These TetAPPswe/ind mice express human APP bearing the Swedish and Indiana mutations in a tet-responsive manner. Amyloid pathology is observed when the transgene is expressed. This strain has been shown to be useful in studies correlating temporal expression of mutant APP expression with Alzheimer's-like amyloid pathology.
Dr. David R Borchelt, University of Florida
Hemizygotes for this tetO-APPswe/ind transgene are viable and fertile. These transgenic mice express a chimeric mouse/human amyloid precursor protein (APP695) bearing the Swedish (KM570/571NL) and Indiana (V617F) mutations associated with Alzheimer's disease (APP695swe/ind) under the control of a tetracycline-responsive promoter element (TRE; tetO). When hemizygotes are bred with another transgenic mouse expressing either reverse tetracycline-controlled transactivator protein (rtTA) or tetracycline-controlled transactivator protein (tTA) under the regulation of a tissue-specific promoter, APP695swe/ind expression can be regulated in the appropriate tissue of the bitransgenic offspring with the tetracycline analog doxycycline (dox). These tetO-APPswe/ind transgenic mice may be useful in studies of Alzheimer's disease and other neurodegenerative diseases.
For example, when bred to a strain expressing tTA in brain tissues (Tg(Camk2a-tTA)1Mmay), bi-transgenic offspring show 10-30 fold greater transgenic APP695swe/ind protein expression than endogenous levels and nearly complete suppression following dox treatment. The donating investigators report some differences in APP695swe/ind expression in bi-transgenic offspring dependent upon which APP695swe/ind founder line was used; line 885 (B6.Cg-Tg(tetO-APPSwInd)885Dbo/Mmjax) shows the highest APP695swe/ind expression with greater dox requirements for transgene suppression, line 102 (B6.Cg-Tg(tetO-APPSwInd)102Dbo/Mmjax) has the greatest sensitivity to dox, and line 107 (B6.Cg-Tg(tetO-APPSwInd)107Dbo/Mmjax) and line 18 are similarly intermediate.
Note that tet alone may affect neuronal degeneration and behavioral phenotypes, depending on the genetic background used (see Han et al, J. Neurosci., 2012).
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. 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.
The mouse amyloid beta (A4) precursor protein (App) sequence was first modified to contain a humanized amyloid-beta (Abeta) domain. This mouse/human chimeric APP (called mo/huAPP695 or APP695) was further mutated to incorporate the Swedish (KM570/571NL) and Indiana (V617F) mutations associated with Alzheimer's disease. This APP695swe/ind sequence was placed downstream of the tetracycline-responsive (TRE; tetO) promoter and mouse prion protein exons 1-2. The complete tetracycline-responsive APP695swe/ind transgene (tet-APPswe/ind) was injected into the pronucleus of fertilized eggs from (C57BL/6J x C3HeJ) F1 matings. Transgene positive founders (line 885) were bred to transgenic Camk2a-tTA mice (B6;CBA-Tg(Camk2a-tTA)1Mmay/J) on a B6;CBA mixed genetic background. After 3-4 generations of brother-sister matings, mice harboring only the tet-APPswe/ind transgene were selected and backcrossed to C57BL/6 for at least 10 generations prior to arrival at the MMRRC at The Jackson Laboratory.
|Expressed Gene||APP, amyloid beta precursor protein, human|
|Site of Expression|
|Allele Name||transgene insertion 885, David R Borchelt|
|Allele Type||Transgenic (Humanized sequence, Inducible, Inserted expressed sequence)|
|Allele Synonym(s)||TetAPPswe/ind line 885; Tg(tetO-APP*Swe*Ind)885Dbo|
|Gene Symbol and Name||Tg(tetO-APPSwInd)885Dbo, transgene insertion 885, David R Borchelt|
|Gene Synonym(s)||TetAPPswe/ind line 885; Tg(tetO-APPSwInd)8-85Dbo|
|Promoter||tetO, tet operator,|
|Expressed Gene||APP, amyloid beta precursor protein, human|
|Strain of Origin||(C57BL/6J x C3H/HeJ)F2|
|General Note||Founder line 8-85 is the highest expressing line, and is representative of a number of lines made with this construct.|
|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 tetracycline-responsive element (tetO). When bred to another transgenic mouse expressing reverse tertracyclin-controlled transactivator protein (rtTA) or tetracycline-controlled transactivator protein (fTA) to creat a bitransgenic animal, tissue APPSwInd transgene expression can be regulated with the tetracycline analog, doxycycline. These double transgenic show the highest APPSwInd expression and have the highest doxycycline requirements for suppression of transgene expression.|
|Mutations Made By|| |
Dr. David Borchelt, University of Florida
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