In the quest to cure Alzheimer’s, the protein known as beta-amyloid has long taken center stage, driving development of a long list of drugs aimed at breaking up “amyloid plaques” in the brain.
But mounting research shows a lesser-known protein called tau, which forms toxic hairball-like tangles inside neurons, plays an equally vital role in fueling this and other neurodegenerative diseases.
New University of Colorado Boulder research published in the journal PNAS offers fresh insight into how tau tangles form and spread. In a companion paper, published in the journal Neuron , the researchers propose a new strategy for preventing this process and show the approach can halt or reverse neurodegeneration in mice.
The findings could ultimately pave the way toward a ‘neuronal vaccine’ that stops neurodegeneration before it can spread.
“If we really want to treat Alzheimer’s and many of these other diseases, we have to block tau as early as possible,” said senior author Roy Parker, distinguished professor of biochemistry and director of the BioFrontiers Institute. “These studies are an important step forward in understanding why tau aggregates in cells and how we can intervene.”
First discovered 50 years ago, tau helps brain cells keep their shape and shuttles important molecules around within them. When it malfunctions, tau can spread through the brain and kill neurons.
This process underlies more than two dozen neurodegenerative diseases called ‘tauopathies.’ In Alzheimer’s, which affects 7 million people in the U.S., amyloid beta forms plaques that kick-start the spread of tau tangles.
“By the time you treat an Alzheimer’s patient, even if you can completely get rid of amyloid plaque in the brain, it’s often too late because tau has already done its damage and is continuing to spread,” said Parker.
Other ‘tauopathies’ include Chronic Traumatic Encephalopathy (CTE), often found among football players with head trauma; and some forms of frontotemporal dementia, a cruel and fast-moving disease which causes personality changes and memory loss in adults as young as 40.
About one in 1,000 children who get measles will acquire a fatal tauopathy called subacute sclerosing panencephalitis (SSPE) six to 10 years after infection, noted Parker.
“That’s the one that scares me the most, as so many people think measles is not a big deal,” Parker said.
To date, there are no FDA approved drugs to target tau. But Parker’s lab and others are making progress toward that goal.
Previous studies looking at postmortem brain tissue of Alzheimer’s patients have found that tau aggregates include unusual proteins containing disordered chains of an amino acid called serine.
This led Parker’s team to wonder whether these “polyserines” somehow drive tau to, essentially, turn bad.
Through a series of experiments described in the PNAS paper, he and his students found that when polyserine makes its way to a budding seed of tau inside a brain cell, it can prompt tau to misfold, clump and spread toxic aggregates to other neurons like a virus.
They also found that when mice with a predisposition to tauopathies have more polyserine on board, they get sicker faster.
“In experiments in human neurons in the test tube, fruit flies, animals and human tissue, we have now shown that overexpression of polyserine increases tau aggregation,” said Parker. “The question now is: How do you target this process to prevent or treat disease?”
In one clever strategy, described in the Neuron paper, they turned polyserine — which naturally gravitates toward tau aggregates— into a sort of Trojan horse.
They administered polyserine, attached to a different protein expressly engineered to bust up tau tangles, to mice. They found that this led to a striking decrease of tau aggregates in the brain, diminished production of new seeds of toxic tau and decreased anxiety and memory deficits in the animals.
“Essentially, if we use this strategy in a mouse that is prone to tau aggregation, it either doesn’t get disease or it slows it way down,” said Parker.
In future work, his lab hopes to get a better sense of why polyserine forms in the first place and what else goes wrong inside cells to turn typically beneficial tau into a lethal threat to neurons.
He imagines a day when his lab’s research can inform development of a preventative treatment, given to people predisposed to tauopathies far earlier in the disease process.
“The holy grail here would be a safe, cheap therapy that is well-tolerated and can be given to people who need it before they have a lot of symptoms,” he said. “Understanding how the cellular environment influences this process, and how to interfere with it, is a huge part of getting there.”
Proceedings of the National Academy of Sciences
Experimental study
Animals
Polyserine domains are toxic and exacerbate tau pathology in mice
2-Jan-2026
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