CRMP2-derived peptide ST2-104 (R9-CBD3) protects SH-SY5Y neuroblastoma cells against Aβ 25-35 -induced neurotoxicity by inhibiting the pCRMP2/NMDAR2B signaling pathway

Yingshi Ji, Yang Hu, Jinghong Ren, Rajesh Khanna, Yuan Yao, Yang Chen, Qi Li, Li Sun

Research output: Contribution to journalArticle

Abstract

Collapsin response mediator protein 2 (CRMP2),by regulating voltage-gated calcium channel activity, is a crucial regulator of neuronal excitability. Hyperphosphorylation of CRMP2 has been reported in brains of Alzheimer's disease (AD) patients and other neurodegenerative diseases. CRMP2 acting on N-methyl-d-aspartate receptors (NMDARs) may contribute to AD pathology. A short peptide from CRMP2, designated the Ca 2+ channel-binding domain 3 (CBD3) peptide, has recently emerged as a Ca 2+ channel blocker that exerts neuroprotective effects in traumatic brain injury and cerebral ischemia by disrupting pCRMP2/NMDAR interaction to inhibit calcium influx. ST2-104, a nona-arginine (R9)-conjugated CBD3 peptide derived from CRMP2, exerts a beneficial effect on neuropathic pain; however, the effect of ST2-104 on AD and its mechanism of action have not been studied. In this study we investigated the effects of ST2-104 on SH-SY5Y neuroblastoma cells stimulated by Aβ 25-35 . To induce neurotoxicity, SH-SY5Y cells were incubated with Aβ 25-35 , the shortest toxic fragment of Aβ. CRMP2 expression was manipulated by knockdown or overexpression of CRMP2 before ST2-104 treatment to further explore if the pCRMP2/NMDAR2B signaling pathway is involved in the action of the ST2-104 peptide. The results show that ST2-104 significantly enhanced cell viability, inhibited cell apoptosis, decreased LDH release, suppressed the expression of the pCRMP2 protein, disrupted pCRMP2/NMDAR2B interaction, inhibited Aβ 25-35 -induced NMDAR currents, and decreased intracellular Ca 2+ levels. The effects of ST2-104 was abolished by overexpression of CRMP2 and intensified by knockdown of CRMP2 in SH-SY5Y cells. Taken together, our results support ST2-104 as a possible biologic therapeutic in the face of Aβ 25-35 -induced injury via the inhibition of the pCRMP2/NMDAR2B signaling pathway.

Original languageEnglish (US)
Pages (from-to)28-39
Number of pages12
JournalChemico-Biological Interactions
Volume305
DOIs
StatePublished - May 25 2019

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Neuroblastoma
Peptides
Alzheimer Disease
Brain Ischemia
Brain
Neurodegenerative diseases
collapsin response mediator protein-2
Poisons
Brain Diseases
Neuralgia
Neuroprotective Agents
Pathology
Calcium Channels
Neurodegenerative Diseases
Arginine
Cell Survival
Cells
Apoptosis
Calcium
Wounds and Injuries

Keywords

  • Alzheimer's disease
  • Ca
  • Neuroprotection
  • NMDAR2B
  • pCRMP2
  • ST2-104

ASJC Scopus subject areas

  • Toxicology

Cite this

CRMP2-derived peptide ST2-104 (R9-CBD3) protects SH-SY5Y neuroblastoma cells against Aβ 25-35 -induced neurotoxicity by inhibiting the pCRMP2/NMDAR2B signaling pathway . / Ji, Yingshi; Hu, Yang; Ren, Jinghong; Khanna, Rajesh; Yao, Yuan; Chen, Yang; Li, Qi; Sun, Li.

In: Chemico-Biological Interactions, Vol. 305, 25.05.2019, p. 28-39.

Research output: Contribution to journalArticle

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abstract = "Collapsin response mediator protein 2 (CRMP2),by regulating voltage-gated calcium channel activity, is a crucial regulator of neuronal excitability. Hyperphosphorylation of CRMP2 has been reported in brains of Alzheimer's disease (AD) patients and other neurodegenerative diseases. CRMP2 acting on N-methyl-d-aspartate receptors (NMDARs) may contribute to AD pathology. A short peptide from CRMP2, designated the Ca 2+ channel-binding domain 3 (CBD3) peptide, has recently emerged as a Ca 2+ channel blocker that exerts neuroprotective effects in traumatic brain injury and cerebral ischemia by disrupting pCRMP2/NMDAR interaction to inhibit calcium influx. ST2-104, a nona-arginine (R9)-conjugated CBD3 peptide derived from CRMP2, exerts a beneficial effect on neuropathic pain; however, the effect of ST2-104 on AD and its mechanism of action have not been studied. In this study we investigated the effects of ST2-104 on SH-SY5Y neuroblastoma cells stimulated by Aβ 25-35 . To induce neurotoxicity, SH-SY5Y cells were incubated with Aβ 25-35 , the shortest toxic fragment of Aβ. CRMP2 expression was manipulated by knockdown or overexpression of CRMP2 before ST2-104 treatment to further explore if the pCRMP2/NMDAR2B signaling pathway is involved in the action of the ST2-104 peptide. The results show that ST2-104 significantly enhanced cell viability, inhibited cell apoptosis, decreased LDH release, suppressed the expression of the pCRMP2 protein, disrupted pCRMP2/NMDAR2B interaction, inhibited Aβ 25-35 -induced NMDAR currents, and decreased intracellular Ca 2+ levels. The effects of ST2-104 was abolished by overexpression of CRMP2 and intensified by knockdown of CRMP2 in SH-SY5Y cells. Taken together, our results support ST2-104 as a possible biologic therapeutic in the face of Aβ 25-35 -induced injury via the inhibition of the pCRMP2/NMDAR2B signaling pathway.",
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AU - Ji, Yingshi

AU - Hu, Yang

AU - Ren, Jinghong

AU - Khanna, Rajesh

AU - Yao, Yuan

AU - Chen, Yang

AU - Li, Qi

AU - Sun, Li

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N2 - Collapsin response mediator protein 2 (CRMP2),by regulating voltage-gated calcium channel activity, is a crucial regulator of neuronal excitability. Hyperphosphorylation of CRMP2 has been reported in brains of Alzheimer's disease (AD) patients and other neurodegenerative diseases. CRMP2 acting on N-methyl-d-aspartate receptors (NMDARs) may contribute to AD pathology. A short peptide from CRMP2, designated the Ca 2+ channel-binding domain 3 (CBD3) peptide, has recently emerged as a Ca 2+ channel blocker that exerts neuroprotective effects in traumatic brain injury and cerebral ischemia by disrupting pCRMP2/NMDAR interaction to inhibit calcium influx. ST2-104, a nona-arginine (R9)-conjugated CBD3 peptide derived from CRMP2, exerts a beneficial effect on neuropathic pain; however, the effect of ST2-104 on AD and its mechanism of action have not been studied. In this study we investigated the effects of ST2-104 on SH-SY5Y neuroblastoma cells stimulated by Aβ 25-35 . To induce neurotoxicity, SH-SY5Y cells were incubated with Aβ 25-35 , the shortest toxic fragment of Aβ. CRMP2 expression was manipulated by knockdown or overexpression of CRMP2 before ST2-104 treatment to further explore if the pCRMP2/NMDAR2B signaling pathway is involved in the action of the ST2-104 peptide. The results show that ST2-104 significantly enhanced cell viability, inhibited cell apoptosis, decreased LDH release, suppressed the expression of the pCRMP2 protein, disrupted pCRMP2/NMDAR2B interaction, inhibited Aβ 25-35 -induced NMDAR currents, and decreased intracellular Ca 2+ levels. The effects of ST2-104 was abolished by overexpression of CRMP2 and intensified by knockdown of CRMP2 in SH-SY5Y cells. Taken together, our results support ST2-104 as a possible biologic therapeutic in the face of Aβ 25-35 -induced injury via the inhibition of the pCRMP2/NMDAR2B signaling pathway.

AB - Collapsin response mediator protein 2 (CRMP2),by regulating voltage-gated calcium channel activity, is a crucial regulator of neuronal excitability. Hyperphosphorylation of CRMP2 has been reported in brains of Alzheimer's disease (AD) patients and other neurodegenerative diseases. CRMP2 acting on N-methyl-d-aspartate receptors (NMDARs) may contribute to AD pathology. A short peptide from CRMP2, designated the Ca 2+ channel-binding domain 3 (CBD3) peptide, has recently emerged as a Ca 2+ channel blocker that exerts neuroprotective effects in traumatic brain injury and cerebral ischemia by disrupting pCRMP2/NMDAR interaction to inhibit calcium influx. ST2-104, a nona-arginine (R9)-conjugated CBD3 peptide derived from CRMP2, exerts a beneficial effect on neuropathic pain; however, the effect of ST2-104 on AD and its mechanism of action have not been studied. In this study we investigated the effects of ST2-104 on SH-SY5Y neuroblastoma cells stimulated by Aβ 25-35 . To induce neurotoxicity, SH-SY5Y cells were incubated with Aβ 25-35 , the shortest toxic fragment of Aβ. CRMP2 expression was manipulated by knockdown or overexpression of CRMP2 before ST2-104 treatment to further explore if the pCRMP2/NMDAR2B signaling pathway is involved in the action of the ST2-104 peptide. The results show that ST2-104 significantly enhanced cell viability, inhibited cell apoptosis, decreased LDH release, suppressed the expression of the pCRMP2 protein, disrupted pCRMP2/NMDAR2B interaction, inhibited Aβ 25-35 -induced NMDAR currents, and decreased intracellular Ca 2+ levels. The effects of ST2-104 was abolished by overexpression of CRMP2 and intensified by knockdown of CRMP2 in SH-SY5Y cells. Taken together, our results support ST2-104 as a possible biologic therapeutic in the face of Aβ 25-35 -induced injury via the inhibition of the pCRMP2/NMDAR2B signaling pathway.

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