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

Yue Liu; Zheng Chen; Ben Li; Hua Yao; Martin Zarka; Jeffrey Welch; Perminder Sachdev; Wallace Bridge; Nady Braidy

doi:10.1016/j.neuint.2020.104931

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

Neurochem Int. 2021 Mar:144:104931. doi: 10.1016/j.neuint.2020.104931. Epub 2020 Dec 2.

Authors

Yue Liu¹, Zheng Chen², Ben Li³, Hua Yao⁴, Martin Zarka⁵, Jeffrey Welch⁵, Perminder Sachdev⁶, Wallace Bridge⁵, Nady Braidy⁷

Affiliations

¹ Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia; Guangdong Mental Health Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
² School of Medicine, Huzhou University, Huzhou Central Hospital Huzhou, China.
³ College of Life and Environmental Sciences, Wenzhou University, Wenzhou, China.
⁴ Institute of Life Sciences and Institute of Neuroscience, Wenzhou University, Wenzhou, China.
⁵ School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, Australia.
⁶ Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia; Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Sydney, Australia.
⁷ Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia. Electronic address: n.braidy@unsw.edu.au.

PMID: 33276023
DOI: 10.1016/j.neuint.2020.104931

Abstract

Introduction: The accumulation of oxidative stress, neuroinflammation and abnormal aggregation of amyloid β-peptide (Aβ) 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 γ-glutamylcysteine (γ-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 γ-GC on oxidative stress and Aβ pathology in the brains of APP/PS1 mice. The APP/PS1 mice were fed γ-GC from 3 months of age with biomarkers of apoptosis and cell death, oxidative stress, neuroinflammation and Aβ load being assessed at 6 months of age.

Results: Our data showed that supplementation with γ-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 Aβ 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 γ-GC may lower inflammation and enhance Aβ plaque clearance in vivo. Spatial memory was also improved by γ-GC as determined using the Morris water maze.

Conclusion: Our data collectively suggested that supplementation with γ-GC may represent a novel strategy for the treatment and/or prevention of cognitive impairment and neurodegeneration.

Keywords: Alzheimer's disease; Antioxidants; Dementia; Glutathione; Oxidative stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Amyloid / antagonists & inhibitors*
Amyloid / metabolism
Animals
Dietary Supplements
Dipeptides / administration & dosage*
Disease Models, Animal
Encephalitis / drug therapy*
Encephalitis / metabolism
Encephalitis / pathology
Male
Mice
Mice, Transgenic
Oxidative Stress / drug effects*
Oxidative Stress / physiology
Spatial Memory / drug effects*
Spatial Memory / physiology

Substances

Amyloid
Dipeptides
gamma-glutamylcysteine