Exploring Sex-Related Differences in Microglia May Be A Game-Changer in Precision Medicine Part 1

One area of microglial biology that has been relatively neglected until recently is sex differences and this is even though sex is a risk factor in several diseases that are characterized by neuroinflammation and, by extension, microglial activation. 

Microglia are an essential type of nerve cells in the brain, and they play a crucial role in the memory process. In recent years, more and more studies have shown that microglia are inextricably linked to human cognitive ability and memory. Microglia have very important functions. They can not only secrete a series of growth factors and substances that maintain the survival of neurons but also regulate signal transmission between neurons and the stability of synapses. These functions not only help the brain maintain normal physiological functions but also promote the interaction and information transmission between neurons, thereby improving people's cognitive ability and memory.

Research shows that microglia play a very important role in both learning and memory processes. They can release a variety of signaling molecules to promote interactions and information transmission between neurons. At the same time, it can also regulate the stability of synaptic connections between neurons, thereby helping people better remember information.

In addition, microglia can also participate in human thinking and attention activities. Research shows that microglia have a certain regulatory effect. They can affect the signal transmission between neurons, thereby affecting people's cognitive and decision-making abilities, and thus affecting people's complex thinking activities.

Taken together, microglia play a very important role in the brain and have a vital impact on human cognition and memory abilities. Therefore, we should pay attention to protecting and maintaining our brain health, maintaining a positive attitude towards life, and a healthy lifestyle to improve our cognitive and memory abilities. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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Why these sex differences exist is not known but the panoply of differences extends to microglial number, genotype, and phenotype. Significantly, several of these sex-related differences are also evident in health and change during life emphasizing the dynamic and plastic nature of microglia. 

This review will consider how age impacts sex-related differences in microglia and ask whether the advancement of personalized medicine demands that a greater focus is placed on studying sex-related differences in microglia in Alzheimer's disease, Parkinson's disease, and models of inflammatory stress and trauma to make true progress in dealing with these conditions.

Keywords: sex-related differences, age, Alzheimer's disease, microglia, inflammation.

INTRODUCTION

Several diseases are marked by differences in incidence, symptoms, and progression between males and females and sex is an acknowledged risk factor in diseases that are characterized by neuroinflammation, including autism spectrum disorders (ASD) Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis and migraine (Morgan et al., 2010; Hanamsagar and Bilbo, 2016; Airas et al., 2018; Lecours et al., 2018; Navarro et al., 2018). 

This sex-related difference is unexplained at this point although studies have provided detailed descriptions of differences in microglial number and morphology, microglial gene signature, microglial phenotype including electrophysiological properties, and microglial function including phagocytosis and antigen presentation which shift during early life, with age, and in different pathologies (Guneykaya et al., 2018; Crespo-Castrillo and Arevalo, 2020). 

In the past decade or so, particularly with the development of newer techniques, it has become clear that the simplistic view of microglia being "activated" or not, does not reflect the multiple states that the cells can adopt. Instead, attention must be paid to the stimulus that triggers microglial change and a more precise description of the change that includes not only traditional markers of activation but also cell function. 

While there is a growing appreciation of the need to address these complexities in current and future studies, a great deal of the literature to this point, including that cited in this review, describes microglia as being activated when they adopt a different morphology, and/or express markers of activation, and/or demonstrate a change in function. Therefore the term "microglial activation" is used here but, as far as possible, qualified with a description of the change described by the authors.

SEX DIFFERENCES IN MICROGLIA THROUGHOUT LIFE

Embryonic and Early Postnatal Life

Several groups have highlighted sex-related differences in microglial numbers in the early postnatal period which are greater in several areas of the male brain including cortex and hippocampus at P4 (Schwarz et al., 2012). At P20 no sex-related difference in Iba1+ cell numbers was identified (Thion et al., 2018) while by P30, microglial numbers were increased in the brains of female rats (Schwarz et al., 2012). 

Analysis of markers of microglial activation suggested that female rats generally exhibited a more activated phenotype at P0 and a less activated phenotype at P4 than males. By P30 and P60, microglia had developed processes but a sex-related difference in morphology persisted whereby cells from females had thicker longer processes (Schwarz et al., 2012). 

It has been proposed that the testosterone surge, which occurs in the early post-natal days, is responsible for the differences in the number and activation state of microglia in males and estradiol eliminated this sex-related difference, at least in the pre-optic area in P2 male rats (Lenz et al., 2013). The evidence also indicates time-related and sex-specific changes in phagocytic function. 

The number of phagocytic cells is greater in P2 (Nelson et al., 2017) and P8 (Weinhard et al., 2018) females, compared with males, and this was eliminated by treatment with estradiol (Nelson et al., 2017), but the evidence suggests that, by p28, phagocytic function is greater in microglia from males (Weinhard et al., 2018). In primary neonatal microglia, however, basal phagocytic activity was greater in females compared with males (Yanguas-Casas et al., 2018). 

The sex-related difference in phagocytosis was accompanied by increased expression of phagocytic genes notably Cd68 and Triggering Receptor Expressed on Myeloid cells (Trem)2. The microglia specifically phagocytosed neural progenitor cells and it was proposed that, ultimately, this may mean reduced cell proliferation in females. Recent studies using RNAseq to describe microglia in embryonic development and early life have reported conflicting findings. 

On the one hand, bulk RNAseq analysis identified a low number of differentially expressed genes in male and female E18.5 mice but showed that expression of genes associated with apoptosis and the inflammatory response, particularly interferon-stimulated genes, was higher in microglia from E18.5 female mice compared with males (Thion et al., 2018). 

At a slightly earlier age, E14.5, single-cell RNAseq revealed no changes in the microglial transcriptome between male and female mice, and no differences were found also at P4/5 (Hammond et al., 2019). 

Gene Ontology (GO) analysis at P20 revealed that genes described by terms such as "inflammatory response," "immune response," "immune system processes," and "response to lipopolysaccharide (LPS)" were upregulated in microglia from females compared with males and this was interpreted as indicating that microglia are in a more primed state in females at this age (Thion et al., 2018); this is perhaps also reflected in the morphological changes that have been described at this age (Schwarz et al., 2012). 

While the sex-related differences and very plastic nature of microglia in embryonic and early life are profound, a full understanding of the impact of these changes in infancy, adulthood, and beyond remains a challenge. This is complicated by the knowledge that microglia in different brain areas have different signatures (Bordt et al., 2020), highlighting the need for caution in the interpretation of findings derived from bulk analysis of microglia. 

However there is a good deal of evidence indicating that disturbances in microglial dynamics, arising from stressors including infection, during this period correlate with sex-related differences in disorders like ASD and schizophrenia; several excellent reviews have considered this (Ellman and Susser, 2009; Mccarthy and Wright, 2017; Bilbo et al., 2018; Ardalan et al., 2019; Bergdolt and Dunaevsky, 2019). 

However microglial activation persists into young adulthood (Suzuki et al., 2013), and inflammatory changes have been confirmed in the postmortem brain of individuals with ASD (Li et al., 2009; Tsilioni et al., 2019) suggesting that these ongoing changes may also contribute to ASD, as do environmental factors. Autism spectrum disorders are heritable and genetic analysis has identified disruption in genes that control protein synthesis (De La Torre-Ubieta et al., 2016). 

A recent study reported that increasing protein synthesis, by overexpressing the translation initiation factor eIF4E in microglia, resulted in ASD-like behaviors in male mice but not females (Xu et al., 2020). The increase in protein synthesis triggered a shift from the homeostatic state, altered microglial morphology, and reduced motility which, the authors suggested was responsible for the higher spine density, reduced synapse size, and altered synaptic function. 

The important role of microglia in sculpting the central nervous system (CNS) and neurons in particular suggest that alterations in their function such as these may significantly contribute to the neuroanatomical differences that have been described in ASD. 

Identifying the causes of ASD is not simple but pursuing a greater understanding of sex-related differences in microglial dynamics, in the hope that strategies for reducing the impact of the disorder might be identified, should be a focus.

Sex-Related Differences in Microglia Persist in Adult Animals

Sex-related differences in microglial phenotype endure into adulthood. Guneykaya et al. (2018) reported that microglial density, and cell body volume, were increased in the hippocampus of 13-week-old male mice compared with females, while the opposite is the case in 3-week-old mice. 

This group also reported that microglia from male mice had higher antigen-presenting properties, as indicated by increased expression of MHCII, whereas phagocytic activity of microglia was similar in males and females. 

Marked sex-related differences in gene expression were identified in microglia prepared from the hippocampus and cortex and GO analysis showed that, in the hippocampus, overexpression of genes in males was linked with the terms "defense response to bacteria," "insulin receptor pathway," and "glia cell differentiation," whereas genes related to the terms "GABA and glutamate receptor activity," "ubiquitin protein expression," and "magnesium iron transport" were overexpressed in females (Guneykaya et al., 2018). 

In contrast, proteomic analysis determined that interferon regulatory factor (Irf)3 was enriched in microglia from female mice (Guneykaya et al., 2018) consistent with the finding that these cells are more responsive to interferon (IFN) activation (Thion et al., 2018), and this was also suggested by RNAseq analysis in isolated microglia (Gal-Oz et al., 2019). 

One interpretation of this is that the differential alertness of the female immune system renders it less vulnerable to pathogen-associated molecular patterns (PAMPs) but more reactive to other stimuli that could induce an excessive inflammatory response, an argument that has been used to explain the neuroinflammation that seems to be at the heart of the pathogenesis of some neurodegenerative diseases. 

In short, the responsiveness of microglia to stimuli appears to be sex-dependent in adulthood as it is in earlier life, and the evidence indicates that the plasticity and dynamic nature of these cells persist with time. 

Some of these sex-related changes are illustrated in Figure 1. RNAseq, carried out on microglia from pooled brain samples of slightly older, 3-month-old mice, revealed that genes expressed in the brains of male mice reflected inflammatory processes (Villa et al., 2018) broadly agreeing with the findings summarized above. 

In this study, genes from female brains were more associated with morphogenesis, development, and cytoskeletal organization suggesting that tissue repair is a particular function of microglia from females. 

Interestingly, the reparative phenotype that typified microglia from female mice persisted when transplanted into the brain of male mice following ischemic injury (Villa et al., 2018).

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