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.
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Research reported in this publication was supported by the National Institutes of Health under award numbers P30 AG028383, R35 GM124977, and R21AG066865.
Shahidehpour, Ryan K.; Higdon, Rebecca E.; Crawford, Nicole G.; Neltner, Janna H.; Ighodaro, Eseosa T.; Patel, Ela; Price, Douglas; Nelson, Peter T.; and Bachstetter, Adam D., "Dystrophic Microglia Are Associated with Neurodegenerative Disease and not Healthy Aging in the Human Brain" (2021). Spinal Cord and Brain Injury Research Center Faculty Publications. 34.