Dark microglia: A new phenotype predominantly associated with pathological states

被引:300
作者
Bisht, Kanchan [1 ]
Sharma, Kaushik P. [1 ]
Lecours, Cynthia [1 ]
Sanchez, Maria Gabriela [1 ]
El Hajj, Hassan [1 ]
Milior, Giampaolo [2 ]
Olmos-Alonso, Adrian [3 ]
Gomez-Nicola, Diego [3 ]
Luheshi, Giamal [4 ]
Vallieres, Luc [1 ]
Branchi, Igor [5 ]
Maggi, Laura [2 ]
Limatola, Cristina [2 ]
Butovsky, Oleg [6 ]
Tremblay, Marie-Eve [1 ]
机构
[1] CHU Quebec, Ctr Rech, Axe Neurosci, 2705 Blvd Laurier, Quebec City, PQ G1V 4G2, Canada
[2] Univ Roma La Sapienza, Ist Pasteur, Fdn Cenci Bolognetti, Dept Physiol & Pharmacol, Piazzale Aldo Moro 5, I-00185 Rome, Italy
[3] Univ Southampton, Ctr Biol Sci, Southampton, Hants, England
[4] McGill Univ, Dept Psychiat, Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada
[5] Ist Super Sanita, Dept Cell Biol & Neurosci, Sect Behav Neurosci, Viale Regina Elena 299, I-00161 Rome, Italy
[6] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ann Romney Ctr Neurol Dis, Boston, MA 02115 USA
基金
加拿大自然科学与工程研究理事会; 英国医学研究理事会;
关键词
microglia; synapses; stress; aging; neurodegenerative diseases; PERIVASCULAR MACROPHAGES; AMYLOID-BETA; BONE-MARROW; BRAIN; CELLS; MONOCYTES; ROLES; INFLAMMATION; EXPRESSION; SYNAPSES;
D O I
10.1002/glia.22966
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 (CX(3)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 CX(3)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. GLIA 2016;64:826-839
引用
收藏
页码:826 / 839
页数:14
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