A compound found in the waxy coating of coffee beans may work in synergy with caffeine to protect against Parkinson’s disease (PD), according to research results reported by scientists at Rutgers Biomedical and Health. Prior studies have linked coffee drinking with a reduced risk of PD, and it’s been assumed that the beneficial component in the brew is caffeine.
The new studies, headed M. Maral Mouradian, Ph.D., director of the Rutgers Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and William Dow Lovett professor of neurology, suggest that the protective effects of coffee may, in fact, hinge on another coffee compound, eicosanoyl-5-hydroxytryptamide (EHT), which acts in partnership with caffeine to maintain the activity of an enzyme protein phosphatase 2A (PP2A).
The findings, reported in the Proceedings of the National Academy of Sciences (PNAS) showed that administering low doses of both EHT and caffeine, but not either compound on its own, protected the brains of mice against the neuropathological build-up of α-synuclein protein aggregates that are characteristic of Parkinson’s disease and dementia with Lewy bodies (DLB). The team’s published paper is titled, “Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson’s disease and DLB.”
Parkinson’s disease and DLB are characterized by the formation of hyperphosphorylated α-synuclein deposits inside neurons in the brain, the authors explained. In these cases, the phosphatase PP2A that dephosphorylates α-synuclein is hypomethylated, which reduces its activity. This lack of enzyme function contributes to accumulation of the hyperphosphorylated α-synuclein and formation of the telltale fibrils.
Coffee consumption has been linked with a reduced risk of Parkinson’s disease, and while prior epidemiological and experimental evidence suggests that it’s the caffeine (CAF) in coffee that is protective, “several lines of evidence suggest the presence of additional compound(s) in coffee that can be protective as well,” the team noted. Studies have also found that among early Parkinson’s disease patients, the amount of caffeine consumed doesn’t affect the rate of disease progression, while decaffeinated coffee has been found to be protective in Drosophila models of PD, “raising some questions about the protective effect of only CAF among the numerous other compounds in coffee.”
Previous studies have also found that levels of methylation-regulating enzymes are altered in PD and DLB brains, and that this is linked with lower relative levels of methylated PP2A. Other lines of investigation have shown that EHT treatment increases brain PP2A methylation and phosphatase activity and reduces the accumulation of phosphorylated α-synuclein aggregates in the brain of a mouse model. EHT is a fatty acid derivative of the neurotransmitter serotonin, and is structurally unrelated to caffeine.
The Rutgers’ team’s studies were designed to test whether EHT and caffeine may work together to protect against α-synuclein-mediated pathology in two different mouse models. The results showed that while low doses of either compound alone didn’t prevent the mice from developing behavioural problems, treatment using the two compounds combined did have a protective effect. Combination therapy also reduced the buildup of phosphorylated α-synuclein, and protected against neuronal damage and neuroinflammation. “These findings indicate that the cotreatment has a synergistic effect in protecting neuronal integrity and preventing the inflammatory response to the α-synuclein trans- gene in these mice,” the authors wrote.
Further studies in relevant mouse models suggested that EHT and CAF work together to regulate PP2A activity, and tests in laboratory-grown cells indicated that the two coffee compounds act synergistically to enhance steady-state-levels of PP2A methylation and so phosphatase activity that are associated with protecting the neurons.
“The present findings demonstrate that subtherapeutic doses of CAF and EHT, two unrelated compounds found in coffee, can work in synergy to effect biochemical and molecular changes in the mouse brain leading to protection in two models of α-synucleinopathy,” the authors wrote. “… coffee is a complex chemical mixture containing more than a thousand different compounds. Thus, it is not unlikely that other components of coffee play a beneficial role as well.”
Dr. Mouradian acknowledges that more research will be needed to find the optimum amounts of EHT and caffeine that might protect against α-synuclein pathologies in humans. “EHT is a compound found in various types of coffee but the amount varies,” she commented.” It is important that the appropriate amount and ratio be determined so people don’t over-caffeinate themselves, as that can have negative health consequences.”
The authors also point out that coffee isn’t the only botanical that contains compounds that impact on PP2A methylation. “As we begin to unravel the polypharmacology of the micronutrients in commonly consumed botanical extracts such as coffee, it seems likely that it will be possible to optimize their composition to enhance efficacy so as to provide widely available, inexpensive, and effective therapeutics for the prevention and treatment of neurodegenerative diseases such as PD, DLB, PSP [progressive supranuclear palsy], and AD [Alzheimer’s disease].
