Raj Divya, Yin Zhuoran, Breur Marjolein, Doorduin Janine, Holtman Inge R, Olah Marta, Mantingh-Otter Ietje J, Van Dam Debby, De Deyn Peter P, den Dunnen Wilfred, Eggen Bart J L, Amor Sandra, Boddeke Erik
Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of GroningenGroningen, Netherlands.
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, China.
Front Mol Neurosci. 2017 Jun 30;10:206. doi: 10.3389/fnmol.2017.00206. eCollection 2017.
Chronic neuroinflammation, which is primarily mediated by microglia, plays an essential role in aging and neurodegeneration. It is still unclear whether this microglia-induced neuroinflammation occurs globally or is confined to distinct brain regions. In this study, we investigated microglia activity in various brain regions upon healthy aging and Alzheimer's disease (AD)-related pathology in both human and mouse samples. In purified microglia isolated from aging mouse brains, we found a profound gene expression pattern related to pro-inflammatory processes, phagocytosis, and lipid homeostasis. Particularly in white matter microglia of 24-month-old mice, abundant expression of phagocytic markers including Mac-2, Axl, CD16/32, Dectin1, CD11c, and CD36 was detected. Interestingly, in white matter of human brain tissue the first signs of inflammatory activity were already detected during middle age. Thus quantification of microglial proteins, such as CD68 (commonly associated with phagocytosis) and HLA-DR (associated with antigen presentation), in postmortem human white matter brain tissue showed an age-dependent increase in immunoreactivity already in middle-aged people (53.2 ± 2.0 years). This early inflammation was also detectable by non-invasive positron emission tomography imaging using [C]-(R)-PK11195, a ligand that binds to activated microglia. Increased microglia activity was also prominently present in the white matter of human postmortem early-onset AD (EOAD) brain tissue. Interestingly, microglia activity in the white matter of late-onset AD (LOAD) CNS was similar to that of the aged clinically silent AD cases. These data indicate that microglia-induced neuroinflammation is predominant in the white matter of aging mice and humans as well as in EOAD brains. This white matter inflammation may contribute to the progression of neurodegeneration, and have prognostic value for detecting the onset and progression of aging and neurodegeneration.
慢性神经炎症主要由小胶质细胞介导，在衰老和神经退行性变中起重要作用。目前尚不清楚这种由小胶质细胞诱导的神经炎症是全身性发生还是局限于特定脑区。在本研究中，我们在人类和小鼠样本中研究了健康衰老和阿尔茨海默病（AD）相关病理状态下不同脑区的小胶质细胞活性。在从衰老小鼠大脑中分离出的纯化小胶质细胞中，我们发现了一种与促炎过程、吞噬作用和脂质稳态相关的深刻基因表达模式。特别是在24月龄小鼠的白质小胶质细胞中，检测到包括Mac-2、Axl、CD16/32、Dectin1、CD11c和CD36在内的吞噬标记物的丰富表达。有趣的是，在人类脑组织的白质中，炎症活动的最初迹象在中年时就已被检测到。因此，对死后人类白质脑组织中诸如CD68（通常与吞噬作用相关）和HLA-DR（与抗原呈递相关）等小胶质细胞蛋白的定量分析显示，免疫反应性在中年人（53.2±2.0岁）中就已呈现出年龄依赖性增加。这种早期炎症也可以通过使用[C]-(R)-PK11195的非侵入性正电子发射断层扫描成像检测到，[C]-(R)-PK11195是一种与活化小胶质细胞结合的配体。小胶质细胞活性增加在人类死后早发性AD（EOAD）脑组织的白质中也很明显。有趣的是，晚发性AD（LOAD）中枢神经系统白质中的小胶质细胞活性与临床无症状的老年AD病例相似。这些数据表明，小胶质细胞诱导的神经炎症在衰老小鼠和人类的白质以及EOAD大脑中占主导地位。这种白质炎症可能有助于神经退行性变的进展，并且对检测衰老和神经退行性变的发生及进展具有预后价值。
