Unique lipoproteins secreted by primary astrocytes from wild type, apoE (-/-), and human apoE transgenic mice

Composition of central nervous system lipoproteins affects the metabolism o f lipoprotein constituents within the brain. The epsilon 4 allele of apolip oprotein E (apoE) is a risk factor for Alzheimer's disease via an unknown m echanism(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 ch romatography demonstrates that WT, apoE3, and apoE4 astrocytes secrete part icles the size of plasma high density lipoprotein (HDL) composed of phospho lipid, 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 phosp holipid or free cholesterol despite comparable apoJ expression, suggesting that apoE is required for normal secretion of astrocyte lipoproteins. Furth er, particles were not detected in apoE (-/-) samples by electron microscop y. Nondenaturing immunoprecipitation experiments indicate that apoE and apo J reside predominantly on distinct particles. These studies suggest that ap oE expression influences the unique structure of astrocyte lipoproteins, a process further modified by apoE species.