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The Journal of Neuroscience, December 6, 2006, 26(49):12838-12846; doi:10.1523/JNEUROSCI.1982-06.2006

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Neurobiology of Disease
GGA1 Is Expressed in the Human Brain and Affects the Generation of Amyloid ß-Peptide

Tina Wahle,¹ Dietmar R. Thal,² Magdalena Sastre,¹ Andrea Rentmeister,³ Nenad Bogdanovic,⁴ Michael Famulok,³ Michael T. Heneka,¹ and Jochen Walter¹

¹Department of Neurology, ²Institute of Neuropathology, and ³Kekulé-Institute for Organic Chemistry and Biochemistry, University of Bonn, 53127 Bonn, Germany, and ⁴Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank Klinisk Forskingscentrum, 14186 Stockholm, Sweden

Correspondence should be addressed to Dr. Jochen Walter, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. Email: Jochen.Walter{at}ukb.uni-bonn.de

The ß-amyloid peptide (Aß) is a major component of Alzheimer disease (AD)-associated senile plaques and is generated by sequential cleavage of the ß-amyloid precursor protein (APP) by ß-secretase (BACE1) and -secretase. BACE1 cleaves APP at the N terminus of the Aß domain, generating a membrane-bound C-terminal fragment (CTF-ß) that can be subsequently cleaved by -secretase within the transmembrane domain to release Aß. Because BACE1 initiates Aß generation, it represents a potential target molecule to interfere with Aß production in therapeutic strategies for AD. BACE1 interacts with Golgi-localized, -ear-containing, ADP ribosylation factor-binding (GGA) proteins that are involved in the subcellular trafficking of BACE1. Here, we show that GGA1 is preferentially expressed in neurons of the human brain. GGA1 was also detected in activated microglia surrounding amyloid plaques in AD brains. Functional analyses with cultured cells demonstrate that GGA1 is implicated in the proteolytic processing of APP. Overexpression of GGA1 or a dominant-negative variant reduced cleavage of APP by BACE1 as indicated by a decrease in CTF-ß generation. Importantly, overexpression of GGA1 reduced, whereas RNAi-mediated suppression of GGA1 increased the secretion of Aß. The modulation of APP processing by GGA1 is independent of a direct interaction of both proteins. Because total cellular activity of BACE1 was not affected by GGA1 expression, our data indicate that changes in the subcellular trafficking of BACE1 or other GGA1-dependent proteins contribute to changes in APP processing and Aß generation. Thus, GGA proteins might be involved in the pathogenesis of AD.

Key words: APP; secretase; BACE; trafficking; processing; endosomes

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Received Dec. 23, 2005; revised Oct. 31, 2006; accepted Nov. 3, 2006.

Correspondence should be addressed to Dr. Jochen Walter, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. Email: Jochen.Walter{at}ukb.uni-bonn.de

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