Memory-restoring molecule provides new hope in the search for a cure for Alzheimer’s | Science & Tech

Microscopic image of brain cells from mice that received cerebrospinal fluid from youngsters.Tal Iram

Researchers in the United States have discovered a molecule that rejuvenates aging brains and helps memory recovery. Although this is a preliminary finding that has only been seen in mice, it offers new hope in the search for a cure for Alzheimer’s disease, a still incurable disease that affects people worldwide.

Finding a cure for this neurodegenerative disease is one of the most difficult goals of biomedicine. The human brain is made up of 100 billion neurons that form some 100,000 billion connections between them. The best and worst of the human mind comes from the organ, which weighs barely a kilo and a half. Alzheimer’s disease is called the silent epidemic because it begins to kill neurons in the brain about 20 years before the first symptoms appear, such as the loss of memories stored in brain cells. The moment this happens, it is impossible to stop its progress. No experimental treatment has been able to reverse the disease. Even its causes are unclear. In this context, every new discovery that can help regenerate aging brains deserves attention.

The new study is inspired by something that many doctors and scientists have known for decades: the body’s organs have the ability to regenerate themselves, but as we age, the body begins to produce molecules that hinder or negate this ability. . Lab experiments have shown that something called parabiosis – surgically combining an old and a young rat together, for example – is enough to improve muscle strength, healthy liver function and reverse obesity.

A few years ago, following the idea of ​​parabiosis but with less invasive methods, neurologist Tony Wyss-Coray and his team demonstrated that aged mice recover memory and cognitive abilities after a simple injection of blood plasma extracted from mice. youth. This proves that two types of molecules circulate in the blood: some are in young plasma and activate tissue regeneration and others are present in the plasma of old mice and prevent this renewal. Some of these plasma molecules are currently being tested in clinical trials with people with mild to moderate Alzheimer’s disease. The first results reported by the American company Alkahest and its Spanish partner Grifols are encouraging, even if it has not yet been shown that the disease can be slowed down or cured.

Now a new study, published in Nature Wednesday, gave a boost to the search for new rejuvenating molecules. The research team, which includes Wyss-Coray, replaced plasma with cerebrospinal fluid, the clear, colorless substance that bathes the nervous system and brain and exchanges molecules with them. The researchers extracted this fluid from mice aged two and a half months – the equivalent of nine human years – and injected it into the brains of mice aged 18 months – the equivalent of 70 years. They then tested the memory of these elderly mice, which under normal conditions had been unable to remember a simple sequence of events: a light is turned on and they experience a small electric shock. Rodents that received the brain fluid began to become alert when the light bulb was turned on. They had regained their memory.

There’s a huge chasm between a mouse terrified as she anticipates an electric shock and a person unable to recognize her child due to Alzheimer’s disease, but perhaps the same biological mechanisms are at work. Scientists analyzed the brains of these animals and found that new oligodendrocytes, a type of cell that makes up the white matter of the brain and supports the gray matter where neurons are located, had begun to regenerate. These cells produce proteins that form a protective cable for axons, the projection of a nerve cell that is received by other neurons and can measure up to a meter in length. The study shows that these new oligodendrocytes were produced in the hippocampus, the epicenter of brain memory. The researchers also injected cerebrospinal fluid from young into old mice and recorded a similar rejuvenating effect. In contrast, the same fluid from the elderly reduced the capacity for cell regeneration.

Fgf17 protein is a possible therapeutic target and also suggests that drug delivery to cerebrospinal fluid may be beneficial in dementia

Miriam Zawadzki and Maria Lehtinen, pathologists

Scientists have identified a protein in young cerebrospinal fluid called Fgf17 – short for fibroblast growth factor 17 – which is capable of activating the production of young oligodendrocytes on its own. This protein “is necessary for brain formation during embryonic development, but almost nothing is known about its production and function in adult and elderly brains,” says Stanford University researcher Tal Iram. in the United States and lead author of the study. “Oligodendrocytes are unique because their progenitors are still present in the brain at advanced ages, although their maturation is very slow. Our study suggests that manipulation of cerebrospinal fluid proteins can rejuvenate these cells and improve memory in aging brains,” she says.

Miriam Zawadzki and Maria Lehtinen, pathologists at Boston Children’s Hospital, describe the new study as “groundbreaking.” “The Fgf17 protein is a possible therapeutic target and also suggests that drug delivery into the cerebrospinal fluid may be beneficial in dementia. [caused by Alzheimer’s in 80% of cases]they say in a commentary on the study.

Three independent experts emphasize the originality of the work and its interest in advancing knowledge of neurodegenerative diseases. Alzheimer’s disease has been cured in mice countless times, but we still don’t have a single cure for humans, recalls Jesús Ávila, a veteran Alzheimer’s researcher at the Severo Ochoa Molecular Biology Center in Spain. . “We still don’t know why this is happening,” he says. Part of the explanation may lie in the fact that mice and humans have been evolving separately for millions of years. The tau protein, associated with Alzheimer’s disease, accumulates inside neurons, preventing them from functioning properly. Ávila’s team discovered an alternative form of this protein that does not contribute to the disease and only exists in humans, because neither mice nor primates have the genetic variants needed to make it. It is possible that there are many other similar differences that we do not yet know about, explains the researcher.

Carlos Dotti studies brain aging in the same center as Ávila. This work is “important because it shows that memory can be reclaimed,” he says. The problem is that the Fgf17 protein and the molecular mechanism in which it is involved not only generates new brain cells, but by promoting growth it could also generate tumors, he warns. “In any case, this opens up a very good avenue for searching for other proteins with therapeutic potential in the cerebrospinal fluid,” he adds.

One of the big problems in finding a cure for Alzheimer’s disease is that the brain is isolated from the rest of the body by a strong immunological and hematological barrier that makes drug delivery very difficult. The use of cerebrospinal fluid can also cause difficulties, as it is extracted through a needle inserted into the lower back which passes through the spine until it reaches the nervous system. One option to avoid this operation would be to use subcutaneous pumps like those already implanted in the back to inject morphine into the cerebrospinal fluid to relieve chronic pain, argues Iram. His team is already thinking about how their findings could be applied to the search for a cure for Alzheimer’s disease, but they recognize they still have some time ahead of them.

Eva Carro, an expert in the neurobiology of Alzheimer’s disease at the Carlos III Research Institute in Spain, is skeptical about the possibility of this type of treatment because the transfusion of cerebrospinal fluid is “very invasive”. The expert believes that prevention is the best way to fight Alzheimer’s disease. “The same thing has been done and continues to be done with cardiovascular disease; reduce or eliminate modifiable risk factors such as high calorie diets, sedentary lifestyles, hypertension, diabetes, stress, depression and promote protective factors such as sleep, socialization and physical activity “, she explains. Such factors may be responsible for a surprising drug trend: the incidence of Alzheimer’s disease in Europe and the United States is decreasing by 13% with each passing decade.

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