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J. Biol. Chem., Vol. 279, Issue 33, 34948-34956, August 13, 2004

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Apolipoprotein E Receptors Mediate Neurite Outgrowth through Activation of p44/42 Mitogen-activated Protein Kinase in Primary Neurons^*

Zhihua Qiu, Bradley T. Hyman, and G. William Rebeck¶

From the Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129 and Department of Neuroscience, Georgetown University, Washington, D. C. 20057-1464

Several ligands of the endocytic low density lipoprotein receptor-related protein (LRP), such as apoE-containing lipoproteins and activated 2-macroglobulin (2M^*), promote neurite outgrowth, suggesting that LRP may have signaling functions. In this study, we found that the treatment of neurons with 2M^* significantly increased the individual length (by 71%) and numbers (by 139%) of neurites of primary mouse cortical neurons. These effects were blocked by the LRP antagonist, the receptor-associated protein. We found similar neurite outgrowth with purified apoE3 and a tandem apoE peptide containing only the receptor-binding domain. To investigate the intracellular pathway of the LRP signaling involved in neurite outgrowth, we tested the effects of 2M^* on the phosphorylation of the mitogen-activated protein (MAP) extracellular signal-regulated kinases 1 and 2 (ERK1/2). We found that 1) phospho-MAP kinase levels were altered within 30 min after treatment with 2M^*, 2) the MAP kinase inhibitor, PD98059, specifically blocked the 2M^*-induced neurite outgrowth, 3) manipulating intracellular calcium by BayK or BAPTA altered the neurite outgrowth and associated changes in the phospho-MAP kinase levels, which were blunted by 2M^*, 4) 2M^* promoted the phosphorylation of the transcription factor CREB through MAP kinase, and 5) LRP-specific antibodies increased levels of phosphorylated MAP kinase and phosphorylated CREB. The effects of 2M^*, apoE3, and apoE peptides increased LRP levels in the cortical neurons, whereas LRP receptor-associated protein reduced dendritic LRP expression. These results demonstrate that p44/42 MAP kinase plays an important role in LRP-mediated neurite outgrowth with activation involving the effects on calcium homeostasis and downstream effects involving the activation of gene transcription through CREB.

Received for publication, January 30, 2004 , and in revised form, May 20, 2004.

^* This work was supported by National Institutes of Health Grants R01 AG14473 (to G. W. R.) and R37 AG12406 (to B. T. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 202-687-1534; Fax: 202-687-0617; E-mail: gwr2{at}georgetown.edu.

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