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

Abstract

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

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

“…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). Although the influence of sorLA variants on APP processing has mainly been tested in CHO cells in this study, identical effects of wild type and mutant forms of the receptor on trafficking of APP in neurons (supplemental Figs.…”

Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine

“…Ten-micrometer-thick serial cryosections (10 per mouse, n = 8) with a defined distance were stained for Aβ using antibody 2964 as described in ref. 33 and analyzed by confocal microscopy.…”

Deficiency of Sphingosine-1-phosphate Lyase Impairs Lysosomal Metabolism of the Amyloid Precursor Protein

“…HEK293 cells stably overexpressing human APP695 were described previously (28). The cells were cultured in DMEM supplemented with 10% (MEF and HEK293) or in RPMI supplemented with 15% (SH-SY5Y) fetal calf serum (PAN Biotech) and 1% penicillin/streptomycin (Invitrogen).…”