PDF(Pubmed)
Abstract：
Fundamental 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.
CRISPR/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.
Prior 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.
Marmosets 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.
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.
CRISPR/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.
Prior 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.
Marmosets 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.
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.
摘要：
背景：关于引发阿尔茨海默病（AD）的关键机制和促进其进展的因素的基本问题仍然存在。在这里，我们报告了成功产生的第一个基因工程的marmosets携带敲入（KI）点突变的早老素1（PSEN1）基因，可以从出生到整个生命周期进行研究。
方法：CRISPR/Cas9用于产生在PSEN1中具有C410Y或A426P点突变的Marmoset。创始人和他们的种系后代进行全面的纵向研究使用非侵入性措施，包括行为，生物标志物，神经影像学,和多组学签名。
结果：在成年之前，相对于非携带者,在PSEN1突变携带者中观察到血浆淀粉样β蛋白增加.对大脑的分析显示，成年前γ分泌酶复合物中几种酶-底物相互作用发生了变化。
结论：在PSEN1中携带KI点突变的Marmosets提供了研究最早的灵长类动物特异性机制的机会，这些机制有助于AD发病和进展的分子和细胞根本原因。
结论：我们报道了在PSEN1基因中成功产生了带有敲入点突变的基因工程小鼠。PSEN1猕猴桃及其种系后代概括了AD相关生物标志物的早期出现。在PSEN1猕猴中尽可能早地进行研究将能够识别驱动疾病进展的灵长类动物特异性机制。
方法：CRISPR/Cas9用于产生在PSEN1中具有C410Y或A426P点突变的Marmoset。创始人和他们的种系后代进行全面的纵向研究使用非侵入性措施，包括行为，生物标志物，神经影像学,和多组学签名。
结果：在成年之前，相对于非携带者,在PSEN1突变携带者中观察到血浆淀粉样β蛋白增加.对大脑的分析显示，成年前γ分泌酶复合物中几种酶-底物相互作用发生了变化。
结论：在PSEN1中携带KI点突变的Marmosets提供了研究最早的灵长类动物特异性机制的机会，这些机制有助于AD发病和进展的分子和细胞根本原因。
结论：我们报道了在PSEN1基因中成功产生了带有敲入点突变的基因工程小鼠。PSEN1猕猴桃及其种系后代概括了AD相关生物标志物的早期出现。在PSEN1猕猴中尽可能早地进行研究将能够识别驱动疾病进展的灵长类动物特异性机制。
