| Abstract: | Inducible nitric oxide synthase (iNOS) and high levels of nitric oxide (NO) are present in the CNS of patients with Alzheimer's disease (AD), resulting in both DNA and protein oxidative damage. While iNOS can result in damaging levels of NO, the neuronal constitutive form of NOS (nNOS) has a role in cell signalling and can prevent neuronal apoptosis. iNOS can be induced by inflammatory cytokines such as tumor necrosis alpha (TNFα). TNFα is found in the CNS of AD, where neurons dependent on neurotrophins such as nerve growth factor (NGF) are particularly affected. Here we determined the effect of TNFα on the three NOS isoforms (endothelial, neuronal and inducible) in NGF‐responsive PC12 cells. We found that while TNFα and NGF alone were uneffective, their simultaneous addition resulted in iNOS induction and the release of NO. In addition TNFα and NGF synergistically reduced nNOS, independently of the presence of high NO levels promoted by iNOS, while no effect was observed on eNOS. A similar pattern was observed in the brain of aged human subjects as compared to young individuals. Our results suggest that synergistic iNOS induction by TNFα and NGF may occur in selective populations of NGF‐responsive neurons. Oxidative damage in such neurons could then occur in the presence of elevated levels of TNFα, that potentially occur in the brain of AD patients. This damaging scenario may further be aggravated by a concomitant reduction of nNOS, brought about by similar synergistic effects between TNFα and NGF. Acknowledgements: Supported by NIA (AG13945) and Sealy Res. Dev. grants to GT. |
