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VEGF counteracts amyloid-β-induced synaptic dysfunction
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DOI：10.1016/j.celrep.2021.109121.png)
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摘要
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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 (A beta o). Here, we show that VEGF accumulates in and around A beta 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 A beta o 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 A beta o. We further decipher underlying mechanisms and find that VEGF inhibits the caspase-3-calcineurin pathway responsible for postsynaptic glutamate receptor loss due to A beta o. 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.
Keyword:
ENDOTHELIAL GROWTH-FACTOR
LONG-TERM POTENTIATION
ALZHEIMERS-DISEASE
AMPA RECEPTORS
PHOSPHORYLATION SITES
MOUSE MODEL
EXCITATORY SYNAPSE
DENDRITIC SPINES
GLUR1 SUBUNIT
PLASTICITY
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期刊
IF:
6.9
论文数:
1.7W
被引数:
10.2W
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引用论文
Soluble Oligomers of Amyloid β Protein Facilitate Hippocampal Long-Term Depression by Disrupting Neuronal Glutamate Uptake.png)
NEURON
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NEURONIF15
OAAI分享收藏Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphateNATURE COMMUNICATIONSOAAI
NATURE COMMUNICATIONSIF15.7
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