Though apolipoprotein E ε4 (APOE ε4) is a major genetic risk factor for late-onset Alzheimer's disease, its association with depression remains controversial. In present study, 3-month-old and 8-month-old apoE-targeted replacement (TR) mice were both subjected to chronic unpredictable mild stress (CUMS) for six weeks. The results showed that 8-month apoE4-TR mice were more susceptible to the CUMS-induced depression-like behaviors and cognitive impairment than age-matched apoE3-TR mice. Stress induced a loss of GABAergic neurons and decline of Reelin level in the prefrontal cortex (PFC) and in the dentate gyrus (DG) of the hippocampus in both 3-month-old and 8-month-old apoE-TR mice, which were more pronounced in the 8-month-old apoE4-TR mice. Of note, stress decreased the level of PSD95 in the hippocampal synaptosome and increased the phosphorylation of N-methyl-D-aspartate receptor subunit GluN2B in the hippocampus of 8-month-old apoE4-TR mice. However, the expressions of apoE and apoE receptor 2 (apoER2) were not affected by stress. The study provides rodent evidence that APOE ε4 may increase the risk of depression and dementia in the elderly population by impairing the GABAergic signaling pathway and enhancing the GluN2B phosphorylation, which signifies that GluN2B inhibitors in clinical settings may be effective for elderly depression patients with APOE4 carriers.

尽管载脂蛋白 E ε4 (APOE ε4) 是迟发性阿尔茨海默病的主要遗传风险因素，但其与抑郁症的关系仍存在争议。在本研究中，3 个月大和 8 个月大的 apoE 靶向替代 (TR) 小鼠均受到慢性不可预测的轻度压力 (CUMS) 六周。结果表明，与年龄匹配的apoE3-TR小鼠相比，8个月大的apoE4-TR小鼠更容易出现CUMS诱导的抑郁样行为和认知障碍。压力导致 3 个月大和 8 个月大的 apoE-TR 小鼠的前额叶皮层 (PFC) 和海马齿状回 (DG) 中 GABA 能神经元的损失和 Reelin 水平下降，这些小鼠是在 8 个月大的 apoE4-TR 小鼠中更为明显。值得注意的是，压力降低了海马突触体中 PSD95 的水平，并增加了 8 个月大的 apoE4-TR 小鼠海马中 N-甲基-D-天冬氨酸受体亚基 GluN2B 的磷酸化。然而，apoE 和 apoE 受体 2 (apoER2) 的表达不受压力的影响。该研究提供了啮齿动物的证据表明APOE ε4 可能通过损害 GABAergic 信号通路和增强 GluN2B 磷酸化来增加老年人群患抑郁症和痴呆症的风险，这表明临床环境中的 GluN2B 抑制剂可能对携带APOE4的老年抑郁症患者有效。