PS FAD mutants and γ-secretase inhibition accumulate VEGFR2-derived peptide VCTF1 suppressing brain VEGFR2 dimerization, angiogenesis and neuroprotection

Abstract

Abstract Efficient cerebrovasculature is vital to neuronal health and cognition and evidence shows most dementia patients have cerebrovascular abnormalities. Brain vasculature is regulated by Vascular Endothelial Growth Factors (VEGFs) binding VEGF receptor2 (VEGFR2) and stimulating angiogenic signaling, angiogenesis, and neuroprotection. Presenilin1 (PS1) is main proteolytic component of γ-secretase and PS1 mutants are most common cause of Familial Alzheimer Disease (FAD). Here we show that an ADAM17 cleavage of extracellular VEGFR2 produces membrane-bound γ-secretase substrate VEGFR2/CTF1 (called VCTF1) comprising the transmembrane and intracellular domains of VEGFR2. PS1 FAD mutants or γ-secretase inhibitors accumulate VCTF1 and suppress VEGF-A–induced brain angiogenesis. Moreover, PS1 FAD mutants, γ-secretase inhibitors or PS1 downregulation, each decreases γ-secretase processing of VCTF1 increasing its accumulation and impairing VEGF-A–induced VEGFR2 dimerization/activation, signaling, and endothelial cell (EC) functions. Importantly, VCTF1 binds full-length VEGFR2 monomers suppressing VEGFR2 dimerization/activation, signaling and EC functions. These data show that VCTF1 suppresses VEGFR2 dimerization and downstream signaling and functions of brain VEGF-A-/VEGFR2 system. PS1 FAD mutants exert dominant negative effects on γ-secretase cleavage of brain VCTF1 increasing its concentration and abolishing VEGF-A-induced VEGFR2 dimerization/activation and downstream signaling, neuroprotection, and cognition. Importantly, we detected molecular markers of decreased VEGFR2 dimerization and angiogenic dysfunction in human brain tissue expressing PS1 FAD mutants. Together our data suggests a pathway through which FAD mutants promote dementia by increasing VCTF1 and decreasing brain angiogenesis and neuroprotection supporting that PS1 FAD patients may benefit from therapeutic methods that decrease brain VCTF1.