GGA1 Is Expressed in the Human Brain and Affects the Generation of Amyloid β-Peptide

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Abstract
The β-amyloid peptide (Aβ) is a major component of Alzheimer disease (AD)-associated senile plaques and is generated by sequential cleavage of the β-amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. BACE1 cleaves APP at the N terminus of the Aβ domain, generating a membrane-bound C-terminal fragment (CTF-β) that can be subsequently cleaved by γ-secretase within the transmembrane domain to release Aβ. Because BACE1 initiates Aβ generation, it represents a potential target molecule to interfere with Aβ production in therapeutic strategies for AD. BACE1 interacts with Golgi-localized, γ-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-β generation. Importantly, overexpression of GGA1 reduced, whereas RNAi-mediated suppression of GGA1 increased the secretion of Aβ. 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 Aβ generation. Thus, GGA proteins might be involved in the pathogenesis of AD.