Institute of Anatomy, Universität Leipzig, Leipzig, Germany.
Department of Neuroscience, University of Florida College of Medicine, Gainesville, Florida, USA.
Glia. 2023 Feb;71(2):377-390. doi: 10.1002/glia.24282. Epub 2022 Oct 26.
Aging can cause morphological transformation in human microglia indicative of cell senescence, termed microglial dystrophy. However, cellular senescence is characterized by additional changes, such as an irregular cell cycle arrest, and a variety of metabolic and molecular changes including a senescence-associated secretory phenotype, dysfunction of degradation mechanisms, and altered DNA damage response. Here, we tested whether dystrophic microglia display customary markers of cell senescence by performing double and triple staining in sections of the temporal lobe and brain stem from 14 humans. We found that markers related to oxidative damage, such as upregulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), hemeoxygenase-1 (HO-1), and y-H2AX, as well as inclusion of lipofuscin, do not or only exceptionally colocalize with dystrophic microglia. Further, we did not observe a decline in lamin B1 around nuclear laminae in either dystrophic or ramified microglia within the same microscopic field. Only ferritin expression, which is known to increase with aging in CNS microglia, was frequently observed in dystrophic, but rarely in ramified microglial cells. We conclude that neither dystrophic nor ramified microglia in human brain exhibit significant expression of conventional senescence markers associated with oxidative stress, and that ferritin is the dominant immunophenotypic change related to microglial aging. We suggest that multiple pathogenic mechanisms other than those driving cellular senescence contribute to dystrophic transformation of microglia.
衰老是导致人类小胶质细胞形态转化的原因，这种转化被称为小胶质细胞营养不良。然而，细胞衰老的特征还包括其他变化，如不规则的细胞周期停滞，以及各种代谢和分子变化，包括衰老相关分泌表型、降解机制功能障碍和改变的 DNA 损伤反应。在这里，我们通过对 14 名人类颞叶和脑干切片进行双重和三重染色，测试了营养不良的小胶质细胞是否表现出细胞衰老的典型标志物。我们发现，与氧化损伤相关的标志物，如 8-羟基-2'-脱氧鸟苷（8-OHdG）、血红素加氧酶-1（HO-1）和 y-H2AX 的上调，以及脂褐素的包含物，与营养不良的小胶质细胞不相关或仅偶尔相关。此外，我们在同一显微镜视野中，既没有观察到核层周围核层蛋白 B1 的减少，也没有观察到营养不良或分支状小胶质细胞中的减少。只有铁蛋白表达，已知在中枢神经系统小胶质细胞中随年龄增长而增加，在营养不良的小胶质细胞中经常观察到，而在分支状小胶质细胞中很少观察到。我们得出结论，无论是在人类大脑中的营养不良还是分支状小胶质细胞中，都没有明显表达与氧化应激相关的传统衰老标志物，铁蛋白是与小胶质细胞衰老相关的主要免疫表型变化。我们认为，除了导致细胞衰老的机制外，还有其他多种致病机制导致小胶质细胞的营养不良转化。
