Alzheimer’s, the way more common of dementia, currently has no cure or effective therapy, in part due to gaps in our understanding of how the progressive neurodegenerative disorder arises in the brain.
Now, a Flinders University study has shown how a protein called tau, a critical factor in the development of Alzheimer’s disease, transitions from a normal state to a diseased state, and demonstrates how this discovery could offer a therapeutic target. .
The findings, published in the journal Science Advances, offer hope of preventing the tau transformation process from occurring, thus keeping tau in a healthy state and avoiding toxic effects on brain cells.
“Along with a small peptide called amyloid-beta, the tau protein is a central factor in Alzheimer’s disease. Tau is required for toxic effects on brain cells that then result in impaired memory function,” says study lead author Arne Ittner, a senior fellow in neuroscience at the Flinders Health and Medical Research Institute.
In the course of the development of Alzheimer’s disease, tau accumulates in deposits within brain cells. During this process, Tau becomes highly modified, with various deposits made up of tau carrying multiple small changes at many different positions within the tau molecule.
Although neuropathologists have known about these changes in tau for decades, it has been unclear how tau gets to this multimodified stage. The new study has solved some of this mystery and provides a new mechanism to explain how tau progressively changes.
The study set out to answer whether a change at a specific tau point would make it easier to change another point. The team focused on the relationship between tau and protein kinases, which are enzymes that introduce changes to tau.
“As usual, protein kinases They are directed to specific points, called sites of phosphorylationin tau and other proteins, and introduce changes only at these specific points,” says study lead author Kristie Stefanoska, a researcher at Flinders University.
“However, we suspect that some of these enzymes can attack multiple sites on tau and would do so even more efficiently if tau were already modified at one site to begin with.”
The researchers conducted a large experiment that included up to 20 different changes in tau and 12 enzymes, focusing on the most abundant type of change observed in tau from the brains of Alzheimer’s patients.
While the study found that a change in tau makes it easier to introduce another change, it was also able to identify “master sites” in tau, which are specific points that govern subsequent modifications at most other sites.
“We have shown that this new concept has therapeutic potential, but future work is needed to understand the role of these master sites in health and disease.”
“By modifying these master sites, we were able to drive modification at many other points within tau, leading to a similar state seen in the brains of Alzheimer’s patients,” says Ittner.
The next step for the team was to see if the master sites could be targeted to reduce the toxic properties of tau in Alzheimer’s disease, in an attempt to improve memory function.
The current study used mice that have both amyloid and tau and developed Alzheimer-like symptoms, including memory deficits. The researchers found that mice did not develop memory deficits when they had a version of tau that lacked one of the identified master sites, compared to mice that had the usual version of tau.
The team will now investigate how their findings can be translated into treatment.
“We have shown that this new concept has therapeutic potential, but future work is needed to understand the role of these master sites in health and disease,” says Stefanoska.
“The modification of tau in Alzheimer’s disease is a complicated process. Ours is the first study to link an initial change in tau with a change at multiple sites throughout the entire protein.”
The authors say the new mechanism and the master sites at its core could be applied to a variety of neurological disorders in which tau is involved, including Alzheimer’s disease. Parkinsonconcussion-induced chronic brain injury and stroke.
“Slowing changes at tau master sites in these diseases may slow down tau toxicity and dementia,” Ittner says.
“This new mechanism helps us understand why there is extensive tau modification in Alzheimer’s disease in the first place. This will help researchers and clinicians design means for better and earlier diagnosis.”