A decrease in energy metabolism is associated with Alzheimer’s disease(AD),but it is not known whether the observed decrease exacerbates or protects against the disease.The importance of energy metabolism in AD is re...A decrease in energy metabolism is associated with Alzheimer’s disease(AD),but it is not known whether the observed decrease exacerbates or protects against the disease.The importance of energy metabolism in AD is reinforced by the observation that variants of dihydrolipoamide dehydrogenase(DLD),is genetically linked to late-onset AD.To determine whether DLD is a suitable therapeutic target,we suppressed the dld-1 gene in Caenorhabditis elegans that express human Ab peptide in either muscles or neurons.Suppression of the dld-1 gene resulted in significant restoration of vitality and function that had been degraded by Ab pathology.This included protection of neurons and muscles cells.The observed decrease in proteotoxicity was associated with a decrease in the formation of toxic oligomers rather than a decrease in the abundance of the Ab peptide.The mitochondrial uncoupler,carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone(FCCP),which like dld-1 gene expression inhibits ATP synthesis,had no significant effect on Ab toxicity.Proteomics data analysis revealed that beneficial effects after dld-1 suppression could be due to change in energy metabolism and activation of the pathways associated with proteasomal degradation,improved cell signaling and longevity.Thus,some features unique to dld-1 gene suppression are responsible for the therapeutic benefit.By direct genetic intervention,we have shown that acute inhibition of dld-1 gene function may be therapeutically beneficial.This result supports the hypothesis that lowering energy metabolism protects against Ab pathogenicity and that DLD warrants further investigation as a therapeutic target.展开更多
Development of the use of favin and nicotinamide-adenine nucleotide fluorescence in monitoringthe redox state of the free mitochondrial NADH/NAD+couple in cels,tissues and organs isreviewed.A break-through was the ide...Development of the use of favin and nicotinamide-adenine nucleotide fluorescence in monitoringthe redox state of the free mitochondrial NADH/NAD+couple in cels,tissues and organs isreviewed.A break-through was the identification of dihydrolipoamide dehydrogenase(FpL)asthe major NAD-linked fluorescent fla voprotein of mitochondria.This mitochondrial matrix fla-voprotein is in equilibriwn with the fre NADH/NAD+pool and its mid-potential is suficientlynear to that of NADH/NAD+so that its percentage reduction follows that of the latter.Pos.sibilities of monitoring mitochondial and cytosolic NADH depend on the population density ofmitochondria and thus are tissue-dependent.Upon a shift toward reduction,fluorescenceintensitis of NADH and flavins swing to reciprocal directions,so that the NADH/favin fluo-rescence ratio can be used to increase the sensitivity of redox monitoring.This method is attainingwidening use in studies on metabolic regulation under normal and pathological conditions.展开更多
基金The C.elegans strains were provided by the CGC,which is funded by NIH Office of Research Infrastructure Programs(P40 OD010440)WA was supported by a IPRS scholarship from the Australian Government and the University of Queensland.
文摘A decrease in energy metabolism is associated with Alzheimer’s disease(AD),but it is not known whether the observed decrease exacerbates or protects against the disease.The importance of energy metabolism in AD is reinforced by the observation that variants of dihydrolipoamide dehydrogenase(DLD),is genetically linked to late-onset AD.To determine whether DLD is a suitable therapeutic target,we suppressed the dld-1 gene in Caenorhabditis elegans that express human Ab peptide in either muscles or neurons.Suppression of the dld-1 gene resulted in significant restoration of vitality and function that had been degraded by Ab pathology.This included protection of neurons and muscles cells.The observed decrease in proteotoxicity was associated with a decrease in the formation of toxic oligomers rather than a decrease in the abundance of the Ab peptide.The mitochondrial uncoupler,carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone(FCCP),which like dld-1 gene expression inhibits ATP synthesis,had no significant effect on Ab toxicity.Proteomics data analysis revealed that beneficial effects after dld-1 suppression could be due to change in energy metabolism and activation of the pathways associated with proteasomal degradation,improved cell signaling and longevity.Thus,some features unique to dld-1 gene suppression are responsible for the therapeutic benefit.By direct genetic intervention,we have shown that acute inhibition of dld-1 gene function may be therapeutically beneficial.This result supports the hypothesis that lowering energy metabolism protects against Ab pathogenicity and that DLD warrants further investigation as a therapeutic target.
文摘Development of the use of favin and nicotinamide-adenine nucleotide fluorescence in monitoringthe redox state of the free mitochondrial NADH/NAD+couple in cels,tissues and organs isreviewed.A break-through was the identification of dihydrolipoamide dehydrogenase(FpL)asthe major NAD-linked fluorescent fla voprotein of mitochondria.This mitochondrial matrix fla-voprotein is in equilibriwn with the fre NADH/NAD+pool and its mid-potential is suficientlynear to that of NADH/NAD+so that its percentage reduction follows that of the latter.Pos.sibilities of monitoring mitochondial and cytosolic NADH depend on the population density ofmitochondria and thus are tissue-dependent.Upon a shift toward reduction,fluorescenceintensitis of NADH and flavins swing to reciprocal directions,so that the NADH/favin fluo-rescence ratio can be used to increase the sensitivity of redox monitoring.This method is attainingwidening use in studies on metabolic regulation under normal and pathological conditions.
