NrCAM is a marker for substrate-selective activation of ADAM10 in Alzheimer's disease

EMBO Mol Med. 2019 Apr;11(4):e9695. doi: 10.15252/emmm.201809695.

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.

Keywords: ADAM10; Alzheimer's disease; NrCAM; acitretin; cerebrospinal fluid proteomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM10 Protein / antagonists & inhibitors
  • ADAM10 Protein / metabolism*
  • Acitretin / pharmacology
  • Acitretin / therapeutic use
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Cell Adhesion Molecules / antagonists & inhibitors
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • N-Methylaspartate / pharmacology
  • Neuronal Outgrowth / drug effects
  • Neurons / cytology
  • Neurons / metabolism
  • Proteolysis / drug effects
  • Proteome / analysis
  • Proteome / drug effects
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Substrate Specificity
  • Tetraspanins / genetics
  • Tetraspanins / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • Cell Adhesion Molecules
  • NRCAM protein, human
  • Proteome
  • RNA, Small Interfering
  • TSPAN15 protein, human
  • Tetraspanins
  • N-Methylaspartate
  • ADAM10 Protein
  • Acitretin