GGA1 is expressed in the human brain and affects the generation of amyloid beta-peptide.
The beta-amyloid peptide (Abeta) is a major component of Alzheimer disease (AD)-associated senile plaques and is generated by sequential cleavage of the beta-amyloid precursor protein (APP) by beta-secretase (BACE1) and gamma-secretase. BACE1 cleaves APP at the N terminus of the Abeta domain, generating a membrane-bound C-terminal fragment (CTF-beta) that can be subsequently cleaved by gamma-secretase within the transmembrane domain to release Abeta. Because BACE1 initiates Abeta generation, it represents a potential target molecule to interfere with Abeta production in therapeutic strategies for AD. BACE1 interacts with Golgi-localized, gamma-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-beta generation. Importantly, overexpression of GGA1 reduced, whereas RNAi-mediated suppression of GGA1 increased the secretion of Abeta. 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 Abeta generation. Thus, GGA proteins might be involved in the pathogenesis of AD.
Wahle
Tina
T
Department of Neurology, University of Bonn, 53127 Bonn, Germany.
Thal
Dietmar R
DR
Sastre
Magdalena
M
Rentmeister
Andrea
A
Bogdanovic
Nenad
N
Famulok
Michael
M
Heneka
Michael T
MT
Walter
Jochen
J
D020727:ADP-Ribosylation Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D033942:Adaptor Proteins, Vesicular Transport / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011499:Protein Processing, Post-Translational / Q000502:physiology
D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; C407306:GGA adaptor proteins; D020727:ADP-Ribosylation Factors