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.; Wals, P.; Zhang, C.; Finch, C. E.; Krafft, G. A.; Klein, W. L.

doi:10.1073/pnas.95.11.6448

Cited by 3,506Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins

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Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I. +7 more·1998·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.95.11.6448PMC PMC27787

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Abstract

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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Soluble Aβ oligomers are more neurotoxic than amyloid plaques and most likely responsible for synaptic dysfunction and memory loss in AD.
“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]
Soluble Aβ oligomers are possibly more neurotoxic than amyloid plaques and are likely responsible for synaptic dysfunction and memory loss in AD patients and AD animal models.
“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]
Soluble Aβ oligomers are more neurotoxic than insoluble aggregates both in vitro and in vivo.
“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]
For preformed Aβ42 fibrils, no significant cell toxicity was observed in either the absence or presence of Cu2+.
“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]
Aβ disrupts synaptic transmission and induces synapse loss.
“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]

Amyloid-free Aβ oligomers are potent CNS neurotoxins.
“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
With chronic exposure, Aβ oligomers ultimately kill neurons, selectively for vulnerable subpopulations, and this death is prevented by knockout of Fyn.
“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
Clusterin prevents amyloid formation and promotes accumulation of soluble Aβ oligomers.
“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
Aβ oligomers inhibit functional synaptic plasticity (long-term potentiation) within minutes without affecting baseline excitability.
“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 hippocampal slices, synthetic Aβ oligomers cause rapid LTP inhibition.
“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
ADDL binding is lost upon controlled trypsin treatment of neurons.
“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
Soluble Aβ oligomers impair synaptic plasticity by inhibiting hippocampal long-term potentiation.
“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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Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
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Untitled work
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Molecular Mechanisms of Amyloidosis
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Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models
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APP Processing and Synaptic Function
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Translating cell biology into therapeutic advances in Alzheimer's disease
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Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway
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The Role of Endoplasmic Reticulum Stress in Human Pathology
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Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers
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Unfolding the role of protein misfolding in neurodegenerative diseases
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Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability
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Alzheimer’s Disease: The Challenge of the Second Century
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Amyloid pores from pathogenic mutations
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Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways
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The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation
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Impaired Balance of Mitochondrial Fission and Fusion in Alzheimer's Disease
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Deciphering the Molecular Basis of Memory Failure in Alzheimer's Disease
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The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease
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Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease
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Amyloid β-Protein Fibrillogenesis
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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 · see citing works
Calcium Dysregulation and Membrane Disruption as a Ubiquitous Neurotoxic Mechanism of Soluble Amyloid Oligomers*♦
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Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior
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Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease
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Neurotoxicity of Amyloid -Protein: Synaptic and Network Dysfunction
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Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum?
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Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988 · see citing works
“The original hypothesis focuses on large insoluble Aβ fibrils as the key offender of neuronal damage, while growing evidence supports that the Aβ oligomers exist and exert their neurotoxicity independently of mature fibrils.(61) The amyloidβ oligomer (AβO) hypothesis suggests that AD pathogenesis was instigated by sol…”
Background
Soluble Oligomers of Amyloid β Protein Facilitate Hippocampal Long-Term Depression by Disrupting Neuronal Glutamate Uptake
Li, 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
Exogenous Induction of Cerebral ß-Amyloidogenesis Is Governed by Agent and Host
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Tau phosphorylation: the therapeutic challenge for neurodegenerative disease
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Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers
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Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice
Chapman, P. F., White, G. L., Jones, M. W., Cooper-Blacketer, D., Marshall, V. J., Irizarry, M., Younkin, L., Good, M. A., Bliss, T. V. P., Hyman, B. T., et al. (1999) · Nature Neuroscience · doi:10.1038/6374 · Cited by 946 · see citing works
Self-assembling peptide and protein amyloids: from structure to tailored function in nanotechnology
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Permeabilization of Lipid Bilayers Is a Common Conformation-dependent Activity of Soluble Amyloid Oligomers in Protein Misfolding Diseases
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The Amyloid Beta Peptide: A Chemist’s Perspective. Role in Alzheimer’s and Fibrillization
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Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine
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Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration
Jin, 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
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
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Detection of a Biomarker for Alzheimer's Disease from Synthetic and Clinical Samples Using a Nanoscale Optical Biosensor
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Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques
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An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers
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Alzheimer's Disease: Molecular Understanding Predicts Amyloid-Based Therapeutics
Selkoe, D. J., & Schenk, D. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140248 · Cited by 816 · see citing works
Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
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Protofibrillar Intermediates of Amyloid β-Protein Induce Acute Electrophysiological Changes and Progressive Neurotoxicity in Cortical Neurons
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Therapeutic approaches to protein-misfolding diseases
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The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy
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Review: Alzheimer's Amyloid β-Peptide-Associated Free Radical Oxidative Stress and Neurotoxicity
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Inhibitors of Class 1 Histone Deacetylases Reverse Contextual Memory Deficits in a Mouse Model of Alzheimer's Disease
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The Relationship between Aβ and Memory in the Tg2576 Mouse Model of Alzheimer's Disease
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[AM‐03]: Oligomers/Protofibrials/ADDLs
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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)
ORCID: Morgan, T. E.
Viola, K. L.
Finch, C. E.
Klein, W. L.
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
DOI: 10.1073/pnas.95.11.6448
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: Health Sciences › Medicine › Physiology › 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

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Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins

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