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      Oxidative toxicity in diabetes and Alzheimer’s disease: mechanisms behind ROS/ RNS generation

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          Abstract

          Reactive oxidative species (ROS) toxicity remains an undisputed cause and link between Alzheimer’s disease (AD) and Type-2 Diabetes Mellitus (T2DM). Patients with both AD and T2DM have damaged, oxidized DNA, RNA, protein and lipid products that can be used as possible disease progression markers. Although the oxidative stress has been anticipated as a main cause in promoting both AD and T2DM, multiple pathways could be involved in ROS production. The focus of this review is to summarize the mechanisms involved in ROS production and their possible association with AD and T2DM pathogenesis and progression. We have also highlighted the role of current treatments that can be linked with reduced oxidative stress and damage in AD and T2DM.

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          Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple.

          F Q Schafer, G R Buettner (2001)
          Redox state is a term used widely in the research field of free radicals and oxidative stress. Unfortunately, it is used as a general term referring to relative changes that are not well defined or quantitated. In this review we provide a definition for the redox environment of biological fluids, cell organelles, cells, or tissue. We illustrate how the reduction potential of various redox couples can be estimated with the Nernst equation and show how pH and the concentrations of the species comprising different redox couples influence the reduction potential. We discuss how the redox state of the glutathione disulfide-glutathione couple (GSSG/2GSH) can serve as an important indicator of redox environment. There are many redox couples in a cell that work together to maintain the redox environment; the GSSG/2GSH couple is the most abundant redox couple in a cell. Changes of the half-cell reduction potential (E(hc)) of the GSSG/2GSH couple appear to correlate with the biological status of the cell: proliferation E(hc) approximately -240 mV; differentiation E(hc) approximately -200 mV; or apoptosis E(hc) approximately -170 mV. These estimates can be used to more fully understand the redox biochemistry that results from oxidative stress. These are the first steps toward a new quantitative biology, which hopefully will provide a rationale and understanding of the cellular mechanisms associated with cell growth and development, signaling, and reductive or oxidative stress.
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            High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria.

            S Korshunov, V. Skulachev, A A Starkov (1997)
            Formation of H2O2 has been studied in rat heart mitochondria, pretreated with H2O2 and aminotriazole to lower their antioxidant capacity. It is shown that the rate of H2O2 formation by mitochondria oxidizing 6 mM succinate is inhibited by a protonophorous uncoupler, ADP and phosphate, malonate, rotenone and myxothiazol, and is stimulated by antimycin A. The effect of ADP is abolished by carboxyatractylate and oligomycin. Addition of uncoupler after rotenone induces further inhibition of H2O2 production. Inhibition of H2O2 formation by uncoupler, malonate and ADP+Pi is shown to be proportional to the delta psi decrease by these compounds. A threshold delta psi value is found, above which a very strong increase in H2O2 production takes place. This threshold slightly exceeds the state 3 delta psi level. The data obtained are in line with the concept [Skulachev, V.P., Q. Rev. Biophys. 29 (1996), 169-2021 that a high proton motive force in state 4 is potentially dangerous for the cell due to an increase in the probability of superoxide formation.
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              An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers.

              Theresa R Bomfim, Letícia Forny-Germano, Luciana B. Sathler … (2012)
              Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.
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                Author and article information

                Contributors
                Waqar Ahmad:
                ORCID: http://orcid.org/0000-0003-0474-6558
                +61450733698 , waqarchemist@hotmail.com , waqar.ahmad@uqconnect.edu.au
                Bushra Ijaz: bijaz_009@yahoo.com
                Khadija Shabbiri: k.shabbiri@uq.edu.au
                Fayyaz Ahmed: fayyazahmad.uhs@gmail.com
                Sidra Rehman: sidrarehman@ciit.net.pk
                Journal
                Journal ID (nlm-ta): J Biomed Sci
                Journal ID (iso-abbrev): J. Biomed. Sci
                Title: Journal of Biomedical Science
                Publisher: BioMed Central (London )
                ISSN (Print): 1021-7770
                ISSN (Electronic): 1423-0127
                Publication date (Electronic): 19 September 2017
                Publication date PMC-release: 19 September 2017
                Publication date Collection: 2017
                Volume: 24
                Electronic Location Identifier: 76
                Affiliations
                [1 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, School of Biological Sciences, University of Queensland, ; Brisbane, 4072 Australia
                [2 ]ISNI 0000 0001 0670 519X, GRID grid.11173.35, Centre of Excellence in Molecular Biology, , University of the Punjab, ; Thokar Niaz Baig, Lahore, 54000 Pakistan
                [3 ]ISNI 0000 0000 9284 9490, GRID grid.418920.6, COMSATS Institute of Information Technology Abbottabad, ; Abbottabad, 22010 Pakistan
                Author information
                http://orcid.org/0000-0003-0474-6558
                Article
                Publisher ID: 379
                DOI: 10.1186/s12929-017-0379-z
                PMC ID: 5606025
                PubMed ID: 28927401
                SO-VID: 98e75772-bf1a-4dff-bd96-240bcf680a98
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 5 January 2017
                Date accepted : 5 September 2017
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Molecular medicine
                Keywords: alzheimer’s disease,type-2 diabetes mellitus,oxidative stress,ros production,antioxidant treatments,anti-diabetic drugs
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: alzheimer’s disease, type-2 diabetes mellitus, oxidative stress, ros production, antioxidant treatments, anti-diabetic drugs

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