Alzheimer’s disease, at present, does not have a cure or effective therapy due to gaps in our understanding of how progressive neurodegenerative disorders arise 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, turns from normal to a disease state and demonstrates how this discovery could deliver a therapeutic target. Published in the journal Science Advances, the team’s findings provide hope for preventing the Tau transformation process from happening, thereby keeping Tau in a healthy state and avoiding toxic effects on brain cells. “Alongside a small peptide called amyloid-beta, the tau protein is a central factor in Alzheimer’s disease.” “Tau is necessary for the toxic effects on brain cells that then result in impaired memory function,” says senior study author Dr. Arne Ittner, Senior Research Fellow in Neuroscience at the Flinders Health and Medical Research Institute. In the course of Alzheimer’s disease development, tau accumulates in deposits inside brain cells.
During this process, tau gets heavily modified, with various deposits made up of tau carrying multiple small changes at many different positions within the tau molecule.
While such changes to tau have been known to neuropathologists for decades, it remains unclear how tau arrives at this multi-modified stage.
The new study has solved part of this mystery and provides a new mechanism to explain how tau gets progressively modified. The study sought to determine whether modifying one location in tau would make it easier to modify another. The team focused on the relationship between tau and protein kinases, which are enzymes that introduce changes in tau. “Usually, protein kinases target specific spots, called phosphorylation sites, in tau and other proteins, and introduce changes only at these specific spots,” says study lead author Dr. Kristie Stefanoska, Research Fellow in Dementia at Flinders University.
“However, we suspected that some of these enzymes can target several spots in tau and would do so even more efficiently if tau were already modified at one spot, 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 seen in tau in the brains of Alzheimer’s patients. The study did discover that one change in tau does make it easier for another change to be introduced, it was also able to identify “master sites” in tau, being specific spots 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.
The next step for the team was to see whether master sites could be targeted to reduce the toxic properties of tau in Alzheimer’s, in a bid to improve memory function. The current study employed mice that had both amyloid and tau and developed Alzheimer’s-like symptoms.