Towards a Better Understanding of Pathological Modifications of Tau in the Aging Brain

Tau protein is involved in the pathology of Alzheimer's disease. It is one of the few proteins in the body capable of becoming altered in ways that form harmful aggregates that disrupt cell function and lead to cell death. Given a much better understanding of the biochemistry by which tau protein becomes modified in ways that make it toxic, it might be possible to interfere in that modification process with small molecule drugs. This approach has worked for transthyretin amyloidosis, leading to drugs that significantly reduce the harmful aggregation of transthyretin by interfering in one specific step in the modification of transthyretin molecules. The research here is an example of much the same sort of work, a project that might lead to analogous treatments targeting tau aggregation in the aging brain.

A new 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. The 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. 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 remained 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 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. Researchers 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. 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.

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 treatment.

Link: https://www.eurekalert.org/news-releases/957875