A previously unknown role of cholesterol in the formation of contacts between nerve cells has been discovered by researchers at the Max-Delbrück-Center for Molecular Medicine in Berlin, Germany, and at the Centre de Neurochimie in Strasbourg in France (Science, November 09th, 2001). Their results suggest a link between brain cholesterol metabolism and nerve cell development, learning and memory and hint at new strategies to cure injury- or disease-induced brain lesions.
Brain function depends on the exchange of electrical signals between nerve cells that is mediated by highly specialized contact sites, the socalled synapses. Their formation is a decisive phase during brain development and plays an important role in learning and memory. So far, however, the mechanisms of this process are largely obscure and thus, their elucidation is therefore an important topic of neuroscience research. Moreover, the identification of "synaptogenic" factors is a fundamental prerequisite to repair synaptic connections that have been destroyed by injury, stroke or neurodegenerative diseases like Alzheimer's.
A clue to the existence of a synaptogenic factor came from a study that Dr. Frank Pfrieger, presently leader of a bilateral research group of the Max-Planck Society and the Centre National de Recherche Scientifique, conducted some years ago in the lab of Prof. B. Barres at Stanford University in the USA. The two researchers examined whether neurons can form contacts by themselves or whether they need help from socalled glial cells. Glial cells form a large part of the brain tissue and support its development and function in many different ways. By studying isolated nerve cells in culture dishes Pfrieger and Barres found that neurons survive and grow under glia-free conditions, but show only few of the electrical signals that are generated by synapses. Soluble factors produced by specific types of glial cells, however, induced a strong potentiation of synaptic activity.
After his return from the US, Dr. Pfrieger set out to identify the unknown factor and its mode of action with his own research group at the Max-Delbrück-Center for Molecular Medicine in Berlin. Earlier this year, the groups of Pfrieger and Barres showed independently that the glial factor increases the number of synapses and their transmission efficacy. These results indicated that glial cells play indeed a role during synapse development. However, the identity of the synaptogenic factor remained unknown.
Now, Pfrieger's group achieved the final breakthrough. In the latest issue of Science (November 09th, 2001), they report a surprising result: the long-sought factor turns out to be cholesterol!
Cholesterol, meanwhile one of the most well-known biological substances, is an essential component of the membrane that surrounds every cell in the body. Its bad reputation stems from the fact that high cholesterol levels in the blood raise the risk for atherosclerosis and consequently heart attack and stroke. The identification of cholesterol as synaptogenic factor shows a surprisingly beneficial side of this infamous molecule. Pfrieger believes that "the availability of cholesterol in the brain may limit the extent of synaptogenesis and that a defective cholesterol metabolism in the brain may therefore impair its development and function".
Pfrieger's results indicate that nerve cells produce enough cholesterol to survive and to grow, but too little to form enough synaptic contacts. Thus, they depend on external sources of this component. Where does the extra cholesterol come from? Pfrieger remarks that "the brain cannot tap the cholesterol supply in the blood, since the lipoproteins that mediate the transport of cholesterol - including the notorious ldl and hdl - are too big to pass the blood-brain barrier. Therefore, the brain depends on its own cholesterol synthesis."
According to the new results glial cells produce surplus cholesterol and provide nerve cells with this component. This correlation indicates a new role for glial cells as cholesterol providers and could explain why glial cells secrete cholesterol-rich lipoproteins.
The new results also raise a series of questions: how does cholesterol promote synaptogenesis? Does it serve as building material for synaptic components or does it act as signal triggering subsequent cellular processes? Do changes in availability of cholesterol in the brain influence mental development, learning or memory? Notably, the results imply a new hypothesis concerning Alzheimer's disease. Structural changes in the socalled apolipoprotein E, a crucial component of cholesterol carrier complexes, raise the risk for an age-dependent form of Alzheimer. This may be due to an impaired supply of nerve cells with cholesterol and thus a reduced turnover of synapses. Pfrieger's group will now address these questions in cooperation with other research teams.
All in all, the new results throw new light on an often disdained molecule and provide new perspectives for neurobiological research and strategies to cure brain lesions.