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.
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.
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.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Synaptic Loss
- Changes in LTP/LTD
- Cognitive Impairment
No plaques observed up to 2 years of age.
No tangles observed up to 2 years of age.
Changes in LTP/LTD
Last Updated: 22 Oct 2020
Research Models Citations
No Available Further Reading