Oxidative Stress: Glutathione and Its Potential to Protect Methionine-35 of Aβ Peptide from Oxidation

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder with heterogeneous etiology. Intracellular neurofibrillary tangles caused by tau (τ) protein phosphorylation and extracellular senile plaques caused by aggregation of amyloid-beta (Aβ) peptide are characteristic histopathological hallmarks of AD. Oxidative stress (OS) is also suggested to play a role in the pathophysiology of AD. The antioxidant glutathione (GSH) is able to mitigate OS through the detoxification of free radicals. The clearance of these free radicals is reported to be affected when there is a decline in GSH levels in AD. These radicals further react with the methionine-35 (M-35) residue of Aβ and facilitate its subsequent oligomerization. This review presents a plausible model indicating the role of master antioxidant GSH to protect M35 of Aβ_1-40/Aβ_1-42 from oxidation in pathological conditions as compared to healthy controls.

Figure 1

Structure of methionine. (A) Structure of methionine with the thiol-ether group highlighted. (B) Methionine oxidation. Prolonged oxidation leads to the generation of the reactive oxygen species methionine sulfone. The figure is prepared based on the earlier work.

Figure 2

Schematic representation of the impact of GSH in (A) healthy brain and (B) pathological condition in AD brain. (A) In a normal brain under physiological conditions, glutathione levels are maintained. GSH participates in the GSH cycle. The GSH:GSSG ratio is maintained at 100:1 via the cycle by recycling GSH from oxidized glutathione (GSSG) intracellularly. ROS is actively detoxified by GSH, which acts as a modulator for the radicals, and ROS cannot cause further oxidation of the M35 residue of Aβ. The redox homeostasis is thus maintained in the healthy brain. (B) A model of Alzheimer’s disease pathology due to oxidative stress. Depleted GSH levels can lead to increased levels of free radicals. These free radicals can then oxidize the M35 residue leading to several biochemical modifications like lipid peroxidation and protein modifications as well as formation of amyloid plaques, which can consequently form neurofibrillary tangles. Red star indicates ROS and oxidative damage. Representative image of structure of residues 35–42 of Aβ_1–42 has been adapted with permission from ref (79). Copyright 2008 Elsevier B.V. Representative MRI images of healthy and AD brain are taken from NINS laboratory data.