Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease

Oxidative and nitrosative stress are widely recognized as critical factors in the pathogenesis and progression of Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI). A major source of free radicals that lead to oxidative and nitrosative damage is mitochondria. This review paper discusses oxidative and nitrosative stress and markers thereof in the brain, along with redox proteomics, which are techniques that have been pioneered in the Butterfield laboratory. Selected biological alterations in—and oxidative and nitrosative modifications of—mitochondria in AD and MCI and systems of relevance thereof also are presented. The review article concludes with a section on the implications of mitochondrial oxidative and nitrosative stress in MCI and AD with respect to imaging studies in and targeted therapies toward these disorders. Taken together, this review provides support for the notion that brain mitochondrial alterations in AD and MCI are key components of oxidative and nitrosative stress observed in these two disorders, and as such, they provide potentially promising therapeutic targets to slow—and hopefully one day stop—the progression of AD, which is a devastating dementing disorder

SYPOSIUM: Amyloid-β: A Multifaceted Protein Amyloid β-Peptide(1-42) Contributes to the Oxidative Stress and Neurodegeneration Found in Alzheimer Disease Brain

42) has been shown to induce oxidative stress and neurotoxicity in vitro and in vivo. Genetic mutations that result in increased production of Aβ 1-42 from amyloid precursor protein are associated with an early onset and accelerated pathology of AD. Consequently

Review The critical role of methionine 35 in Alzheimer’s amyloid h-peptide (1–42)-induced oxidative stress and neurotoxicity

Amyloid beta-peptide (1–42) [Ah(1–42)] has been proposed to play a central role in the pathogenesis of Alzheimer’s disease, a neurodegenerative disorder associated with cognitive decline and aging. AD brain is under extensive oxidative stress, and Ah(1–42) has been shown to induce protein oxidation, lipid peroxidation, and reactive oxygen species formation in neurons and synaptosomes, all of which are inhibited by the antioxidant vitamin E. Additional studies have shown that Ah(1–42) induces oxidative stress when expressed in vivo in Caenorhabditis elegans, but when methionine 35 is replaced by cysteine, the oxidative stress is attenuated. This finding coupled with in vitro studies using mutant peptides have demonstrated a critical role for methionine 35 in the oxidative stress and neurotoxic properties of Ah(1– 42). In this review, we discuss the role of methionine 35 in the oxidative stress and neurotoxicity induced by Ah(1–42) and the implications of these findings in the pathogenesis of AD

Role of Phenylalanine 20 in Alzheimer\u27s Amyloid β-peptide (1-42)-induced Oxidative Stress and Neurotoxicity

Senile plaques are a hallmark of Alzheimer\u27s disesae (AD), a neurodegenerative disease associated with cognitive decline and aging. Aβ(1-42) is the primary component of the senile plaque in AD brain and has been shown to induce protein oxidation in vitro and in vivo. Oxidative stress is extensive in AD brain. As a result, Aβ(1-42) has been proposed to play a central role in the pathogenesis of AD; however, the specific mechanism of neurotoxicity remains unknown. Recently, it has been proposed that long distance electron transfer from methionine 35 to the Cu(II) bound at the N terminus of Aβ(1-42) occurs via phenylalanine 20. Additionally, it was proposed that substitution of phenylalanine 20 of Aβ(1-42) by alanine [Aβ(1-42)F20A] would lessen the neurotoxicity induced by Aβ(1-42). In this study, we evaluate the predictions of this theoretical study by determining the oxidative stress and neurotoxic properties of Aβ(1-42)F20A relative to Aβ(1-42) in primary neuronal cell culture. Aβ(1-42)F20A induced protein oxidation and lipid peroxidation similar to Aβ(1-42) but to a lesser extent and in a manner inhibited by pretreatment of neurons with vitamin E. Additionally, Aβ(1-42)F20A affected mitochrondrial function similar to Aβ(1-42), albeit to a lesser extent. Furthermore, the mutation does not appear to abolish the ability of the native peptide to reduce Cu(II). Aβ(1-42)F20A did not compromise neuronal morphology at 24 h incubation with neurons, but did so after 48 h incubation. Taken together, these results suggest that long distance electron transfer from methionine 35 through phenylalanine 20 may not play a pivotal role in Aβ(1-42)-mediated oxidative stress and neurotoxicity

Alzheimer’s A�(1-42): relevance to N-terminal

methionine chemistry in small model peptide