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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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“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Other suggested Aβ binding partners at synapses include the α7-nicotinic receptor [49], Ephrin A4 [73], PSD95 [35, 50, 52] and LilrB2 [32].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [35]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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 cited source says what the claim attributes to it.
In the citing paper
“As previously discussed, amyloid-β oligomers bind to synapses [144] and interfere with the normal process of neurotransmission, long-term potentiation, and thereby memory formation [145].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [144]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“Other binding partners that have been suggested to bind Aβ include the α7-nicotinic receptor [49], Ephrin A4 (EphA4) [73], PSD95 [35, 50, 52] or LilrB2 [32].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [35]
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Citations
Cites
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
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
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Alzheimer's disease: the amyloid cascade hypothesis
Hardy, J. A., & Higgins, G. A. (1992) · Science · doi:10.1126/science.1566067 · Cited by 7,484
Alzheimer's Disease Is a Synaptic Failure
Selkoe, D. J. (2002) · Science · doi:10.1126/science.1074069 · Cited by 4,420
Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., & Selkoe, D. J. (2002) · Nature · doi:10.1038/416535a · Cited by 4,291
Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., & Glabe, C. G. (2003) · Science · doi:10.1126/science.1079469 · Cited by 4,064
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
Self-citationPathways towards and Away from Alzheimer’s Disease
Mattson, M. P. (2004) · Nature · doi:10.1038/nature02621 · Cited by 3,052
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Research works printed but not linked: 2
- Klein WL (2004) Cytotoxic intermediates in the fibrillation pathway: Aβ oligomers in Alzheimer's disease as a case study. In: Protein misfolding, aggregation and conformational diseases (Uversky V, ed). New York: Kluwer Academic/Plenum, in press.
- 2002, Nat Rev Neurosci, 3, 824
Cited by
Sorted by citations
Amyloid 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
Aβ Oligomers – a decade of discovery
Walsh, D. M., & Selkoe, D. J. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04426.x · Cited by 1,938
Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers
Laurén, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W., & Strittmatter, S. M. (2009) · Nature · doi:10.1038/nature07761 · Cited by 1,560
Impaired Balance of Mitochondrial Fission and Fusion in Alzheimer's Disease
Wang, X., Su, B., Lee, H.-G., Li, X., Perry, G., Smith, M. A., & Zhu, X. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.1357-09.2009 · Cited by 1,224
The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease
Spires-Jones, T. L., & Hyman, B. T. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.004 · Cited by 1,201
Metadata
- 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
- 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
- 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
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