Extracellular Vesicle-Serpine-1 Affects Neural Progenitor Cell Mitochondrial Networks and Synaptic Density: Modulation by Amyloid Beta and HIV-1.
Extracellular Vesicle-Serpine-1 Affects Neural Progenitor Cell Mitochondrial Networks and Synaptic Density: Modulation by Amyloid Beta and HIV-1.
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DOI：
10.1007/s12035-023-03456-y
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发表时间：
2023-11
影响因子：
5.1
通讯作者：
Toborek, Michal
中科院分区：
文献类型：
--
作者：
Andras, Ibolya E.;Serrano, Nelson;Djuraskovic, Irina;Fattakhov, Nikolai;Sun, Enze;Toborek, Michal
携带淀粉样蛋白β（amyloid beta，EV-A β）的脑内皮细胞外囊泡可转移至神经祖细胞（neural progenitor cells，NPC），导致NPC功能障碍。然而，这种EV介导的A β病理学中涉及的事件尚不清楚。EV-蛋白质组学研究确定Serpine-1（纤溶酶原激活物抑制剂1，PAI-1）作为几种蛋白质-蛋白质相互作用图谱上的主要连接"枢纽"。Serpine-1被描述为A β病理学的关键参与者，也与HIV-1感染有关。因此，这项工作的目的是解决Serpine-1可以通过EV从脑内皮细胞（HBMEC）转移到NPC并导致NPC功能障碍的假设。HBMEC通过EV浓缩和释放Serpine-1，HIV-1和A β增强了这种作用。装载Serpine-1的EV很容易被NPC吸收，HIV-1增强了这一事件。有趣的是，高度特异性的Serpine-1抑制剂PAI 039在HIV-1存在的情况下增加了EV-A β向NPC的转移。PAI 039还部分阻断了受体NPC中线粒体网络形态的改变，这些改变主要发生在HIV + A β-EV转移后。PAI 039部分减弱了HIV-EV介导的NPC中突触蛋白水平的降低，而增加了NPC投射中的突触蛋白水平。这些发现有助于更好地理解HIV感染背景下EV-Serpine-1相关A β病理学的复杂机制。它们与HIV-1相关的神经认知障碍（HAND）有关，旨在阐明HIV感染的神经病理学机制。 在线版本包含补充材料，可通过10.1007/s12035 - 023 - 03456-y获得。
Brain endothelial extracellular vesicles carrying amyloid beta (EV-Aβ) can be transferred to neural progenitor cells (NPCs) leading to NPC dysfunction. However, the events involved in this EV-mediated Aβ pathology are unclear. EV-proteomics studies identified Serpine-1 (plasminogen activator inhibitor 1, PAI-1) as a major connecting “hub” on several protein–protein interaction maps. Serpine-1 was described as a key player in Aβ pathology and was linked to HIV-1 infection as well. Therefore, the aim of this work was to address the hypothesis that Serpine-1 can be transferred via EVs from brain endothelial cells (HBMEC) to NPCs and contribute to NPC dysfunction. HBMEC concentrated and released Serpine-1 via EVs, the effect that was potentiated by HIV-1 and Aβ. EVs loaded with Serpine-1 were readily taken up by NPCs, and HIV-1 enhanced this event. Interestingly, a highly specific Serpine-1 inhibitor PAI039 increased EV-Aβ transfer to NPCs in the presence of HIV-1. PAI039 also partially blocked mitochondrial network morphology alterations in the recipient NPCs, which developed mainly after HIV + Aβ-EV transfer. PAI039 partly attenuated HIV-EV-mediated decreased synaptic protein levels in NPCs, while increased synaptic protein levels in NPC projections. These findings contribute to a better understanding of the complex mechanisms underlying EV-Serpine-1 related Aβ pathology in the context of HIV infection. They are relevant to HIV-1 associated neurocognitive disorders (HAND) in an effort to elucidate the mechanisms of neuropathology in HIV infection. The online version contains supplementary material available at 10.1007/s12035-023-03456-y.
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DOI：
10.1523/jneurosci.5473-10.2011
发表时间：
2011-03-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
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期刊：
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影响因子：
5.6
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影响因子：
82.9
作者：
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通讯作者：
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DOI：
10.1016/j.mcn.2016.12.006
发表时间：
2017-03
期刊：
Molecular and cellular neurosciences
影响因子：
--
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通讯作者：
Toborek M