Drug Compound Halts Damage Caused by Alzheimer's Disease

A new study indicates that a synthetic drug compound has the ability to stop Alzheimer’s disease-related damage in mouse models.

This drug compound, antisense oligonucleotide, was able to lower tau levels, and prevent neurological damage seen in tau-related neurodegenerative diseases, including Alzheimer’s disease, according to a study published by Science Translational Medicine.

The tau protein contributes to healthy brain neuron function, but in some individuals, tau becomes toxic to brain cells, and causes memory degeneration that is characteristic of Alzheimer’s disease.

The researchers found that antisense oligonucleotide is able to reduce the levels of tau, and even reverse some neurological damage by targeting genetic instructions before the protein is made, according to the study.

"We've shown that this molecule lowers levels of the tau protein, preventing and, in some cases, reversing the neurological damage," said study senior author Timothy Miller, MD, PhD. "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."

The authors examined mice models that were genetically modified to create a form of human tau that aggregates easily. The mice exhibited tau tangles by 6 months, and were observed to have neuronal damage by 9 months.

An antisense oligonucleotide, which interferes with the instructions for building proteins, was used to reduce tau levels in these mice, according to the study. The drug compound binds to messenger RNA, which carriers the instructions, and destroys it before the protein can be made. This can be used to prevent the creation of nearly any protein.

Anti-tau oligonucleotide was administered to 9-month-old mice once daily for 1 month. The researchers measured tau RNA, tau protein, and tau tangles in the brains of the mice at 12-months-old.

Mice treated with the drug compound were observed to have decreased levels of all 3 factors, compared with mice treated with placebo.

The researchers noted that 12-month-old mice treated with the compound had lower levels of tau and tau tangles, compared with untreated 9-month-old mice. This suggests that the anti-tau oligonucleotide stopped and reversed tau aggregation, according to the study.

Hippocampal shrinkage and neuronal death was stopped in mice treated with the compound. These factors were prevalent in the younger, untreated mice models. However, the researchers did not find that neuronal death was reversed.

Mice who received the treatment had longer lifespans, and were better at building nests, which is a combination of social behavior, cognitive function, and motor skills, according to the study. These abilities are typically impaired in patients with tau-related neurodegenerative diseases.

Oligonucleotides were recently approved by the FDA to treat Duchenne’s muscular dystrophy and spinal muscular atrophy, which may speed up the regulatory process if the treatment is successful in human patients with Alzheimer’s disease.

Currently, the drug compound is being tested in neurological conditions, such as Huntington’s disease and amyotrophic lateral sclerosis.

The researchers also tested oligonucleotide in healthy cynomolgus monkeys. The monkeys received 2 doses of placebo or oligonucleotide 1 week apart into the cerebrospinal fluid. After 2 weeks, the researchers measured the levels of tau protein and RNA in the brain and cerebrospinal fluid of the monkeys.

"The monkey study showed us that lower tau in the cerebrospinal fluid correlates with lower tau in the brain," Dr Miller said. "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."

Elevated levels of the protein are not only linked to Alzheimer's disease, but to numerous other neurodegenerative diseases, such as progressive supranuclear palsy and corticobasal ganglionic degeneration, according to the study. Levels of tau also increase after a traumatic brain injury in sustained.

"Tau tangles correlate with cognitive decline in several diseases," Dr Miller concluded. "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."