Sex differences in neurodevelopmental and neurodegenerative disorders: Focus on microglial function and neuroinflammation during development

Abstract

Several neurological conditions are associated with sex differences in prevalence or outcome. For example, autism predominantly affects boys, depression is more common in women, Parkinson's disease more common in men, and Multiple sclerosis in women. In the case of stroke, women have a less favorable outcome and suffer from a more precipitous drop in health status compared to men. As a result, treatment of such diseases is difficult and yields variable results. Despite this, sex is rarely considered when making treatment decisions. The mechanisms underlying sex differences in disease progression are not well understood, however a strong link exists between different inflammation states of men and women and their propensity to develop certain diseases. As neuroinflammation is an important component of pathophysiology in many neurological conditions, it can be speculated that any changes in the state of inflammation in the brain during normal development can potentially lead to an increase in susceptibility to neurological and neurodegenerative diseases. Microglia play a crucial role in onset and modulation of inflammation and thus sex differences in microglial function could explain, at least in part, differences observed in susceptibilities and outcomes of neurological disorders in men and women. Understanding the mechanisms behind sex differences could help develop more targeted therapy with higher success rate, especially in diseases where sex differences are most prominent.

Serum Growth Differentiation Factor 15 in Parkinson Disease

“…Microglia have a crucial role in the onset and modulation of neuroinflammation, and thus gender differences in microglial function may explain, at least in part, the gender disparity observed in PD [51]. Furthermore, higher baseline levels of biomarkers indicative of inflammation and remodeling suggest higher biological activity in the respective pathophysiological pathways in men compared with women [52].…”

Immune and Neuroendocrine Mechanisms of Stress Vulnerability and Resilience

“…Around the beginning of puberty and into early adulthood, female rats develop more microglia than do males in select brain areas including the amygdala, parietal cortex and hippocampus (Schwartz, 2012;Hanamsagar and Bilbo, 2015). During adulthood, females have a greater ratio of primed microglia to ramified microglia compared to males.…”

Environment matters: microglia function and dysfunction in a changing world

“…by disrupting normal processes like pruning or phagocytosis), increasing the risk of disease (Figure 2). Sex differences in the incidence of neurodevelopmental disorders such as autism (4:1 males to females) are well recognized [49], suggesting sex differences in microglial development is an important disease-modifying factor [50], and we return to this concept in a later section.…”