. 2007. Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice. Neurobiol Dis 28(1):76-82. [PubMed: 17659878]  [MGI Ref ID J:134819]

Green KN; Billings LM; Roozendaal B; McGaugh JL; LaFerla FM. 2006. Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer's disease. J Neurosci 26(35):9047-56. [PubMed: 16943563]  [MGI Ref ID J:112193]

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):4125-30. [PubMed: 10097174]  [MGI Ref ID J:54086]

Guo Q; Sebastian L; Sopher BL; Miller MW; Ware CB; Martin GM ; Mattson MP. 1999. Increased vulnerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid beta-peptide toxicity: central roles of superoxide production and caspase activation. J Neurochem 72(3):1019-29. [PubMed: 10037473]  [MGI Ref ID J:53132]

Halagappa VK; Guo Z; Pearson M; Matsuoka Y; Cutler RG; Laferla FM; Mattson MP. 2007. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease. Neurobiol Dis 26(1):212-20. [PubMed: 17306982]  [MGI Ref ID J:134857]

Hirata-Fukae C; Li HF; Hoe HS; Gray AJ; Minami SS; Hamada K; Niikura T; Hua F; Tsukagoshi-Nagai H; Horikoshi-Sakuraba Y; Mughal M; Rebeck GW; LaFerla FM; Mattson MP; Iwata N; Saido TC; Klein WL; Duff KE; Aisen PS; Matsuoka Y. 2008. Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res 1216:92-103. [PubMed: 18486110]  [MGI Ref ID J:138344]

Kitazawa M; Green KN; Caccamo A; LaFerla FM. 2006. Genetically augmenting Abeta42 levels in skeletal muscle exacerbates inclusion body myositis-like pathology and motor deficits in transgenic mice. Am J Pathol 168(6):1986-97. [PubMed: 16723713]  [MGI Ref ID J:109124]

Kitazawa M; Oddo S; Yamasaki TR; Green KN; LaFerla FM. 2005. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J Neurosci 25(39):8843-53. [PubMed: 16192374]  [MGI Ref ID J:101347]

LaFontaine MA; Mattson MP; Butterfield DA. 2002. Oxidative stress in synaptosomal proteins from mutant presenilin-1 knock-in mice: implications for familial Alzheimer's disease. Neurochem Res 27(5):417-21. [PubMed: 12064358]  [MGI Ref ID J:106192]

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):793-8. [PubMed: 10811821]  [MGI Ref ID J:62231]

Malik B; Currais A; Soriano S. 2008. Cell cycle-driven neuronal apoptosis specifically linked to amyloid peptide Abeta1-42 exposure is not exacerbated in a mouse model of presenilin-1 familial Alzheimer's disease. J Neurochem 106(2):912-6. [PubMed: 18466334]  [MGI Ref ID J:139367]

Mattson MP; Zhu H; Yu J; Kindy MS. 2000. Presenilin-1 mutation increases neuronal vulnerability to focal ischemia in vivo and to hypoxia and glucose deprivation in cell culture: involvement of perturbed calcium homeostasis. J Neurosci 20(4):1358-64. [PubMed: 10662826]  [MGI Ref ID J:60290]

Milhavet O; Martindale JL; Camandola S; Chan SL; Gary DS; Cheng A; Holbrook NJ; Mattson MP. 2002. Involvement of Gadd153 in the pathogenic action of presenilin-1 mutations. J Neurochem 83(3):673-81. [PubMed: 12390529]  [MGI Ref ID J:79892]

Oddo S; Caccamo A; Cheng D; Jouleh B; Torp R; LaFerla FM. 2007. Genetically augmenting tau levels does not modulate the onset or progression of Abeta pathology in transgenic mice. J Neurochem 102(4):1053-63. [PubMed: 17472708]  [MGI Ref ID J:124130]

Oddo S; Caccamo A; Green KN; Liang K; Tran L; Chen Y; Leslie FM; LaFerla FM. 2005. Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease. Proc Natl Acad Sci U S A 102(8):3046-51. [PubMed: 15705720]  [MGI Ref ID J:96834]

Oddo S; Caccamo A; Kitazawa M; Tseng BP; LaFerla FM. 2003. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging 24(8):1063-70. [PubMed: 14643377]  [MGI Ref ID J:128565]

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):409-21. [PubMed: 12895417]  [MGI Ref ID J:84847]

Oddo S; Caccamo A; Smith IF; Green KN; Laferla FM. 2006. A Dynamic Relationship between Intracellular and Extracellular Pools of A{beta}. Am J Pathol 168(1):184-94. [PubMed: 16400022]  [MGI Ref ID J:104358]

Oddo S; Caccamo A; Tran L; Lambert MP; Glabe CG; Klein WL; LaFerla FM. 2006. Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem 281(3):1599-604. [PubMed: 16282321]  [MGI Ref ID J:107286]

Payette DJ; Xie J; Guo Q. 2007. Reduction in CHT1-mediated choline uptake in primary neurons from presenilin-1 M146V mutant knock-in mice. Brain Res 1135(1):12-21. [PubMed: 17196556]  [MGI Ref ID J:118185]

Pietropaolo S; Sun Y; Li R; Brana C; Feldon J; Yee BK. 2008. The impact of voluntary exercise on mental health in rodents: A neuroplasticity perspective. Behav Brain Res 192(1):42-60. [PubMed: 18468702]  [MGI Ref ID J:136980]

Resende R; Moreira PI; Proenca T; Deshpande A; Busciglio J; Pereira C; Oliveira CR. 2008. Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radic Biol Med 44(12):2051-7. [PubMed: 18423383]  [MGI Ref ID J:136275]

Rodriguez JJ; Jones VC; Tabuchi M; Allan SM; Knight EM; LaFerla FM; Oddo S; Verkhratsky A. 2008. Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer's disease. PLoS ONE 3(8):e2935. [PubMed: 18698410]  [MGI Ref ID J:140591]

Sensi SL; Rapposelli IG; Frazzini V; Mascetra N. 2008. Altered oxidant-mediated intraneuronal zinc mobilization in a triple transgenic mouse model of Alzheimer's disease. Exp Gerontol 43(5):488-492. [PubMed: 18068923]  [MGI Ref ID J:135291]

Smith IF; Hitt B; Green KN; Oddo S; LaFerla FM. 2005. Enhanced caffeine-induced Ca2+ release in the 3xTg-AD mouse model of Alzheimer's disease. J Neurochem 94(6):1711-8. [PubMed: 16156741]  [MGI Ref ID J:101318]

Stutzmann GE; Caccamo A; LaFerla FM; Parker I. 2004. Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer's-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci 24(2):508-13. [PubMed: 14724250]  [MGI Ref ID J:87452]

Stutzmann GE; Smith I; Caccamo A; Oddo S; Laferla FM; Parker I. 2006. Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer's disease mice. J Neurosci 26(19):5180-9. [PubMed: 16687509]  [MGI Ref ID J:108684]

Tseng BP; Green KN; Chan JL; Blurton-Jones M; LaFerla FM. 2008. Abeta inhibits the proteasome and enhances amyloid and tau accumulation. Neurobiol Aging 29(11):1607-18. [PubMed: 17544172]  [MGI Ref ID J:140906]

Wang R; Dineley KT; Sweatt JD; Zheng H. 2004. Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience 126(2):305-12. [PubMed: 15207348]  [MGI Ref ID J:91277]

Wang R; Wang B; He W; Zheng H. 2006. Wild-type presenilin 1 protects against Alzheimer disease mutation-induced amyloid pathology. J Biol Chem 281(22):15330-6. [PubMed: 16574645]  [MGI Ref ID J:113453]

Xie J; Chang X; Zhang X; Guo Q. 2001. Aberrant induction of Par-4 is involved in apoptosis of hippocampal neurons in presenilin-1 M146V mutant knock-in mice. Brain Res 915(1):1-10. [PubMed: 11578614]  [MGI Ref ID J:72044]

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):224-9. [PubMed: 10526115]  [MGI Ref ID J:57847]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	This strain originated on a B6;129 background, and has been backcrossed to C57BL/6 for at least 7 generations (11/01).
Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryopreserved Embryos This strain is also available as cryopreserved embryos from our Repository. Orders for cryopreserved embryos are supplied subject to a signed agreement that must be returned to the Customer Service Department after order placement. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos from our repository, please visit our Cryopreserved Embryos web page. Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	000664 C57BL/6J
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.

General Terms and Conditions

See Terms of Use

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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Ordering and Purchasing Information

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Contact Information
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Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
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Terms of Use

Terms of Use

General Terms and Conditions

Effective September 26, 2007: License Requirements for Strains using Cre-lox Technology only apply in Canada, see Licenses for Strains using Cre-lox Technology.

Contact information

General inquiries

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

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

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In no event shall The Jackson Laboratory, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, products or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of The Jackson Laboratory, its agents or employees. In purchasing or receiving MICE, products or services from The Jackson Laboratory, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges The Jackson Laboratory from all such causes of action or damages, and further agrees to defend and indemnify The Jackson Laboratory from any costs or damages arising out of any third party claims.

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The foregoing represents the General Terms and Conditions applicable to The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, products and services by The Jackson Laboratory, and by its licensees and distributors.

Acceptance of delivery of MICE, products or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on The Jackson Laboratory, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, products services by The Jackson Laboratory.