Suppression of the dihydrolipoamide dehydrogenase gene (dld-1) protects against the toxicity of human amyloid beta in C. elegans model of Alzheimer’s disease

Abstract

Declines in energy metabolism and associated mitochondrial enzymes are linked to the progression of Alzheimers disease (AD). Dihydrolipoamide dehydrogenase (dld) and two of its enzyme complexes namely, pyruvate dehydrogenase and -ketoglutarate dehydrogenase are associated with AD and have a significant role in energy metabolism. Interestingly, dld gene variants are genetically linked to late-onset AD; and reduced activity of DLD-containing enzyme complexes has been observed in AD patients. To understand how energy metabolism influences AD progression, we suppressed the dld-1 gene in C. elegans expressing the human A{beta} peptide. dld-1 gene suppression improved many aspects of vitality and function directly affected by A{beta} pathology in C. elegans. This includes protection against paralysis, improved fecundity and improved egg hatching rates. Suppression of the dld-1 gene restores normal sensitivity to aldicarb, levamisole and serotonin, and improves chemotaxis. Suppression of dld-1 does not decrease levels of the A{beta} peptide, but does reduce the formation of toxic A{beta} oligomers. The mitochondrial uncoupler, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) acts synergistically with A{beta} to overcome the protective effect of dld-1 gene suppression. Another metabolic toxin, phosphine, acted additively with A{beta}. Our work supports the hypothesis that lowering energy metabolism may protect against A{beta} pathogenicity, but that this may increase susceptibility to other metabolic disturbances.