Today, when an aging parent, relative, or friend starts to forget things, a firm diagnosis can be surprisingly elusive.
Even for Alzheimer's disease, which is the most common dementia, clinicians lean on behavioral observations to diagnose patients. Brain scans and blood tests are much less conclusive. The most definitive diagnosis for any dementia only occurs after death.
To address this gap, chemists at UC San Francisco screened hundreds of industrial dyes to see which ones would stick to the different types of protein clumps that appear in the brain during dementia. The screen offers clues for how to design new diagnostic dyes that will enable scientists to distinguish between dementias.
"Progress with diagnosing and treating all the different dementias has been halting and slow," said Jason Gestwicki , PhD, professor of pharmaceutical chemistry at UCSF and senior author of the paper. "We're optimistic that our streamlined approach to screening dyes can change the landscape of research and, ultimately, the care we provide for these devastating conditions."
The study, which was done with funding from the National Institutes of Health (NIH), was published in Nature Chemistry on Aug. 14.
The team focused first on the tau protein, which clumps into unique shapes in Alzheimer's disease, progressive supranuclear palsy, and frontotemporal dementia. They made tau clumps of different shapes and then tested 300 dyes to see which dyes stuck to which forms of tau.
Over repeated trials, they whittled the list of 300 down to 27 that either stuck to all of the tau clumps, or just to some of them. Additional testing left just 10 sure hits.
One of the dyes illuminated tau clumps in an animal model of Alzheimer's disease, as well as samples taken from deceased Alzheimer's patients.
The scientists also screened the dyes on clumps of two other proteins that form clumps in other diseases and found a few good hits.
These repurposed dyes show how chemists might design new ones that identify the different forms of protein clumps that are hallmarks of each dementia. Gestwicki's group is also excited to see how their dye screening process could be used to address a wider range of diagnostic challenges in neurology, cancer, and other conditions.
"Industrial chemistry has produced thousands of molecules that might fail in their first intended application," Gestwicki said. "But some of them could be repurposed as winners when it comes to biomedicine."
Authors: Other UCSF authors are Emma C. Carroll, PhD, Hyunjun Yang, PhD, Julia G. Jones, Abby Oehler, Annemarie F. Charvat, Kelly M. Montgomery, PhD, Anthony Yung, William F. DeGrado, PhD, Daniel A. Mordes, MD, PhD, Carlo Condello, PhD. For all authors see the paper.
Funding: This work was funded in part by the National Institutes of Health (F32AG076281, R01GM141299, P01AG002132, RF1NS133651, GM122603, K99AG084926) and the Tau Consortium.
