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The Journal of Neuroscience, September 27, 2006, 26(39):9913-9922; doi:10.1523/JNEUROSCI.2290-06.2006

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Neurobiology of Disease
GGA1 Acts as a Spatial Switch Altering Amyloid Precursor Protein Trafficking and Processing

Christine A. F. von Arnim,^1,2 Robert Spoelgen,¹ Ithan D. Peltan,¹ Meihua Deng,¹ Stephanie Courchesne,¹ Mirjam Koker,¹ Toshifumi Matsui,¹ Hisatomo Kowa,¹ Stefan F. Lichtenthaler,³ Michael C. Irizarry,¹ and Bradley T. Hyman¹

¹Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, ²Department of Neurology, Ulm University, D-89081 Ulm, Germany, and ³Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität, D-80336 München, Germany

Correspondence should be addressed to Dr. Bradley T. Hyman, Massachusetts General Institute of Neurodegenerative Diseases, 114 16th Street, Room number 2009, Charlestown, MA 02129. Email: bhyman{at}partners.org

The -amyloid (A) precursor protein (APP) is cleaved sequentially by -site of APP-cleaving enzyme (BACE) and -secretase to release the A peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized -ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from -cleavage but surprisingly reduced A. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP -cleavage products from becoming substrates for -secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP–GGA1 interactions may have pathophysiological relevance in AD.

Key words: Alzheimer's disease; amyloid precursor protein; Golgi-localized -ear-containing ARF binding protein 1; GGA1; BACE; trafficking; amyloid beta

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Received Dec. 23, 2005; revised Aug. 11, 2006; accepted Aug. 13, 2006.

Correspondence should be addressed to Dr. Bradley T. Hyman, Massachusetts General Institute of Neurodegenerative Diseases, 114 16th Street, Room number 2009, Charlestown, MA 02129. Email: bhyman{at}partners.org

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