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首页> 外文期刊>Neuropathology and applied neurobiology >Accumulation of a repulsive axonal guidance molecule RGMa in amyloid plaques: A possible hallmark of regenerative failure in Alzheimer's disease brains
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Accumulation of a repulsive axonal guidance molecule RGMa in amyloid plaques: A possible hallmark of regenerative failure in Alzheimer's disease brains

机译：淀粉样蛋白斑块中的排斥性轴突导向分子RGMa的积累：阿尔茨海默氏病大脑再生失败的可能标志

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Aims: RGMa is a repulsive guidance molecule that induces the collapse of axonal growth cones by interacting with the receptor neogenin in the central nervous system during development. It remains unknown whether RGMa plays a role in the neurodegenerative process of Alzheimer's disease (AD). We hypothesize that RGMa, if it is concentrated on amyloid plaques, might contribute to a regenerative failure of degenerating axons in AD brains. Methods: By immunohistochemistry, we studied RGMa and neogenin (NEO1) expression in the frontal cortex and the hippocampus of 6 AD and 12 control cases. The levels of RGMa expression were determined by qRT-PCR and Western blot in cultured human astrocytes following exposure to cytokines and amyloid beta (Aβ) peptides. Results: In AD brains, an intense RGMa immunoreactivity was identified on amyloid plaques and in the glial scar. In the control brains, the glial scar and vascular foot processes of astrocytes expressed RGMa immunoreactivity, while oligodendrocytes and microglia were negative for RGMa. In AD brains, a small subset of amyloid plaques expressed a weak NEO1 immunoreactivity, while some reactive astrocytes in both AD and control brains showed an intense NEO1 immunoreactivity. In human astrocytes, transforming growth factor beta-1 (TGFβ1), Aβ1-40 or Aβ1-42 markedly elevated the levels of RGMa, and TGFβ1 also increased its own levels. Coimmunoprecipitation analysis validated the molecular interaction between RGMa and the C-terminal fragment β of amyloid beta precursor protein (APP). Furthermore, recombinant RGMa protein interacted with amyloid plaques in situ. Conclusions: RGMa, produced by TGFβ-activated astrocytes and accumulated in amyloid plaques and the glial scar, could contribute to the regenerative failure of degenerating axons in AD brains.
机译：目的：RGMa是一种排斥性指导分子，在发育过程中通过与中枢神经系统中的受体新生蛋白相互作用而引起轴突生长锥的崩溃。 RGMa是否在阿尔茨海默氏病（AD）的神经退行性过程中发挥作用尚不清楚。我们假设RGMa如果集中在淀粉样蛋白斑块上，可能会导致AD脑中轴突变性的再生失败。方法：通过免疫组织化学，我们研究了6例AD患者和12例对照患者额叶皮层和海马中RGMa和新生蛋白（NEO1）的表达。暴露于细胞因子和淀粉样β（Aβ）肽后，通过qRT-PCR和Western印迹测定培养的人星形胶质细胞中RGMa的表达水平。结果：在AD脑中，在淀粉样斑块和神经胶质瘢痕中发现了强烈的RGMa免疫反应性。在对照脑中，星形胶质细胞的神经胶质瘢痕和血管足突表达了RGMa的免疫反应性，而少突胶质细胞和小胶质细胞则对RGMa阴性。在AD脑中，一小部分淀粉样蛋白斑块表现出弱的NEO1免疫反应性，而AD和对照脑中的一些反应性星形胶质细胞表现出强烈的NEO1免疫反应性。在人类星形胶质细胞中，转化生长因子β-1（TGFβ1），Aβ1-40或Aβ1-42显着提高了RGMa的水平，而TGFβ1也增加了其自身的水平。免疫共沉淀分析验证了RGMa与淀粉样β前体蛋白（APP）的C端片段β之间的分子相互作用。此外，重组RGMa蛋白与淀粉样蛋白斑块原位相互作用。结论：由TGFβ激活的星形胶质细胞产生并积聚在淀粉样斑块和神经胶质瘢痕中的RGMa可能导致AD脑变性轴突再生失败。

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