Fenchol, a Natural Compound Found in Basil, May Protect Against Alzheimer’s Disease Pathology

Researchers at the University of South Florida suggest that fenchol, a natural compound found in some plants including basil, may help protect against Alzheimer’s disease pathology in the brain. The discovery of a sensing mechanism associated with the gut, which was published in Frontiers in Aging Neuroscience, shows how fenchol reduces neurotoxicity in Alzheimer’s patients.

A decline in short-chain fatty acids is associated with Alzheimer’s disease

Short-chain fatty acids (SCFAs), which are metabolites produced by beneficial gut bacteria and the primary source of nutrition for colon cells, also contribute to brain health. In older patients with cognitive impairments such as Alzheimer’s disease, there is often a lower level of SCFAs. It is largely unknown how the decline in SCFAs contributes to Alzheimer’s disease.

When SCFAs from the gut travel through the blood to the brain, they can bind to and activate free fatty acid receptor 2 (FFAR2), a cell signaling molecule expressed on neurons in the brain. “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,” said principal investigator, Dr. Hariom Yadav.

Pathologies of Alzheimer’s disease

The two main pathologies of Alzheimer’s disease are the hardened deposits of Aβ that clump together between nerve cells to form amyloid protein plaques in the brain and the neurofibrillary tangles of tau protein in brain cells.

Data from the study showed that inhibiting the FFAR2 receptor, which blocks its ability to sense SCFAs, contributes to the abnormal buildup of Aβ protein. This causes neurotoxicity that is linked to Alzheimer’s disease.

Study principal investigator, Hariom Yadav, PhD, director of the University of South Florida Microbiome Research Center. Credit: USF Health/University of South Florida.

The team virtually screened 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. It was important to find a natural compound alternative because cells in the gut and other organs consume most of these microbial metabolites before they reach the brain.

Dr. Yadav’s team narrowed the list to 15 potential compound candidates, eventually finding fenchol to be the most potent one. Fenchol is a plant-derived compound that gives basil its aromatic scent. It was the best at binding to the FFAR’s active site to stimulate its signaling.

How fenchol works to reduce Aβ accumulation

Further experiments were run in human neuronal cell cultures, as well as C. elegans (worm) and mouse models of Alzheimer’s disease. They all showed that fenchol significantly reduced excess Aβ accumulation and death of neurons by stimulating FFAR2 signaling. After closer investigation, the researchers discovered that fenchol was modulating Aβ-induced neurotoxicity by decreasing senescent (or “zombie”) neuronal cells that are commonly found in brains with Alzheimer’s disease pathology.

Senescent cells stop replicating and eventually die which causes a build up in diseased and aging organs. This causes an inflammatory environment, sending stress signals to neighboring healthy cells which then also eventually change into harmful senescent cells or die.

“Fenchol actually affects the two related mechanisms of senescence and proteolysis,” Dr. 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.”

Future research about fenchol and Alzheimer’s disease

Before we all start including fenchol in our diets, further experiments need to be run, particularly in humans. The next question the research team is asking is whether fenchol consumed in basil itself would be more or less effective than administering the compound in a pill. They are also wondering what type of consumption will get the compound to the brain faster.

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