by Scientists have identified the precise point where healthy brain proteins are shocked into the tangled mess commonly associated with Alzheimer’s disease.
Researchers at the University of California Santa Barbara (UCSB) are hobviously, the new laboratory technique behind the discovery can be used to directly study the “never-before-seen” early stages of many neurodegenerative diseases.
Tau proteins are abundant in the human brain. At first, these proteins look like small pieces of string inside the neurons. However, when folded and bound together with structural elements called microtubules, they create a kind of skeleton for brain cells that help them function properly.
Unfortunately, this folding of ropes can sometimes go wrong. Abnormally tangled tau proteins are a hallmark of many, but not all, cases of Alzheimer’s.
In this tangled state, known as a neurofibrillary tangle, tau proteins are suspected of suffocating neurons from the inside out, disrupting cell function and ultimately leading to cell death.
Other experts argue that rope tangles are not toxic at all, but actually protective in nature, produced in response to another underlying problem.
Being able to see rope as it tangles in the lab could help researchers clarify the protein’s role in brain degeneration. It can also be a great model for testing upcoming treatments.
An interdisciplinary team of researchers at UCSB has now proposed a way to do just that.
With a little less than a volt of electricity, scientists have shown that they can trigger uncontrolled entanglement between a specific type of tau protein.
This current was designed to mimic the molecular signals that naturally cause the “hyperfolding” of tau proteins in the brainallowing researchers to see in real time when tau proteins pass a critical “tipping point” and shift from healthy to diseased states.
When this line is crossed, tangles quickly form.
“This method gives researchers a new way to trigger and simultaneously observe the dynamic changes in the protein as it goes from good to bad,” explains UCSB biochemist Daniel Morse.
“Because we can turn on and fine-tune the process at will, we can use this system to see which molecules can impede or block specific stages of folding and assembly.”
Tau proteins include a group of several soluble variants, but the one used in the current study is called K18, a core peptide that contains the microtubule-binding domain.
Interestingly, the researchers found that when K18 was exposed to one volt of electricity over a long period of time (for hours or days), it led to rapid and irreversible entanglement.
But even with just 15 minutes of brief exposure, tau proteins began to assemble into knots, albeit ones that were easier to untie with a reverse voltage.
This could be a sign that rope entanglement can develop over time, just as the symptoms of Alzheimer’s seem to do.
The transition from a healthy to diseased tau protein, the researchers write, may be “a gradual one rather than the result of a single all-or-none switch.”
That’s an interesting insight into K18, but there are many other forms of tau that are sometimes associated with Alzheimer’s disease.
The way these other proteins are folded and assembled and the consequences that have on cell activity can now be theoretically studied using similar techniques.
The study was published in Journal of Biological Chemistry.
