中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (11): 2131-2142.doi: 10.4103/1673-5374.282261

• 原著:退行性病与再生 • 上一篇    下一篇

淀粉样β蛋白神经毒性与胰岛素样生长因子转运、溶酶体途径和细胞外基质受体的相互作用

  

  • 出版日期:2020-11-15 发布日期:2020-08-23

Amyloid-beta peptide neurotoxicity in human neuronal cells is associated with modulation of insulin-like growth factor transport, lysosomal machinery and extracellular matrix receptor interactions

Liting Deng 1 , Paul A. Haynes 1 , Yunqi Wu 2 , Ardeshir Amirkhani 2 , Karthik Shantharam Kamath 2 , Jemma X. Wu 2 , Kanishka Pushpitha 3 , Veer Gupta 4 , Stuart Graham 3 , Vivek K. Gupta 3 , Mehdi Mirzaei 1, 2, 3#br#   

  1. 1 Department of Molecular Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW, Australia
    2 Australian Proteome Analysis Facility (APAF), Macquarie University, Sydney, NSW, Australia
    3 Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
    4 School of Medicine, Deakin University, Geelong, VIC, Australia
  • Online:2020-11-15 Published:2020-08-23
  • Contact: Mehdi Mirzaei, MD,mehdi.mirzaei@mq.edu.au; Vivek K. Gupta, MD,vivek.gupta@mq.edu.au.

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摘要：

淀粉样β蛋白神经毒性在阿尔茨海默病神经元受到伤害并在大脑中死亡的过程中起重要作用；然而，导致神经变性的淀粉样β蛋白毒性的分子机制尚不清楚。实验以淀粉样β蛋白1-42处理人成神经细胞瘤细胞SH-SY5Y，试图阐明神经元中淀粉样β蛋白影响的分子途径和网络。以同量异序标签标记的定量蛋白质组学技术研究生化网络变化。淀粉样β蛋白对细胞的分子影响呈时间和剂量依赖性，且治疗持续时间引起细胞蛋白质组差异性的变化更大。淀粉样β蛋白诱导溶酶体，细胞外基质受体相互作用，胰岛素样生长因子转运相关蛋白的早期变化。这些新发现进一步分析了淀粉样β蛋白对神经元作用的分子机制，并为更好地了解淀粉样β蛋白对阿尔茨海默病早期神经变性的影响提供了启示。

orcid: 0000-0001-8727-4984 (Mehdi Mirzaei)

         0000-0002-0202-7843 (Vivek K. Gupta)

关键词:

阿尔茨海默病, 淀粉样β蛋白, 神经变性, 溶酶体, 氧化应激, 蛋白质组学, 核糖体, SH-SY5Y细胞

Abstract: Extracellular deposits of the amyloid-beta peptide (Aβ) are known as the main pathological hallmark of Alzheimer’s disease. In Alzheimer’s disease, neurons are injured and die throughout the brain, a process in which Aβ neurotoxicity is considered to play an important role. However, the molecular mechanisms underlying Aβ toxicity that lead to neurodegeneration are not clearly established. Here we have elucidated the molecular pathways and networks which are impacted by Aβ in neurons using SH-SY5Y human neu- roblastoma cells as a model. These cells were treated with Aβ 1–42 peptides to study changes in biochemical networks using tandem mass tag labeled quantitative proteomic technique followed by computational anal- ysis of the data. The molecular impacts of Aβ on cells were evident in a time- and dose-dependent manner, albeit the duration of treatment induced greater differential changes in cellular proteome compared to the effects of concentration. Aβ induced early changes in proteins associated with lysosomes, collagen chain trimerization and extracellular matrix receptor interaction, complement and coagulation cascade, oxida- tive stress induced senescence, ribosome biogenesis, regulation of insulin-like growth factor transport and uptake by insulin-like growth factor-binding protein. These novel findings provide molecular insights on the effects of Aβ on neurons, with implications for better understanding the impacts of Aβ on early neuro- degeneration in Alzheimer’s disease pathology.

Key words: Alzheimer’s disease, amyloid, lysosomes, neurodegeneration, oxidative stress, proteomics, ribosome, SH-SY5Y cells