B6;C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax

Stock number: 004462
Product name: APP/PS1
Research areas: Mouse/Human Gene Homologs, 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. This "humanized" Mo/HuAPP695swe protein is immunodetected in whole brain protein homogenates. The transgenic mutant human presenilin protein (PS1-dE9), which in high levels displaces detectable endogenous mouse protein, is also immunodetected in whole brain protein homogenates. The donating investigator reports that transgenic mice develop beta-amyloid deposits in brain by 6 to 7 months of age. Between 6 and 15 months of age, mice exhibit a gender-based disparity in beta-amyloid burden. Females develop a 5-fold (Aβ₄₂) and 10-fold (Aβ₄₀) increase in beta-amyloid deposits in the cerebellum by 15 months as compared to males. Accumulation of plaques is more abundant in the molecular layer than in the granular layer. In the cortex, the beta-amyloid burden is increased in both sexes in parallel (Ordonez-Guiterrez et al. Jnl Alz Dis 2016).

APP/PS1 hemizygotes on a C57BL/6;C3H genetic background (Stock No. 004462) do not exhibit any seizure phenotype. These animals also display a slight alteration in their tail phenotype (e.g., kinked tail) that is believed to be due to the mixed genetic background of the strain and is not related to transgene expression. This strain does not carry the retinal degeneration allele Pde6b^rd1.

In contrast, APP/PS1 hemizygotes on a C57BL/6J-congenic background (see Stock No. 005864) exhibit seizure activity. Specifically, hemizygous mice on the C57BL/6 background (N9B6) exhibit a high incidence of seizures, as detected by video-EEG. 25% of transgenic mice, 3 to 3.5 months in age, exhibit at least 1 seizure. By 4.5 months of age, seizure incidence increases to 55%. 10-15% mortality is reported for transgenic mice on the congenic (N9) C57BL/6 background (Minkeviciene et al. J Neurosci. 2009). At 17-18 weeks of age, hemizygous mice on the congenic C57BL/6J background (N13) exhibit epileptiform discharges as detected by video-EEG. Mortality was 38% (6/16) and some mutant mice experienced spontaneous seizures during the experiments. Antiepileptic drugs (carbamazepine, phenytoin, valproate) reduce the frequency of spontaneous electrographic epileptiform discharges (Ziyatdinova et al. Epilepsy Res 2011).

Development

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 (also called 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 (C57BL/6 x C3H)F2 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. To avoid re-introduction of the Pde6b^rd1 allele, we do not recommend breeding to B6C3F1/J (Stock#100010). 

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.