Researchers at Washington University School of Medicine in St. Louis have shown that levels of the tau protein can be reduced – and some of the neurological damage caused by tau even reversed ­Â– by a synthetic molecule that targets the genetic instructions for building tau before the protein is made.

The study, in mice and monkeys, was published Jan. 25 in the journal Science Translational Medicine. The findings suggest that the molecule – known as an antisense oligonucleotide – potentially could treat neurodegenerative diseases characterized by abnormal tau, including Alzheimer’s.

“We’ve shown that this molecule lowers levels of the tau protein, preventing and, in some cases, reversing the neurological damage,” said Timothy Miller, MD, PhD, the David Clayson Professor of Neurology and the study’s senior author. “This compound is the first that has been shown to reverse tau–related damage to the brain that also has the potential to be used as a therapeutic in people.”

Miller, then–graduate student Sarah DeVos and colleagues studied genetically modified mice that produce a mutant form of human tau that easily clumps together. These mice start showing tau tangles at around 6 months of age and exhibit some neuronal damage by 9 months.

To reduce tau, the researchers used an antisense oligonucleotide, a kind of molecule that interferes with the instructions for building proteins. Genes in the DNA are copied into RNA, a messenger molecule that carries the instructions for building a protein. Antisense oligonucleotides bind to the messenger RNA and target it for destruction before the protein can be built. Such oligonucleotides can be designed to target the RNA for almost any protein.

The researchers administered a dose of the anti–tau oligonucleotide to 9–month–old mice every day for a month and then measured the amount of tau RNA, total tau protein and tangles of tau protein in their brains when the mice were 12 months old. The levels of all three were significantly reduced in the treated mice compared with mice that received a placebo.

Importantly, levels of total tau and tau tangles in the brains of treated 12–month–old mice were lower than in untreated 9–month–old mice, suggesting that the treatment not only had stopped but reversed the buildup of tau.

By the time this strain of genetically modified mice reaches 9 months of age, the hippocampus – a part of the brain important for memory – typically is visibly shrunken and shows dying neurons. But with the oligonucleotide treatment, the shrinkage and cell death were halted. There was not, however, any evidence of reversal of neuronal death.

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. All of these functions can be impaired in people with Alzheimer’s disease and other tau–related neurodegenerative diseases.