Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice
Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice
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DOI：
10.1016/j.bbi.2015.03.006
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发表时间：
2015-08-01
影响因子：
15.1
通讯作者：
Finsen, Bente
中科院分区：
文献类型：
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作者：
Babcock, Alicia A.;Ilkjaer, Laura;Finsen, Bente
β-淀粉样蛋白（全部）斑块和慢性神经炎症是阿尔茨海默病的重要神经病理学特征。老年大脑中的小胶质细胞有潜力产生细胞因子，例如 TNF 和 IL-1 家族成员（IL-1 α、IL-10 和 IL-1Ra），并在阿尔茨海默病中吞噬 A β，但这些过程之间的相互关系知之甚少。在这里，我们显示 APP(swe)/PS1(Delta E9) Tg 小鼠新皮质中的％所有斑块负荷随年龄呈 S 形轨迹，并与可溶性 Aβ 40 和 Aβ42 呈正相关。所有测量值均与 CD11b、TNF 和 IL-1Ra 的 mRNA 水平中度相关。通过流式细胞术评估新皮质CD11b(+)(CD45(+))小胶质细胞的细胞因子产生和Aβ负荷。虽然老年小鼠中的大多数小胶质细胞产生 IL-1Ra，但相对较低比例的小胶质细胞产生 TNF、IL-1 α 和 IL-1 β。然而，APP/PSI Tg 小鼠中小胶质细胞产生的这些细胞因子普遍增加。吞噬内源产生的小胶质细胞仅在 APP/PSI Tg 小鼠中观察到。在具有特定细胞因子谱的小胶质细胞中观察到吞噬指数和总 Aβ 负荷的差异。 IL-1α(+)和IL-1Ra(+)小胶质细胞的吞噬指数和总Aβ负荷均高于不产生这些细胞因子的小胶质细胞。相反，与IL-1β(-)和TNF-小胶质细胞相比，IL-1β(+)和TNF+小胶质细胞的总All负荷较低，并且TNF+小胶质细胞的吞噬指数也较低。使用GFP骨髓嵌合小鼠，即使在选择性分析通常被认为是浸润细胞的CD11b(+)CD45(high)细胞后，我们也证实APP/PSI Tg小鼠中大多数新皮质CD11b(+)(CD45(+))小胶质细胞是常驻细胞(GFP(-))。总之，我们的数据表明细胞因子表达与年龄和所有病理学选择性相关，并且与 APP/PSI Tg 小鼠吞噬小胶质细胞中 Aβ 负载的改变相关。这些发现对于了解阿尔茨海默病中小胶质细胞细胞因子产生和 Aβ 吞噬作用的调节具有重要意义。 (C) 2015 Elsevier Inc. 保留所有权利。
Beta-amyloid (All) plaques and chronic neuroinflammation are significant neuropathological features of Alzheimer's disease. Microglial cells in aged brains have potential to produce cytokines such as TNF and IL-1 family members (IL-I alpha, IL-10, and IL-1Ra) and to phagocytose A beta in Alzheimer's disease, however the inter-relationship between these processes is poorly understood. Here we show that % All plaque load followed a sigmoidal trajectory with age in the neocortex of APP(swe)/PS1(Delta E9) Tg mice, and correlated positively with soluble A beta 40 and A beta 42. All measures were moderately correlated with mRNA levels of CD11b, TNF, and IL-1Ra. Cytokine production and A beta load were assessed in neocortical CD11b(+)(CD45(+)) microglia by flow cytometry. Whereas most microglia in aged mice produced IL-1Ra, relatively low proportions of microglia produced TNF, IL-1 alpha, and IL-1 beta. However, microglial production of these latter cytokines was generally increased in APP/PSI Tg mice. Microglia that phagocytosed endogenously-produced All were only observed in APP/PSI Tg mice. Differences in phagocytic index and total A beta load were observed in microglia with specific cytokine profiles. Both phagocytic index and total A beta load were higher in IL-1 alpha(+) and IL-1Ra(+) microglia, than microglia that did not produce these cytokines. In contrast, total All load was lower in IL-1 beta(+) and TNF+ microglia, compared to IL-1 beta(-) and TNF- microglia, and TNF+ microglia also had a lower phagocytic index. Using GFP bone marrow chimeric mice, we confirmed that the majority of neocortical CD11b(+)(CD45(+)) microglia were resident cells (GFP(-)) in APP/PSI Tg mice, even after selectively analysing CD11b(+)CD45(high) cells, which are typically considered to be infiltrating cells. Together, our data demonstrate that cytokine expression is selectively correlated with age and All pathology, and is associated with an altered A beta load in phagocytic microglia from APP/PSI Tg mice. These findings have implications for understanding the regulation of microglial cytokine production and phagocytosis of A beta in Alzheimer's disease. (C) 2015 Elsevier Inc. All rights reserved.