APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types.
APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types.
复制标题
DOI：
10.1016/j.neuron.2018.05.008
复制
发表时间：
2018-06-27
期刊：
影响因子：
16.2
通讯作者：
Tsai LH
中科院分区：
文献类型：
--
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
载脂蛋白E4（APOE 4）变异是散发性阿尔茨海默病（sAD）的单一最大遗传风险因素。然而，与AD病理学相关的APOE 4的细胞类型特异性功能仍然研究不足。在这里，我们利用CRISPR/Cas9和诱导多能干细胞（iPSC）来研究APOE 4对人脑细胞类型的影响。转录谱分析确定了每种细胞类型中数百个差异表达的基因，其中受影响最大的涉及突触功能（神经元），脂质代谢（星形胶质细胞）和免疫反应（小胶质细胞样细胞）。相对于同基因APOE 3细胞，APOE 4神经元表现出突触数量增加和Aβ42分泌增加，而APOE 4星形胶质细胞表现出Aβ摄取和胆固醇蓄积受损。值得注意的是，APOE 4小胶质细胞样细胞表现出改变的形态，这与Aβ吞噬作用降低相关。一致地，在来自sAD iPSC的脑细胞类型中将APOE 4转化为APOE 3足以减弱多种AD相关病理。我们的研究建立了与APOE 4变异相关的人类细胞类型特异性变化的参考。
The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer’s disease (sAD). However, the cell type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes) and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell type-specific changes associated with the APOE4 variant.
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.
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
--
作者：
Göritz, C;Mauch, DH;Pfrieger, FW
通讯作者：
Pfrieger, FW
影响因子：
82.9
作者：
Koistinaho, M;Lin, SZ;Paul, SM
通讯作者：
Paul, SM
影响因子：
4.8
作者：
Crowe EP;Tuzer F;Gregory BD;Donahue G;Gosai SJ;Cohen J;Leung YY;Yetkin E;Nativio R;Wang LS;Sell C;Bonini NM;Berger SL;Johnson FB;Torres C
通讯作者：
Torres C