Alzheimer's-associated A{beta} oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal
- Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208 (United States)
- Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104 (United States)
- Department of Psychology, Western Illinois University, Macomb, IL 61455 (United States)
- Instituto de Bioquimica Medica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21955-590 (Brazil)
It now appears likely that soluble oligomers of amyloid-{beta}{sub 1-42} 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 A{beta} 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 A{beta} species, when assayed with both sequence- and conformation-specific A{beta} 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 (A{beta}-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.
- OSTI ID:
- 21272680
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 240, Issue 2; Other Information: DOI: 10.1016/j.taap.2009.07.018; PII: S0041-008X(09)00296-8; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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