A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease.

Hensley, Kenneth; Carney, John M.; Mattson, Mark P.; Aksenova, Marina; Harris, Marni E.; Wu, Jeng-Yue; Floyd, Robert A.; Butterfield, D. Allan

doi:10.1073/pnas.91.8.3270

Cited by 1,012 publications

(749 citation statements)

References 26 publications

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“…In AD, the Aβ peptide plays a central role in the generation of free radicals and oxidative stress [16,18,55,56]. In the aging canine, no significant correlation between the levels of Aβ deposition in brain and oxidative damage is observed [54], however, since the aging canine deposits the more toxic form of Aβ 1-42 as that seen in human aging [19,74] and since Aβ load and decline in cognitive function events develop in parallel, Aβ could still play a significant role in the mechanism of oxidative stress observed in the aging canine [42,43,52].…”

Section: Discussionmentioning

confidence: 99%

Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer's disease

Opii

Joshi

Head

et al. 2008

Neurobiology of Aging

172

133

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Aging and age-related disorders such as Alzheimer's disease (AD) are usually accompanied by oxidative stress as one of the main mechanisms contributing to neurodegeneration and cognitive decline. Aging canines develop cognitive dysfunction and neuropathology similar to those seen in humans, and the use of antioxidants results in reductions in oxidative damage and in improvement in cognitive function in this canine model of human aging. In the present study, the effect of a longterm treatment with an antioxidant fortified diet and a program of behavioral enrichment on oxidative damage was studied in aged canines. To identify the neurobiological mechanisms underlying these treatment effects, the parietal cortex from 23 beagle dogs (8.1-12.4 years) were treated for 2.8 years in one of four treatment groups: i.e., control food-control behavioral enrichment (CC); control food -behavioral enrichment (CE); antioxidant food-control behavioral enrichment (CA); and enriched environment -antioxidant fortified food (EA). We analyzed the levels of the oxidative stress biomarkers, i.e., protein carbonyls, 3-nitrotyroine (3NT), and the lipid peroxidation product, 4- Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurobiol Aging. Author manuscript; available in PMC 2009 January 1. Published in final edited form as:Neurobiol Aging. 2008 January ; 29(1): 51-70. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript hydroxynonenal (HNE), and observed a decrease in their levels on all treatments when compared to control, with the most significant effects found in the combined treatment, EA. Since EA treatment was most effective, we also carried out a comparative proteomics study to identify specific brain proteins that were differentially expressed and used a parallel redox proteomics approach to identify specific brain proteins that were less oxidized following EA. The specific protein carbonyl levels of glutamate dehydrogenase [NAD (P)], glyceraldehyde-3-phosphate dehydrogenase (GAPDH), α-enolase, neurofilament triplet L protein, glutathione S-transferase (GST) and fascin actin bundling protein were significantly reduced in brain of EA-treated dogs compared to control. We also observed significant increases in expression of Cu/Zn superoxide dismutase, fructose-bisphosphate aldolase C, creatine kinase, glutamate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. The increased expression of these proteins and in particular Cu/Zn SOD correlated with improved cognitive function. In addition, there was a significant increas...

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Section: Discussionmentioning

confidence: 99%

Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer's disease

Opii

Joshi

Head

et al. 2008

Neurobiology of Aging

172

133

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“…A␤ can fragment and generate free radical peptides which have potent lipoperoxidising effects on the synaptosomal membranes in the neocortex [12,17,32]. However, studies of autopsied brain tissue cannot clarify whether abnormal oxidative processes are inherent properties of AD cells or are secondary to neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Cecchi

Fiorillo

Baglioni

et al. 2007

Neurobiology of Aging

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Much experimental evidence suggests that an imbalance in cellular redox status is a major factor in the pathogenesis of Alzheimer's disease (AD). Our previous data showed a marked increase in membrane lipoperoxidation in primary fibroblasts from familial AD (FAD) patients. In the present study, we demonstrate that when oligomeric structures of A␤ 1-40 and A␤ 1-42 are added to the culture media, they accumulate quicker near the plasma membrane, and are internalized faster and mostly in APPV717I fibroblasts than in age-matched healthy cells; this results in an earlier and sharper increase in the production of reactive oxygen species (ROS). Higher ROS production leads in turn to an increase in membrane oxidative-injury and significant impairment of cellular antioxidant capacity, giving rise to apoptotic cascade activation and finally to a necrotic outcome. In contrast, healthy fibroblasts appear more resistant to amyloid oxidative-attack, possibly as a result of their plasma membrane integrity and powerful antioxidant capacity. Our data are consistent with increasing evidence that prefibrillar aggregates, compared to mature fibrils, are likely the more toxic species of the peptides. These findings provide compelling evidence that cells bearing increased membrane lipoperoxidation are more susceptible to aggregate toxicity as a result of their reduced ability to counteract amyloid oligomeric attack.

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“…Amyloid β-protein is cytotoxic, and induces oxidative damage in some brain cells [277]. This may involve a receptor response mechanism, although it has been claimed that the protein itself can generate radicals [278], even though freshly dissolved samples were inactive [279]. Variations between samples (e.g.…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

“…Variations between samples (e.g. [278]) and upon ' aging ' of the materials make one wary of these data, as do the detailed characteristics of the EPR spectra. Regardless of this problem, radical metabolism [280] and protein oxidation could lead either to cross-linking and aggregation of proteins into tangles or to cytotoxic signals that alter ion transporters and neurotransmission [281], and in these ways may contribute specifically to the progression of Alzheimer's disease.…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

Biochemistry and pathology of radical-mediated protein oxidation

Dean

Stocker

et al. 1997

Biochemical Journal

1,529

971

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Radical-mediated damage to proteins may be initiated by electron leakage, metal-ion-dependent reactions and autoxidation of lipids and sugars. The consequent protein oxidation is O2-dependent, and involves several propagating radicals, notably alkoxyl radicals. Its products include several categories of reactive species, and a range of stable products whose chemistry is currently being elucidated. Among the reactive products, protein hydroperoxides can generate further radical fluxes on reaction with transition-metal ions; protein-bound reductants (notably dopa) can reduce transition-metal ions and thereby facilitate their reaction with hydroperoxides; and aldehydes may participate in Schiff-base formation and other reactions. Cells can detoxify some of the reactive species, e.g. by reducing protein hydroperoxides to unreactive hydroxides. Oxidized proteins are often functionally inactive and their unfolding is associated with enhanced susceptibility to proteinases. Thus cells can generally remove oxidized proteins by proteolysis. However, certain oxidized proteins are poorly handled by cells, and together with possible alterations in the rate of production of oxidized proteins, this may contribute to the observed accumulation and damaging actions of oxidized proteins during aging and in pathologies such as diabetes, atherosclerosis and neurodegenerative diseases. Protein oxidation may also sometimes play controlling roles in cellular remodelling and cell growth. Proteins are also key targets in defensive cytolysis and in inflammatory self-damage. The possibility of selective protection against protein oxidation (antioxidation) is raised.

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A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease.

Cited by 1,012 publications

References 26 publications

Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer's disease

Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer's disease

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Biochemistry and pathology of radical-mediated protein oxidation

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