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

Content Provider	Semantic Scholar
Author	Miranda, R. Dennis Huang, Ya-Dong
Copyright Year	2002
Abstract	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.
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://www.jbc.org/content/277/24/21821.full.pdf
PubMed reference number	11912196v1
Volume Number	277
Issue Number	24
Journal	The Journal of biological chemistry
Language	English
Access Restriction	Open
Subject Keyword	Adrenergic beta-Antagonists Amyloid beta-Peptides Apolipoprotein E Apolipoprotein E2 Apolipoprotein E3 Apolipoprotein E4 Apolipoproteins Apoptosis BETA-N-ACETYLHEXOSAMINIDASE Cell Death Cell secretion Culture Media, Conditioned Cytoplasmic matrix Dimyristoylphosphatidylcholine Dyes Endosomes Extravasation Hexosaminidases Hydrogen Peroxide Lysosomes Phospholipids Staurosporine Vesicle (morphologic abnormality) caspase-9 chemosensitization/potentiation
Content Type	Text
Resource Type	Article