FAD mutants decrease brain neovascularization and neuronal survival by targeting angiogenic mechanisms of PS1/γ‐secretase

Abstract Background The cerebrovascular system is central to neuronal survival and function and emerging evidence suggests that vascular brain abnormalities are involved in the development of neurodegenerative disorders such as Alzheimer’s 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. Angiogenesis is controlled by growth factors including the Vascular Endothelial Growth Factor (VEGF). By binding to its receptor (VEGFR2), VEGF regulates extension of new blood vessels in damaged areas and maintains blood supply to tissues and organs. FAD variants of Presenilin1 (PS1), the catalytic subunit of γ‐secretase induce Familial AD (FAD) and can serve as systems where mechanisms of AD‐like neurodegeneration can be studied. Methods Mouse brain endothelial cells (ECs) expressing knock‐in PS1 FAD mutants were isolated and cultured and effects of PS1/γ‐secretase on angiogenic functions and processing of VEGFR2 were performed as in literature. VEGF‐induced phosphorylation of kinases downstream of VEGFR2 were determined on WBs. Middle cerebral artery occlusion (MCAO) was performed in mice as in literature. Isolated brains were sectioned using a mouse brain matrix and slices were stained with TTC and fixed with 4% PFA to detect infarct area. Cerebral blood flow (CBF) was assessed using perfusion MRI (pMRI) as in literature. Neurons were stained with anti‐NeuN and positive neurons in lesioned and contralateral areas were counted Results PS1/γ‐secretase process VEGFR2 and regulate crucial functions of the brain VEGF/VEGFR2 system including receptor dimerization, internalization and downstream angiogenic signaling. Importantly, PS1 FAD mutants decrease the VEGF‐induced activation and angiogenic signaling of VEGFR2 and reduce brain neovascularization suggesting mechanisms by which PS1 FAD mutants may cause neuronal dysfunction and death. In this presentation we discuss the importance of the PS1/γ‐secretase on the VEGFA/VEGFR2‐mediated angiogenenic signaling and brain neovascularization and test effects of PS1FAD mutants in brain neoangiogenesis and neuronal survival. Conclusions The PS1/γ‐secretase system regulates brain angiogenesis and neovascularization by activating properties of the VEGF/VEGFR2 system. PS1 FAD mutants decrease brain angiogenesis, neovascularization and neuronal survival by targeting angiogenic mechanisms of PS1 and γ‐secretase.