# Characterizing and Targeting Filament Polymorphism in Tauopathies

> **NIH NIH F30** · OHIO STATE UNIVERSITY · 2022 · $41,183

## Abstract

PROJECT SUMMARY
Tauopathies are a set of clinically-significant neurodegenerative disorders characterized by accumulation of
fibrillar aggregates composed of tau protein within the brain. Alzheimer's disease is the most prevalent tauopathy
as it accounts for the majority cases of dementia worldwide. With the prevalence of dementia expected to at
least double in the next few decades, there is a desperate need to discover novel fundamental information about
the aberrant tau aggregation at the root of these diseases. The recent advent of cryoelectron microscopy allowed
for an unprecedented level of structural insight into the tauopathies, revealing extensive structural polymorphism
among the filaments at the root of these tauopathies. This discovery has many vital implications. First, it directly
suggests that distinct pathologic cellular conditions shape the tau aggregates in disease. Second, all distinct
polymorphs discovered thus far retain at least one of the two key hexapeptide nucleation motifs previously shown
to be vital for aggregation, implying some degree of commonality in the aggregation process that could be
exploited therapeutically. Third, the presence of unique structures in each disease directly suggests the
possibility of developing structure-specific chemical probes. My preliminary data demonstrates the power of
structural biology in elucidating key insights into all three of these areas, and the project proposed in this
fellowship application aims to expand on these results to deliver fundamental insights into tau aggregation,
polymorphism, and ligand binding. Aim 1 will characterize the structural impact of multiple pathological cellular
condition mimics on the structure of tau filaments. This structural analysis specifically aims to uncover novel
information about the potential etiology at the root of tauopathies. Aim 2 will derive detailed mechanisms for how
two in vitro inducers initiate and shape the aggregation process. This approach will uncover novel insight into
how tau aggregation is triggered and identify potential therapeutic targets for disruption of aggregation. Aim 3
will characterize the driving forces behind ligand binding to specific sites on tau filaments. Such fundamental
mechanistic information will unveil specifics for high-affinity ligand design and aid in the targeted development
of disease-specific imaging agents. Overall, this proposal is innovative because it will deliver novel insight into
multiple key aspects of tauopathies utilizing a structure-driven approach. This research is significant as it will
specifically uncover information on the etiology and pathogenesis of aberrant tau aggregation and polymorphism,
thus providing novel avenues for much-needed therapeutic intervention. Additionally, this research is significant
because the mechanistic information derived herein will aid in the future development of disease-specific positron
emission tomography tracers, in turn assisting with many clinical ...

## Key facts

- **NIH application ID:** 10538019
- **Project number:** 1F30AG079573-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Dmitry Malyshka
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $41,183
- **Award type:** 1
- **Project period:** 2022-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10538019

## Citation

> US National Institutes of Health, RePORTER application 10538019, Characterizing and Targeting Filament Polymorphism in Tauopathies (1F30AG079573-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10538019. Licensed CC0.

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