Defects in cytokine-mediated neuroprotective glial responses to excitotoxic hippocampal injury in senescence-accelerated mouse
Defects in cytokine-mediated neuroprotective glial responses to excitotoxic hippocampal injury in senescence-accelerated mouse
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DOI：
10.1016/j.bbi.2010.08.006
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发表时间：
2011-01-01
影响因子：
15.1
通讯作者：
Shimada, Atsuyoshi
中科院分区：
文献类型：
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作者：
Hasegawa-Ishii, Sanae;Takei, Shiro;Shimada, Atsuyoshi
衰老是损伤累积的结果，理解衰老的机制需要探索控制损伤的细胞和分子系统。衰老加速小鼠倾向10（SAMP 10）已被确定为表现出加速衰老的近交系，其具有比抗衰老对照（SAMR 1）品系更早发生的由于神经变性引起的认知障碍。我们假设SAMP 10小鼠神经胶质细胞的组织保护反应受损。我们注射红藻氨酸（KA）诱导海马损伤，并研究了如何使用3个月大的SAMP 10和SAMR 1小鼠在第3天上调细胞因子。在基于微阵列的上调基因筛选之后，我们进行了实时RT-PCR和免疫组织化学。结果表明，在SAMR 1小鼠受损的海马中，马槟榔碱介导的胶质细胞相互作用协调良好，其中小胶质细胞衍生的干扰素（IFN）-γ通过IFN-γ受体刺激星形胶质细胞，从而诱导CXCL 10和巨噬细胞炎性蛋白（MIP）-1 α的表达，活化的小胶质细胞产生粒细胞-巨噬细胞集落刺激因子（GM-CSF）和骨桥蛋白（OPN）。OPN是最强烈上调的细胞因子。CD 44，一种OPN受体，在神经元中也强烈上调，特别是在神经元和星形胶质细胞上。KA诱导的海马上调这些细胞因子显着减少SAMP 10小鼠相比，SAMR 1小鼠。在KA注射后第30天，SAMP 10而不是SAMR 1小鼠表现出海马层萎缩。由于OPN-CD 44系统对神经保护和重塑至关重要，这些发现突出了SAMP 10小鼠在烟碱介导的神经保护性胶质细胞-神经元相互作用中的缺陷，这可能与SAMP 10小鼠易受年龄相关神经变性影响的机制有关。(C)2010年爱思唯尔公司All rights reserved.
Aging is a result of damage accumulation, and understanding of the mechanisms of aging requires exploration of the cellular and molecular systems functioning to control damage. Senescence-accelerated mouse prone 10 (SAMP10) has been established as an inbred strain exhibiting accelerated aging with an earlier onset of cognitive impairment due to neurodegeneration than the senescence-resistant control (SAMR1) strain. We hypothesized that tissue-protective responses of glial cells are impaired in SAMP10 mice. We injected kainic acid (KA) to induce hippocampal injury and studied how cytokines were upregulated on Day 3 using 3-month-old SAMP10 and SAMR1 mice. Following microarray-based screening for upregulated genes, we performed real-time RT-PCR and immunohistochemistry. Results indicated well-orchestrated cytokine-mediated glial interactions in the injured hippocampus of SAMR1 mice, in which microglia-derived interferon (IFN)-gamma stimulated astrocytes via IFN-gamma receptor and thereby induced expression of CXCL10 and macrophage inflammatory protein (MIP)-1 alpha, and activated microglia produced granulocyte-macrophage colony-stimulating factor (GM-CSF) and osteopontin (OPN). OPN was the most strongly upregulated cytokine. CD44, an OPN receptor, was also strongly upregulated in the neuropil, especially on neurons and astrocytes. KA-induced hippocampal upregulation of these cytokines was strikingly reduced in SAMP10 mice compared to SAMR1 mice. On Day 30 after KA injection, SAMP10 but not SAMR1 mice exhibited hippocampal layer atrophy. Since the OPN-CD44 system is essential for neuroprotection and remodeling, these findings highlight the defects of SAMP10 mice in cytokine-mediated neuroprotective glia-neuron interactions, which may be associated with the mechanism underlying the vulnerability of SAMP10 mice to age-related neurodegeneration. (C) 2010 Elsevier Inc. All rights reserved.