Microscope image of brain cells from mice that received cerebrospinal fluid from young people.Tal Iram
US researchers have found a molecule that rejuvenates aging brains and restores memory.
This is still a very preliminary advance and observed only in mice.
It wouldn't matter if it wasn't aimed at finding new ways to attack a devastating disease with no cure and a growing incidence globally: Alzheimer's.
The search for a treatment against this neurodegenerative disease is one of the most infernal goals of biomedicine.
The human brain is a vastness of 100,000 million neurons that form about 100 billion connections with each other.
The best and worst of the human mind emerges from this organic matter weighing just one and a half kilos.
Alzheimer's is called the silent epidemic because it begins to kill neurons about 20 years before the first symptoms appear, such as the loss of memories stored in brain cells and their many connections.
By the time this happens it is already impossible to stop their progress.
No experimental treatment has managed to reverse the disease.
Its causes are not even clear.
In this context,
The new work is inspired by something that many doctors and scientists have known for decades: the body's organs have the ability to regenerate, but with age they begin to produce molecules that hinder or cancel that ability.
Laboratory experiments have shown that something called parabiosis—sewing an old and a young rat side by side, for example—is enough to restore muscle strength, proper liver function, or reverse obesity.
A few years ago, following the idea of parabiosis with less forceful methods, the team of neurologist Tony Wyss-Coray showed that old mice recover memory and cognitive capacity after a simple injection of blood plasma extracted from young mice.
This proved that two types of molecules run through the blood: some are in the 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 already being tested in clinical trials with people with mild Alzheimer's.
The first results advanced by the company Alkahest —in which the Spanish company Grifols participates— are encouraging, although it has not yet been shown that they can stop or cure the disease.
The new study, also led by Wyss-Coray, turns the screw in search of new rejuvenating molecules.
The neurologist has 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 two-and-a-half-month-old mice—equivalent to nine human years—and injected it into the brains of 18-month-old mice—about 70 years old.
The transfusion made it possible for rodents that could not remember a simple sequence of events: first a light is turned on and then they suffer a small electric shock to recover this ability.
When the light bulb came on, they became alert.
They had regained their memory.
Between a mouse terrified because it anticipates a cramp and a person unable to recognize his son because of Alzheimer's there is a huge gulf, but possibly shared biological mechanisms underlie.
The scientists analyzed the brain of these animals and verified that new oligodendrocytes had begun to be generated, a type of cell that makes up the white matter of the brain and serves as a support for the gray matter where the neurons are.
These cells produce proteins that form a protective cable for the axons, the extensions with which neurons communicate and that can measure up to a meter in length.
The study shows that the production of new oligodendrocytes occurs in the hippocampus, the brain epicenter of memory.
And there seems to be a shared biology,
Well, the researchers also injected cerebrospinal fluid from young people into old mice and recorded a similar rejuvenating effect.
In contrast, the same fluid from older people reduces the capacity for cell regeneration.
Scientists have identified a protein in young cerebrospinal fluid called Fgf17 — short for fibroblast growth factor 17 — that is capable of activating the production of young oligodendrocytes on its own.
This protein "is necessary for the formation of the brain during the development of an embryo, but almost nothing is known about its production and function in the brains of adults and older people," explains Tal Iram, a researcher at Stanford University (EE UU) and first author of the study, published in the journal
Nature
,
a reference in world science.
“Oligodendrocytes are unique in that their progenitors are still present in the brain at advanced ages, although their maturation is very slow.
Our study suggests that manipulating cerebrospinal fluid proteins can rejuvenate these cells and improve memory in aging brains,” she highlights.
The pathologists at the Boston Children's Hospital (USA) Miriam Zawadzki and Maria Lehtinen recognize that this work "is groundbreaking".
"The Fgf17 protein is a possible therapeutic target and also suggests that delivering drugs to the cerebrospinal fluid may be beneficial against dementia [caused by Alzheimer's in 80% of cases]", they add in a comment to the study.
Three independent experts highlight the originality of the work and its value as fundamental knowledge of neurodegenerative diseases.
Alzheimer's has been cured in mice countless times, but we still don't have a single cure for people, recalls Jesús Ávila, a veteran researcher of this disease at the Severo Ochoa Molecular Biology Center (CBMSO-CSIC).
“We still don't know why this is happening,” he acknowledges.
Part of the explanation may be that mice and humans have evolved separately for millions of years.
The tau protein, which is associated with Alzheimer's, accumulates inside neurons, preventing them from functioning properly.
Ávila's team has discovered an alternative form of this protein that does not contribute to the disease and that only exists in humans,
because neither mice nor primates have the genetic variants necessary to manufacture it.
It is possible that there are many other similar differences that we do not yet know about, the researcher argues.
Carlos Dotti investigates brain aging at the same center as Ávila.
This work is "important because it shows that memory can be rescued," 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 proliferation it could also generate tumors, he warns.
“In any case, a very good way is opened to look for other proteins with therapeutic potential in the cerebrospinal fluid”, he adds.
One of the great problems in the search for a cure for Alzheimer's is that the brain is isolated from the rest of the body by a strong immune and hematological barrier that makes it very difficult to deliver drugs to it.
Using cerebrospinal fluid can also be difficult, as it is removed with a puncture in the lower back that goes through the spine and into the nervous system.
One option to avoid this operation would be to use subcutaneous pumps like those already implanted in the back under the skin to inject morphine into the cerebrospinal fluid and thus relieve chronic pain, argues Iram.
His team is already weighing how to take their findings to the search for a treatment, but they acknowledge that they still have research time ahead of them.
Eva Carro, an expert in Alzheimer's neurobiology at the Carlos III Research Institute, is skeptical that this type of treatment can be achieved because the transfusion of cerebrospinal fluid is "very invasive."
The expert believes that prevention is the best way to tackle the very complicated fight against Alzheimer's.
“It is the same thing that was done and continues to be done with cardiovascular diseases;
reduce or eliminate modifiable risk factors such as hypercaloric diets, sedentary lifestyle, hypertension, diabetes, stress, depression;
and enhance protective factors such as sleep, socialization, physical activity, ”she details.
Factors like these may be responsible for a surprising phenomenon that no drug has yet achieved:
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