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

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Author(s): Elahe Zarini-Gakiye, Nima Sanadgol*, Kazem Parivar, Gholamhassan Vaezi*

Journal Name: CNS & Neurological Disorders - Drug Targets
Formerly Current Drug Targets - CNS & Neurological Disorders

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Background: In human tauopathies, pathological aggregation of misfolded/unfolded proteins particularly microtubule-associated protein tau (MAPT, tau) is considered to be essential mechanisms that trigger 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 our tauopathy model. Moreover, expression of ERUPR-related proteins involving activating transcription factor 6 (ATF6), inositol regulating enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK) were 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 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 was able to affect the ERUPR via moderation of PERK-ATF4 signaling in the oldest adults. As ALA also exerts their higher protective effects on the locomotor function of younger adults when htauR406W 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.

Keywords: Aging, Alzheimer's disease, IRE1, XBP1, PERK, ATF4

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(E-pub Abstract Ahead of Print)
DOI: 10.2174/1871527320666210126114442
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