Elsevier

Progress in Neurobiology

Volume 57, Issue 3, February 1999, Pages 301-323
Progress in Neurobiology

Alzheimer's disease and oxidative stress: implications for novel therapeutic approaches

https://doi.org/10.1016/S0301-0082(98)00055-0Get rights and content

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a deadly outcome. AD is the leading cause of senile dementia and although the pathogenesis of this disorder is not known, various hypotheses have been developed based on experimental data accumulated since the initial description of this disease by Alois Alzheimer about 90 years ago.

Most approaches to explain the pathogenesis of AD focus on its two histopathological hallmarks, the amyloid β protein- (Aβ-) loaded senile plaques and the neurofibrillary tangles, which consist of the filament protein tau.

Various lines of genetic evidence support a central role of Aβ in the pathogenesis of AD and an increasing number of studies show that oxidation reactions occur in AD and that Aβ may be one molecular link between oxidative stress and AD-associated neuronal cell death.

Aβ itself can be neurotoxic and can induce oxidative stress in cultivated neurons. Aβ is, therefore, one player in the concert of oxidative reactions that challenge neurons besides inflammatory reactions which are also associated with the AD pathology.

Consequently, antioxidant approaches for the prevention and therapy of AD are of central interest. Experimental as well as clinical data show that lipophilic antioxidants, such as vitamin E and estrogens, are neuroprotective and may help patients suffering from AD.

While an additional intensive elucidation of the cellular and molecular events of neuronal cell death in AD will, ultimately, lead to novel drug targets, various antioxidants are already available for a further exploitation of their preventive and therapeutic potential.

Introduction

Following the accumulation of oxygen in the earth's atmosphere ca 2 billion years ago, the existing anaerobic organisms had to adapt to this novel environment in order to survive. While some organism escaped the oxygen by choosing an oxygen-free micro-environment, others evolved which were capable of both respiration and fermentation (facultative anaerobes). Later on, species developed which settled this novel oxygen-niche and used exclusively respiration. But of course, such organisms had to have the ability to screen their environment for oxygen availability and they needed to defend themselves against oxygen-free radicals and reactive oxygen species (ROS), which are permanently generated to some extent during the reduction of molecular oxygen to water.

The occurrence of ROS is referred to as oxidative stress (Halliwell and Gutteridge, 1989). It is now well-known that due to their reactions with macromolecules the generation of ROS can lead to immediate damage or death of cells in various tissues, including the central nervous system (Halliwell and Gutteridge, 1989; Ames et al., 1993; Gutteridge, 1994). Since the identification of the enzyme superoxide dismutase (SOD) (Fridovich, 1989), there is a great interest in the investigation of possible roles of ROS in the physiology and pathophysiology of cells and of the organism (Fridovich, 1978). Because of their potential damaging effects, ROS and oxidative events have been implicated in a variety of non-neuronal and neuronal disorders, including atherosclerosis, cerebral ischemia, seizure disorders, amyotrophic lateral sclerosis and Parkinson's disease (PD) (Lohr, 1991; Parthasarathy et al., 1992; Coyle and Puttfarcken, 1993; Olanow, 1993; Clemens and Panetta, 1994; Sendtner and Thoenen, 1994; Beal, 1995; Ebadi et al., 1996).

The selective sensitivity and vulnerability of neurons are the most important characteristics of age-related disorders, including PD and AD. Aging, in general, is associated with the degeneration of cells and tissues which can result in diseases, such as cancer, cardiovascular failure and neurodegenerative disorders. The free radical theory of aging suggests that oxidative damage is the major player in the degeneration of cells (Harman et al., 1976). As age is the primary risk factor for the majority of AD cases, consistent with the free radical theory of aging, and due to recent increasing evidence, oxidative stress has also been suggested to play a causative role in the pathogenesis and progression of AD (Friedlich and Butcher, 1994; Melhorn and Cole, 1985; Ames et al., 1993; Beal, 1995). Although, various genetic alterations and mutations located on different chromosomes have causally been linked to some familial forms of AD (Sandbrink et al., 1996; Tanzi et al., 1996), age is the only reliable risk factor for the non-genetic sporadic forms and therefore for the majority of this neurodegenerative disease. Approximately 85% of all AD cases are such late-onset (after the age of 65) non-familial, sporadic forms (Evans et al., 1989). Therefore, in every attempt to define a somehow integrative hypothesis of AD that takes into account much of the current experimental data and understanding, age-related physiological and pathophysiological changes have to be considered.

Currently, various hypotheses for the pathogenesis of AD are discussed. Among these are the acetylcholine-hypothesis (Whitehouse et al., 1982), the amyloid-cascade-hypothesis (Hardy and Allsop, 1991; Kang et al., 1987; Selkoe, 1993), the “arthritis of the brain-hypothesis” (Rogers et al., 1992), and the energy-metabolism-hypothesis (Hoyer, 1994). This review will focus on the Oxidative Stress Hypothesis of AD and tries to show that, at least in part, this hypothesis can integrate and combine several of the other hypotheses. In an age-related disorder that develops over decades, many players as well as physiological and pathological conditions are involved, of course. Here, some of the mediators of oxidative stress occurring in AD pathology and their possible role in the AD pathogenesis will be discussed. Consequently and on the basis of first available data on clinical AD trials, the second major topic of this review are antioxidant approaches for the prevention and treatment of AD and also possible future strategies towards the development of more effective antioxidant drugs. The role of oxidants and antioxidants in health and disease and during aging has been discussed in a number of recent reviews (Halliwell and Gutteridge, 1989; Halliwell et al., 1992; Ames et al., 1993; Sies, 1993; Beal, 1995; Smith et al., 1995b; Ebadi et al., 1996). As in every review on a timely topic, it is hard to take into account all the work relevant for the discussion. Moreover, due to the large number of publications currently appearing on oxidative stress and antioxidants, this review cannot be exhaustive.

Section snippets

Alzheimer's disease: “a peculiar disease of the cortex”

In 1907, Alois Alzheimer described a “peculiar disease of the cortex”, stating that in sections that have been silver-stained, he found “strange alterations of the neurofibrils” and “foci which are build up by a peculiar substance” “spread over the whole cortex” (Alzheimer, 1907). Ninety years later, the structures found by Alzheimer are well-known as neurofibrillary tangles (NFTs) and as senile plaques loaded mainly with amyloid β protein (Aβ) (Glenner, 1988; Kang et al., 1987; Braak and

Amyloid β protein toxicity

Aβ is a heterogeneous peptide in size due to differences in its C-terminus varying in the length. While so-called diffuse senile plaques almost exclusively consist of Aβ1–42/43, classic senile plaques or neuritic plaques consists of Aβ1–40, Aβ1–42/43 and of shorter Aβs with truncated N-termini (Wisniewski et al., 1997). The longer form of Aβ, Aβ1–42, is less soluble and, therefore, forms fibrils much faster compared to shorter Aβs (Wisniewski et al., 1997). For the formation of amyloid

Evidence for oxidative stress in AD

Because many excellent reviews exist, which describe the chemistry of free radicals and their possible interactions with macromolecules (Halliwell and Gutteridge, 1989; Sies, 1993), the author will only describe some basics necessary to understand the importance of oxygen free radicals in the context of this review.

From bench to bedside: therapeutic approaches in AD

Because the etiology and pathogenesis of AD has not been clearly defined yet, and therefore, the therapeutic target central to the pathological process still needs to be found, the current strategies to help patients during the course of this devastating disease are directed against various factors and events that are associated with AD (Davis et al., 1993). The major histopathological hallmarks of this neurodegenerative disorder have already been known over 90 years and the modern cell and

Future directions

AD is a complex disorder of the nervous system with many clinical facets. The pathogenesis of this devastating disease is not really understood, a fact that currently prevents an effective treatment. Findings of basic science, such as linking gene mutations to AD, can elucidate possible intrinsic ways of how neurons could degenerate in the brain of AD patients. But extracellular and environmental factors may also play a role in the pathogenesis of this disease (Table 1). Currently, many

Acknowledgements

The author wishes to thank Drs Stefanie Heck and Andreas Klostermann for critically reading the manuscript and a fruitful discussion. Also the excellent secretarial assistance of Ms Sandra Rengsberger is highly appreciated.

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