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

Abstract

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.

SorLA/LR11 Regulates Processing of Amyloid Precursor Protein via Interaction with Adaptors GGA and PACS-1

“…7, A and B). Remarkably, previous studies have implicated GGA-1 in APP processing inasmuch as reduced expression of the adaptor enhanced, whereas overexpression of the adaptor decreased A␤ production (32). These effects were independent of a direct interaction between APP and GGA, suggesting the presence of another factor (such as sorLA) that may link both components (33).…”

Autophagy, amyloidogenesis and Alzheimer disease

“…Alternatively, cell surface APP is internalized within early endosomes, where cleavage at a more distal site along the lumenal/extracellular domain by ␤-site-APPcleaving enzyme (BACE, ␤-secretase) releases a soluble APP fragment (sAPP ␤) and generates a membrane-associated 99-residue CTF (␤CTF) that contains the whole A␤ peptide. A transmembrane aspartyl protease that has optimal activity at low pH distributes predominantly to endosomes (Vassar et al, 1999;Capell et al, 2000;Walter et al, 2001), where ␤CTF has been shown to be generated (Grbovic, 2003;Mathews et al, 2002), although additional BACE is found in the TGN (von Arnim et al, 2006) (Fig. 3).…”

Spectrally resolved fluorescence lifetime imaging microscopy: Förster resonant energy transfer global analysis with a one- and two-exponential donor model

“…3 In the field of Alzheimer's disease (AD), it has been widely used to establish protein-protein interaction and also protein conformation. [4][5][6][7][8] However, FRET measurements and analysis in living cells is very challenging due to suboptimal excitation and emission overlap of donor and acceptor, high autofluorescence, low quantum yield of living color tags, reduced signal intensity of proteins with low abundancy, and hence, poor signal-to-noise (S/N) ratio. A very complex situation arises when more than one compound has to be analyzed.…”

“…Special attention is focused on FRET measurements with respect to protein interactions involved in processing of β-amyloid (Abeta) precursor protein (APP). 6,7 APP is cleaved sequentially by β-site of APP-cleaving enzyme (BACE) and γ -secretase to release the Abeta peptides that accumulate in plaques in AD. GGA1, a member of the Golgi-localized γ -ear-containing ARFbinding (GGA) protein family, interacts with BACE and influences its subcellular distribution.…”