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.