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Journal of Lipid Research, Vol 33, 1677-1688, Copyright © 1992 by Lipid Research, Inc.
GE Handelmann, JK Boyles, KH Weisgraber, RW Mahley and RE Pitas
Previous studies suggest that during nerve regeneration apoE acts as a
lipid transport protein that assists in the rapid initial extension of
axons and then in their myelination. To determine whether apoE and/or
apoE-containing lipoproteins can modulate axon growth, we assessed their
effect on the out-growth of neurites from neurons in mixed cultures of
fetal rabbit dorsal root ganglion cells in vitro. Incubation with beta-very
low density lipoprotein (beta-VLDL) particles, which are rich in apoE and
cholesterol, increased neurite outgrowth and branching. Unesterified
cholesterol added to the cultures had a similar, but less pronounced,
effect. These data suggest that cholesterol might be the component
responsible for the enhanced neurite growth. In contrast, purified,
lipid-free apoE added to the cultures reduced neurite branching. Neurite
branching was also reduced when purified apoE was added along with
beta-VLDL or cholesterol; however, the striking finding was that under
these conditions the neurites extended farther from the neuronal cell body.
Dorsal root ganglion cells were examined for the presence of receptors for
native and apoE- enriched beta-VLDL. Immunocytochemistry, ligand blots,
45Ca2+ blots, and studies of the interaction of the cells with fluorescent
lipoproteins provided evidence of two types of receptors for apoE-
containing lipoproteins on neurons: the low density lipoprotein (LDL)
receptor, which binds native beta-VLDL, and the LDL receptor-related
protein, which binds apoE-enriched beta-VLDL. These findings indicate that
apoE may play two complementary roles in neurite outgrowth. When complexed
with lipoproteins, apoE stimulates neurite growth by the receptor-mediated
delivery of cholesterol and perhaps other components necessary for neurite
outgrowth. When apoE as a free protein is added together with
apoE-containing lipoproteins, apoE decreases neurite branching and promotes
neurite extension away from the cell body. These actions, which would be
complementary in promoting target-directed nerve growth in vivo, provide
the first direct evidence that apoE and apoE-containing lipoproteins can
modulate the outgrowth of neuronal processes.
ARTICLES
Effects of apolipoprotein E, beta-very low density lipoproteins, and cholesterol on the extension of neurites by rabbit dorsal root ganglion neurons in vitro
Gladstone Institute of Cardiovascular Disease, Department of Pathology, University of California 94141-9100.
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