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-?-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.

Public Health Relevance

Misfolding and accumulation of tau protein in the brain is a defining pathology of Alzheimer's disease and a potential cause of neurodegeneration. By dissecting the fundamental mechanisms through which tau aggregates and associates with small molecules, this project will contribute information needed to identify and optimize agents for AD diagnosis and therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
1RF1AG054018-01A1
Application #
9311789
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (56)R)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2017-06-01
Project End
2022-05-31
Budget Start
2017-06-01
Budget End
2022-05-31
Support Year
1
Fiscal Year
2017
Total Cost
$1,987,284
Indirect Cost
$583,984
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Yue, Tao; Jia, Xinghua; Petrosino, Jennifer et al. (2017) Computational integration of nanoscale physical biomarkers and cognitive assessments for Alzheimer's disease diagnosis and prognosis. Sci Adv 3:e1700669