Drug compound halts Alzheimer’s-related damage in mice

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From the WUSTL Newsroom…

Under ordinary circumstances, the protein tau contributes to the normal, healthy functioning of brain neurons. In some people, though, it collects into toxic tangles that damage brain cells. Such tangles are a hallmark of Alzheimer’s and other neurodegenerative diseases.

But 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 ­– by a synthetic molecule that targets the genetic instructions for building tau before the protein is made.

The study, in mice and monkeys, is published Jan. 25 in 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.

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Posted on January 27, 2017
Posted in: HPAN, Neurodegeneration, NeuroRestorative Therapy, News Authors: ,