In a developmentally old part of the brain in the temporal lobe of our telencephalon, the hippocampus, the formation of new neurons can be observed even after birth. This process is called neurogenesis. It is particularly important for some animals including birds. For many years now, a heavily funded research community has been building up around this topic, trying to understand and exploit the postnatal division of neurons in the human brain (assuming it exists to a biologically relevant extent) with the obvious aim to compensate for the loss of neurons in old age. In the course of neurodegeneration, such as Parkinson's disease or Alzheimer's disease, neurons are lost on a massive scale and need to be replaced.
Various therapeutic approaches revolve around a possible stimulation of neurogenesis. But does this phenomenon really exist in the aging brain of people over 50? This question has remained unanswered until now, primarily due to technical difficulties in reliably detecting neurogenesis in adulthood. For this purpose, a microtubule-binding protein, doublecortin (DCX), has been mainly used as a marker so far. It is detectable in neuronal precursor cells (progenitors) that are still dividing and then differentiating into neurons (at which point they no longer contain DCX).
Until now, detection of DCX using antibodies in samples of human and animal brains has been a common method to visualize neurogenesis. The low occurrence of DCX in human brains was explained by the fact that the samples studied were not sufficiently well preserved to demonstrate DCX with confidence.
In a study published today in one of the most respected neuroscience journals (Neuron), Franjic and colleagues from Professor Nenad Sestan's group at Yale University in New Haven (USA) have now impressively demonstrated that DCX is still readily detectable even in brain which were preserved (fixed) at a relatively late stage, but the protein is not specific for neuronal progenitors. In fact, it is also present in differentiated, small interneurons (these inhibit the activity of projection neurons). To this end, the authors used a whole battery of investigative methods that included detailed analysis of gene expression (transcriptome) of individual neurons.
In addition to human samples, the hippocampus of adult pigs and monkeys was studied for comparison. In 139,187 neurons examined in the adult human dentate gyrus, the hippocampal structure that shows neurogenesis in children, the authors found only a single neuron that had all the markers of a dividing cell. Previous studies addressing this question have measured much higher rates of neurogenesis.
Because the work now presented includes a variety of convincing technical and biological control experiments in addition to transcriptome analysis, the question of functionally relevant division of neurons in the older brain can now be answered unequivocally: It practically does not exist. Apparently, in the evolution of vertebrates the decline of neurogenesis from mouse to pig to monkey to human was a selection advantage, i.e. for the human brain the stability of once learned neuronal networks is of crucial importance. It must not be disturbed by newly formed neurons.
The development of new neurons from a so-called radial glia (yellow) via progenitors (ocher) to neuronal stem cells (red) is still well detectable in the adult hippocampus (dentate gyrus) in mice and pigs. In monkeys, neurogenesis declines and is virtually absent in humans (modified Fig. 1 from Nano PR, Bhaduri A , 2022, Mounting evidence suggests human adult neurogenesis is unlikely. Neuron 110:353-355)
This leaves only one door open for the development of stem cell-based therapeutic strategies against neurodegenerative diseases: The transplantation of exogenous neural progenitors that can be differentiated into neurons in the brain tissue of the recipient. Since it is normally not possible to take neural stem cells directly from the brain of patients, such progenitor cells are produced from induced pluripotent stem cells (hiPSCs) in the laboratory.
Neural stem cells can be derived from fetal brain tissue, cultured embryos, or by re-programming of adult somatic cells. They divide mitotically by duplicating their chromosomes, resolving the nucleus and forming two daughter cells, one of which re-enters the cell cycle. Treatment with specific growth factors results in the formation of postmitotic neurons that can be used for transplantation experiments (Fig. 3.1 from Klimaschewski L.P. , Parkinson's and Alzheimer's disease today. Springer, 2021)
As described in chapter 3 of my book on neurodegeneration, the hiPSC technology is applied to obtain stem cells from skin biopsies or from the blood of patients with mutations in a Parkinson's or Alzheimer's gene. The cells are then transformed under special conditions in cell culture, i.e. re-programmed. By introducing the appropriate genes and treating them with special growth factors, they differentiate into functional nerve cells. Neuronal cell death was slowed down and dead nerve cells could be replaced. In fact, hiPSCs differentiate into neurons in the brain and in some cases are even incorporated into existing neuronal networks. Unfortunately, however, the human clinical trials conducted so far have not been successful.
References:
Franjic D, Skarica M, Ma S, ..., Sestan N (2022) Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 110:452-469.e414
Nano PR, Bhaduri A (2022) Mounting evidence suggests human adult neurogenesis is unlikely. Neuron 110:353-355
Image credit: Amitotic cell divisions observed in sympathetic neurons in vitro with brightly fluorescent neuronal nuclei (aus Nindl W, Kavakebi P, Claus P, Grothe C, Pfaller K, Klimaschewski L, 2004, Expression of basic fibroblast growth factor isoforms in postmitotic sympathetic neurons: synthesis, intracellular localization and involvement in karyokinesis. Neuroscience 124:561-572)
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