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A new approach for treatments against central nervous disease : Structure of albumin-derived microglial activating factor

治疗中枢神经疾病的新方法：白蛋白衍生小胶质细胞激活因子的结构

基本信息

批准号：
10558114
负责人：
NAKAMURA Yoichi
金额：
$ 6.66万
依托单位：
EHIME UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

Microglial activation has recently been recognized as a cause of damage in various neurodegenerative diseases. A possible mechanism underlying this damage is the activation of microglia by serum factors leaked through a disruption of the blood-brain barrier, which in turn trigger microglial cell proliferation and the release of various substances toxic to neurons, such as superoxide (OィイD22ィエD2). We recently reported that serum albumin enhanced OィイD22ィエD2 production in cultured rat microglia stimulated by phorbol ester (Si e al., 1997, Glia 21 : 413-418). In the present report, we identify the active site of this enhancement within the albumin molecule. We purified an active subfragment from trypsin-treated bovine serum albumin (BSA) that was composed of 12-mer and 33-mer peptides connected by a disulfide bond. The chemically synthesized 12-mer peptide showed activity within a concentration range (ca. 10ィイD1-7ィエD1 M) equivalent to that of albumin. The activities of a series of synthesized peptides conclusively indicated that the minimum active sequence was Leu-His-Thr-Leu. Enhancement of OィイD22ィエD2 production by this peptide was also observed in macrophages quiescently prepared from rat peritoneal fluid. The present study may contribute toward the development of a tool to suppress the pathological activation of microglia and may also shed light on albumin's role in the biological defense system.

小胶质细胞活化最近被认为是各种神经退行性疾病损伤的原因。这种损伤的一个可能机制是通过血脑屏障破坏而泄漏的血清因子激活小胶质细胞，这反过来又触发小胶质细胞增殖和释放对神经元有毒的各种物质，如超氧化物（O D22 D2）。我们最近报道了血清白蛋白增强了培养的大鼠小胶质细胞中由佛波醇酯刺激的O-22-D2的产生（Si等人，1997，Glia 21：413-418）。在本报告中，我们确定了这种增强白蛋白分子内的活性位点。我们从胰蛋白酶处理的牛血清白蛋白（BSA）中纯化了一个活性亚片段，该片段由12-mer和33-mer肽通过二硫键连接组成。化学合成的12聚体肽在一定浓度范围内（约100 μ g/ml）显示出活性。10 μ g D1-7 μ g D1 M），相当于白蛋白。对一系列合成肽的活性测定结果表明，最小活性序列为Leu-His-Thr-Leu。在大鼠腹腔液中静止制备的巨噬细胞中也观察到该肽对O β D22 β D2产生的增强作用。本研究可能有助于开发一种抑制小胶质细胞病理激活的工具，也可能揭示白蛋白在生物防御系统中的作用。