Cholesterol--Don't Think Without It: Heart clogger helps neurons connect
Authors: Miller Katharine 
Published: August 2003

Sometimes it takes an outsider to make conversational sparks fly. Nerve cells meet at sites called synapses to deliver and receive electrical messages, but building these structures requires help from other cells known as glia. The active substance produced by glia has eluded scientists, however. Researchers have now unveiled the mystery agent: cholesterol, a fatty molecule commonly associated with heart disease and membrane integrity--not nerve development. The finding advances our understanding of how the brain develops and hints at explanations for why one form of a cholesterol-carrying protein increases the risk of some neurodegenerative diseases.
Researchers reported in 1997 that neurons require neighboring glial cells to produce synapses. In the new study, Mauch and colleagues sought the synapse-promoting material that glia presumably secrete. After growing glia in a broth, they removed the cells and collected what remained, including anything that the glia had churned out. In a series of steps, they split this material into portions that share physical and chemical characteristics and identified one that kindled synapse formation in neurons isolated from rat retinas. Further analysis pointed to ApoE--a protein component of the containers that transport cholesterol throughout the body--as the secret agent. But purified ApoE that lacks its cholesterol cargo did not spur neurons to forge synapses. So the researchers added cholesterol by itself. Even without its protein taxi, enough cholesterol gained access to the neurons to exert an effect: It triggered construction of 8 to 10 times more synapses than untreated neurons built. In further experiments, the researchers either prevented glial cells from producing cholesterol or blocked neurons from slurping up ApoE and its associated cholesterol; both conditions reduced synapse activity. Together, the results suggest that synapse development requires glia-made cholesterol.
The findings might suggest a hypothesis for why one version of ApoE (ApoE4) increases the risk of Alzheimer's disease (AD) and other neurodegenerative disorders: Perhaps adults who carry ApoE4 transport insufficient amounts of cholesterol for synapse formation, which in turn impairs learning and short-term memory. However, the idea that cholesterol deficiency might accelerate AD development runs counter to research showing that cholesterol-reducing drugs slow the progression of the disease. Although possible explanations for the apparently conflicting evidence exist--for example, the medications might improve blood flow to the brain--inconsistencies linger. Cholesterol's precise mission in synapse assembly remains unknown: It might stimulate neurons to produce some other substance or become part of the synapse machinery itself. Regardless of the details, glial cholesterol seems to lift neurons out of their isolation by promoting neighborly conversations.
--Katharine Miller

D. H. Mauch, K. Nägler, S. Schumacher, C. Göritz, E.-C. Müller, A. Otto, F. W. Pfrieger, CNS synaptogenesis promoted by glia-derived cholesterol.
Science
294
, 1354-1357 (2001).
[Abstract/Full Text]