Alzheimer's-associated Abeta oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal.
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.
Pitt
Jason
J
Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208, USA. jasonpitt@u.northwestern.edu
Roth
William
W
Lacor
Pascale
P
Smith
Amos B
AB
Blankenship
Matthew
M
Velasco
Pauline
P
De Felice
Fernanda
F
Breslin
Paul
P
Klein
William L
WL
D000447:Aldehydes / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000906:Antibodies; D000937:Antigen-Antibody Reactions; D002478:Cells, Cultured; D000081004:Cyclopentane Monoterpenes; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D018613:Microscopy, Confocal; D008970:Molecular Weight; D009479:Neuropeptides / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology*; D011487:Protein Conformation; D055503:Protein Multimerization; D013569:Synapses / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D000447:Aldehydes; D016229:Amyloid beta-Peptides; D000906:Antibodies; D000081004:Cyclopentane Monoterpenes; D009479:Neuropeptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010636:Phenols; C075222:amyloid beta-protein (1-42); C053386:drebrins; C503534:oleocanthal