Chimeric cerebral organoids reveal the essentials of neuronal and astrocytic APOE4 for Alzheimer's tau pathology.
Chimeric cerebral organoids reveal the essentials of neuronal and astrocytic APOE4 for Alzheimer's tau pathology.
复制标题
嵌合脑类器官揭示了神经元和星形细胞 APOE4 在阿尔茨海默病 tau 病理学中的本质
DOI：
10.1038/s41392-022-01006-x
复制
发表时间：
2022-06-13
影响因子：
39.3
通讯作者：
Pei, Gang
中科院分区：
文献类型：
--
作者：
Huang, Shichao;Zhang, Zhen;Cao, Junwei;Yu, Yongchun;Pei, Gang
载脂蛋白E4（APOE4）基因型是阿尔茨海默病（AD）最强的遗传危险因素之一，并且通常被认为在各种类型的脑细胞中引起广泛的病理改变。在这里，我们开发了一种新的工程方法来创建嵌合人脑类器官（chCO），以评估APOE4在神经元和星形胶质细胞中的不同作用。首先，将星形胶质细胞因子NFIB和SOX 9引入诱导多能干细胞（iPSC）中以加速星形胶质细胞的诱导。然后将上述诱导的iPSC与未感染的iPSC在脑类器官的标准培养条件下混合并共培养。正如预期的那样，早在45天就检测到功能性星形胶质细胞，并且与对照人脑类器官（hCO）相比，它有助于更多的神经元在chCO中成熟。更有趣的是，这种方法使我们能够产生含有不同基因型（即APOE3或APOE4）的神经元和星形胶质细胞的chCO。然后，在chCO中发现星形胶质细胞APOE4已经显著促进神经元中的脂滴形成和胆固醇积累，而星形胶质细胞和神经元APOE4均有助于最大效果。最值得注意的是，我们观察到星形胶质细胞和神经元APOE4的共同出现是chCO中神经元磷酸化tau水平升高所必需的，而在具有神经元APOE4的chCO中Aβ水平升高。总之，我们的结果不仅揭示了神经元和星形胶质细胞APOE4对tau病理学的本质，而且还表明chCO是AD研究和药物发现的有价值的病理模型。
The apolipoprotein E4 (APOE4) genotype is one of the strongest genetic risk factors for Alzheimer’s disease (AD), and is generally believed to cause widespread pathological alterations in various types of brain cells. Here, we developed a novel engineering method of creating the chimeric human cerebral organoids (chCOs) to assess the differential roles of APOE4 in neurons and astrocytes. First, the astrogenic factors NFIB and SOX9 were introduced into induced pluripotent stem cells (iPSCs) to accelerate the induction of astrocytes. Then the above induced iPSCs were mixed and cocultured with noninfected iPSCs under the standard culturing condition of cerebral organoids. As anticipated, the functional astrocytes were detected as early as 45 days, and it helped more neurons matured in chCOs in comparation of the control human cerebral organoids (hCOs). More interestingly, this method enabled us to generate chCOs containing neurons and astrocytes with different genotypes, namely APOE3 or APOE4. Then, it was found in chCOs that astrocytic APOE4 already significantly promoted lipid droplet formation and cholesterol accumulation in neurons while both astrocytic and neuronal APOE4 contributed to the maximum effect. Most notably, we observed that the co-occurrence of astrocytic and neuronal APOE4 were required to elevate neuronal phosphorylated tau levels in chCOs while Aβ levels were increased in chCOs with neuronal APOE4. Altogether, our results not only revealed the essence of both neuronal and astrocytic APOE4 for tau pathology, but also suggested chCOs as a valuable pathological model for AD research and drug discovery.
登录
查看更多内容
影响因子：
16.2
作者：
Kim, Jungsu;Basak, Jacob M.;Holtzman, David M.
通讯作者：
Holtzman, David M.
影响因子：
16.2
作者：
Lin YT;Seo J;Gao F;Feldman HM;Wen HL;Penney J;Cam HP;Gjoneska E;Raja WK;Cheng J;Rueda R;Kritskiy O;Abdurrob F;Peng Z;Milo B;Yu CJ;Elmsaouri S;Dey D;Ko T;Yankner BA;Tsai LH
通讯作者：
Tsai LH
影响因子：
16.6
作者：
Ormel PR;Vieira de Sá R;van Bodegraven EJ;Karst H;Harschnitz O;Sneeboer MAM;Johansen LE;van Dijk RE;Scheefhals N;Berdenis van Berlekom A;Ribes Martínez E;Kling S;MacGillavry HD;van den Berg LH;Kahn RS;Hol EM;de Witte LD;Pasterkamp RJ
通讯作者：
Pasterkamp RJ
影响因子：
5.6
作者：
Getz GS;Reardon CA
通讯作者：
Reardon CA
影响因子：
5.3
作者：
Lian, Hong;Litvinchuk, Alexandra;Zheng, Hui
通讯作者：
Zheng, Hui