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Alzheimer's-associated Aβ oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal
Open accessAbstract
It now appears likely that soluble oligomers of amyloid-beta1-42 peptide, rather than insoluble fibrils, act as the primary neurotoxin in Alzheimer's disease (AD). Consequently, compounds capable of altering the assembly state of these oligomers (referred to as ADDLs) may have potential for AD therapeutics. Phenolic compounds are of particular interest for their ability to disrupt Abeta oligomerization and reduce pathogenicity. This study has focused on oleocanthal (OC), a naturally-occurring phenolic compound found in extra-virgin olive oil. OC increased the immunoreactivity of soluble Abeta species, when assayed with both sequence- and conformation-specific Abeta antibodies, indicating changes in oligomer structure. Analysis of oligomers in the presence of OC showed an upward shift in MW and a ladder-like distribution of SDS-stable ADDL subspecies. In comparison with control ADDLs, oligomers formed in the presence of OC (Abeta-OC) showed equivalent colocalization at synapses but exhibited greater immunofluorescence as a result of increased antibody recognition. The enhanced signal at synapses was not due to increased synaptic binding, as direct detection of fluorescently-labeled ADDLs showed an overall reduction in ADDL signal in the presence of OC. Decreased binding to synapses was accompanied by significantly less synaptic deterioration assayed by drebrin loss. Additionally, treatment with OC improved antibody clearance of ADDLs. These results indicate oleocanthal is capable of altering the oligomerization state of ADDLs while protecting neurons from the synaptopathological effects of ADDLs and suggest OC as a lead compound for development in AD therapeutics.
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“And in fact, not all oligomers are toxic, even those oligomers of a given size. Subtle conformation changes affect toxicity and immunoreactivity (Chromy et al., 2003; Pitt et al., 2009).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Pitt et al., 2009
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Metadata
- Authors
- Pitt, J., Roth, W., Lacor, P., Smith, A. B., Blankenship, M., Velasco, P., De Felice, F., Breslin, P., & Klein, W. L.
- Affiliations
- Northwestern University (US)
- Monell Chemical Senses Center (US)
- Western Illinois University (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Pitt, Jason
- Breslin, Paul
- Klein, William L.
- Venue
- Toxicology and Applied Pharmacology
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 240
- Issue
- 2
- Pages
- 189-197
- ISSN
- 0041-008X (ISSN-L)
- PMC
- PMC2808212
- OpenAlex
- W2025825556
- Cited by
- 134
- References
- 53
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 5 · 2021: 10 · 2020: 5 · 2019: 11 · 2018: 12 · 2017: 13 · 2016: 9 · 2015: 10 · 2014: 5 · 2013: 15 · 2012: 17
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Toxicology and Applied Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Institutes of Health (5p50dc006760-05, 5t32ag020418-08)
- National Institute on Aging (5 T32 AG020418, R01AG022547, R01AG029460, T32-AG020418)
- National Institute on Deafness and Other Communication Disorders (P50 DC06760, P50-DC006760)
- 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
- Alzheimer's disease, amyloid-beta oligomers, oleocanthal, extra virgin olive oil, phenolic compounds, synaptotoxicity, oligomerization, immunoreactivity, drebrin, antibody clearance, neuroprotection, Alzheimer's disease therapeutics
- MeSH terms
- Cyclopentane Monoterpenes, Aldehydes, Animals, Antibodies, Antigen-Antibody Reactions, Cells, Cultured, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Fluorescent Antibody Technique, Hippocampus, Humans, Molecular Weight, Neuropeptides, Peptide Fragments, Phenols, Protein Conformation, Synapses, Immunoblotting, Amyloid beta-Peptides, Microscopy, Confocal, Neuroprotective Agents, Protein Multimerization
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