Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss

Gong, Yuesong; Chang, Lei; Viola, Kirsten L.; Lacor, Pascale N.; Lambert, Mary P; Finch, Caleb E.; Krafft, Grant A.; Klein, William L.

doi:10.1073/pnas.1834302100

Cited by 1,061Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss

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Gong, Yuesong, Chang, Lei, Viola, Kirsten L., Lacor, Pascale N., Lambert, Mary P, Finch, Caleb E., Krafft, Grant A., Klein, William L.·2003·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1834302100PMC PMC193576

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Abstract

A molecular basis for memory failure in Alzheimer's disease (AD) has been recently hypothesized, in which a significant role is attributed to small, soluble oligomers of amyloid beta-peptide (A beta). A beta oligomeric ligands (also known as ADDLs) are known to be potent inhibitors of hippocampal long-term potentiation, which is a paradigm for synaptic plasticity, and have been linked to synapse loss and reversible memory failure in transgenic mouse AD models. If such oligomers were to build up in human brain, their neurological impact could provide the missing link that accounts for the poor correlation between AD dementia and amyloid plaques. This article, using antibodies raised against synthetic A beta oligomers, verifies the predicted accumulation of soluble oligomers in AD frontal cortex. Oligomers in AD reach levels up to 70-fold over control brains. Brain-derived and synthetic oligomers show structural equivalence with respect to mass, isoelectric point, and recognition by conformation-sensitive antibodies. Both oligomers, moreover, exhibit the same striking patterns of attachment to cultured hippocampal neurons, binding on dendrite surfaces in small clusters with ligand-like specificity. Binding assays using solubilized membranes show oligomers to be high-affinity ligands for a small number of nonabundant proteins. Current results confirm the prediction that soluble oligomeric A beta ligands are intrinsic to AD pathology, and validate their use in new approaches to therapeutic AD drugs and vaccines.

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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 [11]
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 [18]
Aβ42 peptide was shown to form neurotoxic soluble Aβ oligomers.
“which was also shown to form neurotoxic soluble Aβ oligomers.18–20”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ42Peptide (2012) · cites this paper as [18]
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 [8]
Aβ42 peptide was shown to form neurotoxic soluble Aβ oligomers.
“the Aβ42 peptide was employed in these studies because it was shown to form neurotoxic soluble Aβ oligomers.5,8,48”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [8]

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Authors: Gong, Y., Chang, L., Viola, K. L., Lacor, P. N., Lambert, M. P., Finch, C. E., Krafft, G. A., & Klein, W. L.
Affiliations: Northwestern University (US)
ORCID: Gong, Yuesong
Chang, Lei
Viola, Kirsten L.
Finch, Caleb E.
Klein, William L.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2003-08-18
Volume: 100
Issue: 18
Pages: 10417-10422
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1834302100
PMC: PMC193576
OpenAlex: W2040721710
Cited by: 1,061
References: 55
Citations by year: 2026: 21 · 2025: 15 · 2024: 19 · 2023: 32 · 2022: 24 · 2021: 33 · 2020: 35 · 2019: 38 · 2018: 44 · 2017: 45 · 2016: 32 · 2015: 42 · 2014: 52 · 2013: 49 · 2012: 53
FWCI: 35.26
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Northwestern University
National Institutes of Health (1p01ag015501-01)
National Institute on Aging (P01-AG15501, R01-AG18877, R01AG018877)
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 oligomers, memory loss, hippocampal long-term potentiation, synaptic plasticity, synaptic loss, frontal cortex, dendrites, protein-ligand binding, amyloid plaques, therapeutic vaccines
MeSH terms: Alzheimer Disease, Animals, Binding Sites, Brain Chemistry, Cells, Cultured, Cerebral Cortex, Ligands, Neurons, Oligopeptides, Peptide Fragments, Tissue Extracts, Immunoblotting, Amyloid beta-Peptides, Rats, Sprague-Dawley, Long-Term Potentiation, Rats

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Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss

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