Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of beta-catenin, a component of the presenilin protein complex

Nat Med. 1999 Feb;5(2):164-9. doi: 10.1038/5526.


The presenilin proteins are components of high-molecular-weight protein complexes in the endoplasmic reticulum and Golgi apparatus that also contain beta-catenin. We report here that presenilin mutations associated with familial Alzheimer disease (but not the non-pathogenic Glu318Gly polymorphism) alter the intracellular trafficking of beta-catenin after activation of the Wnt/beta-catenin signal transduction pathway. As with their effect on betaAPP processing, the effect of PS1 mutations on trafficking of beta-catenin arises from a dominant 'gain of aberrant function' activity. These results indicate that mistrafficking of selected presenilin ligands is a candidate mechanism for the genesis of Alzheimer disease associated with presenilin mutations, and that dysfunction in the presenilin-beta-catenin protein complexes is central to this process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Biological Transport / genetics
  • Cell Line
  • Cell Nucleus / metabolism
  • Cytoskeletal Proteins / metabolism*
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mutation*
  • NF-kappa B / metabolism
  • Presenilin-1
  • Presenilin-2
  • Protein Binding
  • Signal Transduction / genetics
  • Trans-Activators*
  • beta Catenin


  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Membrane Proteins
  • NF-kappa B
  • PSEN1 protein, human
  • PSEN2 protein, human
  • Presenilin-1
  • Presenilin-2
  • Trans-Activators
  • beta Catenin