Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson's disease and DLB.

TitleSynergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson's disease and DLB.
Publication TypeJournal Article
Year of Publication2018
AuthorsYan, R, Zhang, J, Park, H-J, Park, ES, Oh, S, Zheng, H, Junn, E, Voronkov, M, Stock, JB, M Mouradian, M
JournalProc Natl Acad Sci U S A
Volume115
Issue51
PaginationE12053-E12062
Date Published2018 12 18
ISSN1091-6490
Keywordsalpha-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

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 (SynTg) 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 SynTg 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.

DOI10.1073/pnas.1813365115
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID30509990
PubMed Central IDPMC6304960
Grant ListR01 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