Alpha‐lipoic acid ameliorates tauopathy‐induced oxidative stress, apoptosis, and behavioral deficits through the balance of DIAP1/DrICE ratio and redox homeostasis: Age is a determinant factor

Abstract

Tauopathies belong to a heterogeneous class of neuronal diseases resulting in the metabolic disturbance. A disulfide natural compound of Alpha-Lipoic acid (ALA) has shown numerous pharmacologic, antioxidant, and neuroprotective activities under neuropathological conditions. The aim of this study was to investigate the neuroprotective effects of ALA on the tauopathy-induced oxidative disturbance and behavioral deficits. The transgenic Drosophila model of tauopathy induced by human tauR406W using GAL4/UAS system and effects of ALA (0.001, 0.005, and 0.025 % w/w of diet) on the neuropathology of tau in younger (20 days) and older (30 days) adults were investigated via biochemical, molecular, behavioral and in-situ tissue analyses. Expression of apoptosis-related proteins involving Drosophila Cyt-c-d (trigger of intrinsic apoptosis) and DrICE (effector caspase) were upregulated in both ages (20 and 30 days) and DIAP1 (caspase inhibitor) has reduced only in older model flies compared to the controls. Remarkably, all doses of ALA increased DIAP1 and glutathione (GSH) as well as reducing Cyt-c-d and lipid peroxidation (LPO) in the younger flies compared to the model flies. Moreover, the higher doses of ALA were able to decrease thiol concentrations, to increase total antioxidant capacity, and to improve the behavioral deficits (locomotor function, olfactory memory, and ethanol sensitivity) in the younger flies. On the other hand, only a higher dose of ALA was able to decrease DrICE, Cyt-c-d, LPO, and thiol as well as increasing antioxidant capacity and decreasing ethanol sensitivity (ST50, RT50) in the older flies. TUNEL assay showed that all doses of ALA could potentially increase the DIAP1/DrICE ratio and exert anti-apoptotic effects on younger, but not on the older adults. Furthermore, data obtained from the in-situ ROS assay confirmed that only a higher dose of ALA significantly decreased the ROS level at both ages. Our data showed that an effective neuroprotective dose of ALA and its mechanism of action on this model of tauopathy could potentially be influenced by longevity. Moreover, it was shown that ALA prevents apoptosis and decreases the redox homeostasis, and this partially explains the mechanism by which ALA diminishes behavioral deficits.

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Data availability

Data related to this study are either presented in the Results section. Raw data can be obtained from the corresponding author on reasonable request.

Abbreviations

Aβ:

amyloid-beta

AD:

Alzheimer’s disease

ALA:

Alpha-lipoic acid

Cyt-c-d:

Cytochrome c-d

DIAP1:

Drosophila inhibitor of apoptosis protein 1

DrICE:

Drosophila interleukin converting enzyme

Dronc:

Drosophila NEDD-2 like caspase

GAL4:

Galactose-responsive transcription factor 4

hMAPT:

Human microtubule-associated protein tau

NFTs:

Neurofibrillary tangles

Nrf2:

Nuclear factor erythroid 2-related factor 2

Rp49:

Ribosomal protein 49

ROS:

Reactive oxygen species

TRPA1:

Transient receptor potential ankyrin 1

UAS:

Upstream activation sequence

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Acknowledgements

The authors are grateful to all respected research and academic staff in the Department of Biology, University of Zabol, especially Dr. Mohammad Haddadi, for their help with the study.

Funding

This study was partially funded by the University of Zabol (Grant number: UOZ-GR-9618-5).

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EZ-G and NS conceived and designed the experiments, interpreted the data, and drafted the manuscript. EZ-G performed all the experiments as their Ph.D. thesis. KP and GV offered valuable suggestions and helped in the drafting of the manuscript. All authors read and approved the final manuscript. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

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Correspondence to Nima Sanadgol or Gholamhassan Vaezi.

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Zarini-Gakiye, E., Sanadgol, N., Parivar, K. et al. Alpha‐lipoic acid ameliorates tauopathy‐induced oxidative stress, apoptosis, and behavioral deficits through the balance of DIAP1/DrICE ratio and redox homeostasis: Age is a determinant factor. Metab Brain Dis 36, 669–683 (2021). https://doi.org/10.1007/s11011-021-00679-7

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Keywords

  • Aging
  • Apoptosis pathway
  • Metabolic disturbance
  • Oxidative stress
  • Tauopathy