Scientists have identified the exact point at which healthy brain proteins collide with the tangled mess commonly associated with Alzheimer’s disease.
Researchers at the University of California Santa Barbara (UCSB) are hThe benefit is that the new laboratory technology behind the discovery can be used directly to study the “unprecedented” early stages of many neurodegenerative diseases.
tau proteins abundant in the human brain. At first, these proteins look like little pieces of tendon inside nerve cells. Because they fold and are linked together by structural elements called microscopic tubesHowever, they create a kind of skeleton for brain cells that help them function properly.
Unfortunately, this fold can sometimes go awry. Abnormally tangled tau proteins are a sign of many, but not all, cases of Alzheimer’s disease.
In this complex case, known as A Neurofibrillary tanglesTau proteins are suspected of choking neurons from the inside out, interfering with cell function and ultimately leading to cell death.
Other experts argue that tau tangles are not toxic at all, but are in fact protective in nature, produced in response to some other underlying issue.
Being able to watch tau as it tangles in the lab could help researchers elucidate the protein’s role in brain degeneration. It can also be a great template for testing upcoming treatments.
A multidisciplinary team of scientists at the University of California, San Francisco, has proposed a way to do just that.
With just under a volt of electricity, the researchers have shown that they can spark an out-of-control struggle between a specific type of tau protein.
This current is designed to mimic the molecular signals that naturally cause “hyperfolding” of tau proteins in the brainallowing researchers to monitor in real time as tau proteins pass a critical “tipping point” and switch from a healthy state to a diseased state.
When this line is crossed, tangles quickly form.
“This method provides scientists with a new way to simultaneously stimulate and monitor dynamic changes in a protein as it goes from good to bad.” Explain Biochemist Daniel Morse of the University of California.
“Because we can trigger and fine-tune the process, we can use this system to see which molecules can intercept or prevent certain stages of folding and assembly.”
Tau proteins include a range of multiple soluble variants, but the type used in the current study is called K18, and it is a core peptide containing a microtubule-binding domain.
Interestingly, the researchers found that when K18 was exposed to a voltage over a long period of time (hours or days), it triggered a rapid and irreversible twitch.
However, even after only 15 minutes of short exposure, the tau proteins began to aggregate into knots, albeit one that was easier to untangle with reverse voltage.
This could be a sign that tau tangling could develop over time, just as symptoms of Alzheimer’s disease seem to be.
Transition from a healthy tau protein to a diseased protein, researchers He writesit can be “progressive key rather than the result of one all-or-nothing key”.
This is an interesting insight into K18, but there are many other forms of tau that are sometimes associated with Alzheimer’s disease.
The manner in which these other proteins fold and aggregate and the implications for cell activity can now, in theory, be studied using similar techniques.
The study has been published in Journal of Biological Chemistry.
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