Gamma secretase–mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke

Arumugam, Thiruma V.; Chan, Sic L.; Jo, Dong Gyu; Yılmaz, Gökhan; Tang, Sung‐Chun; Cheng, Ann‐Lii; Gleichmann, Marc; Okun, Eitan; Dixit, Vishwa Deep; Chigurupati, Srinivasulu; Mughal, Mohamed R.; Ouyang, Xin; Miele, Lucio; Magnus, Tim; Poosala, Suresh; Granger, D. Neil; Mattson, Mark P.

doi:10.1038/nm1403

Cited by 230 publications

(245 citation statements)

References 14 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: 83%

“…Notch signaling has been hypothesized to have a causative role in brain damage following both acute insults, such as stroke, 14,15 as well as chronic neurodegenerative disorders such as AD. 31 Interestingly, excitotoxicity has been strongly implicated in the pathophysiology of both of these categories of disorders.…”

Section: Discussionmentioning

confidence: 99%

“…12 On the other hand, overactivation of Notch signaling, in response to hypoxic-ischemic or epileptic injury appears to contribute to neuronal demise. 14,15 Here we show that excitotoxic kainic acid (KA) treatment results in S-phase reentry with concomitant nuclear localization of Notch1. Notch signaling upon KA regulates Akt/Cyclind1 axis activation.…”

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confidence: 99%

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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: 83%

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…To recapitulate reperfusion in ischaemic stroke in vivo, we induced transient middle cerebral artery occlusion (tMCAO) 28,[33][34][35] in wild-type and p110d D910A/D910A mice, followed by 24-72 h reperfusion (Fig. 4a-c).…”

Section: Resultsmentioning

confidence: 99%

“…Exclusion criteria were excessive bleeding or death within 24 h after tMCAO. Male, 12-to 22-weekold, mice were anaesthetized for cerebral focal I/R induction by tMCAO 29,[33][34][35] . After a midline neck incision, the left external carotid and pterygopalatine arteries were isolated and ligated with 5-0 silk thread.…”

Section: Article Nature Communications | Doi: 101038/ncomms4450mentioning

confidence: 99%

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

et al. 2014

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Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kd) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kd inhibition confers protection in ischaemia/ reperfusion models of stroke. In vitro, restoration of glucose supply following an episode of glucose deprivation potentiates TNF secretion from primary microglia-an effect that is sensitive to PI3Kd inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kd (p110d D910A/D910A ) or wild-type mice pre-or post-treated with the PI3Kd inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kd as a potential therapeutic target in ischaemic stroke.

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Microphysiological Blood‐Brain Barrier Systems for Disease Modeling and Drug Development

Mulay,

Hwang,

Kim

2024

Adv Healthcare Materials

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The blood‐brain barrier (BBB) is a highly controlled microenvironment that regulates the interactions between cerebral blood and brain tissue. Due to its selectivity, many therapeutics targeting various neurological disorders have not been able to penetrate brain tissue. Pre‐clinical studies using animals and other in vitro platforms have not shown the ability to fully replicate the human BBB leading to the failure of a majority of therapeutics in clinical trials. However, recent innovations in vitro and ex vivo modeling called Organs‐on‐chips have shown the potential to create more accurate disease models for improved drug development. These microfluidic platforms induce physiological stressors on cultured cells and have been able to generate more physiologically accurate BBBs compared to previous in vitro models. In this review, different approaches to creating BBBs‐on‐chips are explored alongside their application in modeling various neurological disorders and potential therapeutic efficacy. Additionally, organs‐on‐chips use in BBB drug delivery studies is discussed, and advances in linking brain organs‐on‐chips onto multiorgan platforms to mimic organ crosstalk are reviewed.This article is protected by copyright. All rights reserved

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Gamma secretase–mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke

Cited by 230 publications

References 14 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

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

Microphysiological Blood‐Brain Barrier Systems for Disease Modeling and Drug Development

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