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The aspartate-257 of presenilin 1 is indispensable for mouse development and production of beta-amyloid peptides through beta-catenin-independent mechanisms.

To differentiate multiple activities of presenilin 1 (PS1), we generated transgenic mice expressing two human PS1 alleles: one with the aspartate to alanine mutation at residue 257 (hPS1D257A) that impairs the proteolytic activity of PS1, and the other deleting amino acids 340-371 of the hydrophilic loop sequence (hPS1Deltacat) essential for beta-catenin interaction. We show here that although hPS1Deltacat is fully competent in rescuing the PS1-null lethal phenotype, hPS1D257A does not exhibit developmental activity. hPS1D257A also leads to the concurrent loss of the proteolytic processing of Notch and beta-amyloid precursor protein (APP) and the generation of beta-amyloid peptides (Abeta). Further, by measuring the levels of endogenous Abeta(X-40) and Abeta(X-42) in primary neuronal cultures, we confirmed the concept that PS1 is indispensable for the production of secreted Abeta.

Pubmed ID: 12070348


  • Xia X
  • Wang P
  • Sun X
  • Soriano S
  • Shum WK
  • Yamaguchi H
  • Trumbauer ME
  • Takashima A
  • Koo EH
  • Zheng H


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

June 25, 2002

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS40039

Mesh Terms

  • Amyloid beta-Peptides
  • Animals
  • Aspartic Acid
  • Cytoskeletal Proteins
  • Hydrolysis
  • Membrane Proteins
  • Mice
  • Mice, Transgenic
  • Presenilin-1
  • Receptors, Notch
  • Trans-Activators
  • beta Catenin