Metformin alleviates the depression-like behaviors of elderly apoE4 mice via improving glucose metabolism and mitochondrial biogenesis
Metformin alleviates the depression-like behaviors of elderly apoE4 mice via improving glucose metabolism and mitochondrial biogenesis
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DOI：
10.1016/j.bbr.2022.113772
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发表时间：
2022-02-07
影响因子：
2.7
通讯作者：
Chen，Xiaochun
中科院分区：
文献类型：
--
作者：
Lin，Yingbin;Dai，Xiaoman;Chen，Xiaochun
载脂蛋白E4（apoE 4）与晚发性抑郁症（LOD）密切相关。此外，二甲双胍治疗抑郁症的益处已在一系列啮齿动物研究和人体试验中得到证实，但很少有研究探讨二甲双胍对抑郁老年小鼠的影响及其相关机制，尤其是在APOE 4携带者中。在这里，我们用二甲双胍（300 mg/kg/d）或生理盐水灌胃给药治疗13个月大的apoE 3靶向替代（TR）和apoE 4-TR小鼠5个月。我们发现二甲双胍对apoE 4小鼠具有抗抑郁作用，包括减少TST和FST的不动时间，增加OFT中心区的时间和距离比值。重要的是，与apoE 3小鼠相比，apoE 4小鼠在海马中表现出更高的乳酸脱氢酶（LDH）和丙酮酸脱氢酶激酶（PDK 1和PDK 4）表达。二甲双胍治疗挽救了LDH水平升高。此外，二甲双胍给药增加了apoE-TR小鼠中转录因子NRF-1和TFAM、mtDNA和大多数线粒体复合物亚基的水平。此外，它上调抗氧化酶，如MnSOD，GPX 1和GSR 1/2的表达。有趣的是，apoE 4减弱了二甲双胍在老年小鼠中的降血糖作用。这些数据表明，二甲双胍可能通过改善老年apoE 4小鼠海马中的葡萄糖代谢和线粒体生物合成来改善抑郁样行为。这些结果表明，长期二甲双胍治疗可以改善apoE 4介导的LOD，为基于apoE 4和年龄的抑郁症预防和治疗提供机制见解。
Apolipoprotein E4 (apoE4) is closely related to late-onset depression (LOD). In addition, the benefits of metformin treatment of depression have been documented in a range of rodent studies and human trials, but few studies have probed into the effect of metformin on and the related mechanism in depressed elderly mice, especially in thoseAPOE4carriers. Here, we treated 13-month-old apoE3-targeted replacement (TR) and apoE4-TR mice with an intragastric administration of metformin (300 mg/kg/d) or normal saline for 5 months. We found that metformin exerted antidepressant effects on apoE4 mice, including reduced immobility time in TST and FST, and increased ratios of time and distance in the central area of OFT. Importantly, compared with apoE3 mice, apoE4 mice showed a higher expression of lactate dehydrogenase (LDH) and pyruvate dehydrogenase kinase (PDK1 and PDK4) in the hippocampus. The increased LDH level was rescued by metformin treatment. Moreover, the metformin administration increased the levels of transcriptional factor NRF-1 and TFAM, mtDNA, and most mitochondrial complex subunits in apoE-TR mice. Furthermore, it upregulated the expressions of antioxidant enzymes, such as MnSOD, GPX1, and GSR1/2. Interestingly, apoE4 blunted the hypoglycemic effect of metformin in aged mice. These data suggest that metformin ameliorates the depression-like behaviors probably by improving glucose metabolism and mitochondria biogenesis in the hippocampus of aged apoE4 mice. These findings imply that chronic metformin treatment can improve apoE4-mediated LOD, providing mechanistic insights for apoE4- and age-based depression prevention and therapy.