PMID:16478525

Citation	Mohmmad Abdul, H, Sultana, R, Keller, JN, St Clair, DK, Markesbery, WR and Butterfield, DA (2006) 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. J. Neurochem. 96:1322-35
Abstract	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.
Links	PubMed Online version:10.1111/j.1471-4159.2005.03647.x
Keywords	Aldehydes/metabolism; Amyloid beta-Peptides/metabolism; Amyloid beta-Peptides/pharmacology; Amyloid beta-Protein Precursor/genetics; Analysis of Variance; Animals; 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; Lipid Peroxidation/genetics; Membrane Proteins/genetics; Mice; Mice, Transgenic; Mutation; Neurons/drug effects; Neurons/metabolism; Oxidation-Reduction/drug effects; Oxidative Stress/drug effects; Oxidative Stress/genetics; Peptide Fragments/metabolism; Peptide Fragments/pharmacology; Presenilin-1
edit table

Annotations

Gene product	Qualifier	GO ID	GO term name	Evidence Code	with/from	Aspect	Notes	Status
edit table

References

See Help:References for how to manage references in GONUTS.