INTRODUCTIONFundamental questions remain about the key mechanisms that initiate Alzheimer's disease (AD) and the factors that promote its progression. Here we report the successful generation of the first genetically engineered marmosets that carry knock‐in (KI) point mutations in the presenilin 1 (PSEN1) gene that can be studied from birth throughout lifespan.METHODSCRISPR/Cas9 was used to generate marmosets with C410Y or A426P point mutations in PSEN1. Founders and their germline offspring are comprehensively studied longitudinally using non‐invasive measures including behavior, biomarkers, neuroimaging, and multiomics signatures.RESULTSPrior to adulthood, increases in plasma amyloid beta were observed in PSEN1 mutation carriers relative to non‐carriers. Analysis of brain revealed alterations in several enzyme–substrate interactions within the gamma secretase complex prior to adulthood.DISCUSSIONMarmosets carrying KI point mutations in PSEN1 provide the opportunity to study the earliest primate‐specific mechanisms that contribute to the molecular and cellular root causes of AD onset and progression.Highlights We report the successful generation of genetically engineered marmosets harboring knock‐in point mutations in the PSEN1 gene. PSEN1 marmosets and their germline offspring recapitulate the early emergence of AD‐related biomarkers. Studies as early in life as possible in PSEN1 marmosets will enable the identification of primate‐specific mechanisms that drive disease progression.

中文翻译：

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PSEN1 突变狨猴中常染色体显性阿尔茨海默病的早期分子事件

引言 关于引发阿尔茨海默病 (AD) 的关键机制以及促进其进展的因素，仍然存在一些基本问题。在此，我们报告了第一批基因工程狨猴的成功培育，这些狨猴在早老素 1 中携带敲入 (KI) 点突变（PSEN1）基因，可以从出生到整个生命周期进行研究。方法CRISPR/Cas9被用来生成具有C410Y或A426P点突变的狨猴PSEN1。使用包括行为、生物标志物、神经影像学和多组学特征在内的非侵入性措施对创始人及其种系后代进行全面的纵向研究。结果在成年之前，相对于非携带者，观察到 PSEN1 突变携带者的血浆淀粉样蛋白有所增加。对大脑的分析揭示了成年前伽玛分泌酶复合物内几种酶-底物相互作用的变化。讨论狨猴在体内携带 KI 点突变PSEN1提供了研究最早的灵长类特异性机制的机会，这些机制有助于 AD 发病和进展的分子和细胞根源。 我们报告了成功培育出带有 PSEN1 基因敲入点突变的基因工程狨猴。 PSEN1 狨猴及其种系后代概括了 AD 相关生物标志物的早期出现。 尽早对 PSEN1 狨猴进行研究将能够识别驱动疾病进展的灵长类特异性机制。