C57BL/6J-Tg(Thy1-APPSw,Thy1-PSEN1*L166P)21Jckr/J

Stock number: 037891
Product name: APPPS1
Strain synonyms: B6.APPPS1-21
Research areas: Mouse/Human Gene Homologs, Neurobiology Research, Research Tools

Description

APPPS1 mice contain the co-injected APPSwe and PSEN1*L166P transgenes under direction of Thy1 promoters and may be useful for studying cerebral amyloid deposition and related fluid biomarker changes.

Detailed description

APPPS1 mice contain the co-injected APPSwe and PSEN1*L166P transgenes under direction of a neuron-specific Thy1 promoter element. APPPS1 mice develop cerebral beta-amyloidosis with very early onset starting at 4-6 weeks. Amyloid-associated pathologies include dystrophic synaptic boutons, hyperphosphorylated tau-positive neuritic structures and robust gliosis, with neocortical microglia number increasing threefold from 1 to 8 months of age. Global neocortical neuron loss is not apparent (at least up to 8 months of age), but local neuron loss in the dentate gyrus is observed. Early and rapid onset of amyloid deposition approaches a plateau, mimicking the phenotype seen in Alzheimer's disease patients before development of neurodegeneration and clinical symptoms. Mice also show fluid core biomarker changes as seen in Alzheimer's disease. Mice breed well as hemizygotes and have no obvious phenotype except for occasional epileptic seizures. The donating investigator reports that homozygotes are born at lower than Mendelian rates (2 homozygotes out of 41 offspring produced from hemizygous breeders), and they do not produce viable offspring. APPPS1 mice die prematurely with an approximate life span of 20-22 months. These mice may be useful for studying cerebral amyloid deposition and related fluid biomarker changes.

Development

The Thy1-APPKM670/671NL transgenic construct was designed to have the human amyloid beta-precursor protein (APP) gene, with the Swedish K670N/M671L mutations, under the control of a mouse thymus cell antigen 1, theta (Thy1) promoter element. The Thy1-PS1L166P transgenic construct was designed to have the mutated human presenilin 1 (PSEN1) gene under the control of a mouse thymus cell antigen 1, theta (Thy1) promoter element. In this transgene, PSEN1 has a CTT to CCT mutation which results in a leucine to proline mutation at position 166. These constructs were coinjected into fertilized C57BL/6J oocytes. Both transgenes integrated at the same site, at the lower arm of chromosome 2 between 40 and 60 cM. Resulting APPPS1 mice from founder line 21 were selected for further analysis because they had a high transgene expression level and showed significant amyloid plaque formation. These mice were further bred to C57BL/6J mice for more than 15 generations. Upon arrival, the mice were bred to C57BL/6J (Stock No. 000664) at least one generation to rederive our live colony. Subsequently, sperm was cryopreserved.

Allele

Symbol: Tg(Thy1-APPSw,Thy1-PSEN1*L166P)21Jckr
Name: transgene insertion 21, Mathias Jucker
MGI accession ID: MGI:3765351
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: APP.PS1; APPPS1; APPPS1-21; Tg(Thy1-APP*Swe,Thy1-PSEN1*L166P)21Jckr
Marker symbol: Tg(Thy1-APPSw,Thy1-PSEN1*L166P)21Jckr
Marker name: transgene insertion 21, Mathias Jucker
Marker synonyms: APPPS1; APPPS1-21
Chromosome: UN
Strain of origin: C57BL/6J
Expressed genes: PSEN1,presenilin 1,human; APP695,amyloid beta (A4) precursor protein (chimeric),mouse/human chimera
Molecular note: The Thy1-APPKM670/671NL was constructed with the mutant human APPKM670/671NL cDNA (Swedish or KM670/671NL mutation of amyloid precursor protein (APP)) placed downstream of the murine Thy1.2 promoter region. Additionally, the Thy1-PS1L166P transgene was constructed with a mutant human PS1L166P cDNA (leucine to proline mutation at position 166 of human presenilin 1 (Alzheimer disease 3, PSEN1 or PS1)) placed downstream of the murine Thy1.2 promoter sequences. These constructs were coinjected to produce founder mice. In addition to line 21, lines 5 and 8 were also established.