Methionine-35 of Aβ(1–42): Importance for Oxidative Stress in Alzheimer Disease

Alzheimer disease (AD) is an age-related progressive neurodegenerative disorder. This devastating disease is characterized by the presence of senile plaques (SP), neurofibrillary tangles (NFTs), and loss of synapses. Amyloid beta-peptide 1–42 (Aβ(1–42)) is the main component of SP and is pivotal to AD pathogenesis. Brain of subjects with AD and arguably its earliest manifestation, mild cognitive impairment (MCI), demonstrate increased levels of oxidative stress markers. Our laboratory combined these two aspects of AD and MCI and proposed the Aβ(1–42)-associated free radical oxidative stress hypothesis to explain oxidative stress under which the MCI and AD brain exist and the loss of synapses in both disorders. A large number of in vitro and in vivo studies showed that Aβ causes protein oxidation, lipid peroxidation, reactive oxygen species formation, and cell death in neuronal and synaptosomal systems. Methionine located at residue 35 of Aβ(1–42) is an important contributor to the oxidative stress associated with this neurotoxic peptide. In this paper, we summarize studies involving Met-35 of Aβ(1–42). Understanding the role of the single methionine residue of Aβ(1–42) may help in understanding underlying disease mechanisms in AD and MCI. 1. Introduction Alzheimer disease (AD) is an age-related progressive neurodegenerative disease. This devastating disease is characterized by the presence of senile plaques (SP), neurofibrillary tangles (NFTs), and loss of synapses [1]. Although AD has been known for over 100 years, the exact mechanism(s) of AD progression or pathogenesis largely remain unknown. Mutations of presenilin-1 (PS-1), presenilin-2 (PS-2), and APP genes cause familial AD (FAD). In addition, other genes, such as apolipoprotein E allele 4 (APOE 4), clusterin (CLU, also called apolipoprotein J (APOJ)), phosphatidylinositol-binding clathrin assembly protein (PICALM), endothelial nitric oxide synthase-3, and alpha-2-macroglobulin, have been suggested as risk factors for AD [2–5]. Studies showed that injection of Aβ cores in rat brain leads to AD-like pathology [6]. 2. Oxidative Stress in AD and Mild Cognitive Impairment Brain Brain of subjects with AD showed increased markers of oxidative stress [7–10]. A number of hypotheses were proposed to explain AD pathogenesis among which oxidative stress hypothesis is well supported by numerous in vitro and in vivo studies [11–15]. Oxidative stress is defined as an imbalance between the amount of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and the antioxidant defense system present (Figure