The DOI matches its Crossref record; 113 of the 115 references it cites were found in a registry or an index.
Apolipoprotein E4 Potentiates Amyloid β Peptide-induced Lysosomal Leakage and Apoptosis in Neuronal Cells
Open accessAbstract
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.
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Metadata
- Authors
- Ji, Z.-S., Miranda, R. D., Newhouse, Y. M., Weisgraber, K. H., Huang, Y., & Mahley, R. W.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Mahley, Robert W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 277
- Issue
- 24
- Pages
- 21821-21828
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2043090568
- Cited by
- 177
- References
- 115
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 9 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 8 · 2019: 6 · 2018: 3 · 2017: 7 · 2016: 8 · 2015: 7 · 2014: 4 · 2013: 6 · 2012: 11
- FWCI
- 5.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01hl047660-10)
- National Heart, Lung, and Blood Institute (HL-47660)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- APOE ε4, apolipoprotein E isoforms, amyloid-beta, amyloid-beta 42, apoptosis, N2a cells, caspase-9, DNA fragmentation, lysosomal membrane destabilization, endosomes, Alzheimer's disease
- MeSH terms
- Animals, Apolipoproteins E, Dimyristoylphosphatidylcholine, Enzyme Inhibitors, Humans, Hydrogen Peroxide, Lysosomes, Microscopy, Fluorescence, Neurons, Time Factors, Transfection, Tumor Cells, Cultured, Amyloid beta-Peptides, Apoptosis, Staurosporine, Protein Isoforms, Mice, Apolipoprotein E4, DNA Fragmentation
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