Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice
Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice
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DOI：
10.1016/j.neulet.2009.01.075
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发表时间：
2009-03-27
影响因子：
2.5
通讯作者：
Deller, Thomas
中科院分区：
文献类型：
--
作者：
Frank, Stefanie;Copanaki, Ekaterini;Deller, Thomas
阿尔茨海默病（Alzheimer's disease，AD）是一种以淀粉样蛋白（amyloid-P）在老年脑组织中的病理性沉积为特征的疾病。淀粉样蛋白β从脑组织中的无效清除被认为在这些沉积物的发病机制中起主要作用。由于淀粉样蛋白-P清除可能涉及通过Toll样受体激活小胶质细胞，并且由于这些受体及其信号传导途径被认为是潜在的治疗靶点，因此我们研究了Toll样受体（TLR）mRNA在AD动物模型（APP 23转基因小鼠）中的表达。激光显微切割用于从老年APP 23转基因小鼠和年龄匹配对照的皮质收获斑块、斑块周围组织和无斑块组织。采用实时RT-PCR定量这些组织中不同tlr mRNA的表达水平。这揭示了tlr 2、tlr 4的强烈上调。与无斑块组织相比，斑块材料中的tlr 5、tlr 7和tlr 9 mRNA。相反，tlr 3没有显著上调。与年龄匹配的对照小鼠相比，无斑块组织没有显示任何tlr mRNA的表达增加。TLR 2和小胶质细胞标记物Iba 1的双重免疫荧光用于证明TLR 2在斑块相关小胶质细胞上的定位。综上所述，这些数据显示了在老年APP 23转基因小鼠的斑块相关脑组织中编码表面TLR的mRNA的强烈上调。由于TLR上调仅限于斑块，因此修饰TLR信号传导可能是去除斑块的有前景的治疗策略。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Alzheimer's disease (AD) is characterized by the pathological deposition of amyloid-P protein in the aged brain. Inefficient clearance of amyloid-beta from brain tissue is believed to play a major role in the pathogenesis of these deposits. Since amyloid-P clearance likely involves activation of microglial cells via toll-like receptors and since these receptors and their signaling pathways are regarded as potential therapeutic targets, we have studied the expression of toll-like receptor (tlr) mRNAs in an animal model of AD (APP23 transgenic mice). Laser microdissection was used to harvest plaques, tissue surrounding plaques and plaque-free tissue from cortex of aged APP23 transgenic mice and age-matched controls. Real-time RT-PCR was employed to quantify expression levels of different tlr mRNAs in these tissues. This revealed a strong upregulation of tlr2, tlr4. tlr5, tlr7 and tlr9 mRNAs in plaque material compared to plaque-free tissue. In contrast, tlr3 was not significantly upregulated. Plaque-free tissue did not show an increased expression of any tlr mRNAs compared to age-matched control mice. Double-immunofluorescence for TLR2 and the microglial marker Iba1 was used to demonstrate localization of TLR2 on plaque-associated microglia. Taken together, these data show a strong upregulation of mRNAs encoding surface TLRs in plaque-associated brain tissue of aged APP23 transgenic mice. Since TLR-upregulation is restricted to plaques, modifying TLR-signaling may be a promising therapeutic strategy for plaque removal. (C) 2009 Elsevier Ireland Ltd. All rights reserved.