Role of glial cells in the generation of sex differences in neurodegenerative diseases and brain aging

Diseases and aging-associated alterations of the nervous system often show sex-specific characteristics. Glial cells play a major role in the endogenous homeostatic response of neural tissue, and sex differences in the glial transcriptome and function have been described. Therefore, the possible role of these cells in the generation of sex differences in pathological alterations of the nervous system is reviewed here. Studies have shown that glia react to pathological insults with sex-specific neuroprotective and regenerative effects. At least three factors determine this sex-specific response of glia: sex chromosome genes, gonadal hormones and neuroactive steroid hormone metabolites. The sex chromosome complement determines differences in the transcriptional responses in glia after brain injury, while gonadal hormones and their metabolites activate sex-specific neuroprotective mechanisms in these cells. Since the sex-specific neuroprotective and regenerative activity of glial cells causes sex differences in the pathological alterations of the nervous system, glia may represent a relevant target for sex-specific therapeutic interventions.We acknowledge support from CIBEROBN, CIBERFES, Fondo de Investigación Sanitaria (PI1900166), Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación (BFU2017-82565-C21-R2; BFU2017-82754-R) and Fondo Europeo de Desarrollo Regional (FEDER). Funding sources were not involved in any step of the design and preparation of this article, including the decision to submit it for publication