The DOI matches its Crossref record; 60 of the 61 references it cites were found in a registry or an index.
Neurotoxicity of Alzheimer’s disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio
Open accessAbstract
The amyloid peptides Aβ(40) and Aβ(42) of Alzheimer's disease are thought to contribute differentially to the disease process. Although Aβ(42) seems more pathogenic than Aβ(40), the reason for this is not well understood. We show here that small alterations in the Aβ(42):Aβ(40) ratio dramatically affect the biophysical and biological properties of the Aβ mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo. A minor increase in the Aβ(42):Aβ(40) ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Aβ species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Aβ peptides is more crucial than the absolute amounts of peptides for the induction of neurotoxic conformations has important implications for anti-amyloid therapy. Our work also suggests the dynamic nature of the equilibrium between toxic and non-toxic intermediates.
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“The increased Aβ 42:40 ratio in oligodendrocytes could contribute to the high proportion of soluble aggregates [28,42,43]”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [43]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Aβ40 is present in larger amounts in the brain, yet Aβ42 is more neurotoxic and has a higher tendency to aggregate.8–11”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ42Peptide (2012) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“the longer and more hydrophobic Aβ42 isoform has a higher tendency to generate neurotoxic oligomeric species.9,10”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [10]
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In the citing paper
“Although Aβ40 is present in larger amounts in the brain, Aβ42 was found to be more neurotoxic and have a higher tendency to aggregate.4,5”
From The effect of Cu2+ and Zn2+ on the Aβ42 peptide aggregation and cellular toxicity (2013) · cites this paper as [5]
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“Although it was shown in previous studies9,10,21 that the Aβ42 peptide is more prone to form neurotoxic soluble Aβ oligomers than the Aβ40 peptide”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [10]
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Cites
1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006) · Nature · doi:10.1038/nature04533 · Cited by 2,769 · cited 1×
“…potently disrupt synaptic plasticity (Klyubin et al, 2008; Shankar et al, 2008), an Ab species of 56 kDa has been found neurotoxic in Tg2576 mice (Lesne et al, 2006), lipid-induced oligomers from mature fibrils (Martins et al, 2008), ADDLs (Lambert et al, 1998; Gong et al, 2003; Lacor et al,…”
BackgroundRetractedThe Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864
Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., & Katzman, R. (1991) · Annals of Neurology · doi:10.1002/ana.410300410 · Cited by 4,397
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
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., & Glabe, C. G. (2003) · Science · doi:10.1126/science.1079469 · Cited by 4,064
Shankar, G. M., Li, S., Mehta, T. H., Garcia-Munoz, A., Shepardson, N. E., Smith, I., Brett, F. M., Farrell, M. A., Rowan, M. J., Lemere, C. A., et al. (2008) · Nature Medicine · doi:10.1038/nm1782 · Cited by 3,685
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
Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., et al. (1996) · Nature Medicine · doi:10.1038/nm0896-864 · Cited by 2,599
Jarrett, J. T., & Lansbury, P. T. (1993) · Cell · doi:10.1016/0092-8674(93)90635-4 · Cited by 2,178
Natural oligomers of the amyloid-β protein specifically disrupt cognitive function
Cleary, J. P., Walsh, D. M., Hofmeister, J. J., Shankar, G. M., Kuskowski, M. A., Selkoe, D. J., & Ashe, K. H. (2004) · Nature Neuroscience · doi:10.1038/nn1372 · Cited by 1,722
Cited by
Sorted by citations
Karran, E., Mercken, M., & Strooper, B. D. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3505 · Cited by 2,188
The Cellular Phase of Alzheimer’s Disease
De Strooper, B., & Karran, E. (2016) · Cell · doi:10.1016/j.cell.2015.12.056 · Cited by 1,990
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
Self-citationThe Amyloid State of Proteins in Human Diseases
Eisenberg, D. S., & Jucker, M. (2012) · Cell · doi:10.1016/j.cell.2012.02.022 · Cited by 1,769
Compromised MAPK signaling in human diseases: an update
Kim, E., & Choi, E. (2015) · Archives of Toxicology · doi:10.1007/s00204-015-1472-2 · Cited by 1,033
Metadata
- Authors
- Kuperstein, I., Broersen, K., Benilova, I., Rozenski, J., Jonckheere, W., Debulpaep, M., Vandersteen, A., Segers‐Nolten, I., Van Der Werf, K., Subramaniam, V., Braeken, D., Callewaert, G., Bartic, C., D'Hooge, R., Martins, I. C., Rousseau, F., Schymkowitz, J., & De Strooper, B.
- Affiliations
- Vlaams Instituut voor Biotechnologie (BE)
- Vrije Universiteit Brussel (BE)
- Rega Institute for Medical Research (BE)
- University of Twente (NL)
- IMEC (BE)
- Corresponding author
- Schymkowitz, Joost
- ORCID
- Venue
- The EMBO Journal
- Published
- 2010-09-03
- Volume
- 29
- Issue
- 19
- Pages
- 3408-3420
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2957213
- OpenAlex
- W1966694507
- Cited by
- 532
- References
- 61
- Citations by year
- 2026: 16 · 2025: 23 · 2024: 36 · 2023: 39 · 2022: 27 · 2021: 39 · 2020: 32 · 2019: 33 · 2018: 31 · 2017: 35 · 2016: 48 · 2015: 31 · 2014: 30 · 2013: 42 · 2012: 43
- FWCI
- 24.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion)
- University of Twente Research Information (publishedVersion, other-oa)
- Lirias (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- University of Twente Research Information (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- European Commission (200611)
- Fonds Wetenschappelijk Onderzoek (P6/43)
- Vlaamse regering
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- Alzheimer's disease, amyloid-beta, Aβ42/Aβ40 ratio, neurotoxicity, oligomeric intermediates, fibril morphology, synaptic dysfunction, neuronal cell death, anti-amyloid therapy, peptide mixtures
- MeSH terms
- Alzheimer Disease, Analysis of Variance, Animals, Biophysics, Fluorescent Dyes, Humans, Kinetics, Microelectrodes, Neurons, Peptide Fragments, Protein Binding, Thiazoles, Amyloid beta-Peptides, Spectroscopy, Fourier Transform Infrared, Patch-Clamp Techniques, Microscopy, Electron, Transmission, Mice, Benzothiazoles, Plaque, Amyloid
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