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

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 angiogenesis, and neuroprotection. Presenilin1 (PS1) is the main proteolytic component of {gamma}-secretase and PS1 mutants are the most common cause of Familial Alzheimer Disease (FAD). 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. PS1 FAD mutants and {gamma}-secretase inhibitors both accumulate VCTF1 and suppress VEGF-A-induced brain angiogenesis. Moreover, PS1 FAD mutants, {gamma}-secretase inhibitors, and PS1 downregulation, all decrease {gamma} secretase processing of VCTF1, thereby increasing its accumulation and impairing VEGF-A-induced VEGFR2 dimerization/activation, signaling, and endothelial cell (EC) functions. Importantly, VCTF1 binds fulllength VEGFR2 monomers suppressing VEGFR2 dimerization/activation, signaling, and EC functions. These data show that VCTF1 suppresses VEGFR2 dimerization and downstream signaling and functions of the brain VEGF-A-/VEGFR2 system. PS1 FAD mutants increase vulnerability of brain neurons to ischemic stress and exert antimorphic effects on {gamma}-secretase cleavage of VCTF1, increasing its concentration and abolishing VEGF-A-induced VEGFR2 dimerization/activation, signaling, neuroprotection and cognition. Importantly, we detected molecular markers of decreased VEGFR2 dimerization and angiogenic dysfunction in human brain tissue from PS1 FAD mutant genotypes. Together, our data suggest a pathway through which FAD mutants promote dementia by increasing VCTF1 and decreasing brain angiogenesis and neuroprotection, suggesting that PS1 FAD patients may benefit from therapeutic methods that decrease brain VCTF1.