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Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.

Point mutations in the presenilin-1 gene (PS1) are a major cause of familial Alzheimer's disease. They result in a selective increase in the production of the amyloidogenic peptide amyloid-beta(1-42) by proteolytic processing of the amyloid precursor protein (APP). Here we investigate whether PS1 is also involved in normal APP processing in neuronal cultures derived from PS1-deficient mouse embryos. Cleavage by alpha- and beta-secretase of the extracellular domain of APP was not affected by the absence of PS1, whereas cleavage by gamma-secretase of the transmembrane domain of APP was prevented, causing carboxyl-terminal fragments of APP to accumulate and a fivefold drop in the production of amyloid peptide. Pulse-chase experiments indicated that PS1 deficiency specifically decreased the turnover of the membrane-associated fragments of APP. As in the regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor, PS1 appears to facilitate a proteolytic activity that cleaves the integral membrane domain of APP. Our results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease.

Pubmed ID: 9450754

Authors

  • De Strooper B
  • Saftig P
  • Craessaerts K
  • Vanderstichele H
  • Guhde G
  • Annaert W
  • Von Figura K
  • Van Leuven F

Journal

Nature

Publication Data

January 22, 1998

Associated Grants

None

Mesh Terms

  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Animals
  • Aspartic Acid Endopeptidases
  • Cells, Cultured
  • Endopeptidases
  • Humans
  • Membrane Proteins
  • Mice
  • Neurons
  • Peptide Fragments
  • Point Mutation
  • Presenilin-1
  • Protein Processing, Post-Translational