Neurogenesis, or the development of nerve cells from stem cells, begins in the fetus in the 5th week of pregnancy and is almost complete by the 28th week. It is a complex process with complex processes.
“In humans, neurogenesis takes a particularly long time compared to other species,” explained Khadijeh Shabani, a postdoctoral researcher at the Paris Brain Institute. Neural stem cells remain in the progenitor state for an extended period of time. Only later do they differentiate into glial cells, astrocytes or oligodendrocytes, which will form the architecture of the brain and spinal cord.”
Until now, scientists did not know how the balance between stem cell growth and differentiation into different cell types is controlled. Above all, they neglected the possibility that the extraordinarily long time span of human neurogenesis might pave the way for species-unique vulnerabilities such as neurodegenerative diseases. Researchers from the Paris Brain Institute’s “Brain Development” team, led by Bass Hassan, investigated to better understand how our brains are formed at this critical time.
“We were interested in the amyloid precursor protein, or APP, which is highly expressed during the development of the nervous system,” Hassan said. It is an exciting research target because its fragmentation produces the famous amyloid peptides, the toxic aggregation of which is linked to the neuronal death seen in Alzheimer’s disease. We therefore suspect that APP may play a central role in the early stages of the disease.
In many species, APP is involved in various biological processes, such as the repair of cerebral lesions, the control of the cellular response after oxygen deprivation, or the control of brain plasticity. It is highly expressed during the differentiation and migration of cortical neurons, suggesting an essential role in neurogenesis. But what about people?
To track APP expression during human brain development, the researchers used cell sequencing data obtained from a fetus at ten weeks and then at 18 weeks of gestation. They observed that the protein was first expressed in 6 cell types, then a few weeks later in no fewer than 16 cell types. They then used the CRISPR-Cas9 genetic scissors technique to produce neural stem cells in which APP was not expressed. They then compared these genetically modified cells with cells obtained in vivo.
“This comparison provided us with valuable data,” explains Shabani. We observed that in the absence of APP, neural stem cells produced many more neurons, faster, and were less prone to proliferate in a progenitor cell state. Specifically, the team showed that APP was involved in two fine-tuned genetic mechanisms: on the one hand, canonical WNT signaling, which controls stem cell proliferation, and AP-1 activation, which triggers the production of new neurons. By acting on these two levers, APP is able to regulate the timing of neurogenesis.
While loss of APP strongly accelerates brain neurogenesis in humans, it does not in rodents. “In mouse models, neurogenesis is already very rapid—too rapid to be further accelerated by APP deprivation. We can imagine that the regulatory role of this protein is negligible in mice, while it is essential for the neurodevelopment of our species: for our brain to acquire its final form, it needs to generate a huge number of neurons over a very long time, and according to a certain plan.
APP-related abnormalities could cause premature neurogenesis and significant cellular stress, the consequences of which would be observable later, Hassan suggests. In addition, the areas of the brain that show early symptoms of Alzheimer’s also take the longest to mature during childhood and adolescence.
What if the timing of human neurogenesis was directly linked to the mechanisms of neurodegeneration? Although neurodegenerative diseases are generally diagnosed between the ages of 40 and 60, researchers believe that clinical symptoms appear several decades after the decline of certain neuronal connections begins. This loss of connectivity may itself reflect abnormalities at the molecular scale present from childhood or even earlier.
Further studies will be needed to confirm that APP plays a central role in the neurodevelopmental disorders that pave the way for Alzheimer’s disease. In such a case, we might consider that “these disorders lead to the creation of a brain that functions normally at birth but is particularly vulnerable to certain biological events such as inflammation, excitotoxicity or somatic mutations, and certain environmental factors such as poor diet , lack of sleep, infection, etc., adds the researcher. Over time, these various stresses could lead to neurodegeneration, a phenomenon specific to the human species that is particularly visible in the increase in life expectancy.
Read Now:Study shows that the leading global cause of liver disease increasing
