# Structure and Genesis of tau Aggregates

> **NIH NIH RF1** · OHIO STATE UNIVERSITY · 2020 · $263,276

## Abstract

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.

## Key facts

- **NIH application ID:** 10158623
- **Project number:** 3RF1AG054018-01A1S1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jeff Kuret
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $263,276
- **Award type:** 3
- **Project period:** 2017-06-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158623

## Citation

> US National Institutes of Health, RePORTER application 10158623, Structure and Genesis of tau Aggregates (3RF1AG054018-01A1S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10158623. Licensed CC0.

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