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

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.

Keywords: Alzheimer’s disease; Anti-diabetic drugs; Antioxidant treatments; Oxidative stress; ROS production; Type-2 diabetes mellitus.

Fig. 1

ROS production in mitochondria. Mitochondria is the primary source for ROS production. There are nine different types of enzymes that have the capacity to generate ROS. Among them, some are present on outer mitochondrial membrane (OMM) i.e. Cytochrome b5 reductase and monoamine oxidases (MAO) and while other found in inner membrane, i.e. dihydroorotate dehydrogenase (DHOH), dehydrogenase of α-glycerophosphate (α-GDH), succinate dehydrogenase (SDH), aconitase, α-ketoglutarate dehydrogenase complex (KGDHC), Complex-I and Complex-III. MAO, DHOH and α-GDH produces H₂O₂ via direct or indirect biochemical reactions, while cytochrome b5, Complex-I and complex-III produce superoxides. Complex-I produced superoxides in presence of NADH and require tightly bounded ubiquinone. Rotenone can block electron transport by inhibiting ubiquinone and produce ROS, and requires a high degree of redox reduction on the rotenone binding site. The second process involved in ROS production from Complex-I has been known as ‘reverse electron transfer (RET)’. In RET, electrons are transferred against the flow of redox potentials of electron carriers (i.e. from reduced co-enzyme Q to NAD⁺ not to oxygen). Complex-III can produce a lot of superoxides during Q-cycle (a multifarious reaction system involved oxidation of coenzyme Q while, cytochrome c acts as electron carrier/acceptor) that rapidly generate H₂O₂ by dismutation. Antimycin can inhibit the quinone reducing site and lead to accumulation of unstable semiquinone and stimulate superoxide production. In the same way KCN and oligomycin can inhibit electron transfer in complex-IV and V respectively, leading to ROS production. SDH is thought to produce ROS via its FAD, while aconitase generate hydroxyl radical by releasing Fe²⁺. PDHC and KGDHC can produce both superoxides as well as hydrogen peroxide. After generation, superoxide can react with many available molecules or free radicals to form different types of free radicals who can accelerate the cellular damage. To cop superoxide, manganese superoxide dismutase (MnSOD) can convert superoxide to hydrogen peroxide that can be additional converted to water and oxygen by the action of several enzymes like catalase (CAT) or glutathione peroxidase (GPX). For further details, see the text

Fig. 2

Oxidative stress production and damage in T2DM. Hyperglycemia is considered as major contributor in ROS production and associated- damage in T2DM. Induced glucose concentrations may have led to glucose autoxidation, impaired mitochondrial bioenergetics and over production of ROS. Induced oxidative stress in T2DM can impair a couple of transcription factors and pathways like P13K, JAK/STAT, JNK, p-38, ERK/MAPK and CDC42 that resulted in insulin resistance. The other glycolytic intermediates can have led to microvascular complications and endothelial dysfunctions and prone to several diabetic complications

Fig. 3

Production and mechanism of oxidative stress in AD. Brain consumes more oxygen than the whole body, and is a rich source of fatty acids and metals that are more susceptible to oxidative damage in AD. Two main hallmarks of AD i.e. Aβ plaques and hyper-phosphorylated tau neurofibrillary tangles (T-NFTs) are involved in production as well as promotion of oxidative damage. Any abnormal increase in ROS due to presence of Aβ and NFTs promote mitochondrial DNA/ RNA damage that resulted in mitochondrial dysfunction and membrane damage. Other damages associated with oxidative stress in AD are autoxidation of glucose that resulted in production of AGES and alternatively induce Aβ- toxicity. As oxidative stress, itself induce Aβ and NFTs formation, the result is induced apoptosis, neuronal death and impaired synapsis