In some people, the brain protein tau collects into toxic tangles that damage brain cells and contribute to diseases such as Alzheimer's. Researchers at Washington University School of Medicine in St. Louis have found a drug that can lower tau levels and prevent some neurological damage. In neurons that contain the drug (above, in red) there are no tau tangles (in green). (Credit: Sarah DeVos)

Tau proteins that build up to form toxic tangles in the brain have become a hallmark of Alzheimer’s disease.

A new study in mice and monkeys has found that a drug compound, known as an antisense oligonucleotide, can lower levels of tau proteins and potentially treat neurodegenerative diseases such as Alzheimer’s.

“We’ve shown that this molecule lowers levels of the tau protein, preventing and, in some cases, reversing the neurological damage,” said senior study author Timothy Miller, M.D., Ph.D., professor of neurology at Washington University in St. Louis, in a statement. “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 a therapeutic in people.”

The Food and Drug Administration already approved oligonucleotide treatments for Duchenne’s muscular dystrophy and spinal muscular atrophy (SMA).  Miller is also co-leading a human trial of oligonucleotides for amyotrophic lateral sclerosis (ALS).

The antisense oligonucleotide works by binding to messenger RNA and destroying it before the protein can be made, according to the researchers.

For the study, published Jan. 25 Science Translational Medicine, 9-month-old genetically modified mice were given a daily dose of anti-tau oligonucleotide for 30 days.  When the mice reached 12 months old the researchers found that the amount of tau RNA, total tau protein and tangles of tau protein in the brains were all significantly reduced compared to a placebo-controlled group.

The treatment also stopped cell death and shrinkage of the hippocampus, which is usually visible in the 9-month-old mice. Neuron death was not reversed, the researchers noted.

A number of functions that often decline in people with Alzheimer’s disease, such as social behavior, motor capabilities and cognitive performance, were improved in the treated mice compared to the untreated group. This was observed by better nest building.

Mice on the oligonucleotide treatment also outlived the placebo-group by an average of 36 days.

Following the promising results in mice, the researchers moved on to monkeys.

Healthy crab-eating macaques received a once-weekly dose of oligonucleotide or a placebo for two weeks, into the cerebrospinal fluid as a human patient would receive it.

After two weeks, the researchers found that the treatment reduced the amount of tau protein and RNA in the brain.  This reduction was also reflected in the cerebrospinal fluid.

“The monkey study showed us that lower tau in the cerebrospinal fluid correlates with lower tau in the brain,” Miller said in a statement.  “This is important if we’re going to evaluate this treatment approach in people, because there’s no non-invasive way of measuring tau levels in the brain. This correlation tells us that we can use levels of tau in the cerebrospinal fluid as a proxy for levels of tau in the brain.”

While the approach is promising, further studies need to be done to test its safety in humans and whether it actually lowers tau, Miller noted.

“But everything we’ve seen so far says that this is worth investigating as a potential treatment for people,” he added. 

Carlsbad, Calif. –based biopharmaceutical company Ionis Pharmaceuticals Inc., discovered the oligonucleotide for SMA and holds joint patent applications with Washington University for the use of oligonucleotides for reducing tau levels. 

Contributing Editor/Science Writer