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J Biol Chem, Vol. 274, Issue 42, 30001-30007, October 15, 1999
/), and Human apoE Transgenic
Mice
§,§**,§,§,
From the Composition of central nervous system
lipoproteins affects the metabolism of lipoprotein constituents within
the brain. The Center for the Study of Nervous System
Injury and the Departments of § Neurology, ** Molecular
Biology, and Pharmacology, Washington
University School of Medicine, St. Louis, Missouri 63110 and the
§§ Department of Pathology, University of
Chicago, Chicago, Illinois 60637
4 allele of apolipoprotein E (apoE) is a
risk factor for Alzheimer's disease via an unknown mechanism(s). As
glia are the primary central nervous system cell type that synthesize
apoE, we characterized lipoproteins secreted by astrocytes from wild
type (WT), apoE (
/), and apoE transgenic
mice expressing human apoE3 or apoE4 in a mouse
apoE (/) background. Nondenaturing size exclusion chromatography demonstrates that WT, apoE3, and apoE4 astrocytes secrete particles the size of plasma high density lipoprotein (HDL)
composed of phospholipid, free cholesterol, and protein, primarily apoE
and apoJ. However, the lipid:apoE ratio of particles containing human
apoE is significantly lower than WT. ApoE localizes across HDL-like
particle sizes. ApoJ localizes to the smallest HDL-like particles.
ApoE (/) astrocytes secrete little phospholipid or free
cholesterol despite comparable apoJ expression, suggesting that apoE is
required for normal secretion of astrocyte lipoproteins. Further,
particles were not detected in apoE (/) samples by electron microscopy. Nondenaturing immunoprecipitation experiments indicate that apoE and apoJ reside predominantly on distinct particles. These studies suggest that apoE expression influences the unique structure of astrocyte lipoproteins, a process further modified by apoE species.
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