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.