scholarly journals Cross-species metabolomic analysis of DDT and Alzheimer's disease-associated tau toxicity

2021 ◽  
Author(s):  
Vrinda Kalia ◽  
Megan M Niedzwiecki ◽  
Joshua M Bradner ◽  
Fion K Lau ◽  
Meghan L Bucher ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Population Study ◽  
Mitochondrial Function ◽  
Tau Protein ◽  
Human Population ◽  
Environmental Toxicants ◽  
C Elegans ◽  
Increased Risk

Background. The formation of hyperphosphorylated tau (p-tau) protein tangles in neurons is a pathological marker of Alzheimer's disease (AD). Exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) has been associated with an increased risk of AD. Objectives. To determine if there was a connection between DDT exposure and tau toxicity we investigated whether exposure to DDT can exacerbate tau protein toxicity in C. elegans. In addition, we examined the association between p-tau protein and metabolism in a human population study and in a transgenic C. elegans strain neuronally expressing a mutant tau protein fragment that is prone to aggregation. Methods. In the human population study, we used a metabolome-wide association framework to determine the association between p-tau measured in the cerebrospinal fluid (CSF) and metabolomic features measured in both plasma (n = 142) and CSF (n = 78) using high-resolution metabolomics (HRM). Using the same HRM method, we determined changes in metabolomic features in the transgenic C. elegans strain compared to its control strain. Metabolites associated with p-tau in both species were analyzed for overlap. We also examined the effect of DDT and aggregating tau protein on growth, swim behavior, mitochondrial function, metabolism, learning, and lifespan in C. elegans. Results. Plasma and CSF-derived features associated with p-tau level were related to drug, amino acid, fatty acid, and mitochondrial metabolism pathways. Five metabolites overlapped between plasma and C. elegans, and 4 between CSF and C. elegans. DDT exacerbated the inhibitory effect of aggregating tau protein on growth and basal respiration. In the presence of aggregating tau protein, DDT induced more curling and was associated with reduced levels of amino acids but increased levels of uric acid and adenosylselenohomocysteine. Developmental exposure to DDT blunted the lifespan reduction caused by aggregating tau protein. Conclusion. The model organism C. elegans can complement human studies by providing a means to study mechanisms of environmental toxicants. Specifically, our C. elegans data show that DDT exposure and tau protein aggregation both inhibit mitochondrial function and DDT exposure can exacerbate the mitochondrial inhibitory effects of tau protein aggregation providing a plausible explanation for the observed human associations.

scholarly journals In SilicoInsight into Potent of Anthocyanin Regulation of FKBP52 to Prevent Alzheimer’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-20 ◽  
Author(s):  
Tzu-Chieh Hung ◽  
Tung-Ti Chang ◽  
Ming-Jen Fan ◽  
Cheng-Chun Lee ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acids ◽  
Protein Aggregation ◽  
Tau Protein ◽  
Hydrophobic Interactions ◽  
Dynamics Simulation ◽  
Binding Potential ◽  
Ligand Interaction ◽  
Structure Variation

Alzheimer’s disease (AD) is caused by the hyperphosphorylation of Tau protein aggregation. FKBP52 (FK506 binding protein 52) has been found to inhibit Tau protein aggregation. This study found six different kinds of anthocyanins that have high binding potential. After analyzing the docking positions, hydrophobic interactions, and hydrogen bond interactions, several amino acids were identified that play important roles in protein and ligand interaction. The proteins’ variation is described using eigenvectors and the distance between the amino acids during a molecular dynamics simulation (MD). This study investigates the three loops based around Glu85, Tyr113, and Lys121—all of which are important in inducing FKBP52 activation. By performing a molecular dynamic simulation process between unbound proteins and the protein complex with FK506, it was found that ligand targets that docked onto the FK1 domain will decrease the distance between Glu85/Tyr113 and Glu85/Lys121. The FKBP52 structure variation may induce FKBP52 activation and inhibit Tau protein aggregation. The results indicate that anthocyanins might change the conformation of FKBP52 during binding. In addition, the purple anthocyanins, such as cyanidin-3-glucoside and malvidin-3-glucoside, might be better than FK506 in regulating FKBP52 and treating Alzheimer’s disease.

scholarly journals Tau aggregates possibly compromise neuronal health in the C. elegans model of Alzheimer’s disease

2020 ◽  
Vol 1 (6) ◽  
pp. 46-48
Author(s):  
Sanjib Guha ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Tau Protein ◽  
Intercellular Space ◽  
Senile Plaques ◽  
Aβ Peptide ◽  
Progressive Decline ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease

Alzheimer’s disease (AD) is the most common degenerative brain disease in the aged population [1]. By 2050, AD prevalence is expected to increase from 4.7 million (based on 2010 census) to 13.8 million people [2]. It is characterized by the progressive decline of cognition and memory, as well as changes in behavior and personality [1]. Pathological hallmarks of AD include mainly formation of senile plaques consisting of amyloid-beta (Aβ) peptide in the intercellular space and neurofibrillary tangles (NFTs) in the cell bodies, which are primarily composed of abnormally modified tau protein [3].

scholarly journals Dihydrolipoamide dehydrogenase suppression induce human tau phosphorylation by increasing whole body glucose levels in a C. elegans model of Alzheimer’s Disease

2017 ◽  
Author(s):  
Waqar Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Energy Metabolism ◽  
Tau Protein ◽  
Tau Phosphorylation ◽  
Whole Body ◽  
Ionophore A23187 ◽  
Dihydrolipoamide Dehydrogenase ◽  
C Elegans ◽  
Glucose Levels

AbstractThe microtubule associated tau protein becomes hyperphosphorylated in Alzheimer’s disease (AD). While hyperphosphorylation promotes neurodegeneration, the cause and consequences of this abnormal modification are poorly understood. As impaired energy metabolism is an important hallmark of AD progression, we tested whether it could trigger phosphorylation of human tau protein in a transgenic C. elegans model of AD. We found that inhibition of a mitochondrial enzyme of energy metabolism, dihydrolipoamide dehydrogenase (DLD) resulted in elevated whole-body glucose levels as well as increased phosphorylation of tau. Hyperglycemia and tau phosphorylation were induced by either epigenetic suppression of the dld-1 gene or by inhibition of the DLD enzyme by the inhibitor, 2-methoxyindole-2-carboxylic acid (MICA). Although the calcium ionophore A23187 could reduce tau phosphorylation induced by either chemical or genetic suppression of DLD, it was unable to reduce tau phosphorylation induced by hyperglycemia. While inhibition of the dld-1 gene or treatment with MICA partially reversed the inhibition of acetylcholine neurotransmission by tau, neither treatment affected tau inhibited mobility. Conclusively, any abnormalities in energy metabolism were found to significantly affect the AD disease pathology.

Tau Protein Aggregation in Alzheimer's Disease: Recent Advances in the Development of Novel Therapeutic Agents

2020 ◽  
Vol 26 (15) ◽  
pp. 1682-1692
Author(s):  
Kadja L.C. Monteiro ◽  
Marcone G. dos S. Alcântara ◽  
Thiago M. de Aquino ◽  
Edeildo F. da Silva-Júnior
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Tau Protein ◽  
Therapeutic Agents ◽  
Model Systems ◽  
Aggregation Inhibitors ◽  
Disease Modifying Agents ◽  
Tau Aggregation

: Major research in Alzheimer’s disease (AD) related to disease-modifying agents is concentrated on pharmacological approaches related to diagnostic markers, neurofibrillary tangles and amyloid plaques. Although most studies focus on anti-amyloid strategies, investigations on tau protein have produced significant advances in the modulation of the pathophysiology of several neurodegenerative diseases. Since the discovery of phenothiazines as tau protein aggregation inhibitors (TAGIs), many additional small molecule inhibitors have been discovered and characterized in biological model systems, which exert their interaction effects by covalent and noncovalent means. In this paper, we summarize the latest advances in the discovery and development of tau aggregation inhibitors using a specialized approach in their chemical classes. The design of new TAGIs and their encouraging use in in vivo and clinical trials support their potential therapeutic use in AD.

Shedding light on tau protein aggregation: the progress in developing highly selective fluorophores

2018 ◽  
Vol 47 (7) ◽  
pp. 2249-2265 ◽  
Author(s):  
Peter Verwilst ◽  
Hyeong Seok Kim ◽  
Soobin Kim ◽  
Chulhun Kang ◽  
Jong Seung Kim
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Tau Protein ◽  
Protein Aggregates

The development of highly selective fluorophores for tau protein aggregates, a key feature of Alzheimer's disease, is highlighted.

scholarly journals Microfluidic Protein Imaging Platform: Study of Tau Protein Aggregation and Alzheimer’s Drug Response

2020 ◽  
Vol 7 (4) ◽  
pp. 162
Author(s):  
Shubha Jain ◽  
Sarpras Swain ◽  
Lopamudra Das ◽  
Sarita Swain ◽  
Lopamudra Giri ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Tau Protein ◽  
Drug Response ◽  
Drug Evaluation ◽  
Confocal Imaging ◽  
Tau Imaging ◽  
On Chip ◽  
Tau Aggregation

Tau protein aggregation is identified as one of the key phenomena associated with the onset and progression of Alzheimer’s disease. In the present study, we performed on-chip confocal imaging of tau protein aggregation and tau–drug interactions using a spiral-shaped passive micromixing platform. Numerical simulations and experiments were performed in order to validate the performance of the micromixer design. We performed molecular modeling of adenosine triphosphate (ATP)-induced tau aggregation in order to successfully validate the concept of helical tau filament formation. Tau aggregation and native tau restoration were realized using an immunofluorescence antibody assay. The dose–response behavior of an Alzheimer’s drug, methylthioninium chloride (MTC), was monitored on-chip for defining the optimum concentration of the drug. The proposed device was tested for reliability and repeatability of on-chip tau imaging. The amount of the tau protein sample used in our experiments was significantly less than the usage for conventional techniques, and the whole protein–drug assay was realized in less than two hours. We identified that intensity-based tau imaging could be used to study Alzheimer’s drug response. In addition, it was demonstrated that cell-free, microfluidic tau protein assays could be used as potential on-chip drug evaluation tools for Alzheimer’s disease.

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