A new Australian study has identified what may be a critical factor in the development of Alzheimer’s disease.
Alzheimer’s disease is the most common form of dementia and currently has no cure and few effective treatments. The challenge of developing therapeutic interventions for the progressive neurodegenerative disorder has been compounded by significant gaps in understanding of why and how it develops.
A new study from Flinders University in Adelaide has highlighted how the protein 'tau' turns from normal to diseased and becomes a critical factor in the development of Alzheimer’s disease. The researchers said the study could contribute to the development of therapeutic targets.
The study team say they hope the findings "provide hope" for preventing the tau transformation process.
“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,” said senior study author Dr Arne Ittner, senior research fellow in neuroscience in 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.
Changes to tau have been known for some time. However, the new study has revealed some understanding of how it evolves into this multi-modified stage.
The researchers focussed 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,” said study lead author Dr Kristie Stefanoska, research fellow in Dementia at Flinders University.
“However, we suspected that some of these enzymes are able to 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, focussing on the most abundant type of change seen in tau from the brains of Alzheimer’s patients.
The study discovered that one change in tau does make it easier for another change to be introduced. Yet 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,” said Dr Ittner.
The researchers said the next step is 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, and how the study findings can be translated into a 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,” said Dr Stefanoska.
“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.”
The researchers said the study findings could apply to other neurological disorders, 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,” added Dr Ittner.
“This new mechanism helps us understand why there is extensive tau modification in Alzheimer’s disease in the first place. This will assist researchers and clinicians in designing means for better and earlier diagnosis.”