Modification: App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: Long Evans
Availability: Available through Lutgarde Serneels.
Apphu/hu rats carry a humanized Aβ sequence within the rat App gene. In this knock-in model, created using CRISPR/Cas9 technology, expression of App is driven by its natural promoter and is expected to show normal cell-type and temporal specificity. Levels of APP are similar in the brains of Apphu/hu and wild-type rats, but the knock-in rats contain more CTFβ, consistent with more efficient BACE1 processing of human APP than rodent APP.
Levels of APP and its metabolites have been measured in the brains of 14-week-old rats. As mentioned, the amount of full-length APP did not differ between Apphu/hu and wild-type rats. However, brains of the knock-in animals contained approximately four times more CTFβ and about two-thirds less CTFα than wild-type controls. Levels of Aβ40 nearly tripled in the knock-ins compared with wild-type rats. Aβ38 and Aβ42 were not detectable in wild-type animals but were present at measurable levels in the knock-in animals, as was Aβ43.
Levels of tau (total, 3R, or 4R isoforms) did not differ between Apphu/hu and wild-type rats at 14 weeks. However, levels of 3R tau decreased over time in the knock-in line, accompanied by the appearance of phospho-tau recognized by monoclonal antibody AT100.
No plaques or tangles were observed up to two years of age.
These rats have served as controls for studies examining the effects of an AD-related Psen1 mutation (Serneels et al., 2020).
CRISPR/Cas9 was used to introduce the following mutations into the endogenous App gene: G676R (G5R), F681Y (F10Y), R684H (R13H), numbered according to the 770 amino-acid isoform of human APP (position within the Aβ sequence).
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
- Serneels L, T'Syen D, Perez-Benito L, Theys T, Holt MG, De Strooper B. Modeling the β-secretase cleavage site and humanizing amyloid-beta precursor protein in rat and mouse to study Alzheimer's disease. Mol Neurodegener. 2020 Oct 19;15(1):60. PubMed.
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