Strain Detail Sheet

Strain Name: B6.Cg-Tg(APP695)3Dbo Tg(PSEN1dE9)S9Dbo/Mmjax

Stock Number: 034833-JAX

Other Names:

This strain was formerly available as JaxMice stock number 5866. APPswe line C3-3 x PS1dE9 line S-9

Gene Details: (provided by MGI)

Transgene: Tg(APP695)3Dbo
Name: transgene insertion 3, David R Borchelt
Alteration at locus: Transgenic

Transgene: Tg(PSEN1dE9)S9Dbo
Name: transgene insertion S9, David R Borchelt
Alteration at locus: Transgenic

Genetic Alterations:

Genotype Determination:

ES Cell Line: Not applicable

Strain Description

Phenotype
Homozygous phenotype: Not evaluated
Hemizygous phenotype: Double transgenic mice are viable and fertile. At 6 months of age, double-transgenic mice show visible amyloid plaque deposition but are indistinguishable from nontransgenic animals in all cognitive measures. By 18 months, amyloid deposits were much higher in APPswe/PS1dE9 mice with statistically significant but mild decreases in cholinergic markers (cortex and hippocampus) and somatostatin levels (cortex). Performance of older double-transgenic mice is impaired in all cognitive tasks, and deficits in episodic-like memory tasks correlate with total amyloid-beta peptide loads in the brain. Mutant mice, hemizygous for each transgene, and on the C57BL/6J background (N6), have altered EEG (decreased cortical theta activity and increased beta and gamma activity). EEG differences are detected as early as 7 month of age (Wang et al. Brain Res 2002).

Mammalian Phenotype Terms:(provided by MGI)

Extend all MPTs
assigned by genotype

Tg(PSEN1dE9)S9Dbo/-

B6.Cg-Tg(APP695)3Dbo Tg(PSEN1dE9)S9Dbo/Mmjax

The following phenotype information may relate to one or more alleles on a genetic background differing from this MMRRC strain.

Tg(PSEN1dE9)S9Dbo/-

Background Not Specified

nervous system phenotype
- abnormal amacrine cell morphology (MGI Ref ID J:139070)
  - distribution of amacrine cell processes is disrupted as determined by syntaxin 1 staining
- abnormal microglial cell morphology (MGI Ref ID J:139070)
  - increase in microglial cell activity in retina is observed in 12-15 month old transgenics
  - microglia processes in the retina are thicker and display a dendritic-like appearance as compared to control
  - microglia density, but not cell body size, is increased in transgenics
- amyloid beta deposits (MGI Ref ID J:139070)
  - thioflavine-S positive plaques are observed in the retina beginning at 12 months of age
  - plaques have radial branches with a central core
  - plaque size ranges from 5-20 um, larger plaques are observed at 15-16 months
  - plaques appear earlier in females than in males and increase in number over time
  - 100% of females and 75% of males have plaques in retina by 15-16 months
vision/eye phenotype
- abnormal eye electrophysiology (MGI Ref ID J:139070)
  - amplitudes of a and b waves are decreased in 12-16 month old mice when tested at lower light intensity, but not a higher intensity
  - latency and implicit time as determined by ERG measurement are similar to control
- abnormal retina morphology (MGI Ref ID J:139070)
  - thioflavine-S positive plaques are observed in the retina beginning at 12 months of age
  - most plaques (34.7% and 41 % respectively) are found in the inner and outer plexiform layers
  - thickness of the retinal nuclear layers is similar to control, suggesting that there is no obvious neuronal cell loss
  - abnormal amacrine cell morphology (MGI Ref ID J:139070)
    - distribution of amacrine cell processes is disrupted as determined by syntaxin 1 staining
  - abnormal retinal inner plexiform layer morphology (MGI Ref ID J:139070)
    - thioflavine-S positive plaques are first observed in females in the IPL at 12 months
    - plaques are first observed in males at 13 months
    - plaques are embedded within IPL cholinergic bands
  - abnormal retinal outer plexiform layer morphology (MGI Ref ID J:139070)
    - thioflavine-S positive plaques are first observed in females in the OPL at 12 months
    - plaques are first observed in males at 13 months
immune system phenotype
- abnormal microglial cell morphology (MGI Ref ID J:139070)
  - increase in microglial cell activity in retina is observed in 12-15 month old transgenics
  - microglia processes in the retina are thicker and display a dendritic-like appearance as compared to control
  - microglia density, but not cell body size, is increased in transgenics
other phenotype
- amyloid beta deposits (MGI Ref ID J:139070)
  - thioflavine-S positive plaques are observed in the retina beginning at 12 months of age
  - plaques have radial branches with a central core
  - plaque size ranges from 5-20 um, larger plaques are observed at 15-16 months
  - plaques appear earlier in females than in males and increase in number over time
  - 100% of females and 75% of males have plaques in retina by 15-16 months
hematopoietic system phenotype
- abnormal microglial cell morphology (MGI Ref ID J:139070)
  - increase in microglial cell activity in retina is observed in 12-15 month old transgenics
  - microglia processes in the retina are thicker and display a dendritic-like appearance as compared to control
  - microglia density, but not cell body size, is increased in transgenics

Tg(PSEN1dE9)S9Dbo/-

involves: 129S1/Sv * 129X1/SvJ * C3H/HeJ * C57BL/6J

behavior/neurological phenotype
- behavior/neurological phenotype (MGI Ref ID J:123534)
  - abnormal spatial learning (MGI Ref ID J:123534)
    - mice travel shorter distance in open-field and show less activity or excursions into central area; mice remain near periphery of apparatus rather than entering open center of field
  - abnormal spatial reference memory (MGI Ref ID J:123534)
    - 16-18 month-old mice swim farther to find platform and spend less time in platform vicinity than controls
nervous system phenotype
- amyloid beta deposits (MGI Ref ID J:123534)
  - one month following neuron injection with virus expressing short hairpin RNA to silence Bace1, there is a 38% reduction in amyloid beta burden in hippocampus compared to uninjected hippocampus
other phenotype
- amyloidosis (MGI Ref ID J:123534)
  - mice display amyloid beta aggregates at 12 and 20 months
  - amyloid beta deposits (MGI Ref ID J:123534)
    - one month following neuron injection with virus expressing short hairpin RNA to silence Bace1, there is a 38% reduction in amyloid beta burden in hippocampus compared to uninjected hippocampus

Tg(PSEN1dE9)S9Dbo/-

& nbsp; involves: C3H/HeJ * C57BL/6J

nervous system phenotype
- amyloid beta deposits (MGI Ref IDs J:87691, J:104236)
  - at 7 months of age, mice exhibit amyloid plaques in the hippocampus and cortex (MGI Ref ID J:104236)
  - develops diffuse, compact, birefringent congophilic plaques in cortex and hippocampus (MGI Ref ID J:87691)
  - ratio of amyloid beta peptide 40:42 is 0.75:1 (MGI Ref ID J:87691)
  - 150% increase in amyloid beta peptide 42 (MGI Ref ID J:87691)
other phenotype
- amyloid beta deposits (MGI Ref IDs J:87691, J:104236)
  - at 7 months of age, mice exhibit amyloid plaques in the hippocampus and cortex (MGI Ref ID J:104236)
  - develops diffuse, compact, birefringent congophilic plaques in cortex and hippocampus (MGI Ref ID J:87691)
  - ratio of amyloid beta peptide 40:42 is 0.75:1 (MGI Ref ID J:87691)
  - 150% increase in amyloid beta peptide 42 (MGI Ref ID J:87691)

Founder genetic background: C3B6

Strain genetic background: B6.Cg

Strain Development: Mutant amyloid precursor protein (APPswe) transgenic mice (line C3-3) express a chimeric mouse/human APP-695 with mutations linked to familial Alzheimers disease (KM 593/594 NL). The C3-3 line was backcrossed to C57BL/6J mice for 10 generations. Presenilin 1 (PSEN1) transgenic mice (line S-9) express human PSEN1 carrying the exon-9-deleted variant (PSEN1dE9) associated with familial Alzheimer's disease. Originally created on a hybrid strain background (C3H/HeJ;C57BL/6J), the S-9 line was backcrossed to C57BL/6J for six generations. Both are under the control of the mouse prion protein (PrP) promoter, directing transgene expression predominantly to CNS neurons. APPswe/PS1dE9 double transgenic mice were produced by mating APP-695 line C3-3 males to PS1dE9 line S-9 females, and then backcrossing double transgenic males to C57BL/6J mice for >10 generations before arriving at The Repository.

Suggested Control Mice: Wild-ype littermates

Research Applications

Models for Human Disease
Neurobiology

Strain Origin

Donor: David Borchelt, Ph.D., McKnight Brain Institute, University of Florida

Primary Reference:

Savonenko A; Xu GM; Melnikova T; Morton JL; Gonzales V; Wong MP; Price DL; Tang F; Markowska AL; Borchelt DR, Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities., Neurobiol Dis 2005 Apr;18(3):602-17 (Medline PMID: 15755686)
Jankowsky JL; Fadale DJ; Anderson J; Xu GM; Gonzales V; Jenkins NA; Copeland NG; Lee MK; Younkin LH; Wagner SL; Younkin SG; Borchelt DR, Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase., Hum Mol Genet 2004 Jan 15;13(2):159-70 (Medline PMID: 14645205 )
Borchelt DR; Davis J; Fischer M; Lee MK; Slunt HH; Ratovitsky T; Regard J; Copeland NG; Jenkins NA; Sisodia SS; Price DL, A vector for expressing foreign genes in the brains and hearts of transgenic mice., Genet Anal 1996 Dec;13(6):159-63 (Medline PMID: 9117892)
Jankowsky JL; Slunt HH; Ratovitski T; Jenkins NA; Copeland NG; Borchelt DR, Co-expression of multiple transgenes in mouse CNS: a comparison of strategies., Biomol Eng 2001 Jun;17(6):157-65 (Medline PMID: 11337275)

Special Considerations

When maintaining a live colony, The Jackson Laboratory will maintain this line by mating (APP695/0, +/+) females with (+/+, PSEN1/0) males (or reciprocal). The transgenes are not linked (only 1 in 4 pups is a double transgenic); and the integration site is unknown.

Health Status Report

Colony's Current Health Status Report

For more information about this colony's health status contact csmmrrc@jax.org

Order Request Information

Availability Level:

Limited quantities of breeder mice (up to 2 males and 2 females or 4 mice) per investigator per month are available from a live colony, usually available to ship in under 12 weeks. Larger quantities may be available, please contact the distributing center directly at csmmrrc@jax.org for more details.

Conditions of Distribution:

Distribution of this strain requires submission of the MMRRC Conditions of Use (COU). A link to the COU web form will be provided via email after an order has been placed; the form should be completed then or the email forwarded to your institutional official for completion.

The donor or their institution limits the distribution to non-profit institutions only.

Fees:

Additional charges may apply for any special requests. Shipping costs are in addition to the basic distribution/resuscitation fees. Information on shipping costs and any additional charges will be provided by the supplying MMRRC facility.

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MMRRC Item #	Description

Distribution
Fee/unit (US $)

Units

Notes

034833-JAX-MIX1-F	Hemizygous Transgene / WT Transgene female
034833-JAX-MIX1-M	Hemizygous Transgene / WT Transgene male
034833-JAX-MIX2-F	WT Transgene / Hemizygous Transgene female
034833-JAX-MIX2-M	WT Transgene / Hemizygous Transgene male
034833-JAX-MIX3-F	Hemizygous Transgene / Hemizygous Transgene female
034833-JAX-MIX3-M	Hemizygous Transgene / Hemizygous Transgene male

$218.00

Non-Profit

The csmmrrc@jax.org may assess additional fees for any special requests (e.g., specific age or weight of mice, etc.).

¹ The distribution fee covers the expense of resuscitating mice from the cryo-archive; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.

² An aliquot is one straw or vial with sufficient sperm to recover at least one litter of mice, as per provided protocols, when performed at the MMRRC facility. The MMRRC makes no guarantee concerning the success of these procedures when performed outside the MMRRC facilities.

³ An aliquot contains a sufficient number of embryos (in one or more vials and based on the transfer success rate of the MMRRC facility) to transfer to at least two recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.

To request material from the MMRRC: Please fill out our on-line request form (accessible from the catalog search results page, or click the "Request this Strain" button above). If you have questions or need assistance completing this form, you may call Customer Service at (800) 910-2291 (in USA or Canada) or (530) 757-5710 (international calls). Before you call, please have with you: the MMRRC item number, quantity needed, Bill-to and Ship-to contact information.