γ-Glutamyl-Transpeptidase-Resistant Glutathione Analog Attenuates Progression of Alzheimer’s Disease-Like Pathology and Neurodegeneration in a Mouse Model

Christopher Kwon, Wei Xie, Haizhou Zhu, Jiashu Xie, Keaton Shinn, Nicholas Juckel, Robert Vince, Swati S More, Michael K Lee

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7 Scopus citations

Abstract

Oxidative stress in Alzheimer’s disease (AD) is mediated, in part, by the loss of glutathione (GSH). Previous studies show that γ-glutamyl transpeptidase (GGT)-resistant GSH analog, Ψ-GSH, improves brain GSH levels, reduces oxidative stress markers in brains of APP/PS1 transgenic mice, a mouse model of AD, and attenuates early memory deficits in the APP/PS1 model. Herein, we examined whether Ψ-GSH can attenuate the disease progression when administered following the onset of AD-like pathology in vivo. Cohorts of APP/PS1 mice were administered Ψ-GSH for 2 months starting at 8 month or 12 months of age. We show that Ψ-GSH treatment reduces indices of oxidative stress in older mice by restoration of enzyme glyoxalase-1 (Glo-1) activity and reduces levels of insoluble Aβ. Quantitative neuropathological analyses show that Ψ-GSH treatment significantly reduces Aβ deposition and brain inflammation in APP/PS1 mice compared to vehicle-treated mice. More importantly, Ψ-GSH treatment attenuated the progressive loss of cortical TH+ afferents and the loss of TH+ neurons in the locus coeruleus (LC). Collectively, the results show that Ψ-GSH exhibits significant antioxidant activity in aged APP/PS1 mice and chronic Ψ-GSH treatment administered after the onset of AD pathology can reverse/slow further progression of AD-like pathology and neurodegeneration in vivo.

Original languageEnglish (US)
Article number1796
JournalAntioxidants
Volume10
Issue number11
DOIs
StatePublished - Nov 2021

Bibliographical note

Funding Information:
Funding: This research was funded by National Institutes of Health Grants to SSM (R01-AG0624069) and MKL (RF1-AG062135, R01-NS108686) and by funding from the Center for Drug Design (CDD), University of Minnesota.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Advanced glycation end products (AGEs)
  • Alzheimer’s disease
  • Glyoxalase 1
  • Neuroinflammation
  • Oxidative stress
  • Progressive neurodegeneration

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