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Structure and Genesis of tau Aggregates

tau 聚集体的结构和成因

基本信息

批准号：
9311789
负责人：
Jeff Kuret
金额：
$ 236.34万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9311789
关键词：
Adopted Affinity Alzheimer&apos s Disease Amyloid beta-Protein Binding Biological Biological Models Brain Brain imaging Cell Nucleus Centrifugation Clinical Trials Complex Conflict (Psychology)Data Dementia Depressed mood Descriptor Development Diagnosis Diagnostic Dimerization Disease Disease Vectors Equilibrium Event Filament Fostering Generations Goals Human Image Kinetics Lead Length Lesion Ligand Binding Ligands Literature Maps Mass Spectrum Analysis Mediator of activation protein Methods Microtubules Modeling Molecular Molecular Conformation Molecular Probes Morphology Nature Nerve Degeneration Nervous system structure Neurofibrillary Tangles Neurons Pathogenesis Pathology Pathway interactions Patients Peptides Pharmacology Population Positron-Emission Tomography Process Research Role Site Source Staging Structure Study Section Surface Surrogate Markers Tauopathies Testing Therapeutic Agents Thermodynamics Toxic effect Transgenic Organisms Work aggregation pathway beta pleated sheet biophysical techniques chemical synthesis cheminformatics density dimer disease diagnosis drug discovery extracellular inhibitor/antagonist insight mathematical model molecular dynamics monomer novel novel diagnostics novel therapeutics overexpression polymerization prion-like radiotracer single molecule small molecule tau Proteins tau aggregation tomography

项目摘要

Project Summary/Abstract The study of tau misfunction in tauopathic neurodegenerative disorders such as Alzheimer's disease is at a crossroads. Recent discoveries point to tau aggregation as being essential for prion-like spread of misfolding from neuron to neuron, implying a key role for aggregation in neurodegeneration, yet are contradicted by evidence from transgenic tau overexpression models that aggregation lies downstream of toxicity and may actually be neuroprotective. Indeed, it is well established that tau is hyperphosphorylated in disease, and that this event alone can lead to loss of microtubule function irrespective of aggregation, yet a clinical trial involving a potent inhibitor of tau hyperphosphorylation failed to modify the course of a human tauopathy. Classic studies showed that filamentous aggregates dominate the population of tau that accumulates in authentic neurofibrillary lesions, but other evidence implicates soluble oligomers potentially unrelated to cross-β-sheet structure as mediators of tau misfunction. With respect to aggregation kinetics, recent work has identified a role for secondary processes such as breakage and secondary nucleation that produce abundant small species, yet authentic lesions are dominated by aggregates that adopt filamentous morphology and achieve substantial lengths. Small-molecules that bind to tau aggregates or modulate their formation have been disclosed in the literature, but the mechanisms through which they act are ambiguous or involve substantial off-target liability. As a result of these conflicting ideas, the full potential of tau lesion pharmacology remains ambiguous. This project seeks to harmonize the many disparate observations made on tau aggregation and pharmacology using a biophysical approach. First, it will characterize and quantify tau aggregation kinetics while including a novel secondary pathway involving aggregate annealing. The analysis will be extended to the level of energetics, and to the relationship between aggregate structure and biological toxicity. Second, it will identify descriptors of ligand binding to tau aggregates, providing insight into the molecular features that influence binding affinity and therefore utility for premortem diagnosis. Finally, it will characterize the mechanism of action of non-covalent tau aggregation inhibitors associated with clearance of tau aggregates, including the nature of their binding targets, and the structure of their protective complexes. Successfully completed, the project will impact the field by clarifying targets for tauopathy drug discovery and by deducing molecular concepts important for optimizing premortem diagnostic agents.

项目总结/文摘