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Molecular and Cellular Biology, November 2005, p. 9259-9268, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9259-9268.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

F-Spondin Interaction with the Apolipoprotein E Receptor ApoEr2 Affects Processing of Amyloid Precursor Protein

Department of Neuroscience,¹ Department of Neurology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, D.C. 20057-1464,² Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046³

Received 12 July 2005/ Accepted 8 August 2005

A recent study showed that F-spondin, a protein associated with the extracellular matrix, interacted with amyloid precursor protein (APP) and inhibited ß-secretase cleavage. F-spondin contains a thrombospondin domain that we hypothesized could interact with the family of receptors for apolipoprotein E (apoE). Through coimmunoprecipitation experiments, we demonstrated that F-spondin interacts with an apoE receptor (apoE receptor 2 [ApoEr2]) through the thrombospondin domain of F-spondin and the ligand binding domain of ApoEr2. Full-length F-spondin increased coimmunoprecipitation of ApoEr2 and APP in transfected cells and primary neurons and increased surface expression of APP and ApoEr2. Full-length F-spondin, but none of the individual F-spondin domains, increased cleavage of APP and ApoEr2, resulting in more secreted forms of APP and ApoEr2 and more C-terminal fragments (CTF) of these proteins. In addition, full-length F-spondin, but not the individual domains, decreased production of the ß-CTF of APP and Aß in transfected cells and primary neurons. The reduction in APP ß-CTF was blocked by receptor-associated protein (RAP), an inhibitor of lipoprotein receptors, implicating ApoEr2 in the altered proteolysis of APP. ApoEr2 coprecipitated with APP - and ß-CTF, and F-spondin reduced the levels of APP intracellular domain signaling, suggesting that there are also intracellular interactions between APP and ApoEr2, perhaps involving adaptor proteins. These studies suggest that the extracellular matrix molecule F-spondin can cluster APP and ApoEr2 together on the cell surface and affect the processing of each, resulting in decreased production of Aß.

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