Elsevier

Progress in Neurobiology

Volume 62, Issue 6, 15 December 2000, Pages 633-648
Progress in Neurobiology

The role of oxidative stress in the toxicity induced by amyloid β-peptide in Alzheimer’s disease

https://doi.org/10.1016/S0301-0082(00)00015-0Get rights and content

Abstract

One of the theories involved in the etiology of Alzheimer’s disease (AD) is the oxidative stress hypothesis. The amyloid β-peptide (Aβ), a hallmark in the pathogenesis of AD and the main component of senile plaques, generates free radicals in a metal-catalyzed reaction inducing neuronal cell death by a reactive oxygen species mediated process which damage neuronal membrane lipids, proteins and nucleic acids. Therefore, the interest in the protective role of different antioxidants in AD such as vitamin E, melatonin and estrogens is growing up. In this review we summarize data that support the involvement of oxidative stress as an active factor in Aβ-mediated neuropathology, by triggering or facilitating neurodegeneration, through a wide range of molecular events that disturb neuronal cell homeostasis.

Introduction

The hallmark of Alzheimer’s disease (AD) is the neuronal degeneration associated to senile plaques (Vickers et al., 2000). Such plaques are composed of the amyloid β-peptide (Aβ) which is a 40–43 amino acid peptide (Vitek et al., 1994, Soto et al., 1995, Selkoe, 1998). Aβ is originated by the proteolytic processing of a transmembrane glycoprotein called β-amyloid precursor protein (β-APP) which is coded by a gene located in the chromosome 21 (Soto et al., 1994, Selkoe, 1996). This glycoprotein can be secreted (Saitoh et al., 1989) or cleaved releasing Aβ by the action of β- and γ-secretases (Haass and de Strooper, 1999). Besides β-APP mutations in other genes, such as presenilins determine an early onset of the disease (Haass, 1997) and produce increased amounts of Aβ. On the other hand, the deposition of soluble Aβ produces the aggregation of the peptide forming amyloid fibrils which have been reported to be neurotoxic in vitro (Yankner, 1996, Alvarez et al., 1998, Muñoz and Inestrosa, 1999) and in vivo (Inestrosa and Reyes, 1998, Soto et al., 1998; Inestrosa and Larrondo, 2000; Reyes et al., 2000).

The mechanisms involved in the Aβ-mediated neurotoxicity are unknown, but there is evidence suggesting that oxidative stress plays a key role. The Aβ aggregation process is accelerated by transition metals via metal-catalyzed oxidation of Aβ peptide (Dyrks et al., 1992). Recently, it has been shown that Aβ peptide produces hydrogen peroxide (H2O2) through metal ion reduction, with concomitant release of thiobarbituric acid-reactive substances (TBARS), a process probably mediated by formation of hydroxyl radicals (Huang et al., 1999a, Huang et al., 1999b). Free radicals peroxidize membrane lipids (Butterfield et al., 1997) and oxidize proteins (Stadtman, 1990) producing drastic cellular damages. The cytotoxicity of Aβ fibrils had been attributed to an oxidative mechanism and increased levels of H2O2 were detected (Behl et al., 1994a, Schubert et al., 1995). Antioxidants such as vitamin E, estrogens or melatonin have demonstrated neuroprotective effects on Aβ-mediated cytotoxicity (Behl et al., 1992, Goodman et al., 1994, Pappolla et al., 1997, Bonnefont et al., 1998). A receptor could mediate the Aβ-mediated neurotoxicity and its characterization would be crucial to understand the neurodegeneration and apoptotic mechanisms reported to take place in AD brains (Smith et al., 1996). Several candidates have been proposed, including the receptor for advanced glycation end products (RAGE) (Yan et al., 1996), the low-density lipoprotein receptor-related protein (LRP) (Knauer et al., 1996) and a scavenger receptor (Paresce et al., 1996). Furthermore, microglial cells are present in senile plaques (Dickson et al., 1988) suggesting that the damage in AD brains is also due to an auto-immune response from microglia which produces free radicals (Colton and Gilbert, 1987). In cellular mechanisms of neuroprotection a central role is played by antioxidant enzymes such as catalase and superoxide dismutase (SOD) (Pappolla et al., 1992, Richardson, 1993) and anti-apoptotic molecules as heme oxigenase-1 (Applegate et al., 1991).

Here we review the evidences for the involvement of free radicals in the etiopathology of AD. We examine the role of free radicals in the initial steps that occur with amyloid fibril aggregation, and in the neurotoxic intracellular processes associated to Aβ fibrils, as well as the capacity of antioxidants to inhibit AD related neurotoxicity.

Section snippets

Transition metals and AD

It is well known that a wide number of enzymatic and non-enzymatic oxygen free radical-generating systems are able to catalyze the oxidative modification of proteins when Fe(III) or Cu(II) are in the presence of O2 and an appropriate electron donor (Stadtman, 1990, Multhaup et al., 1997). In fact, the conversion of superoxide radicals (O·−2) and H2O2 to the highly cytotoxic hydroxyl radical (HO·) can only take place when catalytic concentrations of transition metals are present (Halliwell and

Lipid, protein and nucleic acid modifications

Lipids are modified by ROS, and there is a strong regional correlation between lipid peroxides visualized as TBARS, antioxidant enzymes, the presence of senile plaques and neurofibrillary tangles in AD brain (Lovell et al., 1995). The Aβ induces lipoperoxidation of membranes (Koppal et al., 1998, Mark et al., 1999) and lipid peroxidation products that are involved in modifications of proteins by covalent binding. 4-hydroxynonenal (4-HNE) an aldehydic product of membrane lipid peroxidation (

Aβ peptide and the generation of ROS

Some of the evidences indicating that the Aβ peptide cytotoxicity is mediated by free radical damage are the following: (1) micromolar concentrations of Aβ peptide increases H2O2 in cells in culture (Behl et al., 1994a), although there is controversy on the role of H2O2 in Aβ mediated cell damage (Zhang et al., 1996), (2) catalase, an enzyme that converts H2O2 to O2 and H2O, blocks Aβ toxicity (Behl et al., 1994a), (3) cells selected for resistance to Aβ toxicity are also highly resistant to H2O

The receptor for Aβ-mediated actions

The existence of a specific receptor mediating the neurotoxicity induced by Aβ has been proposed, although the need of cell surface receptors for amyloid toxicity is controversial (Schubert et al., 1995). The lipoperoxidation of membranes (Butterfield et al., 1997, Koppal et al., 1998, Mark et al., 1999), could explain its ability to disturb signal transduction pathways (Kelly et al., 1996) and impair the function of membrane-regulatory proteins, including ion ATPases (Mark et al., 1995, Mark

Cell death in AD

Different studies reported both necrotic and apoptotic mechanisms for Aβ-mediated neurotoxicity (Loo et al., 1993, Behl et al., 1994b). In particular, oxidative-mediated DNA damage, with a pattern indicative of apoptosis, was found in AD brain (Smith et al., 1996), which is consistent with several lines of experimental evidence linking oxidative stress and neuronal apoptosis. Apoptosis is induced by micromolar concentrations of Aβ in cultured CNS neurons (Loo et al., 1993), however,

Immune mediated oxidative damage in AD

The immune response in inflamation generates ROS which damage the surrounding tissue. Although acute inflamation, which includes edema and neutrophil invasion, is not a characteristic of AD (Rogers et al., 1993) there are evidences that immune-mediated damage may occur in AD. A potentially important source of brain ROS, for long time overlooked, is the microglia, now accepted as the resident macrophages in the brain (Marzolo et al., 1999). Similar to blood monocytes and to peritoneal

Oxidative metabolism dysfunction

Disturbed energy metabolism is an early, predominant feature of AD (Duara et al., 1986) and the appearance of degenerating mitochondria in axonal terminals is apparently the first indication of plaque formation (Harman, 1996). Increased oxidation has been reported to produce mitochondrial DNA damage (Mecocci et al., 1994) while loss of mitochondrial DNA integrity could lead to increase in ROS generation (Miranda et al., 1999) further enhancing oxidative damage. In addition, deficits in

Action of antioxidant enzymes

The high metabolic rate of the brain, the low concentration of glutathione and the high proportion of polyunsaturated fatty acids, makes the brain a tissue particularly susceptible to oxidative damage (Smith et al., 1996, Smith et al., 1998). With regards to enzymatic defenses, one of the first evidences that AD brain reacts to oxidative stress activating its antioxidant mechanisms, was the finding that SOD was elevated in a fibroblast cell line derived from familial AD patients (Zemlan et al.,

Anti-apoptotic mechanisms

The induction of heme oxygenase-1 is widely accepted as a molecular marker of oxidative stress (Applegate et al., 1991) and recent data also suggest that over expression of this enzyme confers protection against oxidative injury and apoptosis in vivo (Otterbein et al., 1999). Brain expression of heme oxygenase is increased under critical conditions for neuronal survival, such as hyperthermia, ischemic injury and aging (Takeda et al., 1996), suggesting that this enzyme may be related to the

Antioxidants and neuroprotection

The neuroprotection described for antioxidants is represented mainly by classic antioxidants such as vitamin E (Behl et al., 1992, Behl, 1999), lazaroids and hormones like estrogens (Goodman et al., 1996, Behl et al., 1997, Bonnefont et al., 1998, Behl, 1999) or melatonin (Pappolla et al., 1997). Vitamin E is an antioxidant with neuroprotective properties in cytotoxicity induced by Aβ in vitro (Behl et al., 1992) which prevents lipid peroxidation (Halliwell and Gutteridge, 1984, Jeandel et al.,

Conclusions

Since the direct mechanism inducing neurotoxicity by Aβ peptide remain unclear, the evidence presented in this review suggests that the damage described in AD brains is consistent with some degree of oxidative stress induced by the Aβ peptide. This damage is produced by free radicals probably generated by Aβ metal ion-catalyzed oxidation at the early steps of Aβ folding and later continued through different mechanisms including membrane lipoperoxidation, receptor-mediated mechanisms and

Acknowledgements

This work was supported by Predoctoral Fellowships from FONDECYT to S.M. and C.O., and Fundación Andes to L.F.L., Grants from FONDECYT No. 3980024 to F.J.M., No. 2990085 to S.M., No. 2990087 to C.O., No. 1971240 to N.C.I. PUC-PMEC 99 to F.L. and a Presidential Chair in Science from the Chilean Government (1999–2001) a grant from CIMM-ICA/006 to N.C.I. and FONDAP No. 13980001.

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