Microglia, Lifestyle Stress, and Neurodegeneration

Abstract

Recent years have witnessed a revolution in our understanding of microglia biology, including their major role in the etiology and pathogenesis of neurodegenerative diseases. Technological advances have enabled the identification of microglial signatures in health and disease, including the development of new models to investigate and manipulate human microglia in vivo in the context of disease. In parallel, genetic association studies have identified several gene risk factors associated with Alzheimer's disease that are specifically or highly expressed by microglia in the central nervous system (CNS). Here, we discuss evidence for the effect of stress, diet, sleep patterns, physical activity, and microbiota composition on microglia biology and consider how lifestyle might influence an individual's predisposition to neurodegenerative diseases. We discuss how different lifestyles and environmental factors might regulate microglia, potentially leading to increased susceptibility to neurodegenerative disease, and we highlight the need to investigate the contribution of modern environmental factors on microglia modulation in neurodegeneration.

Figure 1.. Lifestyle Factors Might Hijack Microglia Regulation and Predispose Individuals to Neurodegeneration

ELS, chronic adult stress, or changes in diet, microbiota, or social contexts might predispose individuals to neurodegenerative disease onset, as observed by associations with neuronal loss, cognitive deficits, and AD-related pathology. These phenotypes during aging could be influenced by a change in an individual’s dietary pattern, changes in an individual’s microbiota, and drug medications such as SSRIs. This preventive mechanism could be acting through astrocyte release of TGF-b that could modulate microglial functions and restore a phenotype that can stop neurodegeneration.

Figure 2.. Microbiome Depletion Modulates Microglial Phenotype and Neurodegenerative Disease Pathology

The microbiome can communicate with CNS resident cells, including microglia, through various pathways, including the vagus nerve, microbial metabolites (SCFAs), and direct and in-direct immune signaling pathways. Upon microbiome depletion either in a GF context or after antibiotic administration, microglia adopt an immature phenotype associated with impaired responses to LPS and viral infections. In the context of neurodegeneration, microbiome depletion in AD and PD is associated with amelioration of disease progression and pathology, with increased M0-homeostatic gene expression in microbiome-deplete AD mice and evidence of less inflammatory microglia in microbiome-deplete PD mice. In ALS, disease pathology is markedly worsened in a microbiome-depleted context. Microglial phenotype remains to be explored in microbiome-depleted ALS mice.

Figure 3.. Sleep Loss Might Promote Neurodegenerative Functions of Microglia and Can Be Prevented by Physical Exercise

Forms of sleep loss, including deprivation, restriction, and fragmentation, could promote neurodegeneration by decreased neurogenesis, elevated stress, altered microbiome composition, synaptic loss, increased neuroinflammation, and protein aggregation. These conditions could lead to the acquisition of MGnD, which could exacerbate disease. Conversely, physical exercises might support increased neurogenesis, reduced stress, altered microbiome composition, reduced neuroinflammation, and protein aggregation, which might restore microglial phenotype and prevent neurodegeneration.