GGA1 acts as a spatial switch altering amyloid precursor protein trafficking and processing

The β-amyloid (Aβ) precursor protein (APP) is cleaved sequentially by β-site of APP-cleaving enzyme (BACE) and γ-secretase to release the Aβ peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized γ-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 β-cleavage but surprisingly reduced Aβ. 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 β-cleavage products from becoming substrates for γ-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.