Regulation of LC3-associated endocytosis and neuroinflammation

项目摘要 神经炎症是一个关键组成部分的建立和发展， 神经退行性疾病，包括阿尔茨海默病（AD）。我们最近发现了一本小说 LC 3相关内吞作用（LANDO），并发现它对减轻 在AD模型中的神经炎症和神经变性。我们有初步证据 有证据表明LANDO的功能是抑制小胶质细胞中的炎症信号， 大脑中固有的免疫细胞。活化本署的土地， 受体识别β-淀粉样蛋白，一个贡献者的AD病理。LANDO结果的废除 在AD的所有标志物的严重恶化中，不仅包括β-淀粉样蛋白沉积， 增加的tau病理、神经元损失和记忆损伤。此外，针对 LANDO缺乏症中的炎症信号传导能够几乎完全抑制神经元死亡， 恢复小胶质细胞功能和改善记忆。然而，控制的机制 LANDO在小胶质细胞中的作用以及LANDO与炎症信号的最终联系尚不清楚。我们 提供令人信服的证据表明，包括VPS 35和 Rab 11b对于LANDO是必需的，但是对于相关的途径是必需的，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， LANDO通过限制炎性小体组装改变炎症激活， 降低促炎活性氧水平。我们进一步提供数据， 提示上游LANDO激活的消除及其在炎症机制中的作用 导致神经元细胞死亡的不同程序，包括坏死性凋亡的假定作用， 死亡和炎症的机制。我们建议使用各种新颖的动物模型 以及我们建立的评估LANDO调节、炎症和神经元死亡的检测方法 在分子水平和生理水平上都是如此。这些研究将提供新的机会 用于AD治疗方法的操作和开发， 增加我们对这个复杂的、多方面的生物系统的理解。

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.