Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers
Open accessAbstract
The cognitive hallmark of early Alzheimer's disease (AD) is an extraordinary inability to form new memories. For many years, this dementia was attributed to nerve-cell death induced by deposits of fibrillar amyloid beta (Abeta). A newer hypothesis has emerged, however, in which early memory loss is considered a synapse failure caused by soluble Abeta oligomers. Such oligomers rapidly block long-term potentiation, a classic experimental paradigm for synaptic plasticity, and they are strikingly elevated in AD brain tissue and transgenic-mouse AD models. The current work characterizes the manner in which Abeta oligomers attack neurons. Antibodies raised against synthetic oligomers applied to AD brain sections were found to give diffuse stain around neuronal cell bodies, suggestive of a dendritic pattern, whereas soluble brain extracts showed robust AD-dependent reactivity in dot immunoblots. Antigens in unfractionated AD extracts attached with specificity to cultured rat hippocampal neurons, binding within dendritic arbors at discrete puncta. Crude fractionation showed ligand size to be between 10 and 100 kDa. Synthetic Abeta oligomers of the same size gave identical punctate binding, which was highly selective for particular neurons. Image analysis by confocal double-label immunofluorescence established that >90% of the punctate oligomer binding sites colocalized with the synaptic marker PSD-95 (postsynaptic density protein 95). Synaptic binding was accompanied by ectopic induction of Arc, a synaptic immediate-early gene, the overexpression of which has been linked to dysfunctional learning. Results suggest the hypothesis that targeting and functional disruption of particular synapses by Abeta oligomers may provide a molecular basis for the specific loss of memory function in early AD.
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Soluble Aβ aggregates are more toxic than monomers or insoluble fibrils.
“Among these various forms, soluble Aβ aggregates are more toxic than monomers or insoluble fibrils; thus, reducing these soluble Aβ aggregates could represent a practical treatment approach in the early stages of AD [10,11,12].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [12]
The Discussion (page not available) describes soluble Aβ oligomers as neurologically harmful and potent CNS neurotoxins. The ‘Synthetic oligomeric species bind specifically to clustered sites’ section reports that larger oligomers bound hippocampal dendrites whereas a fraction containing monomers and small oligomers did not. The paper does not establish that soluble aggregates are more toxic than insoluble fibrils, and the binding result is not a direct toxicity comparison with monomers. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAβ accumulation, whether as insoluble plaques or soluble oligomers, appears to be a primary driver of Alzheimer's disease, particularly linked to synapse dysfunction.
“Despite ongoing debate, Aβ accumulation, whether in the form of insoluble plaques, or smaller soluble oligomers does appear to be a primary driver of the disease process, particularly linked to synapse dysfunction [3].”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [3]
The Introduction describes evidence implicating Aβ in Alzheimer’s disease and a hypothesis that soluble oligomers cause early synapse failure. It contrasts that mechanism with the original plaque-related hypothesis, which attributed memory loss to neuron death caused by fibrillar Aβ. The paper therefore supports the soluble-oligomer link to synaptic dysfunction, but not the claim that insoluble plaques are likewise linked to it. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOverexpression of APP and its proteolytic product Aβ have been implicated in the synaptic losses seen early in the development of AD.
“Conversely, overexpression of APP and its proteolytic product, Aβ, have been implicated in the synaptic losses seen early in the development of AD [27].”
From FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein (2007) · cites this paper as [27]
The Introduction (page unavailable) links soluble Aβ oligomers to early synapse failure and notes their elevation in hAPP transgenic mice. The Discussion (page unavailable) proposes that oligomers may cause physical synaptic degeneration and reports terminal loss in some transgenic models, but it does not establish that APP overexpression itself causes the synaptic losses claimed, or that physical synapse loss occurs early in human AD. (LLM, conf=0.84)
Experimental — accuracy not yet measuredReducing soluble Aβ aggregates could represent a practical treatment approach in the early stages of AD.
“Among these various forms, soluble Aβ aggregates are more toxic than monomers or insoluble fibrils; thus, reducing these soluble Aβ aggregates could represent a practical treatment approach in the early stages of AD [10,11,12].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [12]
Aβ oligomers associate with neurons, accumulating very early in disease progression, in loci distinct from amyloid deposits.
“Immunohistochemistry confirms that oligomers associate with neurons, accumulating very early in disease progression (Lacor et al., 2004), in loci distinct from amyloid deposits (Kayed et al., 2003).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lacor et al., 2004
Aβ oligomers cause dysfunctional trafficking of ionotropic glutamate receptors and metabotropic glutamate receptors.
“as have the related predictions that oligomers cause dysfunctional trafficking of ionotropic glutamate receptors and metabotropic glutamate receptors (Gong et al., 2003; Lacor et al., 2004).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lacor et al., 2004
The possible source of extracellular oligomers and how they interact with neurons in human brain are suggested by their peri-somatic localization, observed in early-stage disease.
“The possible source of extracellular oligomers and how they interact with neurons in human brain are suggested by their peri-somatic localization, observed in early-stage disease (Figure 1, left; (Lacor et al., 2004)).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lacor et al., 2004
The same binding specificity and punctate pattern is observed for synthetic oligomers, particularly those greater than 50 kDa.
“The same binding specificity and punctate pattern is observed for synthetic oligomers, particularly those greater than 50 kDa (Lacor et al., 2004).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lacor et al., 2004
Oligomers show greater than 90% co-localization with the post-synaptic marker PSD-95.
“Oligomers show > 90% co-localization with the post-synaptic marker PSD-95 (Lacor et al., 2004).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lacor et al., 2004
The prediction that aberrant Arc expression disrupts receptor trafficking was first confirmed for NMDA receptors.
“This prediction was first confirmed for NMDA-Rs (Lacor et al., 2004; Lacor et al., 2007; Snyder et al., 2005).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lacor et al., 2004
One rapid consequence of oligomer exposure is an aberrant expression of Arc.
“One rapid consequence is an aberrant expression of Arc (Activity-Regulated Cytoskeletal associated protein; (Lacor et al., 2004)).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lacor et al., 2004
Because Arc is an actin binding protein, its aberrant expression was predicted to disrupt receptor trafficking, which could consequently disrupt plasticity.
“Because Arc is an actin binding protein, its aberrant expression was predicted to disrupt receptor trafficking (Lacor et al., 2004), which could consequently disrupt plasticity (Gong et al., 2003).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lacor et al., 2004
Coupled with the potential of dendrites for activity-stimulated exocytosis, such a phenomenon could account for the perineuronal deposits of oligomers seen in Figure 1.
“Coupled with the potential of dendrites for activity-stimulated exocytosis (Kennedy et al., 2010), such a phenomenon could account for the “perineuronal deposits” of oligomers seen in Figure 1 (Lacor et al., 2004).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Lacor et al., 2004
All of these processes are affected by Aβ oligomers in vitro, using primary neuronal cultures.
“All of these processes are affected by Aβ oligomers in vitro, using primary neuronal cultures (12, 15, 36, 37).”
From Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein (2010) · cites this paper as [37]
Extracellular Aβ1-42 oligomers preferentially target synapses when added to neurons.
“Furthermore, extracellular Aβ1-42 oligomers preferentially target synapses when added to neurons [43, 91].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [91]
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Self-citationAPP depletion alters selective pre- and post-synaptic proteins
Martinsson, I., Capetillo-Zarate, E., Faideau, M., Willén, K., Esteras, N., Frykman, S., Tjernberg, L. O., & Gouras, G. K. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2019.02.003 · Cited by 29 · see citing works
Intracerebroventricular passive immunization with anti‐oligoAβ antibody in TgCRND8
Chauhan, N. B. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21110 · Cited by 24 · see citing works
- Authors
- Lacor, P. N., Buniel, M. C., Chang, L., Fernandez, S. J., Gong, Y., Viola, K. L., Lambert, M. P., Velasco, P. T., Bigio, E. H., Finch, C. E., Krafft, G. A., & Klein, W. L.
- Affiliations
- Northwestern University (US)
- University of Southern California (US)
- Acumen Pharmaceuticals (United States) (US)
- Corresponding author
- Klein, William L.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-11-10
- Volume
- 24
- Issue
- 45
- Pages
- 10191-10200
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6730194
- OpenAlex
- W2162807572
- Cited by
- 954
- References
- 64
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 24 · 2023: 41 · 2022: 35 · 2021: 28 · 2020: 26 · 2019: 32 · 2018: 41 · 2017: 50 · 2016: 51 · 2015: 50 · 2014: 54 · 2013: 65 · 2012: 59
- FWCI
- 25.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Illinois Department of Public Health
- Northwestern University
- National Institutes of Health (AG11385)
- National Institute on Aging (R01 AG11385, P30AG13854, R01AG022547, R01-AG22547, R01AG011385, R03AG022237, R01-AG18877, P30AG013854, R01AG018877)
- Topics
- Health Sciences › Medicine › Physiology › 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
- Alzheimer's disease, amyloid-beta oligomers, synaptic targeting, long-term potentiation, synaptic plasticity, PSD-95, Arc, hippocampal neurons, memory loss, early Alzheimer's disease
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Binding Sites, Cerebral Cortex, Cerebrospinal Fluid Proteins, Chromatography, High Pressure Liquid, Cytoskeletal Proteins, Female, Hippocampus, Humans, Male, Nerve Tissue Proteins, Neurons, Peptide Fragments, Protein Binding, Synapses, Tissue Extracts, Amyloid beta-Peptides, Rats
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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