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- W2981043714 abstract "Alzheimer's disease (AD) is the most common cause of dementia worldwide. A small number of patients with autosomal-dominant inheritance are known to carry mutations in Amyloid precursor protein (App) or PRESENILIN-1 (PSEN1) genes. Knock-in mice with those familial AD-related mutations have several advantages over overexpressing transgenic mice. Because conventional gene targeting technology is time-consuming and inapplicable to some cases, we have utilized a novel RNA-guided gene editing technology based on the CRISPR/Cas9 system to generate new AD mouse models. The Cas9 nucleases fused with a cytidine deaminase, named Base editor (BE) and Target-AID, are known to efficiently substitute the target C to T (or G to A) under presence of targeting RNAs (single guide RNA, sgRNA). We designed several sgRNAs targeting mouse App or Psen1, and injected them with BE mRNA or Target-AID mRNA into mouse zygotes. Two out of 43 mice that were injected with BE had a P436S mutation (4.7%), and 14 had a P436L mutation (32.6%). On the other hand, one out of 34 mice that were edited by Target-AID had a P436S mutation (2.9%). When we targeted PS1-P117 using a mutant version of BE, we were able to generate multiple mouse lines harboring various point mutations which were familial AD-related (such as PS1-P117L, and -P117S) and unrelated (such as PS1-P117V). These mice showed elevation of Aβ42: Aβ40 ratio in brain, which is one of the key pathologic changes in AD. Interestingly, not only PS1-P436S and -P117L mice, but also PS1-P436L mice exhibited pathological features characteristic of amyloid β (Aβ) production in the brain, suggesting that the PS1-P436L mutation is likely pathogenic although it has not been clinically identified as a familial AD-causing mutation. BE and Target-AID enable us to generate animal models with high efficiency in a short time. Using a similar strategy, we will try to generate a non-human primate model of AD." @default.
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- W2981043714 date "2019-07-01" @default.
- W2981043714 modified "2023-09-27" @default.
- W2981043714 title "P2-076: GENERATION OF AD ANIMAL MODELS USING A NOVEL RNA-GUIDED GENE EDITING TECHNOLOGY" @default.
- W2981043714 doi "https://doi.org/10.1016/j.jalz.2019.06.2483" @default.
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