# Drivers of Pathological Tau Aggregation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA BARBARA · 2022 · $711,751

## Abstract

PROJECT SUMMARY
The bottleneck for tauopathy therapy development is the lack of validated tauopathy models, mouse, cell or in vitro.
This is reflected in the current reality that tauopathy-specific fibril structures solved by cryo-EM from post mortem
patient brain tissue have never been replicated outside a patient, i.e. not in a mouse, cell or in vitro. While the patient-
derived tauopathy fibrils offer critical goal posts, they are not in and of themselves viable therapeutic targets. For
example, the development of Positron Emission Tomography (PET) ligands to diagnose and track Alzheimer’s disease
(AD) or corticobasal degeneration (CBD) disease progression relies on screening small molecule binding to CBD- or
AD-phenotypic fibrils—the very construct that nobody knows how to build yet. There are many more factors to consider
for replicating the pathological pathway of tau aggregation, but replicating disease phenotypic tau fibrils is a minimal
and necessary requirement, and so far an unattained tool for therapy development. The major knowledge gap that
this proposal aims to close is the mechanism and tools to replicate tauopathy specific fibrils in vitro (Aim 1),
and the key cellular and molecular factors that initiate misfolding of tau in cell to disease phenotypic shapes
and facilitate aggregation (Aim 2). If we can successfully replicate any one tauopathy-phenotypic tau fold, or even
a part of a folded tau structure, such as a mini-hairpin fold of CBD or AD with seeding competency, it will have an
immediate impact on ongoing therapy developments, such as on the development of tauopathy-specific PET ligands,
antibodies and small molecule drugs. This team will employ an innovative set of structural biology tools encompassing
pulsed double electron-electron resonance (DEER), TEM and cryo-EM, as well as computational tools to focus on
capturing the full folding and aggregation pathway of the tau protein ensemble from its intrinsically disordered to
partially folded and fully converged fibril states. This team will concurrently use innovative cell biological tools with a
strong premise of the knowledge of a dedicated tau receptor and transporter that can enhance tau seeding by
endosomal escape and the knowledge that enhanced hydrophobicity of the local environment of tau is a potent factor
to initiate misfolding, aggregation and propagation. While discovering the defining property of a competent seed and
achieving shape propagation with seeds developed in this proposal will be a breakthrough, independent of this
success, we will have developed experimental and computational tools to evaluate whether seeded shape
propagation has occurred, or whether all, part, or none of the shape propagates. To have the tools to evaluate the
mechanism of shape propagation will be a game changer. The lack of progress in closing the above-described
knowledge gap is not due to a lack of investment by top notch laboratories around the world, but due to shortcomings
o...

## Key facts

- **NIH application ID:** 10446174
- **Project number:** 2R01AG056058-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA BARBARA
- **Principal Investigator:** Songi Han
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $711,751
- **Award type:** 2
- **Project period:** 2017-04-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446174

## Citation

> US National Institutes of Health, RePORTER application 10446174, Drivers of Pathological Tau Aggregation (2R01AG056058-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10446174. Licensed CC0.

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