Supplementation with γ-glutamylcysteine (γ-GC) lessens oxidative stress, brain inflammation and amyloid pathology and improves spatial memory in a murine model of AD

Introduction: The accumulation of oxidative stress, neuroinflammation and abnormal aggregation of amyloid beta-peptide (A beta) have been shown to induce synaptic dysfunction and memory deficits in Alzheimer's disease (AD). Cellular depletion of the major endogenous antioxidant Glutathione (GSH) has been linked to cognitive decline and the development of AD pathology. Supplementation with gamma-glutamylcysteine (gamma-GC), the immediate precursor and the limiting substrate for GSH biosynthesis, can transiently augment cellular GSH levels by bypassing the regulation of GSH homeostasis. Methods: In the present study, we investigated the effect of dietary supplementation of gamma-GC on oxidative stress and A beta pathology in the brains of APP/PS1 mice. The APP/PS1 mice were fed gamma-GC from 3 months of age with biomarkers of apoptosis and cell death, oxidative stress, neuroinflammation and A beta load being assessed at 6 months of age. Results: Our data showed that supplementation with gamma-GC lowered the levels of brain lipid peroxidation, protein carbonyls and apoptosis, increased both total GSH and the glutathione/glutathione disulphide (GSH/GSSG) ratio and replenished ATP and the activities of the antioxidant enzymes (superoxide dismutase (SOD), catalase, glutamine synthetase and glutathione peroxidase (GPX)), the latter being a key regulator of ferroptosis. Brain A beta load was lower and acetylcholinesterase (AChE) activity was markedly improved compared to APP/PS1 mice fed a standard chow diet. Alteration in brain cytokine levels and matrix metalloproteinase enzymes MMP-2 and MMP-9 suggested that gamma-GC may lower inflammation and enhance A beta plaque clearance in vivo. Spatial memory was also improved by gamma-GC as determined using the Morris water maze. Conclusion: Our data collectively suggested that supplementation with gamma-GC may represent a novel strategy for the treatment and/or prevention of cognitive impairment and neurodegeneration.

Automated summary

Supplementation with gamma-GC decreased brain lipid peroxidation, protein carbonyls, and apoptosis, while increasing total GSH levels and enhancing antioxidant enzyme activities. Additionally, gamma-GC improved Aβ pathology and cognitive function in APP/PS1 mice.