Study of Reactive Astrocytes-Derived Oxidative Stress and Proinflammation Leading to Neurodegenerative Microglial Activation in Alzheimer’s Disease

2019

As the recent failures of clinical trials in Alzheimer’s disease have raised questions as to the amyloid hypothesis validity, the “neuroinflammation hypothesis” begins to gain attention to explain AD pathogenesis. The interactions among the innate immune system—astrocytes and microglia—elevate inflammatory impact on AD pathogenesis; however, the mechanisms involved remain poorly understood. The project accomplished a physiologically relevant human AD brain model by adopting human-induced pluripotent stem cell-derived neurons, astrocytes and microglia, the investigation of oxidative stress and proinflammatory cytokines produced by reactive astrocytes in response to AD cues, and the determination of the combined involvement of the oxidative stress and cytokines leading to microglial proinflammation. The project’s chief goal remains identifying promising drug candidates that aim to reduce the oxidative stress as well as inflammatory response, thus showing great potential to cure AD in advance.

2015-2018

Over the past couple of decades, we have learned a great deal about the mechanisms of Alzheimer’s disease (AD) pathogenesis, but many critical questions remain unanswered. As the recent failures of clinical trials in AD have raised questions as to the amyloid hypothesis validity, the “neuroinflammation hypothesis” begins to gain attention to explain AD pathogenesis. More research into the interactions between astrocytes and microglia—key players of the innate immune system—is required. Immune cells are dynamic and complex, giving rise to challenges in characterizing their function. The goal of this project is to determine the significant impact of astrocyte-derived oxidative stress on microglial inflammation and neurodegeneration during progression of Alzheimer’s disease. To achieve the goal, we will create a physiologically relevant human Alzheimer’s disease brain model by adopting human-induced pluripotent stem cell-derived AD neural progenitor cells. This project subsequently will investigate how oxidative stress is induced by reactive astrocytes in response to AD cues. Finally, this research will determine the involvement of oxidative stress in microglial neurodegeneration. Taken together, the application of technologies and quantitative analysis tools to create 3D microfluidic cellular platforms of human AD brain models (Alzheimer’s in a Dish) will allow us to explore the pathways underlying AD pathology. We expect these experiments to aid in identifying new points for therapeutic intervention in the treatment of the disease.