@article{b1a31767bfca42eb96cefeadc92b930c,
title = "VEGF counteracts amyloid-β-induced synaptic dysfunction",
abstract = "The vascular endothelial growth factor (VEGF) pathway regulates key processes in synapse function, which are disrupted in early stages of Alzheimer's disease (AD) by toxic-soluble amyloid-beta oligomers (Aβo). Here, we show that VEGF accumulates in and around Aβ plaques in postmortem brains of patients with AD and in APP/PS1 mice, an AD mouse model. We uncover specific binding domains involved in direct interaction between Aβo and VEGF and reveal that this interaction jeopardizes VEGFR2 activation in neurons. Notably, we demonstrate that VEGF gain of function rescues basal synaptic transmission, long-term potentiation (LTP), and dendritic spine alterations, and blocks long-term depression (LTD) facilitation triggered by Aβo. We further decipher underlying mechanisms and find that VEGF inhibits the caspase-3-calcineurin pathway responsible for postsynaptic glutamate receptor loss due to Aβo. These findings provide evidence for alterations of the VEGF pathway in AD models and suggest that restoring VEGF action on neurons may rescue synaptic dysfunction in AD.",
keywords = "Alzheimer, VEGF, amyloid-beta oligomers, amyloid-beta peptide, glutamate receptors, long-term potentiation, synapse, synaptic transmission",
author = "Laurent Martin and Pauline Bouvet and Naura Chounlamountri and Chantal Watrin and Roger Besan{\c c}on and Delphine Pinatel and David Meyronet and J{\'e}r{\^o}me Honnorat and Alain Buisson and Salin, {Paul Antoine} and Claire Meissirel",
note = "Funding Information: We thank Smatti Batoule, Annabelle Bouchardon, Bruno Chapuis, and Denis Ressnikoff from the Centre d{\textquoteright}Imagerie Quantitative Lyon-Est; Corinne Perrin and Anthony Terra from the CRB HCL; and Aur{\'e}lie Mongope and Jean-Michel Vicat from the Animalerie Lyon-Est Module SPF facility (University Lyon 1) for assistance. We are grateful to Kevin Baranger, Anne Didier, Gilles Pages, and Laure Verret for helpful discussions. This study was supported by grants from the Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale and the French foundations Fondation Vaincre Alzhemer ( R17004CC ) (to C.M.) and Fondation d{\textquoteright}Entreprise Caisse d{\textquoteright}Epargne Rh{\^o}ne-Alpes (CERA; R14154CC ) (to C.M.). L.M. was supported by a doctoral research contract ADR ARC2 from the R{\'e}gion Rh{\^o}ne-Alpes , and P.B was supported by a doctoral research contract from the French Ministry of Higher Education and Research . Funding Information: We thank Smatti Batoule, Annabelle Bouchardon, Bruno Chapuis, and Denis Ressnikoff from the Centre d'Imagerie Quantitative Lyon-Est; Corinne Perrin and Anthony Terra from the CRB HCL; and Aur?lie Mongope and Jean-Michel Vicat from the Animalerie Lyon-Est Module SPF facility (University Lyon 1) for assistance. We are grateful to Kevin Baranger, Anne Didier, Gilles Pages, and Laure Verret for helpful discussions. This study was supported by grants from the Institut National de la Sant? et de la Recherche M?dicale and the French foundations Fondation Vaincre Alzhemer (R17004CC) (to C.M.) and Fondation d'Entreprise Caisse d'Epargne Rh?ne-Alpes (CERA; R14154CC) (to C.M.). L.M. was supported by a doctoral research contract ADR ARC2 from the R?gion Rh?ne-Alpes, and P.B was supported by a doctoral research contract from the French Ministry of Higher Education and Research. L.M. and P.B. contributed to the conception and study design, conducted experiments, analyzed and discussed data, and commented on the paper. N.C. C.W. and D.P. performed experiments. R.B. J.H. and A.B. discussed the data and commented on the paper, and J.H. provided financial support. D.M. provided human biopsies. P.-A.S. contributed to the study design, conducted electrophysiological experiments, analyzed and discussed data, and commented on the paper. C.M. conceptualized and supervised the study, wrote the manuscript, and provided financial support. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = may,
day = "11",
doi = "10.1016/j.celrep.2021.109121",
language = "English (US)",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}