The DOI matches its Crossref record; 76 of the 78 references it cites were found in a registry or an index.
Reactivity of Apolipoprotein E4 and Amyloid β Peptide
Open accessAbstract
We previously demonstrated that apolipoprotein E4 (apoE4) potentiates lysosomal leakage and apoptosis induced by amyloid beta (Abeta) peptide in cultured Neuro-2a cells and hypothesized that the low pH of lysosomes accentuates the conversion of apoE4 to a molten globule, inducing reactive intermediates capable of destabilizing cellular membranes. Here we report that neutralizing lysosomal pH with bafilomycin or NH4Cl abolished the apoE4 potentiation of Abeta-induced lysosomal leakage and apoptosis in Neuro-2a cells. Consistent with these results, apoE4 at acidic pH bound more avidly to phospholipid vesicles and disrupted them to a greater extent than at pH 7.4. Comparison of "Arctic" mutant Abeta, which forms multimers, and GM6 mutant Abeta, which remains primarily monomeric, showed that aggregation is essential for apoE4 to potentiate Abeta-induced lysosomal leakage and apoptosis. Both apoE4 and Abeta1-42 had to be internalized to exert these effects. Blocking the low density lipoprotein receptor-related protein with small interfering RNA abolished the enhanced effects of apoE4 and Abeta on lysosomes and apoptosis. In cultured Neuro-2a cells, Abeta1-42 increased lysosome formation to a greater extent in apoE3- or apoE4-transfected cells than in Neo-transfected cells, as shown by immunostaining for lysosome-associated membrane protein 1. Similarly, in transgenic mice expressing apoE and amyloid precursor protein, hippocampal neurons displayed increased numbers of lysosomes. Thus, apoE4 and Abeta1-42 may work in concert in neurons to increase lysosome formation while increasing the susceptibility of lysosomal membranes to disruption, release of lysosomal enzymes into the cytosol, and neuronal degeneration.
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Metadata
- Authors
- Ji, Z.-S., Müllendorff, K., Cheng, I. H., Miranda, R. D., 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
- 2006-02
- Volume
- 281
- Issue
- 5
- Pages
- 2683-2692
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2048371394
- Cited by
- 127
- References
- 78
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 1 · 2022: 7 · 2021: 6 · 2020: 12 · 2019: 9 · 2018: 6 · 2017: 7 · 2016: 9 · 2015: 3 · 2014: 2 · 2013: 5 · 2012: 6
- FWCI
- 4.59
- 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 (1c06rr018928-01)
- National Institute on Aging (P01AG022074)
- National Institute of Neurological Disorders and Stroke (R21NS046465)
- National Center for Research Resources (C06RR18928)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, amyloid-beta, apoptosis, lysosomal pH, molten globule, lysosomal membrane disruption, amyloid fibril formation, amyloid-beta 42, low density lipoprotein receptor-related protein, lysosome-associated membrane protein 1, lysosome formation, hippocampal neurons, Alzheimer's disease, N2a cells
- MeSH terms
- Animals, Apolipoproteins E, Cell Line, Humans, Hydrogen-Ion Concentration, Intracellular Membranes, Liposomes, Lysosomes, Mice, Transgenic, Neurons, Transfection, Amyloid beta-Peptides, Apoptosis, Dimerization, Neurodegenerative Diseases, Mice, Apolipoprotein E4
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