Abstract
The metalloprotease ADAM10 is a drug target in Alzheimer's disease, where it cleaves the amyloid precursor protein (APP) and lowers amyloid‐beta. Yet, ADAM10 has additional substrates, which may cause mechanism‐based side effects upon therapeutic ADAM10 activation. However, they may also serve—in addition to APP—as biomarkers to monitor ADAM10 activity in patients and to develop APP‐selective ADAM10 activators. Our study demonstrates that one such substrate is the neuronal cell adhesion protein NrCAM. ADAM10 controlled NrCAM surface levels and regulated neurite outgrowth in vitro in an NrCAM‐dependent manner. However, ADAM10 cleavage of NrCAM, in contrast to APP, was not stimulated by the ADAM10 activator acitretin, suggesting that substrate‐selective ADAM10 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 ADAM10, spared most other ADAM10 substrates in brain, including NrCAM. Taken together, this study demonstrates an NrCAM‐dependent function for ADAM10 in neurite outgrowth and reveals that a substrate‐selective, therapeutic ADAM10 activation is possible and may be monitored with NrCAM.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and affects over 40 million patients worldwide (Scheltens et al, 2016; Selkoe & Hardy, 2016), but no causative or preventive treatment is currently available
a disintegrin and metalloprotease 10” (ADAM10) but not ADAM17 cleaves NrCAM in primary neurons To determine whether the cleaved, soluble ectodomain of NrCAM may be a suitable biomarker for ADAM10 activity, we first analyzed in detail the proteolytic processing of NrCAM in cultured neurons
Our study demonstrates that soluble, ADAM10-cleaved Soluble NrCAM (sNrCAM) is an excellent marker in AD patients for developing and testing drugs that selectively activate cleavage of amyloid precursor protein (APP) over other ADAM10 substrates
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and affects over 40 million patients worldwide (Scheltens et al, 2016; Selkoe & Hardy, 2016), but no causative or preventive treatment is currently available. Rare, partial loss-of-function mutations of ADAM10 are genetically linked to late-onset AD in patients (Kim et al, 2009) This reinforces the notion that an activation of ADAM10 may be beneficial to treat or even prevent AD and has led to a first, phase 2 clinical trial with AD patients treated over 4 weeks with the ADAM10 activator acitretin (Endres et al, 2014). Despite the positive outcome of the acitretin study, a key question is the safety profile of prolonged ADAM10 activation This is of particular concern, because ADAM10 cleaves numerous other substrates besides APP— generally referred to as ectodomain shedding (Lichtenthaler et al, 2018)—, both during embryonic development and in different adult tissues, including the adult brain (Saftig & Lichtenthaler, 2015; Kuhn et al, 2016).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
