Abstract
There is a striking sex-related difference in the prevalence of many neurodegenerative diseases, highlighting the need to consider whether treatments may exert sex-specific effects. A change in microglial activation state is a common feature of several neurodegenerative diseases and is considered to be a key factor in driving the inflammation that characterizes these conditions. Among the changes that have been described is a switch in microglial metabolism towards glycolysis which is associated with production of inflammatory mediators and reduced function. Marked sex-related differences in microglial number, phenotype and function have been described in late embryonic and early postnatal life in rodents and some reports suggest that sexual dimorphism extends into adulthood and age and, in models of Alzheimer’s disease, the changes are more profound in microglia from female, compared with male, mice. Dimethyl fumarate (DMF) is a fumaric acid ester used in the treatment of psoriasis and relapsing remitting multiple sclerosis and, while its mechanism of action is unclear, it possesses anti-inflammatory and anti-oxidant properties and also impacts on cell metabolism. Here we treated 16–18-month-old female and male mice with DMF for 1 month and assessed its effect on microglia. The evidence indicates that it exerted sex-specific effects on microglial morphology and metabolism, reducing glycolysis only in microglia from female mice. The data suggest that this may result from its ability to inactivate glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
Highlights
Uncontrolled microglial activation is a significant factor in the pathogenesis of many neurodegenerative diseases, but it is known that these cells become activated with age, and this is associated with neuroinflammation and compromised neuronal function
Among the many cellular events triggered by Dimethyl fumarate (DMF) are decreased NFκB activation and the present findings shows that DMF decreases NFκB activation in Iba1+ cells, the effect was similar in male and female mice and is unlikely to be key to the sexual dimorphism observed in relation to the effects of DMF on microglial morphology
The data presented add to the limited findings describing the effect of DMF on microglia but, most importantly, demonstrate that DMF acts on microglia in a sex-specific manner and attenuates the age-related metabolic change in cells from female mice, probably because it inactivates glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
Summary
Uncontrolled microglial activation is a significant factor in the pathogenesis of many neurodegenerative diseases, but it is known that these cells become activated with age, and this is associated with neuroinflammation and compromised neuronal function. Sexual dimorphism is recognized in microglial cells with evidence of sex-related differences in the number, phenotype, function and transcriptome of microglia and, in some cases, the differences extend to different brain regions [2–4]. More recent evidence has suggested that sex-related differences in microglia persist into adulthood [4] with evidence of male mice exhibiting evidence of greater inflammation [2]. With age, this changes and it has been shown that genes which reflect primed or activated microglia are upregulated to a greater extent in females [6]
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