Metformin alleviates the depression-like behaviors of elderly apoE4 mice via improving glucose metabolism and mitochondrial biogenesis.

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 those APOE4 carriers. 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.