Project Summary The objective of the parent grant is to elucidate the normal physiological functions of the extracellular domain of the Amyloid Precursor Protein (APP) in multiple cell types. Despite the known effects of the APP ectodomain on cellular and cognitive functions and the potential applications to disease, the precise molecular mechanisms mediating the function of the secreted APP ectodomain and the various forms of soluble APP generated by ectodomain shedding are not well understood. Our approaches are designed to address the mechanistic gaps in knowledge by leveraging our recent discovery that sAPP functions as a ligand for the GABA type B Receptor (GABABR) and our recent identification of Phosphoglycerate Mutase Family Member 5 (PGAM5), a mitochondrial serine/threonine protein phosphatase, as a novel candidate interactor of the APP ectodomain. One line of research is aimed at elucidating the cellular responses of multiple cell types to sAPP and GABABR modulation, identify signaling pathways downstream of the sAPP and GABABR interaction, and determine mechanisms involved in the positive regulation of GABABR signaling by sAPP. The proposed research of the candidate in this supplement is related to that line of research but is unique from the proposed studies in that he will examine the effects and mechanisms involved in APP and GABABR signaling in developmental processes in neuronal cells, which is an area of research that strongly aligns with the long-term research and career interests of the candidate. The candidate will also expand on their background and interest in biophysics to establish intravital imaging techniques and address the in vivo relevance of the APP- GABABR interaction.