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

doi:10.1016/j.jsbmb.2015.09.039

The Journal of Steroid Biochemistry and Molecular Biology

Volume 160, June 2016, Pages 127-133

https://doi.org/10.1016/j.jsbmb.2015.09.039 Get rights and content

Highlights

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There are sex differences in the incidence and outcome of many neurodevelopmental and neurodegenerative diseases.
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Sex differences in microglia number and morphology exist at crucial time points during development.
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Perturbation of microglial function during development can impact behavior and cognition later in life in a sex-dependent manner.
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Studying sex differences in microglial function could be crucial to the understanding of sex differences in the emergence of neurological conditions as well as their treatment.

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.

Introduction

Neurological and neuropsychiatric diseases are a complex set of diseases affecting brain health and the general well-being of patients. According to the World Health Organization (WHO), neurological disorders affect up to 1 billion people, whereas 450 million people suffer from a mental or behavioral disorder worldwide. An estimated 6.8 million people die every year as a result of brain-related disorders. Not only is the economic cost for treatment very high, patients suffering from mental illnesses and neurological diseases are subject to stigma and social exclusion as well as acute loss of quality of life.

Many neurological diseases follow a clear developmental pattern. For example autism is detected in children as early as 2 years of age, depression is generally first diagnosed in adolescents, schizophrenia in young adults, and Alzheimer’s disease in aged individuals. One hypothesis is that perturbation of factors affecting normal neurodevelopment could be implicated in the occurrence of certain neurological disorders and their age of onset. Specifically, the immune system, both in the central nervous system (CNS) and in the periphery, is crucial in shaping and influencing normal brain functions, and any disruption of immune function could adversely impact the brain too. Immune signaling via microglial cells during CNS development is critical for maintaining homeostasis, neurogenesis, synaptic plasticity and circuit formation [11], [29]. Notably, our laboratory has shown that activation of the immune system with diverse challenges during early development in rodents can have far-reaching consequences on neuroimmune function and behavior later in life [10], [12], [13]. Thus, perturbation of the fine balance between the immune system and developing brain may pre-dispose individuals to an array of neurodevelopmental disorders.

For several neurological disorders mentioned above, there is a stark sex difference in their incidence, severity, and/or progression. For example autism is more prevalent in male children whereas females suffer from depression and anxiety disorders on a much larger scale [2], [51]. Females have a lower incidence of stroke (which depends on age as well), however they display poorer outcomes and suffer a more precipitous decline in function following stroke compared to males [70]. Sex differences in occurrence and outcome of neurological disease pose complications for diagnosis and treatment of patients, thus further emphasizing the need to understand the molecular pathways underlying these differences.

In this review, we discuss in further detail functions of the immune system, in particular that of microglia, the resident immune cells of the CNS, and their likely contribution to sex differences in the incidence and/or outcomes of neurological and neuropsychiatric disorders.

Section snippets

Sex differences in disease prevalence

Sex differences in disease prevalence and resistance are well described. Females of many species including humans generally exhibit enhanced immune responses and increased resistance to disease and infection than males [28], [45], [52], [56], [72], [88]. The more robust nature of the female peripheral immune response may significantly increase the risk of developing autoimmune diseases when compared to males [44], [53]. For example, more than 80% of the patients diagnosed with diseases such as

Sex differences in brain disorders (human clinical studies)

As mentioned previously, robust sex differences in neurological disorders, many with origins in development, are increasingly being recognized. Here, we consider and discuss in detail what is perhaps the best described sexually dimorphic neurodevelopmental disorder, autism, and the role that neuroinflammation, and microglial activation in particular, likely plays in its etiology. Thereafter, we consider the canonical neurodegenerative disorder, Alzheimer’s disease, which also presents

Mechanisms underlying sex differences

Autism and Alzheimer’s disease appear to be two distinct diseases on the outside—affecting patients in a quite disparate manner, both from the point of view of pathology as well as age of onset. Furthermore, sex differences associated with these diseases seem to follow opposite trajectories as discussed above. However, we believe that for both AD and ASD, a root cause may lie in brain development, for which microglia are especially critical.

Conclusion

Inflammation is an important component of several neurological disorders. Most studies look at the role of reactive microglia from the point of view of response to a pathological insult. Although this might be a reasonable approach, it should also be taken into account that basal differences in microglia do exist at different time points, in different areas of the brain and between males and females. It will be important to investigate and understand these differences. Interactions of the brain

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

Highlights

Abstract

Introduction

Section snippets

Sex differences in disease prevalence

Sex differences in brain disorders (human clinical studies)

Mechanisms underlying sex differences

Conclusion

Horm. Behav.

Front. Neuroendocrinol.

Front. Neuroendocrinol.

Brain Behav. Immun.

Autoimmun. Rev.

J. Clin. Epidemiol.

Domest. Anim. Endocrinol.

Mol. Cell. Neurosci.

Front. Neuroendocrinol.

Neurobiol. Aging

Res. Dev. Disabil.

J. Affect Disord.

Neurosci. Biobehav. Rev.

Mol. Cell. Endocrinol.

Gend. Med.

J. Am. Acad. Child Adolesc. Psychiatry

Lancet Neurol.

Horm. Behav.

Exp. Neurol.

Neuron

J. Steroid Biochem.

Best Pract. Res. Clin. Rheumatol.

Vaccine

Neurotherapeutics

Psychiatry Res.

Physiol. Behav.

Biochim. Biophys. Acta

Sex differences in the risk of schizophrenia: evidence from meta-analysis

Arch. Gen. Psychiatry

Alzheimer’s disease facts and figures

Alzheimer’s Dementia

Sex differences in stroke epidemiology: a systematic review

Stroke

Parkinson’s disease and parkinsonism in a longitudinal study: two-fold higher incidence in men. ILSA Working Group. Italian Longitudinal Study on Aging

Neurology

Attention deficit hyperactivity disorder (ADHD): gender- and age-related differences in neurocognition

Psychol. Med.

Why are autism spectrum conditions more prevalent in males?

PLoS Biol.

Testosterone decreases reactive astroglia and reactive microglia after brain injury in male rats: role of its metabolites, oestradiol and dihydrotestosterone

Eur. J. Neurosci.

Early-life programming of later-life brain and behavior: a critical role for the immune system

Front. Behav. Neurosci.

Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner

FASEB J.

Sex hormones and the immune response in humans

Hum. Reprod. Update

The origin of microglial cells

J. Anat.

Prevalence of attention deficit hyperactivity disorder among children and adolescents in Spain: a systematic review and meta-analysis of epidemiological studies

BMC Psychiatry

Genotype to phenotype relationships in autism spectrum disorders

Nat. Neurosci.

Females experience a more severe disease course in Batten disease

J. Inherit. Metab. Dis.

Age-related changes in motor subtle signs among girls and boys with ADHD

Neurology

Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process

Brain

Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity

Lupus

The impact of hormone replacement therapy on humoral and cell-mediated immune responses in vivo in post-menopausal women with rheumatoid arthritis

Scand. J. Immunol.

Prognosis in amyotrophic lateral sclerosis: a population-based study

Neurology

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