Dark microglia: A new phenotype predominantly associated with pathological states.
Dark microglia: A new phenotype predominantly associated with pathological states.
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作者：
Bisht K;Sharma KP;Lecours C;Sánchez MG;El Hajj H;Milior G;Olmos-Alonso A;Gómez-Nicola D;Luheshi G;Vallières L;Branchi I;Maggi L;Limatola C;Butovsky O;Tremblay MÈ
过去十年见证了我们对小胶质细胞的理解发生了一场革命。这些免疫细胞被证明能积极重塑神经元回路，从而提出了新的致病机制。为了研究小胶质细胞在突触丧失中的作用，这是慢性应激、衰老和疾病中认知能力下降的最佳病理关联，我们最近进行了超微结构分析。我们的工作揭示了一种新的小胶质细胞表型的存在，这种表型在稳态条件下很少存在，在海马、大脑皮层、杏仁核和下丘脑中，但在慢性应激、衰老、fractalkine信号缺陷（CX3CR1敲除小鼠）和阿尔茨海默病病理（APP - PS1小鼠）中变得丰富。尽管这些细胞表现出小胶质细胞的超微结构特征，但它们与迄今为止在超微结构水平上描述的其他表型明显不同。它们表现出氧化应激的几种迹象，包括浓缩的、电子密集的细胞质和核质，使它们像线粒体一样“黑暗”，伴随着核染色质的明显重塑。暗小胶质细胞似乎比正常小胶质细胞更活跃，到达突触间隙，同时广泛环绕轴突终末和树突棘，其高度分枝和细突起。他们对髓细胞标记物IBA1和GFP进行染色（在CX3CR1‐GFP小鼠中），在环绕突触元件的过程中强烈表达CD11b和小胶质细胞特异性4D4，在与淀粉样蛋白斑块相关的过程中强烈表达TREM2。总的来说，这些发现表明，暗小胶质细胞，我们根据其独特的特性发现的一种新的表型，可能在神经元回路的病理重塑中发挥重要作用，特别是在突触。神经胶质2016;64:826 - 839
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 (CX3CR1 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 CX3CR1‐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