Double transgenic mice express a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) both directed to CNS neurons. These mice may be useful in studies of neurological disorders of the brain, specifically Alzheimers disease, amyloid plaque formation, and aging.
Dr. David R Borchelt, University of Florida
Double transgenic mice express 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 transgenic mice develop beta-amyloid deposits in the brains of transgenic animals 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).
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).Hemizygous mice, on the congenic C57BL/6J background (N13), 17-18 weeks in age, 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).
In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.
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 Alzheimers. 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 8 generations.
|Expressed Gene||APP, amyloid beta precursor protein, human|
|Expressed Gene||PSEN1, presenilin 1, human|
|Site of Expression|
|Allele Name||transgene insertion 85, David R Borchelt|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence)|
|Allele Synonym(s)||2xTg Ad; APP-PS1; APP/PS1; APPswe/PS1dE9; APPswe/PS1deltaE9; APdE9; Mo/Hu APPswe PS1dE9; Tg(APP*Swe,PSEN1*)85Dbo|
|Gene Symbol and Name||Tg(APPswe,PSEN1dE9)85Dbo, transgene insertion 85, David R Borchelt|
|Gene Synonym(s)||APP/PS1; APPswe/PS1dE9; APdE9; Mo/Hu APPswe PS1dE9|
|Promoter||Prn, prion protein readthrough transcript, mouse, laboratory|
|Expressed Gene||APP, amyloid beta precursor protein, human|
|Expressed Gene||PSEN1, presenilin 1, human|
|Strain of Origin||(C57BL/6 x C3H)F2|
|General Note||Mice carrying this double transgene develop beta-amyloid deposits in the brain by 6 to 7 months of age.|
|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.|
|Mutations Made By|| |
Dr. David Borchelt, University of Florida
When maintaining a live colony, hemizygous mice are bred to C57BL/6J. While the donating investigator indicates aggressive behavior has been observed (particularly for transgenic males) and transgenic females can exhibit suboptimal mothering of litters, no such complications have been observed in our colonies to date at The Jackson Laboratory (Jun 2006).
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