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Author Notes:

Correspondence: Manuel Yepes, Department of Neurology and Center for Neurodegenerative Disease, Whitehead Biomedical Research Building, 615 Michael Street, Suite 505J, Atlanta, Georgia 30322; Telephone: (404) 712 8358; Fax: (404) 727 3728; Email: myepes@emory.edu


Research Funding:

This work was supported in part by National Institutes of Health Grants NS-062073 and HL-095063 (to M.Y)


  • Cerebral ischemia
  • Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)
  • Fibroblast growth factor-inducible 14 (Fn14)
  • Poly(ADP-ribose)polymerase-1 (PARP-1)
  • Poly(ADP-ribose) polymers (PAR)

Tumor necrosis factor-like weak inducer of apoptosis and fibroblast growth factor-inducible 14 mediate cerebral ischemia-induced poly(ADP-ribose) polymerase-1 activation and neuronal death


Journal Title:



Volume 171, Number 4


, Pages 1256-1264

Type of Work:

Article | Post-print: After Peer Review


Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Fn14) are expressed in neurons. Here we demonstrate that TWEAK induces a dose-dependent increase in neuronal death and that this effect is independent of TNF-α and mediated by NF-κB pathway activation. Incubation with TWEAK induces apoptotic cell death in wild-type (Wt) but not in Fn14 deficient (Fn14−/−) neurons. Intracerebral injection of TWEAK induces accumulation of poly(ADP-ribose) polymers (PAR) in Wt but not in Fn14−/− mice. Exposure to oxygen-glucose deprivation (OGD) conditions increases TWEAK and Fn14 mRNA expression in Wt neurons, and decreases cell survival in Wt but not in Fn14−/− or TWEAK deficient (TWEAK−/−) neurons. Experimental middle cerebral artery occlusion (MCAO) increases the expression of TWEAK and Fn14 mRNA and active caspase-3, and the cleavage of poly(ADP-ribose)polymerase-1 with accumulation of PAR in the ischemic area in Wt but not Fn14−/− mice. Together, these results suggest a model where in response to hypoxia/ischemia the interaction between TWEAK and Fn14 in neurons induces PARP-1 activation with accumulation of PAR polymers and cell death via NF-κB pathway activation. This is a novel pathway for hypoxia/ischemia-induced TWEAK-mediated cell death and a potential therapeutic target for ischemic stroke.

Copyright information:

© 2010, Elsevier

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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