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Androgens Show Sex-dependent Differences in Myelination in Immune and Non-immune Murine Models of CNS Demyelination

Abstract

Neuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis. In female mice, androgens and estrogens act in a synergistic way while androgens drive microglia response towards regeneration. Transcriptomic comparisons of demyelinated mouse spinal cords indicate that, regardless of the sex, androgens up-regulate genes related to neuronal function integrity and myelin production. Depending on the sex, androgens down-regulate genes related to the immune system in females and lipid catabolism in males. Thus, androgens are required for proper myelin regeneration in females and therapeutic approaches of demyelinating diseases need to consider male-female differences.

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References
1.
Khalaj A, Yoon J, Nakai J, Winchester Z, Moore S, Yoo T . Estrogen receptor (ER) β expression in oligodendrocytes is required for attenuation of clinical disease by an ERβ ligand. Proc Natl Acad Sci U S A. 2013; 110(47):19125-30. PMC: 3839759. DOI: 10.1073/pnas.1311763110. View

2.
Liddelow S, Barres B . Reactive Astrocytes: Production, Function, and Therapeutic Potential. Immunity. 2017; 46(6):957-967. DOI: 10.1016/j.immuni.2017.06.006. View

3.
Safaiyan S, Besson-Girard S, Kaya T, Cantuti-Castelvetri L, Liu L, Ji H . White matter aging drives microglial diversity. Neuron. 2021; 109(7):1100-1117.e10. DOI: 10.1016/j.neuron.2021.01.027. View

4.
Palaszynski K, Loo K, Ashouri J, Liu H, Voskuhl R . Androgens are protective in experimental autoimmune encephalomyelitis: implications for multiple sclerosis. J Neuroimmunol. 2003; 146(1-2):144-52. DOI: 10.1016/j.jneuroim.2003.11.004. View

5.
Dalal M, Kim S, Voskuhl R . Testosterone therapy ameliorates experimental autoimmune encephalomyelitis and induces a T helper 2 bias in the autoantigen-specific T lymphocyte response. J Immunol. 1997; 159(1):3-6. View