PWK.Cg-Tg(APPswe,PSEN1dE9)85Dbo/How

Stock number: 025971
Product name: PWK.APP/PS1
Research areas: Neurobiology Research

Description

APP/PS1 are double transgenic mice expressing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9), both directed to CNS neurons. Both mutations are associated with early-onset Alzheimer's disease. These mice may be useful in studying neurological disorders of the brain, specifically Alzheimer's disease, amyloid plaque formation and aging.

Detailed description

APP/PS1 are double transgenic mice expressing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9), both directed to CNS neurons. Both mutations are associated with early-onset Alzheimer's disease. The "humanized" Mo/HuAPP695swe transgene allows the mice to secrete a human A-beta peptide. Both the transgenic peptide and holoprotein can be detected by antibodies specific for human sequence within this region (Signet Laboratories' monoclonal 6E10 antibody). The included Swedish mutations (K595N/M596L) elevate the amount of A-beta produced from the transgene by favoring processing through the beta-secretase pathway. PWK.APP/PS1 hemizygotes exhibit increased aggression compared to controls, as well as significant neuroinflammation. No neuronal cell loss detected. Cortical and hippocampal plaques are fewer in number compared to B6.APP/PS1 mice. Hemizygotes are viable and fertile. Homozygous viability/fertility has not been tested (May 2019). Of note, pregnant mutant female mice are removed from mating boxes and house individually due to increased pup mortality and given treats (BioServ Supreme) to discourage pup cannibalism. Mutant PWK.APP/PS1 mice are separated from wildtype littermates at 3 months of age due to increased aggression, and may require individual housing.

APP/PS1 mice are also available on the WSB/EiJ (WSB.APP/PS1, Stock No. 025970) and CAST/EiJ (CAST.APP/PS1, Stock No. 025973) wild derived backgrounds.

Development

B6.Cg-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax (Stock No. 34832-JAX) mice were backcrossed to PWK/PhJ (Stock No. 003715) for 11 generations.

To generate B6.Cg-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax (Stock No. 34832-JAX) two expression plasmids (Mo/HuAPP695swe and PS1-dE9) were designed to each be controlled by independent mouse prion protein (PrP) promoter elements, directing transgene expression predominantly to CNS neurons. The Mo/HuAPP695swe transgene expresses a "humanized" mouse amyloid beta (A4) precursor protein gene modified at three amino acids to reflect the human residues and further modified to contain the K595N/M596L (otherwise known as K670N/M671L) mutations linked to familial Alzheimer's. The PS1-dE9 transgene expresses a mutant human presenilin 1 carrying the exon-9-deleted variant (PSEN1dE9) associated with familial Alzheimer's disease. These constructs were coinjected into B6C3HF2 pronuclei and insertion of the transgenes occured at a single locus. Founder line 85 was obtained and the resulting colony was maintained as a hemizygote by crossing transgenic mice to B6C3F1/J mice. Transgenic mice were then backcrossed to C57BL/6J for at least eight generations. The mice were backcrossed to PWK/PhJ (Stock No. 003715) for 11 generations to produce this strain.

Allele

Symbol: Tg(APPswe,PSEN1dE9)85Dbo
Name: transgene insertion 85, David R Borchelt
MGI accession ID: MGI:3524957
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(APPswe,PSEN1dE9)85Dbo
Marker name: transgene insertion 85, David R Borchelt
Chromosome: 9
Strain of origin: (C57BL/6 x C3H)F2
Expressed genes: APP,amyloid beta precursor protein,human; PSEN1,presenilin 1,human
Site of expression: Co-injected transgenes encoding a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9), both have independent mouse prion protein (PrP) promoter elements directing expression predominantly to CNS neurons.
Molecular note: Two transgenes inserted at a single locus in Chromosome 9 between Arpp21 and Pdcd6ip. Each transgene is controlled by the mouse prion promoter and contains a cDNA sequence. In one transgene the cDNA encodes a chimeric amyloid beta (A4) precursor protein (APPswe). In the second transgene the cDNA encodes the "DeltaE9" mutation of human presenilin 1. The DeltaE9 mutation of the human presenilin 1 gene is a deletion of exon 9 and corresponds to a form of early-onset Alzheimer's disease. The amyloid beta precursor protein coding sequences were altered by replacing mouse sequence encoding three amino acids of the A-beta domain with the human coding sequence for these residues. The chimeric amyloid beta (A4) precursor protein sequence was then further modified to encode the Swedish mutations K595N/M596L found in human. Both the transgenic peptide and holoprotein are detected by Signet Laboratories' monoclonal 6E10 antibody, which is specific for human sequence within this region. Human presenilin protein, which in high levels displaces detectable endogenous mouse protein, is immunodetected in the double transgenic mouse in whole brain protein homogenates. Human amyloid precursor protein is also immunodetected in these mice in whole brain protein homogenates. Transgene insertion occurred on Chr 9, causing a 1 bp duplication.
General note: Mice carrying this double transgene develop beta-amyloid deposits in the brain by 6 to 7 months of age.