The DOI matches its Crossref record; 15 of the 15 references it cites were found in a registry or an index.
Aβ42 Neurotoxicity Is Mediated by Ongoing Nucleated Polymerization Process Rather than by Discrete Aβ42 Species
Open accessAbstract
The identification of toxic Aβ species and/or the process of their formation is crucial for understanding the mechanism(s) of Aβ neurotoxicity in Alzheimer disease and also for the development of effective diagnostic and therapeutic interventions. To elucidate the structural basis of Aβ toxicity, we developed different procedures to isolate Aβ species of defined size and morphology distribution, and we investigated their toxicity in different cell lines and primary neurons. We observed that crude Aβ42 preparations, containing a monomeric and heterogeneous mixture of Aβ42 oligomers, were more toxic than purified monomeric, protofibrillar fractions, or fibrils. The toxicity of protofibrils was directly linked to their interactions with monomeric Aβ42 and strongly dependent on their ability to convert into amyloid fibrils. Subfractionation of protofibrils diminished their fibrillization and toxicity, whereas reintroduction of monomeric Aβ42 into purified protofibril fractions restored amyloid formation and enhanced their toxicity. Selective removal of monomeric Aβ42 from these preparations, using insulin-degrading enzyme, reversed the toxicity of Aβ42 protofibrils. Together, our findings demonstrate that Aβ42 toxicity is not linked to specific prefibrillar aggregate(s) but rather to the ability of these species to grow and undergo fibril formation, which depends on the presence of monomeric Aβ42. These findings contribute significantly to the understanding of amyloid formation and toxicity in Alzheimer disease, provide novel insight into mechanisms of Aβ protofibril toxicity, and important implications for designing anti-amyloid therapies.
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Citations
Cites
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Cited by
Self-propagation of pathogenic protein aggregates in neurodegenerative diseases
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Self-citationStructural Basis for Increased Toxicity of Pathological Aβ42:Aβ40 Ratios in Alzheimer Disease
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Metadata
- Authors
- Jan, A., Adolfsson, O., Allaman, I., Buccarello, A.-L., Magistretti, P. J., Pfeifer, A., Muhs, A., & Lashuel, H. A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 286
- Issue
- 10
- Pages
- 8585-8596
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2073298789
- Cited by
- 173
- References
- 15
- FWCI
- 9.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- CoChat. (2026). Citation check: Aβ42 Neurotoxicity Is Mediated by Ongoing Nucleated Polymerization Process Rather than by Discrete Aβ42 Species. https://app.cochat.ai/papers/10.1074/jbc.m110.172411
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- Jan, A., Adolfsson, O., Allaman, I., Buccarello, A.-L., Magistretti, P. J., Pfeifer, A., Muhs, A., & Lashuel, H. A. (2011). Aβ42 Neurotoxicity Is Mediated by Ongoing Nucleated Polymerization Process Rather than by Discrete Aβ42 Species. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m110.172411
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
