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J. Biol. Chem., Vol. 279, Issue 5, 3862-3868, January 30, 2004

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Astroglial Regulation of Apolipoprotein E Expression in Neuronal Cells

IMPLICATIONS FOR ALZHEIMER'S DISEASE^*

Faith M. Harris, Ina Tesseur¶, Walter J. Brecht, Qin Xu, Karin Mullendorff, Shengjun Chang, Tony Wyss-Coray¶||, Robert W. Mahley**, and Yadong Huang**

From the Gladstone Institute of Neurological Disease, Gladstone Institute of Cardiovascular Disease, and Departments of ^||Neurology, ^**Pathology, and Medicine, University of California, San Francisco, California 94141-9100

Although apolipoprotein (apo) E is synthesized in the brain primarily by astrocytes, neurons in the central nervous system express apoE, albeit at lower levels than astrocytes, in response to various physiological and pathological conditions, including excitotoxic stress. To investigate how apoE expression is regulated in neurons, we transfected Neuro-2a cells with a 17-kilobase human apoE genomic DNA construct encoding apoE3 or apoE4 along with upstream and downstream regulatory elements. The baseline expression of apoE was low. However, conditioned medium from an astrocytic cell line (C6) or from apoE-null mouse primary astrocytes increased the expression of both isoforms by 3-4-fold at the mRNA level and by 4-10-fold at the protein level. These findings suggest that astrocytes secrete a factor or factors that regulate apoE expression in neuronal cells. The increased expression of apoE was almost completely abolished by incubating neurons with U0126, an inhibitor of extracellular signal-regulated kinase (Erk), suggesting that the Erk pathway controls astroglial regulation of apoE expression in neuronal cells. Human neuronal precursor NT2/D1 cells expressed apoE constitutively; however, after treatment of these cells with retinoic acid to induce differentiation, apoE expression diminished. Cultured mouse primary cortical and hippocampal neurons also expressed low levels of apoE. Astrocyte-conditioned medium rapidly up-regulated apoE expression in fully differentiated NT2 neurons and in cultured mouse primary cortical and hippocampal neurons. Thus, neuronal expression of apoE is regulated by a diffusible factor or factors released from astrocytes, and this regulation depends on the activity of the Erk kinase pathway in neurons.

Received for publication, August 26, 2003 , and in revised form, October 27, 2003.

^* This work was supported in part by National Institutes of Health Grants P01 AG022074 and R01 HL37063. 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.

^¶ Current address: Dept. of Neurology and Neurological Sciences, Stanford University Medical Center, Rm. A343, Stanford, CA 94305-5235.

To whom correspondence should be addressed: Gladstone Institute of Neurological Disease, P. O. Box 419100, San Francisco, CA 94141-9100. Tel.: 415-826-7500; Fax: 415-285-5632; E-mail: yhuang{at}gladstone.ucsf.edu.

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