Document Detail

Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), HO and kainic acid: implications for Alzheimer's disease.
MedLine Citation:
PMID:  16478525     Owner:  NLM     Status:  MEDLINE    
Oxidative stress is observed in Alzheimer's disease (AD) brain, including protein oxidation and lipid peroxidation. One of the major pathological hallmarks of AD is the brain deposition of amyloid beta-peptide (Abeta). This 42-mer peptide is derived from the beta-amyloid precursor protein (APP) and is associated with oxidative stress in vitro and in vivo. Mutations in the PS-1 and APP genes, which increase production of the highly amyloidogenic amyloid beta-peptide (Abeta42), are the major causes of early onset familial AD. Several lines of evidence suggest that enhanced oxidative stress, inflammation, and apoptosis play important roles in the pathogenesis of AD. In the present study, primary neuronal cultures from knock-in mice expressing mutant human PS-1 and APP were compared with those from wild-type mice, in the presence or absence of various oxidizing agents, viz, Abeta(1-42), H2O2 and kainic acid (KA). APP/PS-1 double mutant neurons displayed a significant basal increase in oxidative stress as measured by protein oxidation, lipid peroxidation, and 3-nitrotyrosine when compared with the wild-type neurons (p < 0.0005). Elevated levels of human APP, PS-1 and Abeta(1-42) were found in APP/PS-1 cultures compared with wild-type neurons. APP/PS-1 double mutant neuron cultures exhibited increased vulnerability to oxidative stress, mitochondrial dysfunction and apoptosis induced by Abeta(1-42), H2O2 and KA compared with wild-type neuronal cultures. The results are consonant with the hypothesis that Abeta(1-42)-associated oxidative stress and increased vulnerability to oxidative stress may contribute significantly to neuronal apoptosis and death in familial early onset AD.
Hafiz Mohmmad Abdul; Rukhsana Sultana; Jeffrey N Keller; Daret K St Clair; William R Markesbery; D Allan Butterfield
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  96     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-02-15     Completed Date:  2006-05-11     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  1322-35     Citation Subset:  IM    
Department of Chemistry and Center of Membrane Sciences, University of Kentucky, Lexington, Kentucky 40506, USA.
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MeSH Terms
Aldehydes / metabolism
Amyloid beta-Protein / metabolism,  pharmacology*
Amyloid beta-Protein Precursor / genetics*
Analysis of Variance
Apoptosis / drug effects
Blotting, Western / methods
Cell Survival / drug effects
Cells, Cultured
Cytochromes c / metabolism
Dose-Response Relationship, Drug
Gene Expression / drug effects
Hydrogen Peroxide / pharmacology*
Kainic Acid / pharmacology*
Lipid Peroxidation / drug effects,  genetics
Membrane Proteins / genetics*
Mice, Transgenic
Neurons / drug effects*,  metabolism
Oxidation-Reduction / drug effects
Oxidative Stress / drug effects*,  genetics
Peptide Fragments / metabolism,  pharmacology*
Grant Support
Reg. No./Substance:
0/Aldehydes; 0/Amyloid beta-Protein; 0/Amyloid beta-Protein Precursor; 0/Membrane Proteins; 0/PSEN1 protein, human; 0/Peptide Fragments; 0/Presenilin-1; 0/amyloid beta-protein (1-42); 0/tert-4-hydroxy-2-nonenal; 487-79-6/Kainic Acid; 7722-84-1/Hydrogen Peroxide; 9007-43-6/Cytochromes c

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