VEGF counteracts amyloid-β-induced synaptic dysfunction

• Published in: Cell reports (Cambridge) 2021-05, Vol.35 (6), p.109121-109121, Article 109121
• Main Authors: Martin, Laurent, Bouvet, Pauline, Chounlamountri, Naura, Watrin, Chantal, Besançon, Roger, Pinatel, Delphine, Meyronet, David, Honnorat, Jérôme, Buisson, Alain, Salin, Paul-Antoine, Meissirel, Claire
• Format: Article
• Language: English
• Subjects: Alzheimer; Alzheimer Disease - genetics; Amyloid beta-Peptides - metabolism; amyloid-beta oligomers; amyloid-beta peptide; Animals; glutamate receptors; Humans; Life Sciences; long-term potentiation; Mice; Neurobiology; Neurons and Cognition; synapse; Synapses - metabolism; synaptic transmission; Vascular Endothelial Growth Factor A - metabolism; VEGF
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109121

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. [Display omitted] •Aβo directly interact with VEGF and impairs VEGFR2 activation•VEGF prevents Aβo-induced AMPA-R loss and caspase-3-calcineurin activation at synapses•Hippocampal LTP and LTD impairments due to Aβo are rescued by VEGF•VEGF counteracts Aβo-induced morphological alteration and loss of dendritic spines Martin et al. show that VEGF rescues synaptic dysfunction triggered by Aβo through direct action on synapses. It precludes deleterious activation of the signaling pathways induced by Aβo and restores glutamate-receptor content at synapses. Thus, VEGF preserves hippocampal synaptic plasticity and dendritic spine integrity, which are compromised by Aβo.