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

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Abstract

The microtubule associated tau protein becomes hyperphosphorylated in Alzheimer’s disease (AD). While 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 Caenorhabditis elegans model of AD. We found that inhibition of a mitochondrial enzyme of energy metabolism, dihydrolipoamide dehydrogenase (DLD) results in elevated whole-body glucose levels as well as increased phosphorylation of tau. Hyperglycemia and tau phosphorylation were induced by either RNAi suppression of the dld-1 gene or by inhibition of the DLD enzyme by the inhibitor, 2-methoxyindole-2-carboxylic acid (MICA). Although the calcium ionophore A23187 could reduce tau phosphorylation induced by either chemical 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. Conclusively, any abnormalities in energy metabolism were found to significantly affect the AD disease pathology.

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Acknowledgements

I thank Dr. Paul Ebert, Jürgen Goetz (Queensland Brain Institute), and Dr. Khadija Shabbiri for providing valuable suggestions and guidance related to experimental design and tau immunoblotting. The C. elegans strains were purchased from the CGC, University of Minnesota, USA. WA was supported by an IPRS PhD scholarship from the Australian government as well as UQCent scholarship from the University of Queensland.

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  1. School of Biological Sciences, The University of Queensland, Brisbane, 4072, Australia

    Ahmad Waqar

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Ahmad, W. Dihydrolipoamide dehydrogenase suppression induces human tau phosphorylation by increasing whole body glucose levels in a C. elegans model of Alzheimer’s Disease. Exp Brain Res 236, 2857–2866 (2018). https://doi.org/10.1007/s00221-018-5341-0

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