Home Therapeutic relationship Revealing one of the drivers of Alzheimer’s disease

Revealing one of the drivers of Alzheimer’s disease

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The study explored how a protein called tau, essential for Alzheimer’s disease, changes from a normal state to a diseased state

Alzheimer’s disease, the most common form of dementia, currently has no cure or effective treatment, in part due to gaps in our understanding of how the progressive neurodegenerative disorder occurs in the brain.

Now, a study from Flinders University has shown how a protein called tau, a critical factor in the development of Alzheimer’s disease, changes from a normal state to a diseased state – and demonstrates how this discovery could provide a target therapeutic.

Published in the journal Science Advances, the team’s findings offer hope of preventing the process of tau transformation from occurring, thereby keeping tau in a healthy state and avoiding toxic effects on brain cells.

“Alongside a small peptide called beta-amyloid, the tau protein is a central factor in Alzheimer’s disease. Tau is required for toxic effects on brain cells that then lead to impaired memory function,” says study lead author Dr. Arne Ittner, a senior neuroscientist at Flinders Health and Medical Research Institute.

During the development of Alzheimer’s disease, the tau protein accumulates in deposits inside brain cells. During this process, tau is heavily modified, with various deposits consisting of tau bearing multiple small changes at many different positions within the tau molecule.

Although such changes in tau have been known to neuropathologists for decades, it is still unclear how tau gets to this multi-modified stage. The new study solved some of that mystery and provides a new mechanism to explain how tau is gradually altered.

The study aimed to determine whether changing one specific location of tau would facilitate changing another location. The team focused on the relationship between tau and protein kinases, which are enzymes that introduce changes in tau.

Dr. Kristie Stefanoska and Dr. Arne Ittner

“Usually, protein kinases target specific points, called phosphorylation sites, in tau and other proteins, and only introduce changes at those specific points,” says the study’s lead author, Dr. Kristie Stefanoska, dementia researcher at Flinders University.

“However, we suspected that some of these enzymes are able to target multiple locations in tau and would do so even more effectively if tau was already modified in one location 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 patients with Alzheimer’s disease.

Although the study found that one change in tau facilitates the introduction of another change, it was also able to identify “master sites” in tau, being specific points that govern subsequent changes on most other Site (s.

“By altering these master sites, we were able to drive changes at multiple other points within tau, leading to a similar state seen in the brains of Alzheimer’s disease patients,” says Dr. 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, with the aim of improving memory function.

The current study used mice that have both amyloid and tau and developed Alzheimer’s-like symptoms, including memory deficits. The researchers found that the 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 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,” says Dr. Stefanoska.

“Tau modification in Alzheimer’s disease is a complicated process. Ours is the first study to link an initial change in tau to a multisite modification along the entire protein.

The authors say the new mechanism and the lead sites at its center could apply to a range of neurological disorders in which tau is implicated, including Parkinson’s disease, concussion-induced chronic brain injury, and stroke. .

“Slowing down changes at tau master sites in these diseases can curb tau toxicity and dementia,” says Dr. Ittner.

“This new mechanism helps us understand why there is a large tau modification in Alzheimer’s disease in the first place. This will help researchers and clinicians design ways for better and earlier diagnosis.

The article – Alzheimer’s disease: Single master site ablation abolishes tau hyperphosphorylation by Kristie Stefanoska, Mehul Gajwani, Amanda RP Tan, Holly I. Ahel, Prita Riana Asih, Alexander Volkerling, Anne Poljak and Arne Ittner – is published in Science Advances. DOI: 10.1126/sciadv.abl8809.

Funding:

This work was supported by funding from the National Health and Medical Research Council (grant nos. 1143978 and 1176628); the Australian Research Council (grant numbers DP170100843, DP200102396 and DP220101900); the Australian Dementia Research Foundation; the Flinders Foundation, Flinders University and Macquarie University; and the BrightFocus Foundation (to KS; grant number A2022022F). Dr. Stefanoska is Henry Brodaty Postdoctoral Fellow, Scientia Professor, at the Dementia Australia Research Foundation. Dr. Ittner is a member of the National Health and Medical Research Council Emerging Leadership 2 (Grant No. 1176628).

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