No abstract

The metalloprotease ADAM 10 is a drug target in Alzheimer's disease, where it cleaves the amyloid precursor protein ( APP ) and lowers amyloid‐beta. Yet, ADAM 10 has additional substrates, which may cause mechanism‐based side effects upon therapeutic ADAM 10 activation. However, they may also serve—in addition to APP —as biomarkers to monitor ADAM 10 activity in patients and to develop APP ‐selective ADAM 10 activators. Our study demonstrates that one such substrate is the neuronal cell adhesion protein Nr CAM . ADAM 10 controlled Nr CAM surface levels and regulated neurite outgrowth in vitro in an Nr CAM ‐dependent manner. However, ADAM 10 cleavage of Nr CAM , in contrast to APP , was not stimulated by the ADAM 10 activator acitretin, suggesting that substrate‐selective ADAM 10 activation may be feasible. Indeed, a whole proteome analysis of human CSF from a phase II clinical trial showed that acitretin, which enhanced APP cleavage by ADAM 10, spared most other ADAM 10 substrates in brain, including Nr CAM . Taken together, this study demonstrates an Nr CAM ‐dependent function for ADAM 10 in neurite outgrowth and reveals that a substrate‐selective, therapeutic ADAM 10 activation is possible and may be monitored with Nr CAM .