title: Dark microglia: A new phenotype predominantly associated with pathological states.
abstract: The past decade has witnessed a revolution in our understanding of microglia. These immune cells were shown to actively remodel neuronal circuits, leading to propose new pathogenic mechanisms. To study microglial implication in the loss of synapses, the best pathological correlate of cognitive decline across chronic stress, aging, and diseases, we recently conducted ultrastructural analyses. Our work uncovered the existence of a new microglial phenotype that is rarely present under steady state conditions, in hippocampus, cerebral cortex, amygdala, and hypothalamus, but becomes abundant during chronic stress, aging, fractalkine signaling deficiency (CX3 CR1 knockout mice), and Alzheimer's disease pathology (APP-PS1 mice). Even though these cells display ultrastructural features of microglia, they are strikingly distinct from the other phenotypes described so far at the ultrastructural level. They exhibit several signs of oxidative stress, including a condensed, electron-dense cytoplasm and nucleoplasm making them as "dark" as mitochondria, accompanied by a pronounced remodeling of their nuclear chromatin. Dark microglia appear to be much more active than the normal microglia, reaching for synaptic clefts, while extensively encircling axon terminals and dendritic spines with their highly ramified and thin processes. They stain for the myeloid cell markers IBA1 and GFP (in CX3 CR1-GFP mice), and strongly express CD11b and microglia-specific 4D4 in their processes encircling synaptic elements, and TREM2 when they associate with amyloid plaques. Overall, these findings suggest that dark microglia, a new phenotype that we identified based on their unique properties, could play a significant role in the pathological remodeling of neuronal circuits, especially at synapses.
authors: Axe Neurosciences, Centre De Recherche Du CHU De Québec, Québec, Québec, Canada.
authors: Kanchan
authors: K
authors: Bisht
authors: Axe Neurosciences, Centre De Recherche Du CHU De Québec, Québec, Québec, Canada.
authors: Kaushik P
authors: KP
authors: Sharma
authors: Axe Neurosciences, Centre De Recherche Du CHU De Québec, Québec, Québec, Canada.
authors: Cynthia
authors: C
authors: Lecours
authors: Axe Neurosciences, Centre De Recherche Du CHU De Québec, Québec, Québec, Canada.
authors: Maria Gabriela
authors: MG
authors: Sánchez
authors: Axe Neurosciences, Centre De Recherche Du CHU De Québec, Québec, Québec, Canada.
authors: Hassan
authors: H
authors: El Hajj
authors: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
authors: Giampaolo
authors: G
authors: Milior
authors: Centre for Biological Sciences, University of Southampton, Southampton, United Kingdom.
authors: Adrián
authors: A
authors: Olmos-Alonso
authors: Centre for Biological Sciences, University of Southampton, Southampton, United Kingdom.
authors: Diego
authors: D
authors: Gómez-Nicola
authors: Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Québec, Canada.
authors: Giamal
authors: G
authors: Luheshi
authors: Axe Neurosciences, Centre De Recherche Du CHU De Québec, Québec, Québec, Canada.
authors: Luc
authors: L
authors: Vallières
authors: Section of Behavioural Neurosciences, Department of Cell Biology and Neurosciences, Istituto Superiore Di Sanità, Rome, Italy.
authors: Igor
authors: I
authors: Branchi
authors: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
authors: Laura
authors: L
authors: Maggi
authors: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
authors: Cristina
authors: C
authors: Limatola
authors: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Oleg
authors: O
authors: Butovsky
authors: Axe Neurosciences, Centre De Recherche Du CHU De Québec, Québec, Québec, Canada.
authors: Marie-Ève
authors: MÈ
authors: Tremblay
mesh_terms: D000375:Aging / Q000473:pathology*; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002540:Cerebral Cortex / Q000473:pathology*; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000587:Oxidoreductases Acting on CH-NH Group Donors; D010641:Phenotype; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics / Q000473:pathology*; D000099295:Formyltetrahydrofolate Dehydrogenase
chemical_list: D000444:Aldehyde Dehydrogenase; D016564:Amyloid beta-Protein Precursor; D015703:Antigens, CD; D000073883:CX3C Chemokine Receptor 1; D049452:Green Fluorescent Proteins; D009419:Nerve Tissue Proteins; D000587:Oxidoreductases Acting on CH-NH Group Donors; D053764:Presenilin-1; D019707:Receptors, Chemokine; D000099295:Formyltetrahydrofolate Dehydrogenase; C471885:Cx3cr1 protein, mouse
keywords: aging; microglia; neurodegenerative diseases; stress; synapses