Beta-amyloidolysis and glutathione in Alzheimer's disease

Abstract

In this review, we hypothesized the importance of the interaction between the brain glutathione (GSH) system, the proteolytic tissue plasminogen activator (t-PA)/plasminogen/ plasmin system, regulated by plasminogen activator inhibitor (PAI-1), and neuroserpin in the pathogenesis of Alzheimer’s disease. The histopathological characteristic hallmark that gives personality to the diagnosis of Alzheimer’s disease is the accumulation of neurofibroid tangles located intracellularly in the brain, such as the protein tau and extracellular senile plaques made primarily of amyloidal substance. These formations of complex etiology are intimately related to GSH, brain protective antioxidants, and the proteolytic system, in which t-PA plays a key role. There is scientific evidence that suggests a relationship between aging, a number of neurodegenerative disorders, and the excessive production of reactive oxygen species and accompanying decreased brain proteolysis. The plasminogen system in the brain is an essential proteolytic mechanism that effectively degrades amyloid peptides (“beta-amyloidolysis”) through action of the plasmin, and this physiologic process may be considered to be a means of prevention of neurodegenerative disorders. In parallel to the decrease in GSH levels seen in aging, there is also a decrease in plasmin brain activity and a progressive decrease of t-PA activity, caused by a decrease in the expression of the t-PA together with an increase of the PAI-1 levels, which rise to an increment in the production of amyloid peptides and a lesser clearance of them. Better knowledge of the GSH mechanism and cerebral proteolysis will allow us to hypothesize about therapeutic practices.

Glutathione redox imbalance in brain disorders

“…Lasierra-Cirujeda et al [34] suggested that GSH has an important interaction with the plasminogen/plasmin system, which is one of the enzymes that degrade Ab. Lasierra-Cirujeda et al [34] suggested that GSH has an important interaction with the plasminogen/plasmin system, which is one of the enzymes that degrade Ab.…”

Sulodexide and Alzheimer’s Disease: A Preliminary Prospective Study

“…We reported, in fact, that the pharmacological effect that is obtained after the administration of buthionine sulfoximine (BSO) or dietil maleate in rabbits, is a significant decrease in the levels of GSH with the inhibition of fibrinolytic activity measured in the fibrin plates, due to a decrease of cellular t-PA release with a significant increase of its inhibitor PAI-1 [13] [127].…”

“…The Aβ peptide is a substratum capable of being degraded, via beta-amyloidolysis [13], by various proteases known as AβDPs (Aβ-degrading proteases) [14]. Among all AβDPs that can degrade the Aβ peptides, for their clearing and cerebral elimination, such as neprilysin (NEP) [15]- [24], insulin-degrading enzyme (IDE) [16] [25]- [27], and plasmin [28]- [33].…”

“…The extent of accumulation of the Aβ peptides depends on an imbalance between their production, proteolytic degradation and cerebral elimination [34], being the relationship between glutathione (GSH or L-gamma-glutamyl-L-cysteinyl-glycine) and plasminogen/plasmin system of great importance for normal cerebral function, since the deficit of Aβ-degrading enzymes and the decrease of GSH affect the Aβ balance in aging, and are very important mechanisms in the brain accumulation of Aβ [13] [35]. Several groups of investigators have suggested the possibility that the amyloidal deposits may be amenable by these proteases.…”

Aging: Thromboembolic Disease, Metabolic Syndrome, Type 2 Diabetes Mellitus, and Alzheimer’s Disease

“…Among the substances that modify the normal physiologic operation, oxidative stress-direct consequence of the oxygenate metabolism of the aerobic cells [6]- [10], hemostatic changes in systemic fibrinolytic mechanism, changes in cerebral b-amyloidolytic mechanism, an increase in the expression of plasminogen activator inhibitor (PAI-1)-main inhibitor of the tissue plasminogen activator (t-PA) [11]- [13], play a very important role in the thromboembolic disease, metabolic syndrome (MS), (obesity, hyperglycemia, insulin resistance (IR)), type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD). These diseases are associated to clinical processes with glutathione (GSH) depletion and oxidative stress that accompany the aging.…”