Title: 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. 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. Microglia are the resident phagocytes of the innate immune system in the central nervous system (CNS). They are the first responders to neuroinflammation or damage and rapidly adapt their phenotype and functions in response to the brain milieu. They are important for several physiological functions, such as phagocytic activity and cytokine production, and they support other brain cells. New technological advances, including single-cell genomics, quantitative proteomics, and epigenetic studies, identified a role for the molecular and functional regulation of microglia in health and disease (Gosselin et al., 2014Gosselin D. Link V.M. Romanoski C.E. Fonseca G.J. Eichenfield D.Z. Spann N.J. Stender J.D. Chun H.B. Garner H. Geissmann F. Glass C.K. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities.Cell. 2014; 159: 1327-1340Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar, Li et al., 2019Li Q. Cheng Z. Zhou L. Darmanis S. Neff N.F. Okamoto J. Gulati G. Bennett M.L. Sun L.O. Clarke L.E. et al.Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell rna sequencing.Neuron. 2019; 101: 207-223Abstract Full Text Full Text PDF PubMed Google Scholar, Masuda et al., 2019Masuda T. Sankowski R. Staszewski O. Böttcher C. Amann L. Sagar Scheiwe C. Nessler S. 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Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer’s disease, Parkinson’s disease, and related disorders.Am. J. Neurodegener. Dis. 2013; 2: 145-175PubMed Google Scholar). During neurodegeneration, microglia acquire neurodegenerative signatures, including those driven by Triggering receptor expressed on myeloid cells 2 (TREM2)-Apolipoprotein E (APOE) (Keren-Shaul et al., 2017Keren-Shaul H. Spinrad A. Weiner A. Matcovitch-Natan O. Dvir-Szternfeld R. Ulland T.K. David E. Baruch K. Lara-Astaiso D. Toth B. et al.A unique microglia type associated with restricting development of Alzheimer’s disease.Cell. 2017; 169: 1276-1290Abstract Full Text Full Text PDF PubMed Scopus (599) Google Scholar, Krasemann et al., 2017Krasemann S. Madore C. Cialic R. Baufeld C. Calcagno N. El Fatimy R. Beckers L. O’Loughlin E. Xu Y. Fanek Z. et al.The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases.Immunity. 2017; 47: 566-581Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar). On the basis of these findings, human induced pluripotent stem cell (iPSC)-derived microglia were generated, allowing researchers to investigate the contribution of microglia-enriched risk genes to human disease. It also resulted in the development of novel humanized mouse models to study human microglia in vivo in the context of neurodegenerative disease. Environmental factors such as chronic stress might influence microglia, which might in turn affect an individual’s susceptibility to neurodegeneration, because microglial dysfunction is a potential risk factor for Alzheimer’s disease (AD) development (Bisht et al., 2018Bisht K. Sharma K. Tremblay M.E. 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In this review, we discuss studies defining the mechanistic regulators and upstream molecular pathways that could be therapeutic targets to ameliorate the negative effects of lifestyle factors and their potential consequences on the brain. Altogether, recognition of the negative consequences resulting from certain lifestyles and the importance of microglia in the etiology and progression of AD might allow people to adopt different lifestyles to modulate their susceptibility to neurodegenerative disease, in addition to other treatments. Suffering from chronic lifestyle stress during certain periods of life has become a common feature of modern societies. Chronic lifestyle stress and, in particular, psychosocial stress might confer a risk factor for late-onset AD (LOAD) and associated cognitive deficits. AD is characterized pathologically by the accumulation of phosphorylated tau and β-amyloid (Aβ) plaques. AD patients have been shown to present 83% increased cortisol levels in their cerebrospinal fluid (CSF) compared with healthy age-matched controls (Sapolsky et al., 1985Sapolsky R.M. Krey L.C. McEwen B.S. Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging.J. Neurosci. 1985; 5: 1222-1227Crossref PubMed Google Scholar, Swaab et al., 1994Swaab D.F. Raadsheer F.C. Endert E. Hofman M.A. Kamphorst W. Ravid R. Increased cortisol levels in aging and Alzheimer’s disease in postmortem cerebrospinal fluid.J. Neuroendocrinol. 1994; 6: 681-687Crossref PubMed Scopus (0) Google Scholar). Reactive gliosis, which consists of a range of molecular, morphological, and functional changes of glia in the CNS, and neuroinflammation are prominent hallmarks of AD (McGeer et al., 1987McGeer P.L. Itagaki S. Tago H. McGeer E.G. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR.Neurosci. 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Interestingly, these regions are among the first regions to be affected in AD pathology. However, potentially common underlying mechanisms between stress and AD pathology have not yet been well characterized. Neuroinflammation is a consequence of chronic stress and has been well characterized in AD. Epidemiological studies showed that PTSD is associated with immune system dysregulation (Hori and Kim, 2019Hori H. Kim Y. Inflammation and post-traumatic stress disorder.Psychiatry Clin. Neurosci. 2019; 73: 143-153Crossref PubMed Scopus (12) Google Scholar). In particular, chronic psychosocial stress induces peripheral and CNS inflammation in the adult (Eidson et al., 2019Eidson L.N. deSousa Rodrigues M.E. Johnson M.A. Barnum C.J. Duke B.J. Yang Y. Chang J. Kelly S.D. Wildner M. Tesi R.J. Tansey M.G. 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Microglia as dynamic and essential components of the amyloid hypothesis.Neuron. 2013; 78: 575-577Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). Transcriptomic analyses have revealed a neurodegenerative signature termed MGnD (neurodegenerative microglia) or DAM (disease-associated microglia) in plaque-associated microglia from both human and mouse AD models (Kamphuis et al., 2016Kamphuis W. Kooijman L. Schetters S. Orre M. Hol E.M. Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer’s disease.Biochim. Biophys. Acta. 2016; 1862: 1847-1860Crossref PubMed Scopus (43) Google Scholar, Keren-Shaul et al., 2017Keren-Shaul H. Spinrad A. Weiner A. Matcovitch-Natan O. Dvir-Szternfeld R. Ulland T.K. David E. Baruch K. Lara-Astaiso D. 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