Overview

Also Known As:J20

These transgenic mice express a mutant form of the human amyloid protein precursor bearing both the Swedish (K670N/M671L) and the Indiana (V717F) mutations (APPSwInd). They show progressive amyloid deposition as they age. This mutant mouse strain represents a model that may be useful in studies of the pathogenesis of Familial Alzheimer's Disease and possible therapeutic treatments.

Donating Investigator

Lennart Mucke, Gladstone Inst of Neurological Disease

Genetic overview

Genetic Background	Generation
	N12+N30 (2020-04-27 00:00:00)

Zbtb20^{Tg(PDGFB-APPSwInd)20Lms}

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

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Research Applications

Mouse/Human Gene Homologs
Neurobiology Research

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Details

Important Note

In March 2010, the donating investigator performed quantitative PCR on genomic DNA and determination of amyloid-beta levels in brain extract from the JAX Stock No. 006293 distribution colony (B6.Cg-Tg(PDGFB-APPSwInd)20Lms/2J also called "J20" line). Results of these analyses demonstrate that the current distribution colony maintains similar transgene copy number and expression as previously published (Mucke et. al. J Neurosci. 2000 Jun 1; 20(11): 4050-8).

Detailed Description

These transgenic mice express a mutant form of the human amyloid protein precursor bearing both the Swedish (K670N/M671L) and the Indiana (V717F) mutations (APPSwInd). Expression of the transgenic insert is directed by the human platelet-derived growth factor beta polypeptide (PDGFB) promoter. The transgene integrated into chromosome 16 causing a 40.7 Kb deletion in an intron of the Zbtb20 (zinc finger and BTB domain containing 20) gene. Founder line 20 has a copy number of greater than 10. Hemizygotes express immunodetectable transgene product in cerebral neurons, with the highest level of expression occurring in the neocortex and hippocampus. Enzyme-linked immunosorbent assay (ELISA) analysis reveals approximate total amyloid beta peptides and 42 amino acid length amyloid beta peptides in neocortical and hippocampal tissue from mutant mice. At five to seven months of age diffuse amyloid beta peptides deposition in the dendate gyrus and neocortex forms. Amyloid deposition is progressive with all transgenic mice exhibiting plaques by age eight to 10 months. Pups born of carrier females have shown an increased mortality rate in our colonies. The Donating Researcher has observed an approximately 15% mortality rate in the first 6 months of life. Video-EEG monitoring of 4 to 7 month old hemizygous transgenic mice, N10+ on the C57BL/6J background, reveals hippocampal hyperexcitability and cortical and hippocampal spontaneous nonconvulsive seizures. The mice are immobile, with no myoclonic behavior observed, during the non-convulsive electroencephalographic seizures. Pentylenetetrazole induced seizures have earlier onset, are more severe and result in more frequent deaths (50% develop fatal status epilepticus) than wildtype controls (Palop et al. Neuron 2007). This mutant mouse strain represents a model that may be useful in studies of the pathogenesis of Familial Alzheimer's Disease and possible therapeutic treatments.

Development

A transgenic construct containing the mutant human amyloid protein precursor APPSwInd under the control of human platelet-derived growth factor beta polypeptide, simian sarcoma viral (v-sis) oncogene homolog, (PDGFB) promoter, was injected into C57BL/6 X DBA/2 F2 one-cell embryos. Heterozygous founder animals were bred to C57BL/6 X DBA/2 F1 mice. The resulting transgenic mice were then backcrossed for 12 generations on the C57BL/6J background.

This strain was previously distributed as B6.Cg-Tg(PDGFB-APPSwInd)20Lms/1J. That strain was found to have undergone a loss of transgenic copy number and consequent delayed onset of the phenotype, so this strain was re-imported from the lab of Dr. Lennart Mucke. Transgenic copy number is assayed using a Multiplex TaqMan assay. The transgene integrated into chromosome 16 causing a 40.7 Kb deletion in an intron of the Zbtb20 (zinc finger and BTB domain containing 20) gene. Founder line 20 has a copy number of greater than 10.

Expression Data

Expressed Gene	APP, amyloid beta precursor protein, human
Site of Expression	APPSwInd is expressed in cerebral neurons, with the highest level in the neocortex and hippocampus.

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Mucke L; Masliah E; Yu GQ; Mallory M; Rockenstein EM; Tatsuno G; Hu K; Kholodenko D; Johnson-Wood K; McConlogue L. 2000. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20(11):4050-8PubMed: 10818140 MGI: J:62290

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Genetics

Zbtb20^{Tg(PDGFB-APPSwInd)20Lms}

Allele Symbol: Zbtb20^{Tg(PDGFB-APPSwInd)20Lms}

Allele Name	transgene insertion 20, Lennart Mucke
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	APP Tg; APP/J20; hAPPJ20; hAPP-J20; J20; PDAPP-J20; PDGF-APPSwInd; PDGF-hAPP695,751,770V171F, KM670/671NL; Tg(PDGFB-APPSweInd)20Lms
Gene Symbol and Name	Zbtb20, zinc finger and BTB domain containing 20
Gene Synonym(s)
Promoter	PDGFB, platelet derived growth factor subunit B, human
Expressed Gene	APP, amyloid beta precursor protein, human
Site of Expression	APPSwInd is expressed in cerebral neurons, with the highest level in the neocortex and hippocampus.
Strain of Origin	(C57BL/6 x DBA/2)F2
Chromosome	16
General Note	This line is also called line J20. Diffuse amyloid beta peptides deposition forms in the dendate gyrus and neocortex at 5 to 7 months of age. Amyloid deposition is progressive, with all transgenic mice exhibiting plaques by age 8 to 10 months.
Molecular Note	The transgene expresses the mutant human amyloid protein precursor APPSwInd, which bears both the Swedish (K670N/M671L) and the Indiana (V717F) mutations, under the control of the human platelet derived growth factor, B polypeptide (PDGFB) promoter. Hemizygous transgenic mice express immunodetectable transgene product in cerebral neurons, with the highest level of expression occurring in the neocortex and hippocampus. ELISA analysis reveals approximate total amyloid beta peptides and 42 amino acid length amyloid beta peptides in neocortical and hippocampal tissue from transgenic mice. Line 20 inserted into an intron of the gene at 43086322-43127049 (Build GRCm38/mm10) resulting in a 40,727 bp deletion. Founder line 20 has a copy number of greater than 10.
Mutations Made By	Lennart Mucke, Gladstone Inst of Neurological Disease

Disease/Phenotype

Disease Terms

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 Phenotype

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
- Behavioral and Learning Defects
- Epilepsy
  - electroconvulsive seizures
  - increased susceptibility to kainate-induced seizures

Genotype: Zbtb20^{Tg(PDGFB-APPSwInd)20Lms} related

Neurobiology Research
- Alzheimer's Disease

Mammalian Phenotype Terms by Genotype

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

Genotype: Zbtb20^{Tg(PDGFB-APPSwInd)20Lms}/0
involves: C57BL/6 * DBA/2

homeostasis/metabolism phenotype

amyloid beta deposits
- all mice exhibit plaques by age 8 to 10 months
- soluble and insoluble Abeta-40 and -42 peptide deposits at 6-10 months
- at 4-7 months and 14-18 months, Abeta plaque deposition is observed, at levels the same as other transgenics heterozygous null for Mapt
- diffuse immunoreactive amyloid deposits detected in dentate gyrus and neocortex of mice aged 5 to 7 months old

mortality/aging

premature death
- high rate of premature (6 months or earlier) death
- mice show premature death of unclear etiology with >15% mortality exhibited by 6 months, compared to all other genotypes

nervous system phenotype

amyloid beta deposits
- all mice exhibit plaques by age 8 to 10 months
- at 4-7 months and 14-18 months, Abeta plaque deposition is observed, at levels the same as other transgenics heterozygous null for Mapt
- diffuse immunoreactive amyloid deposits detected in dentate gyrus and neocortex of mice aged 5 to 7 months old
- soluble and insoluble Abeta-40 and -42 peptide deposits at 6-10 months

abnormal neuron differentiation
- aberrant sprouting of hippocampal axons is observed in transgenic mice

abnormal neuron morphology
- mice show neuritic dystrophy around amyloid plaques

increased susceptibility to pharmacologically induced seizures
- mice are abnormally sensitive to pentylenetetrazole (PTZ)-induced seizures with 20% suffering fatal status epilepticus at a PTZ dose not lethal in non-transgenic controls

neurodegeneration
- neurodegeneration is indicated by an age dependent decrease in density of synaptophysin-immunoreactive presynaptic terminals

behavior/neurological phenotype

abnormal spatial learning
- in a Morris water maze, mice fail to favor the target platform location unlike wild-type mice
- in the hidden platform version of the Morris water maze, non-trangenic controls, regardless of Mapt genotype learn the task over 3 days, whereas transgenic mice with wild-type expression of Mapt show no evidence of learning
- in probe trials where the platform is removed, mice show no learning, displaying no significantly elevated crossings of the target quadrant after 5 days of training

increased susceptibility to pharmacologically induced seizures
- mice are abnormally sensitive to pentylenetetrazole (PTZ)-induced seizures with 20% suffering fatal status epilepticus at a PTZ dose not lethal in non-transgenic controls

abnormal long term object recognition memory
- at 4-7 months of age, mice transgenic mice with wild-type Mapt expression take longer to locate the platform in the cued version of the Morris water maze test compared to transgenic mice heterozygous or homozygous for Mapt deletion

decreased anxiety-related response
- mice exhibit disinhibition-like behaviors in an elevated plus maze compared with wild-type mice

hyperactivity
- mice show hyperactivity in the Y-maze, a new cage, and elevated-plus maze compared to other transgenic mice or non-transgenic controls; this persists in mice 12-16 months of age

cellular phenotype

abnormal neuron differentiation
- aberrant sprouting of hippocampal axons is observed in transgenic mice

The following phenotype relates to a compound genotype created using this strain

Genotype: Zbtb20^{Tg(PDGFB-APPSwInd)20Lms}/0
B6.Cg-Zbtb20

homeostasis/metabolism phenotype

amyloid beta deposits
- mice develop amyloid peptide deposits by 5-7 months of age

nervous system phenotype

abnormal cerebral cortex pyramidal cell morphology
- at 6 months and 12 to 16 months of age, 30% fewer pyramidal cells in the entorhinal cortex express Reelin than in wild-type mice
- Normal - however, no neuron loss is observed

amyloid beta deposits
- mice develop amyloid peptide deposits by 5-7 months of age

abnormal neurite morphology
- dystrophic neurites are associated with plaques

References

Mucke L; Masliah E; Yu GQ; Mallory M; Rockenstein EM; Tatsuno G; Hu K; Kholodenko D; Johnson-Wood K; McConlogue L. 2000. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20(11):4050-8PubMed: 10818140 MGI: J:62290

Additional References

Moreno H; Wu WE; Lee T; Brickman A; Mayeux R; Brown TR; Small SA. 2007. Imaging the abeta-related neurotoxicity of Alzheimer disease. Arch Neurol 64(10):1467-77PubMed: 17923630 MGI: J:125332

Additional - Zbtb20^{Tg(PDGFB-APPSwInd)20Lms} related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Tg(PDGFB-APP)
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, hemizygous males are bred to wildtype siblings or to C57BL/6J inbred females. Pups born of carrier females have shown an increased mortality rate in our colonies. The Donating Researcher has observed an approximately 15% mortality rate in the first 6 months of life.
- Additional Breeding and Husbandry Support
Mating System
- C57BL/6J (000664) x Hemizygote
Citation
When using the J20 mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #34836 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

AX10 (Standard)

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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

Terms Of Use

General Terms and Conditions

See MMRRC for Additional Conditions of Distribution

Questions about Terms of Use

Additional Use Restrictions Apply

Not Available to Companies or for Commercial Use

Use of MICE only available to non-profit entities.

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:J20

Donating Investigator

Genetic overview

Research Applications

Important Note

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Zbtb20Tg(PDGFB-APPSwInd)20Lms

Allele Symbol: Zbtb20Tg(PDGFB-APPSwInd)20Lms

Disease Terms

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 Phenotype

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

Genotype: Zbtb20Tg(PDGFB-APPSwInd)20Lms related

Mammalian Phenotype Terms by Genotype

Genotype: Zbtb20Tg(PDGFB-APPSwInd)20Lms/0involves: C57BL/6 * DBA/2

homeostasis/metabolism phenotype

mortality/aging

nervous system phenotype

behavior/neurological phenotype

cellular phenotype

Genotype: Zbtb20Tg(PDGFB-APPSwInd)20Lms/0B6.Cg-Zbtb20

homeostasis/metabolism phenotype

nervous system phenotype

References

Additional References

Additional - Zbtb20Tg(PDGFB-APPSwInd)20Lms related

Genotyping Protocols

Breeding Considerations

Mating System

Citation

Animal Health Reports

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

Zbtb20^{Tg(PDGFB-APPSwInd)20Lms}

Allele Symbol: Zbtb20^{Tg(PDGFB-APPSwInd)20Lms}

Genotype: Zbtb20^{Tg(PDGFB-APPSwInd)20Lms} related

Genotype: Zbtb20^{Tg(PDGFB-APPSwInd)20Lms}/0
involves: C57BL/6 * DBA/2

Genotype: Zbtb20^{Tg(PDGFB-APPSwInd)20Lms}/0
B6.Cg-Zbtb20

Additional - Zbtb20^{Tg(PDGFB-APPSwInd)20Lms} related