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Glutathione (GSH), antioxidants, & Alzheimer's Disease
Data excerpted from: www.tellpharm.com
See also: Alzheimer's Disease Part 1 and Alzheimer's Disease Part 2
Alzheimer’s disease is characterized by two pathological features: the extracellular beta amyloid plaques and abnormal intracellular cytoskeletal filaments known as neurofibrillary tangles. Amyloid beta-peptide (A beta) forms the core of the plaques and plays a crucial role in disease pathogenesis (1)
Alzheimer's is a disorder associated with oxidative stress due, in part, to the membrane action of A beta. Degenerating neurons are associated with deposits of A beta, and there is evidence for increased membrane lipid peroxidation and protein oxidation in the degenerating neurons.
A beta has been shown to enhance oxidative stress, and stimulate increases in hydrogen peroxide (H2O2) (2,3). Oxidative stress appears to mediate A beta toxicity by free radical production (4,5). A beta can generate free radicals which have the potential to inactivate oxidation-sensitive enzymes and initiate lipid peroxidation (6,7,8). A beta is able to potentiate the free-radical promoting capacity of metal ions such as iron, copper and aluminum. Such potentiation may be a relevant mechanism underlying A beta-induced degeneration of nerve cells (9). The interaction of amyloid fibrils with LDL receptors appears to be another pathway that contributes to A beta cytotoxicity (10). In addition, cell culture studies have shown that A beta can disrupt calcium homeostasis and induce apoptosis in neurons by a mechanism involving oxidative stress (11).
Amyloid beta peptide and other oxidative insults induce peroxidation of membrane lipids which results in release of the aldehyde 4-hydroxynonenal (HNE) (12,13). Lipid peroxidation has been shown to increase in Alzheimer’s disease (14-17). Alzheimer’s patients’ brains show increased levels of HNE, which is a potent neurotoxin (18,19). HNE acts to covalently modify proteins and crosslink neuronal cytoskeletal proteins. It has been shown to alter the conformation of cortical synaptosomal membrane proteins (20). HNE impairs glutamate and glucose transport in rat cortical synaptosomes, and plays important roles in oxidative impairment of synaptic functions that would be expected to promote excitotoxic cascades (21,22).
Glutathione (GSH) is important as a detoxicant of HNE, and exerts a protective effect against different types of HNE-induced damage (12,13,21,22). GSH has been shown to protect cultured cells against various oxidative stressors including beta amyloid, iron, and HNE (11-13). Elevating levels of endogenous glutathione in a rodent model protects against free radical-induced oxidative stress in isolated synaptosomal membranes treated with Fe2+/H2O2, a known hydroxyl free radical producer (23). HNE is a key mediator of oxidative stress-induced neuronal apoptosis, and the antiapoptotic action of glutathione probably involves detoxification of HNE (24).
Neurfibrillary tangles, the other defining feature of Alzheimer’s, are composed of polymerized tau, a protein normally associated with microtubule stabilization. Tau polymerization can be induced by oxidative stress in vitro (25). The polymerization is seeded by a dimerization that depends on the formation of a disulfide linkage via oxidation (26). Oxidized proteins have been detected in neurofibrillary tangles in vivo (27).
Early measurements of brain levels of GSH in Alzheimer’s patients suffered from inadequate tissue preparation techniques, generated conflicting results, and no attempt was made to measure reduced (GSH) versus oxidized (GSSG) glutathione. Recently, intracellular levels of GSH and GSSG were measured in lymphoblast lines from patients with familial and sporadic Alzheimer's disease and from age-matched controls. Lymphoblasts carrying mutations in genes associated with Alzheimer’s showed significantly decreased GSH content with respect to controls. Levels of GSSG were not significantly different. These results indicate that even peripheral cells not involved in the neurodegenerative process show altered GSH content when carrying these mutations. The provided data appear to be in accordance with the known alteration of GSH levels in central nervous system and strengthen the hypothesis of oxidative stress as an important, possibly crucial mechanism in the pathogenesis of Alzheimer’s disease (28).
Oxidative stress-mediated neuronal loss may be initiated by a decline in GSH. GSH depletion can enhance oxidative stress and may also increase the levels of excitotoxic molecules; both types of action can initiate cell death in distinct neuronal populations (29). Differentiated NT2 cells, but not undifferentiated NT2 cells, exhibit low levels of GSH and alpha-tocopherol and of antioxidant enzymatic activities, and are highly susceptible to oxidative stress (30).
Oxidative insults are associated with apolipoprotein E genotype in Alzheimer's disease brain: in the hippocampus the level of oxidized substances and the APOE genotype are linked. Among Alzheimer’s cases, tissues form patients with the epsilon4 allele had lower concentration of glutathione than tissues from patients homozygous for the epsilon3 allele of APOE (31).
Glutamate-induced cytotoxicity in HT-4 cells is due to oxidative stress caused by depletion of cellular GSH and is a useful model system for testing compounds or mixtures for antioxidant activity. The protective effects of thiol-based pro-glutathione agents alpha-lipoic acid (LA) and N-acetyl cysteine (NAC) corresponded with a sparing effect on GSH levels in glutamate-treated HT-4 cells (32). Combined estrogen-antioxidant therapy for neurodegenerative diseases such as Alzheimer's disease may prove useful. Using a murine neuronal cell line, The presence of reduced glutathione in culture media increases the neuroprotective potency of estrogens by an average of 400-fold (33).
Cell protection can depend on the presence of specific thiols. Cysteine promotes reactions of oxidative stress in the brain areas of substantia nigra and septum, but not in other areas. In contrast, exogenous administration of reduced glutathione led to a significant decrease of lipoperoxidation in the brain areas of cortex and hippocampus, corresponding to selective changes in the endogenous pool of thiols (34).
There is a growing body of evidence to implicate excessive or inappropriate generation of nitric oxide (NO) in Alzheimer’s and other neurological disorders. Nitric oxide and its toxic metabolite, peroxynitrite, can inhibit components of the mitochondrial respiratory chain leading, if damage is severe enough, to a cellular energy deficiency state. Within the brain, the susceptibility of different brain cell types to NO and ONOO- exposure may be dependent on factors such as the intracellular reduced glutathione (GSH) concentration and an ability to increase glycolytic flux in the face of mitochondrial damage (35).
AD has also been correlated with environmental factors which may lead to oxidative stress. Aluminum, a trivalent cation unable to undergo redox reactions, has implicated in Alzheimer's disease although this is controversial. A 500-microM concentration of this salt produced a significant increase in reactive oxygen species (ROS) production and a significant decrease in glutathione (GSH) content in glioma cells (36).
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