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One of the driving forces behind Alzheimer’s disease revealed

Summary: The study reveals how the tau protein associated with Alzheimer’s disease changes from normal to diseased.

source: Flinders University

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

Now, a study by Flinders University has shown how a protein called tau, a critical factor in the development of Alzheimer’s disease, switches from normal to pathological — and shows how this discovery could advance a therapeutic goal.

Published in the magazine science progressThe team’s findings offer hope of preventing the tau transformation process from occurring, thus keeping tau in a healthy state and avoiding toxic effects on brain cells.

“Besides a small peptide called amyloid beta, the tau protein is a major factor in Alzheimer’s disease. Tau is essential for toxic effects on brain cells that then lead to impairment in memory function,” says senior study author Dr. Arne Ettner, senior research fellow at Neuroscience at the Flinders Institute for Health and Medical Research.

During the development of Alzheimer’s disease, tau builds up in deposits within brain cells. During this process, tau is highly modified, with different precipitates consisting of tau bearing multiple small changes at many different positions within the tau molecule.

While such changes in tau have been known to neurologists for decades, it remains unclear how tau reaches this multi-modified stage. The new study solves part of this puzzle and provides a new mechanism to explain how the tau is gradually modified.

The study set out to answer whether one change in one place in the tau would facilitate modification in another. The team focused on the relationship between tau and protein kinases, which are enzymes that bring about changes in tau.

“Protein kinases typically target specific regions, called phosphorylation sites, in tau and other proteins, and changes occur only in these specific spots,” says lead study author Dr. Kristi Stefanoska, and a Research Fellow in Dementia at Flinders University.

“However, we suspected that some of these enzymes are able to target multiple regions of the tau and would do so more efficiently if the tau was actually modified in one location to begin with.”

The researchers conducted a large experiment involving up to 20 different tau changes and 12 enzymes, focusing on the most abundant type of tau change seen in the brains of Alzheimer’s patients.

While the study discovered that one change in the tau facilitates the introduction of another, it was also able to identify ‘key sites’ in the tau, being specific regions that govern subsequent modifications at most other sites.

“By modifying these key sites, we were able to make modifications at multiple other points within the tau, resulting in a similar condition seen in the brains of Alzheimer’s patients,” says Dr. Ettner.

The team’s next step was to see if key sites could be targeted to reduce the toxic properties of tau in Alzheimer’s disease, in an effort to improve memory function.

During the development of Alzheimer’s disease, tau builds up in deposits within brain cells. The image is in the public domain

The current study used mice that had both amyloid and tau and showed symptoms similar to Alzheimer’s disease, 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 specific key sites, compared to mice with the usual version of tau.

The team will now investigate how its findings translate into a treatment.

“We’ve shown that this new concept has therapeutic potential, but future work is needed to understand the role of these key sites in health and disease,” says Dr. Stefanoska.

“Modulation of tau in Alzheimer’s disease is a complex process. Our study is the first to link an initial change in tau to multi-site modification along the entire protein.”

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

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This shows an old woman sitting on a park bench

“Slowing changes to key sites of tau in these diseases may halt tau toxicity and dementia,” Dr. Ettner says.

“This new mechanism helps us understand why there is a large-scale modification of Alzheimer’s disease tau in the first place. This will help researchers and clinicians in designing better and early diagnostics.”

About this research on Alzheimer’s disease news

author: press office
source: Flinders University
Contact: Press Office – Flinders University
picture: The image is in the public domain

original search: open access.
“Alzheimer’s disease: resection of a single major site abolishes tau hyperphosphorylation” by Kristi Stefanoska et al. science progress


Summary

Alzheimer’s disease: Resection of a single major site eliminates tau hyperphosphorylation

Hyperphosphorylation of the neuronal tau protein is a hallmark of neurodegenerative tauopathy such as Alzheimer’s disease. The central unanswered question is why tau gradually becomes hyperphosphorylated.

Here, we show that tau phosphorylation is governed by ligand-a mechanistic link between initial site-specific and subsequent multi-site phosphorylation. Systematic evaluation of inter-site cross-dependence identified distinct residues (threonine-50, threonine-69, and threonine-181) as key sites that determine the prevalence of phosphorylation at multiple epitopes.

CRISPR point mutation and expression of human tau in Alzheimer mice demonstrated that in situ ligation governs amyloid-related physiological phosphorylation and cognitive deficits, respectively.

Co-targeting of key sites and p38α, the tau kinase center most closely associated with cross-dependence, and synergistic hyperphosphorylation. In summary, our work demonstrates how complex tau phosphorylation arises to inform therapeutic design and biomarkers of taupathopathies.

#driving #forces #Alzheimers #disease #revealed

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