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.

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.

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 Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Somayra S. A. Mamsa ◽  
Bruno P. Meloni
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Amyloid Beta ◽  
Beneficial Effects ◽  
Therapeutic Development ◽  
Therapeutic Compounds ◽  
Tau Aggregation ◽  
Excitotoxic Cell Death

A substantial body of evidence indicates cationic, arginine-rich peptides (CARPs) are effective therapeutic compounds for a range of neurodegenerative pathologies, with beneficial effects including the reduction of excitotoxic cell death and mitochondrial dysfunction. CARPs, therefore, represent an emergent class of promising neurotherapeutics with multimodal mechanisms of action. Arginine itself is a known chaotrope, able to prevent misfolding and aggregation of proteins. The putative role of proteopathies in chronic neurodegenerative diseases such as Alzheimer’s disease (AD) warrants investigation into whether CARPs could also prevent the aggregation and cytotoxicity of amyloidogenic proteins, particularly amyloid-beta and tau. While monomeric arginine is well-established as an inhibitor of protein aggregation in solution, no studies have comprehensively discussed the anti-aggregatory properties of arginine and CARPs on proteins associated with neurodegenerative disease. Here, we review the structural, physicochemical, and self-associative properties of arginine and the guanidinium moiety, to explore the mechanisms underlying the modulation of protein aggregation by monomeric and multimeric arginine molecules. Arginine-rich peptide-based inhibitors of amyloid-beta and tau aggregation are discussed, as well as further modulatory roles which could reduce proteopathic cytotoxicity, in the context of therapeutic development for AD.

scholarly journals Braiding Braak and Braak: Staging patterns and model selection in network neurodegeneration

2021 ◽  
Author(s):  
Prama Putra ◽  
Travis Thompson ◽  
Alain Goriely
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Tau Proteins ◽  
Histopathological Analysis ◽  
Braak Staging ◽  
New Methods ◽  
Tau Aggregation ◽  
The Brain ◽  
And Diffusion

AbstractA hallmark of Alzheimer’s disease is the aggregation of insoluble amyloid-beta plaques and tau protein neurofibrillary tangles. A key histopathological observation is that tau protein aggregates follow a clear progression pattern through the brain; characterized by six distinct stages. This so-called ‘Braak staging pattern’ has become the gold standard for Alzheimer’s disease progression. It has also been suggested, via a histopathological analysis, that soluble seed-competent tau seeding precedes tau aggregation in the same manner. Mathematical models such as prion-like propagation on networks have the ability to capture key feature of the dynamics. Here, we study the staging of tau proteins using a model of proteopathy that include both local growth due to autocatalytic effects and diffusion along axonal pathways. We develop new methods to capture the staging patterns and use these as a qualitative criterion to identify the best model for diffusion process on networks and to identify possible parameter regimes. Our analysis provides a systematic way to study Braak staging in neurodegenerative processes.

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.

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.

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