Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer’s disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known. Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of persons with AD dementia carrying APOE3/4 compared to APOE3/3. Higher phosphorylated p38 MAPK but not ERK1/2 was found in ApoE4 primary astrocytes and mouse brains than that in ApoE3. Greater cPLA2 translocation to cytosol was observed in human postmortem frontal cortical synaptosomes with recombinant ApoE4 than ApoE3 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition. Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

中文翻译：

---

钙依赖性胞质磷脂酶 A2 激活与 ApoE4 相关的神经炎症和氧化应激有关

载脂蛋白 E4 (APOE4) 与对神经炎症的更大反应和发生迟发性阿尔茨海默病 (AD) 的风险相关，但这种关联的机制尚不清楚。钙依赖性胞质磷脂酶 A2 (cPLA2) 的激活参与炎症信号传导，并在 AD 脑的斑块内升高。APOE4 基因型与 cPLA2 活性之间的关系尚不清楚。收集不同 APOE 基因型的小鼠原代星形胶质细胞、小鼠和人脑样本，用于测量 cPLA2 表达、磷酸化和与炎症和氧化应激测量相关的活性。与原代星形胶质细胞、ApoE 靶向替代 (ApoE-TR) 小鼠大脑中的 ApoE3 相比，在 ApoE4 中鉴定出更高的 cPLA2 磷酸化、cPLA2 活性和白三烯 B4 (LTB4) 水平，与携带 APOE3/4 的 AD 痴呆患者的下额叶皮层的人脑匀浆相比，携带 APOE3/3。在 ApoE4 原代星形胶质细胞和小鼠大脑中发现比在 ApoE3 中更高的磷酸化 p38 MAPK 但不是 ERK1/2。在具有重组 ApoE4 的人死后额叶皮质突触体中观察到比 ApoE3 离体更大的 cPLA2 易位至胞质溶胶。在 ApoE4 星形胶质细胞中，更高水平的 LTB4、活性氧 (ROS) 和诱导型一氧化氮合酶 (iNOS) 在 cPLA2 抑制后降低。我们的研究结果表明 APOE4 可以更大程度地激活 cPLA2 信号系统，这可能是减轻 APOE4 和 AD 增加的神经炎症的潜在药物靶点。