The tau protein is found in abundance in the central nervous system (CNS) and in the peripheral nervous system (PNS) . Its main function is to stabilize axonal microtubules through interaction with tubulin. In this way, it helps regulate the balance of nerve cell traffic, which explains why tau alterations are associated with neurodegenerative pathologies such as Alzheimer’s. Under normal circumstances, the tau protein contributes to the normal and healthy function of brain neurons, but in some people, it accumulates in toxic tangles that damage those cells and lead to Alzheimer’s and other neurodegenerative diseases. Well, researchers at the Washington University School of Medicine in Saint Louis (United States), have shown that the levels of the protein tau and part of the neurological damage caused can be reduced and even reversed thanks to a synthetic molecule that targets the genetic instructions for building tau before the protein is formed.
The results of the study carried out with mice and monkeys have been published in Science Translational Medicine . The study suggests that the molecule – an antisense oligonucleotide – could treat neurodegenerative diseases characterized by the presence of abnormal tau, such as Alzheimer’s. According to Timothy Miller, Professor of Neurology and author of the research, “We have shown that this molecule reduces the levels of the protein tau, and preventing and, in some cases, reversing neurological damage. It also has the potential to be used as a therapeutic method in people”.
Miller and his colleagues studied mice genetically engineered to produce a mutant form of human tau that clusters easily. Rodents begin to develop tau tangles around six months of age and show some neuronal damage by nine months of age. To reduce the tau protein, the scientists used an antisense oligonucleotide, a kind of molecule that interferes with instructions for building proteins. Genes in DNA are copied into RNA, a messenger molecule that carries the instructions for building a protein. Antisense oligonucleotides bind to messenger RNA and set out to be destroyed before the protein can be built. Such oligonucleotides can be designed to target RNA for almost any protein.
The researchers administered a dose of the anti-tau oligonucleotide to nine-month-old mice every day for a month and then measured the amount of tau RNA, total tau protein, and tau protein tangles in their brains when the mice were 12 months of age. The levels of all three were significantly reduced in the treated rodents compared to the animals that received a placebo. Levels of total tau and tau entanglements in the brains of 12-month-old treated mice were lower than in 9-month-old untreated mice, suggesting that the treatment had not only stopped but also reversed. the accumulation of tau.
By the time this strain of genetically modified mice reached nine months of age, the hippocampus – a part of the brain important for memory – is often visibly shrunken and showing dying neurons . But with oligonucleotide treatment, cell contraction and death stopped, although there was no evidence of reversal of neuronal death. Treated rodents lived an average of 36 days longer than untreated rodents and were more adept at nest building, reflecting a combination of social behavior, cognitive performance, and motor skills. All of these functions can be affected in people with Alzheimer’s disease and other neurodegenerative diseases related to the tau protein.
Photo caption: In the brain of some individuals, the tau protein forms toxic tangles that can lead to neurodegenerative diseases. Researchers at the Washington University School of Medicine in St. Louis have created a drug that reduces levels of this protein in mice and prevents brain damage. In neurons containing the drug (in red) there are no tangles (in green).
