The DOI matches its Crossref record; 30 of the 31 references it cites were found in a registry or an index.
Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo
Abstract
Although extensive data support a central pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Abeta and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human Abeta are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant Abeta monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all Abeta species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades Abeta monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, Abeta oligomers, in the absence of monomers and amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic Abeta oligomers can be targeted therapeutically.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The cognitive decline, however, starts well before this stage, and there is growing evidence that one of the toxic protein species believed to be etiologically related to AD, soluble Ab oligomers, causes early memory problems by disrupting LTP and LTD mechanisms (Walsh et al. 2002;Tanzi 2005;Shankar et al. 2008;Cisse et al. 2011).”
From NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). (2012) · cites this paper as Walsh et al. 2002
In the citing paper
“While Aβ disrupts synaptic transmission 32,34,35 and induces synapse loss 17”
From NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer’s disease (2025) · cites this paper as [32]
In the citing paper
“When amyloid-β oligomers bind to PrPc, long-term potentiation and the formation of new memories are disrupted [129,130,131].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [129]
In the citing paper
“As a result of these two mechanisms, activated GSK3β and increased calcineurin and STEP activation, Aβ oligomers reduce LTP [40].”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [40]
In the citing paper
“This was followed by evidence indicating that soluble oligomeric Aβ mediates synaptic dysfunction and neuronal toxicity [31–33].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [32]
In the citing paper
“Many in vitro and in vivo studies have shown that exogenous application of Aβ alters synaptic plasticity [170, 198] and important synaptic proteins [3, 79, 177], although how precisely this occurs remains unclear.”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [198]
Citations
Cites
Alzheimer's Disease: Genes, Proteins, and Therapy
Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063
Self-citationTerry, 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
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
Mucke, L., Masliah, E., Yu, G.-Q., Mallory, M., Rockenstein, E. M., Tatsuno, G., Hu, K., Kholodenko, D., Johnson-Wood, K., & McConlogue, L. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-11-04050.2000 · Cited by 1,856
Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP
Lewis, J., Dickson, D. W., Lin, W.-L., Chisholm, L., Corral, A., Jones, G., Yen, S.-H., Sahara, N., Skipper, L., Yager, D., et al. (2001) · Science · doi:10.1126/science.1058189 · Cited by 1,611
Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease
Lue, L.-F., Kuo, Y.-M., Roher, A. E., Brachova, L., Shen, Y., Sue, L., Beach, T., Kurth, J. H., Rydel, R. E., & Rogers, J. (1999) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65184-x · Cited by 1,530
Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red.
Lorenzo, A., & Yankner, B. A. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.25.12243 · Cited by 1,324
Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models
Hsia, A. Y., Masliah, E., McConlogue, L., Yu, G.-Q., Tatsuno, G., Hu, K., Kholodenko, D., Malenka, R. C., Nicoll, R. A., & Mucke, L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.6.3228 · Cited by 1,123
Amyloid fibrillogenesis: themes and variations
Rochet, J., & Lansbury, P. T. (2000) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(99)00049-4 · Cited by 1,095
Amyloid β-Protein Fibrillogenesis
Walsh, D. M., Hartley, D. M., Kusumoto, Y., Fezoui, Y., Condron, M. M., Lomakin, A., Benedek, G. B., Selkoe, D. J., & Teplow, D. B. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.36.25945 · Cited by 1,046
Self-citation
Flagged first, then by citations
1 of the 31 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
The 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
Self-citationAmyloid 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
Protein folding and misfolding
Dobson, C. M. (2003) · Nature · doi:10.1038/nature02261 · Cited by 4,791
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744
Self-citationAlzheimer's Disease Is a Synaptic Failure
Selkoe, D. J. (2002) · Science · doi:10.1126/science.1074069 · Cited by 4,420
Self-citation
Metadata
- Authors
- Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., & Selkoe, D. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Trinity College Dublin (IE)
- Corresponding author
- Selkoe, Dennis J.
- Venue
- Nature
- Published
- 2002-04
- Volume
- 416
- Issue
- 6880
- Pages
- 535-539
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2150999725
- Cited by
- 4,291
- References
- 31
- Citations by year
- 2026: 83 · 2025: 83 · 2024: 115 · 2023: 120 · 2022: 110 · 2021: 135 · 2020: 162 · 2019: 148 · 2018: 161 · 2017: 194 · 2016: 196 · 2015: 196 · 2014: 215 · 2013: 227 · 2012: 270
- FWCI
- 101.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, amyloid-beta oligomers, Alzheimer's disease, amyloid hypothesis, hippocampal long-term potentiation, synaptic plasticity, synaptotoxicity, intracellular vesicles, gamma-secretase inhibitors, insulin-degrading enzyme, cerebrospinal fluid, neurotoxicity
- MeSH terms
- Alzheimer Disease, Animals, Cricetinae, Hippocampus, Humans, Insulysin, Microsomes, Endopeptidases, Protease Inhibitors, Recombinant Proteins, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, CHO Cells, Culture Media, Conditioned, Long-Term Potentiation, Rats, Amyloid Precursor Protein Secretases, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
