Lipoproteins in the central nervous system.
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 beta-amyloid (A beta) 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 A beta. This process may be further influenced by an interaction between A beta 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 A beta. In biochemical assays, native apoE2 and E3 (associated with lipid particles) form an SDS-stable complex with A beta that is 20-fold more abundant than the apoE4:A beta complex. In cell culture, native apoE3 but not E4 prevents A beta-induced neurotoxicity by a mechanism dependent on cell surface apoE receptors. In addition, apoE and the inhibition of apoE receptors prevent A beta-induced astrocyte activation. Therefore, we hypothesize that the protection from A beta-induced neurotoxicity afforded by apoE3 may result from clearance of the peptide by SDS-stable apoE3:A beta complex formation and uptake by apoE receptors.
Ladu
M J
MJ
Department of Pathology, University of Chicago, Illinois, USA. mjladu@enhri.birl.nwu.edu
Reardon
C
C
Van Eldik
L
L
Fagan
A M
AM
Bu
G
G
Holtzman
D
D
Getz
G S
GS
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002493:Central Nervous System Diseases / Q000378:metabolism; D051152:Clusterin; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D018832:Molecular Chaperones
D001057:Apolipoproteins E; C495242:CLU protein, human; D051152:Clusterin; D006023:Glycoproteins; D008074:Lipoproteins; D018832:Molecular Chaperones