The Swedish APP670/671 Alzheimer’s Disease Mutation: The First Evidence for Strikingly Increased Oxidative Injury in the Temporal Inferior Cortex

Bogdanović, Nenad; Zilmer, Mihkel; Zilmer, Kersti; Rehema, Aune; Karelson, Ello

doi:10.1159/000051282

Cited by 49 publications

(29 citation statements)

References 23 publications

(23 reference statements)

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“…This fact could be related to a mitochondrial dysfunction that would promote the leakage of reactive oxygen species, subsequently increasing protein oxidative damage (27). Furthermore, the results agree with those previously suggesting that increased oxidative damage occurs in AD (2,28), although in these reports it affects specifically some other brain regions such as temporal inferior cortex (29) or parietal lobe cortex (28). The increase in carbonyl concentrations in these reports is lower than that found here for AASA, but not for GSA.…”

Section: Discussionsupporting

confidence: 90%

Proteins in Human Brain Cortex Are Modified by Oxidation, Glycoxidation, and Lipoxidation

Pamplona

Dalfó

Ayala

et al. 2005

Journal of Biological Chemistry

257

242

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Diverse oxidative pathways, such as direct oxidation of amino acids, glycoxidation, and lipoxidation could contribute to Alzheimer disease pathogenesis. A global survey for the amount of structurally characterized probes for these reactions is lacking and could overcome the lack of specificity derived from measurement of 2,4-dinitrophenylhydrazine reactive carbonyls. Consequently we analyzed (i) the presence and concentrations of glutamic and aminoadipic semialdehydes, N ⑀ -(carboxymethyl)-lysine, N ⑀ -(carboxyethyl)-lysine, and N ⑀ -(malondialdehyde)-lysine by means of gas chromatography/mass spectrometry, (ii) the biological response through expression of the receptor for advanced glycation end products, (iii) the fatty acid composition in brain samples from Alzheimer disease patients and agematched controls, and (iv) the targets of N ⑀ -(malondialdehyde)-lysine formation in brain cortex by proteomic techniques. Alzheimer disease was associated with significant, although heterogeneous, increases in the concentrations of all evaluated markers. Alzheimer disease samples presented increases in expression of the receptor for advanced glycation end products with high molecular heterogeneity. Samples from Alzheimer disease patients also showed content of docosahexaenoic acid, which increased lipid peroxidizability. In accordance, N ⑀ -(malondialdehyde)-lysine formation targeted important proteins for both glial and neuronal homeostasis such as neurofilament L, ␣-tubulin, glial fibrillary acidic protein, ubiquinol-cytochrome c reductase complex protein I, and the ␤ chain of ATP synthase. These data support an important role for lipid peroxidationderived protein modifications in Alzheimer disease pathogenesis.

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Section: Discussionsupporting

confidence: 90%

Proteins in Human Brain Cortex Are Modified by Oxidation, Glycoxidation, and Lipoxidation

Pamplona

Dalfó

Ayala

et al. 2005

Journal of Biological Chemistry

257

242

View full text Add to dashboard Cite

show abstract

“…The brain has a high metabolic rate and is exposed to gradually rising levels of oxidative stress during life. In Swedish FAD patients, the levels of oxidative stress are increased in the temporal inferior cortex (28). Our study using a cell model mimicking the in vivo situation in AD brains indicates that probably both increased A␤ production and the gradual rise of oxidative stress throughout life lead to an increased vulnerability to apoptotic cell death in neurons from FAD patients.…”

Section: Discussionmentioning

confidence: 64%

“…AD-related mutations probably enhance oxidative stress. Increased oxidative stress levels have been found in the temporal inferior cortex from Swedish FAD patients (28), and brains of mice transgenic for human presenilin 1 show reduced antioxidative enzyme activity (29).…”

mentioning

confidence: 99%

Neurotoxic Mechanisms Caused by the Alzheimer's Disease-linked Swedish Amyloid Precursor Protein Mutation

Marques

Keil

Bonert

et al. 2003

Journal of Biological Chemistry

163

109

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Autosomal dominant forms of familial Alzheimer's disease (FAD) are caused by mutations of the amyloid precursor protein (APP) gene and by mutations of the genes encoding for presenilin 1 or presenilin 2. Simultaneously, evidence is provided that increased oxidative stress might play a crucial role in the rapid progression of the Swedish FAD. Here we investigated the effect of the Swedish double mutation (K670M/N671L) in the ␤-amyloid precursor protein on oxidative stress-induced cell death mechanisms in PC12 cells. Western blot analysis and cleavage studies of caspase substrates revealed an elevated activity of the executor caspase 3 after treatment with hydrogen peroxide in cells containing the Swedish APP mutation. This elevated activity is the result of the enhanced activation of both intrinsic and extrinsic apoptosis pathways, including activation of caspase 2 and caspase 8. Furthermore, we observed an enhanced activation of JNK pathway and an attenuation of apoptosis by SP600125, a JNK inhibitor, through protection of mitochondrial dysfunction and reduction of caspase 9 activity. Our findings provide evidence that the massive neurodegeneration in early age of FAD patients could be a result of an increased vulnerability of neurons through activation of different apoptotic pathways as a consequence of elevated levels of oxidative stress.

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“…Smith and collaborators (353) observed a strong PCO signal in NFTs, neuronal cell bodies, and apical dendrites as well as neuronal and glial nuclei in hippocampal sections of AD brains. In the frontal cortex of subjects with the Swedish APP670/671 FAD mutation, increased levels of PCO, diene conjugates, and lipid peroxides compared with sporadic AD were found (43). Further, the levels of carbonyl reductase (CR) protein are increased in brain of AD and DS subjects (26), suggesting enzyme induction due to increased levels of PCO.…”

Section: Application Of Redox Proteomics To Selected Neurodegenermentioning

confidence: 99%

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Butterfield

Perluigi

Reed

et al. 2012

Antioxidants & Redox Signaling

156

142

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Several studies demonstrated that oxidative damage is a characteristic feature of many neurodegenerative diseases. The accumulation of oxidatively modified proteins may disrupt cellular functions by affecting protein expression, protein turnover, cell signaling, and induction of apoptosis and necrosis, suggesting that protein oxidation could have both physiological and pathological significance. For nearly two decades, our laboratory focused particular attention on studying oxidative damage of proteins and how their chemical modifications induced by reactive oxygen species/reactive nitrogen species correlate with pathology, biochemical alterations, and clinical presentations of Alzheimer's disease. This comprehensive article outlines basic knowledge of oxidative modification of proteins and lipids, followed by the principles of redox proteomics analysis, which also involve recent advances of mass spectrometry technology, and its application to selected age-related neurodegenerative diseases. Redox proteomics results obtained in different diseases and animal models thereof may provide new insights into the main mechanisms involved in the pathogenesis and progression of oxidativestress-related neurodegenerative disorders. Redox proteomics can be considered a multifaceted approach that has the potential to provide insights into the molecular mechanisms of a disease, to find disease markers, as well as to identify potential targets for drug therapy. Considering the importance of a better understanding of the cause/effect of protein dysfunction in the pathogenesis and progression of neurodegenerative disorders, this article provides an overview of the intrinsic power of the redox proteomics approach together with the most significant results obtained by our laboratory and others during almost 10 years of research on neurodegenerative disorders since we initiated the field of redox proteomics. Antioxid. Redox Signal. 17, 1610-1655.

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The Swedish APP670/671 Alzheimer’s Disease Mutation: The First Evidence for Strikingly Increased Oxidative Injury in the Temporal Inferior Cortex

Cited by 49 publications

References 23 publications

Proteins in Human Brain Cortex Are Modified by Oxidation, Glycoxidation, and Lipoxidation

Proteins in Human Brain Cortex Are Modified by Oxidation, Glycoxidation, and Lipoxidation

Neurotoxic Mechanisms Caused by the Alzheimer's Disease-linked Swedish Amyloid Precursor Protein Mutation

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

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