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

Abstract

Efficient cerebrovasculature is vital to neuronal health and cognition and evidence shows that most dementia patients have cerebrovascular abnormalities. Brain vasculature is regulated by Vascular Endothelial Growth Factors (VEGFs) binding VEGF receptor2 (VEGFR2) and stimulating angiogenesis and neuroprotection. Here we show that an ADAM17 cleavage of extracellular VEGFR2 produces the membrane-bound {gamma}-secretase substrate VEGFR2/CTF1 (called VCTF1), comprising the transmembrane and intracellular domains of VEGFR2. VCTF1 binds full-length VEGFR2 monomers suppressing its dimerization a function that is required for VEGFR2 activation and downstream angiogenesis and neuroprotection. Presenilin1 (PS1) Familial Alzheimers disease (FAD) mutants exert dominant negative effects on the {gamma}-secretase processing of VCTF1 increasing its concentration and abolishing VEGF-A-induced VEGFR2 dimerization/activation and downstream VEGFR2 signaling, endothelial cell functions and angiogenesis. {gamma}-Secretase inhibitors or PS1 reduction have similar effects on VCTF1 accumulation and VEGFR2 dimerization/activation and downstream signaling and functions as PS1 FAD mutants. Moreover, PS1 FAD mutants increase vulnerability of brain neurons to ischemic stress and abolish VEGF-A-induced neuroprotection and cognition. Together, these data show that VCTF1 suppresses VEGFR2 dimerization and downstream signaling and functions of the brains VEGF-A-/VEGFR2 angiogenic and neuroprotection systems. Importantly, we detected molecular markers of decreased VEGFR2 dimerization and angiogenic dysfunction in human brain tissue from PS1 FAD mutant genotypes. Our data reveal a pathway through which FAD mutants may promote dementia by increasing accumulation of VCTF1 and decreasing angiogenesis, neuroprotection, and cognition, suggesting that PS1 FAD patients may benefit from therapeutic methods that decrease brain VCTF1.