Modeling amyloid beta and tau pathology in human cerebral organoids.
Modeling amyloid beta and tau pathology in human cerebral organoids.
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DOI：
10.1038/s41380-018-0229-8
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发表时间：
2018-12
影响因子：
11
通讯作者：
Soto C
中科院分区：
文献类型：
--
作者：
Gonzalez C;Armijo E;Bravo-Alegria J;Becerra-Calixto A;Mays CE;Soto C
阿尔茨海默病(AD)患者大脑中观察到的典型异常包括突触改变、神经元死亡、脑部炎症以及以淀粉样斑块和神经原纤维缠结形式聚集的蛋白质聚集体。尽管已经开发了许多AD的动物和体外模型，但缺乏一种实验方法来完全概括人类细胞中这种疾病的基本方面。在这里，我们报道了一种研究AD的新模型的产生，该模型由人类诱导的多能干细胞(IPSCs)产生的脑器官(Cos)组成。在我们的实验条件下，CoS生长形成三维(3D)结构，其中包含具有皮质样组织的神经区。组织学和生化方法分析显示，家族性AD或唐氏综合征(DS)患者的IPSCs产生的有机类物质会随着时间的推移自发发展AD的病理特征，包括高度类似于淀粉样斑块的结构堆积和神经原纤维缠结。这些病理异常在各种对照中没有观察到，这些对照包括来自健康人的人IPSCs、来自克雅病患者的人IPSCs、小鼠胚胎干细胞(ESCs)或小鼠IPSCs。这些发现使得能够在人类细胞环境中对由患者特定干细胞体外发育的3D皮质样组织中的遗传AD进行建模。与现有方法相比，该系统提供了更相关的疾病模型，并为发现新的靶点和筛选治疗干预药物提供了新的平台。
The typical abnormalities observed in the brain of Alzheimer’s disease (AD) patients include synaptic alterations, neuronal death, brain inflammation, and the accumulation of protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Despite the development of many animal and in vitro models for AD, there is a lack of an experimental approach that fully recapitulates essential aspects of the disease in human cells. Here, we report the generation of a new model to study AD, consisting of cerebral organoids (COs) produced from human-induced pluripotent stem cells (iPSCs). Under our experimental conditions, COs grow to form three-dimensional (3D) structures containing neural areas with cortical-like organization. Analysis of COs by histological and biochemical methods revealed that organoids produced from iPSCs derived from patients affected by familial AD or Down syndrome (DS) spontaneously develop over time pathological features of AD, including accumulation of structures highly reminiscent to amyloid plaques and neurofibrillary tangles. These pathological abnormalities were not observed in COs generated from various controls, including human iPSCs from healthy individuals, human iPSCs from patients affected by Creutzfeldt–Jakob disease, mouse embryonic stem cells (ESCs), or mouse iPSCs. These findings enable modeling genetic AD in a human cellular context in a 3D cortical-like tissue developed in vitro from patient-specific stem cells. This system provides a more relevant disease model compared to pre-existing methods and offers a new platform for discovery of novel targets and screening of drugs for therapeutic intervention.
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影响因子：
64.8
作者：
Israel, Mason A.;Yuan, Shauna H.;Bardy, Cedric;Reyna, Sol M.;Mu, Yangling;Herrera, Cheryl;Hefferan, Michael P.;Van Gorp, Sebastiaan;Nazor, Kristopher L.;Boscolo, Francesca S.;Carson, Christian T.;Laurent, Louise C.;Marsala, Martin;Gage, Fred H.;Remes, Anne M.;Koo, Edward H.;Goldstein, Lawrence S. B.
通讯作者：
Goldstein, Lawrence S. B.
影响因子：
8.8
作者：
Moore S;Evans LD;Andersson T;Portelius E;Smith J;Dias TB;Saurat N;McGlade A;Kirwan P;Blennow K;Hardy J;Zetterberg H;Livesey FJ
通讯作者：
Livesey FJ
影响因子：
25
作者：
Musiek, Erik S.;Holtzman, David M.
通讯作者：
Holtzman, David M.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2.5
作者：
Armijo, Enrique;Gonzalez, Cesar;Soto, Claudio
通讯作者：
Soto, Claudio