Do the extracellular vesicles excreted during neuronal cell death play a neuron-glia signalling role in neurodegeneration.
Do the extracellular vesicles excreted during neuronal cell death play a neuron-glia signalling role in neurodegeneration.
复制标题
神经元细胞死亡过程中分泌的细胞外囊泡在神经退行性变中发挥神经元-胶质细胞信号传导作用吗？
DOI：
10.1002/alz.067065
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Barnard J
中科院分区：
文献类型：
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作者：
Barnard J
研究背景在神经退行性变过程中，垂死的神经元细胞可能通过释放细胞外小泡来触发神经炎症反应或告知邻近的神经胶质细胞其死亡状态。核凋亡是一种由自噬阻断引起的新型细胞死亡，首次在齿状核红核-苍白球路易体萎缩（DRPLA）小鼠模型中发现。在核凋亡期间，细胞表现出噬核（核破裂）和囊泡排出的迹象。了解神经变性的分子基础对于提供可能的治疗干预是重要的。我们的假设是，垂死的神经元释放囊泡被吞噬的小胶质细胞，这导致炎症respons.MethodUsingex vivosamples从DRPLA小鼠模型，免疫荧光，共聚焦成像，我们研究了病理小胶质细胞的表型。我们使用了具有高水平核下垂的疾病相关脑区域，例如齿状核。为了进一步了解小胶质细胞的反应和可视化这些囊泡可能的吞噬作用，我们还使用了人神经母细胞瘤细胞系诱导核凋亡和纯化释放的囊泡应用于培养的BV 2小胶质细胞样celles.ResultOur的初步数据显示，更多的小胶质细胞存在于DRPLA小鼠中具有高核凋亡活性的病理区域。这些小胶质细胞的分析显示，增加细胞索马大小，减少分支长度，减少每个小胶质细胞的交叉点在DRPLA模型，所有这些都表明增加的激活和derivification的小胶质细胞在DRPLA mice.ConclusionThese研究结果表明，在总的数量，活动，和整体表型的差异在该DRPLA模型中具有高核凋亡的地区的小胶质细胞。这表明在细胞死亡过程中释放的囊泡可能影响小胶质细胞。未来的工作将集中在体外复制这些发现。将从人神经母细胞瘤收集的细胞外囊泡应用于培养的小胶质细胞，以可视化囊泡的摄取，解码其内容物，并进一步观察小胶质细胞反应。这项工作将有助于进一步了解神经胶质细胞信号传导如何促进神经变性。
BackgroundDuring neurodegeneration, dying neuronal cells may trigger neuroinflammatory responses or inform neighbouring glial cells of their dying status by releasing extracellular vesicles. Karyoptosis is a novel cell death caused by a block in autophagy which was first discovered in a dentatorubral‐pallidoluysian atrophy (DRPLA) mouse model. During karyoptosis cells exhibit signs of nucleophagy (nuclear breakdown) and vesicle expulsion. Understanding the molecular underpinnings of neurodegeneration is important for informing possible therapeutic intervention. Our hypothesis is that dying neurons release vesicles which are phagocytosed by microglia, and this leads to an inflammatory response.MethodUsingex vivosamples from the DRPLA mouse model, immunofluorescence, and confocal imaging, we studied the phenotype of microglia pathologically. We used disease‐relevant brain regions with high levels of karyoptosis, such as the dentate nucleus. To further understand the microglial response and visualise the likely phagocytosis of these vesicles, we are also using a human neuroblastoma cell line to induce karyoptosis and purify the released vesicles for application to cultured BV2 microglia‐like cells.ResultOur initial data shows that more microglia are present in pathological areas with high karyoptosis activity in the DRPLA mice. Analysis of these microglia revealed an increased cell soma size, decreased branch length, and decreased intersections per microglia in the DRPLA model, all of which suggest the increased activation and de‐ramification of microglia in DRPLA mice.ConclusionThese findings indicate differences in the total number, activity, and overall phenotype of microglia in areas with high karyoptosis in this DRPLA model. This suggests that the vesicles released during this cell death process may be influencing microglia. Future work will focus on replicating these findingsin vitro. Extracellular vesicles collected from human neuroblastoma will be applied to cultured microglia to visualise the uptake of vesicles, decode their contents, and further characterise any microglial response. This work will help further the understanding of how neuron‐glia signalling contributes to neurodegeneration.