I find the work by Stefan Lichtenthaler´s group convincing, and it adds another important piece of evidence for the central role of the metalloproteinase ADAM10 in neuronal APP α-secretase processing. Similar to our recently published work (Jorissen et al., 2010), where we could show a dramatic reduction of the α-secretase generated APP fragments in conditional ADAM10-deleted neurons, this study comes to the same conclusion using knockdown approaches in different cell lines and primary murine neurons. In spite of the apparent central role of ADAM10 for the constitutive APP shedding and the non-amyloidogenic pathway, some open questions remain. Are there triggers/inducers/modulators in the CNS which also allow other (metallo) proteinases to take over the job of ADAM10 (the phorbol ester, PMA, that the authors use is not a very good physiological trigger for the induction of shedding activities)? How is the activity of ADAM10 (and maybe other ADAMs) regulated in vivo? Is ADAM10 needed for neuronal function and survival?

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I find the work by Stefan Lichtenthaler´s group convincing, and it adds another important piece of evidence for the central role of the metalloproteinase ADAM10 in neuronal APP α-secretase processing. Similar to our recently published work (Jorissen et al., 2010), where we could show a dramatic reduction of the α-secretase generated APP fragments in conditional ADAM10-deleted neurons, this study comes to the same conclusion using knockdown approaches in different cell lines and primary murine neurons. In spite of the apparent central role of ADAM10 for the constitutive APP shedding and the non-amyloidogenic pathway, some open questions remain. Are there triggers/inducers/modulators in the CNS which also allow other (metallo) proteinases to take over the job of ADAM10 (the phorbol ester, PMA, that the authors use is not a very good physiological trigger for the induction of shedding activities)? How is the activity of ADAM10 (and maybe other ADAMs) regulated in vivo? Is ADAM10 needed for neuronal function and survival?

Another interesting aspect is that the current work shows that α- and β-secretase do not compete for each other, and the downregulation of ADAM10 (and vice versa BACE) did not increase the activity of the other pathway. In our ADAM10-deleted neurons (Jorissen et al., 2010), we found a surprising co-downregulation of β-secretase-generated APP fragments. More studies are needed to determine, for example, the type of neurons used in both studies and to analyze the influence of the subcellular localization of BACE in ADAM10-deficient neurons.

In summary, the recent work identifying ADAM10 as the major APP α-secretase supports various approaches to promote the non-amyloidogenic pathway and thereby prevent the generation of the toxic amyloid-β peptides. However, ADAM10 cleaves other surface proteins, including Notch receptors and Notch-ligands, and in the meantime, more than 40 substrates (among them a number of neuronal proteins) have been described. One should also take this into account when discussing increasing ADAM10 activity as a suitable therapy in AD.

View all comments by Paul Saftig

This is a nice and quite systematic study of the long-standing question, What protease is responsible for the physiological α-secretase in neurons? Together with our previously published work (Jorissen et al., 2010) using conditionally targeted ADAM10 primary neurons, the conclusion is now quite clear: ADAM10 is the major candidate. It remains intriguing that under artificial stimulation conditions with phorbol esters, ADAM17 can cleave APP at the same site. It is now the question whether such stimulation of ADAM17 can occur under physiological conditions in the brain and whether it is possible to exploit that for pharmacological intervention. As always, more research is needed!

View all comments by Bart De Strooper