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.

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.

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.

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.

Recent Updates in the Alzheimer's Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials.

BACKGROUND: Alzheimer's disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. OBJECTIVE: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. METHODS: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were "Alzheimer's disease" or "dementia" and "medicine" or "drug" or "treatment" and "clinical trials" and "interventions". Manuscripts that met the objective of this study were included for further evaluations. RESULTS: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon ß-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aß) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. CONCLUSION: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aß, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.