Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes
Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes
复制标题
小胶质细胞和单核细胞中α-突触核蛋白寡聚体摄取的依赖性缺陷
DOI：
10.1007/s00401-015-1504-2
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发表时间：
2016-03-01
影响因子：
12.7
通讯作者：
Danzer, Karin M.
中科院分区：
文献类型：
--
作者：
Bliederhaeuser, Corinna;Grozdanov, Veselin;Danzer, Karin M.
细胞外α-突触核蛋白（α-syn）寡聚体，与外泌体相关或游离，在帕金森病（PD）的发病机制中发挥重要作用。越来越多的证据表明，这些细胞外部分激活小胶质细胞，导致增强的神经元损伤。尽管在研究PD中的神经炎症方面进行了广泛的努力，但对年龄对小胶质细胞活化和吞噬作用的影响知之甚少，特别是细胞外α-syn寡聚体。在这里，我们表明，从成年小鼠中分离的小胶质细胞，与年轻小鼠的小胶质细胞相反，显示吞噬缺陷的游离和外泌体相关的α-syn寡聚体结合增强TNF α分泌。此外，我们还描述了小鼠和人类单核细胞亚群随年龄增长的失调。因此，来自老年供体的人单核细胞也显示出细胞外α-syn的吞噬活性降低。这些发现表明，这些年龄相关的改变可能有助于增加易感性的病原体或异常折叠的蛋白质与年龄的神经退行性疾病。
Extracellular alpha-synuclein (alpha syn) oligomers, associated to exosomes or free, play an important role in the pathogenesis of Parkinson's disease (PD). Increasing evidence suggests that these extracellular moieties activate microglia leading to enhanced neuronal damage. Despite extensive efforts on studying neuroinflammation in PD, little is known about the impact of age on microglial activation and phagocytosis, especially of extracellular alpha syn oligomers. Here, we show that microglia isolated from adult mice, in contrast to microglia from young mice, display phagocytosis deficits of free and exosome-associated alpha syn oligomers combined with enhanced TNF alpha secretion. In addition, we describe a dysregulation of monocyte subpopulations with age in mice and humans. Accordingly, human monocytes from elderly donors also show reduced phagocytic activity of extracellular alpha syn. These findings suggest that these age-related alterations may contribute to an increased susceptibility to pathogens or abnormally folded proteins with age in neurodegenerative diseases.