nNOS-CAPON interaction mediates amyloid-β-induced neurotoxicity, especially in the early stages.

Abstract

In neurons, increased protein-protein interactions between neuronal nitric oxide synthase (nNOS) and its carboxy-terminal PDZ ligand (CAPON) contribute to excitotoxicity and abnormal dendritic spine development, both of which are involved in the development of Alzheimer's disease. In models of Alzheimer's disease, increased nNOS-CAPON interaction was detected after treatment with amyloid-β in vitro, and a similar change was found in the hippocampus of APP/PS1 mice (a transgenic mouse model of Alzheimer's disease), compared with age-matched background mice in vivo. After blocking the nNOS-CAPON interaction, memory was rescued in 4-month-old APP/PS1 mice, and dendritic impairments were ameliorated both in vivo and in vitro. Furthermore, we demonstrated that S-nitrosylation of Dexras1 and inhibition of the ERK-CREB-BDNF pathway might be downstream of the nNOS-CAPON interaction.