Title:Age and Dose-Dependent Effects of Alpha-Lipoic Acid on Human Microtubule- Associated Protein Tau-Induced Endoplasmic Reticulum Unfolded Protein Response: Implications for Alzheimer’s Disease
Volume: 20
Issue: 5
Author(s): Elahe Zarini-Gakiye, Gholamhassan Vaezi*, Kazem Parivar and Nima Sanadgol*
Affiliation:
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran,Iran
- Department of Biology, Faculty of Sciences, University of Zabol, Zabol,Iran
Keywords:
Aging, Alzheimer's Disease, IRE1, XBP1, PERK, ATF4.
Abstract:
Background: In human tauopathies, pathological aggregation of misfolded/unfolded proteins,
particularly microtubule-associated protein tau (MAPT, tau) is considered to be an essential
mechanism that triggers the induction of endoplasmic reticulum (ER) stress.
Objective: Here, we assessed the molecular effects of natural antioxidant alpha-lipoic acid (ALA)
in human tauR406W (hTau)-induced ER unfolded protein response (ERUPR) in fruit flies.
Methods: In order to reduce hTau neurotoxicity during brain development, we used a transgenic
model of tauopathy where the maximum toxicity was observed in adult flies. Then, the effects of
ALA (0.001, 0.005, and 0.025% w/w of diet) in htau-induced ERUPR and behavioral dysfunctions
in the ages 20 and 30 days were evaluated in Drosophila melanogaster.
Results: Data from expression (mRNA and protein) patterns of htau, analysis of eyes external morphology
as well as larvae olfactory memory were confirmed by our tauopathy model. Moreover,
the expression of ERUPR-related proteins involving Activating Transcription Factor 6 (ATF6), inositol
regulating enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK) wase upregulated
and locomotor function decreased in both ages of the model flies. Remarkably, the lower dose
of ALA modified ERUPR and supported the reduction of behavioral deficits in youngest adults
through the enhancement of GRP87/Bip, reduction of ATF6, downregulation of PERK-ATF4 pathway,
and activation of the IRE1-XBP1 pathway. On the other hand, only a higher dose of ALA affected
the ERUPR via moderation of PERK-ATF4 signaling in the oldest adults. As ALA also exerts
higher protective effects on the locomotor function of younger adults when htauR406Wis expressed
in all neurons (htau-elav) and mushroom body neurons (htau-ok), we proposed that ALA
has age-dependent effects in this model.
Conclusion: Taken together, based on our results, we conclude that aging potentially influences
the ALA effective dose and mechanism of action on tau-induced ERUPR. Further molecular
studies will warrant possible therapeutic applications of ALA in age-related tauopathies.
