Abstract
SummaryIn 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.
Highlights
Alzheimer’s disease is a neurodegenerative disorder characterized by degeneration of specific neurons and is a heavy burden among the aging population
We found that neuronal nitric oxide synthase (nNOS)–CAPON interaction was increased in both amyloid-b1-42-treated primary cultured neurons in vitro and in the hippocampus of APP/PS1 mice
We reported that nNOS–CAPON interaction contributed to anxiety via Dexras1 (Zhu et al, 2014)
Summary
Alzheimer’s disease is a neurodegenerative disorder characterized by degeneration of specific neurons and is a heavy burden among the aging population. A clinical drug used to treat AD, is a noncompetitive antagonist of NMDA receptors that reduces Ab toxicity by blocking abnormal activation of NMDA receptors, especially extrasynaptic NMDARs (Zadori et al, 2014). CAPON regulates dendritic morphology, dendrite patterning, and dendritic spine development (Candemir et al, 2016; Carrel et al, 2009; Richier et al, 2010) Both excitotoxicity and synaptic dysfunction are major causes of Alzheimer’s disease. Our work presents a potential downstream signal of amyloid b-mediated dysfunction of NMDARs
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