A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing

Biochemistry. 2002 Feb 26;41(8):2825-35. doi: 10.1021/bi015794o.

Abstract

Proteolytic processing of the transmembrane domain of the amyloid precursor protein (APP) is a key component of Alzheimer's disease pathogenesis. Using C-terminally tagged APP derivatives, we have identified by amino-terminal sequencing a novel cleavage site of APP, at Leu-49, distal to the gamma-secretase site. This was termed -cleavage. Brefeldin A treatment and pulse-chase experiments indicate that this cleavage occurs late in the secretory pathway. The level of -cleavage is decreased by expression of presenilin-1 mutants known to impair Abeta formation, and it is sensitive to the gamma-secretase inhibitors MDL28170 and L-685,458. Remarkably, it shares similarities with site 3 cleavage of Notch-1: membrane topology, cleavage before a valine, dependence on presenilins, and inhibition profile.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amino Acid Sequence
  • Amyloid beta-Protein Precursor / chemistry
  • Amyloid beta-Protein Precursor / drug effects
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Base Sequence
  • Blotting, Western
  • COS Cells
  • DNA Primers
  • Hydrolysis
  • Membrane Proteins / metabolism
  • Molecular Sequence Data
  • Presenilin-1
  • Protease Inhibitors / pharmacology
  • Tumor Cells, Cultured

Substances

  • Amyloid beta-Protein Precursor
  • DNA Primers
  • Membrane Proteins
  • Presenilin-1
  • Protease Inhibitors