Mutations: PSEN1 P264L
Modification: PSEN1: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: R1 line of the ES cells (129 mouse strain)
The PS1 P264L knock-in mouse line was derived using a two-step mutagenesis strategy similar to that used to generate the TgAPPSwe-KI line (Reaume et al., 1996). An advantage to this model is the mutant PSEN1 is expressed at normal levels and under endogenous cell-specific and developmental regulation. Neuropathology is not observed in these animals and primary cortical neurons derived from PSEN1 homozygous mutant knock-in mice exhibit basal levels of neurodegeneration comparable to mice expressing wild-type PSEN1. Sensitivity to staurosporine and Aβ42 was not affected, with comparable levels of apoptosis. Similarly, glutamate-induced neuronal necrosis was unaffected (Siman et al., 2000).
This line was crossed with lines expressing APP, including the Tg2576 model, which overexpress human APP with the Swedish mutation, and the line TgAPPswe-KI, which have a targeted knock-in of the Swedish mutation and a "humanized" Aβ domain. When crossed with Tg2576 mice, homozygous knock-in of the PSEN1 P264L mutation increased Aβ42 nearly 3-fold, but did not alter total Aβ or Aβ40 levels, resulting in an elevated Aβ42/Aβ40 ratio evident in one month-old mice. The bigenic mice also had marked acceleration in the onset of amyloid deposition (about four months) and reactive gliosis compared to Tg2576 mice alone (Siman et al., 2000).
An exon replacement strategy was used to generate mice carrying a targeted mutation in the endogenous PSEN1 gene. A proline-to-leucine substitution was targeted to codon 264 in exon 8 by homologous recombination in embryonic stem cells. A Cre-lox system was used to remove the neomycin selection cassette from the targeted gene.
Research Models Citations
- Reaume AG, Howland DS, Trusko SP, Savage MJ, Lang DM, Greenberg BD, Siman R, Scott RW. Enhanced amyloidogenic processing of the beta-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer's disease mutations and a "humanized" Abeta sequence. J Biol Chem. 1996 Sep 20;271(38):23380-8. PubMed.
- Siman R, Reaume AG, Savage MJ, Trusko S, Lin YG, Scott RW, Flood DG. Presenilin-1 P264L knock-in mutation: differential effects on abeta production, amyloid deposition, and neuronal vulnerability. J Neurosci. 2000 Dec 1;20(23):8717-26. PubMed.
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