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