Presenilin1/gamma-secretase regulate the VEGFA/VEGFR2 brain angiogenesis inhibited by FAD mutants.

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Summary The cerebrovascular system is central to neuronal survival and function and recent evidence suggests that vascular brain abnormalities are involved in the development and neuropathophysiology of neurodegenerative disorders such as Alzheimer disease (AD). Angiogenesis, the generation of new blood vessels from existing vasculature, is crucial throughout adult life for maintaining brain blood circulation and for reparative mechanisms of toxic insults such as ischemia and hypoxia. Angiogenesis is controlled by growth factors including the Vascular Endothelial Growth Factors (VEGFs). By binding to their receptors (VEGFRs), VEGFs regulate formation of new blood vessels and maintain blood supply to tissues and organs. Mutants of the protein Presenilin1 (PS1) cause Familial AD (FAD) constituting a system where mechanisms of AD-like neurodegeneration can be studied. A normal function of PS1 is to act as a protease, called γ-secretase, which processes type I membrane receptors. Here we present evidence that the PS1/γ-secretase system processes VEGFR2 that is known to play crucial roles in the regulation of the vascular system, including the brain vasculature. Critical angiogenic functions of VEGFR2 include its dimerization, internalization and downstream angiogenic signaling of endothelial cells (ECs). We also found that inhibition of the γ-secretase activity decreases the VEGFA-induced dimerization of VEGFR2 and the VEGFR2-mediated angiogenenic functions of primary cortical ECs (pCECs) such as sprouting, tube formation, cell migration and angiogenic complex formation. Together, our data suggest that γ-secretase regulates the VEGFA-stimulated angiogenic functions of VEGFR2. Importantly, we found that PS1 FAD mutants decrease the VEGFA-induced γ-secretase processing and dimerization of VEGFR2 and the VEGFA-stimulated angiogenic signaling and functions of ECs. Together, our data indicate that PS1 FAD mutants attenuate the VEGFA-induced angiogenic functions of brain ECs suggesting a mechanism by which FAD mutants cause neuronal dysfunction and death by decreasing angiogenic functions and tissue repair of the brain. In this application, we explore the interactions of PS1 and its FAD mutants with VEGFR2 and explore the importance of this interaction to the VEGFA-induced and VEGFR2-mediated angiogenenic signaling and functions of the brain. We also use mouse models to examine mechanisms by which γ-secretase activity regulates angiogenic signaling of the VEGFA/VEGFR2 system, and test the roles of PS1 and PS1FAD mutants in the VEGFA- and ischemia-stimulated brain angiogenesis. We also explore signatures of angiogenic dysfunction in human FAD and sporadic AD brain tissue.