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First published online 19 March 2009
doi: 10.1242/jcs.040717

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Low-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis

Alban Gaultier^1,*, Xiaohua Wu^2,*, Natacha Le Moan^3,4, Shinako Takimoto¹, Gatambwa Mukandala¹, Katerina Akassoglou^3,4, W. Marie Campana⁵ and Steven L. Gonias^1,

¹ Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA
² The McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Charlotte, NC 28203, USA
³ Gladstone Institute of Neurological Diseases, University of California, San Francisco, San Francisco, CA 94158, USA
⁴ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA
⁵ Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA

Author for correspondence (e-mail: sgonias{at}ucsd.edu)

Accepted 17 December 2008

Multiple sclerosis (MS) is an autoimmune disease in which myelin is progressively degraded. Because degraded myelin may both initiate and accelerate disease progression, clearing degraded myelin from extracellular spaces may be critical. In this study, we prepared myelin vesicles (MV) from rat brains as a model of degraded myelin. Murine embryonic fibroblasts (MEFs) rapidly internalized MVs, which accumulated in lysosomes only when these cells expressed low-density lipoprotein receptor-related protein (LRP1). Receptor-associated protein (RAP), which binds LRP1 and inhibits interaction with other ligands, blocked MV uptake by LRP1-expressing MEFs. As a complementary approach, we prepared primary cultures of rat astrocytes, microglia and oligodendrocytes. All three cell types expressed LRP1 and mediated MV uptake, which was inhibited by RAP. LRP1 gene-silencing in oligodendrocytes also blocked MV uptake. Myelin basic protein (MBP), which was expressed as a recombinant protein, bound directly to LRP1. MBP-specific antibody inhibited MV uptake by oligodendrocytes. In experimental autoimmune encephalomyelitis in mice, LRP1 protein expression was substantially increased in the cerebellum and spinal cord. LRP1 colocalized with multiple CNS cell types. These studies establish LRP1 as a major receptor for phagocytosis of degraded myelin, which may function alone or in concert with co-receptors previously implicated in myelin phagocytosis.

Key words: Myelin, Multiple sclerosis, Low-density lipoprotein receptor-related protein, Phagocytosis, Myelin basic protein, Degeneration

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