Journal Article

The Golgi-Localized gamma -Ear-Containing ARF-Binding (GGA) Proteins Alter Amyloid- beta Precursor Protein (APP) Processing through Interaction of Their GAE Domain with the Beta-Site APP Cleaving Enzyme 1 (BACE1): e0129047

Boeckers, Tobias M, Rueck, Angelika, Wirth, Thomas, Einem, Bjoern von, Schips, Tobias, Danzer, Karin M, Wahler, Anke, Serrano-Pozo, Alberto, Proepper, Christian, Hyman, Bradley T

2015

Overview

Proteolytic processing of amyloid- beta precursor protein (APP) by beta-site APP cleaving enzyme 1 (BACE1) is the initial step in the production of amyloid beta (A beta ), which accumulates in senile plaques in Alzheimer's disease (AD). Essential for this cleavage is the transport and sorting of both proteins through endosomal/Golgi compartments. Golgi-localized gamma -ear-containing ARF-binding (GGA) proteins have striking cargo-sorting functions in these pathways. Recently, GGA1 and GGA3 were shown to interact with BACE1, to be expressed in neurons, and to be decreased in AD brain, whereas little is known about GGA2. Since GGA1 impacts A beta generation by confining APP to the Golgi and perinuclear compartments, we tested whether all GGAs modulate BACE1 and APP transport and processing. We observed decreased levels of secreted APP alpha (sAPP alpha ), sAPP beta , and A beta upon GGA overexpression, which could be reverted by knockdown. GGA-BACE1 co-immunoprecipitation was impaired upon GGA-GAE but not VHS domain deletion. Autoinhibition of the GGA1-VHS domain was irrelevant for BACE1 interaction. Our data suggest that all three GGAs affect APP processing via the GGA-GAE domain.