129S4.Cg-Tg(APPSwe,tauP301L)1Lfa Psen1^tm1Mpm/LfaJ

Stock number: 031988
Product name: 3xTg-AD congenic 129S4 mice
Research areas: Developmental Biology Research, Mouse/Human Gene Homologs, Neurobiology Research, Research Tools

Description

These 3xTg-AD mice harbor a Psen1 mutation (M146V) and the co-injected APPSwe and tauP301L transgenes (Tg(APPSwe,tauP301L)1Lfa)), and may be useful for studying plaque and tangle pathology associated with synaptic dysfunction and Alzheimer's disease.

Of note, 3xTg-AD mice are available on a B6;129 genetic background (Stock No. 004807 B6;129-Tg(APPSwe,tauP301L)1Lfa Psen1^tm1Mpm/Mmjax), a 129S4 genetic background (Stock No. 031988 129S4.Cg-Tg(APPSwe,tauP301L)1Lfa Psen1^tm1Mpm/LfaJ) or a C57BL/6J-congenic background (Stock No. 033930 B6.Cg-Tg(APPSwe,tauP301L)1Lfa Psen1^tm1Mpm/2J).

Detailed description

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 for 3xTg‐AD mice on a C57BL/6;129 genetic background (see Stock No. 004807). We will modify the strain description if necessary as published results become available. Unless noted otherwise, the information below describes C57BL/6;129 genetic background 3xTg‐AD mice.

Mice homozygous for all three mutant alleles (3xTg-AD; homozygous for the Psen1 mutation and homozygous for the co-injected APPSwe and tauP301L transgenes (Tg(APPSwe,tauP301L)1Lfa)) are viable, fertile and display no initial gross physical or behavioral abnormalities. Translation of the overexpressed transgenes appears to be restricted to the central nervous system, notably in Alzheimer's disease-relevant areas including the hippocampus and cerebral cortex. The initial characterization of this mouse line indicated a progressive increase in amyloid beta peptide deposition, with intracellular immunoreactivity being detected in some brain regions as early as 3-4 months. Synaptic transmission and long-term potentiation are demonstrably impaired in mice 6 months of age. Between 12-15 months aggregates of conformationally altered and hyperphosphorylated tau are detected in the hippocampus. This mutant mouse exhibits plaque and tangle pathology associated with synaptic dysfunction, traits similar to those observed in Alzheimer's disease patients.

In February 2014, the donating investigator communicated that, in contrast to the initial observations, male transgenic mice may not exhibit the phenotypic traits originally described. No reports of diminished traits in female carriers have been reported.

Belfiore et al. 2019 Aging Cell 18:e12873 [PMID:30488653] characterized C57BL/6;129 genetic background 3xTg‐AD females for the onset, severity, and incidence of amyloidβ, phosphorylated tau, hippocampal and cortical plaques, neuroinflammation and cognitive decline. Most phenotypes that were evaluated were evident by 6 months of age. However, it was noted that cortical plaques were first detected at 12 months. For more detailed information, please see that publication. If any more detailed characterization is completed by The Jackson Laboratory, we will modify the strain description accordingly.

Development

Single-cell embryos from mice bearing the presenilin PS1M146V knock-in mutation on a mixed C57BL/6;129X1/SvJ;129S1/Sv genetic background (B6;129-Psen1^tm1Mpm) were co-injected with two independent mutant human transgenes; amyloid beta precursor protein (APPSwe) and microtubule-associated protein tau (tauP30IL). Both transgenes integrated at the same locus and are under the control of the mouse Thy1.2 regulatory element. Founder mice (line B1) were mated to B6;129-Psen1^tm1Mpm mice. Offspring from this cross were bred together, resulting in mice homozygous for all three alleles (3xTg-AD; homozygous for the Psen1 mutation and homozygous for the co-injected APPSwe and tauP301L transgenes, Tg(APPSwe,tauP301L)1Lfa). The mice were then backcrossed to 129/SvJaeSorMgr for 11 generations before being inter-crossed. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize 129S4/SvJaeJ oocytes (Stock No. 009104). The transgene inserted on Chromosome 2 causing a 3 bp deletion.

Allele

Symbol: Tg(APPSwe,tauP301L)1Lfa
Name: transgene insertion 1, Frank M LaFerla
MGI accession ID: MGI:2672831
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: Tg(APP*Swe,MAPT*P301L)1Lfa
Marker symbol: Tg(APPSwe,tauP301L)1Lfa
Marker name: transgene insertion 1, Frank M LaFerla
Chromosome: 2
Strain of origin: Not Specified
Expressed genes: MAPT,microtubule associated protein tau,human; APP,amyloid beta precursor protein,human
Molecular note: To develop a model of Alzheimer's Disease, mice harboring mutant human APP (Swedish double mutation; K670N, M671L) and MAPT (P301L) as well as Psen^tm1Mpm were generated by microinjection of the APP and MAPT transgenic constructs into single cell embryos harvested from mice homozygous for Psen1^tm1Mpm. Southern blot analysis indicated that both transgenic constructs integrated into the same site. Western blot analysis showed APP and MAPT levels to be ~4 fold higher in hemizygous mice and ~6 (APP) to ~7 (Mapt) fold higher homozygous mice, relative to non transgenic mice. Amyloid-Beta peptide (both 40 and 42) was detected in transgenic mice, with greater levels in homozygous mice than in hemizygous mice. Expression was confined to the CNS. Highest steady state levels of proteins were detected in Alzheimer's Disease related regions including the hippocampus and cerebral cortex. Transgenic protein was not detected in the cerebellum. The transgene inserted on Chr 2 causing a 3 bp deletion.

Allele

Symbol: Psen1^tm1Mpm
Name: targeted mutation 1, Mark P Mattson
MGI accession ID: MGI:1930937
Generation method: Targeted
Synonyms: PS1M146VKI^-; PS1KI; PS-1 M146V KI; PS1M146V
Marker symbol: Psen1
Marker name: presenilin 1
Chromosome: 12
Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Molecular note: Point mutations were introduced into the coding region of exon 5 that altered the codons corresponding to amino acids 145 and 146 from isoleucine and methionine to valine and valine, respectively, and a BstEII restriction site. A lox-P flanked neomycin cassette was also introduced into exon 4. F2 mice exhibited the expected polymorphism of the targeted allele when genomic DNA was amplified with exon 5 specific primers and the products were digested with the appropriate restriction enzyme. Northern blot analysis of total brain RNA using a Psen1 specific antibody showed that the targeted allele was expressed at normal physiological levels in homozygous mutant mice.