<scp>nNOS</scp>–<scp>CAPON</scp> interaction mediates amyloid‐β‐induced neurotoxicity, especially in the early stages

Zhang, Yu; Zhu, Zhu; Liang, Haiying; Zhang, Lei; Zhou, Qi‐Gang; Ni, Huan‐Yu; Luo, Chunxia; Zhu, Dong‐Ya

doi:10.1111/acel.12754

Cited by 30 publications

(28 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, p38 MAPK activity was linked to amyloid b (Ab )-induced spine loss driven by non-ionotropic NMDAR signaling (Birnbaum et al, 2015). In addition, increased nNOS-NOS1AP interaction was detected after treatment with Ab in vitro and in APP/PS1 mice in vivo (Zhang et al, 2018b). After blocking the nNOS-NOS1AP interaction, memory was rescued in 4-month-old APP/PS1 mice, and dendritic impairments were ameliorated both in vivo and in vitro (Zhang et al, 2018b), further supporting a role for non-ionotropic NMDAR signaling in Alzheimer's disease.…”

Section: Non-ionotropic Nmdar Signaling In Diseasementioning

confidence: 85%

“…Notably, NOS1AP is important for nNOS-mediated nitrosylation of Dexras1, a small GTPase that negatively regulates the MAP kinase Erk (Zhu et al, 2014;Zhang et al, 2018b). Thus, the dual and opposite regulation of p38 and Erk MAPK activities through NOS1AP would allow NOS1AP to locally activate p38 MAPK-dependent LTD and spine shrinkage signaling pathways, and at the same time downregulate Erk-dependent LTP signaling (Zhu et al, 2002;Zhang et al, 2018a).…”

Section: Nos1ap and Nnosmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Mechanisms of Non-ionotropic NMDA Receptor Signaling in Dendritic Spine Shrinkage

et al. 2020

View full text Add to dashboard Cite

Structural plasticity of dendritic spines is a key component of the refinement of synaptic connections during learning. Recent studies highlight a novel role for the NMDA receptor (NMDAR), independent of ion flow, in driving spine shrinkage and LTD. Yet little is known about the molecular mechanisms that link conformational changes in the NMDAR to changes in spine size and synaptic strength. Here, using two-photon glutamate uncaging to induce plasticity at individual dendritic spines on hippocampal CA1 neurons from mice and rats of both sexes, we demonstrate that p38 MAPK is generally required downstream of non-ionotropic NMDAR signaling to drive both spine shrinkage and LTD. In a series of pharmacological and molecular genetic experiments, we identify key components of the non-ionotropic NMDAR signaling pathway driving dendritic spine shrinkage, including the interaction between NOS1AP (nitric oxide synthase 1 adaptor protein) and neuronal nitric oxide synthase (nNOS), nNOS enzymatic activity, activation of MK2 (MAPK-activated protein kinase 2) and cofilin, and signaling through CaMKII. Our results represent a large step forward in delineating the molecular mechanisms of non-ionotropic NMDAR signaling that can drive shrinkage and elimination of dendritic spines during synaptic plasticity.

show abstract

Section: Non-ionotropic Nmdar Signaling In Diseasementioning

confidence: 85%

Section: Nos1ap and Nnosmentioning

confidence: 99%

Molecular Mechanisms of Non-ionotropic NMDA Receptor Signaling in Dendritic Spine Shrinkage

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Also, stroke, neuropathic pain and early‐stage Alzheimer's disease are associated with the co‐morbid anxiety (Bierman, Comijs, Jonker, Scheltens, & Beekman, 2009; Campbell Burton et al, 2013; Knapp et al, 2017; Kwak, Yang, & Koo, 2017; Nicholson & Verma, 2004). Reportedly, nNOS–CAPON association mediates amyloid‐β‐induced neurotoxicity (Zhang et al, 2018), ischaemia‐induced impairment of structural plasticity (Ni et al, 2018) and inflammatory nociception and chemotherapy‐induced neuropathic pain (Lee, Carey, et al, 2018; Lee, Li, et al, 2018). We previously reported that dissociation of nNOS with CAPON by ZLc‐002 produces rapid onset of anxiolytic‐like effect (Zhu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

nNOS‐CAPON blockers produce anxiolytic effects by promoting synaptogenesis in chronic stress‐induced animal models of anxiety

Zhu

Shi

Chang

et al. 2020

British J Pharmacology

View full text Add to dashboard Cite

Background and Purpose Anxiety disorder is a common mental health disorder. However, there are few safe and fast‐acting anxiolytic drugs available that can treat anxiety disorder. We previously demonstrated that the interaction of neuronal NOS (nNOS) with its carboxy‐terminal PDZ ligand (CAPON) is involved in regulating anxiety‐related behaviours. Here, we further investigated the anxiolytic effects of nNOS–CAPON disruptors in chronic stress‐induced anxiety in animals. Experimental Approach Mice were intravenously treated with nNOS–CAPON disruptors, ZLc‐002 or Tat‐CAPON12C, at the last week of chronic mild stress (CMS) exposure. We also infused http://corticosterone (CORT) into the hippocampus of mice to model anxiety behaviours and also delivered ZLc‐002 or Tat‐CAPON12C on the last week of chronic CORT treatment via pre‐implanted cannula. Anxiety‐related behaviours were examined using elevated plus maze, open field, novelty‐suppressed feeding and light–dark (LD) tests. The level of nNOS–CAPON interaction was determined by co‐immunoprecipitation (CO‐IP) and proximity ligation assay (PLA). The neural mechanisms underlying the behavioural effects of nNOS–CAPON uncoupling in anxiety animal models were assessed by western blot, immunofluorescence and Golgi‐Cox staining. Key Results ZLc‐002 and Tat‐CAPON12C reversed CMS‐ or CORT‐induced anxiety‐related behaviours. ZLc‐002 and Tat‐CAPON12C increased synaptogenesis along with improved dendritic remodelling in CMS mice or CORT‐treated cultured neurons. Meanwhile, blocking nNOS–CAPON interaction significantly activated the cAMP response element‐binding protein (CREB)–brain‐derived neurotrophic factor (BDNF) pathway, which is associated with synaptic plasticity. Conclusion and Implications Collectively, these results provide evidence for the anxiolytic effects of nNOS–CAPON uncouplers and their underlying mechanisms in anxiety disorders.

show abstract

“…In addition, it has been shown that nNOS activity is required for NOS1AP recruitment during excitotoxicity and that the interaction with NOS1AP also is important for nNOS-mediated nitrosylation of Dexras1, which negatively regulates Erk (Zhu et al, 2014;Zhang et al, 2018b). Thus, this dual and opposite regulation of p38 and Erk MAPK activity through NOS1AP, if occurring during non-ionotropic NMDAR signaling, would allow NOS1AP to locally activate p38 MAPK-dependent LTD and spine shrinkage signaling pathways and at the same time downregulate Erk-dependent LTP signaling (Zhu et al, 2002;Zhang et al, 2018a).…”

Section: Nos1ap and Nnosmentioning

confidence: 99%

“…Notably, p38 MAPK activity was linked to amyloid beta (Aβ)-induced spine loss driven by non-ionotropic NMDAR signaling (Birnbaum et al, 2015). In addition, in models of Alzheimer's disease, increased nNOS-NOS1AP interaction was detected after treatment with Aβ in vitro and in APP/PS1 mice in vivo (Zhang et al, 2018b). After blocking the nNOS-NOS1AP interaction, memory was rescued in 4-month-old APP/PS1 mice, and dendritic impairments were ameliorated both in vivo and in vitro (Zhang et al, 2018b), further supporting a possible role for non-ionotropic NMDAR signaling in Alzheimer's disease.…”

Section: Non-ionotropic Nmdar Signaling In Diseasementioning

confidence: 99%

Molecular Mechanisms of Non-ionotropic NMDA Receptor Signaling

Stein

Park

Jahncke

et al. 2020

Preprint

View full text Add to dashboard Cite

Structural plasticity of dendritic spines is a key component of the refinement of synaptic connections during learning. Recent studies highlight a novel role for the NMDA receptor (NMDAR), independent of ion flow, in driving spine shrinkage and LTD. Yet little is known about the molecular mechanisms that link conformational changes in the NMDAR to changes in spine size and synaptic strength. Here, using two-photon glutamate uncaging to induce plasticity in hippocampal CA1 neurons from mice and rats, we demonstrate that p38 MAPK is required downstream of conformational NMDAR signaling to drive both spine shrinkage and LTD at individual dendritic spines. In a series of pharmacological and molecular genetic experiments, we identify key components of the non-ionotropic NMDAR signaling pathway driving dendritic spine shrinkage, including the interaction between NOS1AP and nNOS, nNOS enzymatic activity, activation of MK2 and cofilin, and signaling through CaMKII. Our results represent a large step forward in delineating the molecular mechanisms of non-ionotropic NMDAR signaling that drive the shrinkage and elimination of dendritic spines during synaptic plasticity.

show abstract

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

Cited by 30 publications

References 42 publications

Molecular Mechanisms of Non-ionotropic NMDA Receptor Signaling in Dendritic Spine Shrinkage

Molecular Mechanisms of Non-ionotropic NMDA Receptor Signaling in Dendritic Spine Shrinkage

nNOS‐CAPON blockers produce anxiolytic effects by promoting synaptogenesis in chronic stress‐induced animal models of anxiety

Molecular Mechanisms of Non-ionotropic NMDA Receptor Signaling

Contact Info

Product

Resources

About