These mice carry a targeted mutation of the mouse Psen1 gene that results in expression of a presenilin-1 protein with the human familial Alzheimer's disease-linked mutation PS1M146V.
George M Martin, University of Washington
The targeted allele (PS1M146VKI) causes a mutation of the mouse Psen1 gene that results in expression of a presenilin-1 protein with the human familial Alzheimer's disease-linked mutation PS1M146V. The neo cassette was deleted from the targeted allele (using a CMV-Cre transgenic line of mice). Published findings indicate that this alteration should not influence the level of expression of mutant PS1. Northern blot analysis and RT-PCR determined mRNA expression of the targeted mutant allele is normal. Homozygous PS1M146VKI mice produce only the mutant gene product. Mice that express this targeted allele are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Neurodegeneration seen in wild-type mice caused by excitotoxin kainate treatment is increased and accelerated in this mutant strain. Cultured cells expressing the mutant protein exhibit perturbed neuronal calcium homeostasis. This mutant mouse strain represents a model that may be useful in studies of familial Alzheimer's disease in humans.
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was utilized in constructing this mutant. A mutagenized DNA sequence of exon 5 of the mouse Psen1 gene was targeted for the Psen1 allele. The construct was electroporated into 129X1/SvJ x 129S1/Sv-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric male animals were bred to C57BL/6 females to produce mice heterozygous for the mutation. These mice were then bred to a CMV-cre transgenic strain to delete the neo cassette from the targeted allele.
|Allele Name||targeted mutation 1, Mark P Mattson|
|Allele Synonym(s)||PS-1 M146V KI; PS1KI; PS1M146V; PS1M146VKI-|
|Gene Symbol and Name||Psen1, presenilin 1|
|Promoter||Psen1, presenilin 1, mouse, laboratory|
|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.|
|Mutations Made By|| |
George Martin, University of Washington
This strain originated on a B6;129 background, and has been backcrossed to C57BL/6 for at least 7 generations (11/01).
When using the PS1M146VKI mouse strain in a publication, please cite the originating article(s) and include JAX stock #004193 in your Materials and Methods section.