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β-Amyloid-induced changes in cytoskeletons and impairment of axonal transport

β-淀粉样蛋白诱导的细胞骨架变化和轴突运输受损

基本信息

批准号：
15500245
负责人：
HIRUMA Hiromi
金额：
$ 0.9万
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：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15500245/
关键词：
β-Amyloid Axonal transport Cytoskeleton Actin filaments Alzheimer's disease

项目摘要

Impairment of axonal transport leads to neurodegeneration and synapse loss. β-Amyloid (Aβ) has critical roles in the pathogenesis of Alzheimer's disease. The present study demonstrated that Aβ rapidly inhibited fast axonal transport in cultured rat hippocampal neurons. The effect of Aβ was progressive and irreversible, was prevented by the actin-depolymerizing agent latrunculin B, and was mimicked by the actin-polymerizing agent jasplakinolide. Aβ induced intracellular actin aggregation, which was prevented by latrunculin B. Aβ fragments Aβ_<31-35> and Aβ_<25-35> exerted the aggregation of action filaments and the inhibition of axonal transport, but Aβ_<15-20> had no effect. Aβ_<1-42> incubated for 7 days, which specifically contained 30-100 kDa molecular weight assemblies, also caused an inhibition of axonal transport associated with intracellular actin aggregation, whereas freshly dissolved Aβ_<1-40>, incubated Aβ_<1-40>, and fresh Aβ_<1-42> had no effect. These results suggest that AB inhibits axonal transport via actin polymerization and aggregation. The ability of Aβ to inhibit axonal transport seems to require active amino acid residues, which is probably present in the 31-35 sequence. Full-length Aβ may be effective when it represents a structure where these active residues can access the cell membrane. The present results may provide insight into the early pathogenetic mechanisms of Alzheimer's disease.

轴突运输受损会导致神经退行性变和突触丢失。β-淀粉样蛋白（β-Amyloid，Aβ）在阿尔茨海默病（Alzheimer's disease，AD）的发病机制中起重要作用。本研究表明，Aβ可迅速抑制培养的大鼠海马神经元的快速轴突运输。Aβ的作用是进行性的和不可逆的，可被肌动蛋白解聚剂latrunculin B阻止，并被肌动蛋白聚合剂jasplakinaline模拟。Aβ诱导细胞内肌动蛋白聚集，这被latrunculin B阻止。Aβ片段Aβ<31-35>_1和Aβ_2<25-35>具有作用丝聚集和轴突运输抑制作用，而Aβ<15-20>_2无作用。Aβ_<1-42>（30-100 kDa）也能抑制与细胞内肌动蛋白聚集有关的轴突运输，而新鲜溶解的Aβ_（30-100 kDa）<1-40>、孵育的Aβ_（30 - 100 kDa）<1-40>和新鲜的Aβ_（30 - 100 kDa）则<1-42>无此作用。这些结果表明，AB抑制轴突运输通过肌动蛋白聚合和聚集。Aβ抑制轴突运输的能力似乎需要活性氨基酸残基，这可能存在于31-35序列中。当全长Aβ代表这些活性残基可以进入细胞膜的结构时，它可能是有效的。本研究结果可能为阿尔茨海默病的早期发病机制提供新的认识。