When it comes to the drama of Alzheimer's disease, the compound in the starring role as the villain is tau. It's a protein that normally helps our neurons function properly, but one that can clump together into plaques that damage brain cells. Now researchers have figured out a way to lower tau levels by throwing a molecular bomb in the works that lead to its creation. Doing so has not only stopped its damaging effects in tests on monkeys and mice, but also reversed some of the damage it wreaks.

The molecule investigated by researchers at Washington University School of Medicine in St. Louis is called antisense oligonucleotide. They found that it was able to bind to the messenger RNA involved in creating tau proteins and destroy it. mRNA are molecules that copy blueprints from DNA for the creation of proteins. By halting those involved in tau coding, the levels of the runaway protein were dramatically reduced.

In the study, the researchers used mice that were genetically modified to make a mutant form of tau that easily forms clumps. In their brains, the mice started to show tau tangles at six months old, with damage to their neurons forming three months later.

Neurons containing antisense oligonucleotide in red don't contain tau tangles, seen in green(Credit: Sarah Devos)

They then gave the nine-month old mice a dose antisense oligonucleotide every day for a month. Upon measuring the levels of tau tangles along with tau RNA and total tau protein in their brains when they reached a full year of age, they found that all three levels had been reduced. In the case of the total tau and tau tangles, the number were beaten back to those seen prior to those in the nine-month-old mice, showing that the compound not only stopped, but reversed the tau buildup.

"The treated mice lived an average of 36 days longer than untreated mice, and they were better at building nests, which reflects a combination of social behavior, cognitive performance and motor capabilities," says a Washington University School of Medicine report on the breakthrough. "All of these functions can be impaired in people with Alzheimer's disease and other tau-related neurodegenerative diseases."

Because antisense oligonucleotides can be designed to destroy the RNA for nearly any protein, the molecule is being studied in human clinical trials for other applications, such as its ability to fight Huntington's disease and amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

Before testing the compound on humans for it tau-reducing effects though, the researchers had to take the step of testing it on animals more similar to humans. So that's what they did, and saw the same tau-reducing effects in monkeys as they had in mice. What's more, the monkey study showed them that tau levels in the brain could be successfully measured in the primates by sampling the cerbrospinal fluid, an approach that would need to be used on human patients.

Of course, animal studies don't always translate to human treatments, but the researchers remain hopeful.

"Tau tangles correlate with cognitive decline in several diseases," said Timothy Miller, the study's senior author. "This is a promising new approach to lowering tau, but we have to test whether it is safe in people, and whether it actually lowers tau, as it is designed to do, before we get to the question of whether it has any effect on the disease. But everything we've seen so far says that this is worth investigating as a potential treatment for people."

An announcement last year from the Baylor College of Medicine showed promise in fighting tau by stopping the enzymes leading to its production, so the damaging protein is definitely being fought on different fronts.

Results of the recent study have been published in the journal Science Translational Medicine.

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