 | VASCULAR FACTORS IN ALZHEIMER'S DISEASE
Copyright © 2000 by the New York Academy of Sciences
description
Annals of the New York Academy of Sciences 903:167-175 (2000)
© 2000 New York Academy of Sciences
Lipoproteins in the Central Nervous System
MARY JO LADUa,b,
CATHERINE REARDONb,
LINDA VAN ELDIKc,
ANNE M. FAGANd,
GUOJUN BUe,
DAVID HOLTZMANd AND
GODFREY S. GETZb
bDepartment of Pathology, University of Chicago, Chicago, Illinois, USA
cDepartment of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois, USA
dDepartment of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
eDepartment of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
aAddress for correspondence: Mary Jo LaDu, Evanston Northwestern Healthcare Research Institute, 1801 Maple Ave., Suite 6240, Evanston, IL 60201. Tel.: (847) 467-5975; fax: (240) 352-4077.
e-mail: mjladu{at}enhri.birl.nwu.edu
Although the synthesis and metabolism of plasma lipoproteins are well characterized, little is known about lipid delivery and clearance within the central nervous system (CNS). Our work has focused on characterizing the lipoprotein particles present in the cerebrospinal fluid (CSF) and the nascent particles secreted by astrocytes. In addition to carrying lipids, we have found that ß-amyloid (Ab) associates with lipoproteins, including the discoidal particles secreted by cultured astrocytes and the spherical lipoproteins found in CSF. We believe that association with lipoproteins provides a means of transport and clearance for Aß. This process may be further influenced by an interaction between Ab and apoprotein E (apoE), the primary protein component of CNS lipoproteins. Specifically, we have investigated the formation and physiologic relevance of a SDS-stable complex between apoE and Aß. In biochemical assays, native apoE2 and E3 (associated with lipid particles) form an SDS-stable complex with Ab that is 20-fold more abundant than the apoE4:Aß complex. In cell culture, native apoE3 but not E4 prevents Aß-induced neurotoxicity by a mechanism dependent on cell surface apoE receptors. In addition, apoE and the inhibition of apoE receptors prevent Aß-induced astrocyte activation. Therefore, we hypothesize that the protection from Aß-induced neurotoxicity afforded by apoE3 may result from clearance of the peptide by SDS-stable apoE3:Aß complex formation and uptake by apoE receptors.
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