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J. Biol. Chem., Vol. 280, Issue 14, 13913-13920, April 8, 2005

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The Amyloid Precursor Protein (APP) of Alzheimer Disease and Its Paralog, APLP2, Modulate the Cu/Zn-Nitric Oxide-catalyzed Degradation of Glypican-1 Heparan Sulfate in Vivo^*

Roberto Cappai¶, Fang Cheng||, Giuseppe D. Ciccotosto¶, B. Elise Needham¶, Colin L. Masters¶, Gerd Multhaup**, Lars-Åke Fransson||, and Katrin Mani||

From the ^||Department of Cell and Molecular Biology, Section for Cell and Matrix Biology, Lund University, Biomedical Center C13, SE-221 84, Lund, Sweden, Department of Pathology and Center for Neuroscience, The University of Melbourne, Victoria 3010, ^¶The Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia, and ^**Institute for Chemistry/Biochemistry, Free University of Berlin, Thielallee 63, D-14195, Berlin, Germany

Processing of the recycling proteoglycan glypican-1 involves the release of its heparan sulfate chains by copper ion- and nitric oxide-catalyzed ascorbate-triggered autodegradation. The Alzheimer disease amyloid precursor protein (APP) and its paralogue, the amyloid precursor-like protein 2 (APLP2), contain copper ion-, zinc ion-, and heparan sulfate-binding domains. We have investigated the possibility that APP and APLP2 regulate glypican-1 processing during endocytosis and recycling. By using cell-free biochemical experiments, confocal laser immunofluorescence microscopy, and flow cytometry of tissues and cells from wild-type and knock-out mice, we find that (a) APP and glypican-1 colocalize in perinuclear compartments of neuroblastoma cells, (b) ascorbate-triggered nitric oxidecatalyzed glypican-1 autodegradation is zinc ion-dependent in the same cells, (c) in cell-free experiments, APP but not APLP2 stimulates glypican-1 autodegradation in the presence of both Cu(II) and Zn(II) ions, whereas the Cu(I) form of APP and the Cu(II) and Cu(I) forms of APLP2 inhibit autodegradation, (d) in primary cortical neurons from APP or APLP2 knock-out mice, there is an increased nitric oxide-catalyzed degradation of heparan sulfate compared with brain tissue and neurons from wild-type mice, and (e) in growth-quiescent fibroblasts from APLP2 knock-out mice, but not from APP knock-out mice, there is also an increased heparan sulfate degradation. We propose that the rate of autoprocessing of glypican-1 is modulated by APP and APLP2 in neurons and by APLP2 in fibroblasts. These observation identify a functional relationship between the heparan sulfate and copper ion binding activities of APP/APLP2 in their modulation of the nitroxyl anion-catalyzed heparan sulfate degradation in glypican-1.

Received for publication, August 11, 2004 , and in revised form, January 24, 2005.

^* The work was supported by grants from the Swedish Science Council (VR-M), the Cancer Fund, the Alzheimerfonden, the Tegger, Kock, and Österlund Foundations, and the Medical Faculty of Lund University (to L.-Å. F. and K. M.) and in part by the National Health and Medical Research Council of Australia (to R. C. and C. L. M.) and the Deutsche Forschungsgemeinschaft (to G. M.). 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: Dept. of Cell and Molecular Biology, Lund University, BMC C13, SE-221 84, Lund, Sweden. Tel.: 46-46-222-8573; Fax.: 46-46-222-3128; E-mail: lars-ake.fransson{at}medkem.lu.se.

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