Designer Compound May Untangle Damage Leading to Some Dementias

In a study of mice and monkeys, NIH-funded researchers showed that they could prevent and reverse some of the brain injury caused by the toxic form of a protein called tau. The results, published in Science Translational Medicine, suggest that the study of compounds, called tau antisense oligonucleotides, that are genetically engineered to block a cell’s assembly line production of tau, might be pursued as an effective treatment for a variety of disorders.

Cells throughout the body normally manufacture tau proteins. In several disorders, toxic forms of tau clump together inside dying brain cells and form neurofibrillary tangles, including Alzheimer’s disease, tau-associated frontotemporal dementia, chronic traumatic encephalopathy and progressive supranuclear palsy. Currently there are no effective treatments for combating toxic tau.

“This compound may literally help untangle the brain damage caused by tau,” said the study’s senior author, Dr. Timothy Miller of Washington University, St. Louis. 

Grants from NINDS and NIA supported the research.

Antisense oligonucleotides are short sequences of DNA or RNA programmed to turn genes on or off. Led by Sarah L. DeVos, a graduate student in Miller’s lab, the researchers tested sequences designed to turn tau genes off in mice that are genetically engineered to produce abnormally high levels of a mutant form of the human protein. Tau clusters begin to appear in the brains of 6-month-old mice and accumulate with age. The mice develop neurologic problems and die earlier than control mice.

Injections of the compound into the fluid filled spaces of the mice brains prevented tau clustering in 6- to 9-month-old mice and appeared to reverse clustering in older mice. The compound also caused older mice to live longer and have healthier brains than mice that received a placebo. In addition, the compound prevented the older mice from losing their ability to build nests.

“These results open a promising new door,” said NINDS program director Dr. Margaret Sutherland. “They suggest that antisense oligonucleotides may be effective tools for tackling tau-associated disorders.”