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According to a recent study, Alzheimer’s disease, the most prevalent form of dementia, still lacks a cure or effective medication. According to the study, this is owing to gaps in our knowledge of how progressive neurodegenerative disorders develop in the brain.

A Flinders University research has now revealed how a protein called tau, which is important in the development of Alzheimer’s disease, changes from normal to disease condition – and how this discovery might lead to a treatment target. The team’s results, published in the journal Science Advances, provide promise for preventing tau transformation and so maintaining tau healthy and avoiding damaging consequences on brain cells.

“The tau protein, together with a tiny peptide termed amyloid-beta, is a key contributor in Alzheimer’s disease. Tau is required for the damaging effects on brain cells that lead to decreased memory performance “Dr Arne Ittner, Senior Research Fellow in Neuroscience at the Flinders Health and Medical Research Institute, is the senior research author.

Tau accumulates in deposits inside brain cells as Alzheimer’s disease progresses. Tau is highly transformed throughout this process, with numerous deposits made up of tau bearing several minor modifications at many different places within the tau molecule.

While neuropathologists have known about such tau alterations for decades, it has remained unclear how tau gets to this multi-modified state. The current study has shed some light on this issue by proposing a novel mechanism for explaining how tau evolves through time.

The study sought to determine whether modifying one location in tau might make it simpler to modify another. The researchers concentrated on the interaction between tau and protein kinases, which are enzymes that cause tau to alter.

“Typically, protein kinases target particular locations in tau and other proteins called phosphorylation sites and make alterations solely at these precise spots,” explains research main author Dr Kristie Stefanoska, Research Fellow in Dementia at Flinders University.

“However, we predicted that some of these enzymes are capable of targeting several sites in tau and would do so much more efficiently if tau was already changed at a single site to begin with.”

The researchers ran a huge experiment that comprised up to 20 distinct tau modifications and 12 enzymes, focusing on the most common type of tau change identified in Alzheimer’s patients’ brains.

While the study discovered that one alteration in tau makes it simpler to introduce another change, it was also able to identify “master sites” in tau, which are particular locations that dictate future changes at the majority of the other sites.

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“By changing these master sites, we were able to trigger alteration at several additional areas within tau, resulting in a similar condition found in Alzheimer’s patients’ brains,” Dr. Ittner explains.

The scientists then investigated if master sites might be targeted to diminish the harmful characteristics of tau in Alzheimer’s disease in order to improve memory function.

The new study used mice that had amyloid and tau deposits and acquired Alzheimer’s-like symptoms, including memory problems. The researchers discovered that mice with a tau variant lacking one of the identified master sites did not exhibit memory problems when compared to mice with the standard tau variant.

The group will now look at how their discoveries may be turned into a therapy.

“We demonstrated that this novel notion has therapeutic promise,” Dr Stefanoska adds. “However, further research is needed to understand the role of these master sites in health and illness.”

“The mechanism of tau alteration in Alzheimer’s disease is complex.” Ours is the first study to show a relationship between an initial mutation in tau and multi-site modification across the protein.”

According to the scientists, the novel method and the master sites at its heart might be used to a variety of tau-related neurological illnesses, including Parkinson’s disease, concussion-induced chronic brain damage, and stroke.

“Slowing down the alterations at tau master sites in these disorders may put a stop to tau toxicity and dementia,” Dr. Ittner explains.

“This novel process explains why there is so much tau alteration in Alzheimer’s disease in the first place. This will aid academics and physicians in developing methods for more accurate and early diagnosis.”

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