The Department of Biochemistry and Molecular Biology and Bio21 Institute, The University of Melbourne, Victoria 3010, Australia
Alzheimer’s disease (AD) is characterized by the extracellular deposition of amyloid plaques in the brain. These plaques are formed by the accumulation and aggregation of β-amyloid peptide (Aβ) derived through the sequential cleavage of β-amyloid precursor protein (APP) by membrane-bound enzymes β-secretase (BACE1) and γ-secretase, with BACE1 cleavage being the rate-limiting step in Aβ production. The levels of Aβ production have been shown to be dependent on the subcellular localization and trafficking pathways of APP and BACE1. Although the processing of APP has been shown to occur in the secretory pathway, the post-Golgi trafficking of APP is not well understood. Adaptor protein complex 4 (AP-4) has recently been implicated in the post-Golgi trafficking of APP. However, it has been unclear how AP-4 is recruited to the trans-Golgi network (TGN). Here we have identified Arl5b, an Arf-like (Arl) small G protein, to play a role in the TGN recruitment of AP-4. AP-4 has been found to co-immunoprecipitate with active GTP-bound Arl5b, suggesting a potential interaction. The knockdown of Arl5b in cultured cells results in a reduction in TGN localisation of AP-4 but not AP-1 (another TGN localized AP complex), accumulation of APP at the TGN, and increased Aβ production. AP-4 mutations have been discovered in human patients suffering from severe brain abnormalities, thus we now seek to determine the role of AP-4 in the post-Golgi trafficking of APP in neurons. Collectively, we propose that an efficient post-Golgi trafficking of APP is critical in regulating Aβ production.