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: These culture studies were complemented by in vivo measures of the NADPH/NADP redox state of brain tissue homogenates by HPLC from 4-, 11-, and 21-month non-Tg and 3xTg-AD animals. We observed that after middle age (11 month), the NADPH concentration declined similarly in both non-Tg and 3xTg-AD brain (Fig. 6A). Likewise, the redox state of both non-Tg and 3xTg-AD brain was significantly more oxidized with age (Fig. 6B) (ANOVA P = 0.001). However, we did not observe any genotype difference, possibly due to blood and glial compensation for neuronal changes. These results indicate that the redox state in the whole aging brain reflects an oxidative shift as seen in the cultured neurons.
Affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, 62794-9626, USA.