In order to understand the cause of Alzheimer's disease we study the function of Presenilin-1 (PS1), a protein mutated in most cases of familial Alzheimer's disease (FAD). PS1/gamma-secretase activity controls the proteolytic cleavage of many type I transmembrane proteins like APP, Notch-1, ErbB4 and E- and N-cadherin. In our effort to understand the physiological function of PS1 in the cells and the effect that its mutations have on the normal function of the brain we identified new proteins that interact with it. We have found that PS1 interacts with cadherins which are type I transmembrane proteins at cell cell junctions regulating their signaling. We also found that PS1 interacts with ephrinB proteins, which are also type I transmembrane proteins which function as ligands for the ephrinB receptors (EphBs). The ephrinB-EphB system is present at both the neuronal synapse and the endothelial cells in the brain where it transmits signals from both the receptor and the ligand thus constituting a bi-directional signaling system. This system regulates very important cellular processes in development and adulthood including cell migration, axon guidance, angiogenesis and synaptic plasticity. It also participates in the regulation of two forms of long-term synaptic plasticity that are important for information storage in the brain, the long-term potentiation (LTP) and the long-term depression (LTD). PS1/gamma-secretase interacts with and regulates the proteolytic processing of both ephrinB and EphB proteins and the downstream signaling initiated by the ephrinB-EphB interaction. We found that PS1/gamma-secretase regulates angiogenic functions of brain endothelial cells and promotes brain neovascularization and neuronal survival following ischemia. We also found that PS1 FAD mutants impair all the above brain functions impairing brain vasculature and increasing ischemia-induced neuronal death and cognitive decline. In addition we found that PS1/gamma secretase interacts with the Vascular Endothelial Growth Factor Receptor2 (VEGFR2) regulating Vascular Endothelial Growth Factor (VEGF)-induced angiogenic functions in brain endothelial cells and brain neovascularization and PS1 FAD mutants decrease these functions. PS1 mutations found in familial Alzheimer's disease thus disrupt the normal function of the brain vasculature and impair brain functions. Dr. Georgakopoulos research goal is to study the role of PS1/gamma-secretase in the regulation of brain’s vascular integrity and to identify molecular mechanisms via which this regulation is achieved. In vivo and in vitro angiogenesis studies are performed using mouse and human brain tissue and brain endothelial cells and functions of PS1/gamma secretase are explored with molecular and cell biology and transcriptomic tools. His goal is also to identify effects of PS1 FAD mutants on the above brain functions aiming to discover methods to effectively treat and prevent neurodegenerative disorders like AD.