Amyloid beta inhibits ectodomain shedding of N-cadherin via down-regulation of cell-surface NMDA receptor

Neuroscience. 2007 Mar 2;145(1):5-10. doi: 10.1016/j.neuroscience.2006.12.022. Epub 2007 Jan 25.


Dysfunction in the synapse is recognized as an early and the primary pathological process in Alzheimer's disease (AD). N-cadherin, an essential adhesion molecule for excitatory synaptic contact, forms a complex with presenilin 1 (PS1) and beta-catenin in the synaptic membrane. N-cadherin is sequentially cleaved by ADAM10 and PS1/gamma-secretase, producing a cytoplasmic fragment, N-cadherin C-terminal fragment (Ncad/CTF2) after NMDA receptor stimulation [Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK (2003) A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114:635-645; Reiss K, Maretzky T, Ludwig A, Tousseyn T, de Strooper B, Hartmann D, Saftig P (2005) ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and beta-catenin nuclear signalling. EMBO J 24:1762]. Ncad/CTF2 translocates to the nucleus together with beta-catenin to enhance beta-catenin nuclear signaling [Uemura K, Kihara T, Kuzuya A, Okawa K, Nishimoto T, Bito H, Ninomiya H, Sugimoto H, Kinoshita A, Shimohama S (2006a) Activity-dependent regulation of beta-catenin via epsilon-cleavage of N-cadherin. Biochem Biophys Res Commun 345:951-958]. To examine whether an impairment of N-cadherin metabolism is involved in AD pathogenesis, we investigated the effect of amyloid beta peptide (Abeta) treatment on sequential N-cadherin cleavage. Here, we demonstrate that both synthetic and cell-derived Abeta species inhibit ectodomain shedding of mouse N-cadherin. Inhibition of N-cadherin cleavage by Abeta treatment was suggested to be mediated by the enhanced endocytosis of NMDA receptor, resulting in reduced turnover of N-cadherin. Since both N-cadherin and beta-catenin are essential for synaptic plasticity, impairment of N-cadherin cleavage caused by Abeta may underlie the synapse toxicity involved in AD pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / pharmacology
  • ADAM10 Protein
  • Amyloid Precursor Protein Secretases / pharmacology
  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Cadherins / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cricetinae
  • Cricetulus
  • Down-Regulation / drug effects*
  • Drug Interactions
  • Embryo, Mammalian
  • Excitatory Amino Acid Agents / pharmacology
  • Humans
  • Membrane Proteins / pharmacology
  • Mice
  • Models, Biological
  • Mutation
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Protein Structure, Tertiary / drug effects
  • Protein Transport / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Transfection


  • Amyloid beta-Peptides
  • Cadherins
  • Excitatory Amino Acid Agents
  • Membrane Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • ADAM10 protein, human