Relative importance of redox buffers GSH and NAD(P)H in age-related neurodegeneration and Alzheimer disease-like mouse neurons.
Bottom Line: Further, although depletion of NAD(P)H or GSH correlated linearly with neuron death, compared with GSH depletion, higher neurodegeneration was observed when NAD(P)H was extrapolated to zero, especially in old age, and in the 3xTg-AD neurons.Our data indicate that in aging and more so in AD-like neurons, NAD(P)H redox control is upstream of GSH and an oxidative redox shift that promotes neurodegeneration.Thus, NAD(P)H generation may be a more efficacious therapeutic target upstream of GSH and ROS.
Affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, 62794-9626, USA.Show MeSH
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Mentions: As glutathione depletion leads to oxidative redox stress and neurodegeneration in both aging and 3xTg-AD neurons (Ghosh et al., 2012), we wanted to test whether greater neurodegeneration was caused by depletion of NAD(P)H or GSH. As before (Ghosh et al., 2014), we depleted GSH levels by titrating the rate-limiting enzyme glutathione cysteine ligase with BSO (Fig. 5 A–C). We confirmed previous findings that 3xTg-AD neurons are more dependent on GSH availability (steeper slopes) than the non-Tg neurons and that both genotypes accelerated their dependence of neuron loss with GSH decrements with age. The linear relationship between GSH loss and neurodegeneration (Fig. 5 D–F) suggests a simple direct dependence. By extrapolation to zero GSH, the non-Tg cell death increased with age from 21% to 30%, while the 3xTg-AD increased more dramatically from 28 to 45%. Next, we compared these levels of neurodegeneration by GSH depletion to those by NAD(P)H depletion.
Affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, 62794-9626, USA.