Fluorescent micrograph showing synapses forming on a cultured neuron.

© Unité Neurotransmission et sécrétion neuroendocrine

Please explain the circumstances which led to the discovery of the action of cholesterol in brain development.
Frank W. Pfrieger: We set out to look for the molecular mechanisms responsible for a fundamental process known as synaptogenesis which, as its name suggests, refers to the establishment of synapses² connecting neurons. This is an important process for learning abilities and the development of memory. We knew that there was some factor that intervened in this process, and against all expectation it turned out to be cholesterol.

Where does the cholesterol that stimulates synaptogenesis come from?
F. W. P. Cholesterol is a very hydrophobic substance and is not directly soluble in the blood supply. It is transported by another substance, lipoprotein, but the latter is too large a molecule to cross the cerebral barrier. As a result the cholesterol in the blood, which is produced in the liver or comes from food intake, does not get into the brain. The cholesterol implicated in synaptogenesis must then be synthesized locally, but by which cells?
In an in vitro experiment, when external cholesterol is added to neurons in culture, more synaptic connections are generated, which leads us to believe that a cholesterol source other than the neurons themselves is vital to synaptogenesis. As it turns out, in the family of glial cells³ the astrocytes, or star-shaped cells, are known to secrete lipoproteins. Therefore we hypothesize that astrocytes manufacture the cholesterol needed for synaptogenesis and deliver it via lipoproteins.

Your research was carried out on rodents. What does it have to say about new perspectives for understanding human cerebral pathologies?
F. W. P. Most of the mechanisms we describe are fundamental ones and can be transposed to humans. And in fact our findings are the basis for new hypotheses concerning certain neurodegenerative diseases, especially Alzheimer's disease. It has been shown in certain elderly individuals that there is a connection between the development of Alzheimer's and a mutation in a protein (apolipoprotein E) which constitutes lipoprotein. The cerebral degeneration that occurs in this affliction may therefore be due to a problem in cholesterol transport to neurons.
Other degenerative diseases may well benefit from brain cholesterol studies, such as type C Niemann-Pick, a rare genetic disease striking children. Researchers working on this pathology have found that the mutation responsible is implicated in intracellular cholesterol transport. Thanks to these findings, several research avenues have opened up for us.