Inhibition of axonal transport of hippocampal neurons by amyloid proteins: relation to Alzheimer's disease

淀粉样蛋白抑制海马神经元轴突运输：与阿尔茨海默病的关系

• 批准号: 11670638
• 负责人: HIRUMA Hiromi
• 金额: $ 1.47万
• 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: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670638/
• 关键词: amyloid protein; hippocampus; axonal transport; Alzheimer's disease; tau phosphorylation; ニューロフィラメント

Recent studies on Alzheimer's disease have suggested that β-amyloid protein is closely related to the pathogenesis of this disease. In the present study, the effect of β-amyloid protein on axonal transport of particles in neurites of cultured rat hippocampal neurons was investigated using video-enhanced microscopy. Application of β-amyolid protein_<25-35> (Aβ_<25-35>) rapidly decreased the number of particles transported in anterograde and retrograde directions. This effect was sustained during the application. When the concentration of Aβ_<25-35> was increased, the effect was irreversible and progressive. Axonal transport of mitochondria was also reduced. When Aβ_<25-35> was per fused intracellularly using patch pipettes, axonal transport was extremely reduced. The inhibitory effect of Aβ_<25-35> was blocked by the pre-treatment with butyrolactone I, a cyclin-dependent kinase 5 (Cdk5) to hyperphosphorylate tau proteins. These results indicate that β-amyloid protein inhibits axonal transport of particles including mitochondria. This effect may be induced by Cdk5-mediated phosphorylation of tau proteins. Reduction in axonal transport by β-amyloid protein may be related to the pathogenesis of Alzheimer's disease.

最近对阿尔茨海默病的研究表明，β-淀粉样蛋白与该病的发病机制密切相关。本研究用视频增强显微镜观察了β-淀粉样蛋白对培养的大鼠海马神经元轴突内颗粒轴突运输的影响。应用β-淀粉样蛋白25-35&gt；(Aβ_&lt；25-35&gt；)可迅速减少顺行和逆行方向运输的颗粒数量。这一效果在应用过程中一直保持不变。当Aβ_(25-35)浓度增加时，这种作用是不可逆的，是渐进的。线粒体的轴突运输也减少。当Aβ_&lt；25-35；细胞内使用贴片吸管进行细胞内融合时，轴突运输显著减少。β_&lt；25-35&gt；的抑制作用可被丁内酯I(一种细胞周期蛋白依赖性激酶5(CDK5))阻断。这些结果表明，β-淀粉样蛋白抑制了包括线粒体在内的颗粒的轴突运输。这种作用可能是通过CDK5介导的tau蛋白的磷酸化来实现的。β-淀粉样蛋白减少轴突运输可能与阿尔茨海默病的发病机制有关。

项目成果

Hiruma H, Nishida S, Katakura T, Kusakabe T, Takenaka T, Kawakami T: "Extracellular potassium rapidly inhibits axonal transport of particles in cultured mouse dorsal root ganglion neurites"Journal of Neurobiolgy. 38. 225-233 (1999)

Hiruma H、Nishida S、Katakura T、Kusakabe T、Takenaka T、Kawakami T：“细胞外钾快速抑制培养的小鼠背根神经节神经突中颗粒的轴突运输”神经生物学杂志。

Hiruma H, Maruyama H, Simada ZB, Katakura T, Hoka S, Takenaka T, Kawakami T: "Lidocaine inhibits neurite growth in mouse dorsal root ganglion cells in culture"Acta Neurobiol Exp (Warsz). 59. 323-327 (1999)

Hiruma H、Maruyama H、Simada ZB、Katakura T、Hoka S、Takenaka T、Kawakami T：“利多卡因抑制培养物中小鼠背根神经节细胞的神经突生长”Acta Neurobiol Exp (Warsz)。

Hiruma H. Maruyama H. Katakura T. Simada ZB. Nishida S. Hoka S. Takenaka T. Kawakami T.: "Extracellular potassium rapidly inhibits axonal transport of particles in cultured mouse dorsal root ganglion neurites."Journal of Neurobiology. 38・2. 225-233 (1999)

Hiruma H. ​​Maruyama H. ​​Katakura T. Simada ZB. Nishida S. Hoka S. Takenaka T. Kawakami T.：“细胞外钾快速抑制培养的小鼠背根神经节神经突中颗粒的轴突运输。”神经生物学杂志38・2 . 225-233 (1999)

Amano R, Hiruma H, Nishida S, Kawakami T, Shimizu K: "Inhibitory effect of histamine on axonal transport in cultured mouse dorsal root ganglion neurons"Neuroscience Research. 41. 201-206 (2001)

Amano R、Hiruma H、Nishida S、Kawakami T、Shimizu K：“组胺对培养的小鼠背根神经节神经元轴突运输的抑制作用”神经科学研究。

Kanai A, Hiruma H, Katakura T, Sase S, Kawakami T, Hoka S: "Low-concentration lidocaine rapidly inhibits axonal transport in cultured mouse dorsal root ganglion neurons"Anesthesiology. 95. 675-680 (2001)

Kanai A、Hiruma H、Katakura T、Sase S、Kawakami T、Hoka S：“低浓度利多卡因快速抑制培养的小鼠背根神经节神经元的轴突运输”麻醉学。