Apoptotic Regulation and Neuroinflammation in Alzheimer's Disease

项目总结

Project Summary In patients with Alzheimer’s disease (AD), the progressive loss of neurons over time leads to memory loss and other devastating symptoms. Neuronal loss and inflammation in AD are strongly correlated with advanced age, but it remains unknown how age contributes to neuronal cell death or how cell death and neuroinflammation might be linked. This knowledge gap exists in part because previous studies of apoptosis, the canonical regulated cell death pathway, have A) lacked a functional assay to measure the apoptotic sensitivity of cells in the brain and B) relied on readouts of apoptosis that may not be present in neurons or other AD-affected cell types. The goal of my research is to better understand the regulation of apoptosis in the aging brain, investigating the links between aging, AD, inflammation, and apoptosis. Specifically, I propose to use BH3 and caspase profiling (BCP), a functional measurement of apoptotic sensitivity, and other methods to investigate the hypothesis that increased initiation of apoptosis in aging and AD promotes cell death and inflammation in neurons lacking apoptotic caspases. In Aim 1, I will quantify apoptotic priming, caspase activity, and inflammatory signaling in aged mice, measuring changes in each over lifespan and testing the role of the BCL-2 family protein BAX in these changes. In Aim 2, I will investigate these phenomena in human induced pluripotent stem cells (iPSCs), testing the effects of familial AD mutations and modulation of the cGAS/STING signaling pathway. In Aim 3, I will use BCP and other methods to study apoptotic priming and caspase competence in rapid autopsy human brain tissue, investigating potential differences in initiation and execution of apoptosis in neural cells between AD patients and healthy donor controls. The completion of these three aims will generate important new insights into the regulation of apoptosis in aging and AD, potentially revealing new opportunities for therapeutic intervention. The training plan for the proposed fellowship is designed to prepare me to lead my own research laboratory studying cell death in aging and neurodegeneration. This plan includes career development and training in laboratory methodologies, subject matter expertise, bioinformatic analysis, and classroom teaching. These training opportunities are made possible by my selection of Dr. Kristopher Sarosiek and Dr. Mark Albers as mentors, allowing me to draw on their expertise in their respective fields of cell death and neurodegeneration. I have sought out additional guidance and support from the faculty comprising my Career Development Committee and Scientific Advisory Committee, forming a strong network of mentors and collaborators. The research and training environment of the Harvard School of Public Health provides an ideal setting for the proposed activities, and I will draw on all these resources to complete the research and training plans described herein.