Research Models

PSEN1(M146V) Knock-In

Synonyms: PS1M146V KI, PS1M146VKI, The Miles W. Miller Mouse

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Species: Mouse
Genes: PSEN1
Mutations: PSEN1 M146V
Modification: PSEN1: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.129-Psen1tm1Mpm/J
Genetic Background: C57BL/6
Availability: The Jackson Lab: Stock# 004193; Cryopreserved

Summary

These mice expresses human PSEN1 with the M146V mutation, which is associated with familial Alzheimer's disease. These mice are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Homozygous mice produce only the mutant gene product (PSEN1 M146V). Although PSEN1(M146V) knock-in mice have no overt mutant phenotype, they are hypersensitive to kainate-induced degeneration and death of CA3, CA1 and hilar neurons with significantly accelerated and increased degeneration compared to wild-type mice. Cultured hippocampal neurons have increased vulnerability to death induced by glutamate, disrupted calcium homeostasis, increased oxidative stress and mitochondrial dysfunction (Guo et al., 1999). On a PSEN1 null background, the expression of PSEN1(M146V) resulted in impaired hippocampal-dependent associative learning, as measured by a contextual fear conditioning paradigm at three months of age, as well as reduced adult neurogenesis in the dentate gyrus (Wang et al., 2004).

Modification Details

Point mutations were introduced into exon 5 of the endogenous mouse PSEN1 gene altering the codons corresponding to amino acids 145 and 146 from isoleucine and methionine to valine and valine, respectively. The targeting vector contained a lox-P flanked neomycin resistance cassette and herpes simplex virus thymidine kinase genes.

Last Updated: 06 Apr 2022

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References

Paper Citations

  1. Guo Q, Fu W, Sopher BL, Miller MW, Ware CB, Martin GM, Mattson MP. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med. 1999 Jan;5(1):101-6. PubMed.
  2. Wang R, Dineley KT, Sweatt JD, Zheng H. Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience. 2004;126(2):305-12. PubMed.

External Citations

  1. The Jackson Lab: Stock# 004193

Further Reading