ArticleThe Journal of biological chemistry2013
Structural determinants of Tau aggregation inhibitor potency.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Dual modulation of amyloid beta and tau aggregation and dissociation in Alzheimer's disease: a comprehensive review of the characteristics and therapeutic strategies.Translational neurodegeneration · 2025Review
- A novel peptide-based tau aggregation inhibitor as a potential therapeutic for Alzheimer's disease and other tauopathies.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Disrupting pathologic phase transitions in neurodegeneration.The Journal of clinical investigation · 2023Review
- Reversal of Tau-Dependent Cognitive Decay by Blocking Adenosine A1 Receptors: Comparison of Transgenic Mouse Models with Different Levels of Tauopathy.International journal of molecular sciences · 2023Article
- DJ-1 Molecular Chaperone Activity Depresses Tau Aggregation Propensity through Interaction with Monomers.Biochemistry · 2023Article
- The structure and phase of tau: from monomer to amyloid filament.Cellular and molecular life sciences : CMLS · 2021Review
- Pharmacological Modulators of Tau Aggregation and Spreading.Brain sciences · 2020Review
- Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives.Scientific reports · 2019Article
- The role of annealing and fragmentation in human tau aggregation dynamics.The Journal of biological chemistry · 2019Article
- Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells.The Journal of biological chemistry · 2018Article
- Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules.Cold Spring Harbor perspectives in medicine · 2017Review
- Expression and purification of tau protein and its frontotemporal dementia variants using a cleavable histidine tag.Protein expression and purification · 2017Article
- Analyzing Tau Aggregation with Electron Microscopy.Methods in molecular biology (Clifton, N.J.) · 2016Article
- Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease.BioMed research international · 2016Review
- Inhibitory effect of corcin on aggregation of 1N/4R human tau protein in vitro.Iranian journal of basic medical sciences · 2015Article
- Use of genetically modified mesenchymal stem cells to treat neurodegenerative diseases.International journal of molecular sciences · 2014Review
- Structure and mechanism of action of tau aggregation inhibitors.Current Alzheimer research · 2014Review
- Pathogenic Tau Protein Species: Promising Therapeutic Targets for Ocular Neurodegenerative Diseases.Journal of ophthalmic & vision researchReview
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
Small-molecule Tau aggregation inhibitors are under investigation as potential therapeutic agents against Alzheimer disease. Many such inhibitors have been identified in vitro, but their potency-driving features, and their molecular targets in the Tau aggregation pathway, have resisted identification. Previously we proposed ligand polarizability, a measure of electron delocalization, as a candidate descriptor of inhibitor potency. Here we tested this hypothesis by correlating the ground state polarizabilities of cyanine, phenothiazine, and arylmethine derivatives calculated using ab initio quantum methods with inhibitory potency values determined in the presence of octadecyl sulfate inducer under reducing conditions. A series of rhodanine analogs was analyzed as well using potency values disclosed in the literature. Results showed that polarizability and inhibitory potency directly correlated within all four series. To identify putative binding targets, representative members of the four chemotypes were added to aggregation reactions, where they were found to stabilize soluble, but SDS-resistant Tau species at the expense of filamentous aggregates. Using SDS resistance as a secondary assay, and a library of Tau deletion and missense mutants as targets, interaction with cyanine was localized to the microtubule binding repeat region. Moreover, the SDS-resistant phenotype was completely dependent on the presence of octadecyl sulfate inducer, but not intact PHF6/PH6* hexapeptide motifs, indicating that cyanine interacted with a species in the aggregation pathway prior to nucleus formation. Together the data suggest that flat, highly polarizable ligands inhibit Tau aggregation by interacting with folded species in the aggregation pathway and driving their assembly into soluble but highly stable Tau oligomers.
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