Modification: PSEN1: Knock-Out
Disease Relevance: Alzheimer's Disease
Strain Name: B6;129P-Psen1tm1Vln/J
Genetic Background: Origin: 129P2/OlaHsd; backcrossed to C57BL/6
Availability: Jackson Labs: Stock# 007605; Cryopreserved
A targeting vector containing a neomycin resistance gene was inserted downstream of exon 7 of PSEN1; loxP sites were inserted on both sides of exon 7 and downstream of the neomycin resistance gene.
These floxed mice can be used to generate animals with conditional knock-out of Presenilin-1. They can be crossed with strains expressing Cre recombinase to target the gene deletion to specific cell types, such as post-natal neurons (see Jackson labs Stock# 006143). When bred to mice that express Cre recombinase, progeny can have one of three genotypes: only exon 7 deleted, only the neomycin selection cassette deleted, or both exon 7 and the neomycin selection cassette deleted, in the Cre-expressing cells. Mice that are homozygous for this allele are viable, fertile, normal in size, and do not display any gross physical or behavioral abnormalities.
When PS1-flox mice are crossed with those expressing Cre recombinase under the control of the Thy-1 promoter, mice with specific deficiency of PS1 in post-natal neurons are generated, PS1(n-/-). Unlike mice with complete PSEN1 deficiency, which are late embryonic lethal due to skeletal defomation, CNS hemorrhage, and deficiencies in neurogenesis and neuronal survival (Wong et al., 1997; Shen et al., 1997), PS1(n-/-) mice are born at the expected mendelian frequency and are viable and fertile with no gross brain abnormalities or premature lethality. PS1(n−/−) mice have decreased murine Aβ40 and Aβ42 and accumulate C-terminal fragments of APP. They do not have cognitive deficits as measured by an object recognition task, but do have slightly abnormal LTP induction relative to control animals (Dewachter et al., 2002).
- Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, van der Ploeg LH, Sisodia SS. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature. 1997 May 15;387(6630):288-92. PubMed.
- Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997 May 16;89(4):629-39. PubMed.
- Dewachter I, Reversé D, Caluwaerts N, Ris L, Kuipéri C, Van den Haute C, Spittaels K, Umans L, Serneels L, Thiry E, Moechars D, Mercken M, Godaux E, Van Leuven F. Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J Neurosci. 2002 May 1;22(9):3445-53. PubMed.
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