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 Aβ 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 Aβ 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 Aβ peptide. The mitochondrial uncoupler

carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP)

which like

dld-1

gene expression inhibits ATP synthesis

had no significant effect on Aβ 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 Aβ pathogenicity and that DLD warrants further investigation as a therapeutic target.