APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline.

APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline.

Population-based studies reveal that apolipoprotein E (APOE) ε4 gene allele is closely associated with late-life depression (LLD). However, its exact role and underlying mechanism remain obscure. The current study found that aged apoE4-targeted replacement (TR) mice displayed obvious depression-like behavior when compared with age-matched apoE3-TR mice. Furthermore, apoE4 increased stress-induced depression-like behaviors, accompanied by declines in the hippocampal 5-HT (1A) radioligand [18F] MPPF uptake evidenced by positron emission tomography (PET). In [18F]-fluorodeoxyglucose PET ([18F]-FDG PET) analyses, the FDG uptake in the prefrontal cortex, temporal cortex and hippocampus of apoE4-TR mice significantly declined when compared with that of apoE3-TR mice after acute stress. Further biochemical analysis revealed that ATP levels in the prefrontal cortex of apoE4-TR mice decreased during aging or stress process and ATP supplementation effectively rescued the depression-like behaviors of elderly apoE4-TR mice. In primary cultured astrocytes from the cortex of apoE-TR mice, apoE4, when compared with apoE3, obviously decreased the mitochondrial membrane potential, mitochondrial respiration, and glycolysis in a culture time-dependent manner. Our findings highlight that apoE4 is a potential risk factor of depression in elderly population by impairing the glucose metabolism, reducing ATP level, and damaging mitochondrial functions in astrocytes, which indicates that in clinical settings ATP supplementation may be effective for elderly depression patients with apoE4 carrier.

基于人群的研究表明，载脂蛋白E（APOE）ε4基因等位基因与晚期抑郁症密切相关（LLD），但是，其确切的作用和潜在的机制仍然晦涩难懂。与年龄匹配的APOE3-TR小鼠相比，小鼠表现出明显的抑郁行为。在海马5-HT（1A）放射性体系[18F] MPPF摄取中，北极星发射断层扫描（PET）证明了[18F] - 氟乙醇葡萄糖PET（[18F] -fdg PET），在前frontake pet。与APOE3-TR小鼠相比，APOE4-TR小鼠的皮质，临时皮层和海马显着下降。 APOE4-TR小鼠的前额叶皮层在衰老或应力过程中发展出来，ATP补充有效地反应了从APOE-TR小鼠的一级培养的星形胶质细胞中，较早的APOE4-TR小鼠的抑郁样行为，当使用APOE3，显然改善了线粒体膜电位，线粒体呼吸和糖酵解的培养时间依赖性方式。基础人群抑郁症的危险因素通过损害葡萄糖代谢，降低ATP水平并破坏星形胶质细胞中的线粒体功能，这表明在临床环境中，补充ATP可能有效，对极端抑郁症患者的APOE4载体患者有效。