Caffeine Plus Coffee Compound Linked to Serotonin Help Protect Brain from Toxic Damage, Mouse Study Says

Caffeine Plus Coffee Compound Linked to Serotonin Help Protect Brain from Toxic Damage, Mouse Study Says

Two compounds found in coffee — caffeine and EHT, a fatty acid molecule derived from serotonin — work together to protect the brain from damage induced by alpha-synuclein, a study in mice reported.

The study, “Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson’s disease and DLB,” was published in PNAS.

Parkinson’s disease is characterized by alpha-synuclein aggregates. When this protein clumps, it gives rise to small fibrils that accumulate inside brain cells, producing small inclusions called Lewy bodies. These structures are highly toxic and often cause irreparable damage to affected nerve cells, slowly killing them.

Previous studies have shown that alpha-synuclein is abnormally hyperphosphorylated — a chemical modification in which a phosphate group is added to the protein — in the brain of patients with Parkinson’s. This is caused by the lack of activity of the protein phosphatase 2A (PP2A), an enzyme responsible for removing phosphate groups from alpha-synuclein.

Of note, alpha-synuclein phosphorylation is known to occur in Parkinson’s disease, and is thought to be a critical step in disease progression as it enhances alpha-synuclein’s toxicity —possibly by increasing the formation of alpha synuclein aggregates.

Interestingly, studies also report that Eicosanoyl-5-hydroxytryptamide or EHT — a fatty acid molecule found in coffee — promotes the activation of PP2A. In transgenic (or genetically engineered) mice, it was able to reverse the symptoms of phosphorylation to produce large quantities of alpha-synuclein.

The chemical serotonin, a neurotransmitter, is known to serve as a “feel-good” chemical in the brain, influencing a person’s sense of well-being and happiness.

“Considering epidemiologic and experimental evidence suggesting protective effects of CAF [caffeine] in PD [Parkinson’s disease], we sought, in the present study, to test whether there is synergy between EHT and caffeine in models of [alpha]-synucleinopathy,” the researchers wrote.  “[A]mong patients with early PD, the amount of CAF consumption does not impact the rate of progression of the disease, and decaffeinated coffee has been found to be protective in Drosophila models of PD, raising some question about the protective effect of only CAF among the numerous other compounds in coffee.”

Researchers treated alpha-synuclein transgenic mice (SynTg) — which overexpress alpha-synuclein in nerve cells — with either higher doses of caffeine and EHT separately, or with lower doses of both compounds for six months.

SynTg mice treated with caffeine and EHT had lesser accumulation of hyperphosphorylated alpha-synuclein in the brain, which was linked to higher levels of active PP2. These animals also  maintained neuron integrity and function, had lower brain inflammation, and performed better on behavioral tests.

Investigators found the same therapeutic benefits when they used the combined treatment in another mouse model of alpha-synucleinopathy, in which animals were injected with pre-formed fibrils of alpha-synuclein (alpha-Syn PFF).

In both animal models, however treatment with either caffeine or EHT alone failed to produce the same positive effects.

“These findings suggest that these two components of coffee have synergistic effects in protecting the brain against [alpha]-synuclein−mediated toxicity through maintenance of PP2A in an active state,” the researchers wrote.

“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 [dementia with Lewy bodies], PSP [progressive supranuclear palsy], and AD [Alzheimer’s disease],” they concluded.

Joana holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. She is currently finishing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Joana holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. She is currently finishing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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