CommentaryAlzheimer’s disease and oxygen radicals: new insights
Introduction
AD is the most common neurodegenerative disorder of the elderly. Clinically, it is characterized by progressive memory loss, decline in language skills, and other cognitive impairments. AD affects approximately 4 million people in the US, with an incidence rate from 0.5% per year at 65 years to 8–10% at age 85 years [1], [2]. While early-onset familial AD is caused by multiple mutations in different genes, late-onset AD, which is sporadic and accounts for 90% of total patients, is probably due to the effects of genetic risk factors combined with different epigenetic events [3]. Although the initiating causes leading to AD are unknown, it is clear that its pathophysiology is complex and most likely involves multiple distinct and overlapping pathways of neuronal damage [4]. This is supported by the fact that in addition to the pathological hallmarks of the disease, which include senile plaques and neurofibrillary tangles, AD brains exhibit a number of other abnormalities: loss of synapses, gliosis, microglia activation, signs of inflammation, and damage secondary to oxygen radicals [5], [6], [7]. Oxygen radicals are chemically unstable and highly reactive compounds, which are formed during normal cellular metabolism. Due to their reactivity, they can be responsible for cellular and tissue damage anytime their generation exceeds the endogenous ability to destroy them. This condition is also known as oxidant or oxidative stress.
Section snippets
Oxidative stress and AD
A role for oxidative stress has been widely discussed in the pathogenesis of AD [6], [8], [9]. However, the ability to implicate this mechanism directly has been confounded mainly by two factors: the evanescent nature of the oxygen radicals, and the use of non-specific analytical approaches [10]. Isoprostanes are members of a complex family of lipids, isomers of conventional enzymatically derived prostaglandins, which are produced by oxygen radical-catalyzed peroxidation of polyunsaturated
Human studies
An impressive number of studies have been published on oxidative injury and lipid peroxidation in AD. Most of them have been biochemical or histological studies performed on AD post-mortem brain tissues. Historically, malondialdehyde (MDA) and (thiobarbituric acid reactive substances) TBARS assays have been the first and probably the most popular techniques employed to quantitate, biochemically, lipid peroxidation in AD. The majority of these investigations have shown higher MDA and/or TBARS
Transgenic animal studies
An ideal transgenic mouse model for AD should mimic the age-dependent accumulation of amyloid plaques, neurofibrillary tangles, and neuronal cell death, and should also display memory loss and behavioral deficits. Several transgenic mouse lines have been established in the last 5 years, all of which manifest a time-dependent increase in Aβ accumulation in the brain, and some of which also display behavioral impairments [31]. Even though not perfect, these animal models are valuable tools to
Conclusions
AD is a challenging brain disorder with enormous medical and social consequences. The fact that age is a risk factor in AD has provided initial support to the hypothesis that oxygen radicals, like in the aging process, could be involved. Although AD is likely to be associated with multiple etiologies and mechanisms, it is evident that oxidative stress is part of it. For years we have been accumulating evidence that oxidative stress is a feature of AD. However, only recently with the development
Acknowledgements
Part of the research described in this article has been funded by the American Heart Association and the National Institute of Health. I wish to thank Barbara Dallao and Alfredo Praticò for their long-term support and encouragement.
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