A distinct ER/IC gamma-secretase competes with the proteasome for cleavage of APP

Biochemistry. 2000 Feb 1;39(4):810-7. doi: 10.1021/bi991728z.


The deposition of amyloid-beta peptides (Abeta) in senile plaques (SPs) is a central pathological feature of Alzheimer's disease (AD). Since SPs are composed predominantly of Abeta1-42, which is more amyloidogenic in vitro, the enzymes involved in generating Abeta1-42 may be particularly important to the pathogenesis of AD. In contrast to Abeta1-40, which is generated in the trans-Golgi network and other cytoplasmic organelles, intracellular Abeta1-42 is produced in the endoplasmic reticulum/intermediate compartment (ER/IC), where it accumulates in a stable insoluble pool. Since this pool of insoluble Abeta1-42 may play a critical role in AD amyloidogenesis, we sought to determine how the production of intracellular Abeta is regulated. Surprisingly, the production of insoluble intracellular Abeta1-42 was increased by a putative gamma-secretase inhibitor as well as by an inhibitor of the proteasome. We further demonstrate that this increased generation of Abeta1-42 in the ER/IC is due to a reduction in the turnover of Abeta-containing APP C-terminal fragments. We conclude that the proteasome is a novel site for degradation of ER/IC-generated APP fragments. Proteasome inhibitors may augment the availability of APP C-terminal fragments for gamma-secretase cleavage and thereby increase production of Abeta1-42 in the ER/IC. Based on the organelle-specific differences in the generation of Abeta by gamma-secretase, we conclude that intracellular ER/IC-generated Abeta1-42 and secreted Abeta1-40 are produced by different gamma-secretases. Further, the fact that a putative gamma-secretase inhibitor had opposite effects on the production of secreted and intracellular Abeta may have important implications for AD drug design.

Publication types

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

MeSH terms

  • Acetylcysteine / analogs & derivatives
  • Acetylcysteine / pharmacology
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / biosynthesis
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / antagonists & inhibitors
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases
  • Binding, Competitive
  • CHO Cells
  • Cell Compartmentation
  • Cricetinae
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Endopeptidases / metabolism*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / enzymology*
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Hydrolysis
  • Intracellular Fluid / metabolism
  • Leupeptins / pharmacology
  • Multienzyme Complexes / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / biosynthesis
  • Proteasome Endopeptidase Complex
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Recombinant Fusion Proteins / metabolism
  • Tumor Cells, Cultured


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Cysteine Proteinase Inhibitors
  • Leupeptins
  • Multienzyme Complexes
  • Peptide Fragments
  • Recombinant Fusion Proteins
  • amyloid beta-protein (1-42)
  • lactacystin
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Cysteine Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde
  • Acetylcysteine