Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System Homozygote x Homozygote         (Female x Male) Species laboratory mouse Generation N10+N7F8 (04-DEC-07)   Donating Investigator David Borchelt,   McKnight Brain Inst, Univ of Florida

Description
At birth, mice homozygous for the targeted allele are viable, and do not display any gross physical or behavioral abnormalities. No App gene product (mRNA or protein) is detected. Body weight is 15-20% less than that observed in wildtype age-matched control mice. By 14 weeks of age the mice exhibit evidence of reactive gliosis. Neurological evaluation reveals significantly reduced forelimb grip strength and decreased locomotor activity. This mutant strain offers a model useful in studies related to Alzheimer's disease.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt a region of the App gene encoding the promoter and exon 1. The construct was electroporated into 129S7/SvEvBrd-derived AB2.1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals were backcrossed to C57BL/6J mice.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature
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 - Models with phenotypic similarity to human disease where etiologies are distinct.2

2 Human genes are associated with this disease. Orthologs of those genes do not 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.

App^tm1Dbo/App^tm1Dbo

        involves: 129S7/SvEvBrd * C57BL/6J

• behavior/neurological phenotype
• abnormal active avoidance behavior (MGI Ref ID J:53824)
  • age-related impairment in conditioned avoidance tests, seen at 10 months of age, but not at 4 months of age
• abnormal grip strength (MGI Ref ID J:25512)
  • significantly reduced grip strength
• abnormal locomotor activation (MGI Ref ID J:25512)
  • decreased locomotor activity
• hypoactivity (MGI Ref ID J:53824)
• abnormal spatial learning (MGI Ref ID J:53824)
  • impairment in watermaze test of spatial learning, both at 4 and 10 months of age
• nervous system phenotype
• abnormal long term potentiation (MGI Ref ID J:53824)
  • impairment of ability of high frequency stimuli to induce LTP which correlated with extent of gliosis in stratum radiatum
• abnormal neuron morphology (MGI Ref ID J:53824)
  • the branching of dendrites of both cortical and hippocampal neurons was much less extensive, however did not show any loss of cells in the cortex or the hippocampus
• gliosis (MGI Ref ID J:25512)
  • reactive gliosis was observed throughout the cortical layers of the neocortex and extensive astrogliosis was seen in the CA1 region of the hippocampus, however did not observe neuronal cell damage
• astrocytosis (MGI Ref ID J:53824)
  • reactive astrocytosis in many brain areas, but predominantly in the cortex and hippocampus at 14 weeks of age
• growth/size phenotype
• decreased body weight (MGI Ref ID J:25512)
  • body weight was 15-20% less at all ages compared with that of controls

View Research Applications

Research Applications

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

App^tm1Dbo related

Mouse/Human Gene Homologs
Alzheimer's

Neurobiology Research
Alzheimer's Disease
Neurodegeneration

Genes & Alleles

Gene & Allele Information

Allele Symbol		Apptm1Dbo
Allele Name		targeted mutation 1, David R Borchelt
Allele Type		Targeted (knock-out)
Common Name(s)		App-;
Mutation Made By		David Borchelt,   McKnight Brain Inst, Univ of Florida
Strain of Origin		129S7/SvEvBrd-Hprt1
ES Cell Line Name		AB2.1
ES Cell Line Strain		129S7/SvEvBrd-Hprt1
Gene Symbol and Name		App, amyloid beta (A4) precursor protein
Chromosome		16
Gene Common Name(s)		AAA; ABETA; ABPP; AD1; AL024401; APPI; Adap; Alzheimer disease amyloid beta protein; CTFgamma; CVAP; Cvap; E030013M08Rik; PN2; RIKEN cDNA E030013M08 gene; appican; betaAPP; cerebrovascular amyloid peptide; expressed sequence AL024401; protease nexin II;
Molecular Note		A neomycin resistance cassette replaced a 3.8 kb sequence including the promoter region and first exon. Northern blot analysis did not detect mRNA in brain or kidney of homozygous mutant mice. [MGI Ref ID J:25512]

Genotyping

Genotyping Information

Genotyping Protocols

App^tm1Dbo, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Zheng H; Jiang M; Trumbauer ME; Sirinathsinghji DJ; Hopkins R; Smith DW; Heavens RP; Dawson GR; Boyce S; Conner MW; Stevens KA; Slunt HH; Sisodia SS; Chen HY; Van der Ploeg LHT. 1995. beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81(4):525-31. [PubMed: 7758106]  [MGI Ref ID J:25512]

Additional References

von Koch CS; Zheng H; Chen H; Trumbauer M; Thinakaran G; van der Ploeg LH; Price DL; Sisodia SS. 1997. Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol Aging 18(6):661-9. [PubMed: 9461064]  [MGI Ref ID J:45851]

App^tm1Dbo related

Bellingham SA; Ciccotosto GD; Needham BE; Fodero LR; White AR; Masters CL; Cappai R; Camakaris J. 2004. Gene knockout of amyloid precursor protein and amyloid precursor-like protein-2 increases cellular copper levels in primary mouse cortical neurons and embryonic fibroblasts. J Neurochem 91(2):423-8. [PubMed: 15447675]  [MGI Ref ID J:93279]

Cappai R; Cheng F; Ciccotosto GD; Needham BE; Masters CL; Multhaup G; Fransson LA; Mani K. 2005. The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-Nitric Oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo. J Biol Chem 280(14):13913-20. [PubMed: 15677459]  [MGI Ref ID J:98747]

Cataldo AM; Petanceska S; Peterhoff CM; Terio NB; Epstein CJ; Villar A; Carlson EJ; Staufenbiel M; Nixon RA. 2003. App gene dosage modulates endosomal abnormalities of Alzheimer's disease in a segmental trisomy 16 mouse model of down syndrome. J Neurosci 23(17):6788-92. [PubMed: 12890772]  [MGI Ref ID J:84685]

Dawson GR; Seabrook GR; Zheng H; Smith DW; Graham S; O'Dowd G; Bowery BJ; Boyce S; Trumbauer ME; Chen HY; Van der Ploeg LH; Sirinathsinghji DJ. 1999. Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the beta-amyloid precursor protein. Neuroscience 90(1):1-13. [PubMed: 10188929]  [MGI Ref ID J:53824]

Han P; Dou F; Li F; Zhang X; Zhang YW; Zheng H; Lipton SA; Xu H; Liao FF. 2005. Suppression of cyclin-dependent kinase 5 activation by amyloid precursor protein: a novel excitoprotective mechanism involving modulation of tau phosphorylation. J Neurosci 25(50):11542-52. [PubMed: 16354912]  [MGI Ref ID J:103996]

Kamal A; Almenar-Queralt A; LeBlanc JF; Roberts EA; Goldstein LS. 2001. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature 414(6864):643-8. [PubMed: 11740561]  [MGI Ref ID J:73257]

Liu Q; Zerbinatti CV; Zhang J; Hoe HS; Wang B; Cole SL; Herz J; Muglia L; Bu G. 2007. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56(1):66-78. [PubMed: 17920016]  [MGI Ref ID J:126954]

Needham B; Wlodek M; Ciccotosto G; Fam B; Masters C; Proietto J; Andrikopoulos S; Cappai R. 2008. Identification of the Alzheimer's disease amyloid precursor protein (APP) and its homologue APLP2 as essential modulators of glucose and insulin homeostasis and growth. J Pathol 215(2):155-63. [PubMed: 18393365]  [MGI Ref ID J:134311]

Phinney AL; Calhoun ME; Wolfer DP; Lipp HP; Zheng H; Jucker M. 1999. No hippocampal neuron or synaptic bouton loss in learning-impaired aged beta-amyloid precursor protein-null mice. Neuroscience 90(4):1207-16. [PubMed: 10338291]  [MGI Ref ID J:57197]

Pramatarova A; Chen K; Howell BW. 2008. A genetic interaction between the APP and Dab1 genes influences brain development. Mol Cell Neurosci 37(1):178-86. [PubMed: 18029196]  [MGI Ref ID J:132599]

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]

Seabrook GR; Smith DW; Bowery BJ; Easter A; Reynolds T; Fitzjohn SM; Morton RA; Zheng H; Dawson GR; Sirinathsinghji DJ; Davies CH; Collingridge GL; Hill RG. 1999. Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology 38(3):349-59. [PubMed: 10219973]  [MGI Ref ID J:54292]

Stokin GB; Lillo C; Falzone TL; Brusch RG; Rockenstein E; Mount SL; Raman R; Davies P; Masliah E; Williams DS; Goldstein LS. 2005. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science 307(5713):1282-8. [PubMed: 15731448]  [MGI Ref ID J:96346]

Takahashi RH; Milner TA; Li F; Nam EE; Edgar MA; Yamaguchi H; Beal MF; Xu H; Greengard P; Gouras GK. 2002. Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161(5):1869-79. [PubMed: 12414533]  [MGI Ref ID J:79908]

Wang P; Yang G; Mosier DR; Chang P; Zaidi T; Gong YD; Zhao NM; Dominguez B; Lee KF; Gan WB; Zheng H. 2005. Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. J Neurosci 25(5):1219-25. [PubMed: 15689559]  [MGI Ref ID J:98108]

White AR; Multhaup G; Maher F; Bellingham S; Camakaris J; Zheng H; Bush AI; Beyreuther K; Masters CL; Cappai R. 1999. The Alzheimer's disease amyloid precursor protein modulates copper-induced toxicity and oxidative stress in primary neuronal cultures. J Neurosci 19(21):9170-9. [PubMed: 10531420]  [MGI Ref ID J:119903]

White AR; Reyes R; Mercer JF; Camakaris J; Zheng H; Bush AI; Multhaup G; Beyreuther K; Masters CL; Cappai R. 1999. Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice. Brain Res 842(2):439-44. [PubMed: 10526140]  [MGI Ref ID J:58021]

Xu F; Davis J; Miao J; Previti ML; Romanov G; Ziegler K; Van Nostrand WE. 2005. Protease nexin-2/amyloid beta-protein precursor limits cerebral thrombosis. Proc Natl Acad Sci U S A 102(50):18135-40. [PubMed: 16330760]  [MGI Ref ID J:104364]

Yang G; Gong YD; Gong K; Jiang WL; Kwon E; Wang P; Zheng H; Zhang XF; Gan WB; Zhao NM. 2005. Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (APP) and APP-like protein 2. Neurosci Lett 384(1-2):66-71. [PubMed: 15919150]  [MGI Ref ID J:100994]

Zhang YW; Wang R; Liu Q; Zhang H; Liao FF; Xu H. 2007. Presenilin/{gamma}-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Proc Natl Acad Sci U S A 104(25):10613-8. [PubMed: 17556541]  [MGI Ref ID J:122380]

von Koch CS; Zheng H; Chen H; Trumbauer M; Thinakaran G; van der Ploeg LH; Price DL; Sisodia SS. 1997. Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol Aging 18(6):661-9. [PubMed: 9461064]  [MGI Ref ID J:45851]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           FGB29

Colony Maintenance

Breeding & Husbandry	This strain originated on a B6;129S7 background and has been backcrossed to C57BL/6J for at least ten generations (7/01). Coat color expected from breeding:Black
Mating System	Homozygote x Homozygote         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. 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
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

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

Contact information

General inquiries

Contracts Administration

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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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.