The role of reactive oxygen species in cognitive impairment associated with sleep apnea

Abstract

Obstructive sleep apnea (OSA), a common breathing and sleeping disorder, is associated with a broad range of neurocognitive difficulties. Intermittent hypoxia (IH), one major characteristic of OSA, has been shown to impair learning and memory due to increased levels of reactive oxygen species (ROS). Under normal conditions, ROS are produced in low concentrations and act as signaling molecules in different processes. However, IH treatment leads to elevated ROS production via multiple pathways, including mitochondrial electron transport chain dysfunction and in particular complex I dysfunction, and induces oxidative tissue damage. Moreover, elevated ROS results in the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) and increased activity of peroxisomes, such as NADPH oxidase, xanthine oxidase and phospholipase A2. Furthermore, oxidative tissue damage has been found in regions of the brains of patients with OSA, including the cortex and hippocampus, which are associated with memory and executive function. Furthermore, increased ROS levels in these regions of the brain induce damage via inflammation, apoptosis, ER stress and neuronal activity disturbance. The present review focuses on the mechanism of excessive ROS production in an OSA model and the relationship between ROS and cognitive impairment.

Keywords: endoplasmic reticulum; intermittent hypoxia; obstructive sleep apnea; reactive oxygen species; superoxide dismutase; unfolded protein response.

Figure 1

Mitochondria, ER and peroxisomes in the cytosol are major sites of ROS production. (A) Under physiological conditions, the electron transport chain in the inner mitochondrial membrane releases superoxide to both the matrix and the intermembrane space. NOX are localized in the cellular and ER membranes, and release superoxide towards the luminal side of the membranes. XO is localized on the outer surface of the cellular membrane, in the cytosol and in peroxisomes. XO produces both superoxide and H₂O₂. Cytosolic PLA2 is associated with the lipid layer of the cellular membrane and releases superoxide into the cytosol. Secretory PLA2 is localized in the extracellular space where it produces superoxide. (B) Under intermittent hypoxia, the activity of complex I is reduced and electrons cannot be transported, thus resulting in the formation of superoxide via the one-electron reduction of oxygen. ROS are generated in the ER as a part of an oxidative folding process during electron transfer between protein disulfide isomerase and ER oxidoreductin-1. Ca²⁺ ions released from the ER augment the production of mitochondrial ROS. The activity of certain peroxisomes, such as NOX, XO and PLA2, are upregulated to produce additional ROS. Moreover, ROS can induce the expression of hypoxia-inducible factor-1 α and NF-κB, which contribute to aggravated oxidative stress. Red arrows indicate increased activity or production. Black arrows indicate decreased activity. ER, endoplasmic reticulum; ERO-1, ER oxidoreductin 1; HIF-1α, hypoxia inducible factor; ROS, reactive oxygen species; NOX, NADPH oxidases; cPLA2, cytosolic phospholipases A2; sPLA2, secreted phospholipases A2; SOD, superoxide dismutase; XO, xanthine oxidase.

Figure 2

Proposed interactions between cognitive impairment and other pathological processes induced by increased ROS levels. Chronic intermittent hypoxia leads to increased ROS levels. Then, mitochondrial dysfunction, inflammation, ER stress and neuronal activity dysfunction are initiated by activating gene expression and Ca²⁺ release. These factors act together in a synergistic manner to increase apoptosis and impair synaptic plasticity, which underlie memory dysfunction. Therefore, increased ROS generation plays a pivotal role in cognitive impairment in the OSA model. ROS, reactive oxygen species; HO-1, heme oxygenase-1; Mfn2, Mitochondrial fusion protein-2; HIF-1α, hypoxia-inducible factor-1 α; PERK, protein kinase RNA-like endoplasmic reticulum kinase; OSA, obstructive sleep apnea.