For more than seven years, biologist Maria Llorens has carefully compiled brain pieces from deceased people. Some did not suffer from any neurodegenerative disease and others had clear indications of Alzheimer's. A neuropathologist extracted from each brain the hippocampus, the epicenter of memory, took samples of one centimeter on each side, applied chemical products to preserve them without damaging them and sent them to Llorens. She cut them into very fine five micron sheets to be able to observe them under a microscope. In total he got samples of 58 people who were like pure gold, because this type of biological material is scarce due to the small number of bodies donated to science.
Thanks to the study of these brains, the Llorens research group at the Severo Ochoa Molecular Biology Center has confirmed that humans generate new neurons throughout their lives. Even people close to 90 years of age produce tens of thousands of new nerve cells that are essential for memory and learning.
The study, published today in Nature Medicine, is a new and forceful delivery in a scientific controversy that has intensified recently: Are we born with a certain number of neurons and are we losing them throughout life or is there regeneration? The answer has important implications both for the basic functioning of the mind and for addressing its diseases, especially degenerative diseases such as Parkinson's or Alzheimer.
Neuronal regeneration -neurogenesis- in the hippocampus has been observed in mice and primates. Since 1998, several studies have shown with different methods that humans also produce new neurons in the hicocampo. One of the most original was Jonás Frisén, from the Karolinska Institute, who used isotopes of carbon 14 released by nuclear bombs detonated during the Cold War to calculate the age of neurons in brain samples of 55 people who died. The team noted that the dentate gyrus, part of the hippocampus, contained hundreds of neurons born after the explosions when people were already adults
The controversy came with Arturo Álvarez-Buylla, Prince of Asturias Award in 2011 for his study of neurogenesis. His team tried to demonstrate the existence of young neurons in brain samples of 59 people of different ages, from fetuses to adults. Contrary to what he expected, his results, published last year, showed that the production of new neurons plummets after the first year of life and disappears at the end of childhood.
The work detects a slowdown in the production of new neurons as age advances
"Since then, this field has fallen into disarray," says Llorens. His study has analyzed the dentate gyrus of 13 deceased people between 43 and 87 years old who did not suffer from neurological diseases. The scientists applied four antibodies to the samples that bind to doublecortin, a protein of developing neurons. Thus, about 30,000 young neurons per cubic millimeter of brain were detected in an area of the dentate gyrus known as the granular layer. Young neurons account for 4% of the total number of neurons present in this area of the hippocampus, a quantity that is "surprisingly high", acknowledges Llorens.
The work detects a slowdown in the production of new neurons as age advances, so that younger people tend to have more than older ones. "Granular neurons are the first to receive a nerve stimulus from other areas of the brain and allow it to be processed and sent to other areas, so it makes sense that they are regenerating throughout life," Llorens explains. .
The encephalon of 45 people with Alzheimer's has also been analyzed. In the earliest stages of the disease, when even protein aggregations typical of the disease are not even detected, there are about 20,000 young neurons per cubic millimeter, 33% less than in healthy people, according to the study. The most advanced patients have only 11,000 (63% less), and represent only 1.5% of the area of the hippocampus analyzed.
The researchers speculate that this type of neurons could function as an early diagnosis method of Alzheimer–for what previously would have to develop a non-invasive method to use it on living people without causing damage– or even be the basis of a therapeutic intervention to increase the number of regenerated neurons.
"Memory and learning ability are diminished by the disease of Alzheimer and the results we have obtained support it and explain a possible mechanism, "explains Jesús Ávila, Severo Ochoa researcher and co-author of the work, which has also involved researchers from the CSIC, the Center for Biomedical Research in Neurodegenerative Diseases, brain bank of the CIEN Foundation, and the European University of Madrid.
People with advanced Alzheimer's have 60% fewer young neurons than those without the ailment
The chemical treatment that is applied to the brain samples after the person's death may explain why other groups did not see neurogenesis in adults. The longer the samples are left in paraformaldehyde to fix them, the fewer neurons in maturation state are detected. The study shows that in the brain of the same person can be detected thousands of neurons in maturation or not see any when the sample has been set more than 12 hours. This may explain why Álvarez-Buylla did not find them in adult samples.
The Mexican neurobiologist Álvarez-Buylla believes that the issue is not settled. "We studied brains that had been fixed for less than 12 hours and we did not find neurons, although we used a different antibody." "The immature neurons that they detect are very large, they seem in fact totally mature because of the size, and it is surprising that under them there is no other layer with smaller immature cells." This is a very complicated problem that goes back more than a century, to the time of Ramón y Cajal We may need alternative methods to settle the issue, "he points out.
Last year, Maura Boldrini, a psychiatrist at the University of Columbia (USA), detected neuronal regeneration in people from 14 to 79 years old. Although they saw a decline with age, the study showed that older people without neurological diseases retain this regenerative capacity and speculated that this may be a mechanism that protects the mind from the aches and pains of aging. "This study provides a very important confirmation," says the psychiatrist.
Boldrini studies the connection between neurogenesis and depression. "We have shown both in mice and in humans that antidepressants increase the production of new neurons in the hippocampus," he explains. "These types of neurons are involved in the emotional response to stress and memory, two capacities that are depleted by depression. In turn these neurons connect with the amygdala, which controls fear and anxiety, and in turn connects with other points in charge of decision making, which are also affected by depression, "says the psychiatrist.
For Juan Carlos Portilla, member of the Spanish Society of Neurology, "this work clears the doubts that previous studies had raised, which were not so methodologically detailed". "One of the most interesting things is that it reveals a new pathogenic mechanism of Alzheimer's disease," he says.