For years, scientists studying Alzheimer’s disease and related dementias have focused on one version of a protein called tau, a hallmark of Alzheimer’s disease and more than two dozen other neurodegenerative disorders collectively called tauopathies. But University of Kentucky researcher Daniel Lee, Ph.D., believes another form of tau may hold important clues that have gone largely unnoticed.
Now, Lee’s work has earned international recognition.
Lee, a professor at the University of Kentucky’s Sanders-Brown Center on Aging, has been awarded a $750,000 Tauopathy Challenge Workshop grant supported by the Rainwater Charitable Foundation, the Alzheimer’s Association, the Aging Mind Foundation and CurePSP. The highly competitive award will allow Lee and collaborators to investigate a newly recognized modification of the tau protein that could help researchers better understand tau-related disease and other forms of dementia and open the door to new diagnostic tools and future therapies.
The funding follows an extensive selection process that began with 75 letters of intent. Only about a dozen teams were invited to develop full proposals and present their ideas during a two-day workshop in front of an international panel of scientific experts. Ultimately, just four projects received funding.
For Lee, the award represents more than research funding.
“This was one of the most meaningful grants I’ve received,” Lee said. “The Rainwater Foundation is one of the leading organizations focused on primary tauopathies including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD), and what really stood out about this program was that they encouraged bold ideas. Instead of asking researchers to propose the conventional science, they wanted projects that could fundamentally change how we think about tau biology.”
Tau is a protein that normally helps stabilize nerve cells. In Alzheimer’s disease and many other tauopathies, however, the protein changes shape, clumps together and spreads through the brain, contributing to the loss of brain cells. Although researchers have spent decades studying one chemical change to tau — known as phosphorylation — Lee’s laboratory has spent nearly 10 years investigating another modification called citrullination that may influence the protein in an entirely different way.
Unlike phosphorylation, which encourages tau to fold and form harmful tangles, Lee believes citrullination may cause the protein to unfold differently, potentially creating a previously overlooked pathway in disease.
“If we’ve only been looking at one side of tau biology for the last 50 years, there’s a possibility we’ve been missing another important piece of the puzzle,” Lee said. “The question now is whether this biology is meaningful and whether it could change how we diagnose or treat tau-related diseases.”
The discovery itself was unexpected.
Nearly a decade ago, an undergraduate researcher working in Lee’s lab observed evidence of the modification during an experiment. Because the finding challenged conventional thinking, it was initially met with skepticism.
“Many reviewers believed that if this modification were real, someone would have found it already,” Lee said. “We just kept collecting evidence, year after year, until it became clear that it was there.”
Rather than beginning with brain tissue, as researchers traditionally do, Lee’s team simplified the problem by first studying the tau protein itself before looking for evidence in the brain. That unconventional approach helped reveal what had previously been hidden among the complexity of brain tissue.
The new grant will allow Lee’s team to answer some of the biggest remaining questions surrounding the discovery, including how citrullinated tau interacts with phosphorylated tau and whether the two forms contribute differently to disease progression.
The project will also create new antibodies, laboratory tools and research methods that will be shared with scientists around the world, allowing other laboratories to investigate the newly identified pathway in Alzheimer’s disease and more than 25 other tau-related disorders.
“If we can provide the tools for other researchers to study this, then the entire field can move faster,” Lee said. “That’s one of the biggest goals of this award.”
Ultimately, Lee hopes the work contributes to a future where treatments can be tailored more precisely to individual patients.
“There isn’t just one tau disease,” he said. “Different diseases involve different forms of tau and affect different parts of the brain. If we can better distinguish those differences, we can begin moving toward more discriminate biomarkers and, eventually, more precision therapies.”
The research builds on the collaborative environment at UK’s Sanders-Brown Center on Aging, where Lee works alongside experts in dementia research, neuropathology, chemistry and molecular biology. The project includes collaborations with Maj-Linda Selenica, Ph.D., whose research examines similar protein modifications in another dementia-related protein, and Prakash Shrestha, Ph.D., whose advanced single-molecule imaging techniques will allow researchers to examine tau in unprecedented detail.
Lee also credits Sanders-Brown’s access to human brain tissue, patient resources and interdisciplinary expertise with helping move the research beyond laboratory models.
“Being at Sanders-Brown has taken our research to another level,” Lee said. “It allows us to confirm that what we’re seeing in the lab is also relevant in human disease. That’s what makes this work so exciting.”
Over the next two years, Lee hopes the project will provide new insight into an area of biology that has received little attention but may ultimately help researchers better understand the many diseases that fall under the umbrella of dementia.
“If, five or 10 years from now, researchers are using these tools to better distinguish different tau diseases and develop more targeted treatments,” he said, “that would be a tremendous outcome.”