Cholesterol is one of the factors involved in allowing nerve cells (neurons) to communicate with each other and exchange electrical signals. This discovery is of vital importance for the function of the nervous system. It was made by researchers from the Max Delbrück Center for Molecular Medicine (MDC) in Berlin-Buch in conjunction with a group from the Max Planck Gesellschaft (MPG) and the Centre National de la Recherche Scientifique (CNRS) at the Centre de Neurochimie in Strasbourg, France. The latest research results of the neurobiologists, Daniela Mauch and Dr Frank Pfrieger, have been published in the leading American journal, Science (Vol. 294, No.5545, pp.1354-1357). Cholesterol is formed by glial cells which make up a considerable part of the brain tissue and support its development and function in a variety of ways. These results that the researchers have obtained shine a completely new light on the role of cholesterol. They suggest that the cholesterol metabolism in the central nervous system (CNS) affects the development of the brain as well as its learning and memory capabilities. They also signal new areas of neurobiological research and the development of strategies e.g. for the treatment of spinal cord injuries or the pathological changes that lead to brain dysfunction such as occurs in Alzheimer’s disease.
The nervous system operates by exchanging electrical signals between nerve cells which are transmitted via highly specialized contact sites, the so-called synapses. The formation of synaptic connections is, therefore, a critical step during the development of the nervous system in the immature organism. It plays an important role in learning and in the development of memory. Until now, the mechanisms governing this fundamental biological event have remained completely unknown.
The first piece of evidence for the existence of a factor which promoted synapse formation was discovered a few years ago by Dr Pfrieger in collaboration with Prof Ben Barres at Stanford University, Palo Alto, USA. They were trying to see if neurons could make contact on their own or whether they needed the help of glial cells. They found that isolated nerve cells in cultures where there were no glial cells actually survived and grew but only a few electric signals generated by synapses were able to generate electrical signals themselves. The addition of a factor, at that time unidentified, from glial cells resulted in a sharp increase in synaptic activity. This result initially indicated that glial cells could play a role in the formation of synapses. Earlier this year, and quite independently of each other, since Dr Pfrieger was then in charge of his own team at the MDC, the two researchers showed that the factor from glial cells actually strongly promoted synapse formation. Using techniques from protein biochemistry, Dr Pfrieger and his group were able to identify this glial cell factor as cholesterol.
Cholesterol is an essential building block for the thin lipid coat that encircles every cell in the body. Possibly, the availability of cholesterol in the brain determines the degree of synapse formation. This would mean that a disorder of cholesterol metabolism could adversely affect the development of the brain and some of its functions. Nerve cells seem to be able to produce enough cholesterol on their own in order to survive and develop but too little to furnish a sufficient number of synaptic contacts. Therefore, they have to rely on it being supplied from an external source. Unlike all other organs, the brain cannot use the supply in blood since the so-called lipoproteins, which regulate the transport of cholesterol and other lipid-soluble materials, are too large to cross the blood-brain barrier. Therefore, the brain has to ensure its own supply of cholesterol. These new results show that glial cells produce excess cholesterol and supply nerve cells with enough of it to allow them to form synapses. This relationship highlights a completely new role for glial cells.
However, it is still not clear how cholesterol promotes the formation of synapses. Does it act as a building material for synaptic components or does it act as a signal which triggers certain cellular processes? In addition, there is the question of whether changes in the cholesterol content of the brain have an effect on mental development, as well as learning and memory ability. In this context, it is known that structural changes in the so-called Apolipoprotein E, an important component of lipoproteins, increases the risk of a person developing an age-related form of Alzheimer’s disease. Is this connected to an insufficient supply of cholesterol to nerve cells and, so, to a reduced turnover of synapses? Dr. Pfrieger is now working on this in collaboration with other research groups.
CNS Synaptogenesis Promoted by Glia-Derived Cholesterol
Daniela H. Mauch1, Karl Nägler1,3, Stefan Schumacher4, Christian Göritz1,3, Eva-Christina Müller2, Albrecht Otto2, Frank W. Pfrieger1,3.
1AG Synapsen und 2AG Proteinchemie, MDC für Molekulare Medizin, D-13092 Berlin. 3Max-Planck/CNRS Gruppe, UPR 2356, Centre de Neurochimie, F-67084 Strasbourg, France. 4Institut für Zellbiochemie und Klinische Neurobiologie, Universität Hamburg, D-20246 Hamburg.
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