Aging brain needs REST
Why do neurodegenerative diseases such as Alzheimer's only affect the elderly? Why do some people experience the 100-year milestone in a completely sane mind, while others develop dementia decades earlier?
For more than 100 years, research on the causes of senile dementia has revolved around aggregates of abnormal proteins formed in the brain tissue of patients with neurodegenerative diseases. However, now experts are confident that at least one piece of this puzzle is unknown, since the presence of such clusters of abnormal proteins in the brain is not always associated with the extinction of cognitive function.
The results of a new study conducted by scientists at Harvard University, working under the guidance of Professor Bruce Yankner, can serve as an explanation for this phenomenon. The authors found that the REST regulator gene active during the period of intrauterine brain development (this is not "rest", but "repressor element of transcription suppressing factor-1", repressor element 1-silencing transcription factor) resumes its functioning at late stages of life and protects neurons from various stressful influences, including toxicity abnormally altered proteins. They also demonstrated that REST is inactive in certain regions of the brain of patients with Alzheimer's disease and moderate cognitive impairment.
According to Professor Yanker, dementia is not an inevitable result of aging. We know that the human brain can function normally for 100 years or more. This indicates the existence of a mechanism that preserves brain functions and maintains the viability of nerve cells of long-lived organisms. It remains only to identify this mechanism.
It is quite possible that REST is the key to the solution. For the first time, this gene attracted the attention of the authors as the most active transcription regulator in the cells of the aging human brain.
At first glance, this seemed strange, since before that the only known role belonging to REST in the brain was to keep a number of genes inactive until the progenitor cells of the intrauterine developing brain were ready to differentiate into functional mature neurons. REST was thought to be rapidly inactivated in a brain cell shortly after birth. (Its activity persists in other cells of the body to provide protection against certain types of cancer and other diseases.)
Attempts to find an explanation for the observation led the authors to the question: at what stages of human life are brain cells most susceptible to damaging factors? The first of these stages is intrauterine development, when the death of young neurons is disastrous for the body. The second stage is aging, when the brain is exposed to oxidative stress and abnormal aggregated proteins, such as beta-amyloid and tau protein, characteristic of Alzheimer's disease. It is quite natural that it is during these periods that the activation of the neuron defense system occurs.
Having identified this possible new role of REST, the authors began searching for genes whose activity it regulates in aging neurons. It turned out that the REST protein product inactivates genes that stimulate the death of brain cells and are involved in the development of various pathological manifestations of Alzheimer's disease, such as the formation of beta-amyloid plaques and neurofibrillary strands, and simultaneously activates genes that help neurons to tolerate stressful effects.
Laboratory experiments have shown that the removal of REST increases the susceptibility of neurons to the toxic effects of oxidative stress and beta-amyloid. Apparently, REST provides the elimination of free radicals formed during oxidative stress and protection from their effects.
To obtain further confirmation of this role of REST, the authors created genetically modified mice that do not have the corresponding gene only in brain cells, and observed the aging process of these animals.
The young mice of the created line did not differ in any way from normal animals, however, with age, active death of neurons began in their brains. Moreover, neurons died in regions of the brain that usually suffer from Alzheimer's disease – the hippocampus and cortex. This indicated that REST plays an important role in maintaining the viability of neurons in the aging brain.
After that, the researchers identified an analogue of the REST gene in the genome of C.elegans roundworms, in which it is also responsible for protecting cells from the toxicity of free radicals and amyloid. This indicates the universality of the protective function of this gene in different species.
Further comparison of the results of laboratory experiments and the study of brain tissue of elderly people with and without dementia provided new data on the relationship between REST and brain aging.
The authors demonstrated that normal aging of brain tissue is accompanied by REST activation. In people with moderate cognitive impairment, on the contrary, there is an early extinction of the activity of the corresponding regulatory protein. And in the affected regions of the brain of patients with Alzheimer's disease, it is practically not registered at all.
The results of a new study have shown that the REST regulatory gene, which is inactive in the young brain (left), is activated in the normally aging brain (center) and provides protection against various stress factors, including abnormal proteins associated with neurodegenerative diseases. REST is absent in the affected regions of the brain of patients with Alzheimer's disease (right).
According to Jankner, there is a strong correlation between the extinction of REST activity and memory loss, especially episodic and autobiographical memory, the early deterioration of which is characteristic of Alzheimer's disease.
The results of experiments on cell cultures indicate that REST activation occurs in cases when neurons exposed to stress transmit signals to each other. And also the fact that the REST protein synthesized in the cytoplasm must move to the nucleus to perform its function.
Researchers have found that in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST does not reach the nucleus. Instead, in these three most common neurodegenerative diseases that cause dementia, REST is destroyed through autophagy. At the same time, it enters autosomes that break down cellular debris together with abnormal proteins associated with the listed diseases: beta-amyloid, tau protein and alpha-synuclein.
Based on these observations, the authors propose to change the tactics of the fight against Alzheimer's disease. Instead of attempts to reduce the amount of beta-amyloid deposits in brain tissue that do not bring significant results, they want to try to influence REST with the help of drugs that have demonstrated in laboratory experiments the ability to stimulate its function, such as lithium salts.
Yankner and his group also decided to try to figure out why there are pronounced pathological changes characteristic of Alzheimer's disease in the brains of some elderly people, not accompanied by impaired cognitive function.
They analyzed the state of brain tissue, samples of which were posthumously donated to science by participants in two large-scale long-term studies devoted to the study of the processes of normal aging, cognitive impairment and neurodegenerative diseases.
The samples were divided into two groups. One group included samples of people who suffered from dementia and had pathological signs of Alzheimer's disease in the brain. The samples of the second group had similar changes in severity, not accompanied by manifestations of dementia. Comparison of samples showed that the nuclei of neurons in key brain regions of participants who did not suffer from dementia contained at least 3 times more REST.
According to Jankner, it is quite possible that high levels of REST neutralize the toxic effect of pathological changes characteristic of Alzheimer's disease on neurons. He believes that pharmacological activation of a system of genes that provide resistance to stress can be an effective intervention in the early stages of the development of the disease.
Additional studies have shown the existence of a pronounced correlation between the level of REST expression and life expectancy. The highest levels of REST are characteristic of brain cells of people who retain their sanity at the age of 90 years and older.
The last important observation of the authors was the fact that REST increases the expression of several genes known for their ability to increase the lifespan of animal models of aging.
However, Yankner notes that he is confident in the existence of still unknown components of the puzzle, which is a complex of mechanisms of aging and the development of senile dementia. In any case, the findings and observations made by the authors allow us to take a fresh look at this issue and offer new ideas in the fight against the currently incurable disease.
Article by Tao Lu et al. REST and stress resistance in aging and Alzheimer's disease is published in the journal Nature.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Harvard Medical School: The Aging Brain Needs REST.
24.03.2014