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At least 73 records · Page 4Linked to original sources
PubMed1999

Methionine residue 35 is important in amyloid beta-peptide-associated free radical oxidative stress.

Amyloid beta-peptide (Abeta), the central constituent of senile plaques in Alzheimer's disease (AD) brain, has been shown to be a source of free radical oxidative stress that may lead to neurodegeneration. In the current study Abeta(1-40), found in AD brain, and the amyloid fragment Abeta(25-35) were used in conjunction with electron paramagnetic resonance spin trapping techniques to demonstrate that these peptides mediate free radical production. The methionine residue in these peptides is believed to play an important role in their neurotoxicity. Substitution of methionine by structurally similar norleucine in both Abeta(1-40) and Abeta(25-35), and the substitution of methionine by valine, or the removal of the methionine in Abeta(25-35), abrogates free radical production and protein oxidation of and toxicity to hippocampal neurons. These results are discussed with relevance to the hypothesis that neurodegeneration in Alzheimer's disease may be due in part to Abeta-associated free radical oxidative stress that involves methionine, and to the use of spin trapping methods to infer mechanistic information about Abeta.

Alzheimer Disease↗
PubMed2001

Role of spermine in amyloid beta-peptide-associated free radical-induced neurotoxicity.

The polyamines, relatively low-molecular-weight aliphatic compounds, are the main inducers of eukaryotic cell growth and proliferation. Although polyamine requirements for cell growth are well defined, their role is still enigmatic. We have previously reported that amyloid beta-peptide (A beta), the main constituent of senile plaques in Alzheimer's disease (AD) brain, is toxic to neurons through a free radical-dependent oxidative stress mechanism and that A beta(1--42), the principal form of A beta in AD brain, causes an increase in polyamine metabolism manifested by up-regulated polyamine uptake and increased ornithine decarboxylase (ODC) activity. Both effects were prevented by the free radical scavenger vitamin E. Spermine has been reported to function directly as a free radical scavenger. In the current study, we aimed to address whether up-regulation of polyamine metabolism is a defense against, or a result of, A beta-induced oxidative stress by investigating the capability of spermine to quench A beta-associated free radicals in solution and to assert a protective function of spermine in neuronal culture against A beta. Pretreatment of cultured neurons with spermine prior to A beta exposure failed to prevent A beta-induced cell death. Indeed, A beta plus spermine added to cultured neurons was even more neurotoxic than either agent alone. Additionally, inhibition of the polyamine synthesis by difluoromethylornithine (DFMO) did not protect cells from A beta-induced free radical toxicity, and stimulation of the synthesis of putrescine and spermine by the aminopropyltransferase inhibitor S-adenosyl-1,8-diamino-thiooctane (AdoDATO), rather, further enhanced A beta-induced toxicity. Although spermine is capable of scavenging free radicals generated by A beta in solution as measured by electron paramagnetic resonance (EPR) spectroscopy, the up-regulated transport of exogenously added spermine together with A beta may lead to overaccumulation of a cellular spermine pool, with resulting enhanced neurotoxicity.

Adenosine↗
PubMed1995

Model-free association analysis of a rare disease.

Model-free methods of testing for association of a disease with alleles at a marker locus were used to analyze simulated data for a rare disease locus and 360 marker loci distributed at 2 cM intervals along six chromosomes. After adjustment for multiple tests, there was no evidence of significant heterogeneity of parental allele frequencies between a sample of parents with at least one affected child and a sample of parents with no affected children. Several significant deviations from Hardy-Weinberg equilibrium were detected after Bonferroni correction but these were Type I errors. After adjusting for multiple tests, the model-free test for association detected significant associations of alleles at two loci with the disease. These associations were in fact part of the generating model for the simulated data. However, these methods were unable to detect two other major loci contributing to the disease since these loci were not associated with any of the marker loci.

Alleles↗
PubMed1998

Absence of hemoprotein-associated free radical events following oxidant challenge of crosslinked hemoglobin-superoxide dismutase catalase.

Crosslinking hemoglobin with superoxide dismutase and catalase (PolyHb-SOD-CAT) helps to limit free radical reactivity of modified hemoglobin red blood cell substitutes. In the present study, in vitro oxidant challenge experiments were performed with exogenous hydrogen peroxide (H2O2) and xanthine oxidase-derived superoxide (O2.-). PolyHb-SOD-CAT was compared to PolyHb for the presence of secondary hemoprotein-free radical events. PolyHb-SOD-CAT prevents ferrylhemoglobin formation, measured as Na2S-induced absorbance at 620 nm. Similarly, PolyHb-SOD-CAT inhibited ferrozine-detectable iron release at high oxidant-heme ratios. The formation of oxygen radicals, monitored by salicylate hydroxylation, was prevented at high oxidant-heme ratios with PolyHb-SOD-CAT. The peroxidation of liposomal membranes was also inhibited in PolyHb-SOD-CAT mixtures subject to oxidant challenge. These results show that PolyHb-SOD-CAT prevents secondary hemoprotein-associated free radical events. This new type of modified hemoglobin oxygen carrier with antioxidant activity may reduce the potential toxicity of hemoglobin-based substitutes in certain applications, especially during reperfusion of ischemic tissues.

Animals↗
PubMed2001

The relationship between Abeta-associated free radical generation and Abeta fibril formation revealed by negative stain electron microscopy and thioflavine-T fluorometric assay.

In the present study, we investigated whether or not the Abeta peptide itself spontaneously generates free radicals using electron spin resonance (ESR) spectroscopy while also observing the Abeta fibril formation by negative stain electron microscopy. The present results demonstrated a four-line spectrum in the presence of Abeta(1-40) with N-tert-butyl-alpha-phenylnitrone (PBN) but not in the presence of PBN alone in phosphate-buffered saline. Negative stain electron microscopy has shown that Abeta peptides after 96 h of incubation showed more amyloid-like fibrils than those after 72 h of incubation while the four-line spectrum obtained by ESR spectroscopy attained a maximum intensity after 72 h of incubation and thereafter its intensity immediately decreased during the 4-day incubation period. These results were also supported by a thioflavine-T (Th-T) fluorometric assay. In conclusion, the present results suggest that Abeta-associated free radical generation is correlated with Abeta fibril formation while its generation is only observed transiently during the process of Abeta fibril formation.

Amyloid beta-Peptides↗
PubMed2002

Amyloid-beta-protein (A beta) (25-35)-associated free radical generation is strongly influenced by the aggregational state of the peptides.

We investigated whether or not the Amyloid-beta-protein (A beta) itself spontaneously generates free radicals using electron spin resonance (ESR) spectroscopy while also monitoring the aggregational state of A beta and A beta-induced cytotoxicity. The present results demonstrated a four-line spectrum in the presence of A beta25-35 with N-tert-butyl-alpha-phenylnitrone (PBN) but not in the presence of PBN alone in phosphate-buffered saline (PBS). The fact that the four-line spectrum obtained for the A beta25-35/PBN in PBS was completely abolished in the presence of the iron-chelating agent Desferal demonstrated the observed four-line spectrum to be iron-dependent. On the other hand, A beta25-35 with PBN in phosphate buffer (PB) did not produce any definite four-line spectrum. the present results showed the amyloid fibril formation of A beta25-35 in PBS to be much higher than that of A beta25-35 in PB. Moreover, A beta-induced cytotoxicity assays showed A beta incubated in PBS to be more cytotoxic than that incubated in PB. These results thus demonstrate that A beta(25-35)-associated free radical generation is strongly influenced by the aggregational state of the peptides.

Alzheimer Disease↗