Scientists Uncover One of the Driving Forces of Alzheimer’s Disease – New Target
Scientists have now shown how a critical factor in the development of Alzheimer’s disease, a protein called tau, turns from normal to a disease state – and demonstrates how this discovery could provide a new target for treatment.
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Tau accumulates in deposits inside brain cells as Alzheimer’s disease progresses. Tau is highly transformed throughout this process, with various deposits made up of tau bearing multiple minor modifications at many different positions within the tau molecule.
While neuropathologists have known about these changes to tau for decades, it remained unclear how tau arrives at this multi-modified stage. The new research has solved part of this mystery and provides a new mechanism to explain how tau gets progressively modified.
Dr. Kristie Stefanoska and Dr. Arne Ittner. Credit: Flinders University
The study set out to answer whether one change at one specific spot in tau would make it easier for another spot to be modified. The team 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,” says 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.
While the study did discover that one change in tau does makes 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,” says Dr. Ittner.
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 have both amyloid and tau and developed Alzheimer’s-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 with mice that had the usual version of tau.
The team will now investigate how its findings can be translated into a…
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