Amyloid peptides in different assembly states and related effects on isolated and cellular proteasomes

Brain Res. 2008 May 13;1209:8-18. doi: 10.1016/j.brainres.2008.03.003. Epub 2008 Mar 18.

Abstract

The role of amyloid-beta protein (Abeta) in the pathogenesis of Alzheimer's disease (AD) has been widely investigated and amyloid aggregates are considered a major cause of neuronal dysfunction. Increasing evidence has identified a correlation between this protein and the proteasome, the cellular proteolytic machinery, in particular the ubiquitin-proteasome system. The 20S proteasome is the catalytic core of a complex, known as 26S proteasome, and is the main responsible for the clearance of misfolded and oxidized proteins. In this work we have investigated the effects of different assembly states of two major amyloid peptides, Abeta (1-40) and Abeta (1-42) on the 20S proteasome functionality and on the ubiquitin-dependent pathway of protein degradation. In particular, we have tested proteasome activities after Abeta treatment on purified 20S complexes and on lysates of a human neuroblastoma cell line. Our findings show a significant decrease in proteasome activity, more evident in cell lysates than in isolated complexes, and an increased amount of ubiquitin-protein conjugates and of a known proteasome substrate (p27). Furthermore, the altered proteasome functionality is not associated with a decrease in cell viability, but is linked with increased levels of protein oxidation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / toxicity
  • Brain / metabolism*
  • Brain / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Humans
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Peptide Fragments / metabolism*
  • Peptide Fragments / toxicity
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Proteasome Endopeptidase Complex / drug effects
  • Proteasome Endopeptidase Complex / metabolism*
  • Ubiquitination / drug effects
  • Ubiquitination / physiology
  • Ubiquitins / metabolism

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Ubiquitins
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Proteasome Endopeptidase Complex