Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Neuron. 2018 Jun 27;98(6):1141-1154.e7. doi: 10.1016/j.neuron.2018.05.008. Epub 2018 May 31.
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 Aβ 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. VIDEO ABSTRACT.
载脂蛋白 E4 (APOE4) 变体是散发性阿尔茨海默病 (sAD) 的单一最大遗传风险因素。然而，APOE4 在 AD 病理方面的细胞类型特异性功能仍研究不足。在这里，我们利用 CRISPR/Cas9 和诱导多能干细胞 (iPSC) 来研究 APOE4 对人类脑细胞类型的影响。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，受影响最严重的涉及突触功能（神经元）、脂质代谢（星形胶质细胞）和免疫反应（类小胶质细胞）。与同基因 APOE3 细胞相比，APOE4 神经元表现出更多的突触数量和增加的 Aβ 分泌，而 APOE4 星形胶质细胞表现出受损的 Aβ 摄取和胆固醇积累。值得注意的是，APOE4 样小胶质细胞表现出改变的形态，这与 Aβ 吞噬作用的降低有关。一致地，将 sAD iPSC 中的 APOE4 转化为 APOE3 足以减轻多种与 AD 相关的病理。我们的研究为与 APOE4 变体相关的人类细胞类型特异性变化建立了参考。视频摘要。
