Intracellular Itinerary of Internalised β‐Secretase, BACE1, and Its Potential Impact on β‐Amyloid Peptide Biogenesis

Abstract

β-Secretase (BACE1) cleavage of the amyloid precursor protein (APP) represents the initial step in the formation of the Alzheimer's disease associated amyloidogenic Aβ peptide. Substantive evidence indicates that APP processing by BACE1 is dependent on intracellular sorting of this enzyme. Nonetheless, knowledge of the intracellular trafficking pathway of internalised BACE1 remains in doubt. Here we show that cell surface BACE1 is rapidly internalised by the AP2/clathrin dependent pathway in transfected cells and traffics to early endosomes and Rab11-positive, juxtanuclear recycling endosomes, with very little transported to the TGN as has been previously suggested. Moreover, BACE1 is predominantly localised to the early and recycling endosome compartments in different cell types, including neuronal cells. In contrast, the majority of internalised wild-type APP traffics to late endosomes/lysosomes. To explore the relevance of the itinerary of BACE1 on APP processing, we generated a BACE1 chimera containing the cytoplasmic tail of TGN38 (BACE/TGN38), which cycles between the cell surface and TGN in an AP2-dependent manner. Wild-type BACE1 is less efficient in Aβ production than the BACE/TGN38 chimera, highlighting the relevance of the itinerary of BACE1 on APP processing. Overall the data suggests that internalised BACE1 and APP diverge at early endosomes and that Aβ biogenesis is regulated in part by the recycling itinerary of BACE1.

Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase

“…Most studies recognize the importance of endocytic trafficking of APP for Aβ production [reviewed in [6,11,12]. This notion is in agreement with the predominant steady-state localization of BACE1 in endocytic organelles, and its trafficking and recycling between the plasma membrane and endosomes [1,13,14]. Moreover, BACE1 activity has a low pH optimum in vitro [1], supporting a model where APP cleavage by BACE1 occurs in acidic intracellular organelles such as the endosomes.…”

Forty Years of Clathrin‐coated Vesicles

“…There is no doubt that alterations in the cell's trafficking machinery can increase the frequency of the proteolytic event that makes the protein amyloidogenic , and a genome‐wide association study identified the clathrin adaptor CALM as a susceptibility locus for Alzheimer's disease . However, the situation is complicated by the involvement of other proteins that are also trafficked in a clathrin‐dependent manner, such the APP sorting receptor SORL1 , and the β‐secretases, which cleave APP . A further complication is that clathrin‐mediated trafficking can also be used to clear away the amyloidogenic peptide, and thus prevent the build‐up of plaques .…”

A Function for EHD Family Proteins in Unidirectional Retrograde Dendritic Transport of BACE1 and Alzheimer’s Disease Aβ Production

“…In non-neuronal cells, BACE1 cycles between plasma membrane and endosomes, and shows predominant steady-state localization in endocytic organelles (Vassar et al, 1999; Huse et al, 2000; Chia et al, 2013). Two routes of BACE1 endocytosis, a clathrin and adaptor protein-2 complex (AP-2) dependent (clathrin-dependent) and an ADP-ribosylation factor 6 dependent (clathrin-independent), have been described (Prabhu et al, 2012; Sannerud et al, 2011; Das et al, 2013).…”