Perturbation of membrane trafficking can lead to neurodegenerative diseases including Alzheimer’s disease (AD). Amyloid plaques in the brain is a hallmark of AD and are formed by the aggregation of amyloid β peptides (Aβ). Proteolytic processing of the membrane-bound amyloid precursor protein (APP) by the β-secretase, BACE1, is the initial rate-limiting step to generate Aβ. Defining the intracellular trafficking itinerary of newly synthesized BACE1 and APP, especially in neurons, is essential to understand the regulation of Aβ production and design of novel therapeutics. Aβ can be generated in both the endocytic and secretory pathways (1,2). We and others have defined the pathways and signals for internalization and endosomal sorting of BACE1 and APP (3,4). However, the anterograde trafficking pathways of newly synthesised BACE1 and APP are poorly defined.
Using a variety of imaging systems, including live imaging RUSH (5) and TIRF, and biochemical analyses, we show that newly synthesised BACE1 and APP are segregated at the trans-Golgi network (TGN) and take different routes; BACE1 is transported directly to the cell surface whereas APP is transported directly to early endosomes. We have identified distinct small G proteins and adaptor complexes that regulate these distinct pathways. For example, the adaptor complex AP-1 and the small G proteins, Arf1 and Arf4 are required for BACE1 transport from the Golgi-to-plasma membrane. Perturbation of the kinetics of post-Golgi transport by silencing machinery components enhances APP processing and Aβ production in primary neurons. In addition, we have shown that the TGN is an intracellular site for the production of the most cytotoxic Aβ peptide species, Aβ1-42, the major Aβ peptide of neural plaques in Alzheimer’s disease. These findings reveal that Golgi exit of BACE1 and APP in primary neurons is tightly regulated, resulting in their segregation along different transport routes, which limits APP processing.