Free radicals in Alzheimer’s disease

Summary

Alzheimer’s disease is a neurodegenerative disorder comprising multisystem atrophies probably caused by multifactorial processes. The disease is characterized by typical neuropathology, impaired synaptic function and massive cell loss. The pathobiochemistry of this disorder involves oxidative stress, which accumulates free radicals leading to excessive lipid peroxidation and neuronal degeneration in certain brain regions. Moreover, radical induced disturbances of DNA, proteins and lipid membranes have been measured. The hypothesis has been proposed that cellular events involving oxidative stress may be one basic pathway leading to neurodegeneration in Alzheimer’s disease. In this work we report evidence for increased oxidative stress and disturbed defense mechanisms in Alzheimer’s disease, which may result in a self-propagating cascade of neurodegenerative events. Furthermore it is evident from experimental data, that aggregation of β-amyloid and β-amyloid toxicity is favourably caused by oxidative stress. Therefore, oxidative stress plays a key role in the conversion of soluble to unsoluble β-amyloid, suggesting that oxidative stress is primary to the β-amyloid cascade.

Alzheimer’s disease represents the most common cause of senile dementia. However, since the first clinical and neuropathological description 90 years ago (Alzheimer, 1907) etiology and exact pathogenesis of this disease is still not clear. Pathological presentation of Alzheimers disease involves regionalized, transmitter-specific neuronal loss (Braak and Braak, 1991; Greenamyre and Maragos, 1993), synaptic pathology (Adams, 1991) and an accumulation of intracellular and extracellular protein aggregates presenting as neurofibrillary tangles and senile plaques respectively. These prominent neuropathological abnormalities have focused scientific interest on several independent parameters, which have been suggested to be responsible for these pathological changes, including hyperphosphorylation of cytoskeletal proteins (tau-protein), metabolism of β-amyloid and the β-amyloid precursor protein (APP) and the polymorphism of apolipoprotein E (APO-E). There is strong evidence that changes of brain glucose metabolism (Hoyer, 1996), mitochondrial disturbances (Wallace, 1992; Beal, 1996), excitotoxicity (Shaw, 1992), immunological processes (Bauer and Berger, 1993) and the biosynthesis of advanced glycation end products (AGEs) (Thome et al., 1996) might be primary responsible for Alzheimer’s disease pathology. At present, there is no conclusive hypothesis to unify the enormous number of neuropathological and neurochemical findings. It has been concluded, that Alzheimer’s disease might be a heterogenous disease (St George-Hyslop et al., 1990), with a wide spectrum of etiological factors, each of which is able to originate a cascade of pathological processes, leading to an at least uniform condition presenting clinically as dementia.

However, there is now a confluence of opinion that free radical oxidative stress plays a key role among the factors of this pathogenetic cascade of Alzheimer’s disease (Benzi and Moretti, 1995). Oxygen free radicals are of particular interest, because of their interactions with almost all hypotheses about the pathogenesis of Alzheimer’s disease, and the formation of unsoluble beta-amyloid in particular. Moreover, damage due to oxidative stress accumulates with age (Benzi et al., 1989) and age is the most important risk factor for Alzheimer’s disease (Bachman et al., 1993).

Oxygen free radicals are formed as by-products of respiration and oxidative metabolism in all aerobic organisms. It is well established that the generation of radical molecules can lead to damage or destruction of a variety of tissues (McCord and Fridovich, 1988). Consequences of excessive reactive oxygen species are lipid peroxidation, oxidation of proteins and damage of DNA (Götz et al., 1994). It has been hypothesized, that normal aging is a result of permanent oxidative stress (Harman, 1956). Normal age-related radical damage is caused by environmental factors (chemicals, UV radiation, cosmic rays) and endogenous factors including the constant electron leakage in the mitochondrial respiratory chain (Zoccarato et al., 1988), the generation of superoxide and hydrogen peroxide by several enzyme systems, the formation of alkoxy and peroxy radicals from lipids, autooxidation and oxidative deamination of dopamine and the catalytic activity of iron (Götz et al., 1994). On the other hand detoxifying enzymes, e.g. glutathione peroxidase, gluthathione reductase, superoxide dismutase and catalase together with antioxidant mechanisms such as the glutathione system and vitamin E, C and A are involved in the defense system against radical injury (Halliwell and Gutteridge, 1984). An imbalance between the formation of oxygen free radicals due to a increased biosythesis or intake of toxins generating radicals and the protective mechanisms has been proposed as a major factor not only for normal aging, but also for pathological neurodegenerative processes and Alzheimer’s disease in particular (Götz et al., 1994; Smith et al., 1995a).