Involvement of low-density lipoprotein receptor-related protein and ABCG1 in stimulation of axonal extension by apoE-containing lipoproteins

• Published in: Biochimica et biophysica acta 2011, Vol.1811 (1), p.31-38
• Main Authors: Matsuo, Michinori, Campenot, Robert B., Vance, Dennis E., Ueda, Kazumitsu, Vance, Jean E.
• Format: Article
• Language: English
• Subjects: ABCG1; Animals; Apolipoprotein E; Apolipoproteins E - metabolism; Apolipoproteins E - pharmacology; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Axonal extension; Axons - metabolism; Cells, Cultured; Cholesterol; Gene Silencing; Glia; LDL receptor-related protein; Low Density Lipoprotein Receptor-Related Protein-1 - genetics; Low Density Lipoprotein Receptor-Related Protein-1 - metabolism; Mutation; Neurons; Rats; Rats, Sprague-Dawley; Retinal Ganglion Cells - cytology; Retinal Ganglion Cells - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 1388-1981; 0006-3002; 1879-2618
• DOI: 10.1016/j.bbalip.2010.10.004

Apolipoprotein E (apoE)-containing lipoproteins (LpE) are produced by glial cells in the central nervous system (CNS). When LpE are supplied to distal axons, but not cell bodies, of CNS neurons (retinal ganglion cells) the rate of axonal extension is increased. In this study we have investigated the molecular requirements underlying the stimulatory effect of LpE on axonal extension. We show that enhancement of axonal growth by LpE requires the presence of the low-density lipoprotein receptor-related protein-1 (LRP1) in neurons since RNA silencing of LRP1 in neurons, or antibodies directed against LRP, suppressed the LpE-induced axonal extension. In contrast, an alternative LRP1 ligand, α2-macroglobulin, failed to stimulate axonal extension, suggesting that LpE do not exert their growth-stimulatory effect solely by activation of a LRP1-mediated signaling pathway. In addition, although apoE3-containing LpE enhanced axonal extension, apoE4-containing LpE did not. Over-expression of ABCG1 in rat cortical glial cells resulted in production of LpE that increased the rate of axonal extension to a greater extent than did expression of an inactive, mutant form of ABGC1. Furthermore, reconstituted lipoprotein particles containing apoE3, phosphatidylcholine and sphingomyelin, but not cholesterol, stimulated axonal extension, suggesting that sphingomyelin, but not cholesterol, is involved in the stimulatory effect of LpE. These observations demonstrate that LpE and LRP1 promote axonal extension, and suggest that lipids exported to LpE by ABCG1 are important for the enhancement of axonal extension mediated by LpE. ► Glia-derived apoE-containing lipoproteins (LpE) stimulate axonal extension. ► The enhancement of axonal growth by LpE requires LRP1. ► ApoE3-containing LpE stimulate axonal growth, whereas apoE4-containing lipoproteins do not. ► LpE generated by glia over-expressing active ABGG1 enhance axon growth.