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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Citations
Cites
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
The metabolic and molecular bases of inherited disease
Chen, Y.-T. (2001) · Medical Entomology and Zoology · Cited by 6,928
Alzheimer's Disease: Genes, Proteins, and Therapy
Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063
Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028
Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506
Mucke, L., Masliah, E., Yu, G.-Q., Mallory, M., Rockenstein, E. M., Tatsuno, G., Hu, K., Kholodenko, D., Johnson-Wood, K., & McConlogue, L. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-11-04050.2000 · Cited by 1,856
Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836
Schmechel, D. E., Saunders, A. M., Strittmatter, W. J., Crain, B. J., Hulette, C. M., Joo, S. H., Pericak-Vance, M. A., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.20.9649 · Cited by 1,525
Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability
Dahlgren, K. N., Manelli, A. M., Stine, W. B., Baker, L. K., Krafft, G. A., & LaDu, M. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201750200 · Cited by 1,452
Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.8098 · Cited by 1,363
Research works printed but not linked: 3
- Mahley, 2001, Vol. 2, 2835
- Slooter, 1997, J. Am. Med. Assoc., 277, 818, 10.1001/jama.1997.03540340052032 · DOI
- Kaback, 1977, Prog. Clin. Biol. Res., 18, 267
Cited by
Sorted by citations
Items 101–127 of 127
Hashimoto, T., Ogino, K., Shin, R., Kitamoto, T., Kikuchi, T., & Shimizu, N. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.12.015 · Cited by 12
Lysosome Biogenesis and Autophagy
Reggiori, F., & Klumperman, J. (2016) · Wiley eBooks · doi:10.1002/9781118978320.ch2 · Cited by 12
Asiamah, E. A., Feng, B., Guo, R., Yaxing, X., Du, X., Liu, X., Zhang, J., Cui, H., & Ma, J. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-230658 · Cited by 8
Frisardi, V. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-111568 · Cited by 7
Mo, Y., Liu, H., Keszei, A. F. A., Dai, D. L., Makky, A., Ding, L., Pan, A., Bu, J., Mazhab‐Jafari, M. T., Chen, J., et al. (2026) · Journal of the American Chemical Society · doi:10.1021/jacs.5c16025 · Cited by 6
The Lysosome in Aging‐Related Neurodegenerative Diseases
Nixon, R. A. (2016) · Wiley eBooks · doi:10.1002/9781118978320.ch9 · Cited by 5
Ługowska, A., Musielak, M., Jamroz, E., Pyrkosz, A., Kmieć, T., Tylki‐Szymańska, A., & Bednarska‐Makaruk, M. (2013) · Gene · doi:10.1016/j.gene.2013.05.009 · Cited by 4
Molecular Aspects of Memory Dysfunction in Alzheimer’s Disease
Chin, J., Roberson, E. D., & Mucke, L. (2008) · Elsevier eBooks · doi:10.1016/b978-012370509-9.00015-2 · Cited by 5
Wolfe, D. M., & Nixon, R. A. (2012) · WORLD SCIENTIFIC eBooks · doi:10.1142/9789814350457_0010 · Cited by 3
The Delicate Balance of Autophagy in Neurodegeneration
Nassif, M., Woehlbier, U., & Manque, P. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-812146-7.00019-6 · Cited by 3
Yuan, M., Han, X., Luo, C.-Q., Pan, H., & Zhou, H.-Y. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05445-9 · Cited by 3
Mahley, R. W. (2025) · Springer eBooks · doi:10.1007/978-3-031-52641-1_2-1 · Cited by 1
Genetic Risk Factors: Their Function and Comorbidities in Alzheimer′s Disease
Hiltunen, M. O., Bertram, L., & Saunders, A. J. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/925362 · Cited by 1
Stephens, G. S., You, J. C., Fu, C.-H., & Chin, J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809324-5.21126-7 · Cited by 1
Air Pollution in Our Future Longevity
Finch, C. E. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813102-2.00005-4 · Cited by 1
Soluble 4R0N Tau Abrogates Endocytic Vesicular Dynamics
Mahendran, T. S., Suresh, S., Garimella, L., & Manjithaya, R. R. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.537712 · Cited by 1
Crosstalk Between Autophagy and Nutrigenomics in Neurodegenerative Diseases
Russell, A. E., Badr, A., Rai, A., Carafice, C., Rai, A., Daily, K. P., Whitham, O. D., Amer, A. O., Brown, C. M., & Dakhlallah, D. A. (2022) · Nutritional neurosciences · doi:10.1007/978-981-16-9205-5_13 · Cited by 1
Metabolic Abnormalities in Alzheimer Disease
Gebhardt, F. M., & Dodd, P. R. (2008) · Springer eBooks · doi:10.1007/978-0-387-79112-8_22 · Cited by 1
Acidic vesicles of the endo-exocytic pathways as targets for some anti-monoamine oxidase drugs
Dell’Antone, P., IbnLkayat, M., Drago, D., & Zatta, P. F. (2007) · Metabolic Brain Disease · doi:10.1007/s11011-007-9054-5
Albrecht, M. A., & Foster, J. K. (2016) · Springer eBooks · doi:10.1007/978-1-4939-3777-6_7
Perspective Chapter: Alzheimer - A Complex Genetic Background
Calabrò, M., & Crisafulli, C. (2022) · IntechOpen eBooks · doi:10.5772/intechopen.101455
(2007) · Elsevier eBooks · doi:10.1016/b978-012373657-4/50008-8
Nodweddu effaith signalu ghrelin-GHS-R ar awtoffagi niwronaidd
Roberts, L. D. (2022) · Cronfa (Swansea University) · doi:10.23889/suthesis.62285
Chen, Q., Zhong, L., Zhou, C., Feng, Y., Liu, Q.-X., Zhou, D., Lu, X., Du, G.-S., Jian, D., Luo, H., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13468249
Mahley, R. W. (2026) · Springer eBooks · doi:10.1007/978-3-031-96089-5_2
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
