摘要
背景:PDGFβ受体及其配体PDGF-BB在神经元损伤例如局部缺血后在体内被上调。当外源性应用时,PDGF-BB对兴奋性毒性和HIV蛋白具有神经保护作用。 目的:鉴于这种生长因子的神经保护能力,我们试图确定PDGF-BB是否会对抗淀粉样蛋白β(1-42)(与阿尔茨海默病(AD)有关的病理因素之一)具有神经保护作用。 方法和结果:在原代海马神经元和人源神经母细胞瘤细胞系SH-SY5Y中,淀粉样蛋白-β处理24小时以浓度依赖性方式降低存活细胞数目。用PDGF-BB预处理未能在初级神经元中提供针对淀粉样蛋白-β的任何神经保护作用,并且在SH-SY5Y细胞中仅有非常有限的保护作用。除了其神经保护作用外,PDGF促进几种系统中的细胞生长和分裂,并且将PDGFBB单独应用于血清饥饿的SH-SY5Y细胞导致细胞数目增加。淀粉样蛋白-β减弱了PDGF-BB的促有丝分裂效应,抑制了PDGF-BB诱导的PDGFβ受体磷酸化,并且减弱了PDGF-BB保护神经元抵抗NMDA诱导的兴奋性毒性的能力。尽管淀粉样蛋白-β抑制PDGFβ受体活化的能力,但免疫沉淀实验未能检测到淀粉样蛋白-β与PDGF-BB或PDGFβ受体之间的物理相互作用。然而,PDGFβ受体(专属细胞内信号传导途径)的G蛋白偶联受体反式激活仍然不受淀粉样β的存在影响。 结论:由于PDGF系统在神经元损伤时上调,淀粉样蛋白β抑制这种内源性神经保护系统的能力应在AD病理生理学的背景下进一步研究。
关键词: 淀粉样蛋白-β,PDGF-BB,PDGFβ受体,生长因子,神经保护,阿尔茨海默病。
Current Alzheimer Research
Title:Amyloid-β Inhibits PDGFβ Receptor Activation and Prevents PDGF-BBInduced Neuroprotection
Volume: 15 Issue: 7
关键词: 淀粉样蛋白-β,PDGF-BB,PDGFβ受体,生长因子,神经保护,阿尔茨海默病。
摘要: Background: PDGFβ receptors and their ligand, PDGF-BB, are upregulated in vivo after neuronal insults such as ischemia. When applied exogenously, PDGF-BB is neuroprotective against excitotoxicity and HIV proteins.
Objective: Given this growth factor's neuroprotective ability, we sought to determine if PDGF-BB would be neuroprotective against amyloid-β (1-42), one of the pathological agents associated with Alzheimer's disease (AD).
Methods and Results: In both primary hippocampal neurons and the human-derived neuroblastoma cell line, SH-SY5Y, amyloid-β treatment for 24 h decreased surviving cell number in a concentrationdependent manner. Pretreatment with PDGF-BB failed to provide any neuroprotection against amyloid-β in primary neurons and only very limited protective effects in SH-SY5Y cells. In addition to its neuroprotective action, PDGF promotes cell growth and division in several systems, and the application of PDGFBB alone to serum-starved SH-SY5Y cells resulted in an increase in cell number. Amyloid-β attenuated the mitogenic effects of PDGF-BB, inhibited PDGF-BB-induced PDGFβ receptor phosphorylation, and attenuated the ability of PDGF-BB to protect neurons against NMDA-induced excitotoxicity. Despite the ability of amyloid-β to inhibit PDGFβ receptor activation, immunoprecipitation experiments failed to detect a physical interaction between amyloid-β and PDGF-BB or the PDGFβ receptor. However, G protein-coupled receptor transactivation of the PDGFβ receptor (an exclusively intracellular signaling pathway) remained unaffected by the presence of amyloid-β.
Conclusions: As the PDGF system is upregulated upon neuronal damage, the ability of amyloid-β to inhibit this endogenous neuroprotective system should be further investigated in the context of AD pathophysiology.
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Cite this article as:
Amyloid-β Inhibits PDGFβ Receptor Activation and Prevents PDGF-BBInduced Neuroprotection, Current Alzheimer Research 2018; 15 (7) . https://dx.doi.org/10.2174/1567205015666180110110321
DOI https://dx.doi.org/10.2174/1567205015666180110110321 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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