TUMOR NECROSIS FACTOR-LIKE WEAK INDUCER OF APOPTOSIS (TWEAK) AND FIBROBLAST GROWTH FACTOR- INDUCIBLE 14 (Fn14) MEDIATE CEREBRAL ISCHEMIA-INDUCED POLY(ADP-RIBOSE) POLYMERASE-1 ACTIVATION AND NEURONAL DEATH

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(ADPribose)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.