Dark microglia across contexts of health and disease

[Speaker] Marie-Eve Tremblay:1
1:CRCHU de Québec-Université Laval, Quebec City, Canada

In my presentation, I will discuss about our recent characterization of an ultrastructurally distinct microglial phenotype that is predominantly associated with pathological states. These cells are rare in steady state conditions, but become prevalent upon chronic stress, aging, and Alzheimer's disease pathology, where they account for two-thirds of the normal microglial population. They exhibit several signs of cellular stress including a condensed, electron-dense cytoplasm and nucleoplasm giving them a 'dark' appearance in electron microscopy, accompanied by endoplasmic reticulum dilation, mitochondrial alterations, and a loss of nuclear heterochromatin pattern. The physiological significance of these dark microglia has yet to be elucidated but they appear extremely active, frequently reaching for synaptic clefts, while extensively encircling axon terminals, dendritic spines, and excitatory synapses with their highly ramified and extremely thin processes. They strongly express CD11b, which forms complement receptor 3 involved in synaptic pruning, specifically in their processes encircling synaptic elements, and myeloid-cell specific TREM2 when associated with amyloid-β plaques. In addition, our recent work revealed the occurrence of these dark microglia in a schizophrenia mouse model induced by prenatal immunological challenge, as well as in early brain development, two conditions where synaptic pruning is exacerbated. These findings indicate that dark microglia could represent a subset of cells that become stressed as a result of their hyperactive involvement with the remodeling of neuronal circuits across development, plasticity, and disease.
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