Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA; Department of Neuroscience, University of Kentucky, Lexington, KY, USA.
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of Kentucky, Lexington, KY, USA.
Neurobiol Aging. 2021 Mar;99:19-27. doi: 10.1016/j.neurobiolaging.2020.12.003. Epub 2021 Jan 7.
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.
生理小胶质细胞功能丧失可能会加速神经退行性疾病的发展。细胞衰老被认为是衰老的一个标志；因此，我们假设年龄可能是导致变形小胶质细胞的一个原因。我们对人类一生中整个大脑的小胶质细胞总数和两种小胶质细胞形态（肥大和变形）进行了体视学计数。在海马体和额叶皮层中发现，随着年龄的增长，变形小胶质细胞的数量会增加。然而，变形小胶质细胞的增加与小胶质细胞总数的年龄相关性增加成正比。因此，仅仅是衰老并不能解释变形小胶质细胞的存在。接下来，我们测试了变形小胶质细胞是否是一种与疾病相关的小胶质细胞形态。与对照组相比，在患有阿尔茨海默病、路易体痴呆症或边缘为主的与年龄相关的 TDP-43 脑病变的病例中，变形小胶质细胞的数量更多。这些结果表明，与肥大的小胶质细胞相比，小胶质细胞的变形是与疾病相关的小胶质细胞形态。最后，我们发现变形小胶质细胞中铁稳态变化的有力证据，为神经退行性疾病中小胶质细胞退化提供了一个可能的分子机制。
