Oxidative processes in Alzheimer's disease: the role of Aβ-metal interactions (original) (raw)
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Oxidative processes in Alzheimer's disease: the role of A�-metal interactions
Exp Gerontol, 2000
Alzheimer's disease is characterized by signs of a major oxidative stress in the neocortex and the concomitant deposition of Amyloid beta (Ab). Ab is a metalloprotein that binds copper, and is electrochemically active. Ab converts molecular oxygen into hydrogen peroxide by reducing copper or iron, and this may lead to Fenton chemistry. Hydrogen peroxide is a freely permeable prooxidant that may be responsible for many of the oxidative adducts that form in the Alzheimer-affected brain. The electrochemical activity of various Ab species correlates with the peptides' neurotoxicity in cell culture, and participation in the neuropathology of Alzheimer's disease. These reactions present a novel target for Alzheimer therapeutics.
Biochemistry, 1999
Oxidative stress markers characterize the neuropathology both of Alzheimer's disease and of amyloid-bearing transgenic mice. The neurotoxicity of amyloid A peptides has been linked to peroxide generation in cell cultures by an unknown mechanism. We now show that human A directly produces hydrogen peroxide (H 2 O 2 ) by a mechanism that involves the reduction of metal ions, Fe(III) or Cu(II), setting up conditions for Fenton-type chemistry. Spectrophotometric experiments establish that the A peptide reduces Fe(III) and Cu(II) to Fe(II) and Cu(I), respectively. Spectrochemical techniques are used to show that molecular oxygen is then trapped by A and reduced to H 2 O 2 in a reaction that is driven by substoichiometric amounts of Fe(II) or Cu(I). In the presence of Cu(II) or Fe(III), A produces a positive thiobarbituric-reactive substance (TBARS) assay, compatible with the generation of the hydroxyl radical (OH‚). The amounts of both reduced metal and TBARS reactivity are greatest when generated by A 1-42 . A 1-40 > rat A 1-40, a chemical relationship that correlates with the participation of the native peptides in amyloid pathology. These findings indicate that the accumulation of A could be a direct source of oxidative stress in Alzheimer's disease.
Oxidative stress and the amyloid beta peptide in Alzheimer's disease
Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level.
Biochemistry, 2007
The binding stoichiometry between Cu(II) and the full-length β-amyloid Aβ(1-42) and the oxidation state of copper in the resultant complex were determined by electrospray ionization-Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) and cyclic voltammetry. The same approach was extended to the copper complexes of Aβ(1-16) and Aβ(1-28). A stoichiometric ratio of 1:1 was directly observed and the oxidation state of copper was deduced to be 2+ for all the complexes and residues tyrosine-10 and methionine-35 are not oxidized in the Aβ(1-42)-Cu(II) complex. The stoichiometric ratio remains the same in the presence of more than 10 fold excess of Cu(II). Redox potentials of the sole tyrosine residue and the Cu(II) center were determined to be ca. 0.75 V and 0.08 V vs. Ag/AgCl (or 0.95 V and 0.28 V vs. normal hydrogen electrode (NHE)), respectively. More importantly, for the first time, Aβ-Cu(I) complex has been generated electrochemically and was found to catalyze the reduction of oxygen to produce hydrogen peroxide. The voltammetric behaviors of the three Aβ segments suggest that diffusion of oxygen to the metal center can be affected by the length and hydrophobicity of the Aβ peptide. The determination and assignment of the redox potentials clarify some misconceptions in the redox reactions involving Aβ and provide new insight into the possible roles of redox metal ions in the Alzheimer's disease (AD) pathogenesis. In cellular environments, the reduction potential of the Aβ-Cu(II) complex is sufficiently low to react with antioxidants (e.g., ascorbic acid) and cellular redox buffers (e.g., glutathione), and the Aβ-Cu(I) complex produced could subsequently reduce oxygen to form hydrogen peroxide via a catalytic cycle. Using voltammetry, the Aβ-Cu(II) complex formed in solution was found to be readily reduced by ascorbic acid. Hydrogen peroxide produced, in addition to its role in damaging DNA, protein, and lipid molecules, can also be involved in the further consumption of antioxidants, causing their depletion in neurons and eventually damaging the neuronal defense system. Another possibility is that Aβ-Cu(II) could react with species involved in the cascade of electron transfer events of mitochondria and might potentially sidetrack the electron transfer processes in the respiratory chain, leading to mitochondrial dysfunction.
The redox chemistry of the Alzheimer's disease amyloid β peptide
Biochimica Et Biophysica Acta-biomembranes, 2007
There is a growing body of evidence to support a role for oxidative stress in Alzheimer's disease (AD), with increased levels of lipid peroxidation, DNA and protein oxidation products (HNE, 8-HO-guanidine and protein carbonyls respectively) in AD brains. The brain is a highly oxidative organ consuming 20% of the body's oxygen despite accounting for only 2% of the total body weight. With normal ageing the brain accumulates metals ions such iron (Fe), zinc (Zn) and copper (Cu). Consequently the brain is abundant in antioxidants to control and prevent the detrimental formation of reactive oxygen species (ROS) generated via Fenton chemistry involving redox active metal ion reduction and activation of molecular oxygen. In AD there is an over accumulation of the Amyloid β peptide (Aβ), this is the result of either an elevated generation from amyloid precursor protein (APP) or inefficient clearance of Aβ from the brain. Aβ can efficiently generate reactive oxygen species in the presence of the transition metals copper and iron in vitro. Under oxidative conditions Aβ will form stable dityrosine cross-linked dimers which are generated from free radical attack on the tyrosine residue at position 10. There are elevated levels of urea and SDS resistant stable linked Aβ oligomers as well as dityrosine cross-linked peptides and proteins in AD brain. Since soluble Aβ levels correlate best with the degree of degeneration [C.A. McLean, R.A. Cherny, F.W. Fraser, S.J. Fuller, M.J. Smith, K. Beyreuther, A.I. Bush, C.L. Masters, Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease, Ann. Neurol. 46 (1999) 860–866] we suggest that the toxic Aβ species corresponds to a soluble dityrosine cross-linked oligomer. Current therapeutic strategies using metal chelators such as clioquinol and desferrioxamine have had some success in altering the progression of AD symptoms. Similarly, natural antioxidants curcumin and ginkgo extract have modest but positive effects in slowing AD development. Therefore, drugs that target the oxidative pathways in AD could have genuine therapeutic efficacy.
Promotion of transition metal-induced reactive oxygen species formation by β-amyloid
Brain Research, 1998
b-amyloid protein appears to be involved in the neural degeneration associated with Alzheimer's disease. However, its mechanism of Ž. action is poorly understood. The ability of the neurotoxic peptide fragment 25-35 derived from b-amyloid, to promote the generation of Ž. Ž. reactive oxygen species ROS by a postmitochondrial fraction P2 derived from rat cerebrocortex, has been examined. The peptide fragment, when incubated together with P2, did not cause excess ROS formation. However, 10 mM FeSO or 10 mM CuSO were able to 4 4 enhance ROS production in the P2 fraction and this was increased further in the concurrent presence of the 25-35 fragment. The Ž. corresponding inverse sequence non-neurotoxic peptide 35-25 had no parallel ability to augment iron-stimulated ROS production suggesting a degree of specificity for the observed effect. There was no formation of excess ROS when the 25-35 peptide and 0.5 mM Ž. Al SO were incubated with the P2 fraction. However in the presence of both aluminum and iron salts together with the 25-35 2 4 3 peptide, ROS production was augmented to a level significantly higher than that in the absence of aluminum. Polyglutamate, a peptide reported to mitigate aluminum toxicity had no effect on iron-related ROS generation but completely prevented its further potentiation by aluminum. The results indicate that b-amyloid is able to potentiate the free-radical promoting capacity of metal ions such as iron, copper and aluminum. Such potentiation may be a relevant mechanism underlying b-amyloid-induced degeneration of nerve cells.
Oxidative stress mechanisms and potential therapeutics in Alzheimer disease
Journal of Neural Transmission, 2005
Oxidative damage of biological macromolecules is a hallmark of most neurodegenerative disorders such as Alzheimer, Parkinson and diffuse Lewy body diseases. Another important phenomenon involved in these disorders is the alteration of iron and copper homeostasis. Data from the literature support the involvement of metal homeostasis in mitochondrial dysfunction, protein alterations and nucleic acid damage which are relevant in brain function and consequently, in the development of neurodegenerative disorders. Although alterations in transition metal homeostasis, redox activity, and localization are well documented, it must be determined how alterations of specific copper-and iron-containing metalloenzymes are also involved in Alzheimer disease. The clarification of these phenomena can open a new window for understanding the mechanisms underlying neurodegeneration and, consequently, for the development of new therapeutic strategies such as gene therapy and new pharmaceutical formulations with antioxidant and chelating properties.