Apoptotic Dysregulation Across Cell Types in Aging and Neurodegeneration

About This Grant

Apoptotic Dysregulation Across Cell Types in Aging and Neurodegeneration Aging and Alzheimer’s Disease (AD) involve the progressive loss of brain matter, but this phenomenon is poorly understood. One possible contributor to the loss of neurons and other cells is cell death via apoptosis, the canonical pathway for the controlled elimination of cells experiencing lethal stress. Apoptotic sensitivity can vary widely by age and cell type but has never been surveyed in the various cell types of the brain over the lifespan. The goal of the present proposal is to understand the regulation of apoptotic sensitivity in the brain in normal aging, and the potential dysregulation of this sensitivity in AD and other neurodegenerative diseases. The PI, Dr. Zintis Inde, has identified differences among neural cell types in apoptotic regulation, including age- dependent differences, that might contribute to the pathogenesis of AD and other diseases. Here, he proposes to use functional methods for the measurement of apoptotic sensitivity, along with novel applications of induced pluripotent stem cells (iSPCs), viral vectors, and flow cytometric analysis, to investigate these phenomena. In Aim 1, Dr. Inde will use his lab’s functional methods for the measurement of apoptosis sensitivity, quantifying changes in apoptotic priming across aging cell types in normal and AD model mouse brain tissue. In Aim 2, he will examine the role of apolipoprotein E4 (APOE4), a common risk factor for AD, in mouse and iPSC-derived oligodendrocytes. In the R00 phase, Aim 3 will investigate the interplay between neural cell types in the progression of AD, and Aim 4 will validate and implement a newly-developed method for the in vivo measurement of cell type-specific apoptotic sensitivity. The completion of these aims will provide critical insights into normal aging and AD pathogenesis and provide the basis for a future R01 application studying the mechanisms underlying apoptotic dysregulation in these contexts. The proposed training plan encompasses four training goals. First, training in iPSC models will enable Dr. Inde to study cell death regulation in human patient-derived cells, examining the effect of AD-associated genes. Second, training in the use of adeno-associated virus (AAV) vectors will allow for the study of cell death in intact mouse brain tissue. Third, specialized training in aging biology will provide a rigorous foundation for the proposed experiments and the candidate’s future career. Finally, professional development activities, along with the guidance of an experienced group of mentors, will facilitate Dr. Inde’s transition to an independent faculty position. The training plan and experimental goals are supported by an expert team of collaborators and mentors, including primary mentor Dr. Kristopher Sarosiek, a leading expert in cell death, and co-mentor Dr. Mark Albers, an expert in the clinical and translational study of AD. As a whole, the K99/R00 award will enable Dr. Inde’s development into an independent investigator, applying cutting edge methodologies to elucidate the role of cell death in neurodegeneration and pursue novel therapeutic targets arising from this study.