Scientists have identified the exact moment that healthy brain proteins are shocked into the tangled mess that becomes what’s commonly associated with Alzheimer’s disease.
The researchers are hopeful that the new approach responsible for the discovery could be used to directly study the ‘never-before-seen’ early stages of many neurodegenerative diseases.
Tau proteins are prolific in the human brain. The proteins look like tiny pieces of string inside neurons at first glance. But, as they fold and tether together with structural components called microtubules, they construct a skeleton of sorts for brain cells to help them function properly.
Unfortunately, this folding of tau can sometimes backfire. Although not all, oddly tangled tau proteins are a sign of numerous cases of Alzheimer’s.
In this twisted-up state, known as a neurofibrillary tangle, tau proteins are suspected of suffocating neurons from the inside out, interfering with cell function, and leading to cell death. Still, some other experts argue that tau tangles aren’t toxic but actually protective, produced in response to other underlying issues.
Watching tau as it tangles in the lab could facilitate researchers in clarifying the protein’s role in brain degeneration. It could also prove a valuable model for testing up-and-coming treatments.
An interdisciplinary team of scientists at UCSB has now proposed a way to do just that.
With little less than a volt of electricity, researchers have demonstrated they can trigger out-of-control tangling among a specific type of tau protein.
This current, designed to mimic the molecular signals that naturally cause the ‘hyper-folding’ of tau proteins in the brain, allows researchers to watch in real-time as tau proteins pass a critical ‘tipping point’ and shift from healthy to diseased states.
Biochemist Daniel Morse from UCSB explains,
“This method provides scientists a new means to trigger and simultaneously observe the dynamic changes in the protein as it transitions from good to bad. Because we can turn on and fine-tune the process at will, we can use this system to see what molecules could interdict or block specific stages of folding and assembly.”
Tau proteins include a group of several variants, but the one used in this study is called K18, a core peptide containing the microtubule-binding domain.
Shockingly enough, the researchers found that when K18 was exposed to a volt of electricity over a long period (hours or days), it led to rapid and irreversible tangling.
But even with just 15 minutes of quick exposure, tau proteins began to gather into knots, albeit ones that were more manageable and easier to untangle with a reverse voltage — a sign that tau tangling can progress over time, just as the symptoms of Alzheimer’s seem to do.
Researchers say that the transition from a healthy to diseased tau protein could be “a gradual one rather than the result of a single all-or-none switch.” In addition, the authors reported that the technology could also be used as a tool to more rapidly test and identify drugs and antibodies potentially useful for prevention or treatment of Alzheimer’s and other amyloid diseases. “Because we can turn on and fine-tune the process at will,” Morse explained, “we can use this system to see what molecules could interdict or block specific stages of folding and assembly.”
That is extraordinary!
The study was published in the Journal of Biological Chemistry.