INTRACEREBRAL MICROINJECTION OF INTERLEUKIN-4/INTERLEUKIN-13 REDUCES β-AMYLOID ACCUMULATION IN THE IPSILATERAL SIDE AND IMPROVES COGNITIVE DEFICITS IN YOUNG AMYLOID PRECURSOR PROTEIN 23 MICE
INTRACEREBRAL MICROINJECTION OF INTERLEUKIN-4/INTERLEUKIN-13 REDUCES β-AMYLOID ACCUMULATION IN THE IPSILATERAL SIDE AND IMPROVES COGNITIVE DEFICITS IN YOUNG AMYLOID PRECURSOR PROTEIN 23 MICE
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DOI：
10.1016/j.neuroscience.2012.01.049
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发表时间：
2012-04-05
期刊：
影响因子：
3.3
通讯作者：
Nakayama, H.
中科院分区：
文献类型：
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作者：
Kawahara, K.;Suenobu, M.;Nakayama, H.
我们先前报道了抗炎细胞因子白细胞介素（IL）-4诱导大鼠原代2型小胶质细胞中寡聚β-淀粉样蛋白（A β（1-42））的选择性清除。在本研究中，我们研究了IL-4和IL-13是否可以激活小胶质细胞以诱导体内A β清除并改善淀粉样前体蛋白转基因小鼠APP 23小鼠的认知缺陷。我们向4.5和9月龄的APP 23小鼠及其野生型同窝小鼠的一侧半球脑内微量注射IL-4和IL-13的混合物或生理盐水溶剂，之后我们通过Morris水迷宫试验评估这些治疗对空间学习和记忆的影响以及对A β累积量的影响。细胞因子注射显著改善了4.5个月大的APP 23小鼠的记忆缺陷，但在9个月大的APP 23小鼠中没有这样做，尽管在同侧新皮质中在两个年龄组的APP 23小鼠中观察到类似的A β减少。在探针试验中，细胞因子注射改善了9个月大野生型（WT）小鼠的记忆障碍。对4.5个月大的APP 23小鼠的免疫组织化学分析显示，在细胞因子注射后2天，存在增加数量的小胶质细胞。除了在活化的小胶质细胞中诱导CD 36表达外，主要在神经元中脑啡肽酶的表达增加，表明细胞因子通过缓冲液可提取的非斑块形式的神经元内和神经元内A β肽的降解和清除来改善认知缺陷。双重免疫染色还显示，大多数活化的小胶质细胞具有M2样表型。这种IL-4/IL-13诱导A β清除的独特机制可能为早期预防和/或治疗阿尔茨海默病提供了另一种策略。(C)2012年IBRO。由爱思唯尔有限公司出版。保留所有权利。
We previously reported that the anti-inflammatory cytokine interleukin (IL)-4 induced selective clearance of oligomeric beta-amyloid (A beta(1-42)) in rat primary type 2 microglial cells. For the present study, we investigated whether IL-4 and IL-13 could activate microglial cells to induce A beta clearance in vivo and improve cognitive deficits in APP23 mice, which are amyloid precursor protein transgenic mice. We administered an intracerebral microinjection of a mixture of IL-4 and IL-13 or of saline vehicle into one hemisphere of APP23 mice and their wild-type littermates, 4.5 and 9 months old, after which we evaluated the effects of these treatments on spatial learning and memory by Morris Water Maze test and on accumulated amounts of A beta. The cytokine injection significantly improved memory deficits of 4.5-month-old APP23 mice, but did not do so in 9-month-old APP23 mice, even though similar A beta reductions were observed in both age groups of APP23 mice in the ipsilateral neocortex. The cytokine injection improved memory impairment of 9-month-old wild-type (WT) mice in the probe trial. Immunohistochemical analysis of the 4.5-month-old APP23 mice revealed the presence of increased numbers of microglial cells at 2 days after the cytokine injection. In addition to induced CD36 expression in the activated microglia, increased expression of neprilysin, mainly in neurons, suggested that the cytokines improved the cognitive deficits via degradation and clearance of intra- and extraneuronal A beta peptides, of buffer-extractable nonplaque form. Double immunostaining also revealed that most of the activated microglia had the M2-like phenotype. This unique mechanism of IL-4/IL-13 induced clearance of A beta may provide an additional strategy to prevent and/or cure Alzheimer's disease at early stage. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.