This is a very interesting paper. The authors show with a variety of elegant experiments that BACE1, but not APP, endocytosis is regulated by ARF6, most likely via a clathrin-independent pathway. ARF6 is mainly found at the cell membrane and regulates endocytosis of cargo. Interestingly, ARFs bind GGAs (Golgi-localized, γ ear-containing, ADP ribosylation factor-binding proteins), which are involved in protein trafficking, and regulate GGA recruitment to the cell membrane. ARF6 seems also to regulate BACE1 levels similarly to GGA3. This work raises the questions of whether ARF6 regulates BACE1 endocytosis and levels via GGA3 or other adaptors. We have shown that GGA3 levels are decreased in AD brains and inversely correlated with BACE1 levels. It would be interesting to determine whether ARF6 levels are also changed in AD brains.

BACE1 is a primary drug target for AD therapy. However, after a decade since the discovery of β-secretase, the identification of effective BACE1 inhibitors that are active in the CNS has been very difficult. The catalytic site of BACE1 is...  Read more

This is a very interesting paper. The authors show with a variety of elegant experiments that BACE1, but not APP, endocytosis is regulated by ARF6, most likely via a clathrin-independent pathway. ARF6 is mainly found at the cell membrane and regulates endocytosis of cargo. Interestingly, ARFs bind GGAs (Golgi-localized, γ ear-containing, ADP ribosylation factor-binding proteins), which are involved in protein trafficking, and regulate GGA recruitment to the cell membrane. ARF6 seems also to regulate BACE1 levels similarly to GGA3. This work raises the questions of whether ARF6 regulates BACE1 endocytosis and levels via GGA3 or other adaptors. We have shown that GGA3 levels are decreased in AD brains and inversely correlated with BACE1 levels. It would be interesting to determine whether ARF6 levels are also changed in AD brains.

BACE1 is a primary drug target for AD therapy. However, after a decade since the discovery of β-secretase, the identification of effective BACE1 inhibitors that are active in the CNS has been very difficult. The catalytic site of BACE1 is exceptionally long, and it has been very challenging to develop small compounds that efficiently inhibit BACE1, are able to cross the blood-brain barrier, and are reasonably stable. An alternative approach to BACE1 small-molecule inhibitors is the indirect inhibition of BACE1 through the modulation of regulatory mechanisms that control BACE1 levels or BACE1 trafficking to acidic compartments. Thus, both GGA3 and ARF6 represent potential therapeutical targets to decrease Aβ production.

View all comments by Giuseppina Tesco

This study by Sannerud et al. expands our understanding of how BACE1 meets up with APP in endocytic compartments to generate amyloid-β peptides. Although much is known about clathrin-dependent forms of endocytosis and the trafficking itinerary of plasma membrane proteins that enter cells by this mechanism, another parallel endocytic pathway exists that handles membrane proteins entering cells independent of the clathrin coat. There is communication among these membrane systems and exchange of cargo, but we are only beginning to understand the regulation and significance of these membrane trafficking pathways in cellular function. The finding that BACE1 enters cells through clathrin-independent endocytosis prior to meeting up with APP in common endocytic compartments reveals a complexity to their cellular itinerary and raises new potential targets for pharmacological intervention. Furthermore, it highlights important physiological functions for these “phantom” clathrin-independent endocytic pathways that are ubiquitous but underappreciated.

View all comments by Julie Donaldson

This elegant cell biology study adds another important piece to the puzzle of how endocytosis controls amyloid production. A few years ago, we showed that APP and BACE are internalized into early endosomes where β cleavage occurs (Rajendran et al., 2006). Here, the group of Wim Annaert shows that APP and BACE1 are internalized in distinct endocytic routes to reach the early endosome compartment. The authors show that while APP is internalized to early endosomes via a clathrin-dependent mechanism akin to that of the transferrin receptor, BACE1 is internalized via a clathrin-independent way. Certain proteins, particularly the ones associated with specialized lipid domains (lipid rafts) have been shown to be internalized via a clathrin-independent route. GPI anchored proteins and lipid binding toxins take this route to hitch their way into the interior of the cell.

While raft-dependent mechanisms have been implicated in the endocytosis of APP/ BACE1, this study is the first to show that the clathrin-independent endocytosis of BACE1...  Read more

This elegant cell biology study adds another important piece to the puzzle of how endocytosis controls amyloid production. A few years ago, we showed that APP and BACE are internalized into early endosomes where β cleavage occurs (Rajendran et al., 2006). Here, the group of Wim Annaert shows that APP and BACE1 are internalized in distinct endocytic routes to reach the early endosome compartment. The authors show that while APP is internalized to early endosomes via a clathrin-dependent mechanism akin to that of the transferrin receptor, BACE1 is internalized via a clathrin-independent way. Certain proteins, particularly the ones associated with specialized lipid domains (lipid rafts) have been shown to be internalized via a clathrin-independent route. GPI anchored proteins and lipid binding toxins take this route to hitch their way into the interior of the cell.

While raft-dependent mechanisms have been implicated in the endocytosis of APP/ BACE1, this study is the first to show that the clathrin-independent endocytosis of BACE1 requires a GTPase called Arf6. Arf6 is a small GTPase that, similarly to Rab GTPases, regulate membrane trafficking. Interestingly, Arf6 localizes to the plasma membrane and endosomes, and through binding to β-arrestins, Arf6 regulates G protein-coupled receptor internalization and desensitization. Arf6 mediated internalization seems to regulate amyloidogenic processing of APP and Aβ production. Of course, one needs to further understand the implications of this in the light of AD. It would be interesting to check if there is an increase in Arf6-GAP (GTPase activating protein) in Alzheimer's patients. Do age-related lipid alterations (high plasma membrane cholesterol, gangliosides) increase the clathrin-independent endocytosis of BACE1? Can one therapeutically exploit this new finding by targeting specifically the Arf6 pathway?

Arf6 also controls internalization of many other cargoes, and hence, manipulating Arf6 levels or activity might not be desirable, but one could design inhibitors of BACE1 that are trafficked to this route (Rajendran et al., 2008). Cell biological investigations are starting to reveal some of the most fascinating aspects of Alzheimer's disease.

View all comments by Lawrence Rajendran