Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability
Open accessAbstract
Genetic evidence predicts a causative role for amyloid-beta (A beta) in Alzheimer's disease. Recent debate has focused on whether fibrils (amyloid) or soluble oligomers of A beta are the active species that contribute to neurodegeneration and dementia. We developed two aggregation protocols for the consistent production of stable oligomeric or fibrillar preparations of A beta-(1-42). Here we report that oligomers inhibit neuronal viability 10-fold more than fibrils and approximately 40-fold more than unaggregated peptide, with oligomeric A beta-(1-42)-induced inhibition significant at 10 nm. Under A beta-(1-42) oligomer- and fibril-forming conditions, A beta-(1-40) remains predominantly as unassembled monomer and had significantly less effect on neuronal viability than preparations of A beta-(1-42). We applied the aggregation protocols developed for wild type A beta-(1-42) to A beta-(1-42) with the Dutch (E22Q) or Arctic (E22G) mutations. Oligomeric preparations of the mutations exhibited extensive protofibril and fibril formation, respectively, but were not consistently different from wild type A beta-(1-42) in terms of inhibition of neuronal viability. However, fibrillar preparations of the mutants appeared larger and induced significantly more inhibition of neuronal viability than wild type A beta-(1-42) fibril preparations. These data demonstrate that protocols developed to produce oligomeric and fibrillar A beta-(1-42) are useful in distinguishing the structural and functional differences between A beta-(1-42) and A beta-(1-40) and genetic mutations of A beta-(1-42).
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The MOAB-2-based oAβ42 ELISA detects oligomeric but not monomeric Aβ42.
“In addition, the MOAB-2-based oA42 ELISA detects oligomeric but not monomeric A42 using synthetic preparations characterized previously by our laboratory (data not shown) (47,48).”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [47]
The 48 h total incubation leads to mature Aβ42 fibrils, as observed by TEM, while the Western blot shows the presence of higher order Aβ42 oligomers, likely due to an assembly-disassembly equilibrium that is established for mature Aβ fibrils.
“The 48 h total incubation leads to mature Aβ42 fibrils, as observed by TEM (Figure 10, panel a) while the Western blot shows the presence of higher order Aβ42 oligomers (Figure 10, lane a), likely due to an assembly-disassembly equilibrium that is established for mature Aβ fibrils.89–91”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [90]
The approach of inhibiting Aβ40 aggregation and amyloid fibril disaggregation may not be optimal for the Aβ42 peptide, given the increased toxicity observed for the soluble Aβ42 oligomers.
“However, this approach may not be optimal for the Aβ42 peptide, given the increased toxicity observed for the soluble Aβ42 oligomers.90”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [90]
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- Authors
- Dahlgren, K. N., Manelli, A. M., Stine, W. B., Baker, L. K., Krafft, G. A., & LaDu, M. J.
- Affiliations
- Northwestern University (US)
- Corresponding author
- LaDu, Mary Jo
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 277
- Issue
- 35
- Pages
- 32046-32053
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2168025729
- Cited by
- 1,452
- References
- 71
- Citations by year
- 2026: 25 · 2025: 33 · 2024: 40 · 2023: 46 · 2022: 45 · 2021: 47 · 2020: 49 · 2019: 55 · 2018: 65 · 2017: 58 · 2016: 61 · 2015: 70 · 2014: 78 · 2013: 86 · 2012: 86
- FWCI
- 22.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, amyloid-beta oligomers, amyloid fibrils, Alzheimer's disease, neuronal viability, peptide aggregation, protofibrils, neurotoxicity
- MeSH terms
- Alzheimer Disease, Cell Survival, Humans, Neuroblastoma, Neurons, Peptide Fragments, Tumor Cells, Cultured, Amyloid beta-Peptides, Microscopy, Atomic Force
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