Glutathione: An Old and Small Molecule with Great Functions and New Applications in the Brain and in Alzheimer's Disease.

Significance: Glutathione (GSH) represents the most abundant and the main antioxidant in the body with important functions in the brain related to Alzheimer's disease (AD). Recent Advances: Oxidative stress is one of the central mechanisms in AD. We and others have demonstrated the alteration of GSH levels in the AD brain, its important role in the detoxification of advanced glycation end-products and of acrolein, a by-product of lipid peroxidation. Recent in vivo studies found a decrease of GSH in several areas of the brain from control, mild cognitive impairment, and AD subjects, which are correlated with cognitive decline. Critical Issues: Several strategies were developed to restore its intracellular level with the l-cysteine prodrugs or the oral administration of γ-glutamylcysteine to prevent alterations observed in AD. To date, no benefit on GSH level or on oxidative biomarkers has been reported in clinical trials. Thus, it remains uncertain if GSH could be considered a potential preventive or therapeutic approach or a biomarker for AD. Future Directions: We address how GSH-coupled nanocarriers represent a promising approach for the functionalization of nanocarriers to overcome the blood/brain barrier (BBB) for the brain delivery of GSH while avoiding cellular toxicity. It is also important to address the presence of GSH in exosomes for its potential intercellular transfer or its shuttle across the BBB under certain conditions. Antioxid. Redox Signal. 35, 270-292.