Contribution of γ-secretase to calcium-mediated cell death

Choi, Yun-Hyung; Gwon, A-Ryeong; Jeong, Hye-Young; Park, Jong‐Sung; Baik, Sang‐Ha; Jo, Dong-Gyu

doi:10.1016/j.neulet.2009.12.043

Cited by 10 publications

(9 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Li et al (2011) have demonstrated that the overexpression of normal or mutant PS1 is sufficient to increase the amount and activity of g-secretase. A high level of intracellular Ca 21 triggered hippocampal cell deaths in a manner that was attenuated by a g-secretase inhibitor (Choi et al, 2010), suggesting that g-secretase mediates the cell death. A single treatment with a g-secretase inhibitor reduced brain damage associated with ischemia/reperfusion in mice (Arumugam et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

The Role of Presenilin-1 in the Excitotoxicity of Ethanol Withdrawal

Jung

Metzger

Das

2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Presenilin-1 (PS1) is a core component of g-secretase that is involved in neurodegeneration. We have previously shown that PS1 interacts with a mitogen-activated protein kinase [(MAPK) jun-NH2-terminal-kinase], and another MAPK (p38) is activated by ethanol withdrawal (EW), abrupt termination from chronic ethanol exposure. EW is excitotoxic in nature, induces glutamate upregulation, and provokes neuronal damage. Here, we explored a potential mechanistic pathway involving glutamate, p38 (p38a isozyme), and PS1 that may mediate EW-induced excitotoxic stress. We used the prefrontal cortex of male rats withdrawn from a chronic ethanol diet. Additionally, we used ethanol-withdrawn HT22 cells (mouse hippocampal) treated with the inhibitor of glutamate receptors [dizocilpine (MK-801)], p38aduring EW. Separately, ethanol-free HT22 cells were exposed to glutamate with or without SB203580 or DAPT. Protein levels, mRNA levels, and cell viability were assessed using immunoblotting, qualitative polymerase chain reaction, and calcein assay, respectively. The prefrontal cortex of ethanolwithdrawn rats or HT22 cells showed an increase in PS1 and p38a, which was attenuated by MK-801 and SB203580, but mimicked by glutamate treatment to ethanol-free HT22 cells. DAPT attenuated the toxic effect of EW or glutamate on HT22 cells. These results suggest that PS1 expression is triggered by glutamate through p38a, contributing to the excitotoxic stimulus of EW.

show abstract

Section: Discussionmentioning

confidence: 99%

The Role of Presenilin-1 in the Excitotoxicity of Ethanol Withdrawal

Jung

Metzger

Das

2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

show abstract

“…To directly determine whether ␥-secretase-mediated Notch signaling is involved in Ca 2ϩ -induced cell death, we have examined the effect of ␥-secretase inhibitors on Ca 2ϩ -triggered cell death in B103 rat neuroblastoma cells (Choi et al, 2010). However, the role of Notch signaling in Ca 2ϩ -mediated neuronal cell death after ischemic stroke is still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…There is much evidence to suggest that ␥-secretase is involved in the regulation of cellular Ca 2ϩ homeostasis (Leissring et al, 2002;Tu et al, 2006). We have examined the effect of ␥-secretase inhibitors on Ca 2ϩ -triggered cell death in B103 rat neuroblastoma cells (Choi et al, 2010). However, a role for the Notch pathway in Ca 2ϩ -mediated neuronal death after ischemic stroke remains to be established.…”

Section: -Difluorophenacetyl)-l-alanyl]-s-phenylglycine T-butyl Estementioning

confidence: 99%

Evidence that γ-Secretase-Mediated Notch Signaling Induces Neuronal Cell Death via the Nuclear Factor-κB-Bcl-2-Interacting Mediator of Cell Death Pathway in Ischemic Stroke

et al. 2011

Self Cite

View full text Add to dashboard Cite

Notch-1 (Notch) is a cell surface receptor that regulates cell-fate decisions in the developing nervous system, and it may also have roles in synaptic plasticity in the adult brain. Binding of its ligands results in the proteolytic cleavage of Notch by the ␥-secretase enzyme complex, thereby causing the release of a Notch intracellular domain (NICD) that translocates to the nucleus, in which it regulates transcription. Here we show that activation of Notch modulates ischemic neuronal cell death in vitro and in vivo. Specifically, our findings from the use of Notch-1 siRNA or the overexpression of NICD indicate that Notch activation contributes to cell death. Using modified NICD, we demonstrate an apoptosis-inducing function of NICD in both the nucleus and the cytosol. NICD transfectioninduced cell death was reduced by blockade of calcium signaling, caspase activation, and Janus kinase signaling. Inhibition of the Notch-activating enzyme, ␥-secretase, protected against ischemic neuronal cell death by targeting an apoptotic protease, cleaved caspase-3, nuclear factor-B (NF-B), and the pro-death BH3-only protein, Bcl-2-interacting mediator of cell death (Bim). Treatment of mice with a ␥-secretase inhibitor, compound E, reduced infarct size and improved functional outcome in a model of focal ischemic stroke. Furthermore, ␥-secretase inhibition reduced NICD, p-p65, and Bim levels in vivo. These findings suggest that Notch signaling endangers neurons after ischemic stroke by modulating the NF-B, pro-death protein Bim, and caspase pathways.

show abstract

“…Other such novel receptor-mediated signaling mechanisms are activated during ischemic stroke, also include Notch and Adiponectin receptors [63-65]. We have recently shown that gamma secretase, and adiponectin-mediated signaling, through their respective cell-surface receptors; NOTCH-1 and ADR-1 (adiponectin receptor-1), exacerbated neuronal apoptosis during focal ischemic stroke, and in combined oxygen- and glucose-deprived neurons respectively [63,64].…”

Section: Introductionmentioning

confidence: 99%

Pathophysiology, treatment, and animal and cellular models of human ischemic stroke

Woodruff

Thundyil

Tang

et al. 2011

Mol Neurodegeneration

488

367

View full text Add to dashboard Cite

Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions.

show abstract

Contribution of γ-secretase to calcium-mediated cell death

Cited by 10 publications

References 19 publications

The Role of Presenilin-1 in the Excitotoxicity of Ethanol Withdrawal

The Role of Presenilin-1 in the Excitotoxicity of Ethanol Withdrawal

Evidence that γ-Secretase-Mediated Notch Signaling Induces Neuronal Cell Death via the Nuclear Factor-κB-Bcl-2-Interacting Mediator of Cell Death Pathway in Ischemic Stroke

Pathophysiology, treatment, and animal and cellular models of human ischemic stroke

Contact Info

Product

Resources

About