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

轴突运输损伤导致神经变性和突触丢失。β-淀粉样蛋白（Aβ）在阿尔茨海默病的发病机制中起关键作用。本研究表明，Aβ能迅速抑制培养大鼠海马神经元的快速轴突转运。Aβ的作用具有进行性和不可逆性，可被肌动蛋白解聚剂latrunculin B阻断，可被肌动蛋白聚合剂jasplakinolide模拟。Aβ片段Aβ_<31-35>和Aβ_<25-35>发挥了作用丝的聚集和轴突运输的抑制作用，而Aβ_<15-20>则没有作用。含有30-100 kDa分子量的Aβ_<1-42>孵育7天也能抑制与细胞内肌动蛋白聚集相关的轴突运输，而新鲜溶解的Aβ_<1-40>、孵育的Aβ_<1-40>和新鲜的Aβ_<1-42>则没有影响。这些结果表明AB通过肌动蛋白聚合和聚集抑制轴突运输。β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。全长a β可能是有效的，当它代表一个结构，这些活性残基可以进入细胞膜。目前的结果可能为阿尔茨海默病的早期发病机制提供见解。

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.