Title | Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson's disease and DLB. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Yan, R, Zhang, J, Park, H-J, Park, ES, Oh, S, Zheng, H, Junn, E, Voronkov, M, Stock, JB, M Mouradian, M |
Journal | Proc Natl Acad Sci U S A |
Volume | 115 |
Issue | 51 |
Pagination | E12053-E12062 |
Date Published | 2018 Dec 18 |
ISSN | 1091-6490 |
Keywords | alpha-Synuclein, Animals, Brain, Caffeine, Coffee, Disease Models, Animal, Fatty Acids, Lewy Body Disease, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Neuroprotection, Parkinson Disease, Phosphorylation, Protein Phosphatase 2, Serotonin |
Abstract | <p>Hyperphosphorylated α-synuclein in Lewy bodies and Lewy neurites is a characteristic neuropathological feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). The catalytic subunit of the specific phosphatase, protein phosphatase 2A (PP2A) that dephosphorylates α-synuclein, is hypomethylated in these brains, thereby impeding the assembly of the active trimeric holoenzyme and reducing phosphatase activity. This phosphatase deficiency contributes to the accumulation of hyperphosphorylated α-synuclein, which tends to fibrillize more than unmodified α-synuclein. Eicosanoyl-5-hydroxytryptamide (EHT), a fatty acid derivative of serotonin found in coffee, inhibits the PP2A methylesterase so as to maintain PP2A in a highly active methylated state and mitigates the phenotype of α-synuclein transgenic (Syn) mice. Considering epidemiologic and experimental evidence suggesting protective effects of caffeine in PD, we sought, in the present study, to test whether there is synergy between EHT and caffeine in models of α-synucleinopathy. Coadministration of these two compounds orally for 6 mo at doses that were individually ineffective in Syn mice and in a striatal α-synuclein preformed fibril inoculation model resulted in reduced accumulation of phosphorylated α-synuclein, preserved neuronal integrity and function, diminished neuroinflammation, and improved behavioral performance. These indices were associated with increased levels of methylated PP2A in brain tissue. A similar profile of greater PP2A methylation and cytoprotection was found in SH-SY5Y cells cotreated with EHT and caffeine, but not with each compound alone. These findings suggest that these two components of coffee have synergistic effects in protecting the brain against α-synuclein-mediated toxicity through maintenance of PP2A in an active state.</p> |
DOI | 10.1073/pnas.1813365115 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 30509990 |
PubMed Central ID | PMC6304960 |
Grant List | R01 NS101134 / NS / NINDS NIH HHS / United States R33 NS096032 / NS / NINDS NIH HHS / United States R21 NS095003 / NS / NINDS NIH HHS / United States R01 NS070898 / NS / NINDS NIH HHS / United States R21 NS096032 / NS / NINDS NIH HHS / United States R01 NS073994 / NS / NINDS NIH HHS / United States R01 AT006868 / AT / NCCIH NIH HHS / United States P30 NS046593 / NS / NINDS NIH HHS / United States |