Oleocanthal, a naturally-occurring compound found in extra-virgin olive oil, alters the structure of neurotoxic proteins believed to contribute to the debilitating effects of Alzheimer's disease. This structural change impedes the proteins' ability to damage brain nerve cells.
"The findings may help identify effective preventative measures and lead to improved therapeutics in the fight against Alzheimer's disease," said study co-leader Paul A.S. Breslin, PhD, a sensory psychobiologist at the Monell Center.
Known as ADDLs, these highly toxic proteins bind within the neural synapses of the brains of Alzheimer's patients and are believed to directly disrupt nerve cell function, eventually leading to memory loss, cell death, and global disruption of brain function. Synapses are specialized junctions that allow one nerve cell to send information another.
"Binding of ADDLs to nerve cell synapses is thought to be a crucial first step in the initiation of Alzheimer's disease. Oleocanthal alters ADDL structure in a way that deters their binding to synapses," said William L. Klein, PhD, who co-led the research with Breslin. "Translational studies are needed to link these laboratory findings to clinical interventions." Klein is Professor of Neurobiology & Physiology, and a member of the Cognitive Neurology and Alzheimer's Disease Center, at Northwestern University.
Klein and his colleagues identified ADDLs in 1998, leading to a major shift in thinking about the causes, progression and treatment of Alzheimer's disease. Also known as beta-amyloid oligomers, ADDLs are structurally different from the amyloid plaques that accumulate in brains of Alzheimer's patients.
Reporting on a series of in vitro studies, the team of Monell and Northwestern researchers found that incubation with oleocanthal changed the structure of ADDLs by increasing the protein's size.
Knowing that oleocanthal changed ADDL size, the researchers next examined whether oleocanthal affected the ability of ADDLs to bind to synapses of cultured hippocampal neurons. The hippocampus, a part of the brain intimately involved in learning and memory, is one of the first areas affected by Alzheimer's disease.
Measuring ADDL binding with and without oleocanthal, they discovered that small amounts of oleocanthal effectively reduced binding of ADDLs to hippocampal synapses. Additional studies revealed that oleocanthal can protect synapses from structural damage caused by ADDLs.
An unexpected finding was that oleocanthal makes ADDLs into stronger targets for antibodies. This action establishes an opportunity for creating more effective immunotherapy treatments, which use antibodies to bind to and attack ADDLs.
"If antibody treatment of Alzheimer's is enhanced by oleocanthal, the collective anti-toxic and immunological effects of this compound may lead to a successful treatment for an incurable disease," Breslin said. "Only clinical trials will tell for sure."
In earlier work at Monell, Breslin and co-workers used the sensory properties of extra virgin olive oil to identify oleocanthal based on a similar oral irritation quality to ibuprofen. Oleocanthal and ibuprofen also have similar anti-inflammatory properties, and ibuprofen – like extra virgin olive oils presumably rich in oleocanthal – is associated with a decreased risk of Alzheimer's when used regularly.
Future studies to identify more precisely how oleocanthal changes ADDL structure may increase understanding of the pharmacological actions of oleocanthal, ibuprofen, and structurally related plant compounds. Such pharmacological insights could provide discovery pathways related to disease prevention and treatment.
The findings appear in the October 15 issue of Toxicology and Applied Pharmacology.
It now appears likely that soluble oligomers of amyloid-? 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? 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? species, when assayed with both sequence- and conformation-specific A? 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?-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.
First author Jason Pitt, a graduate student in Klein's lab, conducted the studies. Also contributing to the work were chemist Amos B. Smith, III, of Monell and the University of Pennsylvania, who supplied the oleocanthal; William Roth, Pascale Lacor and Pauline Velasco from Northwestern; Matthew Blankenship from Western Illinois University; and Fernanda De Felice from the Universidade Federal do Rio de Janeiro. In addition to his faculty appointment at Monell, Breslin is Professor of Nutritional Sciences in the School of Environmental and Biological Sciences at Rutgers University.
The National Institute on Aging funded the research; Dr. Breslin is funded by the National Institute on Deafness and Other Communication Disorders.
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