The increased iron content in the brain of subjects with aceruloplasminemia has implicated ceruloplasmin (CP) as a major factor in the regulation of regional brain iron content. In this study, we investigated the effects of age and iron on CP expression in rat brain. In all four regions, the iron concentrations increased with developmental age. There is a similar trend in age-induced changes in CP mRNA and protein. The CP mRNA and protein levels were both lowest at postnatal day (PND) 7. The expression increased gradually with age, reaching the highest at PND196 in the striatum and substantia nigra, and at PND21 and PND63 in the cortex and hippocampus, respectively. This suggests the existence of an age-dependent pre-transcriptional regulation and a regionally specific effect of age on CP expression in the brain. Although total iron in all four regions was significantly lower in the rats fed with a low-iron diet for 6 weeks and higher in the rats with a high-iron diet than those in the control animals, no significant between-group differences in CP mRNA and protein were found in these animals, except in the substantia nigra where a significant increase in CP protein in high-iron rats was observed, and the reverse in low-iron rats. These findings suggested that the effects of iron on CP expression in the brain may be region-specific, and that regulation of CP expression by iron in the substantia nigra was at the post-transcriptional level.
Previous postmortem and animal studies have shown decreases in the prefrontal cortex (PFC) volume and the number of glial cells in the PFC of depression. Running exercise has been shown to alleviate depressive symptoms. However, the effects of running exercise on the medial prefrontal cortex (mPFC) volume and oligodendrocytes in the mPFC of depressed patients and animals have not been investigated. To address these issues, adult male rats were subjected to chronic unpredictable stress (CUS) for 5 weeks, followed by treadmill running for 6 weeks. Then, the mPFC volume and the mPFC oligodendrocytes were investigated using stereology, immunohistochemistry, immunofluorescence and western blotting. Using a CUS paradigm that allowed for the analysis of anhedonia, we found that running exercise alleviated the deficits in sucrose preference, as well as the decrease in the mPFC volume. Meanwhile, we found that running exercise significantly increased the number of CNPase+ oligodendrocytes and Olig2+ oligodendrocytes, reduced the ratio between Olig2+/NG2+ oligodendrocytes and Olig2+ oligodendrocytes and increased myelin basic protein (MBP), CNPase and Olig2 protein expression in the mPFC of the CUS rat model. However, running exercise did not change NG2+ oligodendrocyte number in the mPFC in these rats. These results indicated that running exercise promoted the differentiation of oligodendrocytes and myelin-forming ability in the mPFC in the context of depression. These findings suggest that the beneficial effects of running exercise on mPFC volume and oligodendrocytes in mPFC might be an important structural basis for the antidepressant effects of running exercise.
Background
The role of physical exercise in the prevention of Alzheimer’s disease (AD) has been widely studied. Microglia play an important role in AD. Triggering receptor expressed in myeloid cells 2 (TREM2) is expressed on microglia and is known to mediate microglial metabolic activity and brain glucose metabolism. However, the relationship between brain glucose metabolism and microglial metabolic activity during running exercise in APP/PS1 mice remains unclear.
Methods
Ten-month-old male APP/PS1 mice and wild-type mice were randomly divided into sedentary groups or running groups (AD_Sed, WT_Sed, AD_Run and WT_Run, n = 20/group). Running mice had free access to a running wheel for 3 months. Behavioral tests, [18]F-FDG-PET and hippocampal RNA-Seq were performed. The expression levels of microglial glucose transporter (GLUT5), TREM2, soluble TREM2 (sTREM2), TYRO protein tyrosine kinase binding protein (TYROBP), secreted phosphoprotein 1 (SPP1), and phosphorylated spleen tyrosine kinase (p-SYK) were estimated by western blot or ELISA. Immunohistochemistry, stereological methods and immunofluorescence were used to investigate the morphology, proliferation and activity of microglia.
Results
Long-term voluntary running significantly improved cognitive function in APP/PS1 mice. Although there were few differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) showed enriched glycometabolic pathways in APP/PS1 running mice. Running exercise increased FDG uptake in the hippocampus of APP/PS1 mice, as well as the protein expression of GLUT5, TREM2, SPP1 and p-SYK. The level of sTREM2 decreased in the plasma of APP/PS1 running mice. The number of microglia, the length and endpoints of microglial processes, and the ratio of GLUT5+/IBA1+ microglia were increased in the dentate gyrus (DG) of APP/PS1 running mice. Running exercise did not alter the number of 5-bromo-2′-deoxyuridine (BrdU)+/IBA1+ microglia but reduced the immunoactivity of CD68 in the hippocampus of APP/PS1 mice.
Conclusions
Running exercise inhibited TREM2 shedding and maintained TREM2 protein levels, which were accompanied by the promotion of brain glucose metabolism, microglial glucose metabolism and morphological plasticity in the hippocampus of AD mice. Microglia might be a structural target responsible for the benefits of running exercise in AD. Promoting microglial glucose metabolism and morphological plasticity modulated by TREM2 might be a novel strategy for AD treatment.
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