Nucleation-Dependent Polymerization Is an Essential Component of Amyloid-Mediated Neuronal Cell Death
Open accessAbstract
Accumulating evidence suggests that amyloid protein aggregation is pathogenic in many diseases, including Alzheimer's disease. However, the mechanisms by which protein aggregation mediates cellular dysfunction and overt cell death are unknown. Recent reports have focused on the potential role of amyloid oligomers or protofibrils as a neurotoxic form of amyloid-β (Aβ) and related amyloid aggregates. Here we describe studies indicating that overt neuronal cell death mediated by Aβ 1-40 is critically dependent on ongoing Aβ 1-40 polymerization and is not mediated by a single stable species of neurotoxic aggregate. The extent and rate of neuronal cell death can be controlled by conditions that alter the rate of Aβ polymerization. The results presented here indicate that protofibrils and oligomeric forms of Aβ most likely generate neuronal cell death through a nucleation-dependent process rather than acting as direct neurotoxic ligands. These findings bring into question the use of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide formazan assay (MTT assay) as a reporter of Aβ-mediated neuronal cell death and suggest that diffusible Aβ protofibrils and oligomers more likely mediate subtle alterations of synaptic function and long-term potentiation rather than overt neuronal cell death. These results have been extended to Aβ 1-42, the non-Aβ component of Alzheimer's disease amyloid plaques, and human amylin, suggesting that nucleation-dependent polymerization is a common mechanism of amyloid-mediated neuronal cell death. Our findings indicate that ongoing amyloid fibrillogenesis may be an essential mechanistic process underlying the pathogenesis associated with protein aggregation in amyloid disorders.
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The Alamar Blue cell viability assay has been shown to give more reproducible results than the MTT assay.
“using an Alamar Blue cell viability assay, which has been shown to give more reproducible results than the MTT assay.93,94”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [93]
In the section on MTT as an indicator of Aβ-mediated neuronal cell death (page unavailable), alamarBlue and other assays did not show the apparent loss of viability indicated by MTT. The paper therefore supports a difference in reliability for this specific application, but does not show that alamarBlue gives more reproducible results than MTT. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe Alamar Blue cell assay is more appropriate for Aβ toxicity studies than the MTT assay.
“The viability of Neuro-2A (N2A) cells57 was probed using the Alamar Blue cell assay, which was shown to be more appropriate for Aβ toxicity studies vs. the MTT assay.58,59”
From The effect of Cu2+ and Zn2+ on the Aβ42 peptide aggregation and cellular toxicity (2013) · cites this paper as [58]
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Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., & Selkoe, D. J. (2002) · Nature · doi:10.1038/416535a · Cited by 4,291 · see citing works
Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids
Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., Sinha, S., Schiossmacher, M., Whaley, J., Swindlehurst, C., et al. (1992) · Nature · doi:10.1038/359325a0 · Cited by 1,731 · see citing works
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 · see citing works
Amyloid β-Protein Fibrillogenesis
Walsh, D. M., Hartley, D. M., Kusumoto, Y., Fezoui, Y., Condron, M. M., Lomakin, A., Benedek, G. B., Selkoe, D. J., & Teplow, D. B. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.36.25945 · Cited by 1,046 · see citing works
Self-Assembly of Aβ <sub>1</sub> <sub>-</sub> <sub>42</sub> into Globular Neurotoxins
Chromy, B. A., Nowak, R. J., Lambert, M. P., Viola, K. L., Chang, L., Velasco, P. T., Jones, B. W., Fernandez, S. J., Lacor, P. N., Horowitz, P., et al. (2003) · Biochemistry · doi:10.1021/bi030029q · Cited by 522 · see citing works
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The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes
Benilova, I., Karran, E., & De Strooper, B. (2012) · Nature Neuroscience · doi:10.1038/nn.3028 · Cited by 1,962 · see citing works
The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide
Soscia, S. J., Kirby, J. E., Washicosky, K. J., Tucker, S. M., Ingelsson, M., Hyman, B., Burton, M. A., Goldstein, L. E., Duong, S., Tanzi, R. E., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009505 · Cited by 1,060 · see citing works
Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques
Condello, C., Yuan, P., Schain, A., & Grutzendler, J. (2015) · Nature Communications · doi:10.1038/ncomms7176 · Cited by 718 · see citing works
Zempel, H., Thies, E., Mandelkow, E., & Mandelkow, E.-M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2357-10.2010 · Cited by 686 · see citing works
“This can be done in a variety of ways, and there is a debate on which is most appropriate for assessing A toxicity (Wogulis et al., 2005).”
BackgroundKuperstein, I., Broersen, K., Benilova, I., Rozenski, J., Jonckheere, W., Debulpaep, M., Vandersteen, A., Segers‐Nolten, I., Van Der Werf, K., Subramaniam, V., et al. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.211 · Cited by 532 · see citing works
Jan, A., Gokce, O., Luthi-Carter, R., & Lashuel, H. A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803159200 · Cited by 291 · see citing works
Zempel, H., Luedtke, J., Kumar, Y., Biernat, J., Dawson, H., Mandelkow, E., & Mandelkow, E. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.207 · Cited by 283 · see citing works
The aggregation potential of human amylin determines its cytotoxicity towards islet β‐cells
Konarkowska, B., Aitken, J. F., Kistler, J., Zhang, S., & Cooper, G. J. S. (2006) · The FEBS Journal · doi:10.1111/j.1742-4658.2006.05367.x · Cited by 219 · see citing works
Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide
Sharma, A. K., Pavlova, S. T., Kim, J., Finkelstein, D., Hawco, N. J., Rath, N. P., Kim, J., & Mirica, L. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja210588m · Cited by 202 · see citing works
Broersen, K., Rousseau, F., & Schymkowitz, J. (2010) · Alzheimer's Research & Therapy · doi:10.1186/alzrt36 · Cited by 168 · see citing works
The effect of Cu2+ and Zn2+ on the Aβ42 peptide aggregation and cellular toxicity
Sharma, A. K., Pavlova, S. T., Kim, J., Kim, J., & Mirica, L. M. (2013) · Metallomics · doi:10.1039/c3mt00161j · Cited by 135 · see citing works
Site-Specific Blockade of RAGE-V<sub>d</sub>Prevents Amyloid-β Oligomer Neurotoxicity
Sturchler, E., Galichet, A., Weibel, M., Leclerc, E., & Heizmann, C. W. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4878-07.2008 · Cited by 136 · see citing works
Amyloid-β nanotubes are associated with prion protein-dependent synaptotoxicity
Nicoll, A. J., Panico, S., Freir, D. B., Wright, D., Terry, C., Risse, E., Herron, C. E., O’Malley, T., Wadsworth, J. D. F., Farrow, M. A., et al. (2013) · Nature Communications · doi:10.1038/ncomms3416 · Cited by 119 · see citing works
Intracerebroventricular passive immunization with anti‐oligoAβ antibody in TgCRND8
Chauhan, N. B. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21110 · Cited by 24 · see citing works
- Authors
- Wogulis, M., Wright, S., Cunningham, D., Chilcote, T., Powell, K., & Rydel, R. E.
- Affiliations
- Elan Pharmaceuticals, Inc. (Ireland) (IE)
- Biogen (United States) (US)
- ORCID
- Wright, Sarah
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-02-02
- Volume
- 25
- Issue
- 5
- Pages
- 1071-1080
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725948
- OpenAlex
- W1995309381
- Cited by
- 233
- References
- 5
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 5 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 3 · 2019: 7 · 2018: 8 · 2017: 8 · 2016: 14 · 2015: 12 · 2014: 14 · 2013: 15 · 2012: 20
- FWCI
- 11.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA092191, P01CA095616)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, neuronal cell death, amyloid protofibrils, amyloid oligomers, Alzheimer's disease, amylin, amyloid fibril formation, MTT assay, synaptic function, long-term potentiation, protein aggregation
- MeSH terms
- Amyloid, Biopolymers, Cell Membrane Permeability, Cells, Cultured, Cerebral Cortex, Crystallization, Coloring Agents, Formazans, Humans, Models, Chemical, Neurons, Oxidation-Reduction, Peptide Fragments, Solubility, Structure-Activity Relationship, Tetrazolium Salts, Thiazoles, Amyloid beta-Peptides, Artifacts, Cell Death, Microscopy, Atomic Force, Microscopy, Electron, Transmission, Islet Amyloid Polypeptide
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