Oxidative Stress in Alzheimer’s Disease: Pathogenesis, Biomarkers and Therapy

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly with profound medical and social consequences. The pathogenesis of AD is a complex and heterogeneous process which classical neuropathological hallmarks found in the brain are extracellular deposits of beta-amyloid (A)-containing plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. Mutation of presenilin-1 (PS-1), presenilin-2 (PS-2), and altered amyloid precursor protein (APP) genes has been reported to cause inherited AD. In addition, other genes such as apolipoprotein E-4 (APOE), endothelial nitric oxide synthase-3, and alpha-2-macroglubulin have also been associated with AD. A further number of hypothesis have been proposed for AD mechanism, which include: the amyloid cascade, vascular damage, excitotoxicity, deficiency of neurotrophic factors, mitochondrial dysfunction, trace element neurotoxicity, inflammation and oxidative stress hypothesis. The oxidative stress (OS) hypothesis of aging postulated by Dr. Denham Harman in 1956 proposed that brain aging is associated to a progressive imbalance between the anti-oxidant defenses and the pro-oxidant species that can occur as a result of either an increase in free radical production or a decrease in antioxidant defence. The fact that age is the main risk factor for AD development provides considerable support to the OS hypothesis since the effects produced by reactive oxygen species (ROS) can accumulate over the years (Nunomura et al., 2001). The link between AD and OS is additionally supported by the finding of decreased levels of antioxidant enzymes, increased protein, lipid and DNA oxidation and advanced glycation end products (AGEs) and ROS formation in neurons of AD patients (Perry et al., 2000; Barnham et al., 2004). It has been reported that the accumulation of the oligomeric form of A, the most toxic form of the peptide, induces OS in neurons (Butterfield, 2002), supporting the hypothesis and suggesting that OS plays a causative role in the development of AD. Then, a large amount of literature has demonstrated that OS is an important feature in AD pathogenesis that deserves to be deeply studied (Perry et al, 2002: Markesbery et al, 1999). In this Chapter, we address the main factors involved in the generation of oxidative stress and provide an overview of the oxidative stress biomarkers status in Alzheimer’s disease. The Chapter concludes with a revision of the controversial efficacy of antioxidants as potential treatment in AD therapy as well as an update of the main antioxidant compounds found to have a beneficial effect in AD.