Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain

Loss of physiological microglial function may increase the propagation of neurodegenerative diseases. Cellular senescence is a hallmark of aging; thus, we hypothesized age could be a cause of dystrophic microglia. Stereological counts were performed for total microglia, 2 microglia morphologies (hypertrophic and dystrophic) across the human lifespan. An age-associated increase in the number of dystrophic microglia was found in the hippocampus and frontal cortex. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia. Thus, aging alone does not explain the presence of dystrophic microglia. We next tested if dystrophic microglia could be a disease-associated microglia morphology. Compared with controls, the number of dystrophic microglia was greater in cases with either Alzheimer's disease, dementia with Lewy bodies, or limbic predominant age-related TDP-43 encephalopathy. These results demonstrate that microglia dystrophy, and not hypertrophic microglia, are the disease-associated microglia morphology. Finally, we found strong evidence for iron homeostasis changes in dystrophic microglia, providing a possible molecular mechanism driving the degeneration of microglia in neurodegenerative disease. (C) 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.

Automated summary

The study found an age-associated increase in dystrophic microglia in the hippocampus and frontal cortex, but this increase was proportional to the total number of microglia, suggesting aging alone does not explain the presence of dystrophic microglia. Dystrophic microglia, rather than hypertrophic microglia, were found to be the disease-associated microglia morphology. Furthermore, changes in iron homeostasis in dystrophic microglia were identified as a potential molecular mechanism driving the degeneration of microglia in neurodegenerative disease.