The decline of the mechanism of neurogenesis (formation of new neurons) during aging is implicated in the emergence of neurodegenerative pathologies such as Alzheimer disease.
Studies by researchers in the Brain and Spine Institute (Inserm/CNRS/Pierre and Marie Curie University), in collaboration with a team from the Centre of Cardiovascular Research of Yale, showed the importance of the factor VEGF-C in the activation of neural stem cells and consequently the production of new neurons. These results, published in Cell Reports, bring new hope for the development of therapies aimed at increasing the production of neurons that would alleviate cognitive decline in patients with Alzheimer disease.
An adult, throughout his life, is capable of generating new neurons from neural stem cells (NSC), in order to maintain cognitive function. Neurogenesis takes place in the hippocampus, a brain structure that plays a central role in memory. However, age and certain cerebrovascular accidents cause this function to decline, which can result in serious cognitive disorders such as Alzheimer disease.
Although the stages of production of new neurons are known, the molecular mechanisms underlying this phenomenon are less well understood. In effect, NSCs remain quiescent most of the time; the cells no longer cycles and do not divide. Repressors that maintain this state of quiescence have been identified, but many questions remain as to the factors that induce the cell to exist from this state of “sleep.”
In this context, Jean-Léon Thomas and Anne Eichmann decided to investigate the vascular endothelium growth factors (VEGF) and their receptors (VEGFR) – already suspected to participate in the regulation of the growth and maintenance of neural cells. More specifically, they focused on the activating potential of VEGF-C and its receptor VEGFR3.
Their experiments in vitro and in vivo confirm that rodent NSCs express VEGFR3 receptors and also produce VEGF-C. Stimulation of NSCs by VEGF-C leads to activation of these cells, i.e. their entry into the cell cycle, their conversion into neural progenitors and finally new neurons. VEGF-C, unlike other vascular growth factors such as VEGF-A, induces a response in NSCs at concentrations that do not promote vascular proliferation. VEGF-C may therefore be a specific activator of brain NSCs.
In mice the brains of which are deficient in VEGFR3, the phenomenon of neurogenesis is abolished. The researchers showed, thus, that the VEGF-C/VEGFR3 signal not only participates in but is absolutely essential for “awakening” neural stem cells and the creation of new neurons.
This mutant model also enabled the team to observe a correlation between affective disorders and the deterioration of neurogenesis in the hippocampus. As suspected, these mice, in which activation of NSCs is affected, develop with age an exaggerated anxiety similar to that observed in patients with Alzheimer disease. This result suggests that neural VEGF-C/VEGFR3 signalling participates in the maintenance of cognitive functions in the mouse model.
Observations validated in humans
Following this study in rodents, the researchers logically looked for the presence of similar mechanisms in humans. They discovered that this signalling pathway is conserved in human neural cells, in which it promotes the proliferation and survival of cells in vitro.
Although these results are still preliminary, they argue in favour of the idea that the activity of NSCs in adults could contribute to physiological and behavioural control at the level of the whole organism. Similarly, the regression of this activity during ageing might be associated with the development of affective disorders such as anxiety and depression.
From a therapeutic point of view, these results are encouraging: VEGF-C might be a good candidate for a therapeutic agent that would increase the production of new neurons to compensate for cognitive decline in persons with Alzheimer disease.