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

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.

Dipeptide of ψ-GSH Inhibits Oxidative Stress and Neuroinflammation in an Alzheimer’s Disease Mouse Model

“…Designed to restore glyoxalase enzyme function in the brain, antioxidant ψ-GSH presents additional benefits such as mitigation of oxidative stress and inflammatory pathology of AD. The compound was efficacious in transgenic mouse models of AD when administered in asymptomatic and symptomatic stages [ 22 , 23 ]. Thus, ψ-GSH presents a promising true disease-modifying option for AD.…”

“…Then, the anti-rabbit IgG HRP conjugated secondary antibody was applied for 1 h before the DAB kit was used for visualization, with counterstaining by Mayer’s hematoxylin solution. Expression of GFAP was quantitated by manual counting of GFAP-positive neurons and confirmation with stereological counting of the section, similar to the methods described in our previous publication [ 23 ].…”

“…When tested in enzymatic and cellular models, ψ-GSH substituted for GSH in the GSH-dependent enzymatic reactions utilized GSH transport mechanisms to cross the blood–brain barrier and detoxified cellular oxidative stress [ 21 ]. We have demonstrated efficacy of this compound in AD transgenic mice APP/PS1 in a preventative [ 22 ] and therapeutic [ 23 ] treatment regimens. Mechanistic investigations highlighted restoration of glyoxalase enzyme activity by ψ-GSH as a significant contributor to the latter’s neuroprotective activity.…”

Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregatesin vivoin a mouse model of Alzheimer’s disease

“…Previous in vitro and in vivo studies suggest that mitochondrial oxidative stress is related to AD pathology (47)(48)(49)(50)(51). However, the sequence of pathological events was not well understood in the in vivo living brain, as well as whether the use of mitochondrial antioxidant targeted compounds could prevent these effects.…”

Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo

“…Stereological Analysis of Aβ pathology and neuroinflammation. Quantitative analysis of Aβ pathology and neuroinflammation were performed using immunostained brain sections as previously described [ 55 ]. Briefly, frozen coronal sections (40 μm) were incubated with a primary antibody of interest, followed by detection using the ABC method (Vector Laboratories, Burlingame, CA, USA) with the chromogen, 3,3′-diaminobenzidine (DAB; Sigma Aldrich, St. Louis, MO, USA) for visualization.…”