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

Arumugam, Thiruma V.; Cheng, Yuxiang; Choi, Yong-Sung; Choi, Yun-Hyung; Yang, Seung Koo; Yun, Young-Kwang; Park, Jong‐Sung; Yang, Dong Kwon; Thundyil, John; Gelderblom, Mathias; Karamyan, Vardan T.; Tang, Sung‐Chun; Chan, Sic L.; Magnus, Tim; Sobey, Christopher G.; Jo, Dong-Gyu

doi:10.1124/mol.111.071076

Cited by 79 publications

(72 citation statements)

References 33 publications

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“…Similarly, systemic γ-secretase inhibition can provide significant neuroprotection in a model of stroke in mice. 15,41 We further showed that excitotoxic KA treatment leads to increase in phosphorylation of Akt, through PTEN-mediated disinhibition and partially through the activation of PI3Kγ. Our study indicates that PTEN is negatively regulated by canonical Notch signaling in line with repression of PTEN by Hes1.…”

Section: Discussionmentioning

confidence: 84%

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

et al. 2015

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Neurological disorders such as Alzheimer's disease, stroke and epilepsy are currently marred by the lack of effective treatments to prevent neuronal death. Erroneous cell cycle reentry (CCR) is hypothesized to have a causative role in neurodegeneration. We show that forcing S-phase reentry in cultured hippocampal neurons is sufficient to induce neurodegeneration. We found that kainic-acid treatment in vivo induces erroneous CCR and neuronal death through a Notch-dependent mechanism. Ablating Notch signaling in neurons provides neuroprotection against kainic acid-induced neuronal death. We further show that kainic-acid treatment activates Notch signaling, which increases the bioavailability of CyclinD1 through Akt/GSK3β pathway, leading to aberrant CCR via activation of CyclinD1-Rb-E2F1 axis. In addition, pharmacological blockade of this pathway at critical steps is sufficient to confer resistance to kainic acid-induced neurotoxicity in mice. Taken together, our results demonstrate that excitotoxicity leads to neuronal death in a Notch-dependent manner through erroneous CCR.

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Section: Discussionmentioning

confidence: 84%

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

et al. 2015

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“…Notch-1 is a cell surface receptor that regulates cell-fate decisions during neural development, and it may also have roles in synaptic plasticity in the adult brain (Arumugam et al, 2011;VanDussen et al, 2011). Binding of its ligands results in the proteolytic cleavage of Notch by the γ-secretase enzyme complex, thereby causing the release of a Notch intracellular domain (NICD) that translocates to the nucleus, in which it regulates transcription.…”

Section: Discussionmentioning

confidence: 99%

The effect of simvastatin treatment on proliferation and differentiation of neural stem cells after traumatic brain injury

Xie¹,

Cong²,

Wang³

et al. 2015

Brain Research

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“…It has been confirmed that inactivation of Notch signaling protects neuronal cells from apoptotic death and further brain injury following ischemic stroke. 3 There is a positive correlation between Notch signaling and apoptosis. Thus, the inhibition of Notch signaling is the biological response to radiosurgery, not the secondary negative effect of apoptosis.…”

Section: Radiosurgery Inhibits Notch Signaling In the Rat Avf Modelmentioning

confidence: 99%

Radiosurgery inhibition of the Notch signaling pathway in a rat model of arteriovenous malformations

Hu³

et al. 2014

JNS

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R adiosuRgeRy has been used to manage patients with cerebral arteriovenous malformations (AVMs) for more than 4 decades. 56 It offers an important option for patients with AVMs that are unsuitable for resection or embolization. 47,54 Studies reveal that radiosurgery induces thrombosis in AVM vessels, and by 2-3 years approximately 75% of AVM vessels are completely obliterated. 37,48,63 Although overexpression of endothelial adhesion and inflammatory and thrombotic molecules has been reported in irradiated endothelial cells in an AVM model in rats, 22,57,61 Department of Electromagnetic and Laser Biology, Beijing Institute of Radiation Medicine, Beijing, ChinaObject. Notch signaling has been suggested to promote the development and maintenance of arteriovenous malformations (AVMs), but whether radiosurgery inhibits Notch signaling pathways in AVMs is unknown. The aim of this study was to examine molecular changes of Notch signaling pathways following radiosurgery and to explore mechanisms of radiosurgical obliteration of "nidus" vessels in a rat model of AVMs.Methods. One hundred eleven rats received common carotid artery-to-external jugular vein anastomosis to form an arteriovenous fistula (AVF) model. Six weeks postoperatively, dilated small vessels and capillaries formed a nidus. The rats with AVFs received 25-Gy radiosurgery. The expression of Notch1 and Notch4 receptors and their ligands, Delta-like1 and Delta-like4, Jagged1, Notch downstream gene target HES1, and an apoptotic marker caspase-3 in nidus vessels in the AVF rats was examined immunohistochemically and was quantified using LAS-AF software at 7 time points over a period of 42 days postradiosurgery. The interaction events between Notch1 receptor and Jagged1, as well as Notch4 receptor and Jagged1, were quantified in nidus vessels in the AVF rats using proximity ligation assay at different time points over 42 days postradiosurgery.Results. The expression of Notch1 and Notch4 receptors, Delta-like1, Delta-like4, Jagged1, and HES1 was observed in nidus vessels in the AVF rats pre-and postradiosurgery. Radiosurgery enhanced apoptotic activity (p < 0.05) and inhibited the expression of Notch1 and Notch4 receptors and Jagged1 in the endothelial cells of nidus vessels in the AVF rats at 1, 2, 3, 7, 21, 28, and 42 days postradiosurgery (p < 0.05). Radiosurgery suppressed the interaction events between Notch1 receptor and Jagged1 (p < 0.001) as well as Notch4 receptor and Jagged1 (p < 0.001) in the endothelial cells of nidus vessels in the AVF rats over a period of 42 days postradiosurgery. Radiosurgery induced thrombotic occlusion of nidus vessels in the AVF rats. There was a positive correlation between the percentage of fully obliterated nidus vessels and time after radiosurgery (r = 0.9324, p < 0.001).Conclusions. Radiosurgery inhibits endothelial Notch1 and Notch4 signaling pathways in nidus vessels while inducing thrombotic occlusion of nidus vessels in a rat model of AVMs. The underlying mechanisms of radiosurgeryinduced AVM shrinkage could be a c...

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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

Cited by 79 publications

References 33 publications

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

The effect of simvastatin treatment on proliferation and differentiation of neural stem cells after traumatic brain injury

Radiosurgery inhibition of the Notch signaling pathway in a rat model of arteriovenous malformations

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