Redox signaling and metabolism in Alzheimer's disease.

Reduction and oxidation reactions are essential for biochemical processes. They are part of metabolic pathways and signal transduction. Reactive oxygen species (ROS) as second messengers and oxidative modifications of cysteinyl (Cys) residues are key to transduce and translate intracellular and intercellular signals. Dysregulation of cellular redox signaling is known as oxidative distress, which has been linked to various pathologies, including neurodegeneration. Alzheimer's disease (AD) is a neurodegenerative pathology linked to both, abnormal amyloid precursor protein (APP) processing, generating Aß peptide, and Tau hyperphosphorylation and aggregation. Signs of oxidative distress in AD include: increase of ROS (H2O2, O2 •-), decrease of the levels or activities of antioxidant enzymes, abnormal oxidation of macromolecules related to elevated Aß production, and changes in mitochondrial homeostasis linked to Tau phosphorylation. Interestingly, Cys residues present in APP form disulfide bonds that are important for intermolecular interactions and might be involved in the aggregation of Aß. Moreover, two Cys residues in some Tau isoforms have been shown to be essential for Tau stabilization and its interaction with microtubules. Future research will show the complexities of Tau, its interactome, and the role that Cys residues play in the progression of AD. The specific modification of cysteinyl residues in redox signaling is also tightly connected to the regulation of various metabolic pathways. Many of these pathways have been found to be altered in AD, even at very early stages. In order to analyze the complex changes and underlying mechanisms, several AD models have been developed, including animal models, 2D and 3D cell culture, and ex-vivo studies of patient samples. The use of these models along with innovative, new redox analysis techniques are key to further understand the importance of the redox component in Alzheimer's disease and the identification of new therapeutic targets in the future.

Redox Enzymes of the Thioredoxin Family as Potential and Novel Markers in Pemphigus.

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease affecting both skin and mucous membranes. Its pathogenesis is related to IgG autoantibodies primarily targeting the cellular adhesion protein desmoglein (Dsg) 3, one of the major desmosome components. Impaired redox regulation is considered a major player in the pathogenesis of autoimmune diseases such as pemphigus by enhancing inflammation and breakdown of immunological tolerance by structural protein modifications. Despite many recent advances, local and systemic redox profiles that characterize the immune response in pemphigus are virtually unknown but potentially crucial in further advancing our understanding of redox-dependent modifications that eventually lead to clinical manifestation. Here, we have analyzed the individual expression pattern of four major redox enzymes that are members of the thioredoxin (Trx) fold superfamily (peroxiredoxins (Prxs) 1 and 4, glutaredoxin (Grx) 2, and Trx1) in serum and PBMCs as well as their distribution in the skin of pemphigus patients compared to healthy controls. We show that in groups of five pemphigus patients, Prx1 is upregulated in both serum and PBMCs, while its epithelial distribution remains within the spinous epithelial layer. Expression of Grx2 and Prx4 is both reduced in serum and PBMCs, while their distinct and similar expression in the skin changes from an even distribution throughout the basal layer (healthy) to ubiquitous nuclear localization in pemphigus patients. In PV patients, Trx1 is secreted into serum, and cellular distribution appears membrane-bound and cytosolic compared to healthy controls. We furthermore showed that a 3D ex vivo human skin model can indeed be used to reproduce similar changes in the protein levels and distribution of redox enzymes by application of cold atmospheric plasma. Deciphering the relationship between redox enzyme expression and autoimmunity in the context of pemphigus could be critical in elucidating key pathogenic mechanisms and developing novel interventions for clinical management.

Thioredoxin 1 Plays a Protective Role in Retinas Exposed to Perinatal Hypoxia-Ischemia.

Thioredoxin family proteins are key modulators of cellular redox regulation and have been linked to several physiological functions, including the cellular response to hypoxia-ischemia. During perinatal hypoxia-ischemia (PHI), the central nervous system is subjected to a fast decrease in O2 and nutrients with a subsequent reoxygenation that ultimately leads to the production of reactive species impairing physiological redox signaling. Particularly, the retina is one of the most affected tissues, due to its high oxygen consumption and exposure to light. One of the main consequences of PHI is retinopathy of prematurity, comprising changes in retinal neural and vascular development, with further compensatory mechanisms that can ultimately lead to retinal detachment and blindness. In this study, we have analyzed long-term changes that occur in the retina using two well established in vivo rat PHI models (perinatal asphyxia and carotid ligation model), as well as the ARPE-19 cell line that was exposed to hypoxia and reoxygenation. We observed significant changes in the protein levels of the cytosolic oxidoreductase thioredoxin 1 (Trx1) in both animal models and a cell model. Knock-down of Trx1 in ARPE-19 cells affected cell morphology, proliferation and the levels of specific differentiation markers. Administration of recombinant Trx1 decreased astrogliosis and improved delayed neurodevelopment in animals exposed to PHI. Taken together, our results suggest therapeutical implications for Trx1 in retinal damage induced by hypoxia-ischemia during birth.