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 the discovery could deliver a potential therapeutic target. Researchers hope to prevent the process from happening, thereby keeping tau in a healthy state and avoiding the toxic effects on brain cells that then result in impaired memory function.
From: Flinders University [in Australia]
July 8, 2022 -- Alzheimer's
disease, the most common form of dementia, currently has no cure or effective
therapy, in part due to gaps in our understanding of how the progressive
neurodegenerative disorder arises in the brain.
Now, a Flinders
University 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.
Published in the
journal Science Advances, the team's 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.
"Alongside a small
peptide called amyloid-beta, the tau protein is a central factor in Alzheimer's
disease. Tau is necessary for the toxic effects on brain cells that then result
in impaired memory function," says senior study author Dr Arne Ittner,
Senior Research Fellow in Neuroscience in the Flinders Health and Medical
Research Institute.
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," 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 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 with multi-site modification along the entire
protein."
The authors say the new
mechanism and the master sites at its centre could apply to a range of
neurological disorders in which tau is involved, including Parkinson's disease,
concussion-induced chronic brain injury and stroke.
"Slowing down the
changes at master sites of tau in these diseases may put the brakes on tau
toxicity and dementia," says Dr Ittner.
"This new
mechanism helps us understand why there is extensive tau modification in
Alzheimer's disease in the first place. This will assist researchers and
clinicians in designing means for better and earlier diagnosis."
The paper -- Alzheimer's
disease: Ablating single master site abolishes tau hyperphosphorylation by
Kristie Stefanoska, Mehul Gajwani, Amanda R. P. Tan, Holly I. Ahel, Prita Riana
Asih, Alexander Volkerling, Anne Poljak and Arne Ittner -- is published
in Science Advances.
https://www.sciencedaily.com/releases/2022/07/220706153031.htm
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