Title

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

Abstract

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 γ-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 transfection-induced cell death was reduced by blockade of calcium signaling, caspase activation, and Janus kinase signaling. Inhibition of the Notch-activating enzyme, γ-secretase, protected against ischemic neuronal cell death by targeting an apoptotic protease, cleaved caspase-3, nuclear factor-κB (NF-κB), and the pro-death BH3-only protein, Bcl-2-interacting mediator of cell death (Bim). Treatment of mice with a γ-secretase inhibitor, compound E, reduced infarct size and improved functional outcome in a model of focal ischemic stroke. Furthermore, γ-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-κB, pro-death protein Bim, and caspase pathways. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics.

Publication Date

7-1-2011

Publication Title

Molecular Pharmacology

Volume

80

Issue

1

Number of Pages

23-31

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1124/mol.111.071076

Socpus ID

79959320245 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/79959320245

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