A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations

Cell. 2003 Sep 5;114(5):635-45. doi: 10.1016/j.cell.2003.08.008.


Presenilin1 (PS1), a protein implicated in Alzheimer's disease (AD), forms complexes with N-cadherin, a transmembrane protein with important neuronal and synaptic functions. Here, we show that a PS1-dependent gamma-secretase protease activity promotes an epsilon-like cleavage of N-cadherin to produce its intracellular domain peptide, N-Cad/CTF2. NMDA receptor agonists stimulate N-Cad/CTF2 production suggesting that this receptor regulates the epsilon-cleavage of N-cadherin. N-Cad/CTF2 binds the transcription factor CBP and promotes its proteasomal degradation, inhibiting CRE-dependent transactivation. Thus, the PS1-dependent epsilon-cleavage product N-Cad/CTF2 functions as a potent repressor of CBP/CREB-mediated transcription. Importantly, PS1 mutations associated with familial AD (FAD) and a gamma-secretase dominant-negative mutation inhibit N-Cad/CTF2 production and upregulate CREB-mediated transcription indicating that FAD mutations cause a gain of transcriptional function by inhibiting production of transcriptional repressor N-Cad/CTF2. These data raise the possibility that FAD mutation-induced transcriptional abnormalities maybe causally related to the dementia associated with FAD.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • Blotting, Western
  • Cadherins / chemistry
  • Cadherins / metabolism*
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Cysteine Endopeptidases / metabolism
  • Cytoplasm / metabolism
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Endopeptidases / metabolism
  • Genes, Dominant
  • Genetic Vectors
  • Humans
  • Immunoblotting
  • Membrane Proteins / metabolism
  • Mice
  • Microscopy, Fluorescence
  • Multienzyme Complexes / metabolism
  • Mutation
  • Neurons / metabolism
  • Peptides / chemistry
  • Precipitin Tests
  • Presenilin-1
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Protein Structure, Tertiary
  • Reverse Transcriptase Polymerase Chain Reaction
  • Subcellular Fractions / metabolism
  • Synapses / metabolism
  • Time Factors
  • Transcription, Genetic*
  • Transcriptional Activation
  • Tubulin / metabolism


  • Cadherins
  • Carrier Proteins
  • Membrane Proteins
  • Multienzyme Complexes
  • PSEN1 protein, human
  • Peptides
  • Presenilin-1
  • Tubulin
  • citrate-binding transport protein
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Cysteine Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse
  • Proteasome Endopeptidase Complex