title: Dual-energy precursor and nuclear erythroid-related factor 2 activator treatment additively improve redox glutathione levels and neuron survival in aging and Alzheimer mouse neurons upstream of reactive oxygen species.
abstract: To determine whether glutathione (GSH) loss or increased reactive oxygen species (ROS) are more important to neuron loss, aging, and Alzheimer's disease (AD), we stressed or boosted GSH levels in neurons isolated from aging 3xTg-AD neurons compared with those from age-matched nontransgenic (non-Tg) neurons. Here, using titrating with buthionine sulfoximine, an inhibitor of γ-glutamyl cysteine synthetase (GCL), we observed that GSH depletion increased neuronal death of 3xTg-AD cultured neurons at increasing rates across the age span, whereas non-Tg neurons were resistant to GSH depletion until old age. Remarkably, the rate of neuron loss with ROS did not increase in old age and was the same for both genotypes, which indicates that cognitive deficits in the AD model were not caused by ROS. Therefore, we targeted for neuroprotection activation of the redox sensitive transcription factor, nuclear erythroid-related factor 2 (Nrf2) by 18 alpha glycyrrhetinic acid to stimulate GSH synthesis through GCL. This balanced stimulation of a number of redox enzymes restored the lower levels of Nrf2 and GCL seen in 3xTg-AD neurons compared with those of non-Tg neurons and promoted translocation of Nrf2 to the nucleus. By combining the Nrf2 activator together with the NADH precursor, nicotinamide, we increased neuron survival against amyloid beta stress in an additive manner. These stress tests and neuroprotective treatments suggest that the redox environment is more important for neuron survival than ROS. The dual neuroprotective treatment with nicotinamide and an Nrf2 inducer indicates that these age-related and AD-related changes are reversible.
authors: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
authors: Debolina
authors: D
authors: Ghosh
authors: Kelsey R
authors: KR
authors: LeVault
authors: Gregory J
authors: GJ
authors: Brewer
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005721:Glutamate-Cysteine Ligase / Q000502:physiology; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D006034:Glycyrrhetinic Acid / Q000494:pharmacology* / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009243:NAD; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000473:pathology* / Q000502:physiology*; D018696:Neuroprotective Agents; D009536:Niacinamide / Q000494:pharmacology* / Q000627:therapeutic use*; D010084:Oxidation-Reduction / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D009243:NAD; D009536:Niacinamide; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D006034:Glycyrrhetinic Acid
keywords: 3xTg-AD; Aging; Glutathione; Neurodegeneration; Neuroprotection; Nrf2; ROS; Stress
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