Abstract：
Microglia are crucial for maintaining brain health and neuron function. Here, we report that microglia establish connections with neurons using tunneling nanotubes (TNTs) in both physiological and pathological conditions. These TNTs facilitate the rapid exchange of organelles, vesicles, and proteins. In neurodegenerative diseases like Parkinson\'s and Alzheimer\'s disease, toxic aggregates of alpha-synuclein (α-syn) and tau accumulate within neurons. Our research demonstrates that microglia use TNTs to extract neurons from these aggregates, restoring neuronal health. Additionally, microglia share their healthy mitochondria with burdened neurons, reducing oxidative stress and normalizing gene expression. Disrupting mitochondrial function with antimycin A before TNT formation eliminates this neuroprotection. Moreover, co-culturing neurons with microglia and promoting TNT formation rescues suppressed neuronal activity caused by α-syn or tau aggregates. Notably, TNT-mediated aggregate transfer is compromised in microglia carrying Lrrk22(Gly2019Ser) or Trem2(T66M) and (R47H) mutations, suggesting a role in the pathology of these gene variants in neurodegenerative diseases.
摘要：
小胶质细胞对于维持大脑健康和神经元功能至关重要。这里,我们报道小胶质细胞在生理和病理条件下使用隧道纳米管（TNTs）与神经元建立联系。这些TNT促进了细胞器的快速交换，囊泡，和蛋白质。在神经退行性疾病如帕金森病和阿尔茨海默病，α-突触核蛋白（α-syn）和tau的毒性聚集体在神经元内积累。我们的研究表明，小胶质细胞使用TNTs从这些聚集体中提取神经元，恢复神经元健康。此外,小胶质细胞与负重的神经元共享其健康的线粒体，减少氧化应激和正常化基因表达。在TNT形成之前用抗霉素A破坏线粒体功能消除了这种神经保护。此外，将神经元与小胶质细胞共培养并促进TNT形成可以挽救由α-syn或tau聚集体引起的神经元活性抑制。值得注意的是,TNT介导的聚集体转移在携带Lrrk22（Gly2019Ser）或Trem2（T66M）和（R47H）突变的小胶质细胞中受损，提示这些基因变异在神经退行性疾病的病理学中的作用。
