Research Article: nNOS–CAPON interaction mediates amyloid‐β‐induced neurotoxicity, especially in the early stages

Date Published: March 25, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Yu Zhang, Zhu Zhu, Hai‐Ying Liang, Lei Zhang, Qi‐Gang Zhou, Huan‐Yu Ni, Chun‐Xia Luo, Dong‐Ya Zhu.


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.

Partial Text

Alzheimer’s disease is a neurodegenerative disorder characterized by degeneration of specific neurons and is a heavy burden among the aging population. In pathology, abnormal accumulation of amyloid‐β (Aβ), dysfunction of synapses, and hyperphosphorylated tau are typical manifestations of Alzheimer’s disease (Scheltens et al., 2016). Multiple mechanisms of Alzheimer’s disease have been proposed among which the amyloid cascade hypothesis is the most popular. In the amyloid cascade hypothesis, Aβ triggers damage to neurons and induces disease. However, the toxic mechanism of Aβ is complicated. Several studies have shown that Aβ binds to receptors on neurons and triggers downstream cytotoxic signaling processes (Jarosz‐Griffiths, Noble, Rushworth & Hooper, 2016).

The amyloid cascade hypothesis is one of the most prominent theories in Alzheimer’s disease research, while Aβ1‐42 and/or its oligomers are thought as the major toxic components. Clinical evidence suggests that increases in Aβ1‐42 and its oligomers are associated with disease, and laboratory evidence suggests that Aβ1‐42 oligomers induce abnormal synaptic function and neuronal death (Wilcox, Lacor, Pitt & Klein, 2011). Based on the amyloid cascade hypothesis, studies of Alzheimer’ disease have generally focused on two common treatment strategies: 1. decreasing the level of Aβ, especially toxic forms; and 2. protecting neurons or maintaining neuronal function.

Yu Zhang participated in designing the study, supervising the analysis, and writing the manuscript. Zhu Zhu, Hai‐Ying Liang, and Lei Zhang carried out the analysis and participated in designing the study. Huan‐Yu Ni participated in the analysis. Qi‐Gang Zhou participated the progress of the revision and helped to write the manuscript. Chun‐Xia Luo and Dong‐Ya Zhu participated in the study design, coordinating the study, and drafting and finalizing the manuscript.

All authors read and approved the final manuscript and declare no conflict of interest.




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