Regulation of LC3-associated endocytosis and neuroinflammation

项目总结 神经炎症是脑血管病发生和发展的关键因素。 包括阿尔茨海默病(AD)在内的神经退行性疾病。我们最近确定了一部小说 被称为LC3相关的内吞作用(LANDO)的途径，并发现它对于缓解 阿尔茨海默病模型中的神经炎症和神经变性。我们有很好的初步结果 有证据表明，Lando具有抑制小胶质细胞炎症信号的功能， 居住者大脑中的先天免疫细胞。兰多的激活促进了对 识别β-淀粉样蛋白的受体，这是AD病理的一个贡献者。废除LANDO结果 在所有AD标志物的严重恶化中，不仅包括β-淀粉样蛋白沉积，而且 Tau病理增加，神经元丢失，记忆障碍。此外，目标是 Lando缺乏症的炎症信号能够几乎完全抑制神经元死亡，而 恢复小胶质细胞功能，改善记忆力。然而，控制的机制 LANDO在小胶质细胞中的表达，并最终将LANDO与炎症信号联系起来，目前尚不清楚。我们 提供令人信服的证据，证明包括VPS35和VPS35在内的逆转录机械部件 Rab11b对于Lando是必不可少的，但对于相关的通路是必不可少的，包括 自噬和LC_3相关的吞噬作用。此外，我们提供的证据表明 兰多通过限制炎性小体组装改变炎性激活 降低促炎活性氧的水平。我们还提供了以下数据 提示上游LANDO激活的取消及其在炎症机制中的作用 导致神经细胞死亡的不同程序，包括对坏死性上皮症的假定作用 死亡和炎症中的机械。我们建议使用各种新的动物模型 我们已经建立了评估LANDO调节、炎症和神经元死亡的分析方法 在阿尔茨海默病的分子水平和生理水平。这些研究将提供新的机会 用于操作和开发AD的治疗方法 增加了我们对这个复杂的、多方面的生物系统的了解。

PROJECT SUMMARY Neuroinflammation is a key component to the establishment and progression of neurodegenerative diseases including Alzheimer’s Disease (AD). We recently identified a novel pathway called LC3-associated endocytosis (LANDO) and found it is important for mitigating neuroinflammation and neurodegeneration in a model of AD. We have robust preliminary evidence demonstrating that LANDO functions to suppress inflammatory signaling in microglia, the resident innate immune cells in the brain. Activation of LANDO facilitates the recycling of receptors that recognize β-amyloid, a contributor to AD pathology. Abrogation of LANDO results in a severe exacerbation of all markers of AD including not only β-amyloid deposition, but increased tau pathology, neuronal loss, and memory impairment. Furthermore, targeting inflammatory signaling in LANDO-deficiency is able to almost fully inhibit neuronal death while restoring microglial function and improving memory. However, the mechanisms that control LANDO in microglia and ultimately link LANDO to inflammatory signaling are unknown. We provide convincing evidence that components of retromer machinery including VPS35 and Rab11b are essential for LANDO, however are dispensable for related pathways including autophagy and LC3-associated phagocytosis. Additionally, we provide evidence that suggests LANDO alters inflammatory activation through restriction of inflammasome assembly and decreases pro-inflammatory reactive oxygen species levels. We further provide data that suggests abrogation of upstream LANDO activation and its role in inflammatory mechanisms leads to diverse programs of neuronal cell death including putative roles for the necroptotic machinery in both death and inflammation. We propose to use a variety of novel animal models and assays we have established to evaluate LANDO regulation, inflammation, and neuronal death at both the molecular and physiological levels in AD. These studies will provide new opportunities for the manipulation and development of therapeutic methodologies for AD in addition to increasing our understanding of this complex, multifaceted biological system.