Fenchol-A Phytochemical Found In Basil May Protect Against Alzheimer’s Disease By Reducing Neurotoxic Amyloid-Beta In The Brain

Phytochemical News: A new study led by researchers from University of South Florida Health has discovered that the phytochemical compound Fenchol has the same beneficial effect as gut-derived metabolites such as short-chain fatty acids (SCFAs) in reducing neurotoxic amyloid-beta in the brain.

 
To date, multiple emerging evidence indicates that the gut microbiota contributes to the pathology of Alzheimer’s disease (AD) which is a debilitating public health problem in older adults. However, strategies to beneficially modulate gut microbiota and its sensing signaling pathways remain largely unknown.
 
The study team validated, and established the agonists of free fatty acid receptor 2 (FFAR2) signaling, which senses beneficial signals from short chain fatty acids (SCFAs) produced by microbiota. The abundance of SCFAs, is often low in the gut of older adults with AD.
 
The study team demonstrated that inhibition of FFAR2 signaling increases amyloid-beta (Aβ) stimulated neuronal toxicity.
 
Hence the team screened FFAR2 agonists using an in-silico library of more than 144,000 natural compounds and selected 15 of them based on binding with FFAR2-agonist active sites.
 
Significantly Fenchol (A natural phytochemical compound commonly present in basil) was recognized as a potential FFAR2 stimulator in neuronal cells and demonstrated protective effects against Aβ-stimulated neurodegeneration in an FFAR2-dependent manner.
 
Furthermore, the study findings showed that Fenchol reduced AD-like phenotypes, such as Aβ-accumulation, and impaired chemotaxis behavior in Caenorhabditis (C.) elegans and mice models, by increasing Aβ-clearance via the promotion of proteolysis and reduced senescence in neuronal cells.
 
The Fenchol-Alzheimer’s-Disease study findings suggest that the inhibition of FFAR2 signaling promotes Aβ-induced neurodegeneration, while the activation of FFAR2 by Fenchol ameliorates these abnormalities by promoting proteolytic Aβ-clearance and reducing cellular senescence. Thus, stimulation of FFAR2 signaling by Fenchol as a natural compound can be a therapeutic approach to ameliorate AD pathology.
 
The study findings were published in the peer reviewed journal: Frontiers In Aging Neuroscience. https://www.frontiersin.org/articles/10.3389/fnagi.2021.735933/full
 
Fenchol or 1,3,3-trimethyl-2-norbornanol is a monoterpenoid and an isomer of borneol. It is a colorless or white solid. It occurs widely in nature but is abundant in basil.
 
The study led by principal investigator Dr Hariom Yadav, PhD, professor of neurosurgery and brain repair at the University of South Florida Health Morsani College of Medicine, where he directs the USF Center for Microbiome Research demonstrates that Fenchol can help protect the brain against Alzheimer’s disease pathology.
 
Importantly the study d iscovered a sensing mechanism associated with the gut microbiome that explains how fenchol reduces neurotoxicity in the Alzheimer’s brain.
 
So far, emerging evidence indicates that short-chain fatty acids (SCFAs) ie metabolites produced by beneficial gut bacteria and the primary source of nutrition for cells in the colon-contribute to brain health.
 
However, the abundance of SCFAs is often reduced in older patients with mild cognitive impairment and Alzheimer’s disease, the most common form of dementia. How this decline in SCFAs contributes to Alzheimer’s disease progression remains largely unknown.
 
The study found that gut-derived SCFAs that travel through the blood to the brain can bind to and activate free fatty acid receptor 2 (FFAR2), a cell signaling molecule expressed on brain cells called neurons.
 
Dr Yadav told Thailand Medical News, “Our study is the first to discover that stimulation of the FFAR2 sensing mechanism by these microbial metabolites (SCFAs) can be beneficial in protecting brain cells against toxic accumulation of the amyloid-beta (Aβ) protein associated with Alzheimer’s disease.”
 
Two of the hallmark pathologies of Alzheimer’s disease are hardened deposits of Aβ that clump together between nerve cells to form amyloid protein plaques in the brain and neurofibrillary tangles of tau protein inside brain cells.
 
Importantly these pathologies contribute to the neuron loss and death that ultimately cause the onset of Alzheimer’s, a neurodegenerative disease characterized by loss of memory, thinking skills, and other cognitive abilities.
 
The study team delved into molecular mechanisms to explain how interactions between the gut microbiome and the brain might influence brain health and age-related cognitive decline.
 
In this study, Dr. Yadav said, the research team set out to uncover the “previously unknown” function of FFAR2 in the brain.
 
The study team first showed that inhibiting the FFAR2 receptor (thus blocking its ability to “sense” SCFAs in the environment outside the neuronal cell and transmit signaling inside the cell) contributes to the abnormal buildup of the Aβ protein causing neurotoxicity linked to Alzheimer’s disease.
 
Subsequently the team 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.
 
The study team led by Dr Yadav narrowed 15 leading compound candidates to the most potent one. Fenchol, a plant-derived compound that gives basil its aromatic scent, was best at binding to the FFAR’s active site to stimulate its signaling.
 
Additional detailed experiments in human neuronal cell cultures, as well as Caenorhabditis (C.) elegans (worm) 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 study team 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.
 
These” zombie” cells stop replicating and die a slow death. Meanwhile, Dr Yadav said, they build up in diseased and aging organs, create a damaging inflammatory environment, and send stress or death signals to neighboring healthy cells, which eventually also change into harmful zombie cells or die.
 
Dr Yadav further added, “Fenchol actually affects the two related mechanisms of senescence and proteolysis. 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.”
 
More research will be required especially clinical trials to validate Fenchol’s ability to stave off Alzheimer’s Disease or other neurodegenerative diseases including dementia.
 
The study team will be next conducting further studies on Fenchol including exploring whether fenchol consumed in basil itself would be more or less bioactive (effective) than isolating and administering the compound in a pill.
 
Dr Yadav said, “We also want to know whether a potent dose of either basil or fenchol, if it could be delivered by nasal spray, would be a quicker way to get the compound into the brain.”
 
For researchers wanting to also conduct further studies or clinical trials on Fenchol, Thailand Medical News sister company-Northern Thai Herbs will be giving away complimentary stocks of Fenchol pending certain conditions.Kindly contact us directly.
 
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