Increased non-protein bound iron in Down syndrome: contribution to lipid peroxidation and cognitive decline

Abstract

Down syndrome (DS, trisomy 21) is the leading cause of chromosomal-related intellectual disability. At an early age, adults with DS develop with the neuropathological hallmarks of Alzheimer's disease, associated with a chronic oxidative stress. To investigate if non-protein bound iron (NPBI) can contribute to building up a pro-oxidative microenvironment, we evaluated NPBI in both plasma and erythrocytes from DS and age-matched controls, together with in vivo markers of lipid peroxidation (F-isoprostanes, F-dihomo-isoprostanes, F-neuroprostanes) and in vitro reactive oxygen species (ROS) formation in erythrocytes. The serum iron panel and uric acid were also measured. Second, we explored possible correlation between NPBI, lipid peroxidation and cognitive performance. Here, we report NPBI increase in DS, which correlates with increased serum ferritin and uric acid. High levels of lipid peroxidation markers and intraerythrocyte ROS formations were also reported. Furthermore, the scores of Raven's Colored Progressive Matrices (RCPM) test, performed as a measure of current cognitive function, are inversely related to NPBI, serum uric acid, and ferritin. Likewise, ROS production, F-isoprostanes, and F-neuroprostanes were also inversely related to cognitive performance, whereas serum transferrin positively correlated to RCPM scores. Our data reveal that increased availability of free redox-active iron, associated with enhanced lipid peroxidation, may be involved in neurodegeneration and cognitive decline in DS. In this respect, we propose chelation therapy as a potential preventive/therapeutic tool in DS.

Disturbance of redox homeostasis in Down Syndrome: Role of iron dysmetabolism

“…According to a recent paper, DS patients show increased levels of serum ferritin but decreased levels of Tf. Furthermore, despite a slight reduction of total iron content, increased levels of free redox-active iron in both plasma and erythrocytes were found [90]. In addition, increased iron levels were significantly associated with increased lipid peroxidation products such as F2-isoprostane and a worsening of cognitive functions [90].…”

“…Furthermore, despite a slight reduction of total iron content, increased levels of free redox-active iron in both plasma and erythrocytes were found [90]. In addition, increased iron levels were significantly associated with increased lipid peroxidation products such as F2-isoprostane and a worsening of cognitive functions [90]. In agreement, a previous study comparing DS and DS/AD subjects showed increased plasma ferritin concentration in DS/AD, and the authors proposed that the onset of AD-like dementia in DS may possibly be related to the increased uptake and deposition of iron following alteration in plasma iron transport [91].…”

Isoprostanoids in Clinical and Experimental Neurological Disease Models

“…Moreover, AdA oxidation form four series of regioisomers (7-, 10-, 14-, and 17-series) [ 31 ], and were detected in AD patients [ 31 , 32 ], and also in Rett syndrome (RTT) [ 25 ], Down syndrome [ 33 ], and epileptic [ 34 ] patients. The myelin sheath is concentrated with AdA and F 2 -dihomo-IsoPs have been suggested to be specific in assessing the extent of free radical damage of the myelin [ 31 ].…”

“…This is mainly due to the limited availability of purified molecules to be used as reference compounds in the identification of isoprostanoids in biological samples, which is an indispensable step in the exploration of the cause-effect relationship between the neurological damage and the levels of isoprostanoids in the bloodstream or in other fluids and tissues. Nevertheless, assays performed in plasma or urine samples are proving useful to predict clinical presentation/evolution of neurological diseases [ 25 , 27 , 31 , 32 , 33 , 34 , 38 , 52 , 57 , 59 , 69 , 70 ] ( Table 2 ). Plasma 10-F 4t -NeuroP and 4-F 4t -NeuroP levels were shown to be useful to discriminate between different brain diseases and the association to clinical severity appeared to be distinctive for different neurological conditions, thus suggesting that in vivo DHA oxidation follows preferential chemical rearrangements according to different human brain diseases.…”

A Comprehensive Diverse ‘-omics’ Approach to Better Understanding the Molecular Pathomechanisms of Down Syndrome

“…The dyshomeostasis of intrinsic metals, such as zinc, copper, and iron, may play a role in cognitive impairment in individuals with DS, as intersectin 1 coded in the trisomic region in DS is suggested to be involved in iron internalization. Indeed, increases in the levels of non-protein-bound iron in serum and iron-binding protein lactotransferrin in the brain have been demonstrated in individuals with DS [48,49]. Other ‘-omics’ analyses, such as metabolomic and elementomics analyses, for DS samples are expected to help unravel the pathophysiological mechanisms underlying abnormalities in the DS brain.…”