Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer’s disease brains
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Abstract
Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed to be upstream initiators of synaptic dysfunction, but little is known about their structures. We now report the unexpected presence of Aβ fibrils in synaptotoxic high-speed supernatants from AD brains extracted by soaking in an aqueous buffer. The fibrils did not appear to form during preparation, and their counts by EM correlated with Aβ ELISA quantification. Cryo-EM structures of aqueous Aβ fibrils were identical to those from sarkosyl-insoluble homogenates. The fibrils in aqueous extracts were labeled by lecanemab, an Aβ aggregate-directed antibody reported to improve AD cognitive outcomes. Lecanemab provided protection against aqueous fibril synaptotoxicity. We conclude that fibrils are abundant in aqueous extracts from AD brains and have the same structures as those from plaques. These findings have implications for AD pathogenesis and drug design.
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The size of aggregates between 20 nm and 200 nm is consistent with the reported size of synaptotoxic amyloid beta aggregates from human Alzheimer's disease brains.
“consistent with the reported size of synaptotoxic Aβ aggregates from human AD brains [32]”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [32]
The Results (p. 9) indicate that most Aβ assemblies in fresh AD-brain extracts were at least 20 nm, and the Discussion (p. 13) reports that similarly prepared extracts impair synaptic plasticity. The paper does not report a 20–200 nm size range for synaptotoxic aggregates or establish that the measured fibrils themselves cause the synaptic effects; it proposes that partial fibril disassembly may be required for neurotoxicity. (LLM, conf=0.84)
Experimental — accuracy not yet measuredEffects of amyloid beta on neuronal activity and synaptic function often stem from soluble aggregates similar to those produced in much greater numbers by oligodendrocytes.
“Rather than being plaque dependent, the effects of Aβ on neuronal activity and synaptic function often stem from soluble aggregates similar to those we see produced in much greater numbers by oligodendrocytes [32,39].”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [32]
The Introduction (p. 3) reports that soluble Aβ assemblies disrupt synaptic plasticity, and the Discussion (p. 13) reports neurotoxic effects of comparable aqueous brain extracts. The paper does not establish that these effects are independent of plaques: the Discussion says diffusible fibrils may be in equilibrium with plaques. The oligodendrocyte comparison is framed as the citing authors’ own observation, not a finding attributed to this source. (LLM, conf=0.82)
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Cites
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
UCSF ChimeraX : Structure visualization for researchers, educators, and developers
Pettersen, E. F., Goddard, T. D., Huang, C. C., Meng, E. C., Couch, G. S., Croll, T. I., Morris, J. H., & Ferrin, T. E. (2020) · Protein Science · doi:10.1002/pro.3943 · Cited by 9,327 · see citing works
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164 · see citing works
Self-citationLecanemab in early Alzheimer's disease
van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2212948 · Cited by 5,678 · see citing works
CTFFIND4: Fast and accurate defocus estimation from electron micrographs
Rohou, A. L., & Grigorieff, N. (2015) · Journal of Structural Biology · doi:10.1016/j.jsb.2015.08.008 · Cited by 4,926 · see citing works
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 · see citing works
Self-citationCryo-EM structures of tau filaments from Alzheimer’s disease
Fitzpatrick, A. W. P., Falcon, B., He, S., Murzin, A. G., Murshudov, G., Garringer, H. J., Crowther, R. A., Ghetti, B., Goedert, M., & Scheres, S. H. W. (2017) · Nature · doi:10.1038/nature23002 · Cited by 2,061 · see citing works
Self-citationThe 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 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation
Nilsberth, C., Westlind-Danielsson, A., Eckman, C. B., Condron, M. M., Axelman, K., Forsell, C., Stenh, C., Luthman, J., Teplow, D. B., Younkin, S. G., et al. (2001) · Nature Neuroscience · doi:10.1038/nn0901-887 · Cited by 1,209 · see citing works
Chen, S., McMullan, G., Faruqi, A. R., Murshudov, G. N., Short, J. M., Scheres, S. H. W., & Henderson, R. A. (2013) · Ultramicroscopy · doi:10.1016/j.ultramic.2013.06.004 · Cited by 1,005 · see citing works
Self-citationLi, S., Hong, S., Shepardson, N. E., Walsh, D. M., Shankar, G. M., & Selkoe, D. (2009) · Neuron · doi:10.1016/j.neuron.2009.05.012 · Cited by 972 · see citing works
Self-citationA Bayesian approach to beam-induced motion correction in cryo-EM single-particle analysis
Zivanov, J., Nakane, T., & Scheres, S. H. W. (2018) · IUCrJ · doi:10.1107/s205225251801463x · Cited by 947 · see citing works
Self-citationJin, M., Shepardson, N., Yang, T., Chen, G., Walsh, D., & Selkoe, D. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1017033108 · Cited by 876 · see citing works
Self-citationKoffie, R. M., Meyer-Luehmann, M., Hashimoto, T., Adams, K. W., Mielke, M. L., Garcia-Alloza, M., Micheva, K. D., Smith, S. J., Kim, M. L., Lee, V. M., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811698106 · Cited by 850 · see citing works
Swanson, C. J., Zhang, Y., Dhadda, S., Wang, J., Kaplow, J., Lai, R. Y. K., Lannfelt, L., Bradley, H., Rabe, M., Koyama, A., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00813-8 · Cited by 847 · see citing works
Casañal, A., Lohkamp, B., & Emsley, P. (2019) · Protein Science · doi:10.1002/pro.3791 · Cited by 812 · see citing works
Zivanov, J., Nakane, T., & Scheres, S. H. W. (2020) · IUCrJ · doi:10.1107/s2052252520000081 · Cited by 804 · see citing works
Self-citationThe amyloid hypothesis in Alzheimer disease: new insights from new therapeutics
Karran, E., & De Strooper, B. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00391-w · Cited by 742 · see citing works
Helical reconstruction in RELION
He, S., & Scheres, S. H. W. (2017) · Journal of Structural Biology · doi:10.1016/j.jsb.2017.02.003 · Cited by 563 · see citing works
Self-citationLoss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deussing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0296-9 · Cited by 555 · see citing works
Cryo-EM structures of amyloid-β 42 filaments from human brains
Yang, Y., Arseni, D., Zhang, W., Huang, M., Lövestam, S., Schweighauser, M., Kotecha, A., Murzin, A. G., Peak-Chew, S. Y., Macdonald, J., et al. (2022) · Science · doi:10.1126/science.abm7285 · Cited by 546 · see citing works
Self-citationTau molecular diversity contributes to clinical heterogeneity in Alzheimer’s disease
Dujardin, S., Commins, C., Lathuiliere, A., Beerepoot, P., Fernandes, A. R., Kamath, T. V., De Los Santos, M. B., Klickstein, N., Corjuc, D. L., Corjuc, B. T., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0938-9 · Cited by 438 · see citing works
Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers
De Felice, F. G., Wu, D., Lambert, M. P., Fernandez, S. J., Velasco, P. T., Lacor, P. N., Bigio, E. H., Jerecic, J., Acton, P. J., Shughrue, P. J., et al. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.02.029 · Cited by 432 · see citing works
Takeda, S., Wegmann, S., Cho, H., DeVos, S. L., Commins, C., Roe, A. D., Nicholls, S. B., Carlson, G. A., Pitstick, R., Nobuhara, C. K., et al. (2015) · Nature Communications · doi:10.1038/ncomms9490 · Cited by 371 · see citing works
Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold
Falcon, B., Zhang, W., Schweighauser, M., Murzin, A. G., Vidal, R., Garringer, H. J., Ghetti, B., Scheres, S. H. W., & Goedert, M. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1914-z · Cited by 362 · see citing works
Self-citationLoss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deußing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., et al. (2019) · doi:10.7892/boris.125653 · Cited by 352 · see citing works
Yang, T., Li, S., Xu, H., Walsh, D. M., & Selkoe, D. J. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.1698-16.2016 · Cited by 347 · see citing works
Self-citationCryo-EM single-particle structure refinement and map calculation using Servalcat
Yamashita, K., Palmer, C. M., Burnley, B. T., & Murshudov, G. N. (2021) · Acta Crystallographica Section D Structural Biology · doi:10.1107/s2059798321009475 · Cited by 339 · see citing works
Self-citationTucker, S., Möller, C., Tegerstedt, K., Lord, A., Laudon, H., Sjödahl, J., Söderberg, L., Spens, E., Sahlin, C., Waara, E. R., et al. (2015) · Journal of Alzheimer’s Disease · doi:10.3233/jad-140741 · Cited by 272 · see citing works
McLaurin, J., Golomb, R., Jurewicz, A., Antel, J. P., & Fraser, P. E. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m906994199 · Cited by 265 · see citing works
Soluble Aβ Seeds Are Potent Inducers of Cerebral β-Amyloid Deposition
Langer, F., Eisele, Y. S., Fritschi, S. K., Staufenbiel, M., Walker, L. C., & Jucker, M. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3088-11.2011 · Cited by 237 · see citing works
Alzheimer's Disease-Like Pathology Induced by Amyloid-β Oligomers in Nonhuman Primates
Forny‐Germano, L., Silva, N. M. L. E., Batista, A. F., Brito‐Moreira, J., Gralle, M., Boehnke, S. E., Coe, B. C., Lablans, A., Marques, S. A., Martinez, A. M. B., et al. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1353-14.2014 · Cited by 232 · see citing works
Meilandt, W. J., Ngu, H., Gogineni, A., Lalehzadeh, G., Lee, S.-H., Srinivasan, K., Imperio, J., Wu, T., Weber, M., Kruse, A. J., et al. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.1871-19.2019 · Cited by 210 · see citing works
Casali, B. T., MacPherson, K. P., Reed-Geaghan, E. G., & Landreth, G. E. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104956 · Cited by 186 · see citing works
Hong, W., Wang, Z., Liu, W., O’Malley, T. T., Jin, M., Willem, M., Haass, C., Frosch, M. P., & Walsh, D. M. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1846-7 · Cited by 166 · see citing works
Self-citationJackson, S. J., Kerridge, C., Cooper, J., Cavallini, A., Falcon, B., Cella, C. V., Landi, A., Szekeres, P. G., Murray, T. K., Ahmed, Z., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.3542-15.2016 · Cited by 153 · see citing works
Self-citationLannfelt, L., Möller, C., Basun, H., Osswald, G., Sehlin, D., Satlin, A., Logovinsky, V., & Gellerfors, P. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt246 · Cited by 152 · see citing works
Soluble Amyloid-beta Aggregates from Human Alzheimer’s Disease Brains
Esparza, T. J., Wildburger, N. C., Jiang, H., Gangolli, M., Cairns, N. J., Bateman, R. J., & Brody, D. L. (2016) · Scientific Reports · doi:10.1038/srep38187 · Cited by 124 · see citing works
Yang, T., O’Malley, T. T., Kanmert, D., Jerecı̀ć, J., Zieske, L. R., Zetterberg, H., Hyman, B. T., Walsh, D. M., & Selkoe, D. J. (2015) · Alzheimer s Research & Therapy · doi:10.1186/s13195-015-0100-y · Cited by 115 · see citing works
Self-citationIdentification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer’s brain
Brinkmalm, G., Hong, W., Wang, Z., Liu, W., O’Malley, T. T., Sun, X., Frosch, M. P., Selkoe, D. J., Portelius, E., Zetterberg, H., et al. (2019) · Brain · doi:10.1093/brain/awz066 · Cited by 114 · see citing works
Self-citationHughes, C., Choi, M. L., Yi, J.-H., Kim, S.-C., Drews, A., George-Hyslop, P. S., Bryant, C., Gandhi, S., Cho, K., & Klenerman, D. (2020) · Communications Biology · doi:10.1038/s42003-020-0792-9 · Cited by 107 · see citing works
Aβ oligomers trigger and accelerate Aβ seeding
Katzmarski, N., Ziegler‐Waldkirch, S., Scheffler, N., Witt, C. C., Abou‐Ajram, C., Nuscher, B., Prinz, M., Haass, C., & Meyer‐Luehmann, M. (2019) · Brain Pathology · doi:10.1111/bpa.12734 · Cited by 85 · see citing works
Donald, J. M. M., O’Malley, T. T., Liu, W., Mably, A. J., Brinkmalm, G., Portelius, E., Wittbold, W. M., Frosch, M. P., & Walsh, D. M. (2015) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2015.01.005 · Cited by 71 · see citing works
Self-citationAn in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease
Jin, M., O’Nuallain, B., Hong, W., Boyd, J. D., Lagomarsino, V. N., O’Malley, T. T., Liu, W., Vanderburg, C. R., Frosch, M. P., Young‐Pearse, T. L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05068-w · Cited by 70 · see citing works
Self-citationSideris, D. I., Danial, J. S. H., Emin, D., Ruggeri, F. S., Xia, Z., Zhang, Y. P., Lobanova, E., Dakin, H., De, S., Miller, A., et al. (2021) · Brain Communications · doi:10.1093/braincomms/fcab147 · Cited by 69 · see citing works
An ultra‐sensitive immunoassay detects and quantifies soluble Aβ oligomers in human plasma
Liu, L., Kwak, H., Lawton, T., Jin, S., Meunier, A. L., Dang, Y., Ostaszewski, B. L., Pietras, A., Stern, A. M., & Selkoe, D. J. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12457 · Cited by 49 · see citing works
Self-citationJin, M., & Selkoe, D. J. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.05.020 · Cited by 44 · see citing works
Self-citationWeismiller, H. A., Murphy, R., Wei, G., Ma, B., Nussinov, R., & Margittai, M. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.005316 · Cited by 44 · see citing works
Elevated soluble amyloid beta protofibrils in Down syndrome and Alzheimer's disease
Johannesson, M., Sahlin, C., Söderberg, L., Basun, H., Fälting, J. M., Möller, C., Zachrisson, O., Sunnemark, D., Svensson, A., Odergren, T., et al. (2021) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2021.103641 · Cited by 32 · see citing works
Jin, S., Liu, L., Li, S., Meunier, A. L., & Selkoe, D. J. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105816 · Cited by 27 · see citing works
Self-citationStern, A. M., Liu, L., Jin, S., Liu, W., Meunier, A. L., Ericsson, M., Miller, M. B., Batson, M., Sun, T., Kathuria, S. V., et al. (2022) · Brain · doi:10.1093/brain/awac023 · Cited by 16 · see citing works
Self-citationBetter Inference in Neuroscience: Test Less, Estimate More
Calin-Jageman, R. J. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.1133-22.2022 · Cited by 6 · see citing works
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Alger, B. E. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.1134-22.2022 · Cited by 4 · see citing works
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- Authors
- Stern, A. M., Yang, Y., Jin, S., Yamashita, K., Meunier, A. L., Liu, W., Cai, Y., Ericsson, M., Liu, L., Goedert, M., Scheres, S. H. W., & Selkoe, D. J.
- Affiliations
- Brigham and Women's Hospital (US)
- MRC Laboratory of Molecular Biology (GB)
- Harvard University (US)
- Corresponding author
- Selkoe, Dennis J.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2023-07
- Volume
- 111
- Issue
- 13
- Pages
- 2012-2020.e4
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC10330525
- OpenAlex
- W4376225808
- Cited by
- 91
- References
- 53
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 20 · 2023: 21 · 2022: 1
- FWCI
- 15.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (RF1AG006173, K08NS128329, P01AG015379)
- Medical Research Council (MC_U105184291)
- Prothena
- Alzheimer's Association (AACSF-21-849687)
- 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 fibrils, Alzheimer's disease, synaptotoxicity, lecanemab, amyloid oligomers, fibril structure, cryo-electron microscopy, amyloid plaques, synaptic dysfunction, amyloid fibril formation
- MeSH terms
- Alzheimer Disease, Brain, Humans, Amyloid beta-Peptides, Plaque, Amyloid
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