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.

Sex Chromosomes and Gonads Shape the Sex-Biased Transcriptomic Landscape in Tlr7-Mediated Demyelination During Aging

“…However, it is also conceivable that other gonadal hormones, such as progesterone, testosterone, follicle-stimulating hormone (FSH), or luteinizing hormone, may also contribute the differences in myelin loss attributed to ovaries. For example, a recent study showed a combined beneficial effect of testosterone and estrogens on microglial responses favoring regeneration in a mouse model of EAE ( 31 ). Reduced estrogen can also induce higher levels of FSH, which were found to impair cognition and exacerbate AD pathology in an ovariectomized mouse model of AD ( 32 ).…”

The Smoothened agonist SAG Modulates the Male and Female Peripheral Immune Systems Differently in an Immune Model of Central Nervous System Demyelination

“…The pathology was induced by the subcutaneous injection of an emulsion of the MOG 35-55 peptide in complete Freund's adjuvant, as previously described [17]. Vehicle, SAG, testosterone, or SAG-testosterone treatments were administered at the onset of neurological disabilities (n = 10 animals per group) and evaluated blindly until Day 30 post-immunization according to the classical scale, as described [14]. Drugs or the vehicles were administered daily via the intranasal route at the onset of clinical symptoms until Day 30 or Day 14 after immunization.…”

“…The intranasal route is a non-invasive method for drug administration. Previously, we validated the intranasal administration of testosterone as a privileged delivery of the hormone to the CNS in both males and females [9,14]. Therefore, it appeared interesting to also assess this administration route instead of the oral route previously used for the Smo agonist SAG, hence the need to determine the dose of intranasal SAG leading to an effect comparable to the oral administration.…”

“…However, these data regarded only male animals. Since we recently reported that androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination [14], it is questionable whether this drug combination has comparable effects in female animals. To this purpose, we assessed the molecules alone or in combination in female mice demyelinated using immune and non-immune demyelination models.…”

Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

“…90 In addition to the abnormal myelin formation caused by genetic factors, other environments or mutations of genes directly related to myelin can cause myelin lesion. 91 Sufficient OPCs are required for the repair of demyelination in AD. With the aging process, the number of differentiated…”