Protection against beta-amyloid-induced apoptosis by peptides interacting with beta-amyloid

J Biol Chem. 2007 Oct 26;282(43):31238-49. doi: 10.1074/jbc.M705558200. Epub 2007 Aug 30.


beta-Amyloid peptide produces apoptosis in neurons at micromolar concentrations, but the mechanism by which beta-amyloid exerts its toxic effect is unknown. The normal biological function of beta-amyloid is also unknown. We used phage display, co-precipitation, and mass spectrometry to examine the protein-protein interactions of beta-amyloid in normal rabbit brain in order to identify the biochemical receptors for beta-amyloid. beta-Amyloid was found to bind primarily to proteins involved in low density lipoprotein and cholesterol transport and metabolism, including sortilin, endoplasmic reticulum-Golgi intermediate compartment 2 (ERGIC2), ERGIC-53, steroid 5alpha-reductase, and apolipoprotein B. beta-Amyloid also bound to the C-reactive protein precursor, a protein involved in inflammation, and to 14-3-3, a protein that regulates glycogen synthase kinase-3beta, the kinase involved in tau phosphorylation. Of eight synthetic peptides identified as targets of beta-amyloid, three were found to be effective blockers of the toxic effect of beta-amyloid on cultured neuronal cells. These peptides bound to the hydrophobic region (residues 17-21) or to the nearby protein kinase C pseudo-phosphorylation site (residues 26-30) of beta-amyloid, suggesting that these may be the most critical regions for beta-amyloid effector action and for aggregation. Peptides or other small molecules that bind to this region may protect against beta-amyloid toxic effect by competitively blocking its ability to bind beta-amyloid effector proteins such as sortilin and 14-3-3.

MeSH terms

  • 14-3-3 Proteins / metabolism
  • 2',3'-Cyclic-Nucleotide Phosphodiesterases / analysis
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / metabolism
  • Adaptor Proteins, Vesicular Transport
  • Amyloid beta-Peptides / physiology
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Apolipoproteins B / metabolism
  • Apoptosis / drug effects*
  • Binding Sites
  • Blotting, Western
  • Caspase 3 / analysis
  • Cell Line
  • Hippocampus / cytology
  • Humans
  • Mannose-Binding Lectins / metabolism
  • Mass Spectrometry
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / metabolism
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Peptide Library
  • Peptides / metabolism*
  • Phosphoric Diester Hydrolases / analysis
  • Precipitin Tests
  • Protein Binding
  • Rats


  • 14-3-3 Proteins
  • Adaptor Proteins, Vesicular Transport
  • Amyloid beta-Peptides
  • Apolipoproteins B
  • Lman1 protein, rat
  • Mannose-Binding Lectins
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Peptide Library
  • Peptides
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
  • 2',3'-Cyclic-Nucleotide Phosphodiesterases
  • Phosphoric Diester Hydrolases
  • Caspase 3
  • sortilin