Suppression of a core metabolic enzyme dihydrolipoamide dehydrogenase (dld) protects against amyloid beta toxicity in C. elegans model of Alzheimer's disease

Abstract

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 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.

Activation of Microbiota Sensing – Free Fatty Acid Receptor 2 Signaling Ameliorates Amyloid-β Induced Neurotoxicity by Modulating Proteolysis-Senescence Axis

“…For example, the CL2006 strain overexpresses human Aβ proteins, while the CL4176 strain overexpresses human Aβ in a temperature-sensitive manner (i.e., the worms grow and live normally at 16°C but overexpress Aβ and develop paralysis due to substantial neuronal death at 22°C). Additionally, the CL2355 strain overexpresses human Aβ when grown at 22°C and develops paralysis, but grows normally at 16°C (Ahmad and Ebert, 2020 ). CL2355 is a good model for measuring AD-like chemotactic cognition/memory behaviors compared to the CL2122 strain, which shows normal chemotaxis (cognition/memory; He et al, 2017 ).…”

Modeling Alzheimer’s Disease in Caenorhabditis elegans

“…It has also been described that the activation of PPARα / nhr-49 (nuclear hormone receptor involved in lipid signaling) inhibits the steroid signaling pathway, which increases the nuclear translocation of DAF-16 and inhibits the Aβ-induced phenotype in an AD model in C. elegans [ 58 ]. Finally, deletion of the dld-1 gene, which encodes for dihydrolipoamide dehydrogenase, has also been shown to have a protective effect in C. elegans models overexpressing Aβ, probably through reduced energy metabolism and proteasome activation [ 59 , 60 ]. This effect is consistent with the fact that variants of the human orthologue of this enzyme are linked to LOAD.…”

“…We have previously mentioned that knockout of the dld-1 gene, which encodes for dihydrolipoamide dehydrogenase, has a protective effect in C. elegans models overexpressing Aβ [ 59 , 60 ]. An inhibitor of this enzyme, 2-methoxyindole-5-carboxylic acid (MICA), alleviated Aβ-induced paralysis and improved cholinergic neurotransmission in C. elegans expressing Aβ in muscle cells [ 59 ].…”

Dichloroacetate and thiamine improve survival and mitochondrial stress in a C. elegans model of dihydrolipoamide dehydrogenase deficiency

“…Therefore, we utilized feeding RNAi to variably deplete DLD-1 protein in N2 Bristol wild-type worms (N2). Depletion of DLD-1 was achieved by bacterial feeding of worms with the RNAi clone LLC1.3 (https://wormbase.org/search/gene/LLC1.3) (21), which encodes a dsRNA against dld-1 when induced by isopropyl-β-d-thiogalactoside (IPTG) that reduces DLD-1 expression in C. elegans (22). Previous work demonstrated that graded feeding of this dld-1(RNAi) led to variation in animal phenotype depending on the amount of RNAi expressed (23).…”