星形胶质细胞-神经元线粒体跨细胞转运失稳态介导脑衰老进程中基底前脑胆碱能退行性变的机制研究

Our country is already an aging society. It is of great significance to study the mechanism of brain aging and its evolution to neurodegeneration. Recent studies have found that there is mitochondrial transcellular transport between astrocytes (AS) and neurons. The previous studies of our group have demonstrated that estrogen mediates AS against oxidative stress, and AS dysfunction plays a central role in the degeneration of basal forebrain cholinergic system. Therefore, we speculate that the decline of estrogen during senescence exacerbates astrocyte damage caused by oxidative stress and other factors, and leads to dysfunction of astrocytes in providing health mitochondria to adjacent cholinergic axonal terminals and clearance of degenerated mitochondria from the axonal terminals, which will results in neuronal mitochondrial energy metabolism dysfunction, and then neurodegeneration. In this project, neuronal and astrocyte mitochondrial specific marker transgenic animal models will be used to systemically verify this hypothesis from the overall, cellular and molecular levels. We will also investigate detailed steps of estrogen-CD38 signaling pathway mediated impairment of transcellular transport of mitochondria between AS and neurons during the ageing process. The expected results will find a new mechanism of brain aging and its evolution to degeneration, and provide academic and experimental basis for exploring new neuroprotective strategies via targeting trans-neural cellular transport of mitochondria.

我国已进入老龄化社会，研究脑老化及其向神经变性的演变机制具有重要意义。最近研究发现星形胶质细胞（AS）和神经元之间存在线粒体跨细胞转运。本课题组前期研究证实雌激素调控AS抗氧化应激以及AS功能障碍在基底前脑胆碱系统退行性变中发挥核心作用。因此，我们推测衰老过程中雌激素下降加剧了氧化应激等因素对AS的损害作用，导致AS向邻近的胆碱能轴突终末提供健康的线粒体以及清除轴突终末所释放的变性线粒体的能力下降，引起神经元线粒体能量代谢障碍，进而发生退行性变。本项目拟应用胆碱能神经元和AS线粒体特异性转基因模式动物，从整体、细胞和分子水平系统验证此假设，并研究雌激素-CD38信号通路介导衰老进程中AS-神经元线粒体跨细胞转运功能障碍的具体环节。预期研究成果有望发现脑衰老及其向退行性变性演化的新机制，并为探索调节线粒体跨神经细胞转运作为神经保护新策略提供学术基础与实验依据。

我国已进入老龄化社会，研究脑老化及其向神经变性的演变机制具有重要意义。近年来的研究提示星形胶质细胞（astrocytes, AS）在调控中枢线粒体新陈代谢稳态的过程中发挥主导和关键作用，清除老化的AS可能是防治脑衰老及其退行性变性的新策略。本项目对此科学问题进一步进行了探索，主要研究内容和结果如下：.1）阐明星形胶质细胞（astrocytes, AS）和神经元线粒体转运稳态破坏在脑衰老和阿尔茨海膜病（Alzheimer’s disease, AD）进程中的作用，揭示CD38介导有氧运动促进AS向神经元转运健康线粒体，为防治脑衰老和AD提供新靶标。.2）发现胶质-脑膜淋巴系统具有清除老化AS新功能， VEGF-C/VEGFR3/CCL21信号通路介导此过程，为靶向提供脑淋巴清除系统防治脑衰老提供新策略。.3）发现有氧运动增强AD小鼠模型中β淀粉样蛋白和老化AS的脑膜淋巴引流，揭示AS 源性血栓形成素-1为关键靶标。.4）发现抗真菌药咪康唑具有减轻AD小鼠少突胶质细胞前体细胞老化，从而保护退行性变性早期阶段的社会合作能力。.总之，上述研究结果揭示了胶质细胞及其线粒体功能老化在脑衰老及其向退行性变性演化的新机制，并为探索新型药物和有氧运动等非药物疗法保护胶质细胞，防治AD提供了理论基础和实验依据。部分研究结果已发表在《脑、行为学和免疫学》、《国际神经精神药理学杂志》、《脑病理学》《阿尔茨海默病研究与治疗》，另有2篇论文待发表。通过项目实施，项目组继续与国内外同行保持稳定的合作关系，培养博士后1名，博士研究生和硕士研究生各2名。项目主持人应邀参加国际和国内学术会议，作报告6次。项目组成员和培养的博士研究生分别获得2022和2021年度国家自然基青年项目。

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