The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.
Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins
Open accessAbstract
Abeta1-42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer's pathogenesis. Neurotoxicity of amyloid beta protein (Abeta) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible Abeta oligomers (referred to as ADDLs, for Abeta-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer's disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Abeta-derived diffusible ligands acting upon particular neural signal transduction pathways.
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In the citing paper
“However, recent in vivo studies have shown that soluble Aβ oligomers are more neurotoxic than amyloid plaques and most likely responsible for synaptic dysfunction and memory loss in AD.7–11”
From The effect of Cu2+ and Zn2+ on the Aβ42 peptide aggregation and cellular toxicity (2013) · cites this paper as [10]
In the citing paper
“However, recent in vivo studies have shown that the soluble Aβ oligomers are possibly more neurotoxic than amyloid plaques,14–17 and are likely responsible for synaptic dysfunction and memory loss in AD patients and AD animal models.18–21”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ42Peptide (2012) · cites this paper as [14]
In the citing paper
“recent studies have shown that the soluble Aβ oligomers are more neurotoxic both in vitro and in vivo.5−8”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [7]
In the citing paper
“For the preformed Aβ42 fibrils, no significant cell toxicity was observed in either the absence or presence of Cu2+ (Figure 9, lanes 1 and 2), supporting the previously reported diminished toxicity of Aβ42 fibrils.5,7,54−56”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [7]
In the citing paper
“This function may be critical in controlling Aβ deposition as well as levels of potentially neurotoxic Aβ oligomers (Lambert et al., 1998).”
From CX3CR1 in Microglia Regulates Brain Amyloid Deposition through Selective Protofibrillar Amyloid-β Phagocytosis (2010) · cites this paper as Lambert et al., 1998
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 [34]
In the citing paper
“In vitro, apoE and apoJ form stable complexes with A (11, 16 -20), alter the aggregation of various A peptides (21)(22)(23), and affect A neurotoxicity (24 -27).”
From Apolipoprotein E Receptors Mediate the Effects of β-Amyloid on Astrocyte Cultures (2000) · cites this paper as [27]
In the citing paper
“A 1-42 aged according to this protocol is a mixture of fibrils and soluble globular aggregates, and is active to astrocytes (37,38) and toxic to neurons (26,27).”
From Apolipoprotein E Receptors Mediate the Effects of β-Amyloid on Astrocyte Cultures (2000) · cites this paper as [27]
In the citing paper
“ApoJ has been shown to potentiate the formation of a neurotoxic species of A (26,27).”
From Apolipoprotein E Receptors Mediate the Effects of β-Amyloid on Astrocyte Cultures (2000) · cites this paper as [27]
In the citing paper
“ApoE, apoJ, and most recently ␣ 2 -macroglobulin have been shown to form a complex with A that may facilitate clearance of the peptide (25-27, 50, 51).”
From Apolipoprotein E Receptors Mediate the Effects of β-Amyloid on Astrocyte Cultures (2000) · cites this paper as [27]
In the citing paper
“Evidence suggests that increased uptake of these neurotoxic Aβ42 peptides results in accumulation and aggregation within neurons eventually leading the formation of plaques and neuronal death [40, 41].”
From The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates (2020) · cites this paper as [41]
In the citing paper
“Most importantly, these amyloid-free Aβ oligomers were potent CNS neurotoxins.”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lambert et al., 1998
In the citing paper
“With chronic exposure, neurons ultimately were killed. Death was selective for subpopulations of vulnerable neurons and was prevented by knockout of Fyn, a protein tyrosine kinase linked to NMDA receptor signaling.”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lambert et al., 1998
In the citing paper
“Investigation into the action of clusterin by Lambert, Klein and colleagues established that, concomitant with inhibition of amyloid formation, clusterin promotes accumulation of soluble Aβ oligomers (Lambert et al., 1998).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lambert et al., 1998
In the citing paper
“oligomers were found to inhibit functional synaptic plasticity (Lambert et al., 1998). Long-term potentiation (LTP) was inhibited within minutes. This rapid loss of LTP, measured in rat brain slices and in situ in mice, occurred without impact on baseline excitability, indicating impairment of signaling rather than degeneration.”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lambert et al., 1998
In the citing paper
“In hippocampal slices, synthetic oligomers cause rapid LTP inhibition (Barghorn et al., 2005; Fa et al., 2010; Jurgensen et al., 2011; Lambert et al., 1998; Nimmrich et al., 2008; Rammes et al., 2011; Wang et al., 2002).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lambert et al., 1998
In the citing paper
“early studies showed that binding is lost upon controlled trypsin treatment of neurons (Lambert et al., 1998).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lambert et al., 1998
In the citing paper
“In vitro and in vivo studies have now indicated that soluble Aβ oligomers impair synaptic plasticity, inhibiting hippocampal long-term potentiation (LTP), the electrophysiological correlate of learning and memory (3 –6).”
From Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein (2010) · cites this paper as [3]
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“There is a moderate decrease of ATP which is more apparent with F12 than with Nb medium, suggesting that F12, which was used in the original procedure (Lambert et al., 1998), could have some toxic effects on its own.”
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Metadata
- Authors
- 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., Wals, P., Zhang, C., Finch, C. E., Krafft, G. A., & Klein, W. L.
- Affiliations
- Northwestern University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-05-26
- Volume
- 95
- Issue
- 11
- Pages
- 6448-6453
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC27787
- OpenAlex
- W2165021720
- Cited by
- 3,506
- References
- 68
- Citations by year
- 2026: 61 · 2025: 69 · 2024: 82 · 2023: 81 · 2022: 101 · 2021: 115 · 2020: 137 · 2019: 105 · 2018: 127 · 2017: 138 · 2016: 139 · 2015: 152 · 2014: 171 · 2013: 188 · 2012: 196
- FWCI
- 29.85
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta 42, neurotoxicity, Alzheimer's disease, Fyn tyrosine kinase, neuroprotection, hippocampal long-term potentiation, synaptic plasticity, signal transduction, organotypic brain cultures
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cell Membrane, Cells, Cultured, Ligands, Neurotoxins, Amyloid beta-Peptides, Cell Death, Mice
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.
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