A new study suggests how a protein called tau drives the development of Alzheimer’s disease, possibly leading to more targeted treatments and earlier diagnoses. Photo by Carola68/Pixabay
July 6 (UPI) — A new study suggests how a protein called tau drives the development of Alzheimer’s disease, and researchers anticipate this could lead to more targeted treatments and earlier diagnoses.
The investigators at Flinders University in Adelaide, South Australia, reported they have discovered the mechanism by which tau protein turns from normal to a disease state — a process that spurs the development of the progressive neurodegenerative disorder.
So, they said, their findings offer hope for preventing the tau transformation process from occurring, thereby keeping the protein in a healthy state and avoiding toxic effects on brain cells that result in impaired memory function.
The study was published Wednesday in Science Advances.
The study’s senior author, Dr. Arne Ittner, senior research fellow in neuroscience in the Flinders Health and Medical Research Institute, explained in a news release that the tau protein, along with a small peptide called amyloid-beta, is key to Alzheimer’s disease.
As Alzheimer’s develops, tau accumulates in deposits inside brain cells and, during this process, becomes heavily modified. This results in “various deposits made up of tau carrying multiple small changes at many different positions within the tau molecule.”
Neuropathologists have known about such changes to tau for decades, but it has remained unclear how tau arrives at this “multi-modified stage.” Researchers said their new study has partially solved this mystery and provides a new mechanism to explain how tau gets progressively modified.
Basically, the scientists sought to determine whether one change at one specific spot in tau would make it easier for another spot to be modified. They focused on the relationship between tau and protein kinases — enzymes that introduce changes in tau.
Typically, protein kinases target specific spots called phosphorylation sites in tau and other proteins, and introduce changes only at these specific spots, the researchers explained.
But they suspected that some of these enzymes could target several spots in tau and could do this even more efficiently if tau were already modified at one spot.
So they took a broad approach in their experiment that included up to 20 different changes in tau and 12 enzymes, focusing on the most abundant type of change seen in tau from the brains of Alzheimer’s patients.
The upshot? The investigators found that while one change in the tau protein does make it easier for another change to be introduced, they also could identify specific “master sites” in tau that govern subsequent modifications at most of the other sites.
“By modifying these master sites, we were able to drive modification at multiple other spots within tau, leading to a similar state seen in the brains of Alzheimer’s patients,” Ittner said in a news release.
The next step was to see whether the tau protein’s master sites could be targeted to reduce the toxic properties of tau in Alzheimer’s, in a bid to improve memory function.
The researchers found that mice did not develop memory deficits when they had a version of tau lacking one of the identified master sites, compared with mice that had the usual version of tau.
“Tau modification in Alzheimer’s disease is a complicated process. Ours is the first study to link an initial change in tau with multi-site modification along the entire protein,” said the study’s lead author, Dr. Kristie Stefanoska, research fellow in dementia at Flinders University.
Now, Stefanoska and her colleagues intend to explore how these findings can be translated into treatment, perhaps beyond Alzheimer’s.
The authors said the new mechanism with tau’s master sites at its center may apply to a range of neurological disorders in which tau is involved, including Parkinson’s disease, concussion-induced chronic brain injury and stroke.
“Slowing down the changes at master sites of tau in these diseases may put the brakes on tau toxicity and dementia,” Ittner said.
“This new mechanism helps us understand why there is extensive tau modification in Alzheimer’s disease in the first place,” he said. “This will assist researchers and clinicians in designing means for better and earlier diagnosis.”