Research Models

App knock-in (humanized Aβ) (Leuven); Psen1 knock-in (M139T)

Synonyms: Apphu/hu;Psen1M139T+/+

Species: Rat
Genes: App, Psen1
Mutations: PSEN1 M139T
Modification: App: Knock-In; Psen1: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: Long Evans
Availability: Available through Lutgarde Serneels.

Summary

Apphu/hu;Psen1M139T+/+ rats carry a humanized Aβ sequence within the rat App gene and the AD-linked M139T mutation in the rat Psen1 gene. These knock-in animals are homozygous for both humanized App and Psen1 M139T.

Levels of APP and its metabolites have been measured in the brains of 14-week-old rats. The amount of full-length APP did not differ between Apphu/hu;Psen1M139T+/+, Apphu/hu (rats homozygous for the humanized Aβ sequence, but without the Psen1 mutation), and wild-type rats. The brains of Apphu/hu;Psen1M139T+/+ knock-ins, similar to Apphu/hu rats, contained approximately four times more CTFβ than wild-type animals. The levels of total soluble Aβ (Aβ38, Aβ40, Aβ42, and Aβ43) were also similar in Apphu/hu;Psen1M139T+/+and Apphu/hu brains, although the presence of the Psen1 mutation increased the proportion of Aβ42. Both knock-in lines produced more Aβ than did wild-type rats.

Levels of tau (total, 3R, or 4R isoforms) did not differ between Apphu/hu;Psen1M139T+/+, Apphu/hu and wild-type rats at 14 weeks. However, levels of 3R tau decreased over time in the knock-in lines, accompanied by the appearance of phospho-tau recognized by monoclonal antibody AT100.

No plaques or tangles were observed up to 2 years of age.

Modification Details

Crispr/Cas9 was used to introduce the M139T mutation into the endogenous rat Psen1 gene. Rats carrying the Psen1 mutation were crossed with Apphu/hu rats to establish a colony homozygous for the humanized App gene and heterozygous for Psen1 M139T. Animals from this colony were used to produce rats homozygous for both humanized APP and the Psen1 M139T mutation.

 

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Plaques
  • Tangles

No Data

  • Neuronal Loss
  • Gliosis
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

No plaques observed up to 2 years of age.

Tangles

No tangles observed up to 2 years of age.

Neuronal Loss

No data.

Gliosis

No data.

Synaptic Loss

No data.

Changes in LTP/LTD

No data.

Cognitive Impairment

No data.

Last Updated: 22 Oct 2020

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References

Mutations Citations

  1. PSEN1 M139T

Research Models Citations

  1. App knock-in (humanized Aβ) (Leuven)

External Citations

  1. Lutgarde Serneels

Further Reading

No Available Further Reading