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.
Highlights
Mitochondria plays an important role in cell bioenergetics and survival while mitochondrial dysfunction proposed as a key mediator of neurodegenerative diseases such as Alzheimer’s disease (AD) [1,2,3]
As we are interested to find association between impaired energy metabolism and AD, here in this study we investigated the effects of suppression of core metabolism enzyme dihydrolipoamide dehydrogenase (DLD) on tau-mediated toxicity in C. elegans
Previous studies revealed that Ser-46, Ser-198, Ser-199, Ser-202, Thr-205, thr-212, Thr-231/Ser-235, Ser-262/Ser-356, Ser-396, Ser-404, and Ser-422 are among critical sites in AD and hyperphosphorylation on these residues hinders its binding with microtubules and promote neurofibrillary tangles (NFTs) formation[9, 12, 35,36,37]
Summary
Mitochondria plays an important role in cell bioenergetics and survival while mitochondrial dysfunction proposed as a key mediator of neurodegenerative diseases such as Alzheimer’s disease (AD) [1,2,3]. Decline in cerebral glucose utilization, glucosedependent energy production and associated enzyme's activities such as pyruvate dehydrogenase (PDH) and α-ketoglutare dehydrogenase (KGDH) are observed in AD patients, which highlights the importance of glucose energy metabolism in disease progression [4,5,6,7,8]. Maintains and stabilizes microtubule assembly under normal physiological conditions. Under such conditions, an average of 2-3 phosphate groups is present on each tau molecule, whereas in the AD brain the level of tau phosphorylation is 3-4 times higher [11, 12]. Hyperphosphorylation leads to self-aggregation of tau filaments and activation of caspase-3 in vitro. Hyperphosphorylation is associated with tissue deterioration and cell death [13, 14]
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