A revised model for APP trafficking in the presynaptic terminal.

The figure illustrates the various recycling pathways proposed for synaptic vesicles in the presynaptic terminal, and how APP recycling can be integrated. Synaptic vesicle precursors are brought to the presynaptic terminal in transport vesicles. It is thought that these transport vesicles undergo a round of fusion with the plasma membrane followed by retrieval and sorting, possibly in an endosomal intermediate, to form fully functional synaptic vesicles, which are capable of undergoing fusion with the plasma membrane. Following exocytosis, vesicles are retrieved from the plasma membrane by endocytosis. Under physiological conditions this is thought to occur via a clathrin-mediated endocytosis (CME) pathway; it is still unclear whether vesicles lose their coats and are recycled directly, or whether they pass through an endosomal sorting intermediate. Putative endosomes may in fact be formed by activity dependend bulk endocytosis (ADBE) of plasma membrane, which is thought to occur during periods of heavy stimulation. APP trafficking at the synapse can be integrated into our current understanding of synaptic vesicle recycling. It is known that APP is also delivered to the presynaptic terminal in transport vesicles. These transport vesicles either fuse with the plasma membrane, depositing APP on the plasma membrane surface, or alternatively they fuse with an endosomal sorting intermediate (which we postulate is identical to that used during recycling of synaptic vesicles). Hence, synaptic vesicles could incorporate APP when recycling through the endosome (1). During synaptic vesicle exocytosis, APP cleavage products would then be released (2). Slight infidelities in the endocytic process might also mean small amounts of surface-resident APP could be endocytosed, along with bona fide synaptic vesicle proteins. These vesicles may then recycle directly for subsequent rounds of fusion and APP release, or pass through the endosomal system (3). Alternatively APP may be internalized and recycled into vesicles as a result of bulk endocytosis.