Dihydrolipoamide dehydrogenase suppression induce human tau phosphorylation by increasing whole body glucose levels in a C. elegans model of Alzheimer’s Disease

The microtubule associated tau protein becomes hyperphosphorylated in Alzheimers disease (AD). While tau hyperphosphorylation promotes neurodegeneration, the cause and consequences of this abnormal modification are poorly understood. As impaired energy metabolism is an important hallmark of AD progression, we tested whether it could trigger phosphorylation of human tau protein in a transgenic C. elegans model of AD. We found that suppression or inhibition of a mitochondrial enzyme of energy metabolism, dihydrolipoamide dehydrogenase (DLD) either by RNAi or 2-methoxyindole-2-carboxylic acid (MICA) respectively, resulted in elevated whole-body glucose levels as well as increased phosphorylation of tau. Although the calcium ionophore A23187 could reduce tau phosphorylation induced by either chemical inhibition or genetic suppression of DLD, it was unable to reduce tau phosphorylation induced by hyperglycemia. While inhibition of the dld-1 gene or treatment with MICA partially reversed the inhibition of acetylcholine neurotransmission by tau, neither treatment affected tau inhibited mobility.