ReviewOxidative stress: A bridge between Down's syndrome and Alzheimer's disease
Section snippets
Introduction: the oxidative phenotype in Down's syndrome
In 1866, John Langdon Down, an English physician, published the first clinical description of the condition that now bears his name. Down's syndrome (DS) is one of the most common genetic abnormalities in liveborn children (1 in 700–1000), leading to an early mental decline and premature aging. These patients often suffer from other aberrations, e.g. specific cardiac and gastrointestinal congenital malformations, various types of leukemias, cataracts and growth retardation [286]. Moreover,
Role of Cu2+/Zn2+ superoxide dismutase in Down's syndrome and Alzheimer's disease
Oxygen is necessary for life, but paradoxically, by-products of its metabolism produce ROS, including free radicals (superoxide (O2–) and hydroxyl (OH) species) and other molecules, such as hydrogen peroxide (H2O2) and peroxynitrite, which have the ability to become highly toxic to cells [10] (Fig. 2). The latter molecules can lead to the generation of free radicals through various chemical reactions. Thus, via the Fenton reaction, in the presence of reduced metal ions (e.g. ferrous or copper)
Role of the amyloid precursor protein in the appearance of oxidative stress in Down's syndrome and Alzheimer's disease
The APP gene, mapped to Chr 21q21.3–22.05, codes for a transmembrane protein expressed in both neurons and astrocytes (Fig. 1). Recent years have seen significant advances in the understanding of Aβ pathogenesis and the functional consequences of Aβ accumulation in DS, but there are still large gaps in our knowledge of the pathways involved in Aβ degradation and clearance [144]. Although the function of APP is not entirely clear, it is implicated in the neuroprotection against oxidative insults
Mechanisms of lipid peroxidation
Lipid peroxidation is the mechanism by which lipids are attacked by ROS with sufficient energy to form an organic radical that reacts with oxygen and results in a peroxyl radical [141]. The outcomes of the lipid peroxidation could be, for example, structural damage to membranes and the generation of oxidized products, some of which are chemically reactive and covalently modify macromolecules thought to be the main effectors of tissue damage [228]. Moreover, these reactive products of lipid
Mechanisms of protein oxidation
ROS can also attack amino acid residues (particularly histidine, arginine and lysine) to produce carbonyl functions that can be measured after reaction with 2,4-dinitrophenylhydrazine (“carbonyl assay”) [271], [281]. Another potential mechanism of protein oxidation involves the highly toxic radical peroxynitrite, formed in the reaction of the superoxide anion with NO [340], which can be measured by a nitrotyrosine (NT) assay. Peroxynitrite formation may occur under conditions of OS in
DNA damage
ROS-mediated oxidative injury can result in DNA modifications, including base alterations (Fig. 4), single (SSBs) and double strand breaks (DSBs), sister chromatid exchanges (SCEs) and DNA-protein crosslinks [324]. The contributions of free radical-mediated DNA cleavage, ongoing or incomplete DNA repair processes or endonuclease cleavage as part of an apoptotic cascade to the generation of DNA strand breaks are unknown [89], but recent evidence suggests that they may have fundamental and
Antioxidant strategies
On the basis of the foregoing, it is not surprising that one of the leading theories on the pathogenesis of DS and AD is that ROS have a very early role in neuronal cell death, contributing to the development and expression of AD and of AD in DS. Therefore, the possibility of the therapeutic use of antioxidants seems to be rational, reducing the incidence and severity of disease, although evidence for the use of antioxidants has been mixed (Table 3). Current ROS-associated clinical research
Summary
DS appears to be a suitable natural human model for an understanding of the early alterations leading to AD, in view of the genetic, biochemical and neuropathological analogies between these two disorders. In both, a growing body of evidence indicates that OS is a crucial factor in their pathogenesis. In DS, an extra copy of Chr 21 has the consequence that the genes located on it are consecutively overexpressed, resulting in OS, which manifests as lipid, protein and DNA modifications, and
Acknowledgments
This work was supported by grants from the Hungarian Health Science Board (ETT IV/93/2003), the National Scientific Research Fund (OTKA T046152/2004 and K60589/2006) and the Hungarian Ministry of Education (RET 08/2004).
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