A.129(B6)-Tg(APPSw)40Btla/Mmjax

Stock number: 006555
Strain synonyms: A-R1.40
Research areas: Mouse/Human Gene Homologs, Neurobiology Research, Research Tools

Description

These R1.40 transgenic mice express all mRNA and protein isoforms of the human amyloid beta (A4) precursor protein APP containing the Familial Alzheimer's Disease (FAD) Swedish mutation K670N/M671L, and may be useful in studying the pathogenesis of Familial Alzheimer's Disease and possible therapeutic treatments.

Detailed description

These R1.40 transgenic mice express all mRNA and protein isoforms of the human amyloid beta (A4) precursor protein APP containing the Familial Alzheimer's Disease (FAD) Swedish mutation K670N/M671L. Transgene expression (mRNA and full-length protein) is 2 to 3 fold the endogenous mouse App expression level in the hemizygous state in brain tissue as revealed by RT-PCR and Western Blot analysis. Transgene expression pattern mimics endogenous mouse gene expression patterns. The donating investigator reports increased mortality in young homozygous animals (higher incidence in females). 3 to 4 month old transgenic mice, maintained on a C57BL/6J background, exhibit spontaneous seizure-like events (abnormal spiking) in EEG readings, without abnormal behavior and are more susceptible to kainic acid induced seizures (Vogt et al. Neurobiol Aging 2009). These R1.40 transgenic mice may be useful in studying the pathogenesis of Familial Alzheimer's Disease and possible therapeutic treatments.

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. A publication (Lehman et al. 2003 Hum Mol Genet 12:2949) compares the well characterized B6-R1.40 strain (B6.129-Tg(APPSw)40Btla/Mmjax) with two additional congenic strains, D2-R1.40 (D2.129(B6)-Tg(APPSw)40Btla/Mmjax) and 129S1-R1.40 (129S1.129(Cg)-Tg(APPSw)40Btla/Mmjax). While these three congenic strains have similar levels of holo-APP in brain tissue, the levels of brain APP C-terminal fragments (CTFs) vary depending upon genetic background. Brain and plasma levels of amyloid beta-40 and -42 are variable as well (B6-R1.40 > 129S1-R1.40 > D2-R1.40). In addition, the congenic strains exhibited dramatic alterations in the age of onset of amyloid beta deposition; in contrast to 14 month old homozygous B6-R1.40 mice, homozygous D2-R1.40 and 129S1-R1.40 mice do not develop amyloid beta deposits in the parietal or frontal cortex even by 20 months of age. The donating investigator further reports that the A-R1.40 strain (A.129(B6)-Tg(APPSw)40Btla/Mmjax) exhibits levels of amyloid beta comparable to the B6-R1.40 strain, but with later onset. Therefore, APP processing and amyloid beta metabolism and deposition are modified by the genetic background. While the 129S1-R1.40 strain can be easily maintained as homozygotes, the donating investigator reports increased mortality in young homozygotes on the other genetic backgrounds, with D2-R1.40 and A-R1.40 more severely affected than B6-R1.40.

Development

A 650 kb YAC transgene containing the entire human amyloid beta (A4) precursor protein (APP) gene, and approximately 250 kb of flanking sequence, was altered to include the Swiss mutation K670N/M671L associated with Familial Alzheimer's Disease (FAD). This transgene was injected into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Founder animals (line R1.40) were established and bred to C57BL/6J for eight generations. After this, transgenic mice were bred to A/J for at least 21 generations prior to arrival at the MMRRC at The Jackson Laboratory. This transgene inserted on Chromosome 13.

Allele

Symbol: Tg(APPSw)40Btla
Name: transgene insertion 40, Bruce Lamb
MGI accession ID: MGI:3510594
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(APPSw)40Btla
Marker name: transgene insertion 40, Bruce Lamb
Chromosome: 13
Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Expressed genes: APP,amyloid beta precursor protein,human
Molecular note: The transgenic insertion comprises four to eight copies of a 650-kb YAC containing the entire 400-kb human amyloid precursor protein gene with the Swiss familial Alzheimer disease (FAD) mutation and approximately 250 kb of flanking human DNA. The double mutation (K670N/M671N) comprises a G-to-A transition converting the lysine codon at position 670 to an asparagine codon and an A-to-C transversion replacing the methionine at amino acid 671 with leucine. RT-PCR and western blot analysis revealed that hemizygous transgenic mice express all major human APP mRNA and protein isoforms in brain, in parallel with the corresponding mouse versions, at approximately three times the levels of the latter. Total brain levels of the Alzheimer disease- associated 42-amino acid amyloid-beta peptide detected by ELISA are 7-8-fold and 15-20-fold higher, respectively, in mice hemizygous and homozygous for the mutant gene than in hemizygotes for the wildtype human gene. Levels of a cell-associated, beta-secretase-generated 13.5 kDa C-terminal peptide containing the amyloid beta domain and of soluble amyloid beta peptides are significantly elevated in brains of mice with the mutant, versus wildtype, transgene, while alpha-secretase products are diminished.