5-Methoxyindole-2-carboxylic acid (MICA) suppresses Aβ-mediated pathology in C. elegans

Abstract

Alzheimer's disease (AD) is an age-related disease characterized by loss of memory and disrupted thinking that is associated with altered energy metabolism. Variants of an important enzyme of energy metabolism, dihydrolipoamide dehydrogenase (dld), have been genetically linked to late-onset AD. Moreover, reduced activity of DLD-containing enzyme complexes is associated with AD progression. To understand how energy metabolism influences AD progression, we exposed C. elegans expressing human Aβ peptide to the chemical inhibitor of DLD, 2-methoxyindole-5-carboxylic acid (MICA). Expression of human Aβ in C. elegans causes a variety of pathologies that can be used to monitor the efficacy of treatments against proteotixicity. We found that MICA alleviated the Aβ-induced paralysis and improved cholinergic neurotransmission in C. elegans that express Aβ in muscle cells. MICA also reduced both hypersensitivity to serotonin and perturbation of chemotaxis associated with neuronal expression of human Aβ. Furthermore, low doses of MICA helped to alleviate an Aβ-mediated decrease in fecundity. Protection against AD pathogenesis by MICA in the C. elegans model was associated with a decrease in Aβ oligomerization that could be reversed by the calcium ionophore, A23187. MICA also caused a decrease in oxidative stress, which could also contribute to the protective effect of MICA against Aβ toxicity.