Alzheimer’s disease and oxygen radicals: new insights

Abstract

Alzheimer’s disease (AD) is the most common form of neurodegenerative disease, with dementia, in the elderly. In addition to the presence of senile plaques and neurofibrillary tangles, the AD brain exhibits evidence for oxygen radical-mediated damage, a situation commonly known as oxidative stress. However, the ability to directly implicate this mechanism in AD has been a difficult task for several reasons. First, most of the analytical approaches used to investigate oxidative stress turned out to be unreliable. Second, the majority of the published studies have been performed in post-mortem tissues with advanced disease, leaving open the question as to whether oxidative stress is an early event or a common final step secondary to the degenerative process. The discovery of the isoprostanes, recent studies performed in living patients, and the development of transgenic animal models of AD-amyloidosis are three important factors that are helping us to better understand and define the role that oxygen radicals might play in AD pathogenesis. Here we review some of the most recent works that have supported the importance of oxygen radical-mediated damage in AD. The accumulated information points toward an earlier involvement than previously thought of oxidative stress in the pathogenesis of the disease, making this a potential target for therapeutic intervention, especially in subjects at high risk for developing AD.

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.