Structural Basis for Increased Toxicity of Pathological Aβ42:Aβ40 Ratios in Alzheimer Disease
Open accessAbstract
The β-amyloid peptide (Aβ) is directly related to neurotoxicity in Alzheimer disease (AD). The two most abundant alloforms of the peptide co-exist under normal physiological conditions in the brain in an Aβ(42):Aβ(40) ratio of ∼1:9. This ratio is often shifted to a higher percentage of Aβ(42) in brains of patients with familial AD and this has recently been shown to lead to increased synaptotoxicity. The molecular basis for this phenomenon is unclear. Although the aggregation characteristics of Aβ(40) and Aβ(42) individually are well established, little is known about the properties of mixtures. We have explored the biophysical and structural properties of physiologically relevant Aβ(42):Aβ(40) ratios by several techniques. We show that Aβ(40) and Aβ(42) directly interact as well as modify the behavior of the other. The structures of monomeric and fibrillar assemblies formed from Aβ(40) and Aβ(42) mixtures do not differ from those formed from either of these peptides alone. Instead, the co-assembly of Aβ(40) and Aβ(42) influences the aggregation kinetics by altering the pattern of oligomer formation as evidenced by a unique combination of solution nuclear magnetic resonance spectroscopy, high molecular weight mass spectrometry, and cross-seeding experiments. We relate these observations to the observed enhanced toxicity of relevant ratios of Aβ(42):Aβ(40) in synaptotoxicity assays and in AD patients.
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Aβ40 is present in larger amounts in the brain, yet Aβ42 is more neurotoxic and has a higher tendency to aggregate.
“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 Aβ<sub>42</sub>Peptide (2012) · cites this paper as [11]
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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 · see citing works
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 · see citing works
Kuperstein, 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
Self-citationSnyder, S. W., Ladror, U. S., Wade, W. S., Wang, G. T., Barrett, L. W., Matayoshi, E. D., Huffaker, H. J., Krafft, G. A., & Holzman, T. F. (1994) · Biophysical Journal · doi:10.1016/s0006-3495(94)80591-0 · Cited by 381 · see citing works
Aβ40 Inhibits Amyloid Deposition<i>In Vivo</i>
Kim, J., Onstead, L., Randle, S., Price, R., Smithson, L., Zwizinski, C., Dickson, D. W., Golde, T., & McGowan, E. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4849-06.2007 · Cited by 359 · see citing works
Klyubin, I., Betts, V., Welzel, A. T., Blennow, K., Zetterberg, H., Wallin, A., Lemere, C. A., Cullen, W. K., Peng, Y., Wisniewski, T., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.5161-07.2008 · Cited by 321 · see citing works
Mann, D. M. A., Iwatsubo, T., Cairns, N. J., Lantos, P. L., Nochlin, D., Sumi, S. M., Bird, T. D., Poorkaj, P., Hardy, J., Hutton, M., et al. (1996) · Annals of Neurology · doi:10.1002/ana.410400205 · Cited by 184 · see citing works
Flagged first, then by citations
Research works printed but not linked: 5
- Petkova, A. T., Ishii, Y., Balbach, J. J., Antzutkin, O. N., Leapman, R. D., Delaglio, F., and Tycko, R. (2002) A structural model for Alzheimer  amyloid fibrils based on experimental constraints from solid state NMR. Proc. Natl. Acad. Sci. U.S.A. 99, 16742-16747
- Schmidt, M., Sachse C., Richter, W., Xu, C., Fändrich, M., and Grigorieff, N. (2009) Comparison of Alzheimer A(1-40) and A(1-42) amyloid fibrils reveals similar protofilament structures. Proc. Natl. Acad. Sci. U.S.A. 106, 19813-19818
- Kirschner, D. A., Abraham, C., and Selkoe, D. J. (1986) X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross- conformation. Proc. Natl. Acad. Sci. U.S.A. 83, 503-507
- Marshall, K. E., Morris, K. L., Charlton, D., O'Reilly, N., Lewis, L., Walden, H., and Serpell, L. C. (2011) Hydrophobic, aromatic, and electrostatic interactions play a central role in amyloid fibril formation and stability. Biochemistry 50, 2061-2071
- Lührs, T., Ritter, C., Adrian, M., Riek-Loher, D., Bohrmann, B., Döbeli, H., Schubert, D., and Riek, R. (2005) Three-dimensional structure of Al- zheimer amyloid-(1-42) fibrils. Proc. Natl. Acad. Sci. U.S.A. 102, 17342-17347
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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
Modeling Alzheimer’s disease with iPSC-derived brain cells
Penney, J., Ralvenius, W. T., & Tsai, L.-H. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0468-3 · Cited by 471 · see citing works
Michailidis, M., Moraitou, D., Tata, D. A., Kalinderi, K., Papamitsou, T., & Papaliagkas, V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052687 · Cited by 330 · see citing works
Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease
Cioffi, F., Adam, R. H. I., & Broersen, K. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190863 · Cited by 204 · 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
A <i>β</i> 42 and A <i>β</i> 40: similarities and differences
Qiu, T., Liu, Q., Chen, Y., Zhao, Y., & Li, Y. (2015) · Journal of Peptide Science · doi:10.1002/psc.2789 · Cited by 180 · see citing works
Zhang, Y., Rempel, D. L., Zhang, J., Sharma, A. K., Mirica, L. M., & Gross, M. L. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1309175110 · Cited by 118 · see citing works
Quantitative analysis of co-oligomer formation by amyloid-beta peptide isoforms.
Iljina, M., Garcia, G. A., Dear, A. J., Flint, J., Narayan, P., Michaels, T. C. T., Dobson, C. M., Frenkel, D., Knowles, T. P. J., & Klenerman, D. (2016) · Scientific Reports · doi:10.1038/srep28658 · Cited by 68 · see citing works
Glycation affects fibril formation of Aβ peptides
Emendato, A., Milordini, G., Zacco, E., Sicorello, A., Dal Piaz, F., Guerrini, R., Thorogate, R., Picone, D., & Pastore, A. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002275 · Cited by 65 · see citing works
Self-citationMerino-Zamorano, C., Fernández-de Retana, S., Montañola, A., Batlle, A., Saint-Pol, J., Mysiorek, C., Gosselet, F., Montaner, J., & Hernández-Guillamon, M. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-150976 · Cited by 63 · see citing works
A multifactorial model of pathology for age of onset heterogeneity in familial Alzheimer’s disease
Sepulveda-Falla, D., Chavez-Gutierrez, L., Portelius, E., Vélez, J. I., Dujardin, S., Barrera-Ocampo, A., Dinkel, F., Hagel, C., Puig, B., Mastronardi, C., et al. (2021) · Acta Neuropathologica · doi:10.1007/s00401-020-02249-0 · Cited by 54 · see citing works
Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease
Rosen, R. F., Tomidokoro, Y., Farberg, A. S., Dooyema, J., Ciliax, B., Preuss, T. M., Neubert, T. A., Ghiso, J. A., LeVine, H., & Walker, L. C. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.04.019 · Cited by 46 · see citing works
Dinkel, F., Trujillo-Rodriguez, D., Villegas, A., Streffer, J., Mercken, M., Lopera, F., Glatzel, M., & Sepulveda-Falla, D. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00220 · Cited by 23 · see citing works
- Authors
- Pauwels, K., Williams, T. L., Morris, K. L., Jonckheere, W., Vandersteen, A., Kelly, G., Schymkowitz, J., Rousseau, F., Pastore, A., Serpell, L. C., & Broersen, K.
- Affiliations
- National Institute for Medical Research (GB)
- University of Sussex (GB)
- Vrije Universiteit Brussel (BE)
- Corresponding author
- Broersen, Kerensa
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 287
- Issue
- 8
- Pages
- 5650-5660
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3285338
- OpenAlex
- W2091913778
- Cited by
- 253
- References
- 7
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 21 · 2023: 14 · 2022: 15 · 2021: 20 · 2020: 22 · 2019: 13 · 2018: 18 · 2017: 23 · 2016: 22 · 2015: 19 · 2014: 13 · 2013: 19 · 2012: 9
- FWCI
- 8.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Twente Research Information (publishedVersion)
- Scuola Normale Superiore di Pisa (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- University of Twente Research Information (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- Vlaamse regering
- Medical Research Council
- Biotechnology and Biological Sciences Research Council (BB/E009042/1)
- 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
- Alzheimer's disease, amyloid-beta 42, Aβ40, Aβ42/Aβ40 ratio, peptide mixtures, co-assembly, aggregation kinetics, oligomerization, synaptotoxicity, neurotoxicity, familial Alzheimer's disease, cross-seeding
- MeSH terms
- Alzheimer Disease, Kinetics, Peptide Fragments, Amyloid beta-Peptides, Protein Structure, Secondary, Protein Multimerization
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