A $3m research programme will fund four projects investigating the molecular mechanisms behind tau-driven neurodegenerative diseases and potential diagnostic and therapeutic approaches.

Four projects target tau biology

The Rainwater Charitable Foundation, working with the Aging Mind Foundation, the Alzheimer’s Association and CurePSP, has awarded $3m to four research projects through its 2026 Tauopathy Challenge Workshop.

Each researcher will receive $750,000 over two years to investigate different aspects of tau biology, including how the protein changes structure, aggregates and behaves in different brain cell environments.

Tauopathies are neurodegenerative diseases associated with abnormal accumulation of tau protein. They include progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), while abnormal tau is also a major feature of Alzheimer’s disease.

The four projects are focused on understanding mechanisms that could ultimately inform the development of new biomarkers, diagnostics and treatments.

Investigating cell-specific tau

Carlo Condello at the University of California, San Francisco, will investigate whether different brain cell types influence the formation of distinct disease-associated forms of tau.

His project will focus on 4-repeat tauopathies including PSP and CBD, using human brain samples, stem cell models and animal models. The research will examine how neuronal and glial environments influence tau conformers, or different three-dimensional forms of the protein.

The researchers will combine these models with imaging and other analytical techniques to investigate whether distinct molecular signatures could help explain differences in disease biology and identify potential biomarkers or therapeutic targets.

Animal models are therefore part of this research programme.

Exploring an overlooked tau modification

Daniel C. Lee at the University of Kentucky will investigate citrullination, an irreversible chemical modification of tau that could affect how the protein behaves and forms aggregates.

The project will examine how citrullination interacts with phosphorylation, a modification that has been more widely studied in tauopathies.

Lee’s team will measure how these modifications affect tau structure, aggregation and the formation of oligomers, with the aim of developing tools that can be used to investigate protein misfolding.

The researchers hope the work will provide a better understanding of how chemical changes to tau contribute to disease-associated protein structures.

Examining tau structures in PSP

Edward B. Lee at the University of Pennsylvania will investigate how tau fibres bundle together and interact with surrounding cellular structures in PSP.

The project will examine tau pathology in neurons, astrocytes and oligodendrocytes to determine whether the protein forms distinct structures depending on the cell type in which it accumulates.

The team will use cryo-electron tomography to study tau structures in their cellular environment. Understanding these differences could help explain why PSP affects particular areas of the brain and why symptoms can vary between patients.

Sue-Ann Mok at the University of Alberta will take a different approach, examining the earliest stages of tau aggregation.

Her project will investigate how different versions of tau interact during the formation of disease-associated aggregates, using techniques including single-molecule mass photometry and cryo-electron microscopy.

The aim is to identify molecular features that either drive or disrupt tau aggregation and could eventually support new diagnostic or therapeutic approaches.

“As the burden of neurodegenerative disease continues to grow, it’s paramount we invest in innovative science that can unlock new paths toward diagnosis, treatment, and prevention,” Jeremy Smith, president of the Rainwater Charitable Foundation, said.

The Tauopathy Challenge Workshop was established in 2023 to bring researchers from different disciplines together around specific unanswered questions in primary tauopathies. The 2026 workshop focused on the structural and thermodynamic properties of tau and its interactions with other pathologies.

The foundation said it has invested more than $165m in medical research to date, with its programmes having helped advance eight treatments into human trials.