Apolipoprotein E4 (ApoE4) is involved in the stress‐response processes and is hypothesized to be a risk factor for depression by means of mitochondrial dysfunction. However, their exact roles and underlying mechanisms are largely unknown. ApoE4 transgenic mice (B6. Cg‐ApoEtm1UncCdh18Tg(GFAP−APOE i4)1Hol/J) were subjected to stress (lipopolysaccharides, LPS) to elucidate the aetiology of ApoE4‐induced depression. LPS treatment significantly aggravated depression‐like behaviours, concurrent with neuroinflammation and impaired mitochondrial changes, and melatonin/Urolithin A (UA) + 5‐aminoimidazole‐4‐carboxamide 1‐β‐D‐ribofuranoside (AICAR) reversed these effects in ApoE4 mice. Concurrently, ApoE4 mice exhibited mitophagy deficits, which could be further exacerbated by LPS stimulation, as demonstrated by reduced Atg5, Beclin‐1 and Parkin levels, while PINK1 levels were increased. However, these changes were reversed by melatonin treatment. Additionally, proteomic profiling suggested mitochondria‐related signalling and network changes in ApoE4 mice, which may underlie the exaggerated response to LPS. Furthermore, HEK 293T cells transfected with ApoE4 showed mitochondria‐associated protein and mitophagy defects, including PGC‐1α, TFAM, p‐AMPKα, PINK1 and LC3B impairments. Additionally, it aggravates mitochondrial impairment (particularly mitophagy), which can be attenuated by triggering autophagy. Collectively, ApoE4 dysregulation enhanced depressive behaviour upon LPS stimulation.

中文翻译：

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ApoE4 失调会引发小鼠抑郁症状和线粒体损伤

载脂蛋白 E4 (ApoE4) 参与应激反应过程，并被认为是通过线粒体功能障碍导致抑郁症的危险因素。然而，它们的确切作用和潜在机制在很大程度上尚不清楚。 ApoE4 转基因小鼠 (B6.Cg-载脂蛋白Etm1UncCDH18玻璃化温度(GFAP−APOE i4)1Hol/J) 受到压力（脂多糖，LPS）以阐明 ApoE4 诱导的抑郁症的病因。 LPS 治疗显着加重抑郁样行为，同时伴有神经炎症和线粒体变化受损，而褪黑素/尿石素 A (UA) + 5-氨基咪唑-4-甲酰胺 1-β-D-呋喃核苷 (AICAR) 逆转了 ApoE4 小鼠的这些影响。同时，ApoE4 小鼠表现出线粒体自噬缺陷，LPS 刺激可能会进一步加剧这种缺陷，Atg5、Beclin-1 和 Parkin 水平降低，而 PINK1 水平升高就证明了这一点。然而，褪黑激素治疗逆转了这些变化。此外，蛋白质组分析表明 ApoE4 小鼠中线粒体相关信号和网络发生变化，这可能是对 LPS 过度反应的基础。此外，转染 ApoE4 的 HEK 293T 细胞显示线粒体相关蛋白和线粒体自噬缺陷，包括 PGC-1α、TFAM、p-AMPKα、PINK1 和 LC3B 损伤。此外，它还会加剧线粒体损伤（特别是线粒体自噬），而线粒体损伤可以通过触发自噬来减弱。总的来说，ApoE4 失调增强了 LPS 刺激后的抑郁行为。