Joachim Gerber, MD, from the Department of Neurology of RWTH University Hospital in Aachen, Germany, discusses his paper "Increased neuronal proliferation in human bacterial meningitis," which was recently published in Neurology® (2009;73:1026-1032). He spoke with AAN.com Science editor José G. Merino, MD, MPhil.
AAN.com: Please summarize the methodology and major findings of the study.
Gerber: We used immunohistochemical methods to study neurogenesis in brain sections of patients who underwent autopsy subsequent to bacterial meningitis, stroke, or brain trauma. We found increased proliferation of neuronal progenitor cells in the three diseases investigated.
AAN.com: In what other conditions has neurogenesis been documented? What triggers neurogenesis after brain injury?
Gerber: Neurogenesis is a universal phenomenon of the mammalian brain that can be stimulated by environmental factors. Enhancement of neurogenesis has been reported in several models of experimental central nervous system (CNS) injury, including ischemic and traumatic lesions, and after epileptic seizures. In humans, increased proliferation in the hippocampus has been observed after stroke and in patients with epilepsy and Alzheimer's disease.
AAN.com: In the adult brain, where does neurogenesis take place?
Gerber: Two brain regions are the main source of new cells in the brain: the subgranular layer of the hippocampal formation and the subependymal zone of the lateral ventricles.
AAN.com: How is the process of neurogenesis after brain injury initiated and regulated?
Gerber: We do not completely understand the mechanisms that lead to neurogenesis after brain injury. Adult neurogenesis is initiated and regulated through the complex interaction of several factors: inflammatory mediators, neurotrophic and mitogenic factors, and transcriptional regulators. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), for example, can stimulate neurogenesis. On a molecular level, there is evidence that Wnt and Beta-catenin dependent pathways are involved in the regulation of neurogenesis. Newly generated cells can differentiate into different cell types including neurons, astrocytes, and glial cells.
AAN.com: What are the Wnt proteins?
Gerber: The proteins of the Wnt family are a group of highly conserved proteins that regulate proliferation and cell-to-cell interactions during embryogenesis. They bind to specific receptors on the cell surface and induce the expression of transcriptional factors (e.g., NeuroD1). Wnt-signaling in neurogenesis has been observed in vitro and in hippocampal neurogenesis. There is also evidence for Wnt-mediated regulation of neurogenesis in the subventricular zone.
AAN.com: Why do you thinkyour study found an increased neuronal proliferation in the dentate gyrus but not in the subventricular zone in patients with bacterial meningitis?
Gerber: In the subventricular zone—which is near the cerebrospinal fluid (CSF) compartment—bacterial invasion and inflammation may have caused enhanced cellular damage in adult progenitor cells resulting in a limited capacity to generate newborn cells.
AAN.com: How is neuronal migration controlled in the adult brain?
Gerber: Neuronal migration seems to require contact of the new cells with other neurons, astrocytes, and blood vessels. Control of neuronal migration is a complex process, and a variety of factors seem to be involved. Molecules such as the ephrins that are involved in angiogenesis may regulate the process. In stroke, metalloproteinases may play a role. The receptor-mediated system of laminins/integrins also seems to be important. Doublecortin, a marker for immature neurons, has been described as essential for neuronal migration in the adult brain.
AAN.com: Please comment on the different markers of newborn neurons used in your study. Could the choice of marker affect the results and their interpretation?
Gerber: Today, several marker proteins are available for use in the investigation and quantification of neuronal proliferation and differentiation. Temporarily expressed proteins in neuroblasts and immature neurons are used to detect this cell population. One marker protein may not display the whole process and, therefore, quantification of several markers (or co-labeling) is recommended. In our study we used several markers: the proliferating cell nuclear antigen (PCNA), TUC-4, and doublecortin. The PCNA protein is expressed in the early G1 and the S-phase of mitosis and is used as a marker for cellular proliferation and DNA synthesis. We used it as a nonspecific cellular marker for cell division. TUC-4 (also called Ulip-1 or CRMP-4, initially also TOAD-64) belongs to a family of Unc-33-like phosphoproteins. It is a membrane-associated protein that is functionally involved in axonal outgrowth, neuronal differentiation, and is transiently expressed in the cytoplasm and processes of young but not adult neuronal cells. Doublecortin is a protein required for normal migration of neurons into the cerebral cortex and transiently expressed in newly formed neuroblasts.
AAN.com: Are there known mechanisms to stimulate neurogenesis after brain insults?
Gerber: Experimental data suggest that neurogenesis is susceptible to pharmacological interventions. NMDA receptor antagonists stimulate neurogenesis, as does adrenalectomy. Glucocorticoids, on the other hand, decrease the proliferation of dentate progenitor cells. Furthermore, environmental stimuli and physical exercise are able to stimulate neurogenesis. Experimental studies have been performed in models of brain injury using trophic factors, environmental stimuli, NMDA antagonists, sodium butyrate and other substances that were—to a limited degree—effective. To develop effective new treatment strategies, however, we need a better understanding of the underlying mechanisms of neurogenesis.
AAN.com: What are the major implications of your findings for clinicians?
Gerber: Clinicians should be aware of the high endogenous potential of the central nervous system for regeneration, even after acute brain injury. We need further research to understand the mechanisms of this potential and to develop new treatment strategies that may help to alleviate consequences of neuronal destruction.
Dr. Gerber has nothing to disclose.
Dr. Merino performed a one-time consultation with staff from Bell, Falla and Associates.