Impact and regional aspects of glia to neuron exosome transfer in the CNS

中枢神经系统中神经胶质细胞到神经元外泌体转移的影响和区域方面

• 批准号: 254941261
• 负责人: Professorin Dr. Eva-Maria Krämer-Albers
• 金额: --
• 依托单位: Institut für Entwicklungsbiologie und Neurobiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/254941261?language=en
• 关键词: Impact; regional; aspects; glia; neuron

Oligodendrocytes myelinate axons and in addition maintain axonal integrity by providing support to neurons. We have shown that oligodendrocytes secrete nano-sized vesicles termed exosomes, which mediate bidirectional neuron-glia communication. However, their impact on brain physiology is largely unresolved. Exosomes are released by oligodendrocytes upon neurotransmitter signalling and internalized by neurons via endocytosis delivering a variety of biomolecules, including RNA, from oligodendrocytes to neurons. Cultured neurons that have received exosomes are more resilient to stress suggesting that oligodendroglial exosomes mediate neuroprotection. Modification of exosomes to carry reporter enzymes such as Cre recombinase is utilized to illustrate transfer of exosomes and their cargo to target neurons allowing the identification of target neurons in the brain. In this project, we aim to determine the brain regions, where exosome transfer from oligodendrocytes to neurons is prevalent, and the specific neuronal subpopulations targeted by exosomes. Our strategy utilizes tamoxifen-inducible CreERT2-mediated recombination of target cells to trace exosome transfer in the brain of reporter mice. In addition, the coupling of exosome transfer to neural electrical activity will be assessed. Exosome transfer from NG2-cells to neurons and mature oligodendrocytes to neurons will be compared regarding their targeting characteristics revealing potentially distinct functional implications. Furthermore, we will determine the influence of glial exosomes on the transcriptomic profile of target neurons. The project will reveal deeper insight into the prevalence of exosome-dependent neuron-glia communication in distinct brain regions and its functional relevance for neural performance and neural plasticity. This is particularly relevant for myelin diseases, where axons degenerate as a result of lacking oligodendrocyte-neuron communication. Establishing a spatio-temporal map of glial exosome transfer in the brain complies with the goals of the Priority Program aiming to resolve local determinants of brain activity and furthermore integrates an innovative concept of cell communication into the glia research network.

少突胶质细胞使轴突髓鞘形成，此外，通过为神经元提供支持来维持轴突的完整性。我们已经证明，少突胶质细胞分泌被称为外体的纳米大小的囊泡，它介导神经元-神经胶质细胞的双向通讯。然而，它们对大脑生理学的影响在很大程度上还没有解决。外切体是由少突胶质细胞根据神经递质信号释放出来的，并通过内吞作用被神经元内化，产生从少突胶质细胞到神经元的各种生物分子，包括RNA。接受外切体的培养神经元对压力更有弹性，这表明少突胶质外切体介导了神经保护。将外切体修饰为携带报告酶，如Cre重组酶，用于说明外切体及其货物向靶神经元的转移，从而识别大脑中的靶神经元。在这个项目中，我们的目标是确定大脑中普遍存在外切体从少突胶质细胞向神经元转移的区域，以及外切体所针对的特定神经元亚群。我们的策略利用他莫昔芬诱导的CreERT2介导的靶细胞重组来追踪报告小鼠大脑中的外切体转移。此外，还将评估外切体转移与神经电活动的耦合。将比较从NG2-细胞到神经元的外切体转移和从成熟的少突胶质细胞到神经元的转移的靶向性，揭示潜在的不同的功能含义。此外，我们还将确定胶质外切体对靶神经元转录图谱的影响。该项目将揭示更深入的洞察力，以了解不同大脑区域中依赖外体的神经元-胶质细胞通讯的普遍程度，以及它与神经表现和神经可塑性的功能相关性。这与髓鞘疾病尤其相关，这些疾病的轴突退化是由于缺乏少突胶质细胞与神经元的沟通。建立脑内胶质外切体转移的时空图符合优先计划的目标，旨在解决大脑活动的局部决定因素，并进一步将细胞通讯的创新概念整合到神经胶质研究网络中。