Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity.
Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity.
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载脂蛋白E4诱导的脂质积累损害小胶质细胞对神经网络活动的监测。
DOI：
10.1016/j.stem.2022.07.005
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发表时间：
2022-08-04
期刊：
影响因子：
23.9
通讯作者：
Tsai, Li-Huei
中科院分区：
文献类型：
--
作者：
Victor, Matheus B.;Leary, Noelle;Luna, Xochitl;Meharena, Hiruy S.;Scannail, Aine Ni;Bozzelli, P. Lorenzo;Samaan, George;Murdock, Mitchell H.;von Maydell, Djuna;Effenberger, Audrey H.;Cerit, Oyku;Wen, Hsin-Lan;Liu, Liwang;Welch, Gwyneth;Bonner, Maeve;Tsai, Li-Huei
载脂蛋白E4（APOE4）是已知的散发性阿尔茨海默病最大的遗传风险因素。APOE4小胶质细胞与神经元的相互作用如何不同于表达疾病中性APOE3等位基因的小胶质细胞，这仍然未知。在此，我们利用CRISPR编辑的诱导多能干细胞（iPSCs）来剖析APOE4在神经元 - 小胶质细胞通讯中的影响。我们的结果显示，APOE4诱导一种脂质蓄积状态，使得小胶质细胞对神经元活动的反应较弱。通过检测APOE3与APOE4小胶质细胞在响应神经元条件培养基时的转录特征，我们确定神经元信号在APOE4小胶质细胞中差异性地诱导一个脂肪生成程序，从而加剧促炎信号。通过减少对细胞外脂肪酸和脂蛋白的摄取，我们发现APOE4小胶质细胞破坏了神经元集群的协同活动。这些发现表明，在携带APOE4的阿尔茨海默病患者中观察到的异常神经元网络水平的紊乱可能部分是由非神经元细胞中脂质稳态的破坏所引发的。
蔡（Tsai）及其同事探索了阿尔茨海默病相关风险基因APOE4对神经元和小胶质细胞细胞通讯的影响。通过对来自CRISPR编辑的APOE同基因系的细胞进行组合实验，这项工作确定了APOE4诱导的小胶质细胞脂质代谢受损对神经元网络活动的功能影响。
Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing sporadic Alzheimer’s disease. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral APOE3 allele remains unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect the impact of APOE4 in neuron-microglia communication. Our results reveal that APOE4 induces a lipid-accumulated state that renders microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia in response to neuronal conditioned media, we established that neuronal cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro-inflammatory signals. Through decreased uptake of extracellular fatty acids and lipoproteins, we identified that APOE4 microglia disrupts the coordinated activity of neuronal ensembles. These findings suggest that abnormal neuronal network-level disturbances observed in Alzheimer’s disease patients harboring APOE4 may in part be triggered by impairment in lipid homeostasis in non-neuronal cells. Tsai and colleagues explored the impact of the Alzheimer’s disease-associated risk gene APOE4 onto the cellular communication of neurons and microglia. Through combinatorial experiments with cells derived from CRISPR-edited APOE isogenic lines, this work defines the functional consequence of impaired microglial lipid metabolism induced by APOE4 onto neuronal network activity.
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影响因子：
16.2
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通讯作者：
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影响因子：
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