Fenchol, a natural compound commonly present in some plants including basil (Ocimum basilicum), decreases Alzheimer’s disease pathology by activating the free fatty acid receptor 2 (FFAR2) signaling, according to new research published in the journal Frontiers in Aging Neuroscience.
Emerging evidence indicates that short-chain fatty acids (SCFAs) — metabolites produced by beneficial gut bacteria and the primary source of nutrition for cells in your colon — contribute to brain health.
The abundance of SCFAs is often reduced in older patients with mild cognitive impairment and Alzheimer’s disease, the most common form of dementia.
However, how this decline in SCFAs contributes to Alzheimer’s disease progression remains largely unknown.
Gut-derived SCFAs that travel through the blood to the brain can bind to and activate FFAR2, a cell signaling molecule expressed on neurons.
“Our study is the first to discover that stimulation of the FFAR2 sensing mechanism by these microbial metabolites can be beneficial in protecting brain cells against toxic accumulation of the amyloid-beta (Aβ) protein associated with Alzheimer’s disease,” said Professor Hariom Yadav, a researcher at the Wake Forest School of Medicine and the University of South Florida.
In the study, Dr. Yadav and colleagues studied the function of FFAR2 in the brain.
They first showed that inhibiting the FFAR2 receptor contributes to the abnormal buildup of the Aβ protein causing neurotoxicity linked to Alzheimer’s disease.
Then, they performed large-scale virtual screening of more than 144,000 natural compounds to find potential candidates that could mimic the same beneficial effect of microbiota produced SCFAs in activating FFAR2 signaling.
“Identifying a natural compound alternative to SCFAs to optimally target the FFAR2 receptor on neurons is important, because cells in the gut and other organs consume most of these microbial metabolites before they reach the brain through blood circulation,” Professor Yadav said.
The researchers narrowed 15 leading compound candidates to the most potent one.
Fenchol was best at binding to the FFAR’s active site to stimulate its signaling.
Further experiments in human neuronal cell cultures as well as Caenorhabditis elegans and mouse models of Alzheimer’s disease demonstrated that fenchol significantly reduced excess Aβ accumulation and death of neurons by stimulating FFAR2 signaling, the microbiome sensing mechanism.
When the scientists more closely examined how fenchol modulates Aβ-induced neurotoxicity, they found that the compound decreased senescent neuronal cells, also known as ‘zombie’ cells, commonly found in brains with Alzheimer’s disease pathology.
“Fenchol actually affects the two related mechanisms of senescence and proteolysis,” Professor Yadav said.
“It reduces the formation of half-dead zombie neuronal cells and also increases the degradation of (nonfunctioning) Aβ, so that amyloid protein is cleared from the brain much faster.”
In exploring fenchol as a possible approach for treating or preventing Alzheimer’s pathology, the team will seek answers to several questions.
“A key one is whether fenchol consumed in basil itself would be more or less bioactive (effective) than isolating and administering the compound in a pill,” Professor Yadav said.
“We also want to know whether a potent dose of either basil or fenchol would be a quicker way to get the compound into the brain.”
Atefeh Razazan et al. Activation of Microbiota Sensing – Free Fatty Acid Receptor 2 Signaling Ameliorates Amyloid-β Induced Neurotoxicity by Modulating Proteolysis-Senescence Axis. Front. Aging Neurosci, published online October 5, 2021; doi: 10.3389/fnagi.2021.735933
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