Targeting Toxic Tau Clusters in Brain May Improve Symptoms in Alzheimer’s, Study Shows

Treatments targeting clusters of a toxic form of the tau protein may become valuable therapeutic approaches for patients with Alzheimer’s disease and other neurological diseases, a new study suggests.

The study, “Tau Reduction Prevents Neuronal Loss And Reverses Pathological Tau Deposition And Seeding In Mice With Tauopathy,” was published in the journal Science Translational Medicine.

Alzheimer’s disease is caused by the accumulation of faulty proteins, such as beta-amyloid or tau, which greatly interferes with proper neuronal activity. Indeed, tau clusters are directly associated with cognitive decline in patients with Alzheimer’s disease, but there has been no known treatment to prevent this from happening.

Researchers designed a group of short molecules called antisense oligonucleotides (ASOs) that specifically bind to the tau gene and block its expression in neurons. In mice expressing the mutant P301S human tau — which produces high levels of a toxic form of the human tau protein — ASOs reduced levels of this protein and its accumulation in young animals. It also improved tau clusters that had already formed in the brain of older animals.

“This compound may literally help untangle the brain damage caused by tau,” Timothy Miller, MD, PhD, the study’s senior author, said in a news release.

This treatment also prevented loss of hippocampal volume (the hippocampus is the brain region involved in learning and memory) and neuronal death. Also, the survival of mice was extended compared to mice treated with a placebo.

ASOs were also effective in monkeys, causing decreased expression of tau in the brain, spinal cord, and cerebrospinal fluid, with few side effects.

“These results open a promising new door,” Margaret Sutherland, PhD and program director at the National Institute of Neurological Disorders and Stroke (NINDS). “They suggest that antisense oligonucleotides may be effective tools for tackling tau-associated disorders.”

Despite the promising results, the safety of these molecules must be further tested before this treatment can be applied to human patients, but researchers are working toward that goal.

The safety and effectiveness of ASOs in other diseases, such as Huntington’s disease and amyotrophic lateral sclerosis (ALS), is currently being testing in early phase trials. The U.S. Food and Drug Administration (FDA) recently approved the use of ASOs to treat spinal muscular atrophy (SMA), a genetic disease that affects the muscles of children.