Apolipoprotein E4 potentiates amyloid beta peptide-induced lysosomal leakage and apoptosis in neuronal cells

J Biol Chem. 2002 Jun 14;277(24):21821-8. doi: 10.1074/jbc.M112109200. Epub 2002 Mar 23.


We assessed the isoform-specific effects of apolipoprotein (apo) E on the response of Neuro-2a cells to the amyloid beta peptide (Abeta1-42). As determined by the intracellular staining pattern and the release of beta-hexosaminidase into the cytosol, apoE4-transfected cells treated with aggregated Abeta1-42 showed a greater tendency toward lysosomal leakage than neo- or apoE3-transfected cells. Abeta1-42 caused significantly greater cell death and more than 2-fold greater DNA fragmentation in apoE4-secreting than in apoE3-secreting or control cells. H2O2 or staurosporine enhanced cell death and apoptosis in apoE4-transfected cells but not in apoE3-transfected cells. A caspase-9 inhibitor abolished the potentiation of Abeta1-42-induced apoptosis by apoE4. Similar results were obtained with conditioned medium from cells secreting apoE3 or apoE4. Cells preincubated for 4 h with a source of apoE3 or apoE4, followed by removal of apoE from the medium and from the cell surface, still exhibited the isoform-specific response to Abeta1-42, indicating that the potentiation of apoptosis required intracellular apoE, presumably in the endosomes or lysosomes. Studies of phospholipid (dimyristoylphosphatidylcholine) bilayer vesicles encapsulating 5-(and-6)-carboxyfluorescein dye showed that apoE4 remodeled and disrupted the phospholipid vesicles to a greater extent than apoE3 or apoE2. In response to Abeta1-42, vesicles containing apoE4 were disrupted to a greater extent than those containing apoE3. These findings are consistent with apoE4 forming a reactive molecular intermediate that avidly binds phospholipid and may insert into the lysosomal membrane, destabilizing it and causing lysosomal leakage and apoptosis in response to Abeta1-42.

Publication types

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

MeSH terms

  • Amyloid beta-Peptides / chemistry*
  • Animals
  • Apolipoprotein E4
  • Apolipoproteins E / chemistry*
  • Apoptosis*
  • DNA Fragmentation
  • Dimyristoylphosphatidylcholine / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Lysosomes / metabolism*
  • Mice
  • Microscopy, Fluorescence
  • Neurons / metabolism*
  • Protein Isoforms
  • Staurosporine / pharmacology
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured


  • Amyloid beta-Peptides
  • Apolipoprotein E4
  • Apolipoproteins E
  • Enzyme Inhibitors
  • Protein Isoforms
  • Hydrogen Peroxide
  • Staurosporine
  • Dimyristoylphosphatidylcholine