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Insertion of beta-amyloid protein into the cell membrane followed by actin aggregation and impairment of axonal transport

将 β-淀粉样蛋白插入细胞膜，随后肌动蛋白聚集并损害轴突运输

基本信息

批准号：
17500260
负责人：
HIRUMA Hiromi
金额：
$ 1.66万
依托单位：
Kitasato University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17500260/
关键词：
axonal transport beta-amyloid protein actin cytoskeleton

项目摘要

Beta-Amyloid protein, the primary pathogenic agent of Alzheimer disease, accumulates in the extracellular space in the brain and induces the degeneration of neurons. We have previously clarified that extracellularly applied beta-amyloid protein aggregates cytoskeletal actin and, as a result, impairs axonal transport (an important neuronal function responsible for transport of materials inside the neuronal cells). The purpose of the present study is to clarify how extracellular beta-amyloid protein aggregates intracellular actin. The present results are as follows. In cultured rat hippocampal neurons, 1) video-enhanced microscopy revealed that beta-amyloid protein progressively and irreversively inhibited anterograde and retrograde axonal transport, 2) beta-amyloid protein changed neurite morphology such as a reduction in neurite width, 3) impairment of axonal transport by beta-amyloid protein was blocked by actin depolymerizing agent and mimicked by actin polymerizing agent, 4) fluorescence staining and fluorescent microscopy observation revealed that beta-amyloid protein was strongly attached to the cell and aggregated intracellular actin, 5) beta-amyloid protein was bound to G-actin (monomer globular actin) and aggregated G-actin. These results, considering the previous others' reports indicating that beta-amyloid protein interacts with cell membrane, indicate that beta-amyloid protein possibly inserts into the cell membrane, directly interacts with intracellular actin, and aggregates actin. As a result, beta-amyloid protein causes impairment of axonal transport.

β -淀粉样蛋白是阿尔茨海默病的主要致病因子，它在大脑细胞外空间积聚并诱导神经元变性。我们之前已经阐明，细胞外应用的β -淀粉样蛋白聚集细胞骨架肌动蛋白，从而损害轴突运输（一种重要的神经元功能，负责神经元细胞内物质的运输）。本研究的目的是阐明细胞外β -淀粉样蛋白如何聚集细胞内肌动蛋白。目前的结果如下。在培养的大鼠海马神经元中，1)视频增强显微镜显示β -淀粉样蛋白进行性和不可逆地抑制轴突的顺行和逆行运输；2)β -淀粉样蛋白改变神经突的形态，如神经突宽度的减少；3)β -淀粉样蛋白对轴突运输的损害被肌动蛋白解聚剂阻断，并被肌动蛋白聚合剂模拟。4)荧光染色和荧光显微镜观察发现β -淀粉样蛋白强烈附着于细胞并聚集胞内肌动蛋白；5)β -淀粉样蛋白与g -肌动蛋白（单体球状肌动蛋白）结合并聚集g -肌动蛋白。这些结果，结合前人关于β -淀粉样蛋白与细胞膜相互作用的报道，表明β -淀粉样蛋白可能插入细胞膜，直接与细胞内肌动蛋白相互作用，并聚集肌动蛋白。因此，β -淀粉样蛋白导致轴突运输受损。